Protocol - heart.bmj.com

Protocol

This trial protocol has been provided by the authors to give readers additional information about their

work.

Protocol for: Yong Liu, Yong Huo, Shiqun Chen, et al. Aggressive hydration and contrast induced acute

kidney injury following primary angioplasty.

BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any relianceSupplemental material placed on this supplemental material which has been supplied by the author(s) Heart

doi: 10.1136/heartjnl-2021-319716–8.:10 2021;Heart, et al. Liu Y

Context

APPENIX A The following individuals participated in the ATTEMPT study

APPENIX B ATTEMEPT Clinical Trial Protocol Version 1.0

APPENIX C ATTEMEPT Clinical Trial Protocol Version 3.0

APPENIX D Changes to ATTEMPT Protocol

APPENIX E ATTEMEPT Clinical Trial Case Report Form

APPENIX F ATTEMEPT Clinical Trial Statistical Analysis Plan Version 1.0

APPENIX G ATTEMEPT Clinical Trial Statistical Analysis Plan Version 3.0

APPENIX H Changes to ATTEMPT Statistical Analysis Plan





Appendix A

The following individuals participated in the

ATTEMPT study:



Title: Aggressive Hydration and Contrast Induced Acute Kidney InjuryFollowing Primary Angioplasty

Acronym: ATTEMPT

The following individuals participated in the ATTEMPT study:

PIDr. Jiyan ChenGuangdong Cardiovascular Institute,Guangdong Provincial Key Laboratory ofCoronary Disease, Guangdong ProvincialPeople’s Hospital, Guangzhou, Guangdong,China

Executive directorDr. Yong LiuGuangdong Cardiovascular Institute,Guangdong Provincial Key Laboratory ofCoronary Disease, Guangdong ProvincialPeople’s Hospital, Guangzhou, Guangdong,China

CO-PIProf. Yong HuoPeking University First Hospital,Beijing, China

Site PIProf. Jun-Bo GeZhongshan Hospital, Fudan University,Shanghai Institute of CardiovascularDiseases, Shanghai, China

Prof. Yun-Dai ChenChinese PLA General Hospital,Beijing, China

Dr. Keng WuThe Affiliated Hospital, Guangdong MedicalUniversity,Zhanjiang, Guangdong, China

Dr. Gui-Fu WuThe Eighth Affiliated Hospital, Sun Yat-senUniversity, Shenzhen, Guangdong, China

Dr. Kai-Hong ChenLongyan First Affiliated Hospital of FujianMedical University, Longyan, Fujian, China

Dr. Jian-Feng YeDongguan TCM Hospital, Dongguan,Guangdong, China

Dr. Yan LiangMaoming People's Hospital, Maoming,Guangdong, China

Dr. Xin-Wu FengFirst People’s Hospital of Zhaoqing City,Zhaoqing, Guangdong, China

Dr. Shao-Hong DongShenzhen People's Hospital, Shenzhen,518020, China

Dr. Qi-Ming WuBeijing Ditan Hospital, Capital MedicalUniversity, Beijing, China

Dr. Xian-Hua YeHangzhou First People’s Hospital,Hangzhou, China

Dr. He-Song ZengTongji Hospital, Tongji Medical College,Huazhong University of Science andTechnology, Wuhan, China

Dr. Min-Zhou ZhangGuangdong Provincial Hospital of ChineseMedicine, Guangzhou, Guangdong, China

Dr. Min DaiMianyang Central Hospital, Mianyang City,Sichuan, China

Data Monitoring CommitteeDr. ChunWangPeking university Shenzhen Hospital

Dr. Chun-Quan OuSouthern Medical University

Dr. Xiao-Qi LiuGuangdong Provincial People’s Hospital

Clinical Event CommitteeDr. Zhi-Min DuThe First Affiliated Hospital, Sun Yat-senUniversity

Dr. Hong TanGuangdong Provincial People’s Hospital

Dr. Xue-Ping YangGuangdong Provincial People’s Hospital

Dr. Hao WangSichuan Provincial People’s Hospital

Dr. Yan Xuethe people's hospital of Guangxi Zhuangautonomous region



Trial Steering Committee members:Dr. Ying XianDuke Clinical Research Institute, Durham, NC, 27705, USA

Investigators and Coordinators

1. Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key

Laboratory of Coronary Disease, Guangdong Provincial People’s Hospital, Affaliated

Guangdong Provincial People’s Hospital of South China University of Technology,

Guangzhou 510100, China: Ning Tan, Ying-Ling Zhou, Jian-Fang Luo, Shi-Qun Chen,

Dan-Qing Yu, Li-Wen Li, Zhu-Jun Chen, Guang Li, Bin Zhang, Li-Jun Jin, Hong Yan, Tai-Ming

Dong, Yuan Liu, Wen-Hui Huang, Jun-Qing Yang, Peng-Cheng He, Nian-Jin Xie,Yong-Quan

Yang, Jing-Ru Deng, Xiao-Yu Huang;

2. Department of Cardiology, the First Medical center, Chinese PLA General Hospital, Beijing,

100853, China: Xiang-Zhu Dong, Ye Zhang, Geng Qian, Dan-Dan Li;

3. Department of Cardiology, The Affiliated Hospital, Guangdong Medical University,Zhanjiang,

Guangdong Province, 524001, P.R. China: Hai-Liang Mo;

4. The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, P.R. China:

Wen-Bin Wei, Xing-Rui Fang;

5. Department of Cardiology, Longyan First Affiliated Hospital of Fujian Medical University,

Longyan, Fujian 364000, P.R. China: Li-Ling Chen;

6. Department of Cardiology, Dongguan TCM Hospital, Dongguan, 523209, China: Shao-Hui Su;

7. Department of Cardiology, Maoming People's Hospital, Maoming, 525000, China: Cong Chen;

8. Department of Cardiology, First People’s Hospital of Zhaoqing City, Zhaoqing City,

Guangdong Province, 526000, P.R. China:Rong-Bin Su;

9. The Department of Cardiology, Shenzhen People's Hospital, Shenzhen, 518020, China:

Hua-Dong Liu, Qian Mou, Rui-Jing Chen, Chuan-Shou Zhang;

10. Department of Cardiology, Beijing Ditan Hospital, Capital Medical University, Beijing 100070,

China: Yu-Qing Song, Qian Dong, Li Fu, Wen-Jing Xu, Wang-Jiang Wei, Chang Ma, Qian Wang,

Yong-Fu Chen, Da-Wei Tan;

11. Department of Cardiology, Hangzhou First People’s Hospital, Hangzhou, 310006, China:

Jian-Min Yang;



12. Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical

College, Huazhong University of Science and Technology, Wuhan, 430030, China:Qiang

Zhou;

13. Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510120, China: Li-Heng

Guo, Lei Wang, Yong-Jie Kong, Huang Ma, Guang-Ping Wu, Shuai Mao;

14. Department of Cardiology, Mianyang Central Hospital, Changjia Alley 12, Fucheng district,

Mianyang City, 621000, Sichuan, China: Yu Li, Min Wang.

15. State Key Laboratory of Organ Failure Research, Department of Biostatistics, Guangdong

Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern

Medical University, Guangzhou, 510515, China: Chong-Yang Duan;

16. Department of Emergency and Critical Care Medicine, Guangdong Provincial People’s

Hospital and Guangdong Academy of Medical Sciences, Guangzhou, 510080, P.R. China:

Fei-er Song;

17. Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of

Cardiovascular Diseases, Shanghai, 200032, China:Shu-Fu Chang, Hao Lu, Li-Li Xu;



Youg Liu: ATTEMPT Cinical Trial Protocol Version 1.0

Appendix B

ATTEMEPT Clinical Trial Protocol Version 1.0

(Appendix independently paginated)




AGGRESSIVE HYDRATION AND CONTRAST INDUCED ACUTE KIDNEY INJURYFOLLOWING PRIMARY ANGIOPLASTY (ATTEMPT):

CONTENTS

RESEARCH CENTERS

EXECUTIVE SUMMARY........................................................................................................1

ABBREVIATIONS................................................................................................................... 3

INTRODUCTION......................................................................................................................5

BACKGROUND....................................................................................................................6

SIGNIFICANCE OF THE PROPOSED RESEARCH...................................................19

STUDY DESIGN....................................................................................................................20

STUDY HYPOTHESES AND OBJECTIVES.................................................................20

OVERVIEW OF STUDY DESIGN...................................................................................21

METHOD.................................................................................................................................28

STUDY POPULATION AND PATIENT RECRUITMENT............................................28

STUDY PROCEDURES...................................................................................................30

POTENTIAL RISKS AND ALTERNATIVE CONSIDERATIONS................................51

FEASIBILITY OF RECRUITMENT...............................................................................555

ANTICIPATED BARRIERS TO RECRUITMENT.......................................................566

PROPOSED ANCILLARY STUDY............................................................................... 577

HUMAN SUBJECTS....................................................................................................... 588

DATA MANAGEMENT......................................................................................................60

QUALITY CONTROL......................................................................................................722

GOOD CLINICAL PRACTICE.......................................................................................822

RESEARCH MONITORING AND AUDIT PLANS........................................................83

RESULT..................................................................................................................................90

BIOSTATISTICAL CONSIDERATIONS.........................................................................90

STUDY ORGANIZATION AND ADMINISTRATION..................................................944

PUBLICATIONS...............................................................................................................977

REFERENCES.................................................................................................................988




Research centers

No. Study Site

01 Guangdong Provincial People’s Hospital

02 Peking University First Hospital

03 Zhongshan Hospital, Fudan University

04 Chinese PLA General Hospital

05 The Affiliated Hospital, Guangdong Medical University

06 The people’s Hospital of Baoan Shenzhen

07 The Eighth Affiliated Hospital, Sun Yat‐sen University

08 Longyan First Affiliated Hospital of Fujian Medical University

09 First People’s Hospital of Zhaoqing City

10 Dongguan TCM Hospital

11 Maoming People's Hospital




1

EXECUTIVE SUMMARY

The intravascular administration of iodinated contrast agent for coronary

angiography (CAG) or percutaneous coronary intervention (PCI) is a common

cause of acute kidney injury (AKI) and a leading cause of iatrogenic renal

disease. Multiple studies have determined that contrast-induced AKI (CI-AKI)

is associated with prolonged hospitalization, increased medical economic

burden, and adverse long-term prognosis.

Patients with ST-elevation myocardial infarction (STEMI) have a higher risk of

CI-AKI, which is a potentially serious complication of angiographic procedures

that are associated with increased mortality, morbidity, and health care use in

patients undergoing PCI. According to guidelines for the management of

STEMI, saline hydration is widely recommended. However, optimal saline

hydration strategy has not been well established in this high-risk population.

The Induced Diuresis With Matched Hydration Compared to Standard

Hydration for Contrast Induced Nephropathy Prevention (MYTHOS) study

found that a loading dose (125/250mL) of isotonic saline matched with

furosemide-induced high urine output significantly reduces the risk of CI-AKI

and might be associated with improved clinical outcomes in patients with

chronic kidney disease (CKD). QIAN G et al suggested that CVP-guided fluid

administration can be safely and effectively reduce the risk of CI-AKI in

patients with CKD and chronic heart failure and substantially reduce composite

major adverse events for these high-risk patients. The Prevention of Contrast

Renal Injury with Different Hydration Strategies (POSEIDON) trial suggested

that intravenous (IV) administration of normal saline guided by the left

ventricular end diastolic pressure (LVEDP) is well tolerated and could

substantially reduce the incidence of CI-AKI and major adverse clinical events

in patients with combined CKD and one or more of several risk factors




2

undergoing cardiac catheterization. Three clinical trials above consistently

demonstrated that saline hydration based on certain guiding strategies was

more effective than general hydration in preventing CI-AKI and reducing the

risk of adverse prognosis.

Patients with STEMI are likely to present with hypotension or even shock, a

large volume of contrast agent, and inability to start a kidney prophylactic

therapy, all of which are associated with an increased risk of CI-AKI. In

previous studies, cardiologists were primarily concerned with rapid

revascularization for occluded culprit arteries instead of adequate

preprocedural hydration to prevent CI-AKI in patients with STEMI; The main

reason is lacking of information regarding baseline kidney function and related

medical history. Conversely, excessive hydration of saline without a definite

guiding strategy may exceed the impaired cardiac tolerance in STEMI patients,

thus increasing the risk of cardiac function deterioration. Therefore, flexible

and individualized hydration therapy based on certain guiding strategy needed

to maintain renal perfusion, given that perioperative IV volume expansion

could potentially compensate for reduced cardiac output, hypotension, and

depletion of intravascular volume in patients with STEMI.

Given these previous data, we designed the ATTEMPT trial to examine the

efficacy of a preprocedural loading dose and postprocedural aggressive

hydration with normal saline guided by LVEDP as compared with general

hydration(Figure A1). We hypothesize that aggressive hydration strategy

reduces the risk of CI-AKI and improves the clinical outcomes in STEMI

patients undergoing primary PCI. The ATTEMPT study is a multicenter,

open-label, investigator-driven, randomized controlled trial in China.

Approximately 560 patients with STEMI undergoing primary PCI will be

randomized (1:1) to receive either periprocedural general hydration (control




3

group) or aggressive hydration (intervention group). Patients in the control

group receive periprocedural general hydration with ≤500 mL normal saline

(within 6 hours) at a normal rate (0.5 or 1 mL/kg*h). Patients in the intervention

group receive a preprocedural loading dose (125/250 mL) of normal saline

within 30 minutes and intravenous hydration at a normal rate until LVEDP is

available, followed by postprocedural aggressive hydration guided by LVEDP

for 4 hours and then continuous intravascular hydration at the normal rate until

24 hours after PCI. The primary endpoint is CI-AKI, defined as a ＞25% or

0.5-mg/dL increase in serum creatinine from baseline during the first 48 to 72

hours after the procedure. The ATTEMPT study has the potential to identify

optimal hydration regimens for STEMI patients undergoing primary PCI.

ABBREVIATIONS

AKI Acute kidney injury

ACS Acute coronary syndrome

AHF Acute heart failure

AMI Acute myocardial infarction

ACEI Angiotensin-Converting Enzyme Inhibitors

ARB Angiotensin Receptor Blockers

BMI Body Mass Index

pPCI Primary Percutaneous Cornary Intervention

RR Risk Ratio

ARR Absolute Risk Ratio

SCr Serum creatinine

DSMB Data and safety monitoring committee

CCU Cardiac care unit

CEC Clinical Event Committee

CI Confidence Interval




4

CI-AKI Contrast-induced Acute Kidney Injury

CK Creatine kinase

CK-MB Creatine kinase-MB

CKD Chronic kidney disease

CAG Coronary Angiography


CVD Cardiovascular disease

CRA Clinical Research Associate

CT Computed Tomography

DM Diabetes Mellitus

DMC Data Monitoring Committee

DVP Data Validation Plan

EDC Electronic Data Capture

eGFR estimated Glomerular Filtration Rate

ESRD End-stage Renal Disease

GCP Good Clinical Practice

HF Heart Failure

HR Hazard Ratio

HCT Hematocrit

ICH International technical committee

IEC Independent Ethics Committee

ITT Intention-to-treat

IABP Intra-aortic Ballon Pump

LVEDP Left Ventricular end-diastolic Pressure

LVEF Left Ventricular Ejection Fraction

MACE Major Adverse Cardiovascular Events

MDRD Modification of Diet in Renal Disease formula

OR Odd Ratio

PCI Percutaneous Coronary Intervention




5

PM Project Manager

PLT Platelets

NT-proBNP N-terminal pro-brain natriuretic peptide

NNT Number needed to treat

NYHA New York Heart Association

STEMI Stsegment Elevation Myocardial Infarction

RR Risk Ratio

WBC White Blood Cell

DCF Data Challenge Form

INTRODUCTION

Contrast-induced acute kidney injury (CI-AKI) is a common complication of

coronary angiography and/or percutaneous coronary intervention (CAG/PCI).

Patients with ST-elevation myocardial infarction (STEMI) undergoing primary

percutaneous coronary intervention (pPCI) have a higher risk of CI-AKI.

Previous trials failed to find out the efficacy of sodium bicarbonate and

acetylcysteine in prevention of CI-AKI and outcomes following pPCI or

angiography. Although previous studies suggested the benefit of intravenous

hydration (vs. no hydration) in reducing risk of CI-AKI following pPCI, recent

systematic review suggested that the most effective regimen of intravenous

hydration has not been determined. According to the guideline for the

management of STEMI, timely reperfusion with shortest delay was the most

important for clinical outcomes, while adequate hydration is also

recommended for CI-AKI prevention in patients undergoing pPCI. Therefore,

adequate preventive hydration including pre-procedural long-term duration

conflicts shortest delay before pPCI among patients with STEMI.




6

MYTHOS study suggested that a loading dose (125/250 mL in short half an

hour) of isotonic saline matched with furosemide-induced high urine output

significantly reduces the risk of CI-AKI, more effective among patients

undergoing emergent PCI, without increased risk of acute heart failure.

POSEIDON trial showed that left ventricular end-diastolic pressure (LVEDP)

guided intensive hydration in short time (4 hours) could substantially reduce

the incidence of CI-AKI and was well safety tolerated. Therefore, our

hypothesis was that aggressive intravenous hydration, including above short

intensive regimen (loading dose, post-reperfusion LVEDP guide) and

long-term maintenance, might be suitable for the special emergent condition

among STEMI patients undergoing pPCI. We designed the Aggressive

hydraTion in patients with ST-Elevation Myocardial infarction undergoing

Primary percutaneous coronary intervention to prevenT Contrast-Induced

Nephropathy (ATTEMPT) trial to investigate the efficacy and safety of the

aggressive hydration strategy in high-risk patients with STEMI undergoing

pPCI.

1. BACKGROUND

1.1 Definition, incidence, and risk factors for CI-AKI in STEMI patients

CI-AKI is defined as a decrease in kidney function following the exposure of

contrast agent1,2. Although the diagnostic criteria of CI-AKI varies in different

studies, the widely accepted definition of CI-AKI is an increase in the serum

creatinine concentration (SCr) of at least 0.5 mg/dL and/or 25% within 2-3

days of intravascular administration of contrast agent3-5.

The previous study found that CI-AKI occurred in 8.5% of with eGFR >60

ml/min/1.73 m2 undergoing non-urgent coronary angiography and 13.2% of

clinically stable Veterans with eGFR <60 ml/min/1.73 m2 undergoing

non-urgent, non-coronary angiography6. Other studies showed that up to 33%




7

of extremely high-risk patients develop this condition following

contrast-enhanced procedures7.

We have made a system review which has illuminated the pivotal risk factors

for CI-AKI in STEMI patients (Figure A1). Renal insufficiency is recognized as

the principal risk factor for the development of CI-AKI, with increasing levels of

kidney dysfunction associated with incremental degree of risk8. Combined with

diabetes mellitus substantially increase the risk for CI-AKI in patients with

chronic kidney disease8-10. Patients with hypovolemia are also vulnerable to

kidney dysfunction due to iodized contrast media, as are patients with

advanced heart failure8. In both clinical states, hypovolemia and reduced renal

perfusion induced renal vasoconstriction after intravascular contrast media

administration. The risk of CI-AKI increases with the administration of contrast

agents in large quantities11, 12. It is also believed that the risk of CI-AKI after

intra-arterial contrast agent administration is greater than that of intravenous

administration. Recognition of these major risk factors helps clinicians to more

accurately determine which patients are most likely to develop CI-AKI, and

studies has been conducted to assess the effectiveness of preventive

interventions for this disease.




8

Figure A1-Major risk factors for CI-AKI in STEMI patients

1.2 Association of CI-AKI with mortality

Observational studies have shown a correlation between CI-AKI (defined by

small absolute and/or relative changes in SCr) and increased short-term

mortality13-20. In a retrospective study, Levy et al. CI-AKI was found to be an

important predictor of in-hospital mortality (OR = 5.5, P < 0.001) in 183

hospitalized patients (an increase of 25% from SCr to at least 2.0 mg/dL).

Follow-up studies by McCullough et al. Among the 1,826 patients receiving

PCI, CI-AKI was found to be related with an in-hospital mortality rate of 7.1%,

compared with 1.1% in patients with no such change in SCr. (p < 0.0001)21.

Among CI-AKI patients who needed renal replacement therapy, the hospital

mortality rate was 35.7%. Many other studies reported an independent

association between CI-AKI and short-term mortality13-15, 17-19. although there is

a close relationship between small changes in SCr and short-term mortality,

most of them are retrospective analysis. Therefore, there may be deterministic

bias in assessing postoperative SCr, and there may be missing potential




9

problem data13, 14, 17-19, 21. However, prospective studies confirm these findings

in the clinical study of Marenzi et al. The study found that the in-hospital

mortality of patients with CI-AKI was significantly higher than that of patients

without renal dysfunction (26% vs. 1.4%, P < 0.001)22. Maioli et al. conducted

several studies that have shown that in-hospital mortality in patients with

CI-AKI is significantly higher than that in patients without complications (11.1%

vs. 0.2%, P = 0.001)23. Therefore, data from observational studies and

randomized trials support the association between postoperative decline of

kidney function and short-term mortality.

In addition to increased short-term complications, CI-AKI has also been linked

with long-term mortality in recent studies17, 24-28. Solomon et al. demonstrated

that CI-AKI was associated with a greater than 3-fold increased risk of major

adverse outcomes (death, stroke, myocardial infarction, end-stage renal

disease requiring renal replacement therapy) at 1-year of follow up28. Four

additional studies found an independent association of CI-AKI with long-term

mortality, although the study by Roghi et al. demonstrated a trend toward

increased long-term mortality that did not reach statistical significance in

multivariable analyses17, 24, 25, 27. Collectively, these findings indicate that

CI-AKI, defined by small decrements in renal function, is associated with

adverse long-term outcomes and more compromised renal function over time.

Despite the abundance of epidemiological and experimental data associating

small changes in SCr with adverse renal and extra-renal outcomes, the

evidence remains inadequate to warrant the use of small changes in SCr as a

surrogate primary endpoint in large transformative clinical trials. Although

serious events following angiography occur as a consequence of CI-AKI, they

may also develop independent of this intermediate event, as many of the

clinical conditions that predispose patients to the development of CI-AKI (e.g.,

CKD, diabetes mellitus, heart failure) are also independently associated with




10

mortality and other adverse outcomes (Figure A2). In addition, not all episodes

of CI-AKI lead to clinically consequential sequelae. For this reason, we believe

that it is most appropriate for a definitive trial of interventions for the prevention

of CI-AKI to demonstrate effectiveness in reducing serious, adverse,

patient-centered outcomes rather than merely focusing on the amelioration of

small changes in SCr. In our ATTEMPT study, the primary end point is CI-AKI,

defined as a >25% or 0.5-mg/dL increase in serum creatinine from baseline

during the first 48 to 72 hours after the procedure. Secondary end points are

as follows: (1) CI-AKI48h, defined as a >50% or 0.3-mg/dL absolute increase in

serum creatinine from baseline during the first 48 hours after the procedure; (2)

CI-AKIcysc, defined as a >10% or 0.3-mg/dL absolute increase in serum

cystatin C during the first 24 hours after the procedure; (3) contrast induced

persistence kidney injury (CI-PKI), defined as residual impairment of renal

function indicated by >25% reduction in creatinine clearance at 3 months in

comparison with baseline; (4) major adverse cardiovascular events, including

all-cause mortality, target vascular revascularization, and nonfatal myocardial

infarction; (5) post-procedural acute heart failure during hospitalization; (6)

major post-procedure in-hospital adverse clinical events, including acute

pulmonary edema, cardiogenic shock, stroke, clinically significant arrhythmias,

and bleeding within the first year; and (7) total hospitalization costs and length

of stay.




11

Figure A2 – Development process of clinical adverse events exposure to

contrast agent

1.3 Prolonged hospitalization and increased costs associated with

CI-AKI

Multiple retrospective studies also focus on clarifying an association of CI-AKI

with economic benefits of health13,19,29-32. In the analysis of over 27,000

patients who underwent CAG, a rise in SCr of 0.25 - 0.5 mg/dL was associated

with prolonged hospitalization after adjusting for underlying severity of illness19.

The length of hospitalization extended with the increase of SCr gradually.

Bartholomew found that patients who developed CI-AKI after PCI were 15

times more likely to extend length of hospitalization more than four days13. In a

clinical trial comparing IV fluids for the prevention of CI-AKI, Adolph found that




12

patients with a postoperative increase in SCr of ≥25% or ≥0.5 mg/dL was

associated with a mean of two days longer than patients without obvious

change of SCr29. Prolonged hospitalization results in increased healthcare

expenditures as documented in an observational study32. In the analysis of 598

diabetics with CKD undergoing CAG, CI-AKI was independently associated

with a 2-fold increase in healthcare expenditures32. Subramanian et al used a

decision analytic model to show that CI-AKI results in an average increase in

hospital-related costs of more than $10,300 and 1-year costs in excess of

$11,80031. Based on the number of CHD and cardiac catheterization

performed across the China, there may be approximately 940,000 cases of

CI-AKI nationwide. In general, these data indicate that CI-AKI is associated

with prolonged hospitalization and huge expenditure on health economics.

1.4 Pathophysiology and prevention strategies of CI-AKI in STEMI

patients

Although the pathophysiological mechanism of renal injury induced by contrast

agents has not been fully elucidated, the following mechanisms are generally

accepted: direct and indirect renal injury induced by contrast agents, and

disturbance of hemodynamic stability (Figure A3)33. Firstly, intravascular

exposure of contrast agents leads to transient systemic vasodilation, followed

by intense contractions of the renal vascular bed. Outside the vasoconstriction

in the renal medulla have particularly low baseline oxygen tension, cause the

oxygen supply and demand do not match, leading to ischemic renal tubular

damage33, 34. Secondly, direct toxic on renal tubular epithelial cells caused by

contrast agents33, 35. Thirdly, the use of contrast agents lead to reactive oxygen

species (ROS) generation, this will accelerate renal tubular cell injury33,36-38.



therapy, all of which are associated with an increased risk of CI-AKI. Patients




13

with STEMI also commonly have other risk factors for CI-AKI such as reduced

cardiac output or hypotension due to myocardial infarction or depletion of

intravascular volume caused by vomiting, diaphoresis, or decreased oral

intake. Despite a considerable prevalence of risk factors, including reduced

LVEF, renal insufficiency, and diabetes mellitus, in patients needing adequate

hydration, cardiologists in previous studies were primarily concerned with rapid


preprocedural hydration to prevent CI-AKI in patients with STEMI; this was

related to a lack of information regarding baseline kidney function and related

medical history. Conversely, excessive hydration of saline without a certain


thus increasing the risk of cardiac function deterioration. Through the

understanding of the above pathogenesis, it is helpful to explore the prevention

and treatment strategy of CI-AKI in STEMI patients.

Figure A3 - Pathophysiology of CI-AKI in STEMI patients




14

Renal injury induced by contrast agents may be preventable. Patients at

increased risk of CI-AKI are easily identified by the presence of known clinical

risk factors. Past efforts to find effective prevention strategies for CI-AKI have

focused on three recommendations39: 1) risk factors assessment of CI-AKI; 2)

minimization and preference of low-osmolar or iso-osmolar contrast media; 3)

adequate hydration. The incidence of CI-AKI has decreased due to the change

in the type of contrast agent over time and risk factors of CI-AKI are gradually

clarified. Recently, Jurado-Román et al40 suggested that the risk of CI-AKI after

IV administration of normal saline is 48% lower than with no IV hydration in

patients with STEMI, which is rarely performed in actual practice, when

following the guideline for the management of STEMI41. However, we still have

to be soberly aware that the optimal saline hydration strategy still remain

controversial9, 42-44.

1.5 Characteristics of randomized clinical trials on prevention of CI-AKI

under different hydration strategies of IV isotonic saline

Previous studies have focused on the optimal composition of hydration therapy.

With the publication of PRESERVE results, acetylcysteine as a component of

hydrated liquids has no obvious benefit for the prevention of CI-AKI. Therefore,

the preferred position of isotonic saline hydration in the prevention strategy of

CI-AKI hydration has been gradually consolidated. At present, the optimal

hydration strategy for the prevention of CI-AKI in high-risk patients still remain

inconclusive. We systematically review the RCT articles published in the past

few years on the prevention of CI-AKI by hydration of isotonic saline under

different guiding strategies. Nine studies were included20,40,45-51. Eight of them

showed that the hydration guidance strategy of the intervention group was

better than that of the control group without special hydration strategy. One

study showed that isotonic saline hydration had no significant benefit in

preventing CI-AKI (Table A1). The different results of nine studies suggest that




15

the optimal hydration strategy of saline is still uncertain, and for high-risk

patients such as STEMI, we lack relevant research evidence. In particular, we

need to focus not only on the different effects of individualized isotonic saline

hydration strategies on preventing CI-AKI, but also to explore the optimal

isotonic saline hydration strategy that can reduce the short-term and long-term

adverse prognosis among high-risk patients such as STEMI.




16

Table A1- Characteristics of randomized clinical trials on prevention of CI-AKI under different hydration strategies of IV isotonic saline

Authors Number

of

patients

Procedure Baseline renal function Definition of

CI-AKI

Hydration strategy of IV isotonic saline Frequency of

CI-AKI in isotonic

saline group

Dialysis Death

WEISBORD S

D et al

4993 Elective CAG ↑ SCr >0.5mg/dL or >25%

within 3-5 days of contrast

exposure

↑

SCr >0.5mg/dL

or >25%

During 1-12h before angiography：1-3ml/kg/h; during angiography：1-1.5ml/kg/h ,

during a period of 2-12h after angiography:1-3ml/kg/h. hydration speed will be

adjusted if overweight.

8.3% 1.2% 2.7%

TRIVEDI H S et

al

53 Elective CAG/PCI ↑ SCr >0.5mg/dL within 2 days

of contrast exposure

↑

SCr >0.5mg/dL

1ml/kg/h, 12h before CAG/PCI for total 24h. 3.7% NA NA

BRAR S S et al 396 Elective CAG/PCI ↑ SCr >0.5mg/dL or ≥25%


exposure

↑

SCr >0.5mg/dL

or ≥25%

A: LVEDP-guided volume expansion

B: Standard fluid administration protocol.

6.7%/16.3% 0.5%/2.0% 0.5%/4.0

%

JURADO-ROM

AN A et al

408 Primary CAG/PCI ↑ SCr >0.5mg/dL or >25%

within 3 days of contrast

exposure

↑

SCr >0.5mg/dL

or >25%

1 ml/kg/h since the beginning of CAG/PCI for total 24 hours. 11% 0% 2.8%

LUO Y et al 216 Primary CAG/PCI ↑ SCr >0.5mg/dL or ≥25%


exposure

↑

SCr >0.5mg/dL

or >25%

1mL/kg/h for 12 hours after CAG/PCI., the rate was reduced to 0.5 mL/kg/h in

patients with LVEF≤30% or a Killip class 2 or 3 status.

20.4% 0.93% 2.78%

MARENZI G et

al

450 Primary CAG/PCI ↑ SCr >0.5mg/dL or ≥25%


exposure

↑

SCr >0.5mg/dL

or >25%

1mL/kg/h for 12 hours immediately after CAG/PCI, rate was reduced to 0.5 mL/kg/h in

patients with LVEF≤40% or NYHA III–IV.

22.7% 0.93% 2.78%

MAIOLI M et al 170 Elective CAG ↑ SCr >0.5mg/dL or ≥25%


exposure

↑

SCr >0.5mg/dL

or >25%

A: Furosemide with matched hydration group(FMH)

B: 1 ml/kg/h (0.5ml/kg/h in case of LVEF<40%) for at least 12 h before and 12 h after

the CAG.

4.6%/18% 1.1%/4% 1.1%/4%

QIAN G et al 264 Elective CAG/PCI ↑ SCr >0.5mg/dL or ≥25%


↑

SCr >0.5mg/dL

A: CVP-guided hydration group

B: standard hydration group.

15.9%/29.5% 3.0%/9.8% 1.1%/4%




17

exposure or ≥25%

NIJSSEN E C

et al

660 Elective CAG ↑ SCr >0.5mg/dL or ≥25%


exposure

↑

SCr >0.5mg/dL

or >25%

A: 3–4mL/kg/h during 4 h before and 4 h after contrast administration;

B: 1mL/kg/h during 12 h before and 12 h after contrast administration/No hydration

group.

2.7%/2.6% 0%/0% 0%/0.9%

CI-AKI denotes contrast induced acute kedney injury, CAG denotes coronary angiogram, NA denotes not assessed, PCI denotes percutaneous coronary intervention.




18

1.6 Summary of limitations of randomized clinical trials on prevention of

CI-AKI under different hydration strategies of IV isotonic saline

AMACING study has the following limitations: Firstly, it is a single center study.

Secondly, the final number of patients participating in this study were less than

half of the planned number of patients, and the overall incidence of CI-AKI was

low. Patients with eGFR<30 mL/min/1.73 m2 were excluded. Therefore, the

efficacy of hydration therapy for the prevention of CI-AKI in high-risk patients

cannot be generalized. The main limitation of the POSEIDON study is the

exclusion of STEMI patients. Therefore, the most effective hydration strategy

for preventing CI-AKI among STEMI patients with high risk of adverse events

after PCI is still inconclusive. The PRESERVE study did not focus on the

discussion of different isotonic saline hydration strategies. In addition to

AMACING, POSEIDON and PRESERVE studies, other studies characterized

in (Table A1) were limited by being single center, unblinded and without clearly

defined allocation concealment mechanisms. Furthermore there was

inconsistent reporting of cross-over between allocated groups and the volume

of fluid received by the control arm was not reported in any study. It is also not

possible to define the most effective hydration strategy as all these studies

used different starting times, rates and durations of hydration. Further

information is expected from the ATTEMPT study evaluating the efficacy of

aggressive hydration therapy guided by LVEDP compared with general

hydration (≤500 mL) for CI-AKI following primary PCI.

1.7 Summary

CI-AKI is a common complication after exposure to iodine-contrast agents,

especially in high risk patients such as STEMI, which is closely associated with

short-term adverse events in hospital and long-term prognosis after discharge.

Isotonic saline hydration strategy has been accepted as an effective strategy

for preventing CI-AKI. After a systematic review of the existing articles




19

comparing different isotonic saline hydration strategy, subject-related articles

are scarce and the starting and ending time of hydration, hydration rate and

total amount of hydration fluid remain great difference. For STEMI patients, the

optimal isotonic saline hydration strategy is still inconclusive. Combined with

the above lack of clinical evidence, we urgently need to design a clinical trial to

solve this complex but extremely important clinical problem. ATTEMPT is the

first multicenter, randomized controlled clinical trial that compare the effect of

saline aggressive hydration guided by LVEDP with general hydration on

CI-AKI among STEMI patients undergoing primary PCI. It aims to provide

reliable evidence to guide the optimal hydration strategy for STEMI patients

undergoing primary PCI. If our hypothesis is supported by the results, the

aggressive hydration protocol could be easily adopted in most cardiac

intervention laboratories in China and benefiting the vast number of STEMI

patients.

2. SIGNIFICANCE OF THE PROPOSED RESEARCH

According to the latest data, the number of CHD in worldwide is about 150

million52. China has about 11 million CHD patients. Although the global

mortality rate of CHD is declining, the mortality rate of CHD in China is still

increasing year by year, especially among STEMI population. As an important

measure of diagnosis and treatment, the number of PCI in China increased to

915,256. PCI/CT consumes about 80 million contrast agents per year

worldwide and 20 million contrast agents per year in China, with an annual

increase of 20-30%. The burden of STEMI in China has become increasingly

serious and has become a major public health problem53. CI-AKI is associated

with poorer outcomes for patients, including prolongation of hospital stay and

higher mortality54. The results of our research group’s previous meta-analysis

showed that the global incidence of CI-AKI was about 8.6%. The risk in

patients with STEMI undergoing primary PCI is even greater55, with increased




20

incidence of CI-AKI about 29% and increased risk of death by 4.75 times.

Despite a considerable prevalence of risk factors, including reduced LVEF,

renal insufficiency, and diabetes mellitus, in patients needing adequate







thus increasing the risk of cardiac function deterioration. Therefore, a flexible

and individualized hydration therapy based on certain guiding strategy is

urgently needed. By determining the effectiveness of aggressive hydration with

normal saline guided by LVEDP on CI-AKI and important clinical outcomes in

patients post-STEMI comparing with general hydration, the findings of this

clinical trial will provide reliable evidence to guide the optimal hydration

strategy for STEMI patients undergoing primary PCI. What’s more, the

aggressive hydration protocol could be easily adopted in most cardiac

intervention laboratories in China and benefiting the vast number of STEMI

patients.

STUDY DESIGN

3. STUDY HYPOTHESES AND OBJECTIVES

3.1 Study hypotheses

Compared to general hydration strategy, aggressive hydration (ie,

pre-procedural IV loading plus post-procedural hemodynamic-guided [LVEDP]

fluid administration) will reduce the risk of CI-AKI and long-term clinical

adverse events in STEMI patients undergoing primary PCI.




21

3.2 Study objectives

To assess the effectiveness of preprocedural loading dose and

postprocedural aggressive hydration with normal saline guided by LVEDP as

compared with general hydration for prevention of CI-AKI and reduction of

long-term adverse events. CI-AKI is defined as a ＞ 25% or 0.5-mg/dL

increase in serum creatinine from baseline during the first 48 to 72 hours after

PCI. Long-term adverse events includes: all-cause mortality, target vascular

revascularization, nonfatal myocardial infarction; acute pulmonary edema,

cardiogenic shock, stroke, clinically significant arrhythmias, bleeding within the

first year, total hospitalization costs and length of stay. Our ultimate objective is

to identify optimal hydration strategy for high-risk patients with STEMI

undergoing primary PCI.

4. OVERVIEW OF STUDY DESIGN

ATTEMPT (trial registration: ClinicalTrials.gov NCT02067195) is an

investigator-initiated, multicenter, open-label, randomized controlled trial

conducted in the departments of cardiology from 15 hospitals in China. The

institutional ethics review board approved the study's design.

The study population will consist of 560 patients 18 years or older with STEMI

who undergo primary PCI and provide written informed consent for this study.

The time limit of the study is May 2014 - June 2016. Patients are excluded for

the following reasons: contrast medium administration within the previous 7

days; end-stage renal failure or renal transplantation; Inferior and/or right

ventricle myocardial infarction combined with hypotension (defined as systolic

pressure ≤90 mmHg) on admission; Preprocedural renal insufficiency (history

of chronic kidney disease or eGFR ≤60 mL/min/1.73 m2 was calculated using

the level-modified Modification of Diet in Renal Disease formula [MDRD]);




22

cardiogenic shock or NYHA IV; acute kidney injury defined as an absolute

serum creatinine increase of 0.5 mg/dL from baseline obtained in the previous

24 hours; lactation; pregnancy; malignant tumor or life expectancy <1 year;

allergy to contrast; periprocedural administration of nonsteroidal

anti-inflammatory drugs; aminoglycosides, cyclosporine, or cisplatin in the

previous 48 hours or during the study period; planned renal catheterization; or

heart valve surgery.

Eligible patients are randomized using computer generated random numbers

and a 1:1 ratio to receive either general hydration (control group) or

intervention hydration with isotonic saline. Randomization is stratified by age

(<60 years, 60-75 years,>75 years), sex (male or female), and myocardial

infarction location (anterior or not anterior). After screening for eligibility based

on the criteria, the patients who have agreed to undergo the procedure in the

emergency department or catheter laboratory are asked to provide consent

and are randomized before the primary PCI. Then, the fluid-loading dose is

administered before the procedure and continued for 30 minutes during the

procedure, if necessary; we do not wait 30 minutes to start the procedure to

avoid a delay in revascularization of the target vessel. General hydration for

the control group consists of a periprocedural continuous IV infusion of ≤500

mL isotonic saline within 6 hours. Aggressive hydration consists of a 250-mL

loading dose of isotonic saline (125 mL for patients with congestive heart

failure, Killip II/III or NYHA III) over a 30-minutes period prior to the procedure48,

followed by IV hydration at a rate of 1 mL/kg/h (0.5 mL/kg/h for patients with

congestive heart failure, Killip II/III or NYHA III) until the LVEDP measurement.

Therefore, in the intervention group, LVEDP is measured after the primary PCI

to guide the hydration. Hydration on a sliding scale is used 4 hours after the

procedure: 5mL/kg d h for LVEDP <13 mm Hg, 3 mL/kg d h for LVEDP 13-18

mm Hg, 1.5mL/kg d h for LVEDP >18mmHg, and 0.5mL/kg d h for LVEDP >20




23

mm Hg. Then, hydration is continued at the normal rate until 24 hours after the

procedure45. When the LVEDP value does not agree with the heart function as

evaluated by the clinical doctors, the rate and duration of hydration are based

on the clinical evaluation for heart function and at the discretion of the

cardiologists.

Blood serum creatinine, cystatin C, C-reactive protein, and serum electrolytes

are evaluated at baseline; before the coronary angiography; at 24 ± 4, 48 ± 4,

and 72 ± 4 hours after the procedure; and at hospital discharge. The time

between symptom onset and reperfusion, including the time at the beginning

and end of the procedure; urine output; and oral hydration volume (waterl in

milliliters) during the 24 hours after the procedure are recorded. Periprocedural

intervention (ie, fluid mixed with medications and normal saline or glucose

injection, furosemide, or statins), PCI technique, contrast agent (nonionic,

low-osmolality, or isotonic), and contrast dose are at the discretion of the

cardiologists in charge of the patient routine and procedure management,

following current practice guidelines56. Patients will be excluded if they receive

contrast again within 72 hours after the procedure57 and undergo CAG but no

PCI or dead during the procedure. All of this information is carefully collected

by the research staff.

The primary end point is CI-AKI, defined as a >25% or 0.5 mg/dL increase in

serum creatinine from baseline during the first 48 to 72 hours after the

procedure58. Secondary end points are as follows: (1) CI-AKI48h, defined as

a >50% or 0.3-mg/dL absolute increase in serum creatinine from baseline

during the first 48 hours after the procedure; (2) CI-AKIcys-c, defined as a >10%

or 0.3-mg/dL absolute increase in serum cystatin C during the first 24 hours

after the procedure59; (3) CI-PKI, defined as residual impairment of renal

function indicated by a >25% reduction in creatinine clearance at 3 months in






25

safety, study conduct and progress, and, when appropriate, efficacy and will

make recommendations to the principal investigators concerning the

continuation, modification of enrollment, or termination of the trial. Details of

any protocol violations (eg, descriptions, reasons, and resolution) will be

reported by the investigators and clinical research associates to the primary

investigators, the Central Event Adjudication committee, and Data and Safety

Monitoring Board, if necessary. In addition, training will be provided to the

researchers, and the study procedure will be supervised, with particular

attention to the reasons for bias and data verification to avoid recurrence of

protocol violations.

Finally, intention-to-treat analysis will be used for the patients with protocol

violations instead of the per-protocol analysis. The sample size calculation was

based on our previous findings60, and a CI-AKI incidence of 23% was

estimated for the control group, and a CI-AKI incidence of 11.5% was

assumed for the intervention group (50% relative reduction). Using nQuery +

nTerim 3.0 (Statistical Solutions Ltd, Farmer's Cross, Cork, Ireland) with a

2-sided χ2 test, a significance level of 0.05, a power of 90%, and a dropout

rate <20%, 280 patients are required in each group, for a total sample size of

560. The primary outcome, that is, rate of CI-AKI, will be compared between 2

groups using χ2 tests, and the 95% CI of the rate difference will be calculated

using the method described by Altman et al (reported in Newcombe61) and

recommended by the Food and Drug Administration and Clinical and

Laboratory Standards Institute. Multivariable logistic regression models will be

developed to adjust for clinical characteristics (eg, age, sex, creatinine

clearance, and left ventricular ejection fraction [LVEF]), and the Mehran risk

score will be calculated62. Odds ratios will be reported with their corresponding

95% CIs. Comparisons between normally distributed continuous variables,

expressed as mean ± SD, will be performed using 2-sample t tests;




26

nonnormally distributed continuous variables, presented as median and

interquartile range, will be analyzed using Wilcoxon rank sum tests. Pearson

χ2 or Fisher exact tests will be used, as appropriate, for categorical data,

which will be expressed as percentages. The primary and secondary end

points will be analyzed based on the intention-to-treat principle. All tests will be

2 tailed, and a P value <.05 will be considered statistically significant. All data

analyses will be performed using SAS version 9.4 (SAS Institute, Cary, NC).




27

Table A2 Timetable of visits and procedures

Visits5 Screening visit1

Operative day

1 daysafter

operation

2 daysafter

operation

3 daysafter

operation2

7 daysafter

operation

90±14daysafter

operation4

360±14daysafter

operation

Informedconsent √

Inclusion/Exclusion criteria √

Baseline √

Routine bloodtest √

Liver function √

Renal function √ √ √ √ √ √3 √

Characteristicsof coronaryintervention

√

Entry audit √

Randomization √

Record drugs √ √ √

Record AEs √ √ √ √ √3 √ √Study directorreviews medicalrecords

√

CRA reviewsmedical records √

Medical recordentry database √

EDC √

Medical recordreturn and filing √

1 Screening and random observation (1 day before direct coronary intervention)

2 Items must be checked on the 3rd day after coronary intervention

3 The renal function included cystatin C from the 4th to 7th day after PCI (daily evaluation: for

patients whose serum creatinine value (SCR) in 48-72 hours after PCI was higher than or equal to

0.3mg/dl than the baseline absolute value).

4.90±14 days.

5.HCG-Items to be tested for women who were likely to be become pregnant.




28

METHOD

5. STUDY POPULATION AND PATIENT RECRUITMENT

5.1 Study population

The study population will consist of 560 patients, aged ≥18 years with STEMI

who provided written informed consent for this study. Since a major risk factor

for subsequent adverse clinical events following STEMI is the delay of PCI, we

will only enroll patients underwent primary PCI.41, 63

Inclusion Criteria:

All consecutive patients with STEMI, age at least 18 years, who were

candidates for primary PCI were considered for enrollment.

STEMI was defined as the onset of chest pain or chest distress lasting

for at least 30 minutes with electrocardiography(ECG) ST-segment

elevation of at least 0.2 mV in two or more contiguous leads and/or the

development of new left bundle-branch block associated with elevation

in the levels of creatinine kinase or its MB isozyme to at least two times

that of normal.46

STEMI patients who were candidates for primary PCI should meet at

least one of the following conditions: 1. Ischemic symptoms <12 h; 2.

Ischemic symptoms <12 h and contraindications to fibrinolytic therapy

irrespective of time delay from FMC; 3. Cardiogenic shock or acute

severe HF irrespective of time delay from MI onset.41

Exclusion Criteria:

Contrast medium administration within the previous 14 days or follow 72

hours,

End-stage renal failure or renal transplantation, and refuse PCI or dead

during the procedure,

Heart failure of cardiac shock or New York Heart Association class IV, (we

are excluding these patients because IV fluid administration may be




29

contraindicated):

Recent acute kidney injury defined as an absolute increase of 0.5 mg/dl in

serum creatinine over baseline in the past 24h.

The presence of lactation, pregnancy,

Malignant tumor or life expectancy less than 1 year,

Allergy to contrast medium, peri-procedural receipt of metformin or

non-steroidal anti-inflammatory drugs in the past 48h and during the study

period,

Planned renal catheterization or heart valvular surgery.

5.2 Screening and patient recruitment

All the potentially eligible patients will be screened out by the chief resident of

the department of cardiology. Then, the chief resident will dial the “ATTEMPT

phone” to report the initial situation of the patient to the ATTEMPT research

personnel on-duty, who must arrive within 15 minutes (for those who are

unable to arrive in time, he/she must contact other members to follow up).

Researchers will contact potentially eligible subjects to describe the study and

complete the screening process. Based on our past experience, almost all the

patients intended to undergo primary PCI will have a SCr measured as part of

routine care before angiography. However due to the urgency, we are unable

to get the result of pre-procedure renal function before angiography. In such

situation, for the majority of patients who do not have a SCr measured before,

we can only exclude them after PCI if they were proven to suffer end-stage

renal failure. Patients with no peri-operative creatinine were found to be

excluded after randomization. We will also require that potentially eligible

female subjects who are able to be pregnant (not considered post-menopausal

[had a menstrual period within previous 12 months], not had tubal ligation, a

hysterectomy or bilateral oophorectomy) and are sexually active, have a

negative pregnancy test before being enrolled in the research. No adult patient




30

(age ≥18 years) will be excluded from participating based on age, gender, race,

ethnicity, or sexual preference.

6. STUDY PROCEDURES

6.1 Assessment of pre-procedural laboratory examinations

Eligible patients will have their SCr measured before angiography, which will

serve as their baseline SCr. At present, the methods for detecting SCr mainly

include basic picric acid method (Jaffe assay) and enzymatic assay. The

enzymatic assay avoids the poor specificity of the Jaffe assay and has a strong

anti-interference ability. Therefore, it is widely accepted as the most reliable

assay in the clinical laboratories. All laboratories in our study are consistently

adopting this methodology to reliably and accurately assess the development

of CI-AKI. The timing of the pre-procedure study SCr (baseline SCr) testing

used to assess the outcomes is also important as the administration of IV fluids

may lead to hemodilution and artifactual lowering of SCr. In addition, variation

in intravascular volume status affects renal function, particularly in patients

with underlying CKD. Therefore, we will standardize the timing of assessment

of the baseline SCr for endpoint ascertainment. This blood sample will be drew

at the same time of patient enrollment and immediately prior to the beginning

of study IV fluids to avoid any potential influence of study interventions on the

baseline SCr level. Although STEMI patients will have some basic laboratory

examinations as soon as they reach the emergency department or a few

minutes after the chest pain onset if it happens in hospital, some examinations

are not routine for such patients, such as cystatin C, hypersensitive C-reactive

protein and so on. For these variables, to make sure that they are not affected

by the interventions, the research personnel needs to check whether the

relevant blood tests of the patient had been done before the intervention

(cystatin C, hypersensitive C-reactive protein, cardiac enzyme, emergency

biochemistry, blood routine). If there is any omission of these tests, the




31

research personnel needs to make a prescription and asks the nurse

completes the blood draw before the intervention begins.

6.2 Randomization procedures

All patients meeting eligibility criteria and providing informed consent will be

randomized to each of the two study groups [general hydration (control group)

versus aggressive hydration with isotonic saline (intervention group)]. Qualified

patients are randomized using computer-generated random numbers at a 1:1

ratio. Randomization will be accomplished using a block random method with 8

units in each group. Some offset or variability will be inserted to prevent

anticipation of the next treatment. Randomization will be stratified by sex, age

and anterior myocardial infarction. Study coordinators at each site will be

responsible for obtaining a randomized treatment assignment for each eligible

patient. A web-based randomization program will be provided to study sites for

this purpose. This web-based program will be tested at each site prior to the

start of the trial and will be reviewed, as per Center guidelines, by the Key

Laboratory of Coronary Heart Disease. At the time of subject enrollment,

research personnel will enter the Subject ID number, sex, age and anterior

myocardial infarction into the randomization program. The program will check

that all eligibility criteria are met. If met, the program will select the first unused

entry from the pre-specified list of random treatment assignments for the

particular site. The lists are stored on a secure server at Southern Medical

University, Department of Biostatistics, Clinical Research Management

System. If the electronic system fails, the random envelope method will be

adopted. The random envelope method is to store a random grouping scheme

of a numbered research object in a sealed and opaque envelope, which is

performed in two steps:1) verifying whether the patient meets the criteria for

inclusion and exclusion, signing informed consent, and giving the case number;

2) Disassemble the random envelopes of the corresponding numbers in order,




32

determine the grouping of a patient according to the distribution plan in the

envelope, and carry out corresponding interventions. Since this is an

open-label study, we do not have the procedure of blinding.

6.3 Study interventions

In this study, patients will receive either general hydration (control group) or

aggressive hydration with isotonic saline guided by LVEDP (intervention

group)

Control group:

The general hydration for the control group is a peri-procedural continuous

intravenous infusion of ≤500 mL isotonic saline within 6h.

Intervention group:

The aggressive hydration consists of a 250mL loading dose of isotonic saline

(125 mL for patients with congestive heart failure, Killip II/III) over 30 min prior

to procedure,48 followed by IV hydration at the rate of 1 mL/kg/h (0.5 mL/kg/h

for patients with congestive heart failure, Killip II/III) until the LVEDP

measurement, which were performed after the coronary revascularization.

Hydration on a sliding-scale is used 4 h after the procedure: 5 mL/kg·h for

LVEDP <13 mmHg, 3 mL/kg·h for LVEDP 13–18 mmHg, 1.5 mL/kg·h for

LVEDP >18 mmHg, and 0.5 mL/kg·h for LVEDP >20 mmHg. Then, hydration

is continued at the normal rate until the 24 h after the procedure reaches.45

When the LVEDP value does not agree with the heart function as evaluated by

the clinical doctors, the rate and duration of hydration is based on the clinical

evaluation for heart function and at the discretion of the cardiologists.

In the intervention group, we will use LVEDP to guide hydration within 4 hours

after the procedure. At the end of the procedure, the research personnel will

remind the operators to make an LVEDP measurement before the catheter is

withdrawn. Although LVEDP is a more objective indicator of left ventricular




33

volume, it cannot be used to diagnose whether a patient has heart failure or

not.64 Therefore, when the LVEDP value does not agree with the heart function

as evaluated by the clinical doctors, the rate and duration of hydration is based


cardiologists. In addition, some sub-centers may not be able to measure

LVEDP for several reasons. In this case, we allow the clinicians to estimate

LVEDP based on the patient's situation and to determine the hydration

strategy within 4 hours after the procedure. We chose this flexible approach

rather than a strict protocol for IV fluid administration for several reasons. First,

though there is a general belief that “more fluid” may be dangerous for HF

patients, the optimal rate, duration, and volume of IV fluid to prevent CI-AKI

and other adverse outcomes for HF patients have not been conclusively

determined. Therefore, the rate and duration of hydration is based on the

clinical evaluation for heart function and at the discretion of the cardiologists.

Second, since LVEDP have not been determined as a golden standard for

making hydration strategy, requiring that IV fluids be administered strictly

based on LVEDP could significantly limit other medical workers` willingness to

help. In clinical practice, the volume and duration of pre and post-procedure IV

fluid often vary based on the clinical setting and individual patient

circumstances. We do not believe that using this flexible approach will

compromise our ability to determine differences in study outcomes between

two groups.

6.4 Peri-procedural management issues

Drug prescription and blood collection time points are strictly in accordance

with the protocol, clinical guidelines and clinical reality. Though all contrast

media may cause potential clinical complications, the osmolality of the contrast

agent is proven to potentially impact the risk for CI-AKI. Previous conclusively

demonstrate that high osmolality (>1200 mOsm/kg) agents pose a greater risk




34

for CI-AKI than low osmolality (500-860 mOsm/kg) agents in high-risk

patients.65, 66 However, data on the comparative incidence of CI-AKI with

low-osmolal contrast and iso-osmolal are on dept and inconclusive. To provide

care that is consistent with prior guidelines issued by the American College of

Cardiology/American Heart Association for the use of iodinated contrast, all

patients in this trial will receive either iso-osmolal contrast media (i.e., iodixanol)

or non-ionic, low-osmolal contrast media.67 Usage of the specific contrast

agent and the volume of contrast media administered will be at the discretion

of the operator as there is no current guideline or consensus on the least

nephrotoxic contrast agent.

Accompanying medications and invasive treatment device, for example IABP,

are also source of potentially nephrotoxicity.68 Aminoglycosides or any other

drugs with significant nephrotoxicity are strictly prohibited. Patients are

recommended to have statin therapy preoperatively. The implication of

perioperative platelet glycoprotein IIb/IIIa receptor antagonists--Ikat (Iroko

Cardio Australia Pty Ltd), the use of loop diuretics and other drugs that are not

prohibited in this study will be at the discretion of the treating provider

according to the condition and treatment routine. We will also defer decisions

on the discontinuation of angiotensin converting enzyme inhibitors or

angiotensin receptor blockers to the treating provider(s) because there are no

conclusive data on the optimal approach to the management of these

medications in patients with STEMI undergoing angiography.

6.5 Post-procedure management issues

Drug prescription and blood collection time points are strictly in accordance

with the protocol, clinical guidelines and clinical reality. Following angiography,

research personnel will follow the patient to cardiac care unit (CCU) and reset

the hydration speed to routine level 4 hours after the procedure. Research




35

personnel are also required to communicate with the patient's responsible

nurse and ask he/she to record the patient's postoperative liquid intake

(including oral and intravenous) as well as the liquid output (mainly urine

volume) in detail (time and volume). Following angiography and prior to

discharge from the hospital, research personnel will also arrange the

participant`s blood specimen collection at 24, 48 and 72 ± 4 hours following

their angiography.

6.6 Study Outcomes

6.6.1Primary study outcome

The primary endpoint consist of:

CI-AKI, defined as a ≥ 25% or 0.5 mg/dL absolute increase in serum

creatinine from baseline during the first 48-72 h post-procedure.

a 10% or 0.3 mg/dL increase in cystatin-C during the first 24h post-procedure.

6.6.2 Secondary study outcomes

The secondary outcomes consist of:

1) CI-AKI48h, defined as a >50% or 0.3-mg/dL absolute increase in serum

creatinine from baseline during the first 48 h post-procedure;

2) CI-AKIcysc, defined as a >10% or 0.3-mg/dL absolute increase in serum

cystatin-C during the first 24 h post-procedure; 58

3) Persistent renal damage, defined as residual impairment of renal function

indicated by a >25% reduction in creatinine clearance at 3 months in

comparison with baseline;59

4) Composite major adverse cardiovascular events, including all-cause

mortality, target vascular revascularization, and non-fatal myocardial infarction;




36

Table A3 - Definitions of components of MACEs

Term Definition

All-cause mortality All cause mortality, defined as any death recorded between

the date of interview and the end of data.

Target vascular

revascularization (TVR)

TVR is defined as any revascularization procedure (PCI or

CABG) involving the vessel treated during the index PCI

procedure for STEMI.

Non-fatal myocardial

infarction

Recurrent MI will be subdivided into MI within the first 24 h of

randomization, between 24 h and 7 d after randomization,

and >7 d after randomization.

MI occurring

between 24 h

and 7 d of

randomization

Recurrent ischemic symptoms >20 min with

new ST elevation >0.1 mV in ≥2 contiguous

leads not due to changes from evolution of

the index MI. Ischemic symptoms >20 min

and either 1) elevation or re-elevation of

cardiac biomarkers(CK-MB or troponin)

greater than twice the upper limit of normal

(ULN) and if already elevated, then further

elevations >50% above a previous value

that was decreasing or 2) new ST-segment

elevation or new significant Q waves in ≥2

contiguous leads, which are separate from

the baseline MI.

MI occurring

after 7 d of

randomization

Typical rise and fall of biochemical markers

of myocardial necrosis to greater than twice

the ULN or if markers were already

elevated, further elevation of a marker

to >50% of a previous value that was

decreasing and >2× ULN, with ≥ 1 of the




37

following: 1) ischemic symptoms, 2)

development of new pathologic Q waves, or

3) ECG changes of new ischemia or (iv)

pathologic evidence of MI.

MI occurring

within 24 h

after nonindex

PCI that is

performed >24

h after

randomization

Cardiac biomarker (creatine kinase-MB

[CK-MB] or troponin) >3× the ULN or

increased by 50% from the preprocedural

valley level and ≥3 times ULN in patients

with already elevated enzymes or new

ST-segment elevation or development of

significant Q waves in ≥2 contiguous leads,

which are discrete from baseline MI.

Within 24 h

post-CABG

CK-MB (or total CK, if CK-MB is

unavailable) ≥5× ULN and increased 50%

from the preprocedural valley level and N

5× ULN in patients with already elevated

enzymes and development new pathologic

Q waves in ≥2 contiguous leads or CK-MB

value ≥10 times ULN without new

pathologic Q waves.

5) Major post-procedure in-hospital adverse clinical events, including acute


and bleeding.

Table A4 - Definitions of components of major post-procedure in-hospital

adverse clinical events

Term Definition

Acute pulmonary edema Acute pulmonary edema, defined as arterial partial pressure




38

of oxygen (PaO2)/inspired oxygen fraction (FiO2) ratio <300

for arterial blood gas, and pulmonary edema or bilateral

infiltrates on chest radiograph as read by radiologists, both

within 24 h.

Cardiogenic shock Cardiogenic shock is defined as systolic blood pressure <90

mmHg not responsive to fluid resuscitation and/or heart rate

correction for ≥1 h or need for vas opressor/inotropic therapy

to maintain systolic blood pressure >90 mm Hg for ≥1 h and

believed to be secondary to cardiac dysfunction and

associated with ≥1 of the following: 1) signs of pulmonary

edema, 2) signs of hypoperfusion (cool clammy skin, oliguria,

or altered sensiorium), or 3) cardiac index <2.2 L/min.

In patients presenting with cardiogenic shock at the time of

randomization, they must have a ≥24 h period with complete

resolution of shock and a new cardiogenic shock event (ie,

due to new stent thrombosis) for this event to be eligible as a

primary outcome event.

Stroke Any stroke is defined as the presence of a new focal

neurologic deficit thought to be vascular in origin, with signs

or symptoms lasting >24 h. It is strongly recommended (but

not required) that an imaging procedure such as a computed

tomography or magnetic resonance imaging be performed.

Clinically significant

arrhythmias

Clinically significant arrhythmias (SA) were defined as 1 or

more of the following: more than 100 VPC or APC (including

VPC2/3 or APC2/3) per 24 h (equalling a rate of 4.17/h) or any

presence of RT, VT, or AT.

Bleeding Major bleeding or vascular events (bleeding requiring

transfusion of hemoglobin drop ≥3 g/dL or need for vascular

surgery).




39

6.7 Data collection

6.7.1 Assessment of baseline demographic and clinical characteristics

Following patient enrollment, research personnel will make a comprehensive

review of the electronic medical record and/or interview the subject and his/her

families to abstract the following data elements:

Demographic characteristics including date of birth, gender and ethnicity

Admission information including

Time of symptoms onset

Time of first medical contact (FMC)

Time of admission

Time of entering catheterization laboratory

Did thrombolytic therapy be used in this case? (If it did, then the time of

thrombolytic therapy should be recorded)

Did cardiac arrest happen in this case? (If it did, then the time should

be recorded)

Did heart failure happen in this case?

Heart function (Killip class)

Use of vasoactive drugs

Use of IABP

Administration of any IV fluid and prior to the initiation of study

Pre-procedure laboratory parameters obtained as part of routine clinical care

including date of test (most proximate to and within the 7 days preceding the

angiogram:

ɸ CK, CKMB, troponin T, troponin I, hsCRP, NT-proBNP or BNP, WBC, Hb,

PLT, Hct, Neut%, SCr, Cystatin C, serum glucose, sodium, potassium, blood

urea nitrogen and pregnancy examination (if available)

medical history:

ɸ Hypertension, diabetes, hyperlipidemia, coronary artery disease (CAD),

myocardial infarction (if available, the happening time should be record),




40

congestive heart failure, peripheral vascular disease, chronic kidney disease,

stroke and chronic pulmonary disease. Standard procedures and definitions

will be developed to systematically evaluate patients records for each of these

conditions.

Family history of CAD

Smoking history

Physical examination, including:

1) Height in centimeter and weight in kilograms. The recommended

method of obtaining the patient`s height and weight will be for research

personnel to measure them. In the event this is not possible, the most recent

measurement (usually at the time of admission) found in the patients medical

record will be recorded. Finally, if there is no measurement in the medical

record, this information will be collected via subject report.

2) Blood pressure and heart rate at the time of admission.

3) Physical examination record on chest (including heart and lung),

abdomen, nervous system, limbs and spinal.

Pre-procedure ECG and cardiac ultrasound (if available)

Names and doses of all pre-procedure medications, including those

prescribed by physicians outside the research centers, regularly taken by

the subject within the 14 days preceding the angiogram.

6.7.2 Collection of oral hydration and urine volume within 24h post-procedure

Research personnel will communicate with and hand over a specially designed

chart to the patient's responsible nurse and ask he/she to record the patient's

postoperative liquid intake (oral) as well as the liquid output (mainly urine

volume) in detail (time and volume) within 24h post-procedure. We will collect

the chart later.




41

6.7.3 Evaluation of procedure-related data

Subsequent to the angiogram, research personnel will review the electronic

medical record and angiogram procedure report to determine:

Primary PCI or not;

The beginning and ending time of procedure;

The time of balloon dilation

Type and volume of contrast administered (Iodixanol, Iopromide,

Iopamidol or iohexol)

The use of GPIIb/IIIa Inhibitors

The implication of thrombus aspiration

The implication of IABP

Post-procedure LVEDP

Coronary artery lesions and performance of percutaneous intervention

Complications during the procedure including:

Hypotension or cardiac shock necessitating the administration of

additional non-study IV fluid including the type of non-study IV fluid

administered

Hypotension or cardiac shock necessitating the insertion of an

intra-aortic balloon pump and/or the administration of vasopressor

therapy

Arrhythmia

Death

Any new accompany medications

Assessment of procedure-related complications will ensure that we capture all

events that could impact on the development of our primary and secondary

outcomes. To clarify and confirm all of these procedure-related data, research

personnel will also organized a brief interview with the angiography operators.




42

6.7.4 Evaluation of study IV fluid administration

Research personnel will track and record from the electronic medical record

the speed, total volume and total duration of study IV fluid administered

pre-procedure, intra-procedure, and post-procedure.

6.7.5 Evaluation of post-procedure course (within 24 ± 4 hours post procedure)

Research personnel will review the electronic record and collect the following

data elements:

Vital signs within 6h and at 24 hours post-procedure;

Renal function assessment and blood electrolytes and the date of test (If

the serum creatinine (SCr) increased by more than 0.3 mg/dL within 72

hours post-procedure, the renal function of the subjects was monitored

until 1 week after operation);

Episodes of primary end point or any major adverse cardiovascular events;

Performance of additional contrast exposure including coronary or

non-coronary angiography or computed tomography with intravascular

iodinated contrast;

6.7.6 Evaluation of post-procedure course (48 ± 4 hours post procedure)


data elements:

Vital signs at 48 hours post-procedure;

Renal function assessment, hsCRP and blood electrolytes and the date of

test (If the serum creatinine (SCr) increased by more than 0.3 mg/dL within

72 hours post-procedure, the renal function of the subjects was monitored








43

iodinated contrast;

Cardiac and Carotid Ultrasound and the date of test (if available);




data elements:









iodinated contrast;


Since this creatinine determination is essential to the determined of primary

end-point, it is very important that the blood collection be done within the 72

hours after angiography. We recognize that unforeseen circumstances may

hinder collection within this window. Under such circumstances the blood

should be collected as soon as possible and most proximate to 72 hours and a

protocol deviation should be noted.

6.7.8 Evaluation of post-procedure hospitalization course (4 – 7 days post

procedure and the day of discharge)

Research personnel will review the electronic record on a daily basis for

patients who remain in the hospital following their angiography procedure and

collect the following data elements:




44

Vital signs have collected for once among 4-7 days post-procedure;







Date of discharge and total hospitalization expenses

Generally speaking, subjects will only have one examination during this period.

For those who have vital signs or renal assessment for many times, we will

record the highest level of each day.

6.9.9 Day 30 post procedure assessment (30 days post angiography,

allowable range 23-37 days post angiography)

Thirty days following the angiography, clinical doctors will review the electronic

medical record (if available) and perform a telephone interview with the patient

to inquire about any adverse events they experienced related to study

participation. The electronic medical record review and telephone interview will

specifically focus on assessing the renal function and the development of any

of the following adverse outcome within the research sites system.

Vital signs and renal function assessment (if available)

Renal replacement therapy

All-cause mortality

Target vascular revascularization

Non-fatal myocardial infarction

Acute heart failure

Cardiogenic shock

Stroke

Clinically significant arrhythmias




45

Bleeding

Heart broken

The 30-day telephone interview with the patient will be a supplement to the

electronic medical record review. This telephone interview will verify data

abstracted from the electronic medical record and enable research personnel

to inquire about death, re-hospitalizations at non-research sites and other

MACEs that would not have been captured in the electronic medical record.

For any patients who were hospitalized outside the research centers, the

research personnel will obtain the hospitalization information from the patient

or his/her families.

To ensure the follow-up quality, before the first time of telephone interviews,

research personnel assistants will help researchers to arrange the follow-up

method and time.

During the telephone interview:

Recording and judgment of events

In the course of follow-up, once considering the events probably occur to the

subjects, research personnel assistants will record the relevant events in

details. And then, they will submit the record to the research personnel who will

make the judgment later.

Quality control

After the start of follow-up, the quality control team needs to check the

follow-up form and EDC regularly (not less than two times a week). Research

personnel assistants who fail to reach the standard will repeat the training and

assessment work, and those who fail three times will be replaced by more

suitable personnel.

Lost to follow-up control

We will control the number of missing calls by dialing the lost calls again,

inquiring the hospital system or the public security system, etc.




46

We recommend that this contact should be made at 30 days after angiography,

with an allowable range of 30±7 days. We recognize that sometimes it may be

difficult to contact with a patient within this window. However, it is important to

collect the required data, which should be done even if done after the

recommended time frame has elapsed. It will not be considered a protocol

deviation as long as the required data are collected and there is progress note

documenting the attempt to schedule the data collection during the

recommended time frame.


allowable range 90 ± 14 days post angiography)

Ninety days following the angiography, research personnel assistants will

review the electronic medical record (if available) and perform a telephone

interview with the patient to inquire about any adverse events they

experienced related to study participation. The electronic medical record

review and telephone interview will specifically focus on assessing the renal

function and the development of any of the following adverse outcome within

the research sites system.



All-cause mortality



Acute heart failure

Cardiogenic shock

Stroke


Bleeding

Heart broken




47

The 90-day telephone interview with the patient will be a complement to the

electronic medical record review. This telephone interview will verify data that

was abstracted from the electronic medical record and enable research

personnel to inquire about death, re-hospitalizations at non-research sites and

other MACEs that would not have been captured in the electronic medical

record. For any patients who were hospitalized outside the research centers,

the research personnel will obtain the hospitalization information from the

patient or his/her family.







Quality control





suitable personnel.





with an allowable range of 90 ± 14 days. We recognize that sometimes it may

be difficult to contact with a patient within this window. However, it is important

to collect the required data, which should be done even if done after the






48




allowable range 180±14 days post angiography)

180 days following the angiography, research personnel assistants will review

the electronic medical record (if available) and perform a telephone interview

with the patient to inquire about any adverse events they experienced related

to study participation. The electronic medical record review and telephone

interview will specifically focus on assessing the renal function and the

development of any of the following adverse outcome within the research sites

system.



All-cause mortality



Acute heart failure

Cardiogenic shock

Stroke


Bleeding

Heart broken










49









Quality control





suitable personnel.




We recommend that this contact should be made at 180 days after

angiography, with an allowable range of 180±14 days. We recognize that

sometimes it may be difficult to contact with a patient within this window.

However, it is important to collect the required data, which should be done

even if done after the recommended time frame has elapsed. It will not be

considered a protocol deviation as long as the required data are collected and

there is progress note documenting the attempt to schedule the data collection

during the recommended time frame.

6.7.12 1 year post procedure assessment (1 year post angiography, allowable

range 1 year ±14 days post angiography)

1 year following the angiography, research personnel assistants will review the




50

electronic medical record (if available) and perform a telephone interview with

the patient to inquire about any adverse events they experienced related to

study participation. The electronic medical record review will specifically focus

on assessing the renal function and the development of any of the following

adverse outcome within the research sites system.



All-cause mortality



Acute heart failure

Cardiogenic shock

Stroke


Bleeding

Heart broken

The 1-year telephone interview with the patient will be a complement to the
















51


Quality control





suitable personnel.




We recommend that this contact should be made at 1 year after angiography,

with an allowable range of 1 year ±14 days. We recognize that sometimes it

may be difficult to contact with a patient within this window. However, it is

important to collect the required data, which should be done even if done after

the recommended time frame has elapsed. It will not be considered a protocol




7. POTENTIAL RISKS AND ALTERNATIVE CONSIDERATIONS

7.1 Study Population

Most past studies of CI-AKI have focused on all patients undergoing coronary

angiography. We propose enrolling STEMI patients only. Patients with STEMI

are likely to present with hypotension or even shock, a large volume of contrast

agent, and inability to start a kidney prophylactic therapy, all of which are

associated with an increased risk of CI-AKI. Patients with STEMI also

commonly have other risk factors for CI-AKI such as reduced cardiac output or

hypotension due to myocardial infarction or depletion of intravascular volume

caused by vomiting, diaphoresis, or decreased oral intake. Despite a




52

considerable prevalence of risk factors, including reduced LVEF, renal

insufficiency, and diabetes mellitus, in patients needing adequate hydration,

cardiologists in previous studies were primarily concerned with rapid








urgently needed. While limiting the enrollment to STEMI patients will restrict

the number of patients available for recruitment and the generalizability of the

study findings, it will increase the homogeneity, find out the optimal hydration

administration regimen in these high-risk patients69 and fill in gaps in

guidelines.


7.2.1 Fluid administration

There is no consensus among experts on the optimal rate and duration of IV

fluid administration for the prevention of CI-AKI or single protocol for the

administration of IV fluid that has been shown to be the most effective.

Nowadays, in CHINA, most PCI center do not pay attention to CI-AKI, and

prescribe hydration with no regimen but a bag of 500ml saline which is exactly

used to maintain the venous channel. Generally speaking, it is well-accepted

that hydration is effective in preventing CI-AKI but there is no consensus on

how to make hydration.70 Therefore, we conduct a comparison between

aggressive hydration and the reality to find out a more suitable regimen in

these high-risk patients.




53

7.2.2 Complications of fluid administration

We anticipate that some patients will develop volume overload/pulmonary

edema during angiography. In such instances, providers performing

angiography may discontinue post-procedure IV fluids resulting in patients

failing to receive the planned hydration regimen following the angiogram. It is

likely that this event will occur in a small proportion of patients and be equally

distributed across treatment arms. While the volume of study IV fluid

administered pre, during and post-procedure will be carefully recorded for all

patients, given the importance of patient safety, we believe it would be

inappropriate to require the administration of post-procedure study IV fluid in

such instances. Since all analyses will be based on the intent-to-treat principle,

these patients will not be excluded from the study analyses.

7.3 Ascertainment of baseline kidney function

In order to ascertain a change in kidney function, it is critical to standardize the

definition of baseline kidney function. SCr often fluctuates over time because

of activities, variations in volume status, protein and salt intake, and drift in the

calibration of laboratory instruments. The timing of the SCr testing used to

screen patients is less critical than the value used to define the baseline SCr

for endpoint ascertainment. For practical purposes, we propose to screen

patients based on a SCr obtained as part of routine clinical care performed by

the doctor as soon as the subject enter the emergency department or cardiac

catheterization laboratory. The SCr was sent for examination after PCI. This

will also be the same pre-angiography study SCr (baseline SCr) that will be

used to assess the development of CI-AKI (a primary endpoint).

7.4 Assessment of primary and secondary outcomes

7.4.1 Assessment of CI-AKI

Most patients who develop CI-AKI will have their SCr increased within 48 to 72




54

hours following contrast exposure. However, previous studies demonstrate

that some patients who develop CI-AKI may not be identified by a single SCr

assessment at 48 hours.43 The optimal timing of assessment of SCr following

the angiogram to determine the development of CI-AKI in our trial was

carefully discussed by the committee members. Finally, though complicated, it

was agreed that multiple SCr assessments (e.g., at 24, 48 and 72 hours)

would ensure the identification of all patients who developed CI-AKI. This

decision is based on several reasons. First, some patients who develop CI-AKI

may manifest an increase in SCr at 24-48 hours following angiography.

Second, multiple SCr assessments may describe the trend of SCr after

contrast exposure. Finally, the planning committee feel that measuring SCr at

multiple time points may be of help in finding the most suitable definition of

CI-AKI.

7.4.2 Assessment of cardiovascular outcomes and clinical events

We acknowledge the potential limitations of using administrative data/medical

records for the assessment of cardiovascular outcomes and clinical events,

including all-cause mortality, target vascular revascularization (TVR), non-fatal

MI, acute pulmonary edema, cardiogenic shock, stroke, clinically significant

arrhythmias and bleeding. Therefore, we will also assess these outcomes by

reviewing the hospital discharge summary for documentation of any of the

events that comprise the secondary outcomes. We have considered the

possibility of adjudicating the secondary outcomes using more comprehensive

medical record review. However, we believe that while this would be a more

robust approach, the additional time, effort and cost required to adjudicate

these secondary outcomes using a comprehensive review of the medical

record was not justified.




55

7.5 Secular trends in the prevention and incidence of CI-AKI

We acknowledge that there will be novel viewpoints gained and changes in

clinical practices related to the prevention of CI-AKI and serious adverse

outcomes following angiography during the conduct of the current trial. A

comparison between the incidence of CI-AKI reported in studies conducted in

the 1980s and the incidence described in recent studies reveals a trend that

fewer patients are suffering this iatrogenic complication. However, much of this

trend is likely related to the transition from the more nephrotoxic high-osmolal

contrast media to low and iso-osmolal contrast media. Over the past decade,

there is no evidence of a continued decline in the incidence of CI-AKI or

attenuation in the relationship between CI-AKI and serious, adverse outcomes.

This can be illustrated by a recent study of over 1,100 hospitalized subjects

who underwent contrast-enhanced procedures that demonstrated that CI-AKI

developed in over 40% of patients and was associated with a 2-fold increase in

hospital duration and a 10-fold increase in mortality.18

8. FEASIBILITY OF RECRUITMENT

While our inclusion and exclusion criteria are strict, there are multiple important

factors that support the feasibility of recruiting this large number of patients.

First, all the 11 research centers involved in this project are the regional central

hospitals. The Guangdong Cardiovascular Institute/Guangdong Provincial

People's Hospital, which is in charge of this study, is the most influential

research and prevention centers of cardiovascular diseases in South China. It

is one of the leading coronary intervention therapy centers in China with about

971 primary PCI finished last year. It also participates in the compilation of

“Expert Consensus of STEMI Treatment in China”. Second, patients

undergoing primary coronary angiography are easily identifiable. All of these

procedures are started under the coordination of the chief resident of the

department of cardiology, which greatly facilitates identification and screening




56

of potential study subjects. Third, unlike trials that recruit from a diverse array

of patient settings (e.g., primary care offices, hospital wards, specialty clinics),

our trial mostly recruit patients from only one hospital venues: emergency

department. This greatly simplifies the process of identifying and locating

potentials participants. Fourth, we have set up a special project management

team, which is directly in charge of the project.

The full-time academic secretary coordinates the management of assets, data

and research results in the process of project implementation. Finally, patient

burden in this study is quite limited since there is no need to return to the

hospital for study visits. Follow up data collection will be performed using

telephone calls. Therefore, patients are unlikely to view participation as unduly

burdensome. All in all, we are highly confident in our capacity to successfully

recruit the number of patients needed to meet our enrollment targets.

9. ANTICIPATED BARRIERS TO RECRUITMENT ANDSTRATEGIES TO ADDRESS POTENTIAL UNDERENROLLMENT

9.1 Development of comprehensive organizational structure

Despite the feasibility of recruitment as outlined above, successful enrollment

of the number of patients we hope to enroll and compliance with the study

protocol will depend on the interest and willingness of chief residents and

interventional cardiologists. We recognize that these practitioners may not be

focused on or necessarily prioritize the prevention of CI-AKI and its associated

outcomes, especially since they are often not involved in the longitudinal care

of patients and may not be notified of delayed complications of angiography.

We believe that comprehensive organizational structure at each site will ease

providers’ burden and optimize the potential for successful subject enrollment

and implication. What is more, we believe that the flexibility built into the




57

protocol for study IV fluid administration rates, volumes, and duration will be

attractive to providers performing angiography and will increase their interest

and willingness to have their patients participate in the study.

9.2 Strategies to address under-recruitment of study subjects

Given the relatively large size of our study and the critical importance of

adequate patient recruitment, we anticipate using a number of strategies to

address under-recruitment should it occur. First, during the process of

calculating the sample size, we have taken into account these relevant

problems and enlarged the target number by 20%. Second, in addition to

Guangdong Provincial People`s Hospital, which conduct nearly 400 primary

PCI yearly, we also include another 14 study sites that mostly are the regional

central hospitals. We believe that having these two strategies to address

potential under-enrollment will help ensure the attainment of the target sample

size without compromising the scientific integrity of the study.

10. PROPOSED ANCILLARY STUDY

In addition to the primary study, we are also proposing to conduct an ancillary

study to follow patients for up to 10 years to track renal and cardiovascular

outcomes and mortality.

The specific aims of the proposed study are as follows:

Specific aim 1: To generate and track long-term clinical outcomes in a

matched cohort of patients participating in the ATTEMPT trial with and without

CIN.

Specific aim 2: To assess whether the development of CIN following

angiography is independently associated with serious, adverse, long-term

renal outcomes (i.e., accelerated rate of decline in kidney function and

development of end-stage renal disease), cardiovascular outcomes (i.e.,

cardiac, cerebrovascular, peripheral arterial events) and mortality.




58

11. HUMAN SUBJECTS

11.1 Informed consent

Potentially eligible patients will be identified by chief residents and research

personnel at each site. After the study is introduced to the patient by an

individual participating in their care, research personnel will contact potentially

eligible subjects and their legal agent to describe the study and present

him/her with the detailed informed consent form and supplementary material to

read and review.

The general purpose of the study will be delineated and the treatment

comparisons will be clearly described. The process of randomization will be

discussed and a clear explanation of what will be expected of the patient will

also be described. The risks associated with treatments and procedures will

also be addressed. The importance of patient confidentiality will be stressed,

including a description of the process for maintaining patient confidentiality.

Research personnel will ensure that the patient understands every aspect of

the trial, including its risks and benefits, prior to signing the informed consent. If

the patient agrees, his/her consent to participate in the study will be

documented. The original will be placed in the patient's medical record.

Informed consent requires that the patient understand the details of the study

and agree, without coercion, to participate in the study. To obtain informed

consent, the following information shall be provided to each subject:

Name of the study

Name of the Principal or Site Investigator(s)

Explanation that the study involves research

Explanation of the purpose of the study

Explanation of the treatment procedures

Description of randomization

Description of the risks and benefits of participation in the study




59

Explanation that all records will be kept confidential

Whom to contact for questions about the research and about subjects'

rights

A statement that participation in the study is voluntary and that a decision

not to participate or to withdraw from the study after initially agreeing involves

no penalty, loss of benefits, or reduction in access to medical care.

A statement that the examinations and treatments provided as part of this

study are mostly clinical routine and will be paid by subject himself.

Merely obtaining signed consent from the patient does not constitute informed

consent. However, the use of a standardized consent form aids in assuring

that subjects receive adequate and consistent information about the trial and

that they have consented to participate.

11.2 Risks and benefits

Any procedure/intervention has potential risks. The interventions used in this

study may cause all, some, or none of the risks and side effects listed. There is

also the potential for rare or unknown risks to occur. Active study participants

will be informed of any information that becomes known during the course of

the study regarding risks of the interventions that might affect their willingness

to continue to participate.

11.2.1 Side effects associated with infusion of intravenous fluids

Reactions due to solution or technique of administration: febrile response,

infection at the site of injection, venous thrombosis or phlebitis extending from

the site of injection, and extravasation of fluids

11.2.2 Side effects associated with infusion of sodium chloride

Cardiovascular: heart failure (aggravated), edema Endocrine and metabolic:

hypernatremia, hyperosmolarity, hypokalemia, metabolic acidosis Respiratory:




60

pulmonary edema

Possible benefits of this study include a reduced risk of serious adverse

outcomes, including death, need for acute dialysis, and persistent decline in

kidney function among subjects receiving aggressive hydration.

12. DATA MANAGEMENT

12.1 Source file management

Source documents comprise of source data, include hospital records, clinical

and office charts, laboratory notes, memoranda, subjects diaries or evaluation

checklists, recorded data from automated instruments, microfiches,

photographic negatives, microfilm or magnetic media, x-rays, subject files, and

records kept at the laboratories, and at medico-technical departments involved

in the clinical trial, including certified copies or transcripts. Source files can be

paper and/or electronic. The original document in the clinical trial refers to the

document that records the clinical observation for the first time, such as the

written record of the trial process, the therapy prescribed by the researcher,

the informed consent form, etc.; or the file contains the laboratory examination

and the image examination data, such as Blood routine examination report, CT,

etc. There are paper and electronic forms or other available forms. When the

original is unfavorable for preservation, inconvenient to obtain or lost, a verified

copy (identical to the original recorded information and produced with a dated

signature or a verifiable procedure, shall be reasonable to explain) would be

saved as a source file.

12.2 Data collection

12.2.1 The source data were recorded and modified according to categories

(objective data and subjective data) during the implementation process.

Objective data is usually generated directly from the testing equipment,




61

instruments or other tools. When the test sample is read by the instrument or

device, the result data or images, such as blood routine examination, blood

biochemistry, electrocardiogram, test atlas, pathological image, photographs

of the body lesions, body temperature, X-ray film, CT film or electronic images,

etc.

Subjective data refers to data for artificial observation and evaluation, including

data judged and recorded by the investigator, or data generated by the

subject's own records, such as a history review (eg, part of medical history,

medication history which cannot trace back by investigator are recorded

according to the subject's statement), oral hydration table, urine table, subject

log record, oral medication record, etc. Prior to the trial enrollment, proper

training or guidance are provided to the recorder, records should be timely,

and indicate the signature and date to avoid recall bias; ensure that the

collection and recording of such data is real and standardized.

Researchers and sponsors should take effective measures to ensure the

quality of data generation and recording, which shall be completed by

qualified personnel according to study protocol. As for correction, the original

content should be retained and marked with strikeout, new content and the

name of the modified person, the reason and the date of the modification shall

be annotated beside. The modification of the electronic document should

ensure that the audit track is kept in the backstage for future reference, and

keep relevant records and explanation of data modification.

12.2.2 Methods of data collection will be listed during the study, such as

paper or electronic CRF (eCRF), name and version of the data

acquisition/management system, Describe the permission control plan of the

system user, or provide corresponding information in the form of attachments,

including permission definition, allocation, monitoring, and measures or




62

methods to prevent unauthorized operations, authority revocation, and so on.

The data acquisition/management system should have the functions of audit

trail, security management, authority control and data backup, and pass the

complete system verification.

12.2.3 CRF record

When filling in the CRF, the person who fills in does the self-examination with

out additional verification. The clinical research associate verify the source

data at the research center to ensure the accuracy of the clinical research data

originally. Proper training will be provided to the investigator or research

coordinator before the study begins. To help the staff at research center fill in

the CRF or eCRF with real, standardized, complete, and accurate data, the

data manager must provide a guidance document that help filling in the CRF

(usually referred as the CRF Completion Guide).

12.2.4 Staff training

After the study is approved, the main research center and the Key Laboratory

of Coronary Heart Disease will prepare the Investigator's Operation Manual,

CRF Guideline, eCRF Entry Guideline, and Training Schedule to guide the site

staff's operation and management, including data collection, data entry, etc.

The training will be conducted at the Investigator Initiative to train all research

fellows and clinical research coordinators to ensure data collection, data entry

consistency, traceability, completeness, and accuracy.

During the research period, all the data management will be trained by the

subject matter expert (SME), including external resource experts (software

developer engineers, training consultants, etc). The content and method of the

training are approved by the research conductor, and the accuracy of the

content must be approved by the SME. The research training is perform by




63

means of centralized training, online training and on-the-job training. All

training shall be tested afterward to understand the effectiveness of training

timely, so that to identify and rectify problems in the training. After the training,

the training conductor shall centrally archive the content, time, place of the

training, trainee list and the signature records.

12.3 Electronic data entry

After the data management department receives the paper CRF from the

researcher, the necessary signature and registration record shall be made.

The primary task of data management is to enter the CRF data into the

database as soon as possible. As for the training of data entry staff, make sure

to familiarize themselves with the data entry system, entering screen settings

and schedules, and also enter test data to ensure their work is accurate and

reliable before the official data entry.

Prior to electronic data entry, a well-trained professional will perform manual

verification to identify abnormal data on paper CRF, including unclear writing,

non-compliance with research protocols, missing data, medically

unreasonable data, and inconsistent data. Once a problem is found, it should

immediately contact the investigator and ask for clarification. Specifically the

verification content include but not limited to:

1) Check if the received CRF uses the latest version.

2) Check the CRF for missing pages

3) Check if the CRF has a subject code.

4) Check if the CRF is filled in with the required ink and whether it is clearly

visible.

5) Check if CRF is damaged.

6) Check if all CRFs have the researcher signature and date.

Electronic data entry and management is the responsibility of the data




64

manager of the statistical department in Key Laboratory of Coronary Heart

Disease. EDC database is adopted for electronic data entry. Electronic data is

entered by trained specialist. If problems or unexpected situations are found

during the entry process, they should be recorded and reported to the project's

data administrator for prompt solution. As for the unidentified data, data

managers(statisticians and data administrators) discuss each other and

require researchers to clarify with queries when data is cleaned up.

Quality control will be taken during electronic data entry:

1) Strengthen training： In order to improve the quality of data entry, it is

necessary to strengthen the training of data entry personnel.

2) Data quality control: Quality control of the entered data ensures that the

entered data is at an acceptable level.

3) Identify problems in time: If problems are found during the entry process,

they should be recorded and reported timely.

4)Establish a quality inspection system: After the data entry is completed,

some CRFs are randomly or irregularly checked to understand the quality of

the entry, analyze and deal with the problems of data entry. Electronic data

Entry is generally completed within 2 weeks since the CRF check.

12.4 Data Verification and Query

Before the data verification, a detailed Data Validation Plan (DVP) should be

made to clarify the content, method and verification requirements of the data

verification. Data verification is completed by data manager, auditors, medical

personnel and statisticians together.

The abnormal data is generally found through source data monitor, manual

inspection before entry, logic check by computer system, database check, and

analysis report of summary statistical analysis. The main content of data

verification is to check the CRF filling quality, check the data validity, integrity,




65

logic and compliance of the data. The methods of data review include manual

review and computer review.

1) Manual review is mainly used to check abnormal data that is not easily

checked by computer programs, such as CRF fill quality, CRF header

information (such as subject code or CRF page number).

2) Computer review, mainly use the data logic check performed by the

computer system.

The following review methods will be used in accordance with the content of

the research data reviewed: source data verification, database data verification

(including logic verification), summary statistics, and CRF-database

verification. The problems found in the research data review are mainly

through internal and external solutions. The internal solution is mainly based

on comparing the data of other parts of the CRF to make a judgment, and

finally solve the problem, mainly by the internal data administrator. The

external solution to the "problem" is mainly solved by the data administrator in

the form of DCF (Data Challenge Form) to obtain the difference data.

For issues with universality found in data review, specific issues such as

revisions to research protocols, revisions to CRF completion guidelines, or

enhanced training for researchers should be addressed. Research centers that

violate research programs should strengthen audits and recommend

improvements within a limited time. When the aggregated descriptive statistics

reveal significant differences between the data of a research center and other

units (such as reporting too many or too few adverse events), audits of

research centers and researchers should also be strengthened.

The problem data that the data administrator cannot solve through the internal

problem needs to be solved in an external way in time, that is, the problem is




66

solved by sending the data clarification table or the data challenge table to the

researcher (following ICH GCP [5.5.3(b)] The requester answers or interprets

the question on the challenge form and returns the DCF to the data

administrator. The challenge form is hand-made by the data administrator, and

each question table has its own unique identity. It is convenient to check the

status of the question list to prevent the missing.

After the challenge table is generated, the data administrator needs to

compare the data on the CRF table with the data in the database again to

determine whether the challenge table is reasonable and valid. If the problem

data of the challenge form is reasonable, send the research center/investigator

to clarify. If the problem data on the challenge form is an error caused by data

entry, or if the logic check program is improperly set, the question form is not

required to be sent to the research center/investigator.

After receiving the question form issued by the Data Management Center of

the Key Laboratory of Coronary Heart Disease, the researcher should reply to

the question and sign the question according to the question on the question

form and check the original data, such as the inpatient medical record and the

laboratory test record. And the date of signing. After the photocopy of the

question form is saved with the CRF in the file file of the research center, the

original is returned to the data management center.

After the challenge form is returned to the data management center, the

recipient needs to record the date received on the challenge form and forward

it to the project data administrator. The data administrator will solve the

problem based on the information provided by the researcher on the challenge

form, if the researcher replies. If you are reasonably satisfied, close the

challenge. If the researcher's answer is unreasonable or leads to the




67

generation of additional problem data, the data administrator needs to raise

another question and ask the researcher to clarify again until the problem is

solved. Regardless of the form in which the question form is generated, the

data management center should have a means of recording and tracking the

challenge form.

12.5 EDC design and Establish

For this study, the EDC designer will create a research-specific database and

design and define the CRF table through the user interface to facilitate data

entry, cleanup, review, export, and reporting. The database will be designed

with the following main considerations in mind:

1) Must comply with the research program process to facilitate data entry.

2) The data export style is comprehensive and complete, easy to analyze

statistically and meet the requirements of statisticians or programmers.

3) The data can be relatively inspected in the data management system to

find the “problem” data in time.

4) Should conform to the database creation theory.

5) Should meet the requirements of the database application software.

The research database will adopt a standardized database structure to store

data, ensuring that the fields in the data table are the most basic elements.

From a database perspective, data types involve numeric data types, date and

time data types, and character data types.

The database needs to support the establishment of logic verification (subject

to the development process of the computer program: logic inspection

requirements, development, testing, production environment application and

change control, etc.), check the entered data to find the "problem" data, so that

Data administrators or auditors review and clean up to improve data quality.




68

12.6 Research Database environment and operation requirement

The system should be installed in a safe physical environment. The security of

the physical environment can generally be guaranteed by the following

measures: restriction, recording and monitoring of the contact person of the

carrier; dual power supply or UPS; shockproof, fireproof, waterproof, heatproof

and moisture proof ( Non-subjective); vandalism, anti-theft (subjective), etc.

The network environment of the system, that is, the environment in which the

electronic network for data transmission (such as the Internet or local area

network) is located, should also be secured. Generally, it can be guaranteed

by the following measures: establishing a firewall or other hardware and

software to prevent viruses, Trojans, hackers, etc. Spyware intrusion.

System servers and their databases should prioritize remote or offsite backups

to ensure system continuity and data security. When this is not possible, you

should use an offline backup device to periodically back up and take away the

physical environment of the online backup. If the EDC system is interrupted

due to force majeure or uncontrollable factors, the EDC supplier shall have a

corresponding emergency plan and return the normal operation of the EDC

system in the shortest time according to the server and database backup.

At present, the system adopts dual hot security backup to ensure the absolute

information security of all projects, independently run the hard disk and the

backup hard disk, and synchronize the data in real time to ensure

uninterrupted data access. Use Linux system scripts to back up the latest data

in time to ensure data is absolutely secure. The latest backup hard disk data,

daily incremental synchronization of local data, so that data is foolproof.




69

12.7 Research data assess authority

The EDC system should have user management, role management and rights

management function modules. All users of the EDC system must have a

unique username and password combination. The password must be stored

encrypted in the system. Both the service provider and the user of the EDC

system should establish an SOP to manage EDC services, operations and

maintenance, and follow the SOP in actual use and management. All records

of the execution or implementation of the SOP are archived for reference.

Access to study data is limited to individuals who have been approved by key

laboratories for coronary heart disease. Individuals must have appropriately

qualified researchers and be compliant with information security awareness

training and confidentiality agreements. All personnel who need access to

research data are required to receive SOP training on the management and

use of their authority. In addition, the permissions of the electronic system are

structured, and users in a single research center can only see data from their

research participants and cannot view or access data from other clinical

research centers or other participants.

When a user no longer needs a certain permission, this permission should be

revoked in time. When the account is changed, the reason for the change and

the process and requirements of the change should be stated. When the user

forgets the password, the process of requesting a new password is recorded

and explained. When the user leaves the research center, all the user's

permissions are revoked, but the user name, inspection traces and other

information are still retained. Once the username is disabled, it should not be

used again.

To ensure system security and monitoring, the following measures will be

taken:




70

1) The system automatically logs out after 10 minutes when the user has

no activity.

2) Unauthorized access is recorded in the system log, which is checked

periodically by the system administrator.

3) The user must keep the password and cannot share it.

4) Users cannot log in or work with other users.

5) Check of expired/disabled accounts.

12.8 Data safety strategy

The clinical research data of this study belongs to the property of the

cooperative research project. It may not be sent outside the research center

without the written permission of the person in charge of the key laboratory of

coronary heart disease. It will strictly abide by the main research unit, key

laboratory for coronary heart disease, cooperative research projects and

various research. All data transmission and data security policies of the Center.

The head of the Key Laboratory of Coronary Heart Disease will work with the

research centers in accordance with the signed agreements to ensure proper

handling of data security and data transmission.

12.9 Data Storage and archive

In the course of this study, regardless of the collection method, clinical

research data will enter the research database, so ensuring the security,

integrity and accessibility of data is the main purpose of data preservation. The

principle of preservation of raw data and original documents (such as case

report forms and electronic documents) is that their safety must be guaranteed.

Paper documents and electronic documents should be kept in a secure room

or file cabinet and have strict access control rights to prevent unauthorized

access. After receiving the paper documents, they should be scanned and

saved the electronic files as much as possible. The backup files should be kept




71

in different places. The electronic data of the research is mainly stored in the

database server, and its security (such as the firewall of the computer) should

also be guaranteed.

The preservation and archiving of clinical data are for different periods of

clinical research, but their purpose is the same, that is, to ensure the security,

accuracy, completeness and accessibility of data/files.

Article 49 of the State Food and Drug Administration General Administration of

Quality Control of Drug Clinical Trials stipulates that the materials in clinical

trials shall be kept and managed as required. The investigator should save the

clinical trial data until five years after the termination of the clinical trial. The

ICH GCP requires at least two years of storage. This study will comply with the

above requirements and will also follow the basic requirements of the following

archives:

1) The archiving of research data needs to be planned and arranged.

2) The content and format of the research data should meet the

requirements of industry standards and regulatory agencies.

3) Archived data should be secure during the specified data retention

period to prevent damage.

4) The responsibility for the archiving work, the division of labor and the

archiving procedures should be clear.

5) The saved records are periodically checked after archiving to ensure

their accuracy, completeness, accessibility and durability.

6) The archived data should have a central directory.

7) After the important upgrade of the clinical research data

acquisition/management system, the archived electronic data accessibility

should be tested.

8) The original data (such as CRF with the signature and signature date of




72

the researcher, CRF correction documents, etc.) should be archived in the

research documents of the key laboratory of coronary heart disease or kept in

an off-site archive.

9) The archive of the research document should indicate the hardware,

software and its version used.

In addition, clinical research data is archived to ensure that archiving meets

the requirements of the main research unit, research organization, and

regulatory requirements. The research data key laboratory of coronary heart

disease will completely retain the database until the primary and secondary

analysis is completed. After the analysis is completed, the research data will

be de-identified and stored indefinitely. The research records of the local

research center may not be destroyed without the written permission of the

Key Laboratory of Coronary Heart Disease.

13. QUALITY CONTROL

13.1 Qualified Measurement/Confirmation

This study will, as far as possible, harmonize the qualifications, qualifications,

clinical work experience, etc. of the physicians involved in the treatment to

ensure the consistency of their research methods. Before the start of the study,

the research center researchers and clinical research coordinators will hold a

meeting review,especially the standard of TCM syndrome classification should

be unified. Research procedures and training in research data collection.

Before starting the meeting, send the research plan, implementation plan, and

execution SOP to each research center and related personnel, collect opinions

from all parties, and confirm the modifications, and organize all participants of

the research center (main researcher, researcher, and research coordinator). ,

research inspectors) accept research programs, research data collection

training; training is conducted during the start-up meeting of each center




73

research, for research doctors, clinical research coordinators, etc. to obtain

and maintain preservation source documents, and complete research

evaluation, CRF fill out , EDC entry and other content training, strict

confirmation of the entry criteria, through oral or written feedback and

discussion, to ensure that the research doctors and clinical research

coordinators understand and clarify the research assessment, the meeting

also on the relevant variables, laboratory tests normal range, each The

implementation characteristics of the Center were thoroughly reviewed and

discussed, and training was strengthened to develop operational reference

guides for each center.

Before the start of the study, the laboratory qualification certificates of each

center and the normal range of laboratory tests were reviewed and confirmed

to prevent research bias.

13.2 Patients Management

For the subjects of the project, the investigator of each clinical research and

testing center will be responsible for the management of the subjects enrolled,

keeping the patient's personal information confidential, and paying attention to

the patient's health during the study, in the informed consent form. The

researcher's contact information corresponding to each sub-center is attached,

and the patient can contact the researcher at any time to make the patient's

safety secure. For patients who are unable to return to the original center for

follow-up and blood samples, the participants of the participating centers will

conduct telephone follow-ups and answer questions about the patients'

questions. They should try to adapt to the patient's schedule and safety issues.

13.3 Protocol deviation

Any program deviations need to be recorded, and the Key Laboratory of




74

Coronary Heart Disease will create a program deviation table to ensure that

events are tracked correctly. The deviation from the program will be evaluated

by the Key Laboratory of Coronary Heart Disease and the effectiveness of the

deviation basis will be determined. Any medical center or subject who has a

program deviation in the absence of a valid reason, and after training in

remedial training, is recommended to terminate it to the Data Monitoring

Committee (DMC) if any member of the DMC or the Inspectorate believes If

the compliance program will impair the health of the subject, the subject's

rights should be prioritized and the subject should be withdrawn from the study

after consultation with the Executive Committee and the program will be

reported to the main research unit IRB as required.

13.4 Randomized control of study treatment

This clinical study is a multicenter, randomized, controlled trial that requires the

necessary uniform standard treatment of routine clinical interventions at

participating centers to rule out confounding due to inconsistent intervention

criteria. Randomized system of the Department of Statistics of Southern

Medical University to ensure random objectivity and reduce selection bias.

13.5 Monitoring and quality control

In order to ensure the uniform and high quality of multi-center participants, the

clinical monitoring group will conduct quality control on the research according

to the audit plan formulated by the Guangdong Provincial Key Laboratory of

Coronary Heart Disease, including but not limited to:

1) Monitoring frequency and report

The first audit was conducted within one week after the first subject was

enrolled;

In the enrollment and follow-up phase (refers to the first case of the center

to be screened to all subjects in the center), the audit is conducted once a




75

month, and the window period of the two allowed audits is within ±60 days.

That is, the last audit date is January 1, 2016, and the next audit can be

scheduled from February 28, 2016 to March 3, 2016. The actual visit date of

the audit report must be the same as the registration date in the central visit

registration form. For centers that are concentrated in the group and faster in

the group, the CRA and PM applications can adjust the monitoring frequency

to 2 weeks in the concentration stage of the group;

The frequency of the audit can be adjusted based on the speed of the center's

entry or the problems found in the center. If the audit plan is changed, please

explain it in the audit report.

The trial initiation visit must be performed prior to screening the patient

The last time the audit activity must be before the data is locked; if there

are any remaining problems before the data lock library, all problems must be

resolved before the audit can be terminated;

End of trial visit will be performed after the data is locked.

2) Monitoring visit report and project management report

Monitoring visit report:

All problems found in the audit and not resolved and their action plans must be

reflected in the audit report; the audit report must be sent to the project

execution leader within 7 working days after the audit occurs;

Site visit report:

The center enrollment stage (the center enrollment stage means that the first

subject of the center is screened to complete the enrollment of all subjects in

the center), and the auditor reports the basic information and progress of the

study to the project execution leader every week;




76

Central treatment stage (central treatment stage refers to completion of all

subjects in the center to complete completion of treatment of all subjects in the

center) and central follow-up stage (central follow-up stage to all subjects in

the center after completion of treatment after follow-up period to this All

subjects in the center are grouped and reported to the project executive

responsible every 4 weeks.

Project team internal project meeting

Project enrollment stage (refers to the first subject of the project to screen all

subjects of the project to complete the group completion): The auditor holds a

conference call with the project execution leader every 4 weeks; the specific

time is notified by the project team;

During the project follow-up phase (the project follow-up phase means that all

subjects in the project are completed in the group until all subjects in the

project are out of the group): the internal meetings of the project team are held

monthly;

For the project in the center according to the program development and the

subject's rights and interests, the auditor needs to promptly feedback to the

project team. For issues that have significant impact, it needs to be reported to

the project executive person within 1 working day after the knowledge is

obtained.

3) Staff training

Auditor training:

Initial training

The training of the project team will be arranged before the start of the

research center, including training in programs, systems and processes, which




77

will ensure the smooth start of the project;

A team member's training was conducted prior to the conference, including

research background, program introduction, ICF management, verification

considerations, project management and entry plan, data management and

EDC profile

Training during the research process

According to the EDC verification situation, the DM summarizes the EDC

entry and common questioning common problems, and the project manager

will share the training of the project team at the project meeting.

According to the audit of the sponsor, etc., the project team summarizes

the problems found, and the project supervisors share the training of the

project team at the project meeting.

For newly joined project team members, the project will arrange relevant

content such as program and process training before undertaking the project

task. Training is generally conducted on-site or on a conference call.

Personnel handover occurred in the project. The project manager handed

over the SOP according to the project team to ensure the smooth handover of

personnel, and systematic training of the new CRA before the handover. The

training was generally conducted by on-site training or conference call.

Add additional training as appropriate.

Research Center Staff Training:

The auditor responsible for each center will provide training to the staff of

the research center at the start-up meeting, CRF filling and testing procedures.

When the first subject is screened or enrolled, the CRA needs to assist

and confirm that the research is familiar with the research process, such as

timely training and reminders.




78

4) eCRF fill in / enter

The CRF is filled in/entered by the designated personnel of the research

center according to the filling instructions. All patients enrolled need to

complete CRF, including rejection of the patient.

Even if you withdraw from the case, you will need to complete the “Completion

Study Page”.

Each case with signed informed consent needs to be registered in the

screening and enrollment form, including screening for losers.

All subjects need to retain their original medical records

5) Verification of original data (SDV plan)

Part 1: Important parameters

100% raw data verification for all patients with the following parameters:

1) Informed consent form

Whether the patient's signature and date appear on the informed consent

form;

Whether the patient signature date is before the start of any research

procedure;

Whether the name and date of the doctor who informed the informed

consent are signed;

The researcher's contact number must be a telephone that can be

contacted 24 hours a day;

Whether the date of signing by the researcher is the same day as the

patient;




79

Ensure that the version of the informed consent form signed by the subject

is correct;

It is recommended that the pen used by the doctor's signature be as

different as possible from the patient;

Informed consent forms for screening losers must also be kept;

- Record on the original record when the patient has signed an informed

consent form and obtained an original.

Part II: Initial Quality Control

1) After the first 5 patients are enrolled, the rest of the SDV needs to be done in

addition to the above, in order to ensure that the original record is complete,

the program is followed, and the eCRF is correctly filled in/entered.

2) In addition to the content mentioned in the first section, the following should

be verified at each visit:

Is the follow-up time recorded on the CRF consistent with the original

medical record?

Changes in vital signs and laboratory tests after baseline

The laboratory tests required in each program are completed; and any

clinical test abnormalities are recorded and explained in the CRF.

Patient diary (hydration table)

Part III: Quality Control in Progress

100% SDV is required during the trial.

If the investigator is replaced during the trial, the auditor will then review

the data of the first two patients enrolled by the new investigator.

If many problems are found in the trial, discuss it with the investigator and




80

not resolve it.

Part IV: Screening failure

The original medical records failed to reflect the reasons for the screening

failure, and the original records must be saved.

Part V: Original Data Verification Record

The researcher must keep all original medical records in the research

center.

The auditor needs to record the important findings of SDV, how to solve it

and the next steps in the audit report. At the same time, feedback these

findings to the researchers and let them correct them in time.

13.6 Participation Center trial/terminate

The research chair and the key laboratory for coronary heart disease will

assess the participation in the hospital. Only hospitals that meet the

corresponding indicators can participate in the study:

1) The hospital has the relevant equipment and technology needed for the

project:

2) Have sufficient patient source that meets the criteria for entry and exit:

meet at least 10 patients with acute myocardial infarction each month;

3) Have sufficient human resources in line with standards: have doctors who

can qualify for such diseases, and receive training for the project. More than

2 doctors are responsible for this project;

During the implementation process, the recruitment rate and operational

aspects of the study are continuously monitored. If the research center is in the

trial stage, it will face the following reasons including but not limited to violation

of the program, violation of GCP or related regulations, and project quality

requirements.




81

The risk of terminating the study.

1) Recruitment rate: divide the number of randomized patients by the

expected number of patients, calculate the recruitment rate, and continuously

monitor the indicator during the research. If the recruitment process is slow, if

there is no randomization in February, the center will receive remediation and

reassess. If the plan is not included in the plan, it will enter the probation period

and be evaluated every 2 months.

2) Follow-up rate: The number of patients in any follow-up window was

divided by the number of patients expected to follow the window, and the

follow-up rate was calculated. Both the numerator and the denominator were

delayed for 4 weeks to schedule a visit to the corresponding follow-up window

and complete the form. Study centers with a cumulative follow-up rate of less

than 90% will enter the probationary period and will be assessed every 2

months.

3) Form Completion Rate: The table completion rate is calculated by

dividing the number of completed forms by the number of expected forms,

where the expected number of forms will be sent out as a "not collected" form.

The table completion rate will be calculated according to the patient and the

form. Research centers with a cumulative follow-up rate of less than 90% will

enter the probationary period and will be assessed every 2 months.

Once the research center enters the probationary period, failure to meet

the requirements of the end of the probationary period will result in the

proposed termination of the study. In addition, those that do not meet the

above requirements, or one of which will not meet the standard after

rectification and remediation, will face the termination of the trial. In addition,

after the relevant performance evaluation of the research center in the key

laboratory of coronary heart disease, if it is considered unsuitable for

continuing research, the research center can be terminated without a formal

trial period.




82

14.GOOD CLINICAL PRACTICE AND RESEARCH CENTERSREVIEW PROJECTS

This study will be conducted in accordance with the Good Clinical Practice

(GCP) for Drug Clinical Trials. During the study period, the research centers

participating in the research will be monitored according to the monitoring plan.

The Research Center Monitoring Team will visit all participating research

centers at least once in accordance with the GCP. The purpose of these visits

is to ensure that trials are performed, documented, and reported in accordance

with research protocols, standard operating procedures (SOPs), clinical trial

quality management practices (GCP), and applicable regulatory requirements.

The auditor will examine the patient study files, including x-rays,

electrocardiograms, and other source files. Particular attention is paid to

patient informed consent, protocol compliance, ethics committee approval, and

researcher folders. After the interview, the monitoring visit report is prepared

and forwarded to the research center researcher and research leader.

In addition to the review visits scheduled by the sponsors, an independent,

comprehensive research center audit can be conducted at any time, as

required by the research management or research center.

All in all, the audit team will do the following:

1) Provide comprehensive research execution tools to the research center,

including important research requirements in the folder catalog, templates, and

source files to help the research center better implement the research program

and meet the requirements of the GCP regulations.

2) Regular visits to participating research centers and provide GCP

training and enhancement at the kick-off meeting.

3) Conduct a review visit to each participating center at least annually to

monitor the compliance, program compliance, and overall research design

performed by the investigator.




83

4) A comprehensive review of the final year of the study to ensure that all

research tasks and related documentation are completed.

15. RESEARCH MONITORING AND AUDIT PLANS

Protecting patients' rights and benefits is a major concern for key coronary

heart disease laboratories. This study will be conducted in accordance with the

local laws of the ICH-GCP, the Helsinki Declaration and the quality

management practices for drug clinical trials.

15.1 Monitoring agency

The study will oversee the scientific and ethical nature of the research through

four external agencies, including the Data Monitoring Committee (DMC), the

Ethics Committee (IRB), the Independent Incidents Committee (CEC), and the

Clinical Monitoring Agency.

15.1.1 Data monitoring committee

The Data Monitoring Board (DMC) will independently monitor and make

recommendations on clinical research processes, safety data, and progress.

(DMC) consists of members of the relevant professional field (meteologists,

cardiology, and clinical research specialists) who regularly evaluate cumulative

data from ongoing clinical trials, including those who have participated or who

will be recruited into the trial. The safety of the tester, the study implementation,

scientific and the integrity of the research data. The DMC will assess the

progress of the enrollment of the subject and make recommendations to the

sponsor, proceeding as planned, continuing or terminating or suspending trials

in one or all of the groups. In the future, it can be adjusted according to the

actual rate of the experiment and the incidence of the event.

15.1.2 Ethics Committee

The Ethics Committee (IEC) provides expert ethics and scientific review of




84

multi-center projects while ensuring solve local problems in each research

center. The Key Laboratory Center for Coronary Heart Diseases conducts a

comprehensive, rapid and ongoing review, and the investigator (PI) first

submits applications, including research protocols, informed consent, and so

on. Once approved, the application materials will be sent to all possible

research centers, and the local research center researchers (LSI) will submit

the application to the ethics committee. After approval, a copy of the research

center approval document will be provided to the key laboratory for coronary

heart disease for backup. During the study period, communication between the

participating centers and the IEC shall be recorded or documented. All

participating centers in the study conducted an annual ethical review.

15.1.3 Clinical Events Committee

The Clinical Event Committee (CEC) will be responsible for determining the

endpoints in clinical studies and avoiding deviations in event determination

between centers and centers in order to achieve a more accurate assessment

of test results. CEC is an independent committee of three research field

experts independent of research sponsors and researchers. Its primary

responsibility is to combine clinical expertise and protocols based on uniform

definition criteria for all endpoint events in the study. In the relevant content,

the objective judgment of the end point event is made to see if it meets the

definition criteria. The frequency of this study review will be determined based

on the incidence of enrollment plans and endpoint events.




85

Suspected

endpoint

Researcher

evaluation

Audit - source

file collection

Source file

submitted to CEC

CEC regular

evaluation Evaluation result

CECquery data

confirm

Data verification and

analysis

Consistency

comparisoneCRF data

collection

Submit to data

department

Figure A5 - CEC review process

The CEC Secretariat will be responsible for the production and regular

updating and maintenance of the CEC Review Folder. The CEC Review

Folder will store all documents related to CEC content, including CEC member

information, confidentiality agreements, review source files and review results.

15.1.4 Clinical monitoring team

Clinical monitors will ensure that trials are performed, documented, and

reported in accordance with research protocols, standard operating

procedures (SOPs), clinical trial quality management practices (GCP), and

applicable regulatory requirements. The audit is usually scheduled by the

monitor and the investigator and/or other participants prior to the first patient

enrollment. According to the research project, the inspection is usually carried

out every four to six weeks, but the interval between inspections can be

extended or shortened due to the difference in research period and schedule.

The clinical monitor will ensure that the submitted data is accurate and

consistent with the source document; verify that the subject's informed consent

has been correctly obtained and recorded; that the study participants in the




86

enrolled study meet the inclusion and exclusion criteria; and that the drug is

ensured. All basic documentation guidelines required by the clinical trial quality

management practices are properly documented.

The auditor will conduct a visit to the research center before the study begins.

At the time of the visit, they will discuss the way the subjects/patients are

recruited, the completion of the case report form and the next management

procedures. In addition, it should be discussed and agreed to: the

investigator's assessment of the program's understanding, his or her

obligations during the study period, and possible recruitment rates. Other

circumstances, such as confirmation of data obtained in the study, should also

be discussed. In addition, they will ensure that appropriate research related

documents exist.

At the end of the study, a study closure visit, the final audit, should be

performed, usually within four to six weeks of the end of the last follow-up of

the last subject in the study center. The preparations and procedures for the

study of closed visits are generally the same as for a regular supervisory visit.

15.2 Monitoring adverse events (AEs) and serious adverse events (SAE)

It should report safety information in a timely and complete manner, assisting

research management in identifying any adverse medical events, ensuring:

protecting the safety of research patients, better understanding the overall

safety characteristics of research interventions and treatment modalities, and

appropriately modifying research protocols Improve research design and

compliance with regulatory requirements.

The participating research centers will be responsible for the AE and SAE

reporting requirements described in this scenario, as described below:




87

1) The subjects were closely monitored for new AE and SAE during the

study.

2) Review the accuracy and completeness of all AE and SAE in the report.

3) Report all SAEs to the research centers IEC within 72 hours of the

event.

4) Compliance with the research center IRB policy on AE and SAE

reporting.

5) In order to address security issues, an implementation plan for the study

group and the executive committee may be developed.

15.2.1 Adverse event

The International Conference on Harmonization (ICH) Clinical Safety Data

Management (ICH2A) defines adverse events (AEs) as “any adverse medical

event that occurs in a clinical study subject and accepts one of the research

interventions that do not necessarily have a causal relationship with the

intervention” . The CFDA of the State Food and Drug Administration defines an

adverse event (AE) as an adverse medical event that occurs after a patient or

clinical trial subject receives a drug, but does not necessarily have a causal

relationship with the treatment. Therefore, the AE will include (any adverse

signs, changes in function (symptoms) that occur during the observation, as

well as other tests (assay, ECG, X-ray, etc.).

Researchers at participating research centers are responsible for collecting AE

information from subjects in the research center with the assistance of the

clinical research coordinator. When an adverse event occurs, both during

hospitalization and during follow-up, the usual principles of recording are as

follows: Fill in the adverse event record form, including the name of the

adverse event, the time of occurrence, the end time, the severity, the

measures taken and the outcome and the corresponding evaluation. Adverse




88

events with serious adverse events (defined below) will be reported as follows

and followed up to regression or stabilization.

15.2.2 Severe adverse event

Serious adverse events (SAEs) are a subset of adverse events defined by

(ICH) Clinical Safety Data Management (ICH2A) as any of the following

adverse medical events that occur during clinical trials:

1) Lead to death.

2) Crisis life.

3) Need hospitalization or extend hospital stay.

4) Lead to persistent or severe disability or loss of energy.

5) Congenital malformations / birth defects.

6) According to medical judgment, any condition that may harm the subject

and require medication or surgery to prevent one of the above outcomes.

The study will collect all SAEs regardless of whether they are considered

relevant to the study intervention. SAEs that have a reasonable causal

relationship with research interventions and related drugs will be reported as

“relevant.” There is no need to establish a clear causal relationship.

Researchers at participating research centers are responsible for collecting

SAE information from subjects in the research center with the assistance of a

clinical research coordinator.

When a serious adverse event occurs, the researcher is required to report to

the relevant department within 24 hours of obtaining a serious adverse event.

The usual principles of treatment are as follows:

First, the subject should be guaranteed timely and appropriate clinical

diagnosis and treatment;

Secondly collect relevant information, such as medical records and




89

inspection results, in order to accurately and timely fill out the Serious Adverse

Event Report and report it to relevant departments.

Ensure that the report is consistent with the original record, CRF, and other

test records. Ensure that the start and end dates and major event descriptions

of serious adverse events are consistent with CRF and other test documents.

Don't delay submitting reports even if the information may be incomplete or

uncertain. When more information is available, it can be supplemented or

revised in the form of follow-up reports. Relevant information should be

collected and recorded continuously until the end of the reporting period.

Reporting forms and reporting procedures for serious adverse events may

have different requirements in different programs and research institutions.

These requirements should be clearly written into the test plan or SOP and

fully trained before the study begins, so that the researcher can follow the

implementation.

During the entire study period, the SAE will be monitored by the Data

Monitoring Committee and all AE and SAE reports will be summarized in

accordance with the time schedule set by the DMC to review the entire study

adverse event data and whether to continue research or Safety reasons stop

the study and give advice. We believe that an independent DMC can

effectively monitor the safety of the trial as it will periodically review all outcome

endpoints based on treatment assignments and will also receive statistical

support to determine the significance of any observed differences.

RESULT

16.BIOSTATISTICAL CONSIDERATIONS




90

A．Overview of design

1. The analytic model

There is one primary hypothesis that will be tested: 1) aggressive hydration

(i.e., preprocedural IV loading plus postprocedural hemodynamic-guided

[LVEDP] fluid administration) reduces the risks of CI-AKI and clinical adverse

events in acute myocardial infarction patients undergoing primary PCI.

The study will enroll 560 subjects over 5 years and evaluate each subject 72

hours after the intervention. Within each site, subjects will be randomly

assigned to one of two study interventions:

1) Aggressive hydration,

2) Control (general hydration).

The rates of primary and key second outcomes were compared by Pearson χ2

or Fisher exact tests.We used relative risk (RR) and absolute risk difference

with their corresponding 95% confidence interval (CI) to describe the

intervention effect. Number needed to treat(NNT) for preventing one CI-AKI

event was caculate by inverse of the absolute risk difference. We used logistic

regression with interaction testing to assess whether the recorded treatment

effect was consistent across prespecified subgroups. All tests will be 2 tailed,

and P value less than 0.05 will be considered statistically significant difference.

All data analyses will be performed using SAS version 9.4 (SAS Institute, Cary,

NC).

Relative risk can be estimated from a 2x2 contingency table:

Group

Intervention (I) Control (C)

Events (E) IE CE

Non-events (N) IN CN

The point estimate of the relative risk is






92

2. Incidence of the CI-AKI and effects of our interventions

CI-AKI, defined as a ＞25% or 0.5mg/dL increase in serum creatinine from

baseline during the first 48 to 72 hours after the procedure. Based on our

previous findings, a CI-AKI incidence of 23% was estimated for the control

group, and a CI-AKI incidence of 11.5% was assumed for the intervention

group (50% relative reduction). Using nQuery + nTerim 3.0 (Statistical

Solutions Ltd, Farmer's Cross, Cork, Ireland) with a 2-sided χ2 test, a

significance level of .05, a power of 90%, and a dropout rate <20%, 280

patients are required in each group, for a total sample size of 560.

Model

Aggressive

hydration

Control Overall event

rate

11.5% 23.0% 17.3%

Therefore, we postulate that:

Under control conditions, the rate for our primary outcome CI-AKI is 23.0%

The intervention will prevent 50% of these events

Under the intervention condition, the rate is 11.5%

The absolute effect of the intervention will be an 11.5% reduction in CI-AKI.

We have one primary hypothesis. We will, and therefore assign the type I error

of 5% to the intervention. No interim analysis will be carried out according to

the statistical design.

B. Primary end-point

We fully describe the aggressive hydration versus control (general hydration)




93

intervention and the CI-AKI outcome. The null hypothesis is that the two

groups (aggressive hydration and control) do not differ in terms of the

proportion of subjects who experience CI-AKI. The alternative hypothesis is

that the absolute difference in the incidence of CI-AKI between the intervention

group and the control group is 5% or more.

The formal statement of the null hypothesis

Under the null hypothesis:

The proportion of CI-AKI for patients administered aggressive hydration is

23.0%

Under the alternative hypothesis, the proportion of CI-AKI for patients

administered general hydration is 23.0%.

The formal hypothesis test is two-sided allowing for aggressive hydration to be

either more or less effective than control (general hydration). However, the

study of aggressive hydration will only be viewed as more successful if

subjects treated with aggressive hydration have a significantly lower proportion

of CI-AKI than patients who receive general hydration. We will test this

hypothesis with one model that contains main clinical characteristics (e.g., age,

sex, eGFR, HV/W), and the Mehran risk score will be calculated.

C. Secondary end-points

Our secondary objectives will be tested using χ2 tests, and the 95% CI of the

rate difference will be calculated using the method described by Altman et al

(reported in Newcombe and recommended by the Food and Drug

Administration and Clinical and Laboratory Standards Institute. The secondary

end-points will be analyzed based on the intention-to-treat principle. These

objectives are:




94

Losses to follow up and missing data

We conservatively estimate that up to 20% of subjects may be lost to follow up

before 72 hours. The site coordinators will make every effort to locate such

subjects including at least two laboratory test of serum creatinine after primary

PCI. If such efforts fail and we have no information indicating the outcome for

these subjects, then we will exclude them from the primary analysis and then

carry out a worst-case analysis to confirm the result of the primary analysis.

Definition of Intention to Treat Sample

All consented and randomized subjects will be accounted for and reported in

the CONSORT diagram for the study, however, only those randomized

subjects who initiated either IV intervention or have finished test a least once

for SCr on preoperation and postoperation (i.e., did not drop out or withdraw

prior to start of the allocated intervention), will be considered as an intention to

treat (ITT) subject to be included in the Data Monitoring Committee (DMC)

reports and primary efficacy analysis.

17. STUDY ORGANIZATION AND ADMINISTRATION

The research group and monitor group will be set up in the Central Office of

the Guangdong Provincial Key Laboratory of Coronary Heart Disease. The

research group is responsible for all operation/implementation procedures of

this study, and the monitor group is responsible for the quality control of this

study. The research team will conduct a face-to-face meeting prior to the start

of the study and thereafter at least once a year (online or offline). Except for

the executive committee (including research center investigators, research

clinicians, and members from academic management centers) will be

responsible for internal progress of research. The research management

structure is shown in the figure below (Figure A6).




95

Figure A6 – Study management structure

17.1 Central Office of Guangdong Provincial Key Laboratory of

Coronary Heart Disease

The Central Office of Guangdong Provincial Key Laboratory of Coronary Heart

Disease organizes relevant personnel through the Executive Committee,

Operation Management Center and Academic Management Center to

formulate management systems and standard operating procedures

applicable to all the research in due course.

17.2 Executive Committee




96

The Executive Committee will monitor the progress of the study, the operation

of the participating centers, and the quality of the data collected. The

committee will also monitor compliance with the study protocol. Except for the

Executive Committee, a publication plan will be developed for the study and

the display of all data will be monitored. Before relevant data is used for

display or publication, it must be approved by the Executive Committee. The

committee members will be selected by the research chair from the operation

and academic center. The Executive Committee may hold a conference call on

a quarterly or annual basis and, if necessary, hold the meeting in person.

C. Research Operation Management Center

The Research Operation Management Center will conduct daily scientific and

management coordination of research. This will include the development of

research protocol, the preparation of operational manuals and source

document worksheets, ensuring appropriate support for participating centers,

organizing meetings, answering programme queries, regularly publishing

research progress briefs, preparing interim and final reports, and the archiving

of research data at the end of the study. Coordinating research involves the

relationship of relevant departments, quality management of the research

projects (including monitor of patient recruitment and data quality), and

ensuring the smooth progress of study.

17.3 Research Academic Management Center

The Research Academic Management Center will assume the overall design

of the entire study, responsible for the design, supervision and management of

clinical study, and is responsible for various monitor organized by the drug

regulatory authorities, such as monitor, audits, on-site inspections, institutional

qualifications or reviews, etc. Work preparation, coordination and participation

in the audit of the sponsor organization. Provide clinical biometric consultation,




97

responsible for DME/evidence-based medicine teaching tasks for medical

graduate students, and provide advice and consultation on academic related

issues during the study.

18. PUBLICATIONS

It is the policy of the DVP that outcome data will not be revealed to the

participating investigators until the data collection phase of the study is

completed. This policy safeguards against possible biases affecting the data

collection. The regular and ex-officio members of the DMC will be monitoring

the outcome results to ensure that the study is stopped if a definitive answer is

reached earlier than the scheduled end of the study. All presentations and

publications from this study will be done in accordance with current DVP

guidelines. The presentation or publication of any or all data collected by

participating investigators on patients entered into the ATTEMPT study is

under the direct control of the study's Executive Committee. This policy is

applicable whether the publication or presentation is concerned with the

results of the principal undertaking or is associated with the study in some

other way. No individual participating investigator has any inherent right to

perform analyses or interpretations or to make public presentations or seek

publication of any or all of the data other than under the auspices and approval

of the Executive Committee.

The Executive Committee has the authority to establish one or more

publication committees, usually made up of sub-groups of participating

investigators and some members of the Executive Committee, for the purpose

of producing manuscripts for presentation and publication. Any presentation or

publication, when formulated by the Executive Committee or its authorized

representatives, should be circulated to all investigators participating in

manuscript prepation for their review, comments, and suggestions at least four




98

weeks prior to submission of the manuscript to the presenting or publication

body. All publications must give proper recognition to the study's funding

source, including the Department of SME, and should list all investigators in

the study. If an investigator's major salary support and/or commitment is from

the SME, it is obligatory for the investigator to list the SME as his/her primary

institutional affiliation. Submission of manuscripts or abstracts must follow the

current DVP policy. Since all publications should state that it is a publication

from ATTEMPT study, ideally, a sub-title is used stating, "ATTEMPT study."

The SME contributions to the research project should be acknowledged in all

written and oral presentations of the research results, including scientific

articles, news releases, news conferences, public lectures, and media

interviews. All clinical study reports and journal manuscripts must be reviewed

and approved by IEC prior to submission for publication.

19. REFERENCES

1. Barrett BJ. Contrast nephrotoxicity. Journal of the American Society of Nephrology :JASN. 1994;5:125-37.

2. Parfrey PS, Griffiths SM, Barrett BJ, Paul MD, Genge M, Withers J, Farid N andMcManamon PJ. Contrast material-induced renal failure in patients with diabetesmellitus, renal insufficiency, or both. A prospective controlled study. The NewEngland journal of medicine. 1989;320:143-9.

3. McCullough PA. Contrast-induced acute kidney injury. Journal of the AmericanCollege of Cardiology. 2008;51:1419-28.

4. Mehran R and Nikolsky E. Contrast-induced nephropathy: definition, epidemiology,and patients at risk. Kidney international Supplement. 2006:S11-5.

5. Reddan D, Laville M and Garovic VD. Contrast-induced nephropathy and itsprevention: What do we really know from evidence-based findings? Journal ofnephrology. 2009;22:333-51.

6. Weisbord SD, Mor MK, Resnick AL, Hartwig KC, Sonel AF, Fine MJ and PalevskyPM. Prevention, incidence, and outcomes of contrast-induced acute kidney injury.Archives of internal medicine. 2008;168:1325-32.

7. Stone GW, McCullough PA, Tumlin JA, Lepor NE, Madyoon H, Murray P, Wang A,Chu AA, Schaer GL, Stevens M, Wilensky RL and O'Neill WW. Fenoldopammesylate for the prevention of contrast-induced nephropathy: a randomizedcontrolled trial. Jama. 2003;290:2284-91.




99

8. McCullough PA, Adam A, Becker CR, Davidson C, Lameire N, Stacul F and Tumlin J.Risk prediction of contrast-induced nephropathy. The American journal of cardiology.2006;98:27k-36k.

9. Laskey W, Aspelin P, Davidson C, Rudnick M, Aubry P, Kumar S, Gietzen F andWiemer M. Nephrotoxicity of iodixanol versus iopamidol in patients with chronickidney disease and diabetes mellitus undergoing coronary angiographic procedures.American heart journal. 2009;158:822-828.e3.

10. Weisberg LS, Kurnik PB and Kurnik BR. Risk of radiocontrast nephropathy in patientswith and without diabetes mellitus. Kidney international. 1994;45:259-65.

11. Cigarroa RG, Lange RA, Williams RH and Hillis LD. Dosing of contrast material toprevent contrast nephropathy in patients with renal disease. The American journal ofmedicine. 1989;86:649-52.

12. Manske CL, Sprafka JM, Strony JT and Wang Y. Contrast nephropathy in azotemicdiabetic patients undergoing coronary angiography. The American journal ofmedicine. 1990;89:615-20.

13. Bartholomew BA, Harjai KJ, Dukkipati S, Boura JA, Yerkey MW, Glazier S, Grines CLand O'Neill WW. Impact of nephropathy after percutaneous coronary intervention anda method for risk stratification. The American journal of cardiology. 2004;93:1515-9.

14. From AM, Bartholmai BJ, Williams AW, Cha SS and McDonald FS. Mortalityassociated with nephropathy after radiographic contrast exposure. Mayo Clinicproceedings. 2008;83:1095-100.

15. Gruberg L, Mintz GS, Mehran R, Gangas G, Lansky AJ, Kent KM, Pichard AD, SatlerLF and Leon MB. The prognostic implications of further renal function deteriorationwithin 48 h of interventional coronary procedures in patients with pre-existent chronicrenal insufficiency. Journal of the American College of Cardiology. 2000;36:1542-8.

16. Levy EM, Viscoli CM and Horwitz RI. The effect of acute renal failure on mortality. Acohort analysis. Jama. 1996;275:1489-94.

17. Rihal CS, Textor SC, Grill DE, Berger PB, Ting HH, Best PJ, Singh M, Bell MR,Barsness GW, Mathew V, Garratt KN and Holmes DR, Jr. Incidence and prognosticimportance of acute renal failure after percutaneous coronary intervention.Circulation. 2002;105:2259-64.

18. Shema L, Ore L, Geron R and Kristal B. Contrast-induced nephropathy among Israelihospitalized patients: incidence, risk factors, length of stay and mortality. The IsraelMedical Association journal : IMAJ. 2009;11:460-4.

19. Weisbord SD, Chen H, Stone RA, Kip KE, Fine MJ, Saul MI and Palevsky PM.Associations of increases in serum creatinine with mortality and length of hospitalstay after coronary angiography. Journal of the American Society of Nephrology :JASN. 2006;17:2871-7.

20. Weisbord SD, Gallagher M, Jneid H, Garcia S, Cass A, Thwin SS, Conner TA,Chertow GM, Bhatt DL, Shunk K, Parikh CR, McFalls EO, Brophy M, Ferguson R, WuH, Androsenko M, Myles J, Kaufman J and Palevsky PM. Outcomes afterAngiography with Sodium Bicarbonate and Acetylcysteine. The New England journalof medicine. 2018;378:603-614.

21. McCullough PA, Wolyn R, Rocher LL, Levin RN and O'Neill WW. Acute renal failure




100

after coronary intervention: incidence, risk factors, and relationship to mortality. TheAmerican journal of medicine. 1997;103:368-75.

22. Marenzi G, Assanelli E, Marana I, Lauri G, Campodonico J, Grazi M, De Metrio M,Galli S, Fabbiocchi F, Montorsi P, Veglia F and Bartorelli AL. N-acetylcysteine andcontrast-induced nephropathy in primary angioplasty. The New England journal ofmedicine. 2006;354:2773-82.

23. Maioli M, Toso A, Leoncini M, Gallopin M, Tedeschi D, Micheletti C and Bellandi F.Sodium bicarbonate versus saline for the prevention of contrast-induced nephropathyin patients with renal dysfunction undergoing coronary angiography or intervention.Journal of the American College of Cardiology. 2008;52:599-604.

24. Brown JR, Malenka DJ, DeVries JT, Robb JF, Jayne JE, Friedman BJ, Hettleman BD,Niles NW, Kaplan AV, Schoolwerth AC and Thompson CA. Transient and persistentrenal dysfunction are predictors of survival after percutaneous coronary intervention:insights from the Dartmouth Dynamic Registry. Catheterization and cardiovascularinterventions : official journal of the Society for Cardiac Angiography & Interventions.2008;72:347-354.

25. Goldenberg I, Chonchol M and Guetta V. Reversible acute kidney injury followingcontrast exposure and the risk of long-term mortality. American journal of nephrology.2009;29:136-44.

26. Harjai KJ, Raizada A, Shenoy C, Sattur S, Orshaw P, Yaeger K, Boura J, AboufaresA, Sporn D and Stapleton D. A comparison of contemporary definitions of contrastnephropathy in patients undergoing percutaneous coronary intervention and aproposal for a novel nephropathy grading system. The American journal of cardiology.2008;101:812-9.

27. Roghi A, Savonitto S, Cavallini C, Arraiz G, Angoli L, Castriota F, Bernardi G, SansaM, De Servi S, Pitscheider W, Danzi GB, Reimers B, Klugmann S, Zaninotto M andArdissino D. Impact of acute renal failure following percutaneous coronaryintervention on long-term mortality. Journal of cardiovascular medicine (Hagerstown,Md). 2008;9:375-81.

28. Solomon RJ, Mehran R, Natarajan MK, Doucet S, Katholi RE, Staniloae CS, SharmaSK, Labinaz M, Gelormini JL and Barrett BJ. Contrast-induced nephropathy andlong-term adverse events: cause and effect? Clinical journal of the American Societyof Nephrology : CJASN. 2009;4:1162-9.

29. Adolph E, Holdt-Lehmann B, Chatterjee T, Paschka S, Prott A, Schneider H, KoerberT, Ince H, Steiner M, Schuff-Werner P and Nienaber CA. Renal InsufficiencyFollowing Radiocontrast Exposure Trial (REINFORCE): a randomized comparison ofsodium bicarbonate versus sodium chloride hydration for the prevention ofcontrast-induced nephropathy. Coronary artery disease. 2008;19:413-9.

30. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, FordE, Furie K, Go A, Greenlund K, Haase N, Hailpern S, Ho M, Howard V, Kissela B,Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott M, Meigs J, Mozaffarian D,Nichol G, O'Donnell C, Roger V, Rosamond W, Sacco R, Sorlie P, Stafford R,Steinberger J, Thom T, Wasserthiel-Smoller S, Wong N, Wylie-Rosett J and Hong Y.Heart disease and stroke statistics--2009 update: a report from the American Heart




101

Association Statistics Committee and Stroke Statistics Subcommittee. Circulation.2009;119:480-6.

31. Subramanian S, Tumlin J, Bapat B and Zyczynski T. Economic burden ofcontrast-induced nephropathy: implications for prevention strategies. Journal ofmedical economics. 2007;10:119-34.

32. Weisbord SD, Bruns FJ, Saul MI and Palevsky PM. Provider use of preventivestrategies for radiocontrast nephropathy in high-risk patients. Nephron Clinicalpractice. 2004;96:c56-62.

33. Mehran R, Dangas GD and Weisbord SD. Contrast-Associated Acute Kidney Injury.The New England journal of medicine. 2019;380:2146-2155.

34. Weisberg LS, Kurnik PB and Kurnik BR. Radiocontrast-induced nephropathy inhumans: role of renal vasoconstriction. Kidney international. 1992;41:1408-15.

35. Nicot GS, Merle LJ, Charmes JP, Valette JP, Nouaille YD, Lachatre GF andLeroux-Robert C. Transient glomerular proteinuria, enzymuria, and nephrotoxicreaction induced by radiocontrast media. Jama. 1984;252:2432-4.

36. Bakris GL, Lass N, Gaber AO, Jones JD and Burnett JC, Jr. Radiocontrastmedium-induced declines in renal function: a role for oxygen free radicals. TheAmerican journal of physiology. 1990;258:F115-20.

37. Katholi RE, Woods WT, Jr., Taylor GJ, Deitrick CL, Womack KA, Katholi CR andMcCann WP. Oxygen free radicals and contrast nephropathy. American journal ofkidney diseases : the official journal of the National Kidney Foundation.1998;32:64-71.

38. Yoshioka T, Fogo A and Beckman JK. Reduced activity of antioxidant enzymesunderlies contrast media-induced renal injury in volume depletion. Kidneyinternational. 1992;41:1008-15.

39. Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U, ByrneRA, Collet JP, Falk V, Head SJ, Juni P, Kastrati A, Koller A, Kristensen SD, NiebauerJ, Richter DJ, Seferovic PM, Sibbing D, Stefanini GG, Windecker S, Yadav R andZembala MO. 2018 ESC/EACTS Guidelines on myocardial revascularization.European heart journal. 2019;40:87-165.

40. Jurado-Roman A, Hernandez-Hernandez F, Garcia-Tejada J, Granda-Nistal C,Molina J, Velazquez M, Albarran A and Tascon J. Role of hydration incontrast-induced nephropathy in patients who underwent primary percutaneouscoronary intervention. The American journal of cardiology. 2015;115:1174-8.

41. O'Gara PT, Kushner FG, Ascheim DD, Casey DE, Jr., Chung MK, de Lemos JA,Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM,Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ,Tamis-Holland JE, Tommaso CL, Tracy CM, Woo YJ and Zhao DX. 2013 ACCF/AHAguideline for the management of ST-elevation myocardial infarction: a report of theAmerican College of Cardiology Foundation/American Heart Association Task Forceon Practice Guidelines. Journal of the American College of Cardiology.2013;61:e78-e140.

42. Jo SH, Youn TJ, Koo BK, Park JS, Kang HJ, Cho YS, Chung WY, Joo GW, Chae IH,Choi DJ, Oh BH, Lee MM, Park YB and Kim HS. Renal toxicity evaluation and




102

comparison between visipaque (iodixanol) and hexabrix (ioxaglate) in patients withrenal insufficiency undergoing coronary angiography: the RECOVER study: arandomized controlled trial. Journal of the American College of Cardiology.2006;48:924-30.

43. Juergens CP, Winter JP, Nguyen-Do P, Lo S, French JK, Hallani H, Fernandes C,Jepson N and Leung DY. Nephrotoxic effects of iodixanol and iopromide in patientswith abnormal renal function receiving N-acetylcysteine and hydration beforecoronary angiography and intervention: a randomized trial. Internal medicine journal.2009;39:25-31.

44. Reed M, Meier P, Tamhane UU, Welch KB, Moscucci M and Gurm HS. The relativerenal safety of iodixanol compared with low-osmolar contrast media: a meta-analysisof randomized controlled trials. JACC Cardiovascular interventions. 2009;2:645-54.

45. Brar SS, Aharonian V, Mansukhani P, Moore N, Shen AY, Jorgensen M, Dua A,Short L and Kane K. Haemodynamic-guided fluid administration for the prevention ofcontrast-induced acute kidney injury: the POSEIDON randomised controlled trial.Lancet (London, England). 2014;383:1814-23.

46. Luo Y, Wang X, Ye Z, Lai Y, Yao Y, Li J and Liu X. Remedial hydration reduces theincidence of contrast-induced nephropathy and short-term adverse events in patientswith ST-segment elevation myocardial infarction: a single-center, randomized trial.Internal medicine (Tokyo, Japan). 2014;53:2265-72.

47. Maioli M, Toso A, Leoncini M, Micheletti C and Bellandi F. Effects of hydration incontrast-induced acute kidney injury after primary angioplasty: a randomized,controlled trial. Circulation Cardiovascular interventions. 2011;4:456-62.

48. Marenzi G, Ferrari C, Marana I, Assanelli E, De Metrio M, Teruzzi G, Veglia F,Fabbiocchi F, Montorsi P and Bartorelli AL. Prevention of contrast nephropathy byfurosemide with matched hydration: the MYTHOS (Induced Diuresis With MatchedHydration Compared to Standard Hydration for Contrast Induced NephropathyPrevention) trial. JACC Cardiovascular interventions. 2012;5:90-7.

49. Nijssen EC, Rennenberg RJ, Nelemans PJ, Essers BA, Janssen MM, Vermeeren MA,Ommen VV and Wildberger JE. Prophylactic hydration to protect renal function fromintravascular iodinated contrast material in patients at high risk of contrast-inducednephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label,non-inferiority trial. Lancet (London, England). 2017;389:1312-1322.

50. Qian G, Fu Z, Guo J, Cao F and Chen Y. Prevention of Contrast-InducedNephropathy by Central Venous Pressure-Guided Fluid Administration in ChronicKidney Disease and Congestive Heart Failure Patients. JACC Cardiovascularinterventions. 2016;9:89-96.

51. Trivedi HS, Moore H, Nasr S, Aggarwal K, Agrawal A, Goel P and Hewett J. Arandomized prospective trial to assess the role of saline hydration on thedevelopment of contrast nephrotoxicity. Nephron Clinical practice. 2003;93:C29-34.

52. Global, regional, and national incidence, prevalence, and years lived with disability for354 diseases and injuries for 195 countries and territories, 1990-2017: a systematicanalysis for the Global Burden of Disease Study 2017. Lancet (London, England).2018;392:1789-1858.




103

53. Summary of the 2018 Report on Cardiovascular Diseases in China. ChineseCirculation Journal，March，2019，Vol. 34 No.3（Serial No.249）

54. Narula A, Mehran R, Weisz G, Dangas GD, Yu J, Genereux P, Nikolsky E, Brener SJ,Witzenbichler B, Guagliumi G, Clark AE, Fahy M, Xu K, Brodie BR and Stone GW.Contrast-induced acute kidney injury after primary percutaneous coronaryintervention: results from the HORIZONS-AMI substudy. European heart journal.2014;35:1533-40.

55. Marenzi G, Lauri G, Assanelli E, Campodonico J, De Metrio M, Marana I, Grazi M,Veglia F and Bartorelli AL. Contrast-induced nephropathy in patients undergoingprimary angioplasty for acute myocardial infarction. Journal of the American Collegeof Cardiology. 2004;44:1780-5.

56. Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, Filippatos G, Hamm C,Head SJ, Juni P, Kappetein AP, Kastrati A, Knuuti J, Landmesser U, Laufer G,Neumann FJ, Richter DJ, Schauerte P, Sousa Uva M, Stefanini GG, Taggart DP,Torracca L, Valgimigli M, Wijns W and Witkowski A. 2014 ESC/EACTS Guidelines onmyocardial revascularization: The Task Force on Myocardial Revascularization of theEuropean Society of Cardiology (ESC) and the European Association forCardio-Thoracic Surgery (EACTS)Developed with the special contribution of theEuropean Association of Percutaneous Cardiovascular Interventions (EAPCI).European heart journal. 2014;35:2541-619.

57. Trivedi H and Foley WD. Contrast-induced nephropathy after a second contrastexposure. Renal failure. 2010;32:796-801.

58. Briguori C, Visconti G, Rivera NV, Focaccio A, Golia B, Giannone R, Castaldo D, DeMicco F, Ricciardelli B and Colombo A. Cystatin C and contrast-induced acute kidneyinjury. Circulation. 2010;121:2117-22.

59. Maioli M, Toso A, Leoncini M, Gallopin M, Musilli N and Bellandi F. Persistent renaldamage after contrast-induced acute kidney injury: incidence, evolution, risk factors,and prognosis. Circulation. 2012;125:3099-107.

60. Tan N, Liu Y, Chen JY, Zhou YL, Li X, Li LW, Yu DQ, Chen ZJ, Liu XQ and Huang SJ.Use of the contrast volume or grams of iodine-to-creatinine clearance ratio to predictmortality after percutaneous coronary intervention. American heart journal.2013;165:600-8.

61. Newcombe RG. Interval estimation for the difference between independentproportions: comparison of eleven methods. Statistics in medicine. 1998;17:873-90.

62. Mehran R, Aymong ED, Nikolsky E, Lasic Z, Iakovou I, Fahy M, Mintz GS, Lansky AJ,Moses JW, Stone GW, Leon MB and Dangas G. A simple risk score for prediction ofcontrast-induced nephropathy after percutaneous coronary intervention:development and initial validation. Journal of the American College of Cardiology.2004;44:1393-9.

63. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, CaforioALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ,Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P and Widimsky P. 2017ESC Guidelines for the management of acute myocardial infarction in patientspresenting with ST-segment elevation: The Task Force for the management of acute




104

myocardial infarction in patients presenting with ST-segment elevation of theEuropean Society of Cardiology (ESC). European heart journal. 2018;39:119-177.

64. Brienesse SC, Davies AJ, Khan A and Boyle AJ. Prognostic Value of LVEDP in AcuteMyocardial Infarction: a Systematic Review and Meta-Analysis. Journal ofcardiovascular translational research. 2018;11:33-35.

65. Barrett BJ and Carlisle EJ. Metaanalysis of the relative nephrotoxicity of high- andlow-osmolality iodinated contrast media. Radiology. 1993;188:171-8.

66. Rudnick MR, Goldfarb S, Wexler L, Ludbrook PA, Murphy MJ, Halpern EF, Hill JA,Winniford M, Cohen MB and VanFossen DB. Nephrotoxicity of ionic and nonioniccontrast media in 1196 patients: a randomized trial. The Iohexol Cooperative Study.Kidney international. 1995;47:254-61.

67. Kushner FG, Hand M, Smith SC, Jr., King SB, 3rd, Anderson JL, Antman EM, BaileySR, Bates ER, Blankenship JC, Casey DE, Jr., Green LA, Hochman JS, Jacobs AK,Krumholz HM, Morrison DA, Ornato JP, Pearle DL, Peterson ED, Sloan MA, WhitlowPL and Williams DO. 2009 focused updates: ACC/AHA guidelines for themanagement of patients with ST-elevation myocardial infarction (updating the 2004guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneouscoronary intervention (updating the 2005 guideline and 2007 focused update) areport of the American College of Cardiology Foundation/American Heart AssociationTask Force on Practice Guidelines. Journal of the American College of Cardiology.2009;54:2205-41.

68. Sun G, Chen P, Wang K, Li H, Chen S, Liu J, He Y, Song F, Liu Y and Chen JY.Contrast-Induced Nephropathy and Long-Term Mortality After PercutaneousCoronary Intervention in Patients With Acute Myocardial Infarction. Angiology.2018:3319718803677.

69. Zeng JF, Chen SQ, Ye JF, Chen Y, Lei L, Liu XQ, Liu Y, Wang Y, Lin JJ and Chen JY.A simple risk score model for predicting contrast-induced nephropathy after coronaryangiography in patients with diabetes. Clinical and experimental nephrology.2019;23:969-981.

70. Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U, ByrneRA, Collet JP, Falk V, Head SJ, Juni P, Kastrati A, Koller A, Kristensen SD, NiebauerJ, Richter DJ, Seferovic PM, Sibbing D, Stefanini GG, Windecker S, Yadav R andZembala MO. [2018 ESC/EACTS Guidelines on myocardial revascularization].Kardiologia polska. 2018;76:1585-1664.




Appendix C

ATTEMEPT Clinical Trial Protocol Version 3.0





AGGRESSIVE HYDRATION AND CONTRAST INDUCED ACUTE KIDNEY INJURYFOLLOWING PRIMARY ANGIOPLASTY (ATTEMPT):

CONTENTS

RESEARCH CENTERS

EXECUTIVE SUMMARY........................................................................................................1

ABBREVIATIONS................................................................................................................... 3

INTRODUCTION......................................................................................................................5

BACKGROUND....................................................................................................................6

SIGNIFICANCE OF THE PROPOSED RESEARCH...................................................19

STUDY DESIGN....................................................................................................................20

STUDY HYPOTHESES AND OBJECTIVES.................................................................20

OVERVIEW OF STUDY DESIGN...................................................................................21

METHOD.................................................................................................................................27

STUDY POPULATION AND PATIENT RECRUITMENT............................................27

STUDY PROCEDURES...................................................................................................29

POTENTIAL RISKS AND ALTERNATIVE CONSIDERATIONS................................49

FEASIBILITY OF RECRUITMENT...............................................................................553

ANTICIPATED BARRIERS TO RECRUITMENT.......................................................564

PROPOSED ANCILLARY STUDY............................................................................... 575

HUMAN SUBJECTS....................................................................................................... 586

DATA MANAGEMENT......................................................................................................58

QUALITY CONTROL......................................................................................................720

GOOD CLINICAL PRACTICE......................................................................................... 79

RESEARCH MONITORING AND AUDIT PLANS........................................................80

RESULT..................................................................................................................................86

BIOSTATISTICAL CONSIDERATIONS.........................................................................86

STUDY ORGANIZATION AND ADMINISTRATION..................................................941

PUBLICATIONS...............................................................................................................974

REFERENCES.................................................................................................................986




Research centers

No. Study Site

01 Guangdong Provincial People’s Hospital

03 Zhongshan Hospital, Fudan University

04 Chinese PLA General Hospital

05 The Affiliated Hospital, Guangdong Medical University

07 The Eighth Affiliated Hospital, Sun Yat‐sen University

08 Longyan First Affiliated Hospital of Fujian Medical University

09 First People’s Hospital of Zhaoqing City

10 Dongguan TCM Hospital

11 Maoming People's Hospital

12 Shenzhen People's Hospital

13 Beijing Ditan Hospital

14 Hangzhou First People’s Hospital

15 Tongji Hospital, Tongji Medical College, Huazhong University of Science and

Technology

16 Guangdong Provincial Hospital of Chinese Medicine

17 Mianyang Central Hospital




1

EXECUTIVE SUMMARY

The intravascular administration of iodinated contrast agent for coronary

angiography (CAG) or percutaneous coronary intervention (PCI) is a common

cause of acute kidney injury (AKI) and a leading cause of iatrogenic renal

disease. Multiple studies have determined that contrast-induced AKI (CI-AKI)

is associated with prolonged hospitalization, increased medical economic

burden, and adverse long-term prognosis.

Patients with ST-elevation myocardial infarction (STEMI) have a higher risk of

CI-AKI, which is a potentially serious complication of angiographic procedures

that are associated with increased mortality, morbidity, and health care use in

patients undergoing PCI. According to guidelines for the management of

STEMI, saline hydration is widely recommended. However, optimal saline

hydration strategy has not been well established in this high-risk population.

The Induced Diuresis With Matched Hydration Compared to Standard

Hydration for Contrast Induced Nephropathy Prevention (MYTHOS) study

found that a loading dose (125/250mL) of isotonic saline matched with

furosemide-induced high urine output significantly reduces the risk of CI-AKI

and might be associated with improved clinical outcomes in patients with

chronic kidney disease (CKD). QIAN G et al suggested that CVP-guided fluid

administration can be safely and effectively reduce the risk of CI-AKI in

patients with CKD and chronic heart failure and substantially reduce composite

major adverse events for these high-risk patients. The Prevention of Contrast

Renal Injury with Different Hydration Strategies (POSEIDON) trial suggested

that intravenous (IV) administration of normal saline guided by the left

ventricular end diastolic pressure (LVEDP) is well tolerated and could

substantially reduce the incidence of CI-AKI and major adverse clinical events

in patients with combined CKD and one or more of several risk factors




2

undergoing cardiac catheterization. Three clinical trials above consistently

demonstrated that saline hydration based on certain guiding strategies was

more effective than general hydration in preventing CI-AKI and reducing the

risk of adverse prognosis.



therapy, all of which are associated with an increased risk of CI-AKI. In

previous studies, cardiologists were primarily concerned with rapid


preprocedural hydration to prevent CI-AKI in patients with STEMI; The main

reason is lacking of information regarding baseline kidney function and related

medical history. Conversely, excessive hydration of saline without a definite


thus increasing the risk of cardiac function deterioration. Therefore, flexible

and individualized hydration therapy based on certain guiding strategy needed

to maintain renal perfusion, given that perioperative IV volume expansion

could potentially compensate for reduced cardiac output, hypotension, and

depletion of intravascular volume in patients with STEMI.

Given these previous data, we designed the ATTEMPT trial to examine the

efficacy of a preprocedural loading dose and postprocedural aggressive

hydration with normal saline guided by LVEDP as compared with general

hydration(Figure A1). We hypothesize that aggressive hydration strategy

reduces the risk of CI-AKI and improves the clinical outcomes in STEMI

patients undergoing primary PCI. The ATTEMPT study is a multicenter,

open-label, investigator-driven, randomized controlled trial in China.

Approximately 560 patients with STEMI undergoing primary PCI will be

randomized (1:1) to receive either periprocedural general hydration (control




3

group) or aggressive hydration (treatment group). Patients in the control group

receive periprocedural general hydration with ≤500 mL normal saline (within 6

hours) at a normal rate (0.5 or 1 mL/kg*h). Patients in the treatment group

receive a preprocedural loading dose (125/250 mL) of normal saline within 30

minutes and intravenous hydration at a normal rate until LVEDP is available,

followed by postprocedural aggressive hydration guided by LVEDP for 4 hours

and then continuous intravascular hydration at the normal rate until 24 hours

after PCI. The primary endpoint is CI-AKI, defined as a ＞25% or 0.5-mg/dL

increase in serum creatinine from baseline during the first 48 to 72 hours after

the procedure. The ATTEMPT study has the potential to identify optimal

hydration regimens for STEMI patients undergoing primary PCI.

ABBREVIATIONS

AKI Acute kidney injury

ACS Acute coronary syndrome

AHF Acute heart failure

AMI Acute myocardial infarction

ACEI Angiotensin-Converting Enzyme Inhibitors

ARB Angiotensin Receptor Blockers

BMI Body Mass Index

pPCI Primary Percutaneous Cornary Intervention

RR Risk Ratio

ARR Absolute Risk Ratio

SCr Serum creatinine

DSMB Data and safety monitoring committee

CCU Cardiac care unit


CI Confidence Interval




4

CI-AKI Contrast-induced Acute Kidney Injury

CK Creatine kinase

CK-MB Creatine kinase-MB

CKD Chronic kidney disease

CAG Coronary Angiography


CVD Cardiovascular disease

CRA Clinical Research Associate

CT Computed Tomography

DM Diabetes Mellitus

DMC Data Monitoring Committee

DVP Data Validation Plan

EDC Electronic Data Capture

eGFR estimated Glomerular Filtration Rate

ESRD End-stage Renal Disease

GCP Good Clinical Practice

HF Heart Failure

HR Hazard Ratio

HCT Hematocrit

ICH International technical committee

IEC Independent Ethics Committee

ITT Intention-to-treat;

IABP Intra-aortic Ballon Pump

LVEDP Left Ventricular end-diastolic Pressure

LVEF Left Ventricular Ejection Fraction

MACE Major Adverse Cardiovascular Events

MDRD Modification of Diet in Renal Disease formula

OR Odd Ratio

PCI Percutaneous Coronary Intervention




5

PM Project Manager

PLT Platelets

NT-proBNP N-terminal pro-brain natriuretic peptide

NNT Number needed to treat

NYHA New York Heart Association

STEMI Stsegment Elevation Myocardial Infarction

RR Risk Ratio

WBC White Blood Cell

DCF Data Challenge Form

INTRODUCTION

Contrast-induced acute kidney injury (CI-AKI) is a common complication of

coronary angiography and/or percutaneous coronary intervention (CAG/PCI).

Patients with ST-elevation myocardial infarction (STEMI) undergoing primary

percutaneous coronary intervention (pPCI) have a higher risk of CI-AKI.

Previous trials failed to find out the efficacy of sodium bicarbonate and

acetylcysteine in prevention of CI-AKI and outcomes following pPCI or

angiography. Although previous studies suggested the benefit of intravenous

hydration (vs. no hydration) in reducing risk of CI-AKI following pPCI, recent

systematic review suggested that the most effective regimen of intravenous

hydration has not been determined. According to the guideline for the

management of STEMI, timely reperfusion with shortest delay was the most

important for clinical outcomes, while adequate hydration is also

recommended for CI-AKI prevention in patients undergoing pPCI. Therefore,

adequate preventive hydration including pre-procedural long-term duration

conflicts shortest delay before pPCI among patients with STEMI.

MYTHOS study suggested that a loading dose (125/250 mL in short half an




6

hour) of isotonic saline matched with furosemide-induced high urine output

significantly reduces the risk of CI-AKI, more effective among patients

undergoing emergent PCI, without increased risk of acute heart failure.

POSEIDON trial showed that left ventricular end-diastolic pressure (LVEDP)

guided intensive hydration in short time (4 hours) could substantially reduce

the incidence of CI-AKI and was well safety tolerated. Therefore, our

hypothesis was that aggressive intravenous hydration, including above short

intensive regimen (loading dose, post-reperfusion LVEDP guide) and

long-term maintenance, might be suitable for the special emergent condition

among STEMI patients undergoing pPCI. We designed the Aggressive

hydraTion in patients with ST-Elevation Myocardial infarction undergoing

Primary percutaneous coronary intervention to prevenT Contrast-Induced

Nephropathy (ATTEMPT) trial to investigate the efficacy and safety of the

aggressive hydration strategy in high-risk patients with STEMI undergoing

pPCI.

1. BACKGROUND

1.1 Definition, incidence, and risk factors for CI-AKI in STEMI patients

CI-AKI is defined as a decrease in kidney function following the exposure of

contrast agent1,2. Although the diagnostic criteria of CI-AKI varies in different

studies, the widely accepted definition of CI-AKI is an increase in the serum

creatinine concentration (SCr) of at least 0.5 mg/dL and/or 25% within 2-3

days of intravascular administration of contrast agent3-5.

The previous study found that CI-AKI occurred in 8.5% of with eGFR >60

ml/min/1.73 m2 undergoing non-urgent coronary angiography and 13.2% of

clinically stable Veterans with eGFR <60 ml/min/1.73 m2 undergoing

non-urgent, non-coronary angiography6. Other studies showed that up to 33%

of extremely high-risk patients develop this condition following




7

contrast-enhanced procedures7.

We have made a system review which has illuminated the pivotal risk factors

for CI-AKI in STEMI patients (Figure A1). Renal insufficiency is recognized as

the principal risk factor for the development of CI-AKI, with increasing levels of

kidney dysfunction associated with incremental degree of risk8. Combined with

diabetes mellitus substantially increase the risk for CI-AKI in patients with

chronic kidney disease8-10. Patients with hypovolemia are also vulnerable to

kidney dysfunction due to iodized contrast media, as are patients with

advanced heart failure8. In both clinical states, hypovolemia and reduced renal

perfusion induced renal vasoconstriction after intravascular contrast media

administration. The risk of CI-AKI increases with the administration of contrast

agents in large quantities11, 12. It is also believed that the risk of CI-AKI after

intra-arterial contrast agent administration is greater than that of intravenous

administration. Recognition of these major risk factors helps clinicians to more

accurately determine which patients are most likely to develop CI-AKI, and

studies has been conducted to assess the effectiveness of preventive

interventions for this disease.




8

Figure A1-Major risk factors for CI-AKI in STEMI patients

1.2 Association of CI-AKI with mortality

Observational studies have shown a correlation between CI-AKI (defined by

small absolute and/or relative changes in SCr) and increased short-term

mortality13-20. In a retrospective study, Levy et al. CI-AKI was found to be an

important predictor of in-hospital mortality (OR = 5.5, P < 0.001) in 183

hospitalized patients (an increase of 25% from SCr to at least 2.0 mg/dL).

Follow-up studies by McCullough et al. Among the 1,826 patients receiving

PCI, CI-AKI was found to be related with an in-hospital mortality rate of 7.1%,

compared with 1.1% in patients with no such change in SCr. (p < 0.0001)21.

Among CI-AKI patients who needed renal replacement therapy, the hospital

mortality rate was 35.7%. Many other studies reported an independent

association between CI-AKI and short-term mortality13-15, 17-19. although there is

a close relationship between small changes in SCr and short-term mortality,

most of them are retrospective analysis. Therefore, there may be deterministic

bias in assessing postoperative SCr, and there may be missing potential




9

problem data13, 14, 17-19, 21. However, prospective studies confirm these findings

in the clinical study of Marenzi et al. The study found that the in-hospital

mortality of patients with CI-AKI was significantly higher than that of patients

without renal dysfunction (26% vs. 1.4%, P < 0.001)22. Maioli et al. conducted

several studies that have shown that in-hospital mortality in patients with

CI-AKI is significantly higher than that in patients without complications (11.1%

vs. 0.2%, P = 0.001)23. Therefore, data from observational studies and

randomized trials support the association between postoperative decline of

kidney function and short-term mortality.

In addition to increased short-term complications, CI-AKI has also been linked

with long-term mortality in recent studies17, 24-28. Solomon et al. demonstrated

that CI-AKI was associated with a greater than 3-fold increased risk of major

adverse outcomes (death, stroke, myocardial infarction, end-stage renal

disease requiring renal replacement therapy) at 1-year of follow up28. Four

additional studies found an independent association of CI-AKI with long-term

mortality, although the study by Roghi et al. demonstrated a trend toward

increased long-term mortality that did not reach statistical significance in

multivariable analyses17, 24, 25, 27. Collectively, these findings indicate that

CI-AKI, defined by small decrements in renal function, is associated with

adverse long-term outcomes and more compromised renal function over time.

Despite the abundance of epidemiological and experimental data associating

small changes in SCr with adverse renal and extra-renal outcomes, the

evidence remains inadequate to warrant the use of small changes in SCr as a

surrogate primary endpoint in large transformative clinical trials. Although

serious events following angiography occur as a consequence of CI-AKI, they

may also develop independent of this intermediate event, as many of the

clinical conditions that predispose patients to the development of CI-AKI (e.g.,

CKD, diabetes mellitus, heart failure) are also independently associated with




10

mortality and other adverse outcomes (Figure A2). In addition, not all episodes

of CI-AKI lead to clinically consequential sequelae. For this reason, we believe

that it is most appropriate for a definitive trial of interventions for the prevention

of CI-AKI to demonstrate effectiveness in reducing serious, adverse,

patient-centered outcomes rather than merely focusing on the amelioration of

small changes in SCr. In our ATTEMPT study, the primary end point is CI-AKI,

defined as a >25% or 0.5-mg/dL increase in serum creatinine from baseline

during the first 48 to 72 hours after the procedure. Secondary end points are

as follows: (1) CI-AKI48h, defined as a >50% or 0.3-mg/dL absolute increase in

serum creatinine from baseline during the first 48 hours after the procedure; (2)

CI-AKIcysc, defined as a >10% or 0.3-mg/dL absolute increase in serum

cystatin C during the first 24 hours after the procedure; (3) contrast induced

persistence kidney injury (CI-PKI), defined as residual impairment of renal

function indicated by >25% reduction in creatinine clearance at 3 months in

comparison with baseline; (4) major adverse cardiovascular events, including

all-cause mortality, target vascular revascularization, and nonfatal myocardial

infarction; (5) post-procedural acute heart failure during hospitalization; (6)

major post-procedure in-hospital adverse clinical events, including acute


and bleeding within the first year; and (7) total hospitalization costs and length

of stay.




11

Figure A2 – Development process of clinical adverse events exposure to

contrast agent

1.3 Prolonged hospitalization and increased costs associated with

CI-AKI

Multiple retrospective studies also focus on clarifying an association of CI-AKI

with economic benefits of health13,19,29-32. In the analysis of over 27,000

patients who underwent CAG, a rise in SCr of 0.25 - 0.5 mg/dL was associated

with prolonged hospitalization after adjusting for underlying severity of illness19.

The length of hospitalization extended with the increase of SCr gradually.

Bartholomew found that patients who developed CI-AKI after PCI were 15

times more likely to extend length of hospitalization more than four days13. In a

clinical trial comparing IV fluids for the prevention of CI-AKI, Adolph found that




12

patients with a postoperative increase in SCr of ≥25% or ≥0.5 mg/dL was

associated with a mean of two days longer than patients without obvious

change of SCr29. Prolonged hospitalization results in increased healthcare

expenditures as documented in an observational study32. In the analysis of 598

diabetics with CKD undergoing CAG, CI-AKI was independently associated

with a 2-fold increase in healthcare expenditures32. Subramanian et al used a

decision analytic model to show that CI-AKI results in an average increase in

hospital-related costs of more than $10,300 and 1-year costs in excess of

$11,80031. Based on the number of CHD and cardiac catheterization

performed across the China, there may be approximately 940,000 cases of

CI-AKI nationwide. In general, these data indicate that CI-AKI is associated

with prolonged hospitalization and huge expenditure on health economics.

1.4 Pathophysiology and prevention strategies of CI-AKI in STEMI

patients

Although the pathophysiological mechanism of renal injury induced by contrast

agents has not been fully elucidated, the following mechanisms are generally

accepted: direct and indirect renal injury induced by contrast agents, and

disturbance of hemodynamic stability (Figure A3)33. Firstly, intravascular

exposure of contrast agents leads to transient systemic vasodilation, followed

by intense contractions of the renal vascular bed. Outside the vasoconstriction

in the renal medulla have particularly low baseline oxygen tension, cause the

oxygen supply and demand do not match, leading to ischemic renal tubular

damage33, 34. Secondly, direct toxic on renal tubular epithelial cells caused by

contrast agents33, 35. Thirdly, the use of contrast agents lead to reactive oxygen

species (ROS) generation, this will accelerate renal tubular cell injury33,36-38.



therapy, all of which are associated with an increased risk of CI-AKI. Patients




13

with STEMI also commonly have other risk factors for CI-AKI such as reduced

cardiac output or hypotension due to myocardial infarction or depletion of

intravascular volume caused by vomiting, diaphoresis, or decreased oral

intake. Despite a considerable prevalence of risk factors, including reduced

LVEF, renal insufficiency, and diabetes mellitus, in patients needing adequate







thus increasing the risk of cardiac function deterioration. Through the

understanding of the above pathogenesis, it is helpful to explore the prevention

and treatment strategy of CI-AKI in STEMI patients.

Figure A3 - Pathophysiology of CI-AKI in STEMI patients




14

Renal injury induced by contrast agents may be preventable. Patients at

increased risk of CI-AKI are easily identified by the presence of known clinical

risk factors. Past efforts to find effective prevention strategies for CI-AKI have

focused on three recommendations39: 1) risk factors assessment of CI-AKI; 2)

minimization and preference of low-osmolar or iso-osmolar contrast media; 3)

adequate hydration. The incidence of CI-AKI has decreased due to the change

in the type of contrast agent over time and risk factors of CI-AKI are gradually

clarified. Recently, Jurado-Román et al40 suggested that the risk of CI-AKI after

IV administration of normal saline is 48% lower than with no IV hydration in

patients with STEMI, which is rarely performed in actual practice, when

following the guideline for the management of STEMI41. However, we still have

to be soberly aware that the optimal saline hydration strategy still remain

controversial9, 42-44.

1.5 Characteristics of randomized clinical trials on prevention of CI-AKI

under different hydration strategies of IV isotonic saline

Previous studies have focused on the optimal composition of hydration therapy.

With the publication of PRESERVE results, acetylcysteine as a component of

hydrated liquids has no obvious benefit for the prevention of CI-AKI. Therefore,

the preferred position of isotonic saline hydration in the prevention strategy of

CI-AKI hydration has been gradually consolidated. At present, the optimal

hydration strategy for the prevention of CI-AKI in high-risk patients still remain

inconclusive. We systematically review the RCT articles published in the past

few years on the prevention of CI-AKI by hydration of isotonic saline under

different guiding strategies. Nine studies were included20,40,45-51. Eight of them

showed that the hydration guidance strategy of the treatment group was better

than that of the control group without special hydration strategy. One study

showed that isotonic saline hydration had no significant benefit in preventing

CI-AKI (Table A1). The different results of nine studies suggest that the optimal




15

hydration strategy of saline is still uncertain, and for high-risk patients such as

STEMI, we lack relevant research evidence. In particular, we need to focus not

only on the different effects of individualized isotonic saline hydration

strategies on preventing CI-AKI, but also to explore the optimal isotonic saline

hydration strategy that can reduce the short-term and long-term adverse

prognosis among high-risk patients such as STEMI.




16

Table A1- Characteristics of randomized clinical trials on prevention of CI-AKI under different hydration strategies of IV isotonic saline

Authors Number

of

patients

Procedure Baseline renal function Definition of

CI-AKI

Hydration strategy of IV isotonic saline Frequency of

CI-AKI in isotonic

saline group

Dialysis Death

WEISBORD S

D et al

4993 Elective CAG ↑ SCr >0.5mg/dL or ≥25%


exposure

↑

SCr >0.5mg/dL

or >25%

During 1-12h before angiography：1-3ml/kg/h; during angiography：1-1.5ml/kg/h ,

during a period of 2-12h after angiography:1-3ml/kg/h. hydration speed will be

adjusted if overweight.

8.3% 1.2% 2.7%

TRIVEDI H S et

al

53 Elective CAG/PCI ↑ SCr >0.5mg/dL within 2 days

of contrast exposure

↑

SCr >0.5mg/dL

1ml/kg/h, 12h before CAG/PCI for total 24h. 3.7% NA NA

BRAR S S et al 396 Elective CAG/PCI ↑ SCr ≥0.5mg/dL or ≤25%


exposure

↑ SCr

≥0.5mg/dL or

≥25%

A: LVEDP-guided volume expansion

B: Standard fluid administration protocol.

6.7%/16.3% 0.5%/2.0% 0.5%/4.0

%

JURADO-ROM

AN A et al



exposure

↑

SCr >0.5mg/dL

or >25%

1 ml/kg/h since the beginning of CAG/PCI for total 24 hours. 11% 0% 2.8%

LUO Y et al 216 Primary CAG/PCI ↑ SCr >0.5mg/dL or ≥25%


exposure

↑

SCr >0.5mg/dL

or >25%

1mL/kg/h for 12 hours after CAG/PCI., the rate was reduced to 0.5 mL/kg/h in

patients with LVEF≤30% or a Killip class 2 or 3 status.

20.4% 0.93% 2.78%

MARENZI G et

al



exposure

↑

SCr >0.5mg/dL

or >25%

1mL/kg/h for 12 hours immediately after CAG/PCI, rate was reduced to 0.5 mL/kg/h in

patients with LVEF≤40% or NYHA III–IV.

22.7% 0.93% 2.78%

MAIOLI M et al 170 Elective CAG ↑ SCr >0.5mg/dL or ≥25%


exposure

↑

SCr >0.5mg/dL

or >25%

A: Furosemide with matched hydration group(FMH)

B: 1 ml/kg/h (0.5ml/kg/h in case of LVEF<40%) for at least 12 h before and 12 h after

the CAG.

4.6%/18% 1.1%/4% 1.1%/4%

QIAN G et al 264 Elective CAG/PCI ↑ SCr >0.5mg/dL or >25%


↑

SCr >0.5mg/dL

A: CVP-guided hydration group

B: standard hydration group.

15.9%/29.5% 3.0%/9.8% 1.1%/4%




17

exposure or ≥25%

NIJSSEN E C

et al

660 Elective CAG ↑ SCr >0.5mg/dL or >25%


exposure

↑

SCr >0.5mg/dL

or >25%

A: 3–4mL/kg/h during 4 h before and 4 h after contrast administration;

B: 1mL/kg/h during 12 h before and 12 h after contrast administration/No hydration

group.

2.7%/2.6% 0%/0% 0%/0.9%

CI-AKI denotes contrast induced acute kedney injury, CAG denotes coronary angiogram, NA denotes not assessed, PCI denotes percutaneous coronary intervention.



1.6 Summary of limitations of randomized clinical trials on prevention of

CI-AKI under different hydration strategies of IV isotonic saline

AMACING study has the following limitations: Firstly, it is a single center study.

Secondly, the final number of patients participating in this study were less than

half of the planned number of patients, and the overall incidence of CI-AKI was

low. Patients with eGFR<30 mL/min/1.73 m2 were excluded. Therefore, the

efficacy of hydration therapy for the prevention of CI-AKI in high-risk patients

cannot be generalized. The main limitation of the POSEIDON study is the

exclusion of STEMI patients. Therefore, the most effective hydration strategy

for preventing CI-AKI among STEMI patients with high risk of adverse events

after PCI is still inconclusive. The PRESERVE study did not focus on the

discussion of different isotonic saline hydration strategies. In addition to

AMACING, POSEIDON and PRESERVE studies, other studies characterized

in (Table A1) were limited by being single center, unblinded and without clearly

defined allocation concealment mechanisms. Furthermore there was

inconsistent reporting of cross-over between allocated groups and the volume

of fluid received by the control arm was not reported in any study. It is also not

possible to define the most effective hydration strategy as all these studies

used different starting times, rates and durations of hydration. Further

information is expected from the ATTEMPT study evaluating the efficacy of

aggressive hydration therapy guided by LVEDP compared with general

hydration (≤500 mL) for CI-AKI following primary PCI.

1.7 Summary

CI-AKI is a common complication after exposure to iodine-contrast agents,

especially in high risk patients such as STEMI, which is closely associated with

short-term adverse events in hospital and long-term prognosis after discharge.

Isotonic saline hydration strategy has been accepted as an effective strategy for

preventing CI-AKI. After a systematic review of the existing articles comparing

different isotonic saline hydration strategy, subject-related articles are scarce

and the starting and ending time of hydration, hydration rate and total amount of




19

hydration fluid remain great difference. For STEMI patients, the optimal isotonic

saline hydration strategy is still inconclusive. Combined with the above lack of

clinical evidence, we urgently need to design a clinical trial to solve this complex

but extremely important clinical problem. ATTEMPT is the first multicenter,

randomized controlled clinical trial that compare the effect of saline aggressive

hydration guided by LVEDP with general hydration on CI-AKI among STEMI

patients undergoing primary PCI. It aims to provide reliable evidence to guide

the optimal hydration strategy for STEMI patients undergoing primary PCI. If

our hypothesis is supported by the results, the aggressive hydration protocol

could be easily adopted in most cardiac intervention laboratories in China and

benefiting the vast number of STEMI patients.

2. SIGNIFICANCE OF THE PROPOSED RESEARCH

According to the latest data, the number of CHD in worldwide is about 150

million52. China has about 11 million CHD patients. Although the global mortality

rate of CHD is declining, the mortality rate of CHD in China is still increasing

year by year, especially among STEMI population. As an important measure of

diagnosis and treatment, the number of PCI in China increased to 915,256.

PCI/CT consumes about 80 million contrast agents per year worldwide and 20

million contrast agents per year in China, with an annual increase of 20-30%.

The burden of STEMI in China has become increasingly serious and has

become a major public health problem53. CI-AKI is associated with poorer

outcomes for patients, including prolongation of hospital stay and higher

mortality54. The results of our research group’s previous meta-analysis showed

that the global incidence of CI-AKI was about 8.6%. The risk in patients with

STEMI undergoing primary PCI is even greater55, with increased incidence of

CI-AKI about 29% and increased risk of death by 4.75 times. Despite a






20









urgently needed. By determining the effectiveness of aggressive hydration with

normal saline guided by LVEDP on CI-AKI and important clinical outcomes in

patients post-STEMI comparing with general hydration, the findings of this

clinical trial will provide reliable evidence to guide the optimal hydration strategy

for STEMI patients undergoing primary PCI. What’s more, the aggressive

hydration protocol could be easily adopted in most cardiac intervention

laboratories in China and benefiting the vast number of STEMI patients.

STUDY DESIGN

3. STUDY HYPOTHESES AND OBJECTIVES

3.1 Study hypotheses

Compared to general hydration strategy, aggressive hydration (ie,

pre-procedural IV loading plus post-procedural hemodynamic-guided [LVEDP]

fluid administration) will reduce the risk of CI-AKI and long-term clinical adverse

events in STEMI patients undergoing primary PCI.

3.2 Study objectives

To assess the effectiveness of preprocedural loading dose and

postprocedural aggressive hydration with normal saline guided by LVEDP as

compared with general hydration for prevention of CI-AKI and reduction of

long-term adverse events. CI-AKI is defined as a ＞25% or 0.5-mg/dL increase




21

in serum creatinine from baseline during the first 48 to 72 hours after PCI.

Long-term adverse events includes: all-cause mortality, target vascular

revascularization, nonfatal myocardial infarction; acute pulmonary edema,

cardiogenic shock, stroke, clinically significant arrhythmias, bleeding within the

first year, total hospitalization costs and length of stay. Our ultimate objective is

to identify optimal hydration strategy for high-risk patients with STEMI

undergoing primary PCI.

4. OVERVIEW OF STUDY DESIGN

ATTEMPT (trial registration: ClinicalTrials.gov NCT02067195) is an

investigator-initiated, multicenter, open-label, randomized controlled trial

conducted in the departments of cardiology from 15 hospitals in China. The

institutional ethics review board approved the study's design.

The study population will consist of 560 patients 18 years or older with STEMI

who undergo primary PCI and provide written informed consent for this study.

The time limit of the study is June 2014 - June 2016.Patients are excluded for

the following reasons: contrast medium administration within the previous 7

days; end-stage renal failure or renal transplantation; Inferior and/or right

ventricle myocardial infarction combined with hypotension (defined as systolic

pressure ≤90 mmHg) on admission; Preprocedural renal insufficiency (history

of chronic kidney disease or eGFR ≤60 mL/min/1.73 m2 was calculated using

the level-modified Modification of Diet in Renal Disease formula [MDRD]);

cardiogenic shock or NYHA IV; acute kidney injury defined as an absolute

serum creatinine increase of 0.5 mg/dL from baseline obtained in the previous

24 hours; lactation; pregnancy; malignant tumor or life expectancy <1 year;

allergy to contrast; periprocedural administration of nonsteroidal

anti-inflammatory drugs; aminoglycosides, cyclosporine, or cisplatin in the

previous 48 hours or during the study period; planned renal catheterization; or




22

heart valve surgery.

Eligible patients are randomized using computergenerated random numbers

and a 1:1 ratio to receive either general hydration (control group) or aggressive

hydration with isotonic saline. Randomization is stratified by age (<60 years,

60-75 years,>75 years), sex (male or female), and myocardial infarction

location (anterior or not anterior). After screening for eligibility based on the

criteria, the patients who have agreed to undergo the procedure in the

emergency department or catheter laboratory are asked to provide consent and

are randomized before the primary PCI. Then, the fluid-loading dose is

administered before the procedure and continued for 30 minutes during the

procedure, if necessary; we do not wait 30 minutes to start the procedure to

avoid a delay in revascularization of the target vessel. General hydration for the

control group consists of a periprocedural continuous IV infusion of ≤500 mL

isotonic saline within 6 hours. Aggressive hydration consists of a 250-mL

loading dose of isotonic saline (125 mL for patients with congestive heart failure,

Killip II/III or NYHA III) over a 30-minutes period prior to the procedure48,

followed by IV hydration at a rate of 1 mL/kg/h (0.5 mL/kg/h for patients with

congestive heart failure, Killip II/III or NYHA III) until the LVEDP measurement.

Therefore, in the treatment group, LVEDP is measured after the primary PCI to

guide the hydration. Hydration on a sliding scale is used 4 hours after the

procedure: 5mL/kg d h for LVEDP <13 mm Hg, 3 mL/kg d h for LVEDP 13-18

mm Hg, 1.5mL/kg d h for LVEDP >18mmHg, and 0.5mL/kg d h for LVEDP >20

mm Hg. Then, hydration is continued at the normal rate until 24 hours after the

procedure45. When the LVEDP value does not agree with the heart function as

evaluated by the clinical doctors, the rate and duration of hydration are based


cardiologists.

Blood serum creatinine, cystatin C, C-reactive protein, and serum electrolytes




23

are evaluated at baseline; before the coronary angiography; at 24 ± 4, 48 ± 4,

and 72 ± 4 hours after the procedure; and at hospital discharge. The time

between symptom onset and reperfusion, including the time at the beginning

and end of the procedure; urine output; and oral hydration volume (waterl in

milliliters) during the 24 hours after the procedure are recorded. Periprocedural

intervention (ie, fluid mixed with medications and normal saline or glucose

injection, furosemide, or statins), PCI technique, contrast agent (nonionic,

low-osmolality, or isotonic), and contrast dose are at the discretion of the

cardiologists in charge of the patient routine and procedure management,

following current practice guidelines56. Patients will be excluded if they receive

contrast again within 72 hours after the procedure57 and undergo CAG but no

PCI or dead during the procedure. All of this information is carefully collected by

the research staff.

The primary end point is CI-AKI, defined as a >25% or 0.5 mg/dL increase in

serum creatinine from baseline during the first 48 to 72 hours after the

procedure58. Secondary end points are as follows: (1) CI-AKI48h, defined as

a >50% or 0.3-mg/dL absolute increase in serum creatinine from baseline

during the first 48 hours after the procedure; (2) CI-AKIcys-c, defined as a >10%

or 0.3-mg/dL absolute increase in serum cystatin C during the first 24 hours

after the procedure59; (3) CI-PKI, defined as residual impairment of renal

function indicated by a >25% reduction in creatinine clearance at 3 months in

comparison with baseline59; (4)major adverse cardiovascular events, including

all-cause mortality, target vascular

revascularization, and nonfatal myocardial infarction; (5) major post-procedure

in-hospital adverse clinical events, including acute pulmonary edema,

cardiogenic shock, stroke, clinically significant arrhythmias, and bleeding within

the first year; (6) AHF and (7) total hospitalization costs and length of stay. A

committee of clinicians, chaired by Zhi-ming Du, MD, who are blinded to the

treatment allocation, will adjudicate all components of the primary outcome




24

(CI-AKI), stent thrombosis, transient ischemic attack, stroke, target vessel

revascularization, and major bleeding.

FIGURE A4. OVERVIEW OF STUDY DESIGN

A committee of clinicians and a biostatistician, chaired by Chun Wang, MD, and

Chun-quan Ou, MS, who are blinded to the treatment allocation, will periodically

review and evaluate the accumulated study data for participant safety, study

conduct and progress, and, when appropriate, efficacy and will make

recommendations to the principal investigators concerning the continuation,

modification of enrollment, or termination of the trial. Details of any protocol

violations (eg, descriptions, reasons, and resolution) will be reported by the

investigators and clinical research associates to the primary investigators, the




25

Central Event Adjudication committee, and Data and Safety Monitoring Board,

if necessary. In addition, training will be provided to the researchers, and the

study procedure will be supervised, with particular attention to the reasons for

bias and data verification to avoid recurrence of protocol violations.

Finally, intention-to-treat analysis will be used for the patients with protocol

violations instead of the per-protocol analysis. The sample size calculation was

based on our previous findings60, and a CI-AKI incidence of 23% was estimated

for the control group, and a CI-AKI incidence of 11.5% was assumed for the

treatment group (50% relative reduction). Using nQuery + nTerim 3.0

(Statistical Solutions Ltd, Farmer's Cross, Cork, Ireland) with a 2-sided χ2 test,

a significance level of 0.05, a power of 90%, and a dropout rate <20%, 280

patients are required in each group, for a total sample size of 560. The primary

outcome, that is, rate of CI-AKI, will be compared between 2 groups using χ2

tests, and the 95% CI of the rate difference will be calculated using the method

described by Altman et al (reported in Newcombe61) and recommended by the

Food and Drug Administration and Clinical and Laboratory Standards Institute.

Multivariable logistic regression models will be developed to adjust for clinical

characteristics (eg, age, sex, creatinine clearance, and left ventricular ejection

fraction [LVEF]), and the Mehran risk score will be calculated62. Odds ratios will

be reported with their corresponding 95% CIs. Comparisons between normally

distributed continuous variables, expressed as mean ± SD, will be performed

using 2-sample t tests; nonnormally distributed continuous variables, presented

as median and interquartile range, will be analyzed using Wilcoxon rank sum

tests. Pearson χ2 or Fisher exact tests will be used, as appropriate, for

categorical data, which will be expressed as percentages. The primary and

secondary end points will be analyzed based on the intention-to-treat principle.

All tests will be 2 tailed, and a P value <.05 will be considered statistically

significant. All data analyses will be performed using SAS version 9.4 (SAS

Institute, Cary, NC).




26

Table A2 Timetable of visits and procedures

VisitsScreeningvisit1

Operative day

1 daysafteroperation



4-7daysafteroperation

30 ±7daysafteroperation

90 ±14daysafteroperation

180±14daysafteroperation

360±14 daysafteroperation

Informedconsent √

Inclusion/Exclusion criteria √

Baseline √

Routine bloodtest √

Liverfunction √

Renalfunction √ √ √ √ √ √3 √

Pregnancytest2 √

Characteristicsof coronaryintervention

√

Entry audit √

Randomization √

Record drugs √ √ √ √ √ √

Record AEs √ √ √ √ √3 √ √ √ √Study directorreviewsmedicalrecords

√

CRA reviewsmedicalrecords

√

Medical recordentry database √

EDC √

Medical recordreturn andfiling

√

1 Screening and random observation (1 day before direct coronary intervention)

2 Items to be tested for women of childbearing age

3 The renal function included cystatin C from the 4th to 7th day after PCI (daily evaluation: for

patients whose serum creatinine value (SCR) in 48-72 hours after PCI was higher than or equal to

0.3mg/dl than the baseline absolute value)




27

METHOD

5. STUDY POPULATION AND PATIENT RECRUITMENT

5.1 Study population

The study population will consist of 560 patients, aged ≥18 years with STEMI

who provided written informed consent for this study. Since a major risk factor

for subsequent adverse clinical events following STEMI is the delay of PCI, we

will only enroll patients underwent primary PCI.41, 63

Inclusion Criteria:

All consecutive patients with STEMI, age at least 18 years, who were

candidates for primary PCI were considered for enrollment.

STEMI was defined as the onset of chest pain or chest distress lasting

for at least 30 minutes with electrocardiography(ECG) ST-segment

elevation of at least 0.2 mV in two or more contiguous leads and/or the

development of new left bundle-branch block associated with elevation

in the levels of creatinine kinase or its MB isozyme to at least two times

that of normal.46

STEMI patients who were candidates for primary PCI should meet at

least one of the following conditions: 1. Ischemic symptoms <12 h; 2.

Ischemic symptoms <12 h and contraindications to fibrinolytic therapy

irrespective of time delay from FMC; 3. Cardiogenic shock or acute

severe HF irrespective of time delay from MI onset.41

Exclusion Criteria:

Contrast medium administration within the previous 14 days or follow 72

hours,

End-stage renal failure or renal transplantation, and refuse PCI or dead

during the procedure,

Heart failure of cardiac shock or New York Heart Association class IV, (we

are excluding these patients because IV fluid administration may be




28

contraindicated):

Recent acute kidney injury defined as an absolute increase of 0.5 mg/dl in

serum creatinine over baseline in the past 24h.

The presence of lactation, pregnancy,

Malignant tumor or life expectancy less than 1 year,

Allergy to contrast medium, peri-procedural receipt of metformin or

non-steroidal anti-inflammatory drugs in the past 48h and during the study

period,


5.2 Screening and patient recruitment

All the potentially eligible patients will be screened out by the chief resident of

the department of cardiology. Then, the chief resident will dial the “ATTEMPT

phone” to report the initial situation of the patient to the ATTEMPT research

personnel on-duty, who must arrive within 15 minutes (for those who are unable

to arrive in time, he/she must contact other members to follow up). Researchers

will contact potentially eligible subjects to describe the study and complete the

screening process. Based on our past experience, almost all the patients

intended to undergo primary PCI will have a SCr measured as part of routine

care before angiography. However due to the urgency, we are unable to get the

result of pre-procedure renal function before angiography. In such situation, for

the majority of patients who do not have a SCr measured before, we can only

exclude them after PCI if they were proven to suffer end-stage renal failure.

Patients with no peri-operative creatinine were found to be excluded after

randomization. We will also require that potentially eligible female subjects who

are able to be pregnant (not considered post-menopausal [had a menstrual

period within previous 12 months], not had tubal ligation, a hysterectomy or

bilateral oophorectomy) and are sexually active, have a negative pregnancy

test before being enrolled in the research. No adult patient (age ≥18 years) will

be excluded from participating based on age, gender, race, ethnicity, or sexual




29

preference.

6. STUDY PROCEDURES

6.1 Assessment of pre-procedural laboratory examinations

Eligible patients will have their SCr measured before angiography, which will

serve as their baseline SCr. At present, the methods for detecting SCr mainly

include basic picric acid method (Jaffe assay) and enzymatic assay. The

enzymatic assay avoids the poor specificity of the Jaffe assay and has a strong

anti-interference ability. Therefore, it is widely accepted as the most reliable

assay in the clinical laboratories. All laboratories in our study are consistently

adopting this methodology to reliably and accurately assess the development of

CI-AKI. The timing of the pre-procedure study SCr (baseline SCr) testing used

to assess the outcomes is also important as the administration of IV fluids may

lead to hemodilution and artifactual lowering of SCr. In addition, variation in

intravascular volume status affects renal function, particularly in patients with

underlying CKD. Therefore, we will standardize the timing of assessment of the

baseline SCr for endpoint ascertainment. This blood sample will be drew at the

same time of patient enrollment and immediately prior to the beginning of study

IV fluids to avoid any potential influence of study interventions on the baseline

SCr level. Although STEMI patients will have some basic laboratory

examinations as soon as they reach the emergency department or a few

minutes after the chest pain onset if it happens in hospital, some examinations

are not routine for such patients, such as cystatin C, hypersensitive C-reactive

protein and so on. For these variables, to make sure that they are not affected

by the interventions, the research personnel needs to check whether the

relevant blood tests of the patient had been done before the intervention

(cystatin C, hypersensitive C-reactive protein, cardiac enzyme, emergency

biochemistry, blood routine). If there is any omission of these tests, the

research personnel needs to make a prescription and asks the nurse completes

the blood draw before the intervention begins.




30

6.2 Randomization procedures

All patients meeting eligibility criteria and providing informed consent will be

randomized to each of the two study groups [general hydration (control group)

versus aggressive hydration with isotonic saline (treatment group)]. Qualified

patients are randomized using computer-generated random numbers at a 1:1

ratio. Randomization will be accomplished using a block random method with 8

units in each group. Some offset or variability will be inserted to prevent

anticipation of the next treatment. Randomization will be stratified by sex, age

and anterior myocardial infarction. Study coordinators at each site will be

responsible for obtaining a randomized treatment assignment for each eligible

patient. A web-based randomization program will be provided to study sites for

this purpose. This web-based program will be tested at each site prior to the

start of the trial and will be reviewed, as per Center guidelines, by the Key

Laboratory of Coronary Heart Disease. At the time of subject enrollment,

research personnel will enter the Subject ID number, sex, age and anterior

myocardial infarction into the randomization program. The program will check

that all eligibility criteria are met. If met, the program will select the first unused

entry from the pre-specified list of random treatment assignments for the

particular site. The lists are stored on a secure server at Southern Medical

University, Department of Biostatistics, Clinical Research Management System.

If the electronic system fails, the random envelope method will be adopted. The

random envelope method is to store a random grouping scheme of a numbered

research object in a sealed and opaque envelope, which is performed in two

steps:1) verifying whether the patient meets the criteria for inclusion and

exclusion, signing informed consent, and giving the case number; 2)

Disassemble the random envelopes of the corresponding numbers in order,

determine the grouping of a patient according to the distribution plan in the

envelope, and carry out corresponding interventions. Since this is an open-label

study, we do not have the procedure of blinding.




31


In this study, patients will receive either general hydration (control group) or

aggressive hydration with isotonic saline guided by LVEDP (intervention group)

Control group:

The general hydration for the control group is a peri-procedural continuous

intravenous infusion of ≤500 mL isotonic saline within 6h.

Treatment group:

The aggressive hydration consists of a 250mL loading dose of isotonic saline

(125 mL for patients with congestive heart failure, Killip II/III) over 30 min prior

to procedure,48 followed by IV hydration at the rate of 1 mL/kg/h (0.5 mL/kg/h for

patients with congestive heart failure, Killip II/III) until the LVEDP measurement,

which were performed after the coronary revascularization. Hydration on a

sliding-scale is used 4 h after the procedure: 5 mL/kg·h for LVEDP <13 mmHg,

3 mL/kg·h for LVEDP 13–18 mmHg, 1.5 mL/kg·h for LVEDP >18 mmHg, and

0.5 mL/kg·h for LVEDP >20 mmHg. Then, hydration is continued at the normal

rate until the 24 h after the procedure reaches.45 When the LVEDP value does

not agree with the heart function as evaluated by the clinical doctors, the rate

and duration of hydration is based on the clinical evaluation for heart function

and at the discretion of the cardiologists.

In the treatment group, we will use LVEDP to guide hydration within 4 hours

after the procedure. At the end of the procedure, the research personnel will

remind the operators to make an LVEDP measurement before the catheter is

withdrawn. Although LVEDP is a more objective indicator of left ventricular

volume, it cannot be used to diagnose whether a patient has heart failure or

not.64 Therefore, when the LVEDP value does not agree with the heart function

as evaluated by the clinical doctors, the rate and duration of hydration is based


cardiologists. In addition, some sub-centers may not be able to measure

LVEDP for several reasons. In this case, we allow the clinicians to estimate




32

LVEDP based on the patient's situation and to determine the hydration strategy

within 4 hours after the procedure. We chose this flexible approach rather than

a strict protocol for IV fluid administration for several reasons. First, though

there is a general belief that “more fluid” may be dangerous for HF patients, the

optimal rate, duration, and volume of IV fluid to prevent CI-AKI and other

adverse outcomes for HF patients have not been conclusively determined.

Therefore, the rate and duration of hydration is based on the clinical evaluation

for heart function and at the discretion of the cardiologists. Second, since

LVEDP have not been determined as a golden standard for making hydration

strategy, requiring that IV fluids be administered strictly based on LVEDP could

significantly limit other medical workers` willingness to help. In clinical practice,

the volume and duration of pre and post-procedure IV fluid often vary based on

the clinical setting and individual patient circumstances. We do not believe that

using this flexible approach will compromise our ability to determine differences

in study outcomes between two groups.

6.4 Peri-procedural management issues

Drug prescription and blood collection time points are strictly in accordance with

the protocol, clinical guidelines and clinical reality. Though all contrast media

may cause potential clinical complications, the osmolality of the contrast agent

is proven to potentially impact the risk for CI-AKI. Previous conclusively

demonstrate that high osmolality (>1200 mOsm/kg) agents pose a greater risk

for CI-AKI than low osmolality (500-860 mOsm/kg) agents in high-risk

patients.65, 66 However, data on the comparative incidence of CI-AKI with

low-osmolal contrast and iso-osmolal are on dept and inconclusive. To provide

care that is consistent with prior guidelines issued by the American College of

Cardiology/American Heart Association for the use of iodinated contrast, all

patients in this trial will receive either iso-osmolal contrast media (i.e., iodixanol)

or non-ionic, low-osmolal contrast media.67 Usage of the specific contrast agent

and the volume of contrast media administered will be at the discretion of the




33

operator as there is no current guideline or consensus on the least nephrotoxic

contrast agent.

Accompanying medications and invasive treatment device, for example IABP,

are also source of potentially nephrotoxicity.68 Aminoglycosides or any other

drugs with significant nephrotoxicity are strictly prohibited. Patients are

recommended to have statin therapy preoperatively. The implication of

perioperative platelet glycoprotein IIb/IIIa receptor antagonists--Ikat (Iroko

Cardio Australia Pty Ltd), the use of loop diuretics and other drugs that are not

prohibited in this study will be at the discretion of the treating provider according

to the condition and treatment routine. We will also defer decisions on the

discontinuation of angiotensin converting enzyme inhibitors or angiotensin

receptor blockers to the treating provider(s) because there are no conclusive

data on the optimal approach to the management of these medications in

patients with STEMI undergoing angiography.

6.5 Post-procedure management issues

Drug prescription and blood collection time points are strictly in accordance with

the protocol, clinical guidelines and clinical reality. Following angiography,

research personnel will follow the patient to cardiac care unit (CCU) and reset

the hydration speed to routine level 4 hours after the procedure. Research

personnel are also required to communicate with the patient's responsible

nurse and ask he/she to record the patient's postoperative liquid intake

(including oral and intravenous) as well as the liquid output (mainly urine

volume) in detail (time and volume). Following angiography and prior to

discharge from the hospital, research personnel will also arrange the

participant`s blood specimen collection at 24, 48 and 72 ± 4 hours following

their angiography.




34

6.6 Study Outcomes

6.6.1Primary study outcome

The primary endpoint is CI-AKI, defined as a ≥ 25% or 0.5 mg/dL absolute

increase in serum creatinine from baseline during the first 48-72 h

post-procedure.

6.6.2 Secondary study outcomes

The secondary outcomes consist of:

1) CI-AKI, defined as a >50% or 0.3-mg/dL absolute increase in serum

creatinine from baseline during the first 48 h post-procedure;

2) CI-AKI, defined as a 0.3-mg/dL absolute increase in serum creatinine from

baseline during the first 48 h post-procedure and a 10% increase in cystatin-C

during the first 24h post-procedure; 58

3) Persistent renal damage, defined as residual impairment of renal function

indicated by a >25% reduction in creatinine clearance at 3 months in

comparison with baseline;59

4) Major adverse cardiovascular events, including all-cause mortality, target

vascular revascularization, and non-fatal myocardial infarction;

Table A3 - Definitions of components of MACEs

Term Definition

All-cause mortality All cause mortality, defined as any death recorded between

the date of interview and the end of data.

Target vascular

revascularization (TVR)

TVR is defined as any revascularization procedure (PCI or

CABG) involving the vessel treated during the index PCI

procedure for STEMI.

Non-fatal myocardial

infarction

Recurrent MI will be subdivided into MI within the first 24 h of

randomization, between 24 h and 7 d after randomization,

and >7 d after randomization.

MI occurring

between 24 h

Recurrent ischemic symptoms >20 min with

new ST elevation >0.1 mV in ≥2 contiguous




35

and 7 d of

randomization

leads not due to changes from evolution of

the index MI. Ischemic symptoms >20 min

and either 1) elevation or re-elevation of

cardiac biomarkers(CK-MB or troponin)

greater than twice the upper limit of normal

(ULN) and if already elevated, then further

elevations >50% above a previous value

that was decreasing or 2) new ST-segment

elevation or new significant Q waves in ≥2

contiguous leads, which are separate from

the baseline MI.

MI occurring

after 7 d of

randomization

Typical rise and fall of biochemical markers

of myocardial necrosis to greater than twice

the ULN or if markers were already

elevated, further elevation of a marker

to >50% of a previous value that was

decreasing and >2× ULN, with ≥ 1 of the

following: 1) ischemic symptoms, 2)

development of new pathologic Q waves, or

3) ECG changes of new ischemia or (iv)

pathologic evidence of MI.

MI occurring

within 24 h

after nonindex

PCI that is

performed >24

h after

randomization

Cardiac biomarker (creatine kinase-MB

[CK-MB] or troponin) >3× the ULN or

increased by 50% from the preprocedural

valley level and ≥3 times ULN in patients

with already elevated enzymes or new

ST-segment elevation or development of

significant Q waves in ≥2 contiguous leads,

which are discrete from baseline MI.

Within 24 h CK-MB (or total CK, if CK-MB is




36

post-CABG unavailable) ≥5× ULN and increased 50%

from the preprocedural valley level and N

5× ULN in patients with already elevated

enzymes and development new pathologic

Q waves in ≥2 contiguous leads or CK-MB

value ≥10 times ULN without new

pathologic Q waves.

6) Major post-procedure in-hospital adverse clinical events, including acute


and bleeding.

Table A4 - Definitions of components of major post-procedure in-hospital

adverse clinical events

Term Definition

Acute pulmonary edema Acute pulmonary edema, defined as arterial partial pressure

of oxygen (PaO2)/inspired oxygen fraction (FiO2) ratio <300

for arterial blood gas, and pulmonary edema or bilateral

infiltrates on chest radiograph as read by radiologists, both

within 24 h.

Cardiogenic shock Cardiogenic shock is defined as systolic blood pressure <90

mmHg not responsive to fluid resuscitation and/or heart rate

correction for ≥1 h or need for vas opressor/inotropic therapy

to maintain systolic blood pressure >90 mm Hg for ≥1 h and

believed to be secondary to cardiac dysfunction and

associated with ≥1 of the following: 1) signs of pulmonary

edema, 2) signs of hypoperfusion (cool clammy skin, oliguria,

or altered sensiorium), or 3) cardiac index <2.2 L/min.

In patients presenting with cardiogenic shock at the time of

randomization, they must have a ≥24 h period with complete




37

resolution of shock and a new cardiogenic shock event (ie,

due to new stent thrombosis) for this event to be eligible as a

primary outcome event.

Stroke Any stroke is defined as the presence of a new focal

neurologic deficit thought to be vascular in origin, with signs

or symptoms lasting >24 h. It is strongly recommended (but

not required) that an imaging procedure such as a computed

tomography or magnetic resonance imaging be performed.

Clinically significant

arrhythmias

Clinically significant arrhythmias (SA) were defined as 1 or

more of the following: more than 100 VPC or APC (including

VPC2/3 or APC2/3) per 24 h (equalling a rate of 4.17/h) or any

presence of RT, VT, or AT.

Bleeding Major bleeding or vascular events (bleeding requiring

transfusion of hemoglobin drop ≥3 g/dL or need for vascular

surgery).

6.7 Data collection

6.7.1 Assessment of baseline demographic and clinical characteristics

Following patient enrollment, research personnel will make a comprehensive

review of the electronic medical record and/or interview the subject and his/her

families to abstract the following data elements:

Demographic characteristics including date of birth, gender and ethnicity

Admission information including

Time of symptoms onset

Time of first medical contact (FMC)

Time of admission

Time of entering catheterization laboratory

Did thrombolytic therapy be used in this case? (If it did, then the time of

thrombolytic therapy should be recorded)

Did cardiac arrest happen in this case? (If it did, then the time should be




38

recorded)

Did heart failure happen in this case?

Heart function (Killip class)

Use of vasoactive drugs

Use of IABP

Administration of any IV fluid and prior to the initiation of study

Pre-procedure laboratory parameters obtained as part of routine clinical care

including date of test (most proximate to and within the 7 days preceding the

angiogram:

ɸ CK, CKMB, troponin T, troponin I, hsCRP, NT-proBNP or BNP, WBC, Hb,

PLT, Hct, Neut%, SCr, Cystatin C, serum glucose, sodium, potassium, blood

urea nitrogen and pregnancy examination (if available)

medical history:

ɸ Hypertension, diabetes, hyperlipidemia, coronary artery disease (CAD),

myocardial infarction (if available, the happening time should be record),

congestive heart failure, peripheral vascular disease, chronic kidney disease,

stroke and chronic pulmonary disease. Standard procedures and definitions will

be developed to systematically evaluate patients records for each of these

conditions.

Family history of CAD

Smoking history

Physical examination, including:

1) Height in centimeter and weight in kilograms. The recommended

method of obtaining the patient`s height and weight will be for research

personnel to measure them. In the event this is not possible, the most recent

measurement (usually at the time of admission) found in the patients medical

record will be recorded. Finally, if there is no measurement in the medical

record, this information will be collected via subject report.

2) Blood pressure and heart rate at the time of admission.

3) Physical examination record on chest (including heart and lung),




39

abdomen, nervous system, limbs and spinal.

Pre-procedure ECG and cardiac ultrasound (if available)

Names and doses of all pre-procedure medications, including those

prescribed by physicians outside the research centers, regularly taken by

the subject within the 14 days preceding the angiogram.

6.7.2 Collection of oral hydration and urine volume within 24h post-procedure

Research personnel will communicate with and hand over a specially designed

chart to the patient's responsible nurse and ask he/she to record the patient's

postoperative liquid intake (oral) as well as the liquid output (mainly urine

volume) in detail (time and volume) within 24h post-procedure. We will collect

the chart later.

6.7.3 Evaluation of procedure-related data

Subsequent to the angiogram, research personnel will review the electronic

medical record and angiogram procedure report to determine:

Primary PCI or not;

The beginning and ending time of procedure;

The time of balloon dilation

Type and volume of contrast administered (Iodixanol, Iopromide, Iopamidol

or iohexol)

The use of GPIIb/IIIa Inhibitors

The implication of thrombus aspiration

The implication of IABP

Post-procedure LVEDP

Coronary artery lesions and performance of percutaneous intervention

Complications during the procedure including:

Hypotension or cardiac shock necessitating the administration of

additional non-study IV fluid including the type of non-study IV fluid

administered




40

Hypotension or cardiac shock necessitating the insertion of an

intra-aortic balloon pump and/or the administration of vasopressor

therapy

Arrhythmia

Death


Assessment of procedure-related complications will ensure that we capture all

events that could impact on the development of our primary and secondary

outcomes. To clarify and confirm all of these procedure-related data, research

personnel will also organized a brief interview with the angiography operators.

6.7.4 Evaluation of study IV fluid administration

Research personnel will track and record from the electronic medical record the

speed, total volume and total duration of study IV fluid administered

pre-procedure, intra-procedure, and post-procedure.

6.7.5 Evaluation of post-procedure course (within 24 ± 4 hours post procedure)


data elements:

Vital signs within 6h and at 24 hours post-procedure;

Renal function assessment and blood electrolytes and the date of test (If

the serum creatinine (SCr) increased by more than 0.3 mg/dL within 72

hours post-procedure, the renal function of the subjects was monitored until

1 week after operation);




iodinated contrast;




41



data elements:









iodinated contrast;

Cardiac and Carotid Ultrasound and the date of test (if available);




data elements:









iodinated contrast;


Since this creatinine determination is essential to the determined of primary

end-point, it is very important that the blood collection be done within the 72




42

hours after angiography. We recognize that unforeseen circumstances may

hinder collection within this window. Under such circumstances the blood

should be collected as soon as possible and most proximate to 72 hours and a

protocol deviation should be noted.

6.7.8 Evaluation of post-procedure hospitalization course (4 – 7 days post

procedure and the day of discharge)

Research personnel will review the electronic record on a daily basis for

patients who remain in the hospital following their angiography procedure and

collect the following data elements:

Vital signs have collected for once among 4-7 days post-procedure;







Date of discharge and total hospitalization expenses

Generally speaking, subjects will only have one examination during this period.

For those who have vital signs or renal assessment for many times, we will

record the highest level of each day.

6.9.9 Day 30 post procedure assessment (30 days post angiography, allowable

range 23-37 days post angiography)

Thirty days following the angiography, clinical doctors will review the electronic

medical record (if available) and perform a telephone interview with the patient

to inquire about any adverse events they experienced related to study

participation. The electronic medical record review and telephone interview will

specifically focus on assessing the renal function and the development of any of

the following adverse outcome within the research sites system.




43



All-cause mortality



Acute heart failure

Cardiogenic shock

Stroke


Bleeding

Heart broken

The 30-day telephone interview with the patient will be a supplement to the

electronic medical record review. This telephone interview will verify data

abstracted from the electronic medical record and enable research personnel to

inquire about death, re-hospitalizations at non-research sites and other MACEs

that would not have been captured in the electronic medical record. For any

patients who were hospitalized outside the research centers, the research

personnel will obtain the hospitalization information from the patient or his/her

families.

To ensure the follow-up quality, before the first time of telephone interviews,

research personnel assistants will help researchers to arrange the follow-up

method and time.




subjects, research personnel assistants will record the relevant events in details.

And then, they will submit the record to the research personnel who will make

the judgment later.

Quality control




44

After the start of follow-up, the quality control team needs to check the follow-up

form and EDC regularly (not less than two times a week). Research personnel

assistants who fail to reach the standard will repeat the training and


suitable personnel.





with an allowable range of 30±7 days. We recognize that sometimes it may be

difficult to contact with a patient within this window. However, it is important to

collect the required data, which should be done even if done after the






allowable range 90 ± 14 days post angiography)

Ninety days following the angiography, research personnel assistants will

review the electronic medical record (if available) and perform a telephone

interview with the patient to inquire about any adverse events they experienced

related to study participation. The electronic medical record review and

telephone interview will specifically focus on assessing the renal function and

the development of any of the following adverse outcome within the research

sites system.



All-cause mortality





45


Acute heart failure

Cardiogenic shock

Stroke


Bleeding

Heart broken














the judgment later.

Quality control





suitable personnel.







46


with an allowable range of 90 ± 14 days. We recognize that sometimes it may








allowable range 180±14 days post angiography)

180 days following the angiography, research personnel assistants will review

the electronic medical record (if available) and perform a telephone interview

with the patient to inquire about any adverse events they experienced related to

study participation. The electronic medical record review and telephone

interview will specifically focus on assessing the renal function and the

development of any of the following adverse outcome within the research sites

system.



All-cause mortality



Acute heart failure

Cardiogenic shock

Stroke


Bleeding

Heart broken





47













the judgment later.

Quality control





suitable personnel.





with an allowable range of 180±14 days. We recognize that sometimes it may










48

6.7.12 1 year post procedure assessment (1 year post angiography, allowable

range 1 year ±14 days post angiography)

1 year following the angiography, research personnel assistants will review the

electronic medical record (if available) and perform a telephone interview with

the patient to inquire about any adverse events they experienced related to

study participation. The electronic medical record review will specifically focus

on assessing the renal function and the development of any of the following

adverse outcome within the research sites system.



All-cause mortality



Acute heart failure

Cardiogenic shock

Stroke


Bleeding

Heart broken

The 1-year telephone interview with the patient will be a complement to the













49




the judgment later.

Quality control





suitable personnel.




We recommend that this contact should be made at 1 year after angiography,

with an allowable range of 1 year ±14 days. We recognize that sometimes it

may be difficult to contact with a patient within this window. However, it is

important to collect the required data, which should be done even if done after

the recommended time frame has elapsed. It will not be considered a protocol




7. POTENTIAL RISKS AND ALTERNATIVE CONSIDERATIONS

7.1 Study Population

Most past studies of CI-AKI have focused on all patients undergoing coronary

angiography. We propose enrolling STEMI patients only. Patients with STEMI

are likely to present with hypotension or even shock, a large volume of contrast

agent, and inability to start a kidney prophylactic therapy, all of which are

associated with an increased risk of CI-AKI. Patients with STEMI also




50

commonly have other risk factors for CI-AKI such as reduced cardiac output or

hypotension due to myocardial infarction or depletion of intravascular volume

caused by vomiting, diaphoresis, or decreased oral intake. Despite a











urgently needed. While limiting the enrollment to STEMI patients will restrict the

number of patients available for recruitment and the generalizability of the study

findings, it will increase the homogeneity, find out the optimal hydration

administration regimen in these high-risk patients69 and fill in gaps in guidelines.


7.2.1 Fluid administration

There is no consensus among experts on the optimal rate and duration of IV

fluid administration for the prevention of CI-AKI or single protocol for the

administration of IV fluid that has been shown to be the most effective.

Nowadays, in CHINA, most PCI center do not pay attention to CI-AKI, and

prescribe hydration with no regimen but a bag of 500ml saline which is exactly

used to maintain the venous channel. Generally speaking, it is well-accepted

that hydration is effective in preventing CI-AKI but there is no consensus on

how to make hydration.70 Therefore, we conduct a comparison between

aggressive hydration and the reality to find out a more suitable regimen in these

high-risk patients.




51

7.2.2 Complications of fluid administration

We anticipate that some patients will develop volume overload/pulmonary

edema during angiography. In such instances, providers performing

angiography may discontinue post-procedure IV fluids resulting in patients

failing to receive the planned hydration regimen following the angiogram. It is

likely that this event will occur in a small proportion of patients and be equally

distributed across treatment arms. While the volume of study IV fluid

administered pre, during and post-procedure will be carefully recorded for all

patients, given the importance of patient safety, we believe it would be

inappropriate to require the administration of post-procedure study IV fluid in

such instances. Since all analyses will be based on the intent-to-treat principle,

these patients will not be excluded from the study analyses.

7.3 Ascertainment of baseline kidney function

In order to ascertain a change in kidney function, it is critical to standardize the

definition of baseline kidney function. SCr often fluctuates over time because of

activities, variations in volume status, protein and salt intake, and drift in the

calibration of laboratory instruments. The timing of the SCr testing used to

screen patients is less critical than the value used to define the baseline SCr for

endpoint ascertainment. For practical purposes, we propose to screen patients

based on a SCr obtained as part of routine clinical care performed by the doctor

as soon as the subject enter the emergency department or cardiac

catheterization laboratory. The SCr was sent for examination after PCI. This will

also be the same pre-angiography study SCr (baseline SCr) that will be used to

assess the development of CI-AKI (a primary endpoint).

7.4 Assessment of primary and secondary outcomes

7.4.1 Assessment of CI-AKI

Most patients who develop CI-AKI will have their SCr increased within 48 to 72

hours following contrast exposure. However, previous studies demonstrate that




52

some patients who develop CI-AKI may not be identified by a single SCr

assessment at 48 hours.43 The optimal timing of assessment of SCr following

the angiogram to determine the development of CI-AKI in our trial was carefully

discussed by the committee members. Finally, though complicated, it was

agreed that multiple SCr assessments (e.g., at 24, 48 and 72 hours) would

ensure the identification of all patients who developed CI-AKI. This decision is

based on several reasons. First, some patients who develop CI-AKI may

manifest an increase in SCr at 24-48 hours following angiography. Second,

multiple SCr assessments may describe the trend of SCr after contrast

exposure. Finally, the planning committee feel that measuring SCr at multiple

time points may be of help in finding the most suitable definition of CI-AKI.

7.4.2 Assessment of cardiovascular outcomes and clinical events

We acknowledge the potential limitations of using administrative data/medical

records for the assessment of cardiovascular outcomes and clinical events,

including all-cause mortality, target vascular revascularization (TVR), non-fatal

MI, acute pulmonary edema, cardiogenic shock, stroke, clinically significant

arrhythmias and bleeding. Therefore, we will also assess these outcomes by

reviewing the hospital discharge summary for documentation of any of the

events that comprise the secondary outcomes. We have considered the

possibility of adjudicating the secondary outcomes using more comprehensive

medical record review. However, we believe that while this would be a more

robust approach, the additional time, effort and cost required to adjudicate

these secondary outcomes using a comprehensive review of the medical

record was not justified.

7.5 Secular trends in the prevention and incidence of CI-AKI

We acknowledge that there will be novel viewpoints gained and changes in

clinical practices related to the prevention of CI-AKI and serious adverse

outcomes following angiography during the conduct of the current trial. A




53

comparison between the incidence of CI-AKI reported in studies conducted in

the 1980s and the incidence described in recent studies reveals a trend that

fewer patients are suffering this iatrogenic complication. However, much of this

trend is likely related to the transition from the more nephrotoxic high-osmolal

contrast media to low and iso-osmolal contrast media. Over the past decade,

there is no evidence of a continued decline in the incidence of CI-AKI or

attenuation in the relationship between CI-AKI and serious, adverse outcomes.

This can be illustrated by a recent study of over 1,100 hospitalized subjects who

underwent contrast-enhanced procedures that demonstrated that CI-AKI

developed in over 40% of patients and was associated with a 2-fold increase in

hospital duration and a 10-fold increase in mortality.18

8. FEASIBILITY OF RECRUITMENT

While our inclusion and exclusion criteria are strict, there are multiple important

factors that support the feasibility of recruiting this large number of patients.

First, all the 15 research centers involved in this project are the regional central

hospitals. The Guangdong Cardiovascular Institute/Guangdong Provincial

People's Hospital, which is in charge of this study, is the most influential

research and prevention centers of cardiovascular diseases in South China. It

is one of the leading coronary intervention therapy centers in China with about

971 primary PCI finished last year. It also participates in the compilation of

“Expert Consensus of STEMI Treatment in China”. Second, patients

undergoing primary coronary angiography are easily identifiable. All of these

procedures are started under the coordination of the chief resident of the

department of cardiology, which greatly facilitates identification and screening

of potential study subjects. Third, unlike trials that recruit from a diverse array of

patient settings (e.g., primary care offices, hospital wards, specialty clinics), our

trial mostly recruit patients from only one hospital venues: emergency

department. This greatly simplifies the process of identifying and locating




54

potentials participants. Fourth, we have set up a special project management

team, which is directly in charge of the project.

The full-time academic secretary coordinates the management of assets, data

and research results in the process of project implementation. Finally, patient

burden in this study is quite limited since there is no need to return to the

hospital for study visits. Follow up data collection will be performed using

telephone calls. Therefore, patients are unlikely to view participation as unduly

burdensome. All in all, we are highly confident in our capacity to successfully

recruit the number of patients needed to meet our enrollment targets.

9. ANTICIPATED BARRIERS TO RECRUITMENT ANDSTRATEGIES TO ADDRESS POTENTIAL UNDERENROLLMENT

9.1 Development of comprehensive organizational structure

Despite the feasibility of recruitment as outlined above, successful enrollment of

the number of patients we hope to enroll and compliance with the study protocol

will depend on the interest and willingness of chief residents and interventional

cardiologists. We recognize that these practitioners may not be focused on or

necessarily prioritize the prevention of CI-AKI and its associated outcomes,

especially since they are often not involved in the longitudinal care of patients

and may not be notified of delayed complications of angiography. We believe

that comprehensive organizational structure at each site will ease providers’

burden and optimize the potential for successful subject enrollment and

implication. What is more, we believe that the flexibility built into the protocol for

study IV fluid administration rates, volumes, and duration will be attractive to

providers performing angiography and will increase their interest and

willingness to have their patients participate in the study.




55

9.2 Strategies to address under-recruitment of study subjects

Given the relatively large size of our study and the critical importance of

adequate patient recruitment, we anticipate using a number of strategies to

address under-recruitment should it occur. First, during the process of

calculating the sample size, we have taken into account these relevant

problems and enlarged the target number by 20%. Second, in addition to

Guangdong Provincial People`s Hospital, which conduct nearly 400 primary

PCI yearly, we also include another 14 study sites that mostly are the regional

central hospitals. We believe that having these two strategies to address

potential under-enrollment will help ensure the attainment of the target sample

size without compromising the scientific integrity of the study.

10. PROPOSED ANCILLARY STUDY

In addition to the primary study, we are also proposing to conduct an ancillary

study to follow patients for up to 10 years to track renal and cardiovascular

outcomes and mortality.

The specific aims of the proposed study are as follows:

Specific aim 1: To generate and track long-term clinical outcomes in a

matched cohort of patients participating in the ATTEMPT trial with and without

CIN.

Specific aim 2: To assess whether the development of CIN following

angiography is independently associated with serious, adverse, long-term renal

outcomes (i.e., accelerated rate of decline in kidney function and development

of end-stage renal disease), cardiovascular outcomes (i.e., cardiac,

cerebrovascular, peripheral arterial events) and mortality.




56

11. HUMAN SUBJECTS

11.1 Informed consent

Potentially eligible patients will be identified by chief residents and research

personnel at each site. After the study is introduced to the patient by an

individual participating in their care, research personnel will contact potentially

eligible subjects and their legal agent to describe the study and present him/her

with the detailed informed consent form and supplementary material to read

and review.

The general purpose of the study will be delineated and the treatment

comparisons will be clearly described. The process of randomization will be

discussed and a clear explanation of what will be expected of the patient will

also be described. The risks associated with treatments and procedures will

also be addressed. The importance of patient confidentiality will be stressed,

including a description of the process for maintaining patient confidentiality.

Research personnel will ensure that the patient understands every aspect of

the trial, including its risks and benefits, prior to signing the informed consent. If

the patient agrees, his/her consent to participate in the study will be

documented. The original will be placed in the patient's medical record.

Informed consent requires that the patient understand the details of the study

and agree, without coercion, to participate in the study. To obtain informed

consent, the following information shall be provided to each subject:

Name of the study

Name of the Principal or Site Investigator(s)

Explanation that the study involves research

Explanation of the purpose of the study

Explanation of the treatment procedures

Description of randomization

Description of the risks and benefits of participation in the study

Explanation that all records will be kept confidential




57

Whom to contact for questions about the research and about subjects' rights

A statement that participation in the study is voluntary and that a decision

not to participate or to withdraw from the study after initially agreeing involves

no penalty, loss of benefits, or reduction in access to medical care.

A statement that the examinations and treatments provided as part of this

study are mostly clinical routine and will be paid by subject himself.

Merely obtaining signed consent from the patient does not constitute informed

consent. However, the use of a standardized consent form aids in assuring that

subjects receive adequate and consistent information about the trial and that

they have consented to participate.

11.2 Risks and benefits

Any procedure/intervention has potential risks. The interventions used in this

study may cause all, some, or none of the risks and side effects listed. There is

also the potential for rare or unknown risks to occur. Active study participants

will be informed of any information that becomes known during the course of

the study regarding risks of the interventions that might affect their willingness

to continue to participate.

11.2.1 Side effects associated with infusion of intravenous fluids

Reactions due to solution or technique of administration: febrile response,

infection at the site of injection, venous thrombosis or phlebitis extending from

the site of injection, and extravasation of fluids

11.2.2 Side effects associated with infusion of sodium chloride

Cardiovascular: heart failure (aggravated), edema Endocrine and metabolic:

hypernatremia, hyperosmolarity, hypokalemia, metabolic acidosis Respiratory:

pulmonary edema

Possible benefits of this study include a reduced risk of serious adverse




58

outcomes, including death, need for acute dialysis, and persistent decline in

kidney function among subjects receiving aggressive hydration.

12. DATA MANAGEMENT

12.1 Source file management

Source documents comprise of source data, include hospital records, clinical

and office charts, laboratory notes, memoranda, subjects diaries or evaluation

checklists, recorded data from automated instruments, microfiches,

photographic negatives, microfilm or magnetic media, x-rays, subject files, and

records kept at the laboratories, and at medico-technical departments involved

in the clinical trial, including certified copies or transcripts. Source files can be

paper and/or electronic. The original document in the clinical trial refers to the

document that records the clinical observation for the first time, such as the

written record of the trial process, the therapy prescribed by the researcher, the

informed consent form, etc.; or the file contains the laboratory examination and

the image examination data, such as Blood routine examination report, CT, etc.

There are paper and electronic forms or other available forms. When the

original is unfavorable for preservation, inconvenient to obtain or lost, a verified

copy (identical to the original recorded information and produced with a dated

signature or a verifiable procedure, shall be reasonable to explain) would be

saved as a source file.

12.2 Data collection

12.2.1 The source data were recorded and modified according to categories

(objective data and subjective data) during the implementation process.

Objective data is usually generated directly from the testing equipment,

instruments or other tools. When the test sample is read by the instrument or

device, the result data or images, such as blood routine examination, blood

biochemistry, electrocardiogram, test atlas, pathological image, photographs of




59

the body lesions, body temperature, X-ray film, CT film or electronic images,

etc.

Subjective data refers to data for artificial observation and evaluation, including

data judged and recorded by the investigator, or data generated by the

subject's own records, such as a history review (eg, part of medical history,

medication history which cannot trace back by investigator are recorded

according to the subject's statement), oral hydration table, urine table, subject

log record, oral medication record, etc. Prior to the trial enrollment, proper

training or guidance are provided to the recorder, records should be timely, and

indicate the signature and date to avoid recall bias; ensure that the collection

and recording of such data is real and standardized.

Researchers and sponsors should take effective measures to ensure the

quality of data generation and recording, which shall be completed by

qualified personnel according to study protocol. As for correction, the original

content should be retained and marked with strikeout, new content and the

name of the modified person, the reason and the date of the modification shall

be annotated beside. The modification of the electronic document should

ensure that the audit track is kept in the backstage for future reference, and

keep relevant records and explanation of data modification.

12.2.2 Methods of data collection will be listed during the study, such as paper

or electronic CRF (eCRF), name and version of the data

acquisition/management system, Describe the permission control plan of the

system user, or provide corresponding information in the form of attachments,

including permission definition, allocation, monitoring, and measures or

methods to prevent unauthorized operations, authority revocation, and so on.

The data acquisition/management system should have the functions of audit

trail, security management, authority control and data backup, and pass the

complete system verification.




60

12.2.3 CRF record

When filling in the CRF, the person who fills in does the self-examination with

out additional verification. The clinical research associate verify the source data

at the research center to ensure the accuracy of the clinical research data

originally. Proper training will be provided to the investigator or research

coordinator before the study begins. To help the staff at research center fill in

the CRF or eCRF with real, standardized, complete, and accurate data, the

data manager must provide a guidance document that help filling in the CRF

(usually referred as the CRF Completion Guide).

12.2.4 Staff training

After the study is approved, the main research center and the Key Laboratory of

Coronary Heart Disease will prepare the Investigator's Operation Manual, CRF

Guideline, eCRF Entry Guideline, and Training Schedule to guide the site staff's

operation and management, including data collection, data entry, etc. The

training will be conducted at the Investigator Initiative to train all research

fellows and clinical research coordinators to ensure data collection, data entry

consistency, traceability, completeness, and accuracy.

During the research period, all the data management will be trained by the

subject matter expert (SME), including external resource experts (software

developer engineers, training consultants, etc). The content and method of the

training are approved by the research conductor, and the accuracy of the

content must be approved by the SME. The research training is perform by

means of centralized training, online training and on-the-job training. All training

shall be tested afterward to understand the effectiveness of training timely, so

that to identify and rectify problems in the training. After the training, the training

conductor shall centrally archive the content, time, place of the training, trainee

list and the signature records.




61

12.3 Electronic data entry

After the data management department receives the paper CRF from the

researcher, the necessary signature and registration record shall be made. The

primary task of data management is to enter the CRF data into the database as

soon as possible. As for the training of data entry staff, make sure to familiarize

themselves with the data entry system, entering screen settings and schedules,

and also enter test data to ensure their work is accurate and reliable before the

official data entry.

Prior to electronic data entry, a well-trained professional will perform manual

verification to identify abnormal data on paper CRF, including unclear writing,

non-compliance with research protocols, missing data, medically unreasonable

data, and inconsistent data. Once a problem is found, it should immediately

contact the investigator and ask for clarification. Specifically the verification

content include but not limited to:

1) Check if the received CRF uses the latest version.

2) Check the CRF for missing pages

3) Check if the CRF has a subject code.

4) Check if the CRF is filled in with the required ink and whether it is clearly

visible.

5) Check if CRF is damaged.

6) Check if all CRFs have the researcher signature and date.

Electronic data entry and management is the responsibility of the data manager

of the statistical department in Key Laboratory of Coronary Heart Disease. EDC

database is adopted for electronic data entry. Electronic data is entered by

trained specialist. If problems or unexpected situations are found during the

entry process, they should be recorded and reported to the project's data

administrator for prompt solution. As for the unidentified data, data

managers(statisticians and data administrators) discuss each other and require




62

researchers to clarify with queries when data is cleaned up.

Quality control will be taken during electronic data entry:

1) Strengthen training： In order to improve the quality of data entry, it is

necessary to strengthen the training of data entry personnel.

2) Data quality control: Quality control of the entered data ensures that the

entered data is at an acceptable level.

3) Identify problems in time: If problems are found during the entry process,

they should be recorded and reported timely.

4)Establish a quality inspection system: After the data entry is completed,

some CRFs are randomly or irregularly checked to understand the quality of

the entry, analyze and deal with the problems of data entry. Electronic data

Entry is generally completed within 2 weeks since the CRF check.

12.4 Data Verification and Query

Before the data verification, a detailed Data Validation Plan (DVP) should be

made to clarify the content, method and verification requirements of the data

verification. Data verification is completed by data manager, auditors, medical

personnel and statisticians together.

The abnormal data is generally found through source data monitor, manual

inspection before entry, logic check by computer system, database check, and

analysis report of summary statistical analysis. The main content of data

verification is to check the CRF filling quality, check the data validity, integrity,

logic and compliance of the data. The methods of data review include manual

review and computer review.

1) Manual review is mainly used to check abnormal data that is not easily

checked by computer programs, such as CRF fill quality, CRF header

information (such as subject code or CRF page number).

2) Computer review, mainly use the data logic check performed by the

computer system.




63

The following review methods will be used in accordance with the content of the

research data reviewed: source data verification, database data verification

(including logic verification), summary statistics, and CRF-database verification.

The problems found in the research data review are mainly through internal and

external solutions. The internal solution is mainly based on comparing the data

of other parts of the CRF to make a judgment, and finally solve the problem,

mainly by the internal data administrator. The external solution to the "problem"

is mainly solved by the data administrator in the form of DCF (Data Challenge

Form) to obtain the difference data.

For issues with universality found in data review, specific issues such as

revisions to research protocols, revisions to CRF completion guidelines, or

enhanced training for researchers should be addressed. Research centers that

violate research programs should strengthen audits and recommend

improvements within a limited time. When the aggregated descriptive statistics

reveal significant differences between the data of a research center and other

units (such as reporting too many or too few adverse events), audits of research

centers and researchers should also be strengthened.

The problem data that the data administrator cannot solve through the internal

problem needs to be solved in an external way in time, that is, the problem is

solved by sending the data clarification table or the data challenge table to the

researcher (following ICH GCP [5.5.3(b)] The requester answers or interprets

the question on the challenge form and returns the DCF to the data

administrator. The challenge form is hand-made by the data administrator, and

each question table has its own unique identity. It is convenient to check the

status of the question list to prevent the missing.

After the challenge table is generated, the data administrator needs to compare




64

the data on the CRF table with the data in the database again to determine

whether the challenge table is reasonable and valid. If the problem data of the

challenge form is reasonable, send the research center/investigator to clarify. If

the problem data on the challenge form is an error caused by data entry, or if

the logic check program is improperly set, the question form is not required to

be sent to the research center/investigator.

After receiving the question form issued by the Data Management Center of the

Key Laboratory of Coronary Heart Disease, the researcher should reply to the

question and sign the question according to the question on the question form

and check the original data, such as the inpatient medical record and the

laboratory test record. And the date of signing. After the photocopy of the

question form is saved with the CRF in the file file of the research center, the

original is returned to the data management center.

After the challenge form is returned to the data management center, the

recipient needs to record the date received on the challenge form and forward it

to the project data administrator. The data administrator will solve the problem

based on the information provided by the researcher on the challenge form, if

the researcher replies. If you are reasonably satisfied, close the challenge. If

the researcher's answer is unreasonable or leads to the generation of additional

problem data, the data administrator needs to raise another question and ask

the researcher to clarify again until the problem is solved. Regardless of the

form in which the question form is generated, the data management center

should have a means of recording and tracking the challenge form.

12.5 EDC design and Establish

For this study, the EDC designer will create a research-specific database and

design and define the CRF table through the user interface to facilitate data

entry, cleanup, review, export, and reporting. The database will be designed




65

with the following main considerations in mind:

1) Must comply with the research program process to facilitate data entry.

2) The data export style is comprehensive and complete, easy to analyze

statistically and meet the requirements of statisticians or programmers.

3) The data can be relatively inspected in the data management system to

find the “problem” data in time.

4) Should conform to the database creation theory.

5) Should meet the requirements of the database application software.

The research database will adopt a standardized database structure to store

data, ensuring that the fields in the data table are the most basic elements.

From a database perspective, data types involve numeric data types, date and

time data types, and character data types.

The database needs to support the establishment of logic verification (subject

to the development process of the computer program: logic inspection

requirements, development, testing, production environment application and

change control, etc.), check the entered data to find the "problem" data, so that

Data administrators or auditors review and clean up to improve data quality.

12.6 Research Database environment and operation requirement

The system should be installed in a safe physical environment. The security of

the physical environment can generally be guaranteed by the following

measures: restriction, recording and monitoring of the contact person of the

carrier; dual power supply or UPS; shockproof, fireproof, waterproof, heatproof

and moisture proof ( Non-subjective); vandalism, anti-theft (subjective), etc. The

network environment of the system, that is, the environment in which the

electronic network for data transmission (such as the Internet or local area

network) is located, should also be secured. Generally, it can be guaranteed by

the following measures: establishing a firewall or other hardware and software




66

to prevent viruses, Trojans, hackers, etc. Spyware intrusion.

System servers and their databases should prioritize remote or offsite backups

to ensure system continuity and data security. When this is not possible, you

should use an offline backup device to periodically back up and take away the

physical environment of the online backup. If the EDC system is interrupted due

to force majeure or uncontrollable factors, the EDC supplier shall have a

corresponding emergency plan and return the normal operation of the EDC

system in the shortest time according to the server and database backup.

At present, the system adopts dual hot security backup to ensure the absolute

information security of all projects, independently run the hard disk and the

backup hard disk, and synchronize the data in real time to ensure uninterrupted

data access. Use Linux system scripts to back up the latest data in time to

ensure data is absolutely secure. The latest backup hard disk data, daily

incremental synchronization of local data, so that data is foolproof.

12.7 Research data assess authority

The EDC system should have user management, role management and rights

management function modules. All users of the EDC system must have a

unique username and password combination. The password must be stored

encrypted in the system. Both the service provider and the user of the EDC

system should establish an SOP to manage EDC services, operations and

maintenance, and follow the SOP in actual use and management. All records of

the execution or implementation of the SOP are archived for reference.

Access to study data is limited to individuals who have been approved by key

laboratories for coronary heart disease. Individuals must have appropriately

qualified researchers and be compliant with information security awareness

training and confidentiality agreements. All personnel who need access to




67

research data are required to receive SOP training on the management and

use of their authority. In addition, the permissions of the electronic system are

structured, and users in a single research center can only see data from their

research participants and cannot view or access data from other clinical

research centers or other participants.

When a user no longer needs a certain permission, this permission should be

revoked in time. When the account is changed, the reason for the change and

the process and requirements of the change should be stated. When the user

forgets the password, the process of requesting a new password is recorded

and explained. When the user leaves the research center, all the user's

permissions are revoked, but the user name, inspection traces and other

information are still retained. Once the username is disabled, it should not be

used again.

To ensure system security and monitoring, the following measures will be

taken:

1) The system automatically logs out after 10 minutes when the user has no

activity.

2) Unauthorized access is recorded in the system log, which is checked

periodically by the system administrator.

3) The user must keep the password and cannot share it.

4) Users cannot log in or work with other users.

5) Check of expired/disabled accounts.

12.8 Data safety strategy

The clinical research data of this study belongs to the property of the

cooperative research project. It may not be sent outside the research center

without the written permission of the person in charge of the key laboratory of

coronary heart disease. It will strictly abide by the main research unit, key




68

laboratory for coronary heart disease, cooperative research projects and

various research. All data transmission and data security policies of the Center.

The head of the Key Laboratory of Coronary Heart Disease will work with the

research centers in accordance with the signed agreements to ensure proper

handling of data security and data transmission.

12.9 Data Storage and archive

In the course of this study, regardless of the collection method, clinical

research data will enter the research database, so ensuring the security,

integrity and accessibility of data is the main purpose of data preservation. The

principle of preservation of raw data and original documents (such as case

report forms and electronic documents) is that their safety must be guaranteed.

Paper documents and electronic documents should be kept in a secure room or

file cabinet and have strict access control rights to prevent unauthorized access.

After receiving the paper documents, they should be scanned and saved the

electronic files as much as possible. The backup files should be kept in different

places. The electronic data of the research is mainly stored in the database

server, and its security (such as the firewall of the computer) should also be

guaranteed.

The preservation and archiving of clinical data are for different periods of

clinical research, but their purpose is the same, that is, to ensure the security,

accuracy, completeness and accessibility of data/files.

Article 49 of the State Food and Drug Administration General Administration of

Quality Control of Drug Clinical Trials stipulates that the materials in clinical

trials shall be kept and managed as required. The investigator should save the

clinical trial data until five years after the termination of the clinical trial. The ICH

GCP requires at least two years of storage. This study will comply with the

above requirements and will also follow the basic requirements of the following




69

archives:

1) The archiving of research data needs to be planned and arranged.

2) The content and format of the research data should meet the

requirements of industry standards and regulatory agencies.

3) Archived data should be secure during the specified data retention

period to prevent damage.

4) The responsibility for the archiving work, the division of labor and the

archiving procedures should be clear.

5) The saved records are periodically checked after archiving to ensure

their accuracy, completeness, accessibility and durability.

6) The archived data should have a central directory.

7) After the important upgrade of the clinical research data

acquisition/management system, the archived electronic data accessibility

should be tested.

8) The original data (such as CRF with the signature and signature date of

the researcher, CRF correction documents, etc.) should be archived in the

research documents of the key laboratory of coronary heart disease or kept in

an off-site archive.

9) The archive of the research document should indicate the hardware,

software and its version used.

In addition, clinical research data is archived to ensure that archiving meets the

requirements of the main research unit, research organization, and regulatory

requirements. The research data key laboratory of coronary heart disease will

completely retain the database until the primary and secondary analysis is

completed. After the analysis is completed, the research data will be

de-identified and stored indefinitely. The research records of the local research

center may not be destroyed without the written permission of the Key

Laboratory of Coronary Heart Disease.




70

13. QUALITY CONTROL

13.1 Qualified Measurement/Confirmation

This study will, as far as possible, harmonize the qualifications, qualifications,

clinical work experience, etc. of the physicians involved in the treatment to

ensure the consistency of their research methods. Before the start of the study,

the research center researchers and clinical research coordinators will hold a

meeting review. Research procedures and training in research data collection.

Before starting the meeting, send the research plan, implementation plan, and

execution SOP to each research center and related personnel, collect opinions

from all parties, and confirm the modifications, and organize all participants of

the research center (main researcher, researcher, and research coordinator). ,

research inspectors) accept research programs, research data collection

training; training is conducted during the start-up meeting of each center

research, for research doctors, clinical research coordinators, etc. to obtain and

maintain preservation source documents, and complete research evaluation,

CRF fill out , EDC entry and other content training, strict confirmation of the

entry criteria, through oral or written feedback and discussion, to ensure that

the research doctors and clinical research coordinators understand and clarify

the research assessment, the meeting also on the relevant variables, laboratory

tests normal range, each The implementation characteristics of the Center were

thoroughly reviewed and discussed, and training was strengthened to develop

operational reference guides for each center.

Before the start of the study, the laboratory qualification certificates of each

center and the normal range of laboratory tests were reviewed and confirmed to

prevent research bias.

13.2 Patients Management

For the subjects of the project, the investigator of each clinical research and

testing center will be responsible for the management of the subjects enrolled,




71

keeping the patient's personal information confidential, and paying attention to

the patient's health during the study, in the informed consent form. The

researcher's contact information corresponding to each sub-center is attached,

and the patient can contact the researcher at any time to make the patient's

safety secure. For patients who are unable to return to the original center for

follow-up and blood samples, the participants of the participating centers will

conduct telephone follow-ups and answer questions about the patients'

questions. They should try to adapt to the patient's schedule and safety issues.

13.3 Protocol deviation

Any program deviations need to be recorded, and the Key Laboratory of

Coronary Heart Disease will create a program deviation table to ensure that

events are tracked correctly. The deviation from the program will be evaluated

by the Key Laboratory of Coronary Heart Disease and the effectiveness of the

deviation basis will be determined. Any medical center or subject who has a

program deviation in the absence of a valid reason, and after training in

remedial training, is recommended to terminate it to the Data Monitoring

Committee (DMC) if any member of the DMC or the Inspectorate believes If the

compliance program will impair the health of the subject, the subject's rights

should be prioritized and the subject should be withdrawn from the study after

consultation with the Executive Committee and the program will be reported to

the main research unit IRB as required.

13.4 Randomized control of study treatment

This clinical study is a multicenter, randomized, controlled trial that requires the

necessary uniform standard treatment of routine clinical interventions at

participating centers to rule out confounding due to inconsistent intervention

criteria. Randomized system of the Department of Statistics of Southern

Medical University to ensure random objectivity and reduce selection bias.




72

13.5 Monitoring and quality control

In order to ensure the uniform and high quality of multi-center participants, the

clinical monitoring group will conduct quality control on the research according

to the audit plan formulated by the Guangdong Provincial Key Laboratory of

Coronary Heart Disease, including but not limited to:

1) Monitoring frequency and report

The first audit was conducted within one week after the first subject was

enrolled;

In the enrollment and follow-up phase (refers to the first case of the center

to be screened to all subjects in the center), the audit is conducted once a

month, and the window period of the two allowed audits is within ±60 days. That

is, the last audit date is January 1, 2016, and the next audit can be scheduled

from February 28, 2016 to March 3, 2016. The actual visit date of the audit

report must be the same as the registration date in the central visit registration

form. For centers that are concentrated in the group and faster in the group, the

CRA and PM applications can adjust the monitoring frequency to 2 weeks in the

concentration stage of the group;

The frequency of the audit can be adjusted based on the speed of the center's

entry or the problems found in the center. If the audit plan is changed, please

explain it in the audit report.

The trial initiation visit must be performed prior to screening the patient

The last time the audit activity must be before the data is locked; if there are

any remaining problems before the data lock library, all problems must be

resolved before the audit can be terminated;

End of trial visit will be performed after the data is locked.

2) Monitoring visit report and project management report




73

Monitoring visit report:

All problems found in the audit and not resolved and their action plans must be

reflected in the audit report; the audit report must be sent to the project

execution leader within 7 working days after the audit occurs;

Site visit report:

The center enrollment stage (the center enrollment stage means that the first

subject of the center is screened to complete the enrollment of all subjects in

the center), and the auditor reports the basic information and progress of the

study to the project execution leader every week;

Central treatment stage (central treatment stage refers to completion of all

subjects in the center to complete completion of treatment of all subjects in the

center) and central follow-up stage (central follow-up stage to all subjects in the

center after completion of treatment after follow-up period to this All subjects in

the center are grouped and reported to the project executive responsible every

4 weeks.

Project team internal project meeting

Project enrollment stage (refers to the first subject of the project to screen all

subjects of the project to complete the group completion): The auditor holds a

conference call with the project execution leader every 4 weeks; the specific

time is notified by the project team;

During the project follow-up phase (the project follow-up phase means that all

subjects in the project are completed in the group until all subjects in the project

are out of the group): the internal meetings of the project team are held

monthly;

For the project in the center according to the program development and the




74

subject's rights and interests, the auditor needs to promptly feedback to the

project team. For issues that have significant impact, it needs to be reported to

the project executive person within 1 working day after the knowledge is

obtained.

3) Staff training

Auditor training:

Initial training

The training of the project team will be arranged before the start of the

research center, including training in programs, systems and processes, which

will ensure the smooth start of the project;

A team member's training was conducted prior to the conference, including

research background, program introduction, ICF management, verification

considerations, project management and entry plan, data management and

EDC profile

Training during the research process

According to the EDC verification situation, the DM summarizes the EDC

entry and common questioning common problems, and the project manager will

share the training of the project team at the project meeting.

According to the audit of the sponsor, etc., the project team summarizes the

problems found, and the project supervisors share the training of the project

team at the project meeting.

For newly joined project team members, the project will arrange relevant

content such as program and process training before undertaking the project

task. Training is generally conducted on-site or on a conference call.

Personnel handover occurred in the project. The project manager handed

over the SOP according to the project team to ensure the smooth handover of

personnel, and systematic training of the new CRA before the handover. The




75

training was generally conducted by on-site training or conference call.

Add additional training as appropriate.

Research Center Staff Training:

The auditor responsible for each center will provide training to the staff of

the research center at the start-up meeting, CRF filling and testing procedures.

When the first subject is screened or enrolled, the CRA needs to assist and

confirm that the research is familiar with the research process, such as timely

training and reminders.

4) eCRF fill in / enter

The CRF is filled in/entered by the designated personnel of the research

center according to the filling instructions. All patients enrolled need to complete

CRF, including rejection of the patient.

Even if you withdraw from the case, you will need to complete the “Completion

Study Page”.

Each case with signed informed consent needs to be registered in the

screening and enrollment form, including screening for losers.

5) Verification of original data (SDV plan)

Part 1: Important parameters

100% raw data verification for all patients with the following parameters:

1) Informed consent form

Whether the patient's signature and date appear on the informed consent

form;




76

Whether the patient signature date is before the start of any research

procedure;

Whether the name and date of the doctor who informed the informed

consent are signed;

The researcher's contact number must be a telephone that can be

contacted 24 hours a day;

Whether the date of signing by the researcher is the same day as the

patient;

Ensure that the version of the informed consent form signed by the subject

is correct;

It is recommended that the pen used by the doctor's signature be as

different as possible from the patient;

Informed consent forms for screening losers must also be kept;

- Record on the original record when the patient has signed an informed

consent form and obtained an original.

Part II: Initial Quality Control

1) After the first 5 patients are enrolled, the rest of the SDV needs to be done in

addition to the above, in order to ensure that the original record is complete, the

program is followed, and the eCRF is correctly filled in/entered.

2) In addition to the content mentioned in the first section, the following should

be verified at each visit:

Is the follow-up time recorded on the CRF consistent with the original

medical record?

Changes in vital signs and laboratory tests after baseline

The laboratory tests required in each program are completed; and any

clinical test abnormalities are recorded and explained in the CRF.




77

Patient diary (hydration table)

Part III: Quality Control in Progress

100% SDV is required during the trial.

If the investigator is replaced during the trial, the auditor will then review the

data of the first two patients enrolled by the new investigator.

If many problems are found in the trial, discuss it with the investigator and

not resolve it.

Part IV: Screening failure

The original medical records failed to reflect the reasons for the screening

failure, and the original records must be saved.

Part V: Original Data Verification Record

The researcher must keep all original medical records in the research

center.

The auditor needs to record the important findings of SDV, how to solve it

and the next steps in the audit report. At the same time, feedback these findings

to the researchers and let them correct them in time.

13.6 Participation Center trial/terminate

The research chair and the key laboratory for coronary heart disease will

assess the participation in the hospital. Only hospitals that meet the

corresponding indicators can participate in the study:

1) The hospital has the relevant equipment and technology needed for the

project:

2) Have sufficient patient source that meets the criteria for entry and exit:

meet at least 10 patients with acute myocardial infarction each month;




78

3) Have sufficient human resources in line with standards: have doctors who

can qualify for such diseases, and receive training for the project. More than 2

doctors are responsible for this project;

During the implementation process, the recruitment rate and operational

aspects of the study are continuously monitored. If the research center is in the

trial stage, it will face the following reasons including but not limited to violation

of the program, violation of GCP or related regulations, and project quality

requirements.

The risk of terminating the study.

1) Recruitment rate: divide the number of randomized patients by the

expected number of patients, calculate the recruitment rate, and continuously

monitor the indicator during the research. If the recruitment process is slow, if

there is no randomization in February, the center will receive remediation and

reassess. If the plan is not included in the plan, it will enter the probation period

and be evaluated every 2 months.

2) Follow-up rate: The number of patients in any follow-up window was

divided by the number of patients expected to follow the window, and the

follow-up rate was calculated. Both the numerator and the denominator were

delayed for 4 weeks to schedule a visit to the corresponding follow-up window

and complete the form. Study centers with a cumulative follow-up rate of less

than 90% will enter the probationary period and will be assessed every 2

months.

3) Form Completion Rate: The table completion rate is calculated by

dividing the number of completed forms by the number of expected forms,

where the expected number of forms will be sent out as a "not collected" form.

The table completion rate will be calculated according to the patient and the

form. Research centers with a cumulative follow-up rate of less than 90% will

enter the probationary period and will be assessed every 2 months.

Once the research center enters the probationary period, failure to meet the

requirements of the end of the probationary period will result in the proposed




79

termination of the study. In addition, those that do not meet the above

requirements, or one of which will not meet the standard after rectification and

remediation, will face the termination of the trial. In addition, after the relevant

performance evaluation of the research center in the key laboratory of coronary

heart disease, if it is considered unsuitable for continuing research, the

research center can be terminated without a formal trial period.

14.GOOD CLINICAL PRACTICE AND RESEARCH CENTERSREVIEW PROJECTS

This study will be conducted in accordance with the Good Clinical Practice

(GCP) for Drug Clinical Trials. During the study period, the research centers

participating in the research will be monitored according to the monitoring plan.

The Research Center Monitoring Team will visit all participating research

centers at least once in accordance with the GCP. The purpose of these visits

is to ensure that trials are performed, documented, and reported in accordance

with research protocols, standard operating procedures (SOPs), clinical trial

quality management practices (GCP), and applicable regulatory requirements.

The auditor will examine the patient study files, including x-rays,

electrocardiograms, and other source files. Particular attention is paid to patient

informed consent, protocol compliance, ethics committee approval, and

researcher folders. After the interview, the monitoring visit report is prepared

and forwarded to the research center researcher and research leader.

In addition to the review visits scheduled by the sponsors, an independent,

comprehensive research center audit can be conducted at any time, as

required by the research management or research center.

All in all, the audit team will do the following:

1) Provide comprehensive research execution tools to the research center,

including important research requirements in the folder catalog, templates, and

source files to help the research center better implement the research program




80

and meet the requirements of the GCP regulations.

2) Regular visits to participating research centers and provide GCP training

and enhancement at the kick-off meeting.

3) Conduct a review visit to each participating center at least annually to

monitor the compliance, program compliance, and overall research design

performed by the investigator.

4) A comprehensive review of the final year of the study to ensure that all

research tasks and related documentation are completed.

15. RESEARCH MONITORING AND AUDIT PLANS

Protecting patients' rights and benefits is a major concern for key coronary

heart disease laboratories. This study will be conducted in accordance with the

local laws of the ICH-GCP, the Helsinki Declaration and the quality

management practices for drug clinical trials.

15.1 Monitoring agency

The study will oversee the scientific and ethical nature of the research through

four external agencies, including the Data Monitoring Committee (DMC), the

Ethics Committee (IRB), the Independent Incidents Committee (CEC), and the

Clinical Monitoring Agency.

15.1.1 Data monitoring committee

The Data Monitoring Board (DMC) will independently monitor and make

recommendations on clinical research processes, safety data, and progress.

(DMC) consists of members of the relevant professional field (meteologists,

cardiology, and clinical research specialists) who regularly evaluate cumulative

data from ongoing clinical trials, including those who have participated or who

will be recruited into the trial. The safety of the tester, the study implementation,

scientific and the integrity of the research data. The DMC will assess the

progress of the enrollment of the subject and make recommendations to the




81

sponsor, proceeding as planned, continuing or terminating or suspending trials

in one or all of the groups. In the future, it can be adjusted according to the

actual rate of the experiment and the incidence of the event.

15.1.2 Ethics Committee

The Ethics Committee (IEC) provides expert ethics and scientific review of

multi-center projects while ensuring solve local problems in each research

center. The Key Laboratory Center for Coronary Heart Diseases conducts a

comprehensive, rapid and ongoing review, and the investigator (PI) first

submits applications, including research protocols, informed consent, and so on.

Once approved, the application materials will be sent to all possible research

centers, and the local research center researchers (LSI) will submit the

application to the ethics committee. After approval, a copy of the research

center approval document will be provided to the key laboratory for coronary

heart disease for backup. During the study period, communication between the

participating centers and the IEC shall be recorded or documented. All

participating centers in the study conducted an annual ethical review.

15.1.3 Clinical Events Committee


endpoints in clinical studies and avoiding deviations in event determination

between centers and centers in order to achieve a more accurate assessment

of test results. CEC is an independent committee of three research field experts

independent of research sponsors and researchers. Its primary responsibility is

to combine clinical expertise and protocols based on uniform definition criteria

for all endpoint events in the study. In the relevant content, the objective

judgment of the end point event is made to see if it meets the definition criteria.

The frequency of this study review will be determined based on the incidence of

enrollment plans and endpoint events.




82

Suspected

endpoint

Researcher

evaluation

Audit - source

file collection

Source file

submitted to CEC

CEC regular

evaluation Evaluation result

CECquery data

confirm

Data verification and

analysis

Consistency

comparisoneCRF data

collection

Submit to data

department

Figure A5 - CEC review process

The CEC Secretariat will be responsible for the production and regular updating

and maintenance of the CEC Review Folder. The CEC Review Folder will store

all documents related to CEC content, including CEC member information,

confidentiality agreements, review source files and review results.

15.1.4 Clinical monitoring team

Clinical monitors will ensure that trials are performed, documented, and

reported in accordance with research protocols, standard operating procedures

(SOPs), clinical trial quality management practices (GCP), and applicable

regulatory requirements. The audit is usually scheduled by the monitor and the

investigator and/or other participants prior to the first patient enrollment.

According to the research project, the inspection is usually carried out every

four to six weeks, but the interval between inspections can be extended or

shortened due to the difference in research period and schedule. The clinical

monitor will ensure that the submitted data is accurate and consistent with the

source document; verify that the subject's informed consent has been correctly

obtained and recorded; that the study participants in the enrolled study meet

the inclusion and exclusion criteria; and that the drug is ensured. All basic




83

documentation guidelines required by the clinical trial quality management

practices are properly documented.

The auditor will conduct a visit to the research center before the study begins.

At the time of the visit, they will discuss the way the subjects/patients are

recruited, the completion of the case report form and the next management

procedures. In addition, it should be discussed and agreed to: the investigator's

assessment of the program's understanding, his or her obligations during the

study period, and possible recruitment rates. Other circumstances, such as

confirmation of data obtained in the study, should also be discussed. In addition,

they will ensure that appropriate research related documents exist.

At the end of the study, a study closure visit, the final audit, should be

performed, usually within four to six weeks of the end of the last follow-up of the

last subject in the study center. The preparations and procedures for the study

of closed visits are generally the same as for a regular supervisory visit.

15.2 Monitoring adverse events (AEs) and serious adverse events (SAE)

It should report safety information in a timely and complete manner, assisting

research management in identifying any adverse medical events, ensuring:

protecting the safety of research patients, better understanding the overall

safety characteristics of research interventions and treatment modalities, and

appropriately modifying research protocols Improve research design and

compliance with regulatory requirements.

The participating research centers will be responsible for the AE and SAE

reporting requirements described in this scenario, as described below:

1) The subjects were closely monitored for new AE and SAE during the

study.

2) Review the accuracy and completeness of all AE and SAE in the report.




84

3) Report all SAEs to the research centers IEC within 72 hours of the event.

4) Compliance with the research center IRB policy on AE and SAE

reporting.

5) In order to address security issues, an implementation plan for the study

group and the executive committee may be developed.

15.2.1 Adverse event

The International Conference on Harmonization (ICH) Clinical Safety Data

Management (ICH2A) defines adverse events (AEs) as “any adverse medical

event that occurs in a clinical study subject and accepts one of the research

interventions that do not necessarily have a causal relationship with the

intervention” . The CFDA of the State Food and Drug Administration defines an

adverse event (AE) as an adverse medical event that occurs after a patient or

clinical trial subject receives a drug, but does not necessarily have a causal

relationship with the treatment. Therefore, the AE will include (any adverse

signs, changes in function (symptoms) that occur during the observation, as

well as other tests (assay, ECG, X-ray, etc.).

Researchers at participating research centers are responsible for collecting AE

information from subjects in the research center with the assistance of the

clinical research coordinator. When an adverse event occurs, both during

hospitalization and during follow-up, the usual principles of recording are as

follows: Fill in the adverse event record form, including the name of the adverse

event, the time of occurrence, the end time, the severity, the measures taken

and the outcome and the corresponding evaluation. Adverse events with

serious adverse events (defined below) will be reported as follows and followed

up to regression or stabilization.

15.2.2 Severe adverse event

Serious adverse events (SAEs) are a subset of adverse events defined by (ICH)




85

Clinical Safety Data Management (ICH2A) as any of the following adverse

medical events that occur during clinical trials:

1) Lead to death.

2) Crisis life.

3) Need hospitalization or extend hospital stay.

4) Lead to persistent or severe disability or loss of energy.

5) Congenital malformations / birth defects.

6) According to medical judgment, any condition that may harm the subject

and require medication or surgery to prevent one of the above outcomes.

The study will collect all SAEs regardless of whether they are considered

relevant to the study intervention. SAEs that have a reasonable causal

relationship with research interventions and related drugs will be reported as

“relevant.” There is no need to establish a clear causal relationship.

Researchers at participating research centers are responsible for collecting

SAE information from subjects in the research center with the assistance of a

clinical research coordinator.

When a serious adverse event occurs, the researcher is required to report to

the relevant department within 24 hours of obtaining a serious adverse event.

The usual principles of treatment are as follows:

First, the subject should be guaranteed timely and appropriate clinical

diagnosis and treatment;

Secondly collect relevant information, such as medical records and inspection

results, in order to accurately and timely fill out the Serious Adverse Event

Report and report it to relevant departments.

Ensure that the report is consistent with the original record, CRF, and other

test records. Ensure that the start and end dates and major event descriptions

of serious adverse events are consistent with CRF and other test documents.




86

Don't delay submitting reports even if the information may be incomplete or

uncertain. When more information is available, it can be supplemented or

revised in the form of follow-up reports. Relevant information should be

collected and recorded continuously until the end of the reporting period.

Reporting forms and reporting procedures for serious adverse events may

have different requirements in different programs and research institutions.

These requirements should be clearly written into the test plan or SOP and fully

trained before the study begins, so that the researcher can follow the

implementation.

During the entire study period, the SAE will be monitored by the Data

Monitoring Committee and all AE and SAE reports will be summarized in

accordance with the time schedule set by the DMC to review the entire study

adverse event data and whether to continue research or Safety reasons stop

the study and give advice. We believe that an independent DMC can effectively

monitor the safety of the trial as it will periodically review all outcome endpoints

based on treatment assignments and will also receive statistical support to

determine the significance of any observed differences.

RESULT

16.BIOSTATISTICAL CONSIDERATIONS

A．Overview of design

1. The analytic model

There is one primary hypothesis that will be tested: 1) aggressive hydration (i.e.,

preprocedural IV loading plus postprocedural hemodynamic-guided [LVEDP]

fluid administration) reduces the risks of CI-AKI and clinical adverse events in

acute myocardial infarction patients undergoing primary PCI.








89

(50% relative reduction). Using nQuery + nTerim 3.0 (Statistical Solutions Ltd,

Farmer's Cross, Cork, Ireland) with a 2-sided χ2 test, a significance level of .05,

a power of 90%, and a dropout rate <20%, 280 patients are required in each

group, for a total sample size of 560.

Model

Aggressive

hydration

Control Overall event

rate

11.5% 23.0% 17.3%

Therefore, we postulate that:

Under control conditions, the rate for our primary outcome CI-AKI is 23.0%

The intervention will prevent 50% of these events

Under the intervention condition, the rate is 11.5%

The absolute effect of the intervention will be an 11.5% reduction in CI-AKI.

We have one primary hypothesis. We will, and therefore assign the type I error

of 5% to the intervention. No interim analysis will be carried out according to the

statistical design.

B. Primary end-point

We fully describe the aggressive hydration versus control (general hydration)

intervention and the CI-AKI outcome. The null hypothesis is that the two groups

(aggressive hydration and control) do not differ in terms of the proportion of

subjects who experience CI-AKI. The alternative hypothesis is that the absolute

difference in the incidence of CI-AKI between the treatment group and the

control group is 5% or more.

The formal statement of the null hypothesis

Under the null hypothesis:

The proportion of CI-AKI for patients administered aggressive hydration is




90

23.0%

Under the alternative hypothesis, the proportion of CI-AKI for patients

administered general hydration is 23.0%.

The formal hypothesis test is two-sided allowing for aggressive hydration to be

either more or less effective than control (general hydration). However, the

study of aggressive hydration will only be viewed as more successful if subjects

treated with aggressive hydration have a significantly lower proportion of CI-AKI

than patients who receive general hydration. We will test this hypothesis with

one model that contains main clinical characteristics (e.g., age, sex, eGFR,

HV/W), and the Mehran risk score will be calculated.

C. Secondary end-points

Our secondary objectives will be tested using χ2 tests, and the 95% CI of the

rate difference will be calculated using the method described by Altman et al

(reported in Newcombe and recommended by the Food and Drug

Administration and Clinical and Laboratory Standards Institute. The secondary

end-points will be analyzed based on the intention-to-treat principle. These

objectives are:

Losses to follow up and missing data

We conservatively estimate that up to 20% of subjects may be lost to follow up

before 72 hours. The site coordinators will make every effort to locate such

subjects including at least two laboratory test of serum creatinine after primary

PCI. If such efforts fail and we have no information indicating the outcome for

these subjects, then we will exclude them from the primary analysis and then

carry out a worst-case analysis to confirm the result of the primary analysis.

Definition of Intention to Treat Sample




91

All consented and randomized subjects will be accounted for and reported in

the CONSORT diagram for the study, however, only those randomized subjects

who initiated either IV intervention or have finished test a least once for SCr on

preoperation and postoperation (i.e., did not drop out or withdraw prior to start

of the allocated intervention), will be considered as an intention to treat (ITT)

subject to be included in the Data Monitoring Committee (DMC) reports and

primary efficacy analysis.

17. STUDY ORGANIZATION AND ADMINISTRATION

The research group and monitor group will be set up in the Central Office of the

Guangdong Provincial Key Laboratory of Coronary Heart Disease. The

research group is responsible for all operation/implementation procedures of

this study, and the monitor group is responsible for the quality control of this

study. The research team will conduct a face-to-face meeting prior to the start

of the study and thereafter at least once a year (online or offline). Except for the

executive committee (including research center investigators, research

clinicians, and members from academic management centers) will be

responsible for internal progress of research. The research management

structure is shown in the figure below (Figure A6).




92

Figure A6 – Study management structure

17.1 Central Office of Guangdong Provincial Key Laboratory of

Coronary Heart Disease

The Central Office of Guangdong Provincial Key Laboratory of Coronary Heart

Disease organizes relevant personnel through the Executive Committee,

Operation Management Center and Academic Management Center to

formulate management systems and standard operating procedures applicable

to all the research in due course.

17.2 Executive Committee

The Executive Committee will monitor the progress of the study, the operation




93

of the participating centers, and the quality of the data collected. The committee

will also monitor compliance with the study protocol. Except for the Executive

Committee, a publication plan will be developed for the study and the display of

all data will be monitored. Before relevant data is used for display or publication,

it must be approved by the Executive Committee. The committee members will

be selected by the research chair from the operation and academic center. The

Executive Committee may hold a conference call on a quarterly or annual basis

and, if necessary, hold the meeting in person.

C. Research Operation Management Center

The Research Operation Management Center will conduct daily scientific and

management coordination of research. This will include the development of

research protocol, the preparation of operational manuals and source

document worksheets, ensuring appropriate support for participating centers,

organizing meetings, answering programme queries, regularly publishing

research progress briefs, preparing interim and final reports, and the archiving

of research data at the end of the study. Coordinating research involves the

relationship of relevant departments, quality management of the research

projects (including monitor of patient recruitment and data quality), and

ensuring the smooth progress of study.

17.3 Research Academic Management Center

The Research Academic Management Center will assume the overall design of

the entire study, responsible for the design, supervision and management of

clinical study, and is responsible for various monitor organized by the drug

regulatory authorities, such as monitor, audits, on-site inspections, institutional

qualifications or reviews, etc. Work preparation, coordination and participation

in the audit of the sponsor organization. Provide clinical biometric consultation,

responsible for DME/evidence-based medicine teaching tasks for medical

graduate students, and provide advice and consultation on academic related




94

issues during the study.

18. PUBLICATIONS

It is the policy of the DVP that outcome data will not be revealed to the

participating investigators until the data collection phase of the study is

completed. This policy safeguards against possible biases affecting the data

collection. The regular and ex-officio members of the DMC will be monitoring

the outcome results to ensure that the study is stopped if a definitive answer is

reached earlier than the scheduled end of the study. All presentations and

publications from this study will be done in accordance with current DVP

guidelines. The presentation or publication of any or all data collected by

participating investigators on patients entered into the ATTEMPT study is under

the direct control of the study's Executive Committee. This policy is applicable

whether the publication or presentation is concerned with the results of the

principal undertaking or is associated with the study in some other way. No

individual participating investigator has any inherent right to perform analyses

or interpretations or to make public presentations or seek publication of any or

all of the data other than under the auspices and approval of the Executive

Committee.

The Executive Committee has the authority to establish one or more publication

committees, usually made up of sub-groups of participating investigators and

some members of the Executive Committee, for the purpose of producing

manuscripts for presentation and publication. Any presentation or publication,

when formulated by the Executive Committee or its authorized representatives,

should be circulated to all investigators participating in manuscript prepation for

their review, comments, and suggestions at least four weeks prior to

submission of the manuscript to the presenting or publication body. All

publications must give proper recognition to the study's funding source,

including the Department of SME, and should list all investigators in the study. If




95

an investigator's major salary support and/or commitment is from the SME, it is

obligatory for the investigator to list the SME as his/her primary institutional

affiliation. Submission of manuscripts or abstracts must follow the current DVP

policy. Since all publications should state that it is a publication from ATTEMPT

study, ideally, a sub-title is used stating, "ATTEMPT study." The SME

contributions to the research project should be acknowledged in all written and

oral presentations of the research results, including scientific articles, news

releases, news conferences, public lectures, and media interviews. All clinical

study reports and journal manuscripts must be reviewed and approved by IEC

prior to submission for publication.






97

medicine. 1989;320:143-9.3. McCullough PA. Contrast-induced acute kidney injury. Journal of the American College of

Cardiology. 2008;51:1419-28.4. Mehran R and Nikolsky E. Contrast-induced nephropathy: definition, epidemiology, and

patients at risk. Kidney international Supplement. 2006:S11-5.5. Reddan D, Laville M and Garovic VD. Contrast-induced nephropathy and its prevention:

What do we really know from evidence-based findings? Journal of nephrology.2009;22:333-51.

6. Weisbord SD, Mor MK, Resnick AL, Hartwig KC, Sonel AF, Fine MJ and Palevsky PM.Prevention, incidence, and outcomes of contrast-induced acute kidney injury. Archives ofinternal medicine. 2008;168:1325-32.

7. Stone GW, McCullough PA, Tumlin JA, Lepor NE, Madyoon H, Murray P, Wang A, Chu AA,Schaer GL, Stevens M, Wilensky RL and O'Neill WW. Fenoldopam mesylate for theprevention of contrast-induced nephropathy: a randomized controlled trial. Jama.2003;290:2284-91.

8. McCullough PA, Adam A, Becker CR, Davidson C, Lameire N, Stacul F and Tumlin J. Riskprediction of contrast-induced nephropathy. The American journal of cardiology.2006;98:27k-36k.

9. Laskey W, Aspelin P, Davidson C, Rudnick M, Aubry P, Kumar S, Gietzen F and WiemerM. Nephrotoxicity of iodixanol versus iopamidol in patients with chronic kidney disease anddiabetes mellitus undergoing coronary angiographic procedures. American heart journal.2009;158:822-828.e3.

10. Weisberg LS, Kurnik PB and Kurnik BR. Risk of radiocontrast nephropathy in patients withand without diabetes mellitus. Kidney international. 1994;45:259-65.

11. Cigarroa RG, Lange RA, Williams RH and Hillis LD. Dosing of contrast material to preventcontrast nephropathy in patients with renal disease. The American journal of medicine.1989;86:649-52.

12. Manske CL, Sprafka JM, Strony JT and Wang Y. Contrast nephropathy in azotemicdiabetic patients undergoing coronary angiography. The American journal of medicine.1990;89:615-20.

13. Bartholomew BA, Harjai KJ, Dukkipati S, Boura JA, Yerkey MW, Glazier S, Grines CL andO'Neill WW. Impact of nephropathy after percutaneous coronary intervention and amethod for risk stratification. The American journal of cardiology. 2004;93:1515-9.

14. From AM, Bartholmai BJ, Williams AW, Cha SS and McDonald FS. Mortality associatedwith nephropathy after radiographic contrast exposure. Mayo Clinic proceedings.2008;83:1095-100.

15. Gruberg L, Mintz GS, Mehran R, Gangas G, Lansky AJ, Kent KM, Pichard AD, Satler LFand Leon MB. The prognostic implications of further renal function deterioration within 48 hof interventional coronary procedures in patients with pre-existent chronic renalinsufficiency. Journal of the American College of Cardiology. 2000;36:1542-8.

16. Levy EM, Viscoli CM and Horwitz RI. The effect of acute renal failure on mortality. A cohortanalysis. Jama. 1996;275:1489-94.

17. Rihal CS, Textor SC, Grill DE, Berger PB, Ting HH, Best PJ, Singh M, Bell MR, BarsnessGW, Mathew V, Garratt KN and Holmes DR, Jr. Incidence and prognostic importance ofacute renal failure after percutaneous coronary intervention. Circulation.




98

2002;105:2259-64.18. Shema L, Ore L, Geron R and Kristal B. Contrast-induced nephropathy among Israeli

hospitalized patients: incidence, risk factors, length of stay and mortality. The IsraelMedical Association journal : IMAJ. 2009;11:460-4.

19. Weisbord SD, Chen H, Stone RA, Kip KE, Fine MJ, Saul MI and Palevsky PM.Associations of increases in serum creatinine with mortality and length of hospital stayafter coronary angiography. Journal of the American Society of Nephrology : JASN.2006;17:2871-7.

20. Weisbord SD, Gallagher M, Jneid H, Garcia S, Cass A, Thwin SS, Conner TA, ChertowGM, Bhatt DL, Shunk K, Parikh CR, McFalls EO, Brophy M, Ferguson R, Wu H,Androsenko M, Myles J, Kaufman J and Palevsky PM. Outcomes after Angiography withSodium Bicarbonate and Acetylcysteine. The New England journal of medicine.2018;378:603-614.

21. McCullough PA, Wolyn R, Rocher LL, Levin RN and O'Neill WW. Acute renal failure aftercoronary intervention: incidence, risk factors, and relationship to mortality. The Americanjournal of medicine. 1997;103:368-75.

22. Marenzi G, Assanelli E, Marana I, Lauri G, Campodonico J, Grazi M, De Metrio M, Galli S,Fabbiocchi F, Montorsi P, Veglia F and Bartorelli AL. N-acetylcysteine andcontrast-induced nephropathy in primary angioplasty. The New England journal ofmedicine. 2006;354:2773-82.

23. Maioli M, Toso A, Leoncini M, Gallopin M, Tedeschi D, Micheletti C and Bellandi F. Sodiumbicarbonate versus saline for the prevention of contrast-induced nephropathy in patientswith renal dysfunction undergoing coronary angiography or intervention. Journal of theAmerican College of Cardiology. 2008;52:599-604.

24. Brown JR, Malenka DJ, DeVries JT, Robb JF, Jayne JE, Friedman BJ, Hettleman BD,Niles NW, Kaplan AV, Schoolwerth AC and Thompson CA. Transient and persistent renaldysfunction are predictors of survival after percutaneous coronary intervention: insightsfrom the Dartmouth Dynamic Registry. Catheterization and cardiovascular interventions :official journal of the Society for Cardiac Angiography & Interventions. 2008;72:347-354.

25. Goldenberg I, Chonchol M and Guetta V. Reversible acute kidney injury following contrastexposure and the risk of long-term mortality. American journal of nephrology.2009;29:136-44.

26. Harjai KJ, Raizada A, Shenoy C, Sattur S, Orshaw P, Yaeger K, Boura J, Aboufares A,Sporn D and Stapleton D. A comparison of contemporary definitions of contrastnephropathy in patients undergoing percutaneous coronary intervention and a proposal fora novel nephropathy grading system. The American journal of cardiology. 2008;101:812-9.

27. Roghi A, Savonitto S, Cavallini C, Arraiz G, Angoli L, Castriota F, Bernardi G, Sansa M, DeServi S, Pitscheider W, Danzi GB, Reimers B, Klugmann S, Zaninotto M and Ardissino D.Impact of acute renal failure following percutaneous coronary intervention on long-termmortality. Journal of cardiovascular medicine (Hagerstown, Md). 2008;9:375-81.

28. Solomon RJ, Mehran R, Natarajan MK, Doucet S, Katholi RE, Staniloae CS, Sharma SK,Labinaz M, Gelormini JL and Barrett BJ. Contrast-induced nephropathy and long-termadverse events: cause and effect? Clinical journal of the American Society of Nephrology :CJASN. 2009;4:1162-9.

29. Adolph E, Holdt-Lehmann B, Chatterjee T, Paschka S, Prott A, Schneider H, Koerber T,




99

Ince H, Steiner M, Schuff-Werner P and Nienaber CA. Renal Insufficiency FollowingRadiocontrast Exposure Trial (REINFORCE): a randomized comparison of sodiumbicarbonate versus sodium chloride hydration for the prevention of contrast-inducednephropathy. Coronary artery disease. 2008;19:413-9.

30. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, Ford E,Furie K, Go A, Greenlund K, Haase N, Hailpern S, Ho M, Howard V, Kissela B, Kittner S,Lackland D, Lisabeth L, Marelli A, McDermott M, Meigs J, Mozaffarian D, Nichol G,O'Donnell C, Roger V, Rosamond W, Sacco R, Sorlie P, Stafford R, Steinberger J, Thom T,Wasserthiel-Smoller S, Wong N, Wylie-Rosett J and Hong Y. Heart disease and strokestatistics--2009 update: a report from the American Heart Association Statistics Committeeand Stroke Statistics Subcommittee. Circulation. 2009;119:480-6.

31. Subramanian S, Tumlin J, Bapat B and Zyczynski T. Economic burden of contrast-inducednephropathy: implications for prevention strategies. Journal of medical economics.2007;10:119-34.

32. Weisbord SD, Bruns FJ, Saul MI and Palevsky PM. Provider use of preventive strategiesfor radiocontrast nephropathy in high-risk patients. Nephron Clinical practice.2004;96:c56-62.

33. Mehran R, Dangas GD and Weisbord SD. Contrast-Associated Acute Kidney Injury. TheNew England journal of medicine. 2019;380:2146-2155.

34. Weisberg LS, Kurnik PB and Kurnik BR. Radiocontrast-induced nephropathy in humans:role of renal vasoconstriction. Kidney international. 1992;41:1408-15.

35. Nicot GS, Merle LJ, Charmes JP, Valette JP, Nouaille YD, Lachatre GF and Leroux-RobertC. Transient glomerular proteinuria, enzymuria, and nephrotoxic reaction induced byradiocontrast media. Jama. 1984;252:2432-4.

36. Bakris GL, Lass N, Gaber AO, Jones JD and Burnett JC, Jr. Radiocontrastmedium-induced declines in renal function: a role for oxygen free radicals. The Americanjournal of physiology. 1990;258:F115-20.

37. Katholi RE, Woods WT, Jr., Taylor GJ, Deitrick CL, Womack KA, Katholi CR and McCannWP. Oxygen free radicals and contrast nephropathy. American journal of kidney diseases :the official journal of the National Kidney Foundation. 1998;32:64-71.

38. Yoshioka T, Fogo A and Beckman JK. Reduced activity of antioxidant enzymes underliescontrast media-induced renal injury in volume depletion. Kidney international.1992;41:1008-15.

39. Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U, Byrne RA,Collet JP, Falk V, Head SJ, Juni P, Kastrati A, Koller A, Kristensen SD, Niebauer J, RichterDJ, Seferovic PM, Sibbing D, Stefanini GG, Windecker S, Yadav R and Zembala MO.2018 ESC/EACTS Guidelines on myocardial revascularization. European heart journal.2019;40:87-165.

40. Jurado-Roman A, Hernandez-Hernandez F, Garcia-Tejada J, Granda-Nistal C, Molina J,Velazquez M, Albarran A and Tascon J. Role of hydration in contrast-induced nephropathyin patients who underwent primary percutaneous coronary intervention. The Americanjournal of cardiology. 2015;115:1174-8.

41. O'Gara PT, Kushner FG, Ascheim DD, Casey DE, Jr., Chung MK, de Lemos JA, EttingerSM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA,Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso CL,




100

Tracy CM, Woo YJ and Zhao DX. 2013 ACCF/AHA guideline for the management ofST-elevation myocardial infarction: a report of the American College of CardiologyFoundation/American Heart Association Task Force on Practice Guidelines. Journal of theAmerican College of Cardiology. 2013;61:e78-e140.

42. Jo SH, Youn TJ, Koo BK, Park JS, Kang HJ, Cho YS, Chung WY, Joo GW, Chae IH, ChoiDJ, Oh BH, Lee MM, Park YB and Kim HS. Renal toxicity evaluation and comparisonbetween visipaque (iodixanol) and hexabrix (ioxaglate) in patients with renal insufficiencyundergoing coronary angiography: the RECOVER study: a randomized controlled trial.Journal of the American College of Cardiology. 2006;48:924-30.

43. Juergens CP, Winter JP, Nguyen-Do P, Lo S, French JK, Hallani H, Fernandes C, JepsonN and Leung DY. Nephrotoxic effects of iodixanol and iopromide in patients with abnormalrenal function receiving N-acetylcysteine and hydration before coronary angiography andintervention: a randomized trial. Internal medicine journal. 2009;39:25-31.

44. Reed M, Meier P, Tamhane UU, Welch KB, Moscucci M and Gurm HS. The relative renalsafety of iodixanol compared with low-osmolar contrast media: a meta-analysis ofrandomized controlled trials. JACC Cardiovascular interventions. 2009;2:645-54.

45. Brar SS, Aharonian V, Mansukhani P, Moore N, Shen AY, Jorgensen M, Dua A, Short Land Kane K. Haemodynamic-guided fluid administration for the prevention ofcontrast-induced acute kidney injury: the POSEIDON randomised controlled trial. Lancet(London, England). 2014;383:1814-23.

46. Luo Y, Wang X, Ye Z, Lai Y, Yao Y, Li J and Liu X. Remedial hydration reduces theincidence of contrast-induced nephropathy and short-term adverse events in patients withST-segment elevation myocardial infarction: a single-center, randomized trial. Internalmedicine (Tokyo, Japan). 2014;53:2265-72.

47. Maioli M, Toso A, Leoncini M, Micheletti C and Bellandi F. Effects of hydration incontrast-induced acute kidney injury after primary angioplasty: a randomized, controlledtrial. Circulation Cardiovascular interventions. 2011;4:456-62.

48. Marenzi G, Ferrari C, Marana I, Assanelli E, De Metrio M, Teruzzi G, Veglia F, FabbiocchiF, Montorsi P and Bartorelli AL. Prevention of contrast nephropathy by furosemide withmatched hydration: the MYTHOS (Induced Diuresis With Matched Hydration Compared toStandard Hydration for Contrast Induced Nephropathy Prevention) trial. JACCCardiovascular interventions. 2012;5:90-7.

49. Nijssen EC, Rennenberg RJ, Nelemans PJ, Essers BA, Janssen MM, Vermeeren MA,Ommen VV and Wildberger JE. Prophylactic hydration to protect renal function fromintravascular iodinated contrast material in patients at high risk of contrast-inducednephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label,non-inferiority trial. Lancet (London, England). 2017;389:1312-1322.

50. Qian G, Fu Z, Guo J, Cao F and Chen Y. Prevention of Contrast-Induced Nephropathy byCentral Venous Pressure-Guided Fluid Administration in Chronic Kidney Disease andCongestive Heart Failure Patients. JACC Cardiovascular interventions. 2016;9:89-96.

51. Trivedi HS, Moore H, Nasr S, Aggarwal K, Agrawal A, Goel P and Hewett J. A randomizedprospective trial to assess the role of saline hydration on the development of contrastnephrotoxicity. Nephron Clinical practice. 2003;93:C29-34.

52. Global, regional, and national incidence, prevalence, and years lived with disability for 354diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis




101

for the Global Burden of Disease Study 2017. Lancet (London, England).2018;392:1789-1858.

53. Summary of the 2018 Report on Cardiovascular Diseases in China. Chinese CirculationJournal，March，2019，Vol. 34 No.3（Serial No.249）

54. Narula A, Mehran R, Weisz G, Dangas GD, Yu J, Genereux P, Nikolsky E, Brener SJ,Witzenbichler B, Guagliumi G, Clark AE, Fahy M, Xu K, Brodie BR and Stone GW.Contrast-induced acute kidney injury after primary percutaneous coronary intervention:results from the HORIZONS-AMI substudy. European heart journal. 2014;35:1533-40.

55. Marenzi G, Lauri G, Assanelli E, Campodonico J, De Metrio M, Marana I, Grazi M, Veglia Fand Bartorelli AL. Contrast-induced nephropathy in patients undergoing primaryangioplasty for acute myocardial infarction. Journal of the American College of Cardiology.2004;44:1780-5.

56. Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, Filippatos G, Hamm C, HeadSJ, Juni P, Kappetein AP, Kastrati A, Knuuti J, Landmesser U, Laufer G, Neumann FJ,Richter DJ, Schauerte P, Sousa Uva M, Stefanini GG, Taggart DP, Torracca L, ValgimigliM, Wijns W and Witkowski A. 2014 ESC/EACTS Guidelines on myocardialrevascularization: The Task Force on Myocardial Revascularization of the EuropeanSociety of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery(EACTS)Developed with the special contribution of the European Association ofPercutaneous Cardiovascular Interventions (EAPCI). European heart journal.2014;35:2541-619.

57. Trivedi H and Foley WD. Contrast-induced nephropathy after a second contrast exposure.Renal failure. 2010;32:796-801.

58. Briguori C, Visconti G, Rivera NV, Focaccio A, Golia B, Giannone R, Castaldo D, De MiccoF, Ricciardelli B and Colombo A. Cystatin C and contrast-induced acute kidney injury.Circulation. 2010;121:2117-22.

59. Maioli M, Toso A, Leoncini M, Gallopin M, Musilli N and Bellandi F. Persistent renaldamage after contrast-induced acute kidney injury: incidence, evolution, risk factors, andprognosis. Circulation. 2012;125:3099-107.

60. Tan N, Liu Y, Chen JY, Zhou YL, Li X, Li LW, Yu DQ, Chen ZJ, Liu XQ and Huang SJ. Useof the contrast volume or grams of iodine-to-creatinine clearance ratio to predict mortalityafter percutaneous coronary intervention. American heart journal. 2013;165:600-8.

61. Newcombe RG. Interval estimation for the difference between independent proportions:comparison of eleven methods. Statistics in medicine. 1998;17:873-90.

62. Mehran R, Aymong ED, Nikolsky E, Lasic Z, Iakovou I, Fahy M, Mintz GS, Lansky AJ,Moses JW, Stone GW, Leon MB and Dangas G. A simple risk score for prediction ofcontrast-induced nephropathy after percutaneous coronary intervention: development andinitial validation. Journal of the American College of Cardiology. 2004;44:1393-9.

63. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio ALP,Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ, Prescott E,Roffi M, Valgimigli M, Varenhorst C, Vranckx P and Widimsky P. 2017 ESC Guidelines forthe management of acute myocardial infarction in patients presenting with ST-segmentelevation: The Task Force for the management of acute myocardial infarction in patientspresenting with ST-segment elevation of the European Society of Cardiology (ESC).European heart journal. 2018;39:119-177.




102

64. Brienesse SC, Davies AJ, Khan A and Boyle AJ. Prognostic Value of LVEDP in AcuteMyocardial Infarction: a Systematic Review and Meta-Analysis. Journal of cardiovasculartranslational research. 2018;11:33-35.

65. Barrett BJ and Carlisle EJ. Metaanalysis of the relative nephrotoxicity of high- andlow-osmolality iodinated contrast media. Radiology. 1993;188:171-8.

66. Rudnick MR, Goldfarb S, Wexler L, Ludbrook PA, Murphy MJ, Halpern EF, Hill JA,Winniford M, Cohen MB and VanFossen DB. Nephrotoxicity of ionic and nonionic contrastmedia in 1196 patients: a randomized trial. The Iohexol Cooperative Study. Kidneyinternational. 1995;47:254-61.

67. Kushner FG, Hand M, Smith SC, Jr., King SB, 3rd, Anderson JL, Antman EM, Bailey SR,Bates ER, Blankenship JC, Casey DE, Jr., Green LA, Hochman JS, Jacobs AK, KrumholzHM, Morrison DA, Ornato JP, Pearle DL, Peterson ED, Sloan MA, Whitlow PL andWilliams DO. 2009 focused updates: ACC/AHA guidelines for the management of patientswith ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focusedupdate) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updatingthe 2005 guideline and 2007 focused update) a report of the American College ofCardiology Foundation/American Heart Association Task Force on Practice Guidelines.Journal of the American College of Cardiology. 2009;54:2205-41.

68. Sun G, Chen P, Wang K, Li H, Chen S, Liu J, He Y, Song F, Liu Y and Chen JY.Contrast-Induced Nephropathy and Long-Term Mortality After Percutaneous CoronaryIntervention in Patients With Acute Myocardial Infarction. Angiology.2018:3319718803677.

69. Zeng JF, Chen SQ, Ye JF, Chen Y, Lei L, Liu XQ, Liu Y, Wang Y, Lin JJ and Chen JY. Asimple risk score model for predicting contrast-induced nephropathy after coronaryangiography in patients with diabetes. Clinical and experimental nephrology.2019;23:969-981.

70. Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U, Byrne RA,Collet JP, Falk V, Head SJ, Juni P, Kastrati A, Koller A, Kristensen SD, Niebauer J, RichterDJ, Seferovic PM, Sibbing D, Stefanini GG, Windecker S, Yadav R and Zembala MO.[2018 ESC/EACTS Guidelines on myocardial revascularization]. Kardiologia polska.2018;76:1585-1664.




103

Appendix D

Changes to ATTEMPT protocol



TableA5. Changes to ATTEMPT protocolOriginalProtocolVersionNumber

NewProtocolVersionNumber

Description of Change Justification forChange

2.0 3.0

Update of cover. The version ofthe program was changed from "2.0,June 11, 2014" to "3.0, February 04,2015".The list of participating units wasdeleted, and the main research unitsand main researchers were added.

These changes do notaffect the safety, data quality orscope of the participants, so theresearch leader held a researchmeeting on February 3, 2015and obtained the consent of theresearch team.

2.0 3.0

Update of scheme summary. Thenumber of test center has beenincreased, such as Shenzhen People'sHospital, Beijing Ditan Hospital, etc.

Since more test centerswished to participate in thestudy during the study, theyparticipated and added to theresearch program. The sponsorselects the institution andinvestigator of the clinicaltrial ,and approves qualificationsas well as conditions to ensurethe completion of the trial.

2.0 3.0The statement of intervention

group was changed to the treatmentgroup.

Standardize statements toensure clear language

2.0 3.0The study deadline was revised

from "May 2014-October 2016" to"June 2014-October 2016"

The study was conductedin June 2014, so the studydeadline was revised.

2.0 3.0

Updated research procedure: 7days after surgery was changed to 4-7days after surgery;the two follow-upsincluding 30±7 days after operationand ±14 days after operation wereadded.

For patients receiving directPCI, the number of hospitalstays is variable. If we need toknow more relevant test itemsafter surgery, the visit timeshould be relaxed to 4-7 days;At the same time, in order toensure the integrity of theresearch data to assess theprogress of contrastnephropathy better, An increaseof two visits of 30 ± 7 days aftersurger and 6 months ± 14 daysafter surgery will reduce thenumber of patients missing themain outcome of this part.



2.0 3.0Update the Timetable of visits and

proceduresUpdated according to new

research process

2.0 3.0

The main endpoint of observationwas to retain only"contrast-inducednephropathy: Serum creatinine (SCr)increased by more than 0.5 mg/dL or25% in 48-72 hours after direct PCIcompared with baseline absolutevalue", and "Contrast-induced acutekidney injury: 10% or 0.3 mg/dL ofCystatin-C increased within 24 hoursafter PCI" was deleted.

Correction of main endpointcriteria was made according toclinical practice.

2.0 3.0

Delete the word " composite " ofthe "secondary endpoint: compositemajor cardiac adverse events:all-cause death, nonfatal myocardialinfarction, target vesselrevascularization".

Correction of secondaryendpoint criteria was madeaccording to clinical practice.

2.0 3.0Correct the 5.1 Study population

sub-heading from the rejection criteriato the exclusion criteria

4.3.2 standard is anexclusion criterion, which is anerror.

2.0 3.0

11.2 Research training, delete the"especially the standard of TCMsyndrome classification should beunified".

This study does not requireresearchers to have a unifiedunderstanding of the criteria forTCM syndrome classification.



Appendix E

ATTEMEPT Clinical Trial Case Report Form




Yong Liu:ATTEMPT Clincal Trial Case Reprot Form Version 3.0

1

1.Inclusion criteria

Items Yes No

a. Age ≥ 18 years. □ □

b. Patients with STEMI were likely to undergo primary PCI. □ □

c. Written informed consent. □ □

Any of item above is“no”，the participant is not allowed to enroll.

2.Exclusion criteria

Items Yes No

a. Did not undergo pPCI or die during the procedure. □ □

b. Severe Heart failure (Cardiac shock or NYHA IV). □ □

c. patients with end-stage renal failure or after renal transplantation. □ □

d. An increase > 0.5mg/dl of Scr within 24 h before the procedure compared to

the baseline value.□ □

e. Intravascular administration of a contrast medium within 1 week before thepPCI or 72 h after pPCI,or has a history of acute infections disease.

□ □

f. Allergic to contrast medium. □ □

g. Pregnancy, lactation, or malignant tumoror life expectancy< 1 year. □ □

h. The use of non-steroidal anti-inflammatory drugs, aminoglycoside drugs,

cyclosporine, cisplatin etc renal toxicity drugs within 48 h before cardiac

catheter surgery and the whole process of the research.

□ □

i. Likely to undergo renal artery intervention or surgical valve replacement in

patients with rheumatic heart disease.□ □

j. Inferior and/or right ventricle myocardial infraction combined with

hypotension on admission (systolic pressure ≤90 mmHg).□ □

k. Pre-procedural renal insufficiency eGFR ≤60 mL/min/1.73 m2. □ □

Any of item above is“yes”，the participant is not allowed to enroll.



http://dict.youdao.com/w/exclusion/

http://dict.youdao.com/w/criteria/


2

1.Random check

a. Did the subjects meet all the inclusion criteria and none of the exclusion criteria?

□yes

□no

2.Random allocation

a. Subject group

□Intervention group (aggressive hydration)

□control group (general hydration)

b. Subject random number □□□□□

c. Date of randomization □□h□□min on□□day□□month□□□□year

Center number Participant numberAbbreviation of phoneticize

spell of participant’s nameInterview 0

（-7～0 d）□□ □□□□ □□□□



http://dict.youdao.com/w/interview/


3

1.Screening data

a. Date of written informed consent □□day□□month□□□□year

b. Date of screening □□day□□month□□□□year

2.Demographics

a. Date of birth □□day□□month□□□□year

b. Gender □male □female

c. Nationality □Han nationality □other

3.Hospital admission information

a. Time of symptoms onset □□h□□min on□□day□□month□□□□year

b. Time of first medical contact (FMC) □□h□□min on□□day□□month□□□□year

c. Time of admission □□h□□min on□□day□□month□□□□year

d. Time of entering catheterization laboratory □□h□□min on□□day□□month□□□□year

e. Did thrombolytic therapy be used in this case? □yes □no

If it did, then the time of thrombolytic therapy □□h□□min on□□day□□month□□□□year

f. Did cardiac arrest happen in this case? □yes □no

If it did, then the time of cardiac arrest □□h□□min on□□day□□month□□□□year

g. Did heart failure happen in this case? □yes □no

h. Heart function (Killip class) □Ⅰ □Ⅱ □Ⅲ □Ⅳ

i. Use of IABP □yes □no

j. Use of vasoactive drugs □yes □no

k. Were intravenous fluids administered before the randomization? □yes □no

If it were,then Specific amount of intravenous fluids □□ml □unknown



（-7～0 d）□□ □□□□ □□□□




4

4.Past medical history and family history

a. Hypertension □yes □no

b. Diabetes mellitus □yes □no

c. Hyperlipidemia □yes □no

d. Coronary artery disease □yes □no

e. Acute myocardial infarction □yes □no

Time of onset-treatment:

f. Congestive heart failure □yes □no

g. Chronic kidney diseases □yes □no

h. History of smoking □yes □no

i. Peripheral arterial disease □yes □no

j. Smoke □yes □no

k. Chronic obstructive pulmonary disease □yes □no

l. Previous family history of coronary heart disease □yes □no

5.Physical examination

a. Height □□□.□cm b. weight □□□.□kg

c. Blood pressure □□□/□□□mm Hg d.Heart beat □□□b.p.m

Items Normal

AbnormalDescribe the abnormal

situation in detailunknownDon’t exsist

clinical valueExsist

clinical value

e. Heart □ □ □ □

f. Lung □ □ □ □

g. Abdomen □ □ □ □

h. Nervous

system

□ □ □ □

i. Limbs □ □ □ □



（-7～0 d）□□ □□□□ □□□□




http://dict.youdao.com/w/chronic/

http://dict.youdao.com/w/kidney/

http://dict.youdao.com/w/diseases/

http://dict.youdao.com/w/nervous/

http://dict.youdao.com/w/system/

5

6.1Echocardiogram tests(ECG)

a. Whether to conduct electrocardiogram examination during the screening period □yes □no

b. Time of conduct electrocardiogram examination □□h□□min on□□day□□month□□□□year

c. Results with electrocardiogram

□ normal ECG

□ ST-segment elevation,specific lead:

□ non-ST-segment elevation

□ arrhythmia

□ Q wave,specific lead:

□ other



（-7～0 d）□□ □□□□ □□□□

6.2Heart ultrasound examination Interview date:□□day□□month201□year

Echocardiography was performed during the screening period □yes □no(if no,then turn to 7)

LVDd □□mm LVDs □□mm LVEF □□%

ventricular

aneurysm

□yes □no

regional wall motion abnormality□yes □no

location（multiple）：□anterior □anteroseptal □ministry of ventricular septal apex

□cardiac apex □inside wall □Paries posterior □inferior □interval □right

ventricle □unknown




http://dict.youdao.com/w/eng/non-st-segment_elevation/

http://dict.youdao.com/w/eng/non-st-segment_elevation/

http://dict.youdao.com/w/arrhythmia/


http://dict.youdao.com/w/ventricular/

http://dict.youdao.com/w/aneurysm/

6

#Clinical significance determination：1=normal；2=abnormal without clinical significance；3= abnormal with clinical

significance



（-7～0 d）□□ □□□□ □□□□

7.cardiac markers

Item Result Unit unknownClinical significance

determination#1 2 3

a. CK U/L □ □ □ □

b. CK-MB U/L □ □ □ □

c. troponinT(quantitative)

ng/L □ □ □ □

d. troponinI(quantitative)

ng/L □ □ □ □

e. high-sensitivitytroponin

pg/ml □ □ □ □

f. NT-proBNP pg/ml □ □ □ □

g. BNP pg/ml □ □ □ □




7


significance


significance


significance



（-7～0 d）□□ □□□□ □□□□

8.routine blood test


determination#1 2 3

a. white blood cell ×109/L □ □ □ □

b. hemoglobin g/L □ □ □ □

c. platelet count ×109/L □ □ □ □

d. hematocrit % □ □ □ □

e. NEU% % □ □ □ □

9.Biochemical examination


determination#1 2 3

a. serum creatinine µmol/L □ □ □ □

b. Serum cystatin C mg/L □ □ □ □

c. Serum urea nitrogen mmol/L □ □ □ □

d. Na mmol/L □ □ □ □

e. K mmol/L □ □ □ □

f. Instant BloodGlucose

mmol/L □ □ □ □

10.Other examination


determination#1 2 3

a. hs-CRP mg/L □ □ □ □




8

11.pregnancy check

ItemResult

unknown UnapplicablePositive Negative

a. pregnancy check* □ □ □ □

*test for the women likely to be pregnant.

Signature of investigator：________________ date: □□day□□month□□□□year



（-7～0 d）□□ □□□□ □□□□

12.concomitant medication

Fill the use of drugs 14 days before screening in “ record of concomitant medication”




http://dict.youdao.com/w/pregnancy/

http://dict.youdao.com/w/check/

http://dict.youdao.com/w/pregnancy/

http://dict.youdao.com/w/check/

http://dict.youdao.com/w/eng/signature_of_principal_investigator/

9



（24±4h after procedure）□□ □□□□ □□□□

Peri-procedural oral hydration

Oral distilled water hydration:□no □yes

coronary diagnostic and intervention within 24 h after procedure

Duration of hydration:□□h□□min □no dataOral fluid volume

□□□□mlStart time:□□h□□min on□□day□□month□□□□year □unknown

End time:□□h□□min on□□day□□month□□□□year □unkonwn

Peri-procedural urine volume

coronary diagnostic and intervention within 24 h after procedure urine volume□□□□ml



10




1.Primary PCI

a. Primary PCI or not □yes □no

b. The beginning time of procedure:□□h□□min on□□day□□month□□□□year

c. The endning time of procedure:□□h□□min on□□day□□month□□□□year

d. The time of balloon dilation:□□h□□min on□□day□□month□□□□year

e. Type of ontrast:□iodixanol □iopromide □iopamidol □iohexol

f. Contrast volume(Accurate to one digit):

g. The use of GPIIb/IIIa Inhibitors □yes □no

h. The use of thrombus aspiration □yes □no

i. The use of IABP □yes □no

j. Post-procedure LVEDP □□mmHg

2.Coronary lesion and interventional treatment

a. LAD:

lesion：□yes □no interventional treatment：□yes □no

interventional measure：□PTCA □PCI □thrombus aspiration

TIMI before intervention □0 □Ⅰ □Ⅱ □Ⅲ

TIMI after intervention □0 □Ⅰ □Ⅱ □Ⅲ

Bailout- stenting：□ no □DES □BMS

Number of stents：□，length of stents□□mm

b. LCX:



TIMI before intervention □0 □Ⅰ □Ⅱ □Ⅲ

TIMI after intervention □0 □Ⅰ □Ⅱ □Ⅲ

Bailout- stenting：□ no □DES □BMS




http://dict.youdao.com/w/iodixanol/

http://dict.youdao.com/w/iopromide/

http://dict.youdao.com/w/iopamidol/

http://dict.youdao.com/w/iohexol/

11




c. RCA:



TIMI before intervention □0 □Ⅰ □Ⅱ □ⅢTIMI after intervention □0 □Ⅰ □Ⅱ □ⅢBailout- stenting：□ no □DES □BMS


d. LM:





e. coronary bypass grafts





f. Culprit lesion：□LAD □LCX □RCA □LM □coronary bypass grafts □unknown

g.CTO：□yes □no location：□LAD □LCX □RCA □LM □coronary bypass grafts

3.Clinical events

All new clinical events should be recorded in clinical events record form

4.concomitant medicationAll new use of drugs should be recorded in 《Combined Medication Record Form》



12





significance

1.Vital signs

a. Blood pressure 1 h after post-procedure:□□□/□□□mmHg Heart beat: □□□b.p.m

b. Blood pressure 2 h after post-procedure:□□□/□□□mmHg Heart beat: □□□b.p.m

c. Blood pressure 3 h after post-procedure:□□□/□□□mmHg Heart beat: □□□b.p.m

d. Blood pressure 4 h after post-procedure:□□□/□□□mmHg Heart beat: □□□b.p.m

e. Blood pressure 5 h after post-procedure:□□□/□□□mmHg Heart beat: □□□b.p.m

f. Blood pressure 6 h after post-procedure:□□□/□□□mmHg Heart beat: □□□b.p.m

g. Blood pressure 24 h after post-procedure:□□□/□□□mmHg Heart beat: □□□b.p.m

2.Renal function(24±4h after procedure)

The date of blood collection：□□day□□month□□□□year

item result unit unknownClinical significance

determination#1 2 3

a. SCr µmol/L □ □ □ □

b. cystatin C mg/L □ □ □ □

c. urea nitrogen mmol/L □ □ □ □


e. K mmol/L □ □ □ □

If the serum creatinine (SCr) increased by more than 0.3 mg/dL within 72 hours post-procedure, the

renal function of the subjects was monitored until 1 week after operation.



13





significance

3.Other examination



determination#1 2 3

a. ALT U/L □ □ □ □

b. AST U/L □ □ □ □

c. Total cholesterol mmol/L □ □ □ □

d. triglyceride mmol/L □ □ □ □

e. LDL-C mmol/L □ □ □ □

f. HDL-C mmol/L □ □ □ □

g. apolipoproteina mmol/L □ □ □ □

h. serum total bilirubin μmol/L □ □ □ □

i.serum direct bilirubin μmol/L □ □ □ □

j. Serum albumin g/L □ □ □ □

k.CK U/L □ □ □ □

l. CKMB U/L □ □ □ □

m. hs-CRP mg/L □ □ □ □

n. Uric acid μmol/L □ □ □ □

o. HbAlc mmol/L □ □ □ □



14





4.Heart and carotid ultrasound examination

Interview date:□□day□□month201□year

Echocardiography on addmision □yes □no

LVDd □□mm LVDs □□mm LVEF □□%

ventricular

aneurysm

□yes □no

regional wall motion abnormality□yes □no

location（multiple）：□anterior □anteroseptal □ministry of ventricular septal apex

□cardiac apex □inside wall □Paries posterior □inferior □interval □right

ventricle □unknown

carotid ultrasound examination on addmision □yes □no

carotid plaque

□no □yes

stenosis：□yes □no Max stenosis：left side□□%, right side□□%

Carotid intimal thickening：□yes □no, IMT thickening ：left side □.□mm，right

side□.□mm

5.Clinical events

All new clinical events should be recorded in 《clinical events record form》





http://dict.youdao.com/w/ventricular/

http://dict.youdao.com/w/aneurysm/

http://dict.youdao.com/w/carotid/

http://dict.youdao.com/w/plaque/


15





significance


Interview date: □□day□□month□□□□year

1.Vital signs





determination#1 2 3





e. K mmol/L □ □ □ □

f. hs-CRP mg/L □ □ □ □



3.Clinical events






16



（4 days after procedure）□□ □□□□ □□□□


significance



1.Vital signs





determination#1 2 3





e. K mmol/L □ □ □ □




3.Clinical events






17



（4-7 days after procedure）□□ □□□□ □□□□


significance



1.Vital signs

a. Blood pressure:□□□/□□□mmHg Heart beat: □□□b.p.m

2.Renal function



determination#1 2 3





e. K mmol/L □ □ □ □


3.Clinical events



5.Date of discharge and total hospitalization expenses

Date of discharge:□□day□□month□□□□year total hospitalization expenses:□□□□yuan




18



（1 month after PCI）□□ □□□□ □□□□


significance



1.Vital signs(optional)


b. weight:□□□.□kg

2.Renal function(optional)



determination#1 2 3





e. K mmol/L □ □ □ □


3.Clinical events






19





significance



1.Vital signs



2.Renal function



determination#1 2 3





e. K mmol/L □ □ □ □


3.Clinical events






20





significance



1.Vital signs(optional)



2.Renal function(optional)



determination#1 2 3





e. K mmol/L □ □ □ □


3.Clinical events






21



（1 year after PCI）□□ □□□□ □□□□


significance


1.Vital signs



2.Renal function



determination#1 2 3





e. K mmol/L □ □ □ □


3.Clinical events






22

Center number Participant number Abbreviation of phoneticize spell of participant’s nameconcomitant medication / page

□□ □□□□ □□□□

Combined Medication Record FormRecord the subject's medication from 14 days before the operation to the completion or suspension of the study.

No.Drug name

(common name)Dose Unit

Route ofadministration

Start date The drug is still used at Visit7 (if yes:□ marked with “×”)

Reason formedicationEnd date

□□day□□month□□□□year□

□□day□□month□□□□year











Note: route of administration (1 = po; 2 =ih; 3 = im; 4 = iv; 5 = local topical; 6 = other)

Investigator Signature：__________________________Data：□□day□□month□□□□year



23


□□ □□□□ □□□□


No.Drug name





















24


□□ □□□□ □□□□


No.Drug name





















25


□□ □□□□ □□□□


No.Drug name





















26

Center number Participant number Abbreviation of phoneticize spell of participant’s nameTable of hydration schemes

□□ □□□□ □□□□

1. Random allocation

a. Which group is the subject randomly assigned to? □Intervention group □Control group

2.Intervention group hydration scheme

a. □No need to fill in (if you are in the control group, □mark with “×”)

Whether the hydration planis adjusted: 1. Yes, 2. No

Reasons foradjustment ofhydration plan

Dose(ml/kg/h)

Hydration start Hydration end

Date (year / month / day) Time (hour: minute) Date (year / month / day) Time (hour: minute)





27

Center number Participant number Abbreviation of phoneticize spell of participant’s nameTable of hydration schemes

□□ □□□□ □□□□

3.Control group hydration scheme

a. □No need to fill in (if you are in the experimental group, □mark with “×”)

b. Whether the patient is hydrated ? □Yes □No (if not, the following form is not required)

Whether the hydration planis adjusted: 1. Yes, 2. No

Reasons foradjustment ofhydration plan

Dose(ml/kg/h)

Hydration start Hydration end

Date (year / month / day) Time (hour: minute) Date (year / month / day) Time (hour: minute)




28

Center number Participant number Abbreviation of phoneticize spell of participant’s nameclinical events record form__/__Page

□□ □□□□ □□□□

Clinical event table

Adverseevent

Occurrence date(year / month / day)

SeverityMeasures taken for

hydrationCausal relationship to

hydration

Action takenwith adverse

eventReturn of adverse event

Was thisEventSerious?

Resolution date(year / month / day)

1. Light2. Medium3. Heavy4. Unknown

1. Continue to hydrate2. Reduce dose3. Resume afterhydration pause4. Disable hydration

1. Definite (clearly related)2. Probable (likely related)3. Unlikely (doubtfullyrelated)4. Unrelated (clearly notrelated)5. Unable to judge

1.Yes2.None

1. Symptoms disappear2. Symptoms disappearwith sequelae3. Symptoms persist4. Death5. Unable to judge

1.Yes2.No

1

2

3




29


spell of participant’s name

Research Summary

Principal Investigator

statement□□ □□□□ □□□□

Research Summary

The date of completion/withdrawal of participant in the study

Whether the participant finish the whole clinical study according to the project

□yes

□no，the main reason for withdrawal（Individual）：

□withdrawal of informed consent/ the participant insist on withdrawing the

trial

□the participant had adverse events

□the participant had serious adverse events

□the participant had taken the drugs forbidden in this study

□Principal investigator consider it ok

□lost to follow-up

□other：

Principal Investigator statement

All the data collected in CRF have been reviewed，the accuracy and completeness of the

information shall be ensured，which bring into correspondence with the original file.

Signature of investigator：________________ date:




30

Record of oral hydration and urine volume ofpatients undergoing coronary intervention

Name: Bed room: AD: Height: cm Weight: kg

In order to facilitate the doctor to understand the patient's access, so as to minimize the risk ofcontrast nephropathy, please carefully fill in the following form!

Pre-procedure water intake(calculate from 22:00 the night before theprocedure)

Pre-procedure urinary output(calculatefrom 22:00 the night before theprocedure)

date time waterintake(ml)

brand date time urinaryoutput(ml)

Date of procedure: Time of return to ward after peocedure:

Post-procedure water intake(calculate from 24hafter the procedure)

Post-procedure urinary output(calculatefrom 24h after the procedure)

date time waterintake(ml)

brand date time urinaryoutput(ml)

Illustrate:1,the recorded water including the corresponding time period only after drinking water,pure water, mineral water, the latter two need to specify the brand, such as: "Kang Huaqing purewater", etc.,please record in the corresponding Spaces in time and water amount, urine output,for example: "22:00 400 ml.



Yong Liu:ATTEMPT Clincal Trial Statistical Analysis Plan Version 1.0

Appendix E

ATTEMEPT Clinical Trial Statistical Analysis Plan

Version 1.0





1

Statistical analysis plan for aggressive hydraTion in patients with ST-elevation

myocardial infarction undergoing primary percutaneous coronary intervention

to prevenT contrast-induced nephropathy (ATTEMPT) study

Abbreviations

SAP = statistical analysis plan;

STEMI = ST-elevation myocardial infarction;

CI-AKI = contrast-induced acute kidney injury;

pPCI = primary percutaneous coronary intervention;

LVEDP = Left ventricular end-diastolic pressure;

LVEF = Left ventricular ejection fraction;

CEC = Clinical Event Committee;

RR = Risk ratio; ARD = Absolute;

NNT = Number needed to treat;

SCr = Serum creatinine;

ITT = intention-to-treat;

DSMB = Data and safety monitoring committee.

1. Introduction

Patients who have ST-segment elevation myocardial infarction (STEMI) carry a

high-risk of contrast-induced acute kidney injury (CI-AKI) following primary

percutaneous coronary intervention (pPCI)1. However, for this high-risk group, the

extent of the effects of optimal hydration strategy is yet to be fully established2,3. The

aggressive hydraTion in patients with ST-Elevation Myocardial infarction undergoing

Primary percutaneous coronary intervention to prevenT contrast-induced nephropathy

(ATTEMPT) study is the first study to evaluate the peri-procedural aggressive

hydration in STEMI patients undergoing pPCI4. Here, we describe the statistical

analysis plan (SAP) for the ATTEMPT study, prior to patient enrollment being

completed (this was completed in June 2018) and the locking of the database for

analysis.

This SAP was written by the study statistician and the principal investigator, both




2

of whom were kept blind to the course of treatment allocated to the patients. We

prospectively defined each analysis described in this SAP.

2. Methods

2.1 Overview of design

The ATTEMPT study is a multicenter, randomized controlled trial which is

investigator-based and open label in nature. A total of 560 patients with STEMI

undergoing pPCI will be randomized (1:1) to undergo treatment either by

peri-procedural aggressive hydration (treatment group) or general hydration (control

group). The ATTEMPT study could prove valuable for the possible identification of

optimal hydration regimens for STEMI patients undergoing pPCI4.

2.2 Inclusion & Exclusion criteria

Inclusion criteria: All consecutive patients with STEMI who were at least 18

years of age and were prepared for pPCI were taken into consideration for enrollment

in the study.

Exclusion criteria:

Contrast medium administration within the 2 weeks prior to the procedure or the

following 3 days;

End-stage renal failure or renal transplantation, and refusal of pPCI or death

while the procedure is taking place;

Heart failure-induced cardiac shock or New York Heart Association class IV

(these patients were excluded because intravenous hydration administration could

potentially prove harmful);

A recent acute kidney injury, which was considered to be an absolute increase of

0.5 mg/dL in serum creatinine (SCr) over baseline in the 24 hours prior;

The existence of lactation, pregnancy;

A tumor of a malignant nature or a predicted life expectancy of 1 year or less;

An allergic reaction induced by contrast medium, peri-procedural receipt of

metformin, or non-steroidal anti-inflammatory drugs in the 2 days prior and while

the study is taking place;


2.3 Randomization




3

All patients meeting the eligibility criteria and provided informed consent will be

randomized into two study groups. A computer will carry out randomization of

eligible patients by producing numbers at random at a 1:1 ratio. Randomization will

be accomplished with using a block random method with 8 units in each group. Some

offset or variability will be inserted to prevent anticipation of the next treatment.

Randomization will be stratified based on age (<60, 60–75, >75 years), sex (male or

female), and STEMI location (anterior wall or no-anterior wall). Study coordinators at

each site will be responsible for obtaining a randomized treatment assignment for

each eligible patient. Study sites will be provided with a web-based randomization

program for this purpose. This web-based http://crdms.echobelt.org program will be

tested at each site prior to the start of the trial and will be reviewed. Since this is an

open-label study, the procedure of blinding will not take place.

2.4 Sample size

The total sample size of 560 patients was calculated based on our previous

findings. The incidence of primary end point was estimated to decrease to 11.5%

(50% relative reduction) in the aggressive hydration group from 23% in the control

group with general hydration5. We established a sample size according to nQuery +

nTerim 3.0 (Statistical Solutions Ltd, Ireland) by employing a 2-sided χ2 test, a power

of 90%, a significance level of 0.05, and a dropout rate <20%.

2.5 The formal statement of the null hypothesis

We fully describe the CI-AKI outcome based on the aggressive hydration versus

general hydration intervention. The null hypothesis is that the two treatment groups

(aggressive hydration and control) do not differ in terms of the proportion of subjects

who experience CI-AKI. The alternative hypothesis is that the absolute difference in

the incidence of CI-AKI between the aggressive hydration group and the control

group.

2.6 Intervention

A pre-procedural loading dose 250 mL of normal saline for 30 minutes (125 mL

for patients with congestive heart failure, Killip II/III or NYHA III) will be

administered to the patients in the treatment group in an emergency department or




4

cardiac catheterization lab over 30-minutes prior to the pPCI. After this, the patients

will receive intravenous hydration at a general rate (1 or 0.5 mL/kg/h for patients with

congestive heart failure, Killip II/III or NYHA III) until LVEDP measurement.

Patients will then undergo 4 hours of post-procedural aggressive hydration guided

by LVEDP [5 mL/kg/h (LVEDP <13 mmHg), 3 mL/kg/h (LVEDP 13–18 mmHg),

1.5mL/kg/h (LVEDP >18 mmHg), and 0.5 mL/kg/h (LVEDP >20 mmHg)] and

continuous intravascular hydration at the normal rate for the 24 hours following PCI.

Control group patients will receive peri-procedural general hydration with ≤500 mL

normal saline (within 6 hours) at a normal rate (0.5 or 1 mL/kg/h).

2.7 Interim analysis

According to the study design, interim analysis to determine if either intervention

shows a substantial beneficial effect will not be carried out.

2.8 Timing of analysis

At the end of the study, the final audit should be performed usually within four to

six weeks of the end of the last follow-up of the last subject in the study center. The

preparations and procedures for the study of closed visits are generally the same as for

a regular supervisory visit. The last patient was enrolled on 10th June 2018 (Table 1).

Table 1 Analysis timing of measurement for endpointsEndpoint Analysis timing

Primary endpoint

CI-AKI 48 to 72 hours after the procedure

Secondary endpoint

CI-AKI48 h 48 hours after the procedure

CI-AKICysC 24 hours after the procedure

Major adverse cardiovascular events Within the first year after enrollment

Major adverse clinical events Within the first year after enrollment

CI-PKI requiring dialysis Within the 3-month after enrollment

Total hospitalization costs Discharge from hospital

Length of stay Discharge from hospital

Safety endpoint

Acute heart failure Within the hospitalization after enrollment

CI-AKI, contrast-induced acute kidney injury; CI-PKI, contrast-induced persistent

renal damage.




5

2.9 Analysis principles

Analysis is to be conducted based on adjusted intention-to-treat (ITT)

(randomization must be finished before emergency surgery, and we will not

include the patients who need to be excluded from the final analysis).

We will not impute missing values, unless specified. The number of subjects

included in an analysis will be reported if there is a substantial amount of missing

data. The last observations will not be carried forward. Multiple imputation will

be used if >5% of patients have missing data on the primary outcome.

Each of the tests will be two-tailed, and a P value of less than 0.05 will be

considered to be statistically significant.

Only analyses conducted up to 1 year after randomization will feature in this

analysis plan and in the primary manuscript.

Pre-specified subgroup analyses will be conducted whether or not a statistically

significant treatment effect on the primary outcome is seen across the total

sample.

We use the t-test for normally distributed continuous variables and expressed as

mean ± SD, and the Wilcoxon rank-sum test was used in non-normal distribution

variables and presented as median and interquartile range.

For categorical variables, we used Pearson χ2 or Fisher’s exact tests to compare

baseline characteristics and study’s endpoints between the aggressive and general

hydration groups; these will be expressed as percentages.

Multivariable logistic regression models will be developed to adjust for clinical

characteristics (eg, age, sex, creatinine clearance, and left ventricular ejection

fraction [LVEF]), and the Mehran risk score will be calculated. Odds ratios will

be reported alongside their related 95% CIs.

2.9.1 Analysis of primary outcome

The primary analysis will be based on adjusted intention to treat principles. Since

the intervention is given and the primary outcome is observed for a very short

duration (72 hours), we expect only a few dropouts or crossovers.

As ATTEMPT study’s protocol pointed out primary outcome would use

multivariable logistic regression with (age, sex, creatinine clearance, and left

ventricular ejection fraction). The analysis for each variable will be performed by OR




6

with their corresponding 95% CIs to describe the intervention effect. All tests will be

two-tailed, and a P value less than 0.05 will be considered statistically significant.

All consented and randomized subjects will be accounted for and reported in the

CONSORT diagram for the study; however, only those randomized subjects who

have finished test for SCr at least once on pre-procedure and 72 hours post-procedure

(i.e., did not drop out or withdraw prior to the start of the allocated intervention) will

be considered as an adjusted ITT subject to be included in the DMC reports and


2.9.2 Subgroup analyses

We will undertake analysis of five pre-specified subgroups defined by the

following baseline criteria: age (<60, 60–75, >75 years), gender (Male or female),

STEMI location (anterior wall or no-anterior wall), and LVEF (≥40% or <40%),

eGFR (≥90 or <90 mL/minute/1.73 m2).

eGFR formula (Modified relative dose response)= [186 × SCr (mg/dL) ]^− 1.154 × age

^− 0.203 × (multiply by 0.742 for women).

Within each subgroup, summary measures will include raw counts and

percentages within each treatment arm. The analysis for each subgroup will be

performed by RR with their corresponding 95% CIs to describe the interaction effect.

The results will be shown on a forest plot including the P-value for heterogeneity

corresponding to the interaction term between the intervention and the subgroup

variable.

2.9.3 Analysis of secondary outcomes

Our secondary objectives will be tested using χ2 tests, and the 95% CI of the rate

difference of RR and ARD will be calculated using the method described by Altman

et al (reported in Newcombe and recommended by the Food and Drug Administration

and Clinical and Laboratory Standards Institute. The secondary end-points will be

analyzed based on the adjusted ITT principle.

2.9.4 Sensitive analyses

To evaluate the stability of primary outcome, we will use logistic regression to

analyze the influence of compliance. It will be performed by OR with their

corresponding 95% CIs. All tests will be two-tailed, and a P value less than 0.05 will




7

be considered statistically significant.

For patients: the volumes of urine and oral hydration (water in milliliters) in the

24 hours following the procedure will be recorded.

For medical staff: intravenous hydration information will be gathered in the 24

hours following the procedure. A preoperative renal function test and details on

postoperative SCr, failure to hydrate according to protocol, and the absence of SCr

will be obtained in the follow-up. All of this information, laboratory tests and vital

signs will be carefully collected by the research staff.

2.9.5 Central effect analysis

To evaluate the central effect, we will use Generalized mixed linear analysis of

primary outcome with different centers. We describe the central effect by P value and

less than 0.05 will be considered statistically significant.

2.9.6 Analysis of safety outcomes

One of the important adverse reactions to aggressive hydration is the increased

risk of heart failure. We will record all information relating to acute heart failure:

acute pulmonary edema, cardiogenic shock, and further auxiliary examination such as

ECG, chest X-ray, laboratory assessment (with specific biomarkers), and

echocardiography.


endpoints in clinical studies and avoiding deviations in event determination between

centers in order to achieve a more accurate assessment of the test results. We will use

RR and ARD with their corresponding 95% CIs to describe the safety endpoint.

2.9.7 Treatment of missing data

We conservatively estimate that up to 20% of subjects may be lost to follow-up

SCr within 72 hours and exclusive patients. The site coordinators will make every

effort to identify such subjects including at least two laboratory tests of SCr after

pPCI. Multiple imputation will be used if >5% of patients have missing data on the

primary outcome.








10

PCI, percutaneous coronary intervention; eGFR, estimate glomerular filtration rate.

Table S2 Proposed format of data tables and figures for main results publication

hPeri-procedural receipt of NSAIDs,aminoglycosides, cyclosporine or cisplatinin the past 48 h and during the studyperiod

xxx (xx) xxx (xx)

Inferior and/or right ventricle myocardialinfraction combined with hypotension onadmission (systolic pressure ≤90 mmHg)

xxx (xx) xxx (xx)

Pre-procedural renal insufficiency eGFR≤60 mL/min/1.73 m2

xxx (xx) xxx (xx)

Characteristic Aggressive group (N=xxx) Control group (N=xxx)Age, yr xxx (xx) xxx (xx)Age >75 yr, no. (%) xxx (xx) xxx (xx)Sex (male), no. (%) xxx (xx) xxx (xx)Weight (kg) xxx (xx) xxx (xx)Anterior myocardial infarction, no. (%) xxx (xx) xxx (xx)Killip class >1, no. (%) xxx (xx) xxx (xx)Creatine kinase MB, U/L† xxx (xx) xxx (xx)Serum creatinine, μmol/L xxx (xx) xxx (xx)Estimate glomerular filtration rate,mL/min/1.73 m2

xxx (xx) xxx (xx)

Estimate glomerular filtration rate <90mL/min/1.73 m2, no. (%)

xxx (xx) xxx (xx)

Cystatin C, mg/L xxx (xx) xxx (xx)LVEF, % xxx (xx) xxx (xx)LVEF <40%, no. (%) xxx (xx) xxx (xx)Hypertension, no. (%) xxx (xx) xxx (xx)Diabetes mellitus, no. (%) xxx (xx) xxx (xx)ACEI/ARB, no. (%) xxx (xx) xxx (xx)Beta-Blockers, no. (%) xxx (xx) xxx (xx)Statin, no. (%) xxx (xx) xxx (xx)Abciximab, no. (%) xxx (xx) xxx (xx)Diuretic, no. (%) xxx (xx) xxx (xx)Volume of contrast medium, mL xxx (xx) xxx (xx)Time from diagnosis to reperfusion, min xxx (xx) xxx (xx)Intra-aortic balloon pump, no. (%) xxx (xx) xxx (xx)Mehran scores† xxx (xx) xxx (xx)Peri-procedures Intravenous Hydrationvolume—ml

xxx (xx) xxx (xx)

Pre-angiography xxx (xx) xxx (xx)Procedure xxx (xx) xxx (xx)0-4 hours Post-angiography xxx (xx) xxx (xx)4-24 hours Post-angiography xxx (xx) xxx (xx)Post-procedures Oral Hydration volume— xxx (xx) xxx (xx)




11

LVEF, left ventricular ejection fraction; ACEI/ARB, angiotension-converting enzyme

inhibitor/angiotension receptor blocker.

Table S3 Baseline characteristics

LVEF, left ventricular ejection fraction.

Table S4 Hydration information

mlPost-procedures Urine volume—ml xxx (xx) xxx (xx)

Demographic Aggressive group (N=xx) Control group (N=xx)Smoke, no. (%) xxx (xx) xxx (xx)Clinical xxx (xx) xxx (xx)Killip class, no. (%) xxx (xx) xxx (xx)I xxx (xx) xxx (xx)II xxx (xx) xxx (xx)III xxx (xx) xxx (xx)

Pre-angiography renal function xxx (xx) xxx (xx)Serum creatinine, μmol/L* xxx (xx) xxx (xx)Estimate glomerular filtration rate,mL/min/1.73 m2*

xxx (xx) xxx (xx)


xxx (xx) xxx (xx)

Cystatin C, mg/L* xxx (xx) xxx (xx)Creatine kinase MB, U/L† xxx (xx) xxx (xx)Hematocrit, % * xxx (xx) xxx (xx)Hbalc, % * xxx (xx) xxx (xx)LVEF, %* xxx (xx) xxx (xx)LVEF <40, no. (%) xxx (xx) xxx (xx)Hypertension, no. (%) xxx (xx) xxx (xx)Diabetes mellitus, no. (%) xxx (xx) xxx (xx)Previous myocardial infarction, no. (%) xxx (xx) xxx (xx)Contrast type, no. (%) xxx (xx) xxx (xx)Iodixanol xxx (xx) xxx (xx)Iopromide xxx (xx) xxx (xx)Iopamidol xxx (xx) xxx (xx)

Other low osmolal agents xxx (xx) xxx (xx)Contrast media volume, total (mmHg)* xxx (xx) xxx (xx)Left ventricular end-diastolic pressure, no./total(mmHg)*

xxx (xx) xxx (xx)

Intra-aortic balloon pump, no. (%) xxx (xx) xxx (xx)Mehran scores xxx (xx) xxx (xx)

Hydration information Aggressive group (N=xx) Control group (N=xx)Pre-procedure’s hydrationadjustment —no.

xxx (xx) xxx (xx)

Intense hydration for hypotension xxx (xx) xxx (xx)Did not undergo aggressive

hydrationxxx (xx) xxx (xx)

Did not undergo general hydration xxx (xx) xxx (xx)




12

3.3 Study outcomes

The primary endpoint is CI-AKI, which is considered to be a >25% or 0.5 mg/dL

increase in SCr from baseline in the 48–72 hours immediately following the

procedure (Table 1, Supplementary Table S5-6)9.

Table S5 Primary and secondary endpoints

CI-AKI, contrast-induced acute kidney injury; CI-PKI, contrast-induced persistent renal

damage.

Table S6 Clinical events

In-procedure‘s hydration adjustment—no.

xxx (xx) xxx (xx)

Intense hydration for hypotension xxx (xx) xxx (xx)Did not undergo aggressive

hydrationxxx (xx) xxx (xx)

Post-procedure’s hydrationadjustment —no.

xxx (xx) xxx (xx)

Intense hydration for hypotension xxx (xx) xxx (xx)

EndpointAggressivegroup(N=xx)

Controlgroup(N=xx)

Relativeratio (95%CI)

Absolutely riskdifference(95% CI)

P value

Primary endpoint, (%)CI-AKI xxx (xx) xxx (xx) xxx (xx-xx)xxx (xx-xx) xx

Secondary endpoint, (%)CI-AKI 48h xxx (xx) xxx (xx) xxx (xx-xx)xxx (xx-xx) xxCI-AKICysC xxx (xx) xxx (xx) xxx (xx-xx)xxx (xx-xx) xxMajor adverse cardiovascular

event, (%) xxx (xx) xxx (xx) xxx (xx-xx)xxx (xx-xx) xx

Major adverse clinical event,(%) xxx (xx) xxx (xx) xxx (xx-xx)xxx (xx-xx) xx

CI-PKI (%) xxx (xx) xxx (xx) xxx (xx-xx)xxx (xx-xx) xxTotal hospitalization costs, $† xxx xxx — — xxLength of stay, d xxx xxx — — xxSafety endpoint, (%)Acute heart failure xxx (xx) xxx (xx) xxx (xx-xx)xxx (xx-xx) xx

Variable name Aggressive group (N=xx) Control group (N=xx)Total events, no. (%) xxx (xx) xxx (xx)CI-AKI xxx (xx) xxx (xx)CI-AKI48 h xxx (xx) xxx (xx)CI-AKICysC xxx (xx) xxx (xx)Death xxx (xx) xxx (xx)




13

CI-AKI, contrast-induced acute kidney injury.

The secondary outcomes consist of: (I) CI-AKI, defined as a >50% or 0.3-mg/dL

absolute increase in SCr from baseline in the 48 hours immediately after the

procedure; (II) CI-AKI, defined as a >10% or 0.3-mg/dL absolute increase in serum

cystatin-C during the 24 hours immediately following the procedure9; (III) persistent

renal damage, which is considered to be residual impairment of renal function

demonstrated by a >25% reduction in creatinine clearance at 3 months compared with

baseline10; (IV) major adverse cardiovascular events, which include all-cause

mortality, target vascular revascularization, and non-fatal myocardial infarction; (V)

major adverse clinical events which take place in hospital following the procedure,

including acute pulmonary edema, cardiogenic shock, stroke, clinically significant

arrhythmias, and bleeding; (VI) total hospitalization costs; (VII) length of stay.

The safe outcome is Acute heart failure (AHF) during hospitalization, defined as

signs/symptoms of heart congestion and/or hypoperfusion by physical examination

and further auxiliary examination such as ECG, chest X-ray, laboratory assessment

(with specific biomarkers), and echocardiography11.

3.4 Primary outcome analysis



have started either intravenous hydration intervention or have finished test for SCr at

least once on pre-procedure and 72 hours post-procedure (i.e., did not drop out or

withdraw prior to the start of the allocated intervention) will be considered as an

adjusted ITT subject to be included in the DMC reports and primary efficacy analysis.

Target vascular revascularization xxx (xx) xxx (xx)Nonfatal myocardial infarction xxx (xx) xxx (xx)Dialysis xxx (xx) xxx (xx)Acute heart failure xxx (xx) xxx (xx)Cardiac shock xxx (xx) xxx (xx)Stroke xxx (xx) xxx (xx)Bleeding xxx (xx) xxx (xx)Arrhythmias xxx (xx) xxx (xx)Infection xxx (xx) xxx (xx)




14

4. Conclusions

The ATTEMPT study will investigate the efficacy and safety of adequate

hydration during the perioperative period among patients who require pPCI treatment.

This SAP is intended to minimize the analysis bias of the study.

References

1. Narula A, Mehran R, Weisz G, et al. Contrast-induced acute kidney injury after

primary percutaneous coronary intervention: results from the HORIZONS-AMI

substudy. Eur Heart J 2014;35:1533-40.

2. Mehran R, Dangas GD, Weisbord SD. Contrast-Associated Acute Kidney Injury.

N Engl J Med 2019;380:2146-55.

3. Liu Y, Hong D, Wang AY, et al. Effects of intravenous hydration on risk of

contrast induced nephropathy and in-hospital mortality in STEMI patients

undergoing primary percutaneous coronary intervention: a systematic review and

meta-analysis of randomized controlled trials. BMC Cardiovasc Disord

2019;19:87.

4. Liu Y, Chen JY, Huo Y, et al. Aggressive hydraTion in patients with

ST-Elevation Myocardial infarction undergoing Primary percutaneous coronary

intervention to prevenT contrast-induced nephropathy (ATTEMPT): Study design

and protocol for the randomized, controlled trial, the ATTEMPT, RESCIND 1

(First study for REduction of contraSt-induCed nephropathy followINg carDiac

catheterization) trial. Am Heart J 2016;172:88-95.

5. Tan N, Liu Y, Chen JY, et al. Use of the contrast volume or grams of

iodine-to-creatinine clearance ratio to predict mortality after percutaneous

coronary intervention. Am Heart J 2013;165:600-8.

6. Moher D, Schulz KF, Altman D. The CONSORT statement: revised

recommendations for improving the quality of reports of parallel-group

randomized trials. JAMA 2001;285:1987-91.

7. Kahan BC, Morris TP. Improper analysis of trials randomised using stratified

blocks or minimisation. Stat Med 2012;31:328-40.

8. Moher D, Hopewell S, Schulz KF et al. CONSORT 2010 explanation and

elaboration: updated guidelines for reporting parallel group randomised trials.




15

BMJ 2010;340:c869.

9. Briguori C, Visconti G, Rivera NV, et al. Cystatin C and contrast-induced acute

kidney injury. Circulation 2010;121:2117-22.

10. Maioli M, Toso A, Leoncini M, et al. Persistent renal damage after

contrast-induced acute kidney injury: incidence, evolution, risk factors, and

prognosis. Circulation 2012;125:3099-107.

11. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the

diagnosis and treatment of acute and chronic heart failure: The Task Force for the

diagnosis and treatment of acute and chronic heart failure of the European

Society of Cardiology (ESC)Developed with the special contribution of the Heart

Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129-200.




Appendix E

ATTEMEPT Clinical Trial Statistical Analysis Plan

Version 2.0





Statistical analysis plan for aggressive hydraTion in patients with ST-elevation

myocardial infarction undergoing primary percutaneous coronary intervention

to prevenT contrast-induced nephropathy (ATTEMPT) study

1. Introduction

Patients who have ST-segment elevation myocardial infarction (STEMI) carry a

high-risk of contrast-induced acute kidney injury (CI-AKI) following primary

percutaneous coronary intervention (pPCI)1. However, for this high-risk group, the

extent of the effects of optimal hydration strategy is yet to be fully established2,3. The

aggressive hydraTion in patients with ST-Elevation Myocardial infarction undergoing

Primary percutaneous coronary intervention to prevenT contrast-induced nephropathy

(ATTEMPT) study is the first study to evaluate the peri-procedural aggressive

hydration in STEMI patients undergoing pPCI4. Here, we describe the statistical

analysis plan (SAP) for the ATTEMPT study, prior to patient enrollment being

completed (this was completed in June 2018) and the locking of the database for

analysis.

This SAP was written by the study statistician and the principal investigator, both

of whom were kept blind to the course of treatment allocated to the patients. We

prospectively defined each analysis described in this SAP.

2. Methods

2.1 Overview of design

The ATTEMPT study is a multicenter, randomized controlled trial which is

investigator-based and open label in nature. A total of 560 patients with STEMI

undergoing pPCI will be randomized (1:1) to undergo treatment either by

peri-procedural aggressive hydration (treatment group) or general hydration (control

group). The ATTEMPT study could prove valuable for the possible identification of

optimal hydration regimens for STEMI patients undergoing pPCI4.

2.2 Inclusion & Exclusion criteria

Inclusion criteria: All consecutive patients with STEMI who were at least 18




years of age and were prepared for pPCI were taken into consideration for enrollment

in the study.

Exclusion criteria:

Contrast medium administration within the 2 weeks prior to the procedure or the

following 3 days;

End-stage renal failure or renal transplantation, and refusal of pPCI or death

while the procedure is taking place;

Heart failure-induced cardiac shock or New York Heart Association class IV

(these patients were excluded because intravenous hydration administration could

potentially prove harmful);

A recent acute kidney injury, which was considered to be an absolute increase of

0.5 mg/dL in serum creatinine (SCr) over baseline in the 24 hours prior;

The existence of lactation, pregnancy;

A tumor of a malignant nature or a predicted life expectancy of 1 year or less;

An allergic reaction induced by contrast medium, peri-procedural receipt of

metformin, or non-steroidal anti-inflammatory drugs in the 2 days prior and while

the study is taking place;


2.3 Randomization

All patients meeting the eligibility criteria and provided informed consent will be

randomized into two study groups. A computer will carry out randomization of

eligible patients by producing numbers at random at a 1:1 ratio. Randomization will

be accomplished with using a block random method with 8 units in each group. Some

offset or variability will be inserted to prevent anticipation of the next treatment.

Randomization will be stratified based on age (<60, 60–75, >75 years), sex (male or

female), and STEMI location (anterior wall or no-anterior wall). Study coordinators at

each site will be responsible for obtaining a randomized treatment assignment for

each eligible patient. Study sites will be provided with a web-based randomization

program for this purpose. This web-based http://crdms.echobelt.org program will be

tested at each site prior to the start of the trial and will be reviewed. Since this is an

open-label study, the procedure of blinding will not take place.




2.4 Sample size

The total sample size of 560 patients was calculated based on our previous

findings. The incidence of primary end point was estimated to decrease to 11.5%

(50% relative reduction) in the aggressive hydration group from 23% in the control

group with general hydration5. We established a sample size according to nQuery +

nTerim 3.0 (Statistical Solutions Ltd, Ireland) by employing a 2-sided χ2 test, a power

of 90%, a significance level of 0.05, and a dropout rate <20%.

2.5 The formal statement of the null hypothesis

We fully describe the CI-AKI outcome based on the aggressive hydration versus

general hydration intervention. The null hypothesis is that the two treatment groups

(aggressive hydration and control) do not differ in terms of the proportion of subjects

who experience CI-AKI. The alternative hypothesis is that the absolute difference in

the incidence of CI-AKI between the aggressive hydration group and the control

group.

2.6 Intervention

A pre-procedural loading dose 250 mL of normal saline for 30 minutes (125 mL

for patients with congestive heart failure, Killip II/III or NYHA III) will be

administered to the patients in the treatment group in an emergency department or

cardiac catheterization lab over 30-minutes prior to the pPCI. After this, the patients

will receive intravenous hydration at a general rate (1 or 0.5 mL/kg/h for patients with

congestive heart failure, Killip II/III or NYHA III) until LVEDP measurement.

Patients will then undergo 4 hours of post-procedural aggressive hydration guided

by LVEDP [5 mL/kg/h (LVEDP <13 mmHg), 3 mL/kg/h (LVEDP 13–18 mmHg),

1.5mL/kg/h (LVEDP >18 mmHg), and 0.5 mL/kg/h (LVEDP >20 mmHg)] and

continuous intravascular hydration at the normal rate for the 24 hours following PCI.

Control group patients will receive peri-procedural general hydration with ≤500 mL

normal saline (within 6 hours) at a normal rate (0.5 or 1 mL/kg/h).

2.7 Interim analysis

According to the study design, interim analysis to determine if either intervention

shows a substantial beneficial effect will not be carried out.




2.8 Timing of analysis

At the end of the study, the final audit should be performed usually within four to

six weeks of the end of the last follow-up of the last subject in the study center. The

preparations and procedures for the study of closed visits are generally the same as for

a regular supervisory visit. The last patient was enrolled on 10th June 2018 (Table 1).

Table 1 Analysis timing of measurement for endpointsEndpoint Analysis timing

Primary endpoint

CI-AKI 48 to 72 hours after the procedure

Secondary endpoint

CI-AKI48 h 48 hours after the procedure

CI-AKICysC 24 hours after the procedure

Major adverse cardiovascular events Within the first year after enrollment

Major adverse clinical events Within the first year after enrollment

CI-PKI requiring dialysis Within the 3-month after enrollment

Total hospitalization costs Discharge from hospital

Length of stay Discharge from hospital

Safety endpoint

Acute heart failure Within the hospitalization after enrollment

CI-AKI, contrast-induced acute kidney injury; CI-PKI, contrast-induced persistent

renal damage.

2.9 Analysis principles

Analysis is to be conducted based on adjusted intention-to-treat (ITT)

(randomization must be finished before emergency surgery, and we will not

include the patients who need to be excluded from the final analysis).

We will not impute missing values, unless specified. The number of subjects

included in an analysis will be reported if there is a substantial amount of missing

data. The last observations will not be carried forward. Multiple imputation will

be used if >5% of patients have missing data on the primary outcome.

Each of the tests will be two-tailed, and a P value of less than 0.05 will be

considered to be statistically significant.




Only analyses conducted up to 1 year after randomization will feature in this

analysis plan and in the primary manuscript.

Pre-specified subgroup analyses will be conducted whether or not a statistically

significant treatment effect on the primary outcome is seen across the total

sample.

We use the t-test for normally distributed continuous variables and expressed as

mean ± SD, and the Wilcoxon rank-sum test was used in non-normal distribution

variables and presented as median and interquartile range.

For categorical variables, we used Pearson χ2 or Fisher’s exact tests to compare

baseline characteristics and study’s endpoints between the aggressive and general

hydration groups; these will be expressed as percentages.

Logistic regression testing to assess whether the recorded treatment effect was

consistent across random stratified variable [age, gender, STEMI location]. Odds

ratios will be reported alongside their related 95% CIs.

Risk ratio (RR) and absolute risk difference (ARD) with their corresponding 95%

confidence interval (CIs) are used to describe the interaction effect (primary,

second, and safe events). The number needed to treat (NNT) for preventing one

CI-AKI-related event was calculated by inverse of the ARD.

2.9.1 Analysis of primary outcome

The primary analysis will be based on adjusted intention to treat principles. Since

the intervention is given and the primary outcome is observed for a very short

duration (72 hours), we expect only a few dropouts or crossovers.

As ATTEMPT study’s protocol pointed out primary outcome would use

multivariable logistic regression with (age, sex, creatinine clearance, and left

ventricular ejection fraction). However, basic on principal component analysis, we

have changed to use multivariable logistic regression to evaluate the intervention

effect with random stratified variable [e.g. age(<60, 60–75, >75 years), gender,

STEMI location]. The analysis for each variable will be performed by OR with their

corresponding 95% CIs to describe the intervention effect. All tests will be two-tailed,

and a P value less than 0.05 will be considered statistically significant.






have finished test for SCr at least once on pre-procedure and 72 hours post-procedure

(i.e., did not drop out or withdraw prior to the start of the allocated intervention) will

be considered as an adjusted ITT subject to be included in the DMC reports and


2.9.2 Subgroup analyses

We will undertake analysis of five pre-specified subgroups defined by the

following baseline criteria: age (<60, 60–75, >75 years), gender (Male or female),

STEMI location (anterior wall or no-anterior wall), and LVEF (≥40% or <40%),

eGFR (≥90 or <90 mL/minute/1.73 m2).

eGFR formula (Modified relative dose response)= [186 × SCr (mg/dL) ]^− 1.154 × age

^− 0.203 × (multiply by 0.742 for women).

Within each subgroup, summary measures will include raw counts and

percentages within each treatment arm. The analysis for each subgroup will be

performed by RR with their corresponding 95% CIs to describe the interaction effect.

The results will be shown on a forest plot including the P-value for heterogeneity

corresponding to the interaction term between the intervention and the subgroup

variable.

2.9.3 Analysis of secondary outcomes

Our secondary objectives will be tested using χ2 tests, and the 95% CI of the rate

difference of RR and ARD will be calculated using the method described by Altman

et al (reported in Newcombe and recommended by the Food and Drug Administration

and Clinical and Laboratory Standards Institute. The secondary end-points will be

analyzed based on the adjusted ITT principle.

2.9.4 Sensitive analyses

To evaluate the stability of primary outcome, we will use logistic regression to

analyze the influence of compliance and use baseline value comparison to assess the

differences between the two groups of excluded cases. It will be performed by

adjusted with [age(<60, 60–75, >75 years), gender, STEMI location]. All tests will

be two-tailed, and a P value less than 0.05 will be considered statistically significant.




For patients: the volumes of urine and oral hydration (water in milliliters) in the

24 hours following the procedure will be recorded.

For medical staff: intravenous hydration information will be gathered in the 24

hours following the procedure. A preoperative renal function test and details on

postoperative SCr, failure to hydrate according to protocol, and the absence of SCr

will be obtained in the follow-up. All of this information, laboratory tests and vital

signs will be carefully collected by the research staff.

2.9.5 Central effect analysis

To evaluate the central effect, we will use Generalized mixed linear analysis of

primary outcome with different centers. We describe the central effect by P value and

less than 0.05 will be considered statistically significant.

2.9.6 Analysis of safety outcomes

One of the important adverse reactions to aggressive hydration is the increased

risk of heart failure. We will record all information relating to acute heart failure:

acute pulmonary edema, cardiogenic shock, and further auxiliary examination such as

ECG, chest X-ray, laboratory assessment (with specific biomarkers), and

echocardiography.


endpoints in clinical studies and avoiding deviations in event determination between

centers in order to achieve a more accurate assessment of the test results. We will use

RR and ARD with their corresponding 95% CIs to describe the safety endpoint.

2.9.7 Treatment of missing data

We conservatively estimate that up to 20% of subjects may be lost to follow-up

SCr within 72 hours and exclusive patients. The site coordinators will make every

effort to identify such subjects including at least two laboratory tests of SCr after

pPCI. Multiple imputation will be used if >5% of patients have missing data on the

primary outcome.

2.9.8 Statistical software








PCI, percutaneous coronary intervention; eGFR, estimate glomerular filtration rate.

Table S2 Proposed format of data tables and figures for main results publication

LVEF, left ventricular ejection fraction; ACEI/ARB, angiotension-converting enzyme

inhibitor/angiotension receptor blocker.

Inferior and/or right ventricle myocardial infractioncombined with hypotension on admission (systolicpressure ≤90 mmHg)

xxx (xx) xxx (xx)

Pre-procedural renal insufficiency eGFR ≤60mL/min/1.73 m2

xxx (xx) xxx (xx)

Characteristic Aggressive group (N=xxx) Control group (N=xxx)Age, yr xxx (xx) xxx (xx)Age >75 yr, no. (%) xxx (xx) xxx (xx)Sex (male), no. (%) xxx (xx) xxx (xx)Weight (kg) xxx (xx) xxx (xx)Anterior myocardial infarction, no. (%) xxx (xx) xxx (xx)Killip class >1, no. (%) xxx (xx) xxx (xx)Creatine kinase MB, U/L† xxx (xx) xxx (xx)Serum creatinine, μmol/L xxx (xx) xxx (xx)Estimate glomerular filtration rate,mL/min/1.73 m2

xxx (xx) xxx (xx)


xxx (xx) xxx (xx)

Cystatin C, mg/L xxx (xx) xxx (xx)LVEF, % xxx (xx) xxx (xx)LVEF <40%, no. (%) xxx (xx) xxx (xx)Hypertension, no. (%) xxx (xx) xxx (xx)Diabetes mellitus, no. (%) xxx (xx) xxx (xx)ACEI/ARB, no. (%) xxx (xx) xxx (xx)Beta-Blockers, no. (%) xxx (xx) xxx (xx)Statin, no. (%) xxx (xx) xxx (xx)Abciximab, no. (%) xxx (xx) xxx (xx)Diuretic, no. (%) xxx (xx) xxx (xx)Volume of contrast medium, mL xxx (xx) xxx (xx)Time from diagnosis to reperfusion, min xxx (xx) xxx (xx)Intra-aortic balloon pump, no. (%) xxx (xx) xxx (xx)Mehran scores† xxx (xx) xxx (xx)Peri-procedures Intravenous Hydrationvolume—ml

xxx (xx) xxx (xx)

Pre-angiography xxx (xx) xxx (xx)Procedure xxx (xx) xxx (xx)0-4 hours Post-angiography xxx (xx) xxx (xx)4-24 hours Post-angiography xxx (xx) xxx (xx)Post-procedures Oral Hydration volume—ml

xxx (xx) xxx (xx)

Post-procedures Urine volume—ml xxx (xx) xxx (xx)




Table S3 Baseline characteristics

LVEF, left ventricular ejection fraction.

Table S4 Hydration information

Demographic Aggressive group (N=xx) Control group (N=xx)Smoke, no. (%) xxx (xx) xxx (xx)Clinical xxx (xx) xxx (xx)Killip class, no. (%) xxx (xx) xxx (xx)I xxx (xx) xxx (xx)II xxx (xx) xxx (xx)III xxx (xx) xxx (xx)

Pre-angiography renal function xxx (xx) xxx (xx)Serum creatinine, μmol/L* xxx (xx) xxx (xx)Estimate glomerular filtration rate,mL/min/1.73 m2*

xxx (xx) xxx (xx)


xxx (xx) xxx (xx)

Cystatin C, mg/L* xxx (xx) xxx (xx)Creatine kinase MB, U/L† xxx (xx) xxx (xx)Hematocrit, % * xxx (xx) xxx (xx)Hbalc, % * xxx (xx) xxx (xx)LVEF, %* xxx (xx) xxx (xx)LVEF <40, no. (%) xxx (xx) xxx (xx)Hypertension, no. (%) xxx (xx) xxx (xx)Diabetes mellitus, no. (%) xxx (xx) xxx (xx)Previous myocardial infarction, no. (%) xxx (xx) xxx (xx)Contrast type, no. (%) xxx (xx) xxx (xx)Iodixanol xxx (xx) xxx (xx)Iopromide xxx (xx) xxx (xx)Iopamidol xxx (xx) xxx (xx)

Other low osmolal agents xxx (xx) xxx (xx)Contrast media volume, total (mmHg)* xxx (xx) xxx (xx)Left ventricular end-diastolic pressure, no./total(mmHg)*

xxx (xx) xxx (xx)

Intra-aortic balloon pump, no. (%) xxx (xx) xxx (xx)Mehran scores xxx (xx) xxx (xx)

Hydration information Aggressive group (N=xx) Control group (N=xx)Pre-procedure’s hydration adjustment —no. xxx (xx) xxx (xx)

Intense hydration for hypotension xxx (xx) xxx (xx)Did not undergo aggressive hydration xxx (xx) xxx (xx)Did not undergo general hydration xxx (xx) xxx (xx)

In-procedure‘s hydration adjustment —no. xxx (xx) xxx (xx)Intense hydration for hypotension xxx (xx) xxx (xx)Did not undergo aggressive hydration xxx (xx) xxx (xx)

Post-procedure’s hydration adjustment —no. xxx (xx) xxx (xx)Intense hydration for hypotension xxx (xx) xxx (xx)




3.3 Study outcomes

The primary endpoint is CI-AKI, which is considered to be a >25% or 0.5 mg/dL

increase in SCr from baseline in the 48–72 hours immediately following the

procedure (Table 1, Supplementary Table S5-6)9.

Table S5 Primary and secondary endpoints

CI-AKI, contrast-induced acute kidney injury; CI-PKI, contrast-induced persistent renal

damage.

Table S6 Clinical events

CI-AKI, contrast-induced acute kidney injury.

Endpoint Aggressivegroup (N=xx)

Control group(N=xx)

Relative ratio(95% CI)

Absolutely riskdifference (95%CI)

P value

Primary endpoint, (%)CI-AKI xxx (xx) xxx (xx) xxx (xx-xx) xxx (xx-xx) xx

Secondary endpoint, (%)CI-AKI 48h xxx (xx) xxx (xx) xxx (xx-xx) xxx (xx-xx) xxCI-AKICysC xxx (xx) xxx (xx) xxx (xx-xx) xxx (xx-xx) xxMajor adverse cardiovascular event,

(%) xxx (xx) xxx (xx) xxx (xx-xx) xxx (xx-xx) xx

Major adverse clinical event, (%) xxx (xx) xxx (xx) xxx (xx-xx) xxx (xx-xx) xxCI-PKI (%) xxx (xx) xxx (xx) xxx (xx-xx) xxx (xx-xx) xx

Total hospitalization costs, $† xxx xxx — — xxLength of stay, d xxx xxx — — xxSafety endpoint, (%)Acute heart failure xxx (xx) xxx (xx) xxx (xx-xx) xxx (xx-xx) xx

Variable name Aggressive group (N=xx) Control group (N=xx)Total events, no. (%) xxx (xx) xxx (xx)CI-AKI xxx (xx) xxx (xx)CI-AKI48 h xxx (xx) xxx (xx)CI-AKICysC xxx (xx) xxx (xx)Death xxx (xx) xxx (xx)Target vascular revascularization xxx (xx) xxx (xx)Nonfatal myocardial infarction xxx (xx) xxx (xx)Dialysis xxx (xx) xxx (xx)Acute heart failure xxx (xx) xxx (xx)Cardiac shock xxx (xx) xxx (xx)Stroke xxx (xx) xxx (xx)Bleeding xxx (xx) xxx (xx)Arrhythmias xxx (xx) xxx (xx)Infection xxx (xx) xxx (xx)




The secondary outcomes consist of: (I) CI-AKI, defined as a >50% or 0.3-mg/dL

absolute increase in SCr from baseline in the 48 hours immediately after the

procedure; (II) CI-AKI, defined as a >10% or 0.3-mg/dL absolute increase in serum

cystatin-C during the 24 hours immediately following the procedure9; (III) persistent

renal damage, which is considered to be residual impairment of renal function

demonstrated by a >25% reduction in creatinine clearance at 3 months compared with

baseline10; (IV) major adverse cardiovascular events, which include all-cause

mortality, target vascular revascularization, and non-fatal myocardial infarction; (V)

major adverse clinical events which take place in hospital following the procedure,

including acute pulmonary edema, cardiogenic shock, stroke, clinically significant

arrhythmias, and bleeding; (VI) total hospitalization costs; (VII) length of stay.

The safe outcome is Acute heart failure (AHF) during hospitalization, defined as

signs/symptoms of heart congestion and/or hypoperfusion by physical examination

and further auxiliary examination such as ECG, chest X-ray, laboratory assessment

(with specific biomarkers), and echocardiography11.

1. Narula A, Mehran R, Weisz G, et al. Contrast-induced acute kidney injury after

primary percutaneous coronary intervention: results from the HORIZONS-AMI

substudy. Eur Heart J 2014;35:1533-40.

2. Mehran R, Dangas GD, Weisbord SD. Contrast-Associated Acute Kidney Injury.

N Engl J Med 2019;380:2146-55.

3. Liu Y, Hong D, Wang AY, et al. Effects of intravenous hydration on risk of

contrast induced nephropathy and in-hospital mortality in STEMI patients

undergoing primary percutaneous coronary intervention: a systematic review and

meta-analysis of randomized controlled trials. BMC Cardiovasc Disord

2019;19:87.

4. Liu Y, Chen JY, Huo Y, et al. Aggressive hydraTion in patients with

ST-Elevation Myocardial infarction undergoing Primary percutaneous coronary

intervention to prevenT contrast-induced nephropathy (ATTEMPT): Study design

and protocol for the randomized, controlled trial, the ATTEMPT, RESCIND 1

(First study for REduction of contraSt-induCed nephropathy followINg carDiac

catheterization) trial. Am Heart J 2016;172:88-95.




5. Tan N, Liu Y, Chen JY, et al. Use of the contrast volume or grams of

iodine-to-creatinine clearance ratio to predict mortality after percutaneous

coronary intervention. Am Heart J 2013;165:600-8.

6. Moher D, Schulz KF, Altman D. The CONSORT statement: revised

recommendations for improving the quality of reports of parallel-group

randomized trials. JAMA 2001;285:1987-91.

7. Kahan BC, Morris TP. Improper analysis of trials randomised using stratified

blocks or minimisation. Stat Med 2012;31:328-40.

8. Moher D, Hopewell S, Schulz KF et al. CONSORT 2010 explanation and

elaboration: updated guidelines for reporting parallel group randomised trials.

BMJ 2010;340:c869.

9. Briguori C, Visconti G, Rivera NV, et al. Cystatin C and contrast-induced acute

kidney injury. Circulation 2010;121:2117-22.

10. Maioli M, Toso A, Leoncini M, et al. Persistent renal damage after

contrast-induced acute kidney injury: incidence, evolution, risk factors, and

prognosis. Circulation 2012;125:3099-107.

11. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the

diagnosis and treatment of acute and chronic heart failure: The Task Force for the

diagnosis and treatment of acute and chronic heart failure of the European

Society of Cardiology (ESC)Developed with the special contribution of the Heart

Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129-200.




Appendix D

Changes to ATTEMPT Statistical Analysis Plan



Table S7. Changes to ATTEMPT SAP

OriginalVersionNumber

NewVersionNumber

Description of Change Justification for Change

1.0 2.0

Analysis principles:

“Multivariable logisticregression models will bedeveloped to adjust for clinicalcharacteristics (eg, age, sex,creatinine clearance, and leftventricular ejection fraction[LVEF])”

Change into “Logisticregression testing to assesswhether the recorded treatmenteffect was consistent acrossrandom stratified variable (age,gender, STEMI location).

”

Because of the age, gender, andSTEMI location are randomstratified variables. To evaluate themain outcome, we need to adjust theintervention method with randomstratified variables.

1.0 2.0

Analysis principles:Add the “Risk ratio (RR) and

absolute risk difference (ARD)with their corresponding 95%confidence interval (CIs) are usedto describe the interaction effect(primary, second, and safeevents). The number needed totreat (NNT) for preventing oneCI-AKI-related event wascalculated by inverse of theARD.”

RR, ARD, and NNT value areimportant intervention effect’sevaluation index.

1.0 2.0

Analysis of soft-ware

Add the “R soft-ware(version 3.6.1; R Core Team,Vienna, Austria)”

R soft-ware is good to drawnsome statistical figures.

1.0 2.0

Analysis of primary outcome

As ATTEMPT study’sprotocol pointed out primaryoutcome would usemultivariable logistic

To evaluate the primaryoutcome, we need to adjust theintervention effect with randomstratified variables.



regression with (age, sex,creatinine clearance, and leftventricular ejection fraction).

Change into “However,basic on principal componentanalysis, we have changed to usemultivariable logistic regressionto evaluate the intervention effectwith random stratified variable(e.g. age(<60, 60–75, >75 years),gender, STEMI location).”

1.0 2.0

Sensitive analyses

To evaluate the stability ofprimary outcome, we will uselogistic regression to analyze theinfluence of compliance. It will beperformed by OR with theircorresponding 95% CIs.

Add the “and use baselinevalue comparison to assess thedifferences between the twogroups of excluded cases. It willbe performed by adjusted with[age(<60, 60–75, >75 years],gender, STEMI location). ”

To evaluate the sensitive ofintervention effect, it still need toadjust with random stratifiedvariables.



Table of Contents

Appendix B/CFigure A1. Major risk factors for CI-AKI in STEMI patients.Figure A2. Development process of clinical adverse events exposure to contrastagent.Figure A3. Pathophysiology of CI-AKI in STEMI patients.Figure A4. Overview of study design.Figure A5. CEC review process.Figure A6. Study management structure.Figure A7. Enrollment by Site.Figure A8. Incidence of CI-AKI among different level of center.

Table A1. Characteristics of randomized clinical trials on prevention of CI-AKI underdifferent hydration strategies of IV isotonic saline.Table A2. Timetable of visits and procedures.Table A3. Definitions of components of MACEs.Table A4. Definitions of components of major post-procedure in-hospital adverseclinical events.Table A5.

Appendix D/EFigure 1. Consort flowchartFigure 2. Consent details

Table S1. Inclusion and exclusion criteria.Table S2. Proposed format of data tables and figures for main results publication.Table S3. Baseline characteristicsTable S4. Hydration informationTable S5. Primary and secondary endpointsTable S6. Clinical eventsTable S7. Changes to ATTEMPT Statistical Analysis Plan





Documents

Protocol - heart.bmj.com