Accepted Manuscript

Clinical Outcomes of Erythropoietin Use in Heart Failure Patients with Anemia ofChronic Kidney Disease

Cynthia Jackevicius, BScPhm, PharmD, MSc, BCPS Cindy Shutieng Fan, PharmDAlberta Warner, MD

PII: S1071-9164(14)00064-5

DOI: 10.1016/j.cardfail.2014.02.001

Reference: YJCAF 3258

To appear in: Journal of Cardiac Failure

Received Date: 18 July 2013

Revised Date: 5 February 2014

Accepted Date: 6 February 2014

Please cite this article as: Jackevicius C, Fan CS, Warner A, Clinical Outcomes of Erythropoietin Use inHeart Failure Patients with Anemia of Chronic Kidney Disease, Journal of Cardiac Failure (2014), doi:10.1016/j.cardfail.2014.02.001.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service toour customers we are providing this early version of the manuscript. The manuscript will undergocopyediting, typesetting, and review of the resulting proof before it is published in its final form. Pleasenote that during the production process errors may be discovered which could affect the content, and alllegal disclaimers that apply to the journal pertain.

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Clinical Outcomes of Erythropoietin Use in Heart Failure Patients with Anemia of Chronic

Kidney Disease

Cynthia Jackevicius, BScPhm, PharmD, MSc, BCPS,1-5 Cindy Shutieng Fan, PharmD,1,2

Alberta Warner, MD2,6

1College of Pharmacy, Western University of Health Sciences, 2VA Greater Los Angeles

Healthcare System, 3Institute for Clinical Evaluative Sciences, 4Institute for Health Policy,

Management and Evaluation, 5University Health Network, 6Department of Medicine, Division of

Cardiology, UCLA

Address for correspondence:

Cynthia Jackevicius, BScPhm, PharmD, MSc, FCSHP, BCPS, AQ Cardiology

Professor, College of Pharmacy, Western University of Health Sciences

309 E. Second St., Pomona CA 91766;

Phone: 909-469-5527; Fax: 909-469-5539; cjackevicius@westernu.edu

Running title: Outcomes of EPO in CRAS

This study was funded by the American College of Clinical Pharmacy Watson Anemia

Investigator Development Research Award.

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Abstract

Background: Anemia and chronic kidney disease are common disorders in heart failure (HF)

patients, and are associated with increased morbidity and mortality. This study assesses clinical

outcomes associated with erythropoietin (EPO) treatment in this cardio-renal-anemia syndrome

(CRAS) population.

Methods and Results: This is a retrospective cohort study of VA patients with CRAS from

January 2003 to December 2006. The primary outcome was a composite of death, acute coronary

syndromes, HF and stroke. Multiple Cox regression modeling was used to evaluate the outcome

in patients prescribed (n=213) and not prescribed EPO (n=1845). Adjusted incidence of mortality

was statistically significantly higher in EPO than non-EPO users (33.8% vs. 19.7%;HR:1.40

95%CI1.06-1.85, p=0.02). The unadjusted composite of cardiovascular events/death was higher

in the EPO group, but not statistically significant when adjusted for confounders (p=0.12). Crude

ACS events were documented in 18.8% and 10.8% patients (p=0.001), and stroke events

occurred in 22.5% and 18.3% patients (p=0.14) in EPO and non-EPO groups, respectively.

Conclusions: We found that in CRAS patients, EPO use was associated with increased risk of

mortality and a trend towards increased cardiovascular events. Therefore, clinicians considering

EPO use in CRAS patients should assess whether any potential benefits outweigh the risks of

use.

Key Words: cardiac, health policy, outcome research

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Introduction

Despite advances in therapy, heart failure (HF), a common and progressive condition,

continues to be associated with a substantial increase in morbidity and mortality.1-3 The majority

of patients with HF also have comorbidities, such as, hypertension, diabetes, dyslipidemia and

coronary artery disease. Treatment used for HF and these comorbidities may contribute to the

development of chronic kidney disease (CKD) if cardiac output is decreased, with such patients

progressing to end-stage renal disease.4 Depending on the severity, both HF and CKD can

complicate management of the other condition.

Anemia is also a common complication that is observed in both CKD and HF.1-3,5 The

prevalence of anemia in HF patients range from 7-70% depending on the patient cohort, and

increases as HF severity worsens.2,4-8 In the OPTIMIZE-HF registry, 51.2% of patients

hospitalized for HF had hemoglobin levels of <12.1g/dl, of which 25% were moderately to

severely anemic.9 In retrospective HF studies,3 reduced hemoglobin levels have been associated

with increased hospitalization, HF severity, decreased functional status, worsened symptoms and

mortality, while prospective studies have shown less promising results.1-5,8,10-12

HF, CKD and anemia often occur concurrently and are coined the cardio-renal-anemia

syndrome (CRAS) which significantly increases in-hospital mortality when compared to HF

alone.13 Although each condition amplifies the risk of the other, individuals with all 3 risk factors

are at particularly high risk for adverse cardiovascular (CV) events. Data regarding the effects of

erythropoietic stimulating agents (ESA) to correct anemia in CRAS patients is limited. Older

evidence in dialysis patients with underlying cardiac disease (ischemic heart disease or HF) and

anemia found increased mortality associated with ESA use.14 Smaller, single center studies have

shown that ESA’s effect of raising hemoglobin levels in anemic HF patients translated into

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benefits on hospitalization rates, functional class, quality of life and exercise capacity, thus

improving HF and CKD.3,15,16 However, more recent studies in anemic CKD patients have

incidentally shown that ESA targeting higher hemoglobin levels were associated with increased

risk of all-cause mortality, adverse CV events and increased stroke events.12,17-19 Subsequently,

the US Food and Drug Administration modified the recommended dosing for ESA in an attempt

to prevent these adverse CV events.20 Furthermore, increased thrombotic events have been

reported in anemic HF patients without CKD with use of ESA.12 Given recent concerns in

isolated HF and CKD populations, more evidence about the potential negative outcomes

associated with treatment of anemia of CKD in HF patients is crucial in determining safe and

appropriate therapy. The aim of this study was to determine the CV clinical outcomes and

mortality associated with use of erythropoietin (EPO) in patients with CRAS.

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Methods

Study Design and Data Sources. We conducted a retrospective cohort study using

administrative and clinical data from Veterans Affairs Greater Los Angeles Healthcare System.

Our administrative databases have been successfully used for utilization and outcomes research

by other investigators.21 For the mortality outcome, we used the VA vital status file, which has

high sensitivity and accuracy when compared with the National Death Index. The study was

approved by institutional review committees at Veterans Affairs Greater Los Angeles Healthcare

System and Western University of Health Sciences.

Population. Patients from Veterans Affairs Greater Los Angeles from January 1, 2003 to

December 31, 2006 were included if they met the following three criteria: 1) ≥1 principal

or secondary diagnosis of HF or cardiomyopathy based on diagnoses from hospitalizations

and ambulatory visits using International Classification of Diseases, 9th Revision, Clinical

Modification [ICD-9-CM] codes 425.x (cardiomyopathy) and 428.x (HF); AND 2)

subsequent to the HF diagnosis, a diagnosis of CKD, as defined by an estimated glomerular

filtration rate <60 mL/min/1.73 m2 body surface area in 2 measurements over at least a 3

month period according to the NKF-K/DOQI guideline definition of CKD. Estimated

glomerular filtration rate is automatically calculated by our laboratory based on the four

variable Modification of Diet in Renal Disease equation;22 AND 3) subsequent to the HF

and CKD diagnoses, a diagnosis of anemia, as defined by the NKF-K/DOQI anemia

guidelines. The 2006 NKF-K/DOQI guidelines for the definition of anemia were used

(hemoglobin < 12 g/dL for adult males and postmenopausal females and hemoglobin < 11

g/dL for premenopausal females) as these guidelines cover the majority of our study

period.23 The index date was defined as the date when the patient had all three diagnoses of

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interest to classify them as having the CRAS diagnosis. Patients were excluded if they had

one or more of the following: died before hospital discharge; received cardiac

transplantation; a diagnosis of anemia based on an episode of recognized acute blood loss,

such as trauma or upper gastrointestinal bleed, which may have accounted for a temporarily

low hemoglobin unrelated to anemia of CKD; documented hypersensitivity reaction to

EPO; or no records of their clinical status. Patient data for demographics, medications,

comorbidities and laboratory values was obtained from the electronic medical records and

linked using a unique encrypted scrambled patient identification number per patient.

Study Group. The exposure group was defined as prescription of EPO therapy (erythropoietin

was only ESA available) after CRAS diagnosis. According to institutional protocol, all EPO

prescriptions need to be approved by the Nephrology Service.

Control. The control group included patients who did not receive EPO therapy after CRAS

diagnosis.

Outcomes. The primary outcome in this study was to determine the composite of death, acute

coronary syndrome (ACS), HF and stroke. The secondary outcome was total mortality.

Statistical analysis. The characteristics of the population were described using mean ± standard

deviation as appropriate for continuous data and proportions for categorical data. The differences

in baseline characteristics between EPO and non-EPO were compared using the t-test for

continuous data and Chi-square test for categorical data. Crude (unadjusted) event rates are

reported and compared using Chi-square test. We then constructed a multivariate Cox regression

model, retaining all covariates with a p-value <0.15 in a backward stepwise regression, as well as

including variables of clinical importance to the outcome of interest. In the backward variable

screening, we deliberately chose to retain a variable in the model even if it was only moderately

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significant. Imputation was used to fill in values for the one variable, ejection fraction (EF), with

missing values in order to retain all observations in the multivariate analysis. EF was then used

as a dichotomous variable (≤50% or >50%) due to the required imputation. The covariates

considered in the models were demographics (age, sex), baseline laboratory values for estimated

glomerular filtration rate, serum creatinine, blood urea nitrogen, hemoglobin, systolic blood

pressure and diastolic blood pressure, EF >50%, comorbidities [coronary artery disease,

cerebrovascular disease, atrial fibrillation, diabetes, hypertension, hyperlipidemia, chronic

obstructive pulmonary disease, malignancy], concomitant medications [angiotensin-converting

enzyme inhibitor, angiotensin receptor blocker, aspirin, beta-blocker, digoxin, diuretic,

hydralazine/nitrates, aldosterone antagonist, iron (oral or intravenous), warfarin, clopidogrel,

statin], use of dialysis, history of renal clinic appointment and participation in a specialty HF

clinic, all documented within 1 year prior to the index date. Hazard ratios and 95% confidence

intervals for the adjusted models are reported. All data were analyzed using SAS® version 9.2

(SAS Institute, Cary, NC). A p-value of <0.05 was considered statistically significant.

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Results

Of a total of 2058 patients with CRAS, 213 (10.3%) were prescribed EPO and 1845

(89.7%) did not receive EPO therapy. Median follow-up was 17.6 months (maximum 44.2

months). There were a number of significant differences in baseline characteristics of those

prescribed and not prescribed EPO (Table 1). There were significant differences between groups

for baseline parameters of renal function (estimated glomerular filtration rate, serum creatinine,

blood urea nitrogen) (p<0.0001), attributed to a more advanced disease process in the EPO-

treated group. Baseline hemoglobin/hematocrit was lower in those treated with EPO (p<0.0001).

Comorbidities were similar between groups except for hypertension and malignancy

which were higher in the EPO group (p=0.02, p=0.04, respectively). Use of aspirin, angiotensin

receptor blockers, iron supplements and hydralazine/nitrates was higher in the EPO group

(p=0.02, p=0.03, p<0.0001, <0.0001, respectively). History of renal clinic appointment and

dialysis were also higher in the EPO group (p<0.0001, p<0.01, respectively).

Unadjusted incidence of CV events and death was statistically significantly higher in the

EPO group (HR 1.19 95% CI 1.00-1.41, p=0.04). Unadjusted mortality was also significantly

higher in the EPO than the non-EPO group (33.8% and 19.7%, respectively; HR=1.62 95% CI

1.26-2.09, p<0.001). ACS events were documented more often (18.8% and 10.8%) in EPO than

non-EPO patients (p=0.001). All-cause hospitalizations were significantly higher in EPO than

non-EPO patients (p<0.001). There was a trend towards a higher proportion of patients receiving

EPO being hospitalized for HF (47.9% vs. 41.2%, p=0.07) as well as towards an increase in

stroke events in 22.5% and 18.3% (p=0.14). (Table 2, Figures 1 and 2)

The adjusted incidence of the composite of CV events and death was numerically higher

in the EPO group, but no longer statistically significant (HR=1.16 95% CI 0.96-1.40, p=0.12).

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(Table 3) Increased age, blood urea nitrogen, hemoglobin < 10g/dL, EF≤50%, comorbidities

[coronary artery disease, cerebrovascular disease, atrial fibrillation, chronic obstructive

pulmonary disease], and medications [aspirin, diuretic, and hydralazine/nitrates] contributed to

increased trend of CV events/death while history of hypertension was associated with reduced

composite events. Even after adjusting for other confounding factors, incidence of mortality

remained higher in the EPO group (HR=1.40 95% CI 1.06-1.85, p=0.02). (Table 4) Other

variables contributing to increased death were increasing age, increasing blood urea nitrogen,

hemoglobin < 10g/dL, EF≤50%, comorbidities [chronic obstructive pulmonary disease and

cancer], while higher systolic blood pressure, history of hypertension and medications [beta

blockers and statins] were associated with reduced mortality. Results were consistent using

propensity score-adjusted models for both mortality (HR for EPO exposure: 1.88 [1.37-2.60],

p<0.0001) and the composite endpoint (HR for EPO exposure: 1.05 [0.84-1.32], p=0.65).

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Discussion

Our study found that patients receiving EPO, as compared with non-EPO users, had a

higher risk of death. Possible explanations for the increased mortality rate in our study could be

that the EPO group consisted of sicker patients with worse renal function and anemia, along with

significantly more patients with cancer and hypertension. However, the increased risk remained

even after adjusting for numerous confounding variables. While several early, uncontrolled,

open label studies found favorable improvements in functional class, EF, hemoglobin and HF

hospitalizations in CRAS patients,1,,15,16 our results are more consistent with other recent studies

that show concerning increases in death, CV and thrombotic events with ESA.12,14 Despite more

recent attention, these concerns date as far back as 1998, with the large NHCT study which

randomized 1,223 patients with HF or ischemic heart disease undergoing hemodialysis to receive

epoetin alfa to achieve either a hematocrit of 45% or 30%. Similar to our study, this trial found a

significant increase in death in the EPO group in this CRAS population, and was stopped early

due to safety concerns.14 Trend towards increased death rates were also found in the CREATE

and CHOIR studies of anemic CKD patients without HF treated with EPO, while a meta-analysis

of ESAs in anemic HF patients showed no difference in mortality.17,24,25

We also observed an increasing trend toward CV events, ACS, and HF hospitalizations.

In a similar CRAS population, the NHCT study found an increase in nonfatal myocardial

infarction (MI) and thrombosis in the higher hematocrit group (39% vs. 29%, p=0.001).14 In

other populations, increased CV events have also been reported. In anemic HF patients in RED-

HF, increased thromboembolic events were reported with darbepoetin (13.5% vs 10.0%,

p=0.01), while they failed to find a reduction in their primary outcome of death and

hospitalization for worsening HF.12,26 There have been mixed findings in the anemic CKD

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population. In the CHOIR trial, darbepoetin was associated with a 34% (p=0.03) increased

composite of death, HF hospitalizations, MI and stroke in anemic CKD patients.17 However,

other studies evaluating anemic, CKD patients observed no increase in CV events. In CREATE

and TREAT, both of which assessed the optimal hemoglobin target in anemic patients with

CKD, there were no significant difference between groups in reduction of CV events.18,24

However, TREAT did find a higher incidence of venous (2.0% vs 1.1%, p=0.02) and arterial

(8.9% vs 7.1%, p=0.04) thromboembolic events with darbepoetin compared with placebo.

The increased risk of stroke has been a recent concern in patients receiving ESA. In our

study, there was a trend towards increased stroke in the EPO group. Although our finding was

not statistically significant, it is consistent with several large trials of ESAs in treating anemia, all

suggesting increasing thrombogenicity concerns when targeting higher hemoglobin or hematocrit

levels.12,14,17,21 Most prominent was the TREAT trial, in which the annualized event rate for

stroke was nearly doubled with darbepoetin alfa (2.1% vs 1.1% in placebo).18

It has been postulated that raising hemoglobin levels may contribute to elevated blood

pressure and vascular thrombosis.7 By elevating hemoglobin, ESA increases platelet

adhesiveness and viscosity, possibly explaining the increased risk of thrombotic and stroke

events in some studies.7,17,24,27 This increased viscosity of the blood from ESA can also

exacerbate uncontrolled hypertension, leading to increased cardiovascular risk.7,27 Although

there are differences between darbepoetin and EPO, with the more potent darbepoetin having a

longer half-life and more efficient iron utilization, increased CV events and death have been

shown with both agents, raising similar concerns.28,29 Without head to head trials between

darbepoetin and EPO, it would be difficult to distinguish which agent has more concerns.

Although the 2009 ACC HF guidelines offer no recommendations for treatment of

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anemia, separate guidelines exist for anemia of CKD in using ESA to raise hemoglobin

levels.23,30 Neither guideline excludes the use of ESA in patients who have HF along with anemia

of CKD, and so its benefits have been extrapolated for use in the CRAS population. Given the

concerns that our study and others have raised in using ESA to elevate hemoglobin levels,

current HF guidelines should address this topic.

Our study has its limitations. Since this study is retrospective, missing data may be

possible as we rely on data from patient care records. However, since the main study variables

are commonly required for routine medical care, most were available for our use. In addition,

there is no reason to expect missing data to differ systematically between groups. EF values were

missing for some patients in both groups. By including primary and secondary diagnoses in our

diagnostic criteria for capturing HF, we hoped to capture the majority of eligible patients. It is

possible that we may have missed patients with milder forms of HF, but they would be less likely

to have CKD and anemia as the severity of HF is correlated with the development of CKD and

anemia. Although we had unequal baseline characteristics of EPO users and nonusers,

imbalances were adjusted for in the multivariate model. There is still the possibility of residual

confounding. Our ability to document iron supplement use from over-the-counter acquisition is

limited within the VA pharmacy prescription claims system. Therefore, we recognize this

limitation and did not focus on iron use in this study. Although we did not record treated BP or

Hb values, or EPO dose or duration in order to evaluate their impact on outcomes, others have

shown higher dose ESA therapy is associated with higher CV events and mortality regardless of

Hb achieved.14,17,18,19,27,31 Our population was primarily comprised of men, which reduces the

generalizability of our findings to women with HF. Although women and men both have a poor

prognosis after HF diagnosis, median survival for women is 1.5 years longer than for men.32,33

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However, women with preserved ejection HF have more HF hospitalizations, greater functional

capacity impairment and lower quality of life than men.34,35 Whether women respond differently

to EPO therapy than men is currently unknown. Despite these limitations, our study combines

administrative and clinical data to further address the knowledge gap regarding ESA use in

patients with anemia, HF and CKD, and complements the concerns of the larger body of

evidence in CKD/anemia and HF/anemia-specific populations.

Our findings do not support the use of EPO in patients with CRAS since it was associated

with increased risk of mortality, along with an increased trend in CV events and stroke. Our

study conclusion is concordant with other studies showing negative clinical outcomes with use of

ESA agents in CRAS, CKD and HF populations. Future studies are needed to explore the safety

of ESAs in CRAS patients. Caution is warranted in the use of EPO in CRAS patients, given the

increased risk of mortality and a trend toward increasing CV events from multiple studies.

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Disclosures

This article is not being considered for publication elsewhere, and contents of the paper have not

been previously published. All authors have read and approved the manuscript, with no

conflicts of interest to disclose. This study was funded by the American College of Clinical

Pharmacy Watson Anemia Investigator Development Research Award.

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Acknowledgements

We would like to acknowledge Mindy Chou, PharmD, for assistance with data management,

Carol Collier for data extraction, and Jeffrey Gornbein, PhD, who was a paid statistical

consultant.

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35. Deswal A, Bozkurt B. Comparison of morbidity in women versus men with heart failure and

preserved ejection fraction. Am J Cardiol 2006;97:1228-31.

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Table 1. Patient Baseline Characteristics

Characteristic EPO

(n=213)

Control

(n=1845) P-Value

Age (mean±SD , yr) 71.9±12 73.2±11 0.15

Sex (% M) 97.2 96.2 <0.45

SCr (mean±SD, g/dL) 3.2±2.4 2.1±1.7 <0.0001

eGFR (mean±SD, mL/min) 31.7±15 43.4±13 <0.0001

BUN (mean±SD, g/dL) 44.1±20 32.2±17 <0.0001

Hgb (mean±SD, g/dL) 10.5±1 11.1±0.89 <0.0001

Hct (mean±SD, g/dL) 33±5 35±4 <0.0001

SBP (mean±SD, mmHg) 133±23 128±22 <0.01

DBP (mean±SD, mmHg) 68±13 68±13 0.98

EF (mean±SD, %) 50.4±15 47.3±17 0.052

Comorbidities (%)

Hypertension 76.1 68.3 0.02

Diabetes 53.1 47.2 0.11

CAD 37.6 37.6 0.99

Cerebrovascular disease 14.6 13.7 0.75

Atrial fibrilllation 17.4 18.2 0.85

COPD 34.2 28.9 0.11

Cancer 32.4 25.9 0.04

Dialysis 5.2 1.1 <0.01

Renal Clinic (%) 69.5 36.9 <0.0001

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Medications (%)

ASA 31.0 23.5 0.02

ACEI 32.9 39.1 0.08

ARB 17.4 12.0 0.03

Beta-blocker 54.0 47.4 0.07

Digoxin 7.0 10.5 0.12

Diuretic 50.2 46.4 0.29

Iron 5.6 0.16 <0.0001

Hydralazine/nitrates 10.8 3.1 <0.0001

Statin 48.4 42.6 0.12

Aldosterone

antagonist

8.5 9.3 0.70

eGFR = estimated glomerular filtrate rate; BUN = blood urea nitrogen; Hgb = Hemoglobin; EF = ejection fraction; CAD = coronary artery disease; COPD = chronic obstructive pulmonary disease; ASA = aspirin; ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; EPO = erythropoietin; SBP = systolic blood pressure; DBP = diastolic blood pressure

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Table 2. Unadjusted (Crude) Clinical Outcomes of Death and Cardiovascular Events

EPO Treatment (n=213) Control (n=1846)

Event n (%) n % P-value

Death 72 33.8 363 19.7 <0.0001

Stroke 48 22.5 338 18.3 0.14

ACS 40 18.8 199 10.8 0.001

HF 102 47.9 761 41.2 0.07

All-cause

hospitalization

133 62.4 929 50.4 <0.001

ACS = acute coronary syndromes; EPO = erythropoietin; HF = heart failure hospitalizations

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Table 3. Adjusted Risk of Cardiovascular Events/Death

Variable HR (95% CI) P-value

EPO (Unadjusted) 1.19 (1.00-1.41) 0.04

EPO (Adjusted) 1.16 (0.96-1.40) 0.12

Age (per year) 1.01 (1.002-1.01) <0.01

eGFR (per unit) 1.00 (0.99-1.01) 0.86

BUN (per unit) 1.003 (1.001-1.006) 0.047

Hgb <10g/dL 1.47 (1.25-1.75) <0.0001

SBP (per mmHg) 1.00 (1.00 – 1.00) 0.90

DBP (per mmHg) 1.00 (1.00 – 1.01) 0.66

EF ≤50% 1.02 (1.01-1.02) <0.0001

Hypertension 0.85 (0.75-0.97) 0.02

Diabetes 0.97 (0.86 – 1.09) 0.61

CAD 1.19 (1.04-1.36) 0.01

Cerebrovascular disease 2.03 (1.75-2.35) <0.0001

Atrial fibrillation 1.30 (1.12-1.50) <0.001

COPD 1.59 (1.41-1.80) <0.0001

Cancer 1.12 (0.98 – 1.27) 0.09

Dialysis 1.39 (0.88 – 2.19) 0.16

ASA 1.23 (1.08-1.41) <0.01

ACEI 1.12 (0.99-1.26) 0.07

Beta-Blocker 1.07 (0.94 – 1.21) 0.30

Digoxin 1.16 (0.96-1.39) 0.14

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Diuretic 1.35 (1.19-1.53) <0.0001

Hydralazine/nitrates 1.21 (1.06-1.37) <0.01

Aldosterone antagonist 1.16 (0.96-1.40) 0.12

Statin 0.94 (0.83 – 1.06) 0.32

eGFR = estimated glomerular filtrate rate; BUN = blood urea nitrogen; Hgb = Hemoglobin; EF = ejection fraction; CAD = coronary artery disease; COPD = chronic obstructive pulmonary disease; ASA = aspirin; ACEI = angiotensin converting enzyme inhibitor; EPO = erythropoietin; SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = hazard ratio; CI = confidence interval

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Table 4. Adjusted Risk of Mortality Variable HR (95% CI) P-value

EPO (Unadjusted) 1.62 (1.26-2.09) <0.001

EPO (Adjusted) 1.40 (1.06-1.85) 0.02

Age (per year) 1.02 (1.01-1.03) <0.001

eGFR (per unit) 1.00 (0.99-1.00) 0.32

BUN (per unit) 1.01 (1.002-1.013) <0.01

Hgb <10g/dL 1.72 (1.34-2.20) <0.0001

SBP (per mmHg) 0.99 (0.99-1.00) 0.03

DBP (per mmHg) 1.01 (1.00-1.02) 0.07

EF ≤50% 1.39 (1.10-1.75) <0.01

Hypertension 0.72 (0.58-0.88) <0.01

Diabetes 0.89 (0.72-1.10) 0.27

CAD 1.05 (0.84-1.31) 0.68

Atrial fibrillation 1.20 (0.95-1.51) 0.13

COPD 1.88 (1.54-2.30) <0.0001

Cancer 1.50 (1.23-1.84) <0.0001

Dialysis 1.08 (0.56-2.10) 0.82

ACEI 0.89 (0.72-1.10) 0.29

Beta-Blocker 0.77 (0.62-0.95) 0.01

Digoxin 1.28 (0.95-1.73) 0.11

Aldosterone antagonist 0.93 (0.66-1.30) 0.67

Statin 0.76 (0.61-0.93) <0.01

eGFR = estimated glomerular filtrate rate; BUN = blood urea nitrogen; Hgb = Hemoglobin; EF = ejection fraction; CAD = coronary artery disease; COPD = chronic obstructive pulmonary disease; ASA = aspirin; ACEI = angiotensin converting enzyme inhibitor; EPO = erythropoietin; SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = hazard ratio; CI = confidence interval

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Figure 1: All-Cause Mortality – Monthly percentage of unadjusted and adjusted rates of all-cause mortality in CRAS patients

receiving EPO or no EPO

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Figure 2: Composite of Cardiovascular Events/Death – Monthly percentage of unadjusted and adjusted rates of composite of

cardiovascular events/death in CRAS patients receiving EPO or no EPO

CRAS: Cardio-renal-anemia syndrome EPO= erythropoietin; HR= Hazard Ratio