Online appendix for:
Bivalirudin Versus Heparin Anticoagulation in Transcatheter Aortic
Valve Replacement
The Randomized BRAVO-3 Trial
Table of contents
Trial Organization and committees..............................................................................................................2
Investigators................................................................................................................................................ 3
Trial inclusion and exclusion criteria............................................................................................................5
Standardized definitions for study outcomes...............................................................................................7
Bleeding scales........................................................................................................................................ 7
Cerebrovascular accident scales...........................................................................................................11
Myocardial infarction.............................................................................................................................. 11
Vascular access site and access-related complications........................................................................12
Acute kidney injury (modified RIFLE classification, adapted from Leon et al. 2011 (7))........................12
Adaptive sample-size scheme................................................................................................................... 13
ONLINE TABLE 1 Additional secondary bleeding outcomes at 30 days...................................................14
ONLINE TABLE 2 Thirty-day mortality rates according to patient complication.........................................15
ONLINE TABLE 3 Adjudicated major vascular complications...................................................................16
ONLINE TABLE 4 Adjudicated acute kidney injury at 48 hours and 30 days according to calculated glomerular filtration rate at baseline...........................................................................................................17
ONLINE TABLE 5 Adjudicated endpoints in patients with a baseline calculated glomerular filtration rate less than 30 ml/min.................................................................................................................................... 18
ONLINE FIGURE 1 Outcomes according to prespecified subgroups........................................................19
REFERENCES.......................................................................................................................................... 21
1
Trial Organization and committees
Executive Committee George D Dangas, Icahn School of Medicine at Mount Sinai, New York, NY, USA (Chair, Mount Sinai)
Eberhard Grube, University Hospital, Bonn, Germany (Co-Principal Investigator)
Thierry Lefevre, Hôpital Privé Jacques Cartier, Massy, France (Co-Principal Investigator)
Antonio Colombo, San Raffaele Hospital, Milan, Italy
Christian Hengstenberg, DZHK (German Centre for Cardiovascular Research), partner site Munich Heart
Alliance, Munich, Germany; and Deutsches Herzzentrum München, Technische Universität München,
Munich, Germany
Christian Kupatt, LMU Munich, Munich, Germany
David Hildick-Smith, Sussex Cardiac Centre – Brighton & Sussex University Hospitals NHS Trust,
Brighton, Sussex, UK
John G Webb, St. Paul's Hospital, Vancouver, BC, Canada
Jurriën M ten Berg, St. Antonius Ziekenhuis, Nieuwegein, Netherlands
Efthymios N Deliargyris, The Medicines Company, Parsippany, NJ, USA
Nicolas Dumonteil. CHU Rangueil, Toulouse, France
Prodromos Anthopoulos, The Medicines Company, Zurich, Switzerland
Roxana Mehran, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at
Mount Sinai, New York, NY, USA
Stephan Windecker, Department of Cardiology, Bern University Hospital, Bern, Switzerland
Data Safety Monitoring Board Michel Bertrand, France (Chair)
Gregory Dehmer, Texas A&M School of Medicine, Temple, Texas, USA
Arie Pieter Kappetein, Thoraxcenter, Erasmus MC, Rotterdam Department of Thoracic Surgery,
Rotterdam, Netherlands
Germano DiSciascio, Campus Biomedico, University of Rome, Rome, Italy
Stuart Pocock, London School of Hygiene & Tropical Medicine, UK
Timothy Clayton, London School of Hygiene & Tropical Medicine, UK (independent statistician)
Clinical Events CommitteeSteven O Marx (Chair), Columbia University, New York, NY
Nicola Corvaja, Stamford Hospital, Stamford, CT, USA
Douglas C DiStefano, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Newsha Z Ghodsi, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Mun K Hong, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Jason Ciril Kovacic, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Jesse Michael Weinberger, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2
InvestigatorsJohn Webb, St. Paul's Hospital, Providence Health Care, Vancouver, BC, Canada
Anita W Asgar, Institut de Cardiologie de Montreal, Montreal, Canada
Jurrien M ten Berg, St. Antonius Ziekenhuis, Nieuwegein, Netherlands
Pieter Stella, University Medical Center Utrecht, Utrecht, Netherlands
Nicolas Dumonteil CHU Rangueil, Toulouse, France
Thierry Lefevre, Hôpital Privé Jacques Cartier, Massy, France
Didier Tchetche, Clinique Pasteur Toulouse, Toulouse, France
Eric Van Belle, Department of Cardiology and INSERM UMR 1011, University Hospital; CHRU de Lille,
Lille, France
Christophe Tron, CHU de Rouen, Rouen, France
Nicolas Meneveau, CHU Jean Minjoz, Besançon, France
Antonio Colombo, San Raffaele Hospital, Milan, Italy
Corrado Tamburino, University of Catania, Catania, Italy
Roberto Violini, Azienda Ospedaliera San Camillo-Forlanini di Roma, Rome, Italy
Marco De Carlo, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
Gennaro Sardella, Policlinico Umberto I, Rome, Italy
Stephan Windecker, Department of Cardiology, Bern University Hospital, Bern, Switzerland
Raban V. Jeger, Cardiology University Hospital Basel, Basel, Switzerland
David Hildick-Smith, Sussex Cardiac Centre – Brighton & Sussex University Hospitals NHS Trust,
Brighton, Sussex, UK
Ghada Mikhail, Hammersmith Hospital, London, UK
Nikos Werner, University Hospital Bonn, Bonn, Germany
Peter Boekstegers, Helios Heart Center, Siegburg, Germany
Julian Widder, Medizinische Hochschule Hannover, Hannover, Germany
Hans Ulrich Hink, Universitätsmedizin Mainz, Mainz, Germany
Christian Kupatt, LMU Munich, Munich, Germany
Axel Linke, Herzzentrum Leipzig, Leipzig, Germany
Christoph Naber, Elisabeth-Krankenhaus Essen, Essen, Germany
Markus Ferrari, University Heart Centre, Clinic of Inner Medicine 1 Cardiology, Jena, Germany
Rainer Hambrecht, Klinikum links der Weser Bremen, Bremen, Germany
Ulrich Schäfer, University Heart Center, Hamburg, Germany; and Asklepios Clinics St. Georg, Hamburg,
Germany.
Christian Hengstenberg, DZHK (German Centre for Cardiovascular Research), partner site Munich Heart
Alliance, Munich, Germany; and Deutsches Herzzentrum München, Technische Universität München,
Munich, Germany
Oliver Husser, Deutsches Herzzentrum München, München, Germany
3
Gennaro Giustino, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at
Mount Sinai, New York, NY, USA
Ioannis Mastoris, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at
Mount Sinai, New York, NY, USA
George Dangas, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at
Mount Sinai, New York, NY, USA
Roxana Mehran, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at
Mount Sinai, New York, NY, USA
Usman Baber, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at
Mount Sinai, New York, NY, USA
Eberhard Grube, University Hospital, Bonn, Germany
Efthymios N Deliargyris, The Medicines Company, Parsippany, NJ, USA
Ilknur Lechthaler, The Medicines Company, Zurich, Switzerland
Prodromos Anthopoulos, The Medicines Company, Zurich, Switzerland
Peter Wijngaard, The Medicines Company, Zurich, Switzerland
Debra Bernstein, The Medicines Company, Parsippany, NJ, USA
Independent statisticiansTimothy Clayton, London School of Hygiene & Tropical Medicine, UK (DSMB)
Sarah Emerson, Oregon State University, USA (adaptive sample size)
4
Trial inclusion and exclusion criteria
Inclusion criteriaPatients may be included in the study if they meet all of the following criteria:
1. ≥ 18 years of age
2. High risk (EuroSCORE ≥18, or considered inoperable) for surgical aortic valve replacement
3. Undergoing transcatheter aortic valve replacement (TAVR) via transfemoral arterial access
4. Provide written informed consent before initiation of any study related procedures.
Exclusion criteriaPatients will be excluded from the study if any of the following exclusion criteria apply prior to enrolment:
1. Any known contra-indication to the use of bivalirudin (except presence of severe renal impairment
[glomerular filtration rate <30 ml/min) since these patients will be included in the trial or UFH
2. Refusal to receive blood transfusion
3. Mechanical valve (any location) or mitral bioprosthetic valve
4. Extensive calcification of the common femoral artery, or minimal luminal diameter <6·5 mm
5. Use of elective surgical cut-down for transfemoral access
6. Concurrent performance of percutaneous coronary intervention with TAVR
7. International normalized ratio ≥2 on the day of TAVR procedure, or known history of bleeding
diathesis
8. History of hemorrhagic stroke, intracranial hemorrhage, intracerebral mass or aneurysm, or
arteriovenous malformation
9. Severe left ventricular dysfunction (left ventricular ejection fraction <15%)
10. Severe aortic regurgitation or mitral regurgitation (4+)
11. Hemodynamic instability (e.g. requiring inotropic or intra-aortic balloon pump support) within 2
hours of the procedure
12. Dialysis dependent
13. Administration of thrombolytics, glycoprotein IIb/IIIa inhibitors, or warfarin in the 3 days prior to the
procedure
14. Acute myocardial infarction, major surgery or any therapeutic cardiac procedure (other than
balloon aortic valvuloplasty) within 30 days
15. Percutaneous coronary intervention within 30 days
16. Upper gastrointestinal or genitourinary bleed within 30 days
17. Stroke or transient ischemic attack within 30 days
18. Any surgery or biopsy within 2 weeks
19. Administration of:
a) Unfractionated heparin within 30 minutes of the procedure
b) Enoxaparin within 8 hours of the procedure
5
c) Fondaparinux or other low molecular weight heparins within 24 hours of the procedure
d) Dabigatran, rivaroxaban or other oral anti-Xa or antithrombin agent within 48 hours of the
procedure
e) Thrombolytics, glycoprotein IIb/IIIa inhibitors, or warfarin within 72 hours of the procedure
20. Absolute contraindications or allergy that cannot be pre-medicated to iodinated contrast
21. Contraindications or allergy to aspirin or clopidogrel
22. Known or suspected pregnant women, or nursing mothers. Women of child-bearing potential will
be asked if they are pregnant and will be tested for pregnancy.
23. Previous enrolment in this study
24. Treatment with other investigational drugs or devices within the 30 days preceding enrolment or
planned use of other investigational drugs or devices before the primary endpoint of this study
has been reached
Patients excluded for any of the above reasons may be re-screened for participation at any time if the
exclusion characteristic has changed.
6
Standardized definitions for study outcomesBleeding scales
1.1) BARC bleeding criteria (modified by Mehran et al. 2011 (1))
Type Definition
0 No bleeding
1 Bleeding that is not actionable and patient does not have unscheduled studies, hospitalization or
treatment by a health care professional
2 Any clinically overt sign of hemorrhage that is actionable but does not meet criteria for type 3, 4
or 5 bleeding. It must meet at least one of the following criteria:
requiring medical or percutaneous intervention guided by a health care professional,
includes (but are not limited to) temporary/permanent cessation or reversal of a
medication, coiling, compression, local injection
leading to hospitalization or an increased level of care
prompting evaluation defined as an unscheduled visit to a healthcare professional
resulting in diagnostic testing (laboratory or imaging)
3 Clinical, laboratory and/or imaging evidence of bleeding with specific healthcare provider
responses, as listed below:
3a.
Any transfusion with overt bleeding
Overt bleeding plus hemoglobin (Hb) drop ≥3 to <5 g/dl* (provided Hb drop is related to
bleeding)
3b.
Overt bleeding plus Hb drop ≥5 g/dl* (where Hb drop is related to bleed)
Cardiac tamponade
Bleeding requiring surgical intervention for control (excluding
dental/nasal/skin/hemorrhoid)
Bleeding requiring intravenous vasoactive drugs
3c.
Intracranial hemorrhage (does not include micro bleeds or hemorrhagic transformation;
does include intraspinal). Subcategories: confirmed by autopsy, imaging or lumbar
puncture
Intraocular bleed compromising vision
4 Coronary artery bypass-related bleeding
Perioperative intracranial bleeding within 48 hours
Reoperation following closure of sternotomy for the purpose of controlling bleeding
7
Transfusion of ≥5 units of whole blood or packed red blood cells within a 48-hour period
Chest tube output ≥2 l within a 24-hour period
5 Fatal bleeding. Bleeding directly causes death with no other explainable cause. Categorized
further as either definite or probable.
a) Probable fatal bleeding is bleeding that is clinically suspicious as the cause of death, but
the bleeding is not directly observed and there is no autopsy or confirmatory imaging.
b) Definite fatal bleeding (Type 5b) is bleeding that is directly observed (either by clinical
specimen – blood, emesis, stool, etc. – or by imaging) or confirmed on autopsy.
*Corrected for transfusion (1 U packed red blood cells or 1 U whole blood = g/dl hemoglobin).
BARC=Bleeding Academic Research Consortium.
1.2) VARC bleeding definitions (modified by Kappetein et al. 2012 (2))
Life threatening or disabling bleeding:
Fatal bleeding OR
Bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, pericardial
necessitating pericardiocentesis, or intramuscular with compartment syndrome OR
Bleeding causing hypovolemic shock or severe hypotension requiring vasopressors or surgery
(BARC type 3b) OR
Overt source of bleeding with drop in hemoglobin of ≥5 g/dl or whole blood or packed red blood
cells transfusion ≥4 U† (BARC type 3b)
Major bleeding (BARC type 3a):
Overt bleeding either associated with a drop in the hemoglobin level of ≥3.0 g/dl* or requiring
transfusion of two or three units of whole blood/RBC AND
Does not meet criteria of life-threatening or disabling bleeding
Minor bleeding (BARC type 2 or 3a, depending on the severity):
Any bleeding worthy of clinical mention (e.g. access site hematoma) that does not qualify as life-
threatening, disabling or major.
BARC=Bleeding Academic Research Consortium; RBC=red blood cells; VARC=Valve Academic
Research Consortium.
*Given that one unit of packed RBC typically will raise the hemoglobin concentration by 1 g/dl, an
estimated decrease in hemoglobin will be calculated.
8
1.3) TIMI bleeding definitions(3)
TIMI bleeding classification*
Major Intracranial hemorrhage or a ≥5 g/dl decrease in the hemoglobin concentration or
a ≥15% absolute decrease in the hematocrit
Minor Observed blood loss (including imaging): ≥3 g/dl decrease in the hemoglobin
concentration or ≥10% decrease in the hematocrit
No observed blood loss: ≥4 g/dl decrease in the hemoglobin concentration or
≥12% decrease in the hematocrit
Minimal Any clinically overt sign of hemorrhage (including imaging) that is associated with
a <3 g/dl decrease in the hemoglobin concentration or <9% decrease in the
hematocrit
*Hemoglobin drop should be corrected for intracurrent transfusion in which 1 unit of packed red blood
cells or whole blood would be expected to increase hemoglobin by 1 g/dl.
TIMI=Thrombolysis In Myocardial Infarction.
1.4) GUSTO bleeding definitions (adapted from the GUSTO investigators, 1993 (4))
Severe or
life-threatening
Either intracranial hemorrhage or bleeding that causes hemodynamic
compromise and requires intervention
Moderate Bleeding that requires blood transfusion but does not result in
hemodynamic compromise
Mild Bleeding that does not meet the criteria for severe or moderate
GUSTO=Global Use of Strategies to Open Occluded Coronary Arteries.
1.5) ACUITY/HORIZONS-AMI bleeding definitions (adapted from Stone et al. 2004 (5) and Mehran, et al. 2008 (6))
Major bleeding:
Intracranial hemorrhage
Intraocular hemorrhage
Bleeding at the access site, with a hematoma that was ≥5 cm or that required intervention
9
A decrease in the hemoglobin level of ≥4 g/dl without an overt bleeding source
A decrease in the hemoglobin level of ≥3 g/dl with an overt bleeding source
Reoperation for bleeding
Transfusion of any blood products
Minor bleeding:
Any bleeding worthy of clinical mention (e.g. access site hematoma) that does not qualify as life-
threatening, disabling or major.
ACUITY=Acute Catheterization and Urgent Intervention Triage Strategy; HORIZONS-AMI=The
Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction.
10
Cerebrovascular accident scalesVARC cerebrovascular eventsTransient ischemic attack:
1. New focal neurological deficit with rapid symptom resolution always within 24 hours AND
2. No acute tissue injury on neuroimaging
Stroke meets ALL of the following diagnostic criteria:
1. Rapid onset of a focal or global neurological deficit with at least one sign or symptom c/w stroke
(includes decreased level of consciousness if associated with unequivocal abnormalities on
neuroimaging)
2. Duration more than 24 hours unless there was a therapeutic intervention, confirmatory
neuroimaging or a neurological deficit resulting in death
3. No other identifiable cause for the clinical presentation AND
4. Diagnosis is confirmed by a specialist in neurology or neurosurgery, with neuroimaging or lumbar
puncture (in the case of intracranial hemorrhage).
Myocardial infarctionPeriprocedural myocardial infarction Periprocedural myocardial infarction fulfills ALL three criteria (but is not a confirmed coronary embolus):
1. ≤72 hours after the index procedure
2. New ischemic symptoms or signs (e.g. ventricular arrhythmias, new or worsening heart failure,
new hemodynamic instability), new ST segment changes OR imaging evidence of new loss of
viable myocardium or new wall motion abnormality.
3. Elevated cardiac biomarkers (preferably Creatine Kinase Myocardial Band [CKMB]) as defined
by:
a. At least two samples that are >6 to 8 hours apart with a 20% increase in the second
sample AND a peak value greater than 10x the 99th percentile upper reference limit OR
b. A peak value exceeding 5x the 99th percentile upper reference limit with new pathological
Q waves in at least 2 contiguous leads
Spontaneous myocardial infarction Spontaneous myocardial infarction includes ANY of the following occurring more than 72 hours after the
index procedure (but note a confirmed coronary embolus is specifically excluded):
1. Rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th
percentile upper reference limit, WITH any one of the following:
a. New ischemic ECG changes (new ST-T changes or new Left bundle branch block
[LBBB]) OR
b. New pathological Q waves in 2 or more contiguous leads OR
c. Imaging evidence of new loss of viable myocardium or new wall motion abnormality
11
2. Sudden unexpected death due to cardiac arrest, often with symptoms suggestive of myocardial
ischemia AND accompanied by presumably new ST elevation, new LBBB and/or evidence of
fresh thrombus on coronary angiography or autopsy.
3. Pathological findings of an acute myocardial infarction
Coronary embolusMeets the definition criteria for periprocedural or spontaneous myocardial infarction but is due to a
confirmed coronary embolus.
Vascular access site and access-related complications
1. Any thoracic aortic dissection is automatically a major vascular complication.2. Access-related vascular injury – major and minor criteria (only 1 criterion required to qualify)
Major MinorComplicated by death YesBlood transfusion 4 or more units 2–3 unitsLocal treatment Unplanned percutaneous or
surgical interventionNon routine compression, thrombin injection
Irreversible end-organ damage Yes
3. Distal embolization – major and minor criteria (only 1 criterion required to qualify)Major Minor
Underwent treatment Surgery Embolectomy and/or thrombectomyIrreversible end-organ damage YesResulted in Amputation Yes
4. Failed access site closureMajor Minor
Complicated by death YesBlood transfusion 4 or more unitsUnderwent treatment Percutaneous intervention or surgical correctionIrreversible end-organ damage Yes
Acute kidney injury (modified RIFLE classification, adapted from Leon et al. 2011 (7))
Stage % Rise in creatinine Absolute creatinine increase
1 (Risk) 150–200%OR
≥0.3 mg/dl
2 (Injury) 200–300%OR
>0.3 but <4.0 mg/dl
3 (Failure) ≥300% OR
Serum Cr ≥ 4 mg/dl + Absolute increase >0.5 mg/dl
OR received new renal replacement therapy
12
Adaptive sample-size schemeTwo interim analyses were pre-specified and the data safety monitoring board (DSMB) reserved the right
to amend this plan after their periodic monitoring of data during the study, according to the DSMB charter.
Prior to these analyses, the protocol was amended by the executive committee on February 12, 2014,
which changed the primary bleeding endpoint from Bleeding Academic Research Consortium (BARC) ≥3
to BARC ≥3b. The first interim analysis occurred after enrolment of the first 170 randomized patients
(approximately one third of the projected enrolment) and the second after enrolment of 340 randomized
patients (approximately two thirds of the projected enrolment). The first analysis was a blinded
determination of the overall major bleeding rate in the study population. Based on the hypothesized major
bleeding rates of 19% and 10% in the two groups, the expected incidence at the first interim analysis was
14.5% (95% confidence interval 9.7–20.1). If the major bleeding rate for the study population at this initial
analysis fell below the lower 95% confidence bounds for the expected rate (<10%), then allowances could
be made to enrich the study population. This interim look took place on August 31, 2013 and resulted in
the study to continue without any changes.
The second interim analysis was an unblinded determination of the adjudicated major bleeding
rates in each group, observed relative risk reduction, and conditional power. The interim analysis plan
included the alpha spending function and the exact methods used to calculate the adaptive sample size
changes.
Accordingly, the DSMB reviewed summary reports of the second interim analysis on 340
completed patients and the adaptive sample size calculations prepared by independent statisticians and
convened on 22 May 2014 to determine their recommendation. A maximum of 800 patients was specified
in the interim statistical analysis plan as the upper limit of the increase in sample size. On 23 May 2014,
the DSMB issued a recommendation to continue the trial unmodified until the final number of inclusions
(800 patients), according to the interim statistical analysis plan.
13
ONLINE TABLE 1 Additional secondary bleeding outcomes at 30 days
Bleeding scale Bivalirudin
(n=404)
Heparin
(n=398)
Relative risk (95% CI)
p Value
VARC (life-threatening or major) 107 (26.5) 98 (24.6) 1.08 (0.85–1.36) 0.55
TIMI (major) 23 (5.7) 29 (7.3) 0.78 (0.46–1.33) 0.36
GUSTO (severe/life-threatening) 17 (4.2) 17 (4.3) 0.99 (0.51–1.90) 0.96
ACUITY/HORIZONS (major) 135 (33.4) 118 (29.6) 1.13 (0.92–1.38) 0.25
BARC types 1 or 2 112 (27.7) 102 (25.6) 1.08 (0.86–1.36) 0.50
TIMI minor 86 (21.3) 77 (19.3) 1.10 (0.84–1.45) 0.49
Data given as number (%).
ACUITY=Acute Catheterization and Urgent Intervention Triage Strategy; BARC=Bleeding Academic
Research Consortium; CI=confidence interval; GUSTO=Global Utilization of Streptokinase and Tissue
Plasminogen Activator for Occluded Coronary arteries; HORIZONS=The Harmonizing Outcomes with
Revascularization and Stents in Acute Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction;
VARC=Valve Academic Research Consortium.
14
ONLINE TABLE 2 Thirty-day mortality rates according to patient complication.
Type of complication
Mortality rates Relative risk (95% CI)
p Value
Overall Bivalirudin Heparin
BARC type ≥3b 16/78 (20.5) 8/36 (22.2) 8/42 (19.0) 1.17 (0.49–2.79) 0.73
BARC type 1 or 2 5/214 (2.3) 5/112 (4.5) 0/102 (0.0) – 0.06
BARC type ≥3 23/216 (10.6) 13/111 (11.7) 10/105 (9.5) 1.23 (0.56–2.68) 0.60
VARC (life-
threatening or
major)
22/205 (10.7) 12/107 (11.2) 10/98 (10.2) 1.10 (0.50–2.43) 0.82
TIMI (major) 11/52 (21.2) 4/23 (17.4) 7/29 (24.1) 0.72 (0.24–2.16) 0.74
GUSTO
(severe/life-
threatening)
12/34 (35.3) 6/17 (35.3) 6/17 (35.3) 1.00 (0.40–2.48) 1.00
ACUITY/
HORIZONS
(major)
26/253 (10.3) 13/135 (9.6) 13/118 (11.0) 0.87 (0.42–1.81) 0.72
TIMI minor 11/163 (6.7) 7/86 (8.1) 4/77 (5.2) 1.57 (0.48–5.15) 0.45
Myocardial
infarction
3/9 (33.3) 0/2 3/7 (42.9) – 0.50
Stroke 5/25 (20.0) 4/14 (28.6) 1/11 (9.1) 3.14 (0.41–
24.27)
0.34
Acute kidney injury 17/131 (13.0) 8/76 (10.5) 9/55 (16.4) 0.64 (0.26–1.56) 0.33
Data given as number (%).
* Composite of all-cause mortality, myocardial infarction, stroke, or major bleeding.
ACUITY=Acute Catheterization and Urgent Intervention Triage Strategy; BARC=Bleeding Academic
Research Consortium; CI=confidence interval; GUSTO=Global Utilization of Streptokinase and Tissue
Plasminogen Activator for Occluded Coronary arteries; HORIZONS=The Harmonizing Outcomes with
Revascularization and Stents in Acute Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction;
VARC=Valve Academic Research Consortium.
15
ONLINE TABLE 3 Adjudicated major vascular complications
Type of complication Overall (n=802)
Bivalirudin group
(n=404)
Heparin group
(n=398)
Relative risk (95% CI)
p Value
At 48 hours
Major vascular
complications
71 (8.9) 35 (8.7) 36 (9.0) 0.96 (0.61–
1.49)
0.85
With major bleed 32/71 (45.1) 13/35 (37.1) 19/36 (52.8) 0.70 (0.41–
1.20)
0.19
Without major bleed 39/71 (54.9) 22/35 (62.9) 17/36 (47.2) 1.33 (0.87–
2.04)
0.19
At 30 days
Major vascular
complications
75 (9.4) 37 (9.2) 38 (9.5) 0.96 (0.62–
1.48)
0.85
With major bleed 35/75 (46.7) 15/37 (40.5) 20/38 (52.6) 0.77 (0.47–
1.26)
0.29
Without major bleed 40/75 (53.3) 22/37 (59.5) 18/38 (47.4) 1.26 (0.82–
1.93)
0.29
Data given as number (%).
16
ONLINE TABLE 4 Adjudicated acute kidney injury at 48 hours and 30 days according to calculated glomerular filtration rate at baseline
Bivalirudin
(n=404)
Heparin
(n=398)
p Value
Acute kidney injury at 48 hours
<30 ml/min 7/18 (38.9) 2/22 (9.1) 0.02
30–59 ml/min 20/205 (9.8) 14/193 (7.3) 0.37
≥60 ml/min 17/181 (9.4) 10/183 (5.5) 0.15
Acute kidney injury at 30 days
<30 ml/min 7/18 (38.9) 2/22 (9.1) 0.02
30–59 ml/min 40/205 (19.5) 30/193 (15.5) 0.30
≥60 ml/min 29/181 (16.0) 23/183 (12.6) 0.35
Data given as number (%).
17
ONLINE TABLE 5 Adjudicated endpoints in patients with a baseline calculated glomerular filtration rate less than 30 ml/min
Type of complication Overall (n=40)
Bivalirudin group (n=18)
Heparin group (n=22)
Relative risk (95% CI)
p Value
At 48 hours
Major vascular
complications
4 (10.0) 3 (16.7) 1 (4.5) 3.67 (0.42–32.30) 0.31
With major bleed 0 0 0 – –
Without major bleed 4/40 (10.0) 3/18
(16.7)
1/22 (4.5) 3.67 (0.42–32.30) 0.31
Death 1 (2.5) 0 1 (4.5) – 1.00
Major bleed 3 (7.5) 2 (11.1) 1 (4.5) 2.44 (0.24–24.83) 0.58
At 30 days
Major vascular
complications
4 (10.0) 3 (16.7) 1 (4.5) 3.67 (0.42–32.30) 0.31
With major bleed 0 0 0 – –
Without major bleed 4/40 (10.0) 3/18
(16.7)
1/22 (4.5) 3.67 (0.42–32.30) 0.31
Death 3 (7.5) 1 (5.6) 2 (9.1) 0.61 (0.06–6.21) 1.00
Major bleed 4 (10.0) 3 (16.7) 1 (4.5) 3.67 (0.42–32.30) 0.31
Data given as number (%).
18
ONLINE FIGURE 1 Outcomes according to prespecified subgroups. A. Major bleed (BARC ≥3b) events at 48 h. COPD=chronic obstructive lung disease; GFR= glomerular filtration rate.
19
B. Net adverse clinical events at 30 days. COPD=chronic obstructive lung disease; GFR=glomerular filtration rate.
20
REFERENCES
1. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011;123:2736-47.
2. Kappetein AP, Head SJ, Genereux P, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. J Am Coll Cardiol 2012;60:1438-54.
3. Rao SV, O'Grady K, Pieper KS, et al. A comparison of the clinical impact of bleeding measured by two different classifications among patients with acute coronary syndromes. J Am Coll Cardiol 2006;47:809-16.
4. The GUSTO investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:673-82.
5. Stone GW, Bertrand M, Colombo A, et al. Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial: study design and rationale. Am Heart J 2004;148:764-75.
6. Mehran R, Brodie B, Cox DA, et al. The Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction (HORIZONS-AMI) Trial: study design and rationale. Am Heart J 2008;156:44-56.
7. Leon MB, Piazza N, Nikolsky E, et al. Standardized endpoint definitions for Transcatheter Aortic Valve Implantation clinical trials: a consensus report from the Valve Academic Research Consortium. J Am Coll Cardiol 2011;57:253-69.
21