trial organization and committees · web viewnicolas dumonteil. chu rangueil, toulouse, france...

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


Ioannis Mastoris, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at


George Dangas, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at


Roxana Mehran, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at


Usman Baber, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at


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


* 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)


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


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


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)


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


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

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