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 Committee
Steven 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
Investigators
John 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 statisticians
Timothy 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 criteria
Patients 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 criteria
Patients 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 outcomes
Bleeding 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 lifethreatening, 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*
 Intracranial hemorrhage or a ≥5 g/dl decrease in the hemoglobin concentration or
Major
a ≥15% absolute decrease in the hematocrit
 Observed blood loss (including imaging): ≥3 g/dl decrease in the hemoglobin
Minor
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
 Either intracranial hemorrhage or bleeding that causes hemodynamic
compromise and requires intervention
life-threatening
Moderate
 Bleeding that requires blood transfusion but does not result in
hemodynamic compromise
 Bleeding that does not meet the criteria for severe or moderate
Mild
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
 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
9
 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 lifethreatening, 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 scales
VARC cerebrovascular events
Transient 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 infarction
Periprocedural 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 embolus
Meets 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
Minor
Complicated by death
Yes
Blood transfusion
4 or more units
2–3 units
Local treatment
Unplanned percutaneous or
Non routine compression,
surgical intervention
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 thrombectomy
Irreversible end-organ damage
Yes
Resulted in Amputation
Yes
4. Failed access site closure
Complicated by death
Blood transfusion
Underwent treatment
Irreversible end-organ damage
Major
Yes
4 or more units
Minor
Percutaneous intervention or surgical correction
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 scheme
Two 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
Relative risk
p Value
Bivalirudin
Heparin
(n=404)
(n=398)
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
(95% CI)
VARC (life-threatening or major)
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
Mortality rates
Relative risk
complication
p Value
(95% CI)
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-
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-
12/34 (35.3)
6/17 (35.3)
6/17 (35.3)
1.00 (0.40–2.48)
1.00
26/253 (10.3)
13/135 (9.6)
13/118 (11.0)
0.87 (0.42–1.81)
0.72
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
17/131 (13.0)
8/76 (10.5)
9/55 (16.4)
0.64 (0.26–1.56)
0.33
threatening or
major)
threatening)
ACUITY/HORIZONS
(major)
TIMI minor
Acute kidney injury
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
Bivalirudin
Heparin
Relative risk
(n=802)
group (n=404)
group
(95% CI)
p Value
(n=398)
At 48 hours
Major vascular
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
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
complications
At 30 days
Major vascular
complications
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
p Value
Bivalirudin
Heparin
(n=404)
(n=398)
<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
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
Acute kidney injury at 48 hours
Acute kidney injury at 30 days
<30 ml/min
Data given as number (%).
17
ONLINE TABLE 5 Adjudicated endpoints in patients with a baseline calculated glomerular
filtration rate less than 30 ml/min
Overall
Bivalirudin
Heparin
Relative risk (95%
(n=40)
group
group
CI)
(n=18)
(n=22)
4 (10.0)
3 (16.7)
1 (4.5)
3.67 (0.42–32.30)
0.31
0
0
0
–
–
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)
4 (10.0)
3 (16.7)
1 (4.5)
3.67 (0.42–32.30)
0.31
0
0
0
–
–
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
Type of complication
p Value
At 48 hours
Major vascular complications
With major bleed
Without major bleed
2.44 (0.24–24.83)
0.58
At 30 days
Major vascular complications
With major bleed
Without major bleed
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.
Age
Bivalirudin
Heparin
Relative Risk
P-value
Int.
P-value
0.47
No./total no. (%)
No./total no. (%)
> 80 yr
20/268 (7.5)
23/267 (8.6)
0.87 [0.49, 1.54]
0.62
≤ 80 yr
8/136 (5.9)
13/131 (9.9)
0.59 [0.25, 1.38]
0.22
Male
14/209 (6.7)
18/202 (8.9)
0.75 [0.38, 1.47]
0.40
Female
14/195 (7.2)
18/196 (9.2)
0.78 [0.40, 1.53]
0.47
≥ 60 ml/min
13/181 (7.2)
17/183 (9.3)
0.77 [0.39, 1.54]
0.46
< 60 ml/min
15/223 (6.7)
19/215 (8.8)
0.76 [0.40, 1.46]
0.41
Yes
10/125 (8.0)
13/114 (11.4)
0.70 [0.32, 1.54]
0.37
No
18/279 (6.5)
23/284 (8.1)
0.80 [0.44, 1.44]
0.45
Balloon expandable 19/251 (7.6)
20/249 (8.0)
0.94 [0.52, 1.72]
0.85
Self expanding
8/140 (5.7)
15/142 (10.6)
0.54 [0.24, 1.24]
0.14
≥ 15 (median)
17/207 (8.2)
19/203 (9.4)
0.88 [0.47, 1.64]
0.68
< 15 (median)
11/195 (5.6)
17/195 (8.7)
0.65 [0.31, 1.35]
0.24
Yes
23/289 (8.0)
27/296 (9.1)
0.87 [0.51, 1.49]
0.61
No
5/107 (4.7)
9/100 (9.0)
0.52 [0.18, 1.50]
0.22
≥ 50%
21/288 (7.3)
28/284 (9.9)
0.74 [0.43, 1.27]
0.27
< 50%
7/115 (6.1)
8/112 (7.1)
0.85 [0.32, 2.27]
0.75
Yes
3/60 (5.0)
9/59 (15.3)
0.33 [0.09, 1.15]
0.06
No
25/344 (7.3)
27/338 (8.0)
0.91 [0.54, 1.53]
0.72
Yes
6/68 (8.8)
6/87 (6.9)
1.28 [0.43, 3.79]
0.66
No
22/336 (6.5)
30/311 (9.6)
0.68 [0.40, 1.15]
0.15
Yes
13/209 (6.2)
19/196 (9.7)
0.64 [0.33, 1.26]
0.20
No
15/195 (7.7)
17/201 (8.5)
0.91 [0.47, 1.77]
0.78
Yes
11/152 (7.2)
14/142 (9.9)
0.73 [0.34, 1.56]
0.42
No
17/250 (6.8)
22/255 (8.6)
0.79 [0.43, 1.45]
0.44
≥ 18 Fr.
20/265 (7.5)
23/263 (8.7)
0.86 [0.49, 1.53]
0.61
< 18 Fr.
8/128 (6.3)
12/127 (9.4)
0.66 [0.28, 1.56]
0.34
Gender
0.94
Estimated GFR
0.98
Diabetes mellitus
0.79
Valve type
0.29
EuroSCORE
0.54
Anemia
0.39
Ejection fraction
0.80
Peripheral artery dis.
0.13
COPD
0.30
Coronary artery dis.
0.47
Clopidogrel loading
0.88
Sheath size
0.01
0.1
Favors
Bivalirudin
1
Favors
Heparin
0.62
10
19
B. Net adverse clinical events at 30 days. COPD=chronic obstructive lung disease; GFR=glomerular
filtration rate.
Age
Bivalirudin
Heparin
Relative Risk
P-value
Int.
P-value
0.34
No./total no. (%)
No./total no. (%)
> 80 yr
42/268 (15.7)
42/267 (15.7)
1.00 [0.67, 1.48]
0.99
≤ 80 yr
16/136 (11.8)
22/131 (16.8)
0.70 [0.39, 1.27]
0.24
Male
31/209 (14.8)
30/202 (14.9)
1.00 [0.63, 1.59]
0.10
Female
27/195 (13.8)
34/196 (17.3)
0.80 [0.50, 1.27]
0.34
≥ 60 ml/min
23/181 (12.7)
28/183 (15.3)
0.83 [0.50, 1.39]
0.48
< 60 ml/min
35/223 (15.7)
36/215 (16.7)
0.94 [0.61, 1.44]
0.77
Yes
16/125 (12.8)
22/114 (19.3)
0.66 [0.37, 1.20]
0.17
No
42/279 (15.1)
42/284 (14.8)
1.02 [0.69, 1.51]
0.93
Balloon expandable 34/251 (13.5)
35/249 (14.1)
0.96 [0.62, 1.49]
0.87
Self expanding
23/140 (16.4)
27/142 (19.0)
0.86 [0.52, 1.43]
0.57
≥ 15 (median)
34/207 (16.4)
36/203 (17.7)
0.93 [0.60, 1.42]
0.72
< 15 (median)
24/195 (12.3)
28/195 (14.4)
0.86 [0.52, 1.42]
0.55
Yes
46/289 (15.9)
48/296 (16.2)
0.98 [0.68, 1.42]
0.92
No
12/107 (11.2)
16/100 (16.0)
0.70 [0.35, 1.41]
0.31
≥ 50%
39/288 (13.5)
45/284 (15.8)
0.85 [0.58, 1.27]
0.44
< 50%
19/115 (16.5)
18/112 (16.1)
1.03 [0.57, 1.85]
0.93
Yes
8/60 (13.3)
10/59 (16.9)
0.79 [0.33, 1.85]
0.58
No
50/344 (14.5)
54/338 (16.0)
0.91 [0.64, 1.30]
0.60
Yes
13/68 (19.1)
12/87 (13.8)
1.39 [0.68, 2.84]
0.37
No
45/336 (13.4)
52/311 (16.7)
0.80 [0.55, 1.16]
0.24
Yes
28/209 (13.4)
34/196 (17.3)
0.77 [0.49, 1.22]
0.27
No
30/195 (15.4)
30/201 (14.9)
1.03 [0.65, 1.64]
0.90
Yes
21/152 (13.8)
22/142 (15.5)
0.89 [0.51, 1.55]
0.68
No
37/250 (14.8)
42/255 (16.5)
0.90 [0.60, 1.35]
0.61
≥ 18 Fr.
41/265 (15.5)
44/263 (16.7)
0.92 [0.63, 1.37]
0.69
< 18 Fr.
17/128 (13.3)
18/127 (14.2)
0.94 [0.51, 1.73]
0.84
Gender
0.50
Estimated GFR
0.73
Diabetes mellitus
0.24
Valve type
0.74
EuroSCORE
0.83
Anemia
0.41
Ejection fraction
0.61
Peripheral artery dis.
0.76
COPD
0.18
Coronary artery dis.
0.39
Clopidogrel loading
0.99
Sheath size
0.1
1
Favors
Bivalirudin
0.97
10
Favors
Heparin
20
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21