Randomized Comparison of Prasugrel and Bivalirudin versus Clopidogrel and Heparin in Patients with ST-Segment Elevation Myocardial Infarction The Bavarian Reperfusion Alternatives Evaluation (BRAVE) 4 Trial Gert Richardt, Adnan Kastrati, Karl-Ludwig Laugwitz, Tanja Morath, Ralph Tölg, Julia Neudecker, Tareq Ibrahim, Ilka Ott, Sebastian Kufner, Kathrin Anette Fiedler, Petra Hoppmann, Robert Byrne, Simon Schneider, Massimiliano Fusaro, Roxana Mehran, Anthony Gershlick, Heribert Schunkert, Julinda Mehilli, Stefanie Schulz Deutsches Herzzentrum München - Herzzentrum Bad Segeberg, Germany 1
Background I Primary PCI is the standard treatment for patients with STEMI. Adjunct antithrombotic therapy is the prerequisite for the safe and effective performance of primary PCI. 2
Background II No specifically designed studies have prospectively assessed the potential advantages of the combination of prasugrel plus bivalirudin with that of clopidogrel plus heparin. Theoretically, prasugrel and bivalirudin have synergistic effects on ischemic and bleeding complication that maximize patients` clinical outcome. 3
Objective to assess the hypothesis that in STEMI patients with planned primary PCI a strategy based on prasugrel plus bivalirudin is superior to a strategy based on clopidogrel plus unfractionated heparin in terms of net clinical outcome. 4
In- / Exclusion Criteria INCLUSION chest pain 20 minutes 24 hours from symptom onset ST-segment elevation 0.1 mv in 2 adjacent limb leads or 0.2 mv in 2 contiguous precordial leads or new left bundle branch block primary PCI planned informed consent EXCLUSION age < 18 years active bleeding or bleeding diathesis history of intracranial bleeding or structural abnormalities prior TIA or stroke refusal to receive blood transfusion heparin-induced thrombocytopenia administration of thrombolysis, bivalirudin, lowmolecular weight heparin or fondaparinux for the index myocardial infarction known allergy to the study medication hemoglobin < 100 g/l platelet count <100 x 10 9 cells/l use of coumadin derivatives within the last 7 days chronic therapy with nonsteroidal anti-inflammatory drugs (except aspirin), cyclooxygenase-2 inhibitors, prasugrel or ticagrelor known severe liver disease glomerular filtration rate (GFR) <30 ml/min dialysis-dependent life expectancy < 1 year 5
Study Endpoints Primary endpoint Composite of all-cause death, recurrent myocardial infarction, unplanned revascularization of the infarct related artery (IRA), definite stent thrombosis, stroke, or major bleeding at 30 days Secondary endpoints Composite of all-cause death, recurrent myocardial infarction, definite stent thrombosis, unplanned IRArevascularization or stroke Major bleeding complications Cardiac death at 30 days after randomization 6
Study Details I BRAVE 4 is an investigator-initiated, randomized, openlabel, multicenter trial. Participating centers Deutsches Herzzentrum München in Munich Medizinische Klinik, Klinikum rechts der Isar in Munich Herzzentrum, Segeberger Kliniken in Bad Segeberg 7
Study Details II Sample size calculation It was assumed that the incidence of the primary endpoint will be reduced from 12.1% with clopidogrel/heparin to 7.2% with prasugrel/bivalirudin. Power of 80, one-sided significance level of 2.5% Random sequence 1:1 Needed total number of patients in each group: 601 8
Study Details III Endpoint assessment Blinded core lab evaluation and blinded adjudication of endpoint events by specialized event adjudication committee members. Recruitment period Enrolment started September 2009 and was stopped December 2013 after 548 patients for slow recruitment. 9
Study Design open label n = 271 n = 277 n = 269 n = 275 10
Baseline Characteristics Prasugrel plus Bivalirudin n=271 Clopidogrel plus Heparin n=277 P Age, years 61.4 [51.9-71.7] 61.4 [52.9-71.5] 0.830 Female % 24 21 0.339 Hypertension % 66 64 0.662 Hypercholesterolemia % 57 51 0.191 Diabetes % 17 15 0.562 Smoker % 57 67 0.016 BMI, kg/m² 26.6 [24.4-29.3] 26.3 [24.3-29.4] 0.951 Prior MI % 8 11 0.214 Prior CABG % 2 3 0.585 - Infarct Localization % 0.516 Anterior 41 44 Posterior or Inferior 51 47 Lateral 7 9 - Arterial Blood Pressure Systolic, mmhg 130 [120-150] 130 [120-150] 0.949 Diastolic, mmhg 78 [70-85] 76 [66-84] 0.256 11
Angiographic Characteristic Prasugrel plus Bivalirudin n=271 Clopidogrel plus Heparin n=277 P Ejection Fraction, % 45 [39-55] 45 [38-51] 0.210 Multivessel Disease % 57.2 61.7 0.279 Infarct-Related Artery % 0.146 LAD 41.4 43.5 RCA 47.4 42.3 LCx 8.4 13.5 Left Main 1.6 0.4 Bypass Graft 1.2 0.4 Initial TIMI Flow Grade % 0.023 0 48.2 61.2 1 6.8 6.9 2 22.1 15.4 3 22.9 16.5 12
Procedural Characteristics Prasugrel plus Bivalirudin n=271 Clopidogrel plus Heparin n=277 P Intervention 0.184 Stent (%) 240 (88.6) 240 (86.6) 0.573 - Drug-Eluting Stent 223 228 - Bare Metal Stent 13 10 - Bioabsorbable Vascular Scaffold 4 2 Balloon Angioplasty % 2.2 5.8 CABG % 0.4 0.4 Conservative % 8.9 7.2 Glycoprotein IIb/IIIa Inhibitors % 3.0 6.1 0.074 Final TIMI Flow Grade % 0.594 0 1.6 2.3 1 0.8 1.9 2 7.2 5.8 3 90.4 90.0 13
Medication at Discharge Prasugrel plus Bivalirudin n=242 Clopidogrel plus Heparin n=254 P Acetylsalicylic acid % 99.6 96.9 0.022 Thienopyridine <0.001 Prasugrel % 94.6 7.1 Clopidogrel % 3.7 90.2 None % 1.7 2.8 Oral Anticoagulation % 5.0 9.1 0.075 Betablocker % 97.5 97.2 0.847 ACE-Inhibitor or AT1- Antagonist % 91.3 95.3 0.077 Diuretic % 48.3 54.3 0.183 Statin % 96.3 96.1 0.899 14
Primary Endpoint Composite of death, myocardial infarction, unplanned revascularization of the infarct-related artery, stent thrombosis, stroke or major bleeding 15
Secondary Ischemic Endpoint Composite of death, myocardial infarction, revascularization of the infarctrelated artery, stent thrombosis or stroke 16
Secondary Bleeding Endpoint non-cabg related bleeding (HORIZONS-AMI definition) 17
30d-Outcome - Individual Endpoints Prasugrel plus Bivalirudin n=269 Clopidogrel plus Heparin n=275 P Relative Risk [Confidence Interval] Secondary Endpoint: Bleeding According to HORIZONS- AMI Criteria % 14.1 12.0 0.543 1.18 [0.74, 1.88] Secondary Endpoint: Cardiac Death % 2.2 1.8 0.970 1.23 [0.32, 5.03] Death % Recurrent Myocardial Infarction % Unplanned IRA -Revascularization % 2.6 2.5 0.848 1.02 [0.31, 3.37] 1.5 1.5 0.799 1.02 [0.19, 5.44] 1.5 2.2 0.779 0.68 [0.14, 2.84] Stroke % 0.7 1.8 0.468 0.41 [0.04, 2.47] - Ischemic % 0.7 1.1 - Hemorrhagic % 0 0.7 Stent Thrombosis (definite) % 1.1 1.5 0.976 0.77 [0.11, 4.49] Bleeding According to TIMI Criteria: - TIMI Major % 2.6 2.9 0.966 0.89 [0.28, 2.78] - TIMI Minor % 9.3 7.3 0.484 1.28 [0.70, 2.37] - TIMI Major or Minor % 11.9 10.2 0.616 1.17 [0.70, 1.96] 18
Subgroup Analysis Thirty-day incidence and relative risk of the primary endpoint 19
Limitations The premature termination of the trial presents a major limitation. It reduced the actual power of the trial from 80% to 51%. The BRAVE 4 trial shares the limitation of an open-label design with previous trials of bivalirudin in STEMI patients. 20
Summary and Conclusions We were not able to demonstrate a difference in net clinical outcome between prasugrel plus bivalirudin and clopidogrel plus heparin in STEMI patients Neither the composite of ischemic complications nor bleeding were favorably affected by prasugrel plus bivalirudin The results, however, must be interpreted in view of the premature termination of the trial 21
Thank you! 22
Time Intervals Prasugrel plus Bivalirudin n=271 Clopidogrel plus Heparin n=277 P Symptom Onset to Admission, min 185 [95-430] 180 [90-527] 0.821 Symptom Onset to Randomisation, min 210 [116-465] 210 [115-560] 0.943 Symptom Onset to Balloon, min 270 [175-533] 281 [185-640] 0.594 Admission to Balloon, min 90 [66-110] 87 [67-114] 0.993 23
30d-Outcome Composite Endpoints Prasugrel plus Bivalirudin n=269 Clopidogrel plus Heparin n=275 P Relative Risk [Confidence Interval] Primary Endpoint: Composite of Death, Myocardial Infarction, Unplanned IRA-Revascularization, Stent Thrombosis, Stroke or Bleeding 42 (15.6) 40 (14.5) 0.680 1.09 [0, 1.79] Secondary Endpoint: Composite Ischemic Endpoint of Death, Myocardial Infarction, Unplanned IRA- Revascularization, Stent Thrombosis or Stroke 13 (4.8) 15 (5.5) 0.894 0.89 [0.40, 1.96] 24