Randomized Comparison of Prasugrel and Bivalirudin versus Clopidogrel and Heparin in Patients with ST-Segment Elevation Myocardial Infarction

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1 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

2 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

3 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

4 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

5 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

6 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

7 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

8 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

9 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

10 Study Design open label n = 271 n = 277 n = 269 n =

11 Baseline Characteristics Prasugrel plus Bivalirudin n=271 Clopidogrel plus Heparin n=277 P Age, years 61.4 [ ] 61.4 [ ] Female % Hypertension % Hypercholesterolemia % Diabetes % Smoker % BMI, kg/m² 26.6 [ ] 26.3 [ ] Prior MI % Prior CABG % Infarct Localization % Anterior Posterior or Inferior Lateral Arterial Blood Pressure Systolic, mmhg 130 [ ] 130 [ ] Diastolic, mmhg 78 [70-85] 76 [66-84]

12 Angiographic Characteristic Prasugrel plus Bivalirudin n=271 Clopidogrel plus Heparin n=277 P Ejection Fraction, % 45 [39-55] 45 [38-51] Multivessel Disease % Infarct-Related Artery % LAD RCA LCx Left Main Bypass Graft Initial TIMI Flow Grade %

13 Procedural Characteristics Prasugrel plus Bivalirudin n=271 Clopidogrel plus Heparin n=277 P Intervention Stent (%) 240 (88.6) 240 (86.6) Drug-Eluting Stent Bare Metal Stent Bioabsorbable Vascular Scaffold 4 2 Balloon Angioplasty % CABG % Conservative % Glycoprotein IIb/IIIa Inhibitors % Final TIMI Flow Grade %

14 Medication at Discharge Prasugrel plus Bivalirudin n=242 Clopidogrel plus Heparin n=254 P Acetylsalicylic acid % Thienopyridine <0.001 Prasugrel % Clopidogrel % None % Oral Anticoagulation % Betablocker % ACE-Inhibitor or AT1- Antagonist % Diuretic % Statin %

15 Primary Endpoint Composite of death, myocardial infarction, unplanned revascularization of the infarct-related artery, stent thrombosis, stroke or major bleeding 15

16 Secondary Ischemic Endpoint Composite of death, myocardial infarction, revascularization of the infarctrelated artery, stent thrombosis or stroke 16

17 Secondary Bleeding Endpoint non-cabg related bleeding (HORIZONS-AMI definition) 17

18 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 % [0.74, 1.88] Secondary Endpoint: Cardiac Death % [0.32, 5.03] Death % Recurrent Myocardial Infarction % Unplanned IRA -Revascularization % [0.31, 3.37] [0.19, 5.44] [0.14, 2.84] Stroke % [0.04, 2.47] - Ischemic % Hemorrhagic % Stent Thrombosis (definite) % [0.11, 4.49] Bleeding According to TIMI Criteria: - TIMI Major % [0.28, 2.78] - TIMI Minor % [0.70, 2.37] - TIMI Major or Minor % [0.70, 1.96] 18

19 Subgroup Analysis Thirty-day incidence and relative risk of the primary endpoint 19

20 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

21 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

22 Thank you! 22

23 Time Intervals Prasugrel plus Bivalirudin n=271 Clopidogrel plus Heparin n=277 P Symptom Onset to Admission, min 185 [95-430] 180 [90-527] Symptom Onset to Randomisation, min 210 [ ] 210 [ ] Symptom Onset to Balloon, min 270 [ ] 281 [ ] Admission to Balloon, min 90 [66-110] 87 [67-114]

24 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, 1.79] Secondary Endpoint: Composite Ischemic Endpoint of Death, Myocardial Infarction, Unplanned IRA- Revascularization, Stent Thrombosis or Stroke 13 (4.8) 15 (5.5) [0.40, 1.96] 24