Bavarian Reperfusion Alternatives Evaluation - BRAVE 4


The majority of trials have separately assessed antiplatelet and antithrombotic therapy for the treatment of patients undergoing primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI). The current trial sought to study the safety and efficacy of combination therapy of prasugrel + bivalirudin compared with clopidogrel + unfractionated heparin (UFH) in these patients.


A planned PPCI strategy of prasugrel + bivalirudin would be superior to clopidogrel + UFH in patients with STEMI.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • 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
  • Age ≥18 years

    Number of enrollees: 548
    Duration of follow-up: 30 days
    Mean patient age: 61 years
    Percentage female: 23%
    Left ventricular ejection fraction: 45%


  • Age <18 years
  • Active bleeding or bleeding diathesis
  • History of intracranial bleeding or structural abnormalities
  • Prior transient ischemic attack or stroke
  • Refusal to receive blood transfusion
  • Heparin-induced thrombocytopenia
  • Administration of thrombolysis, bivalirudin, low-molecular weight heparin, or fondaparinux for the index MI
    Known allergy to the study medication
  • Hemoglobin <10.0 g/dl
  • Platelet count <100,000/cm3
  • 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

Primary Endpoints:

  • Composite of all-cause death, recurrent MI, unplanned revascularization of the IRA, definite stent thrombosis, stroke, or major bleeding at 30 days

Secondary Endpoints:

  • Composite of all-cause death, recurrent MI, definite stent thrombosis, unplanned IRA-revascularization or stroke
  • Major bleeding complications
  • Cardiac death at 30 days after randomization

Drug/Procedures Used:

Patients who were randomized to prasugrel + bivalirudin received 60 mg prasugrel + bivalirudin bolus at 0.75 mg/kg, followed by an infusion at 1.75 mg/kg/hr for the duration of PCI; bivalirudin was continued until the end of PCI. The maintenance dose of prasugrel was 10 mg daily in most patients (5 mg in older patients and low body weight). In the control arm, patients received 600 mg clopidogrel and 70-100 U/kg of UFH as a bolus prior to PCI. Additional UFH boluses were administered during PCI based on activated clotting time (ACT). The maintenance dose of clopidogrel was 75 mg daily.

Concomitant Medications:

Glycoprotein IIb/IIIa inhibitors (5%), statin (96%), and beta-blockers (97%). All patients received 500 mg IV aspirin.

Principal Findings:

The trial was terminated early due to slow recruitment. A total of 548 patients were randomized, 271 to prasugrel + bivalirudin and 277 to clopidogrel + UFH. Baseline characteristics were similar between the two arms. The majority of patients presented with inferior/posterior (50%) or anterior (42%) STEMI. Median systolic blood pressure (BP)/diastolic BP were 130/77 mm Hg. Median ischemic time was 275 minutes. Baseline TIMI flow grade was 0/1 in 63% of the patients. A stent was deployed in approximately 87% of patients, and 8% were conservatively managed. Cross-over was low: prasugrel (7%), clopidogrel (4%).

The primary endpoint of death, MI, unplanned revascularization of the infarct-related artery (IRA), stent thrombosis, stroke, or major bleeding at 30 days was similar between the prasugrel + bivalirudin versus clopidogrel + UFH arms (15.6% vs. 14.5%, p = 0.68). Similarly, the secondary ischemic endpoint (death, MI, revascularization of the infarct-related artery, stent thrombosis, or stroke) was similar (4.8% vs. 5.5%, p = 0.89). Non–coronary artery bypass grafting (CABG)–related bleeding was numerically higher in the prasugrel + bivalirudin arm (14.1% vs. 12.0%, p = 0.54). Definite stent thrombosis was similar (1.1% vs. 1.5%, p = 0.98), as was mortality at 30 days: 2.6% vs. 2.5%, p = 0.85. 


The results of the BRAVE 4 trial indicate that there was no difference for ischemic or bleeding endpoints between a strategy of using prasugrel + bivalirudin compared with clopidogrel + UFH in patients with STEMI undergoing PPCI. The trial was terminated early, and was thus underpowered to test its primary hypothesis.

The optimal antiplatelet/antithrombotic regimen in the patients undergoing PPCI remains an unanswered question, since the majority of trials have been restricted to studying one pharmacological agent versus another (either antithrombotic or antiplatelet), not the combination. In theory, use of more potent agents should be synergistic in high-risk PCIs such as STEMI. This will need to be further assessed in future trials. Long-term follow-up of the current trial is also awaited.


Schulz S, Richardt G, Laugwitz KL, et al., on behalf of the Bavarian Reperfusion Alternatives Evaluation (BRAVE) 4 Investigators. Prasugrel Plus Bivalirudin vs. Clopidogrel Plus Heparin in Patients With ST-Segment Elevation Myocardial Infarction. Eur Heart J 2014;May 9:[Epub ahead of print].

Stone GW. Improving Outcomes With Bivalirudin in Primary Percutaneous Coronary Intervention. Eur Heart J 2014;May 29:[Epub ahead of print].

Presented by Dr. Gert Richardt at the American College of Cardiology Scientific Session, Washington, DC, March 29, 2014.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, EP Basic Science, Aortic Surgery, Cardiac Surgery and Arrhythmias

Keywords: Myocardial Infarction, Stroke, Follow-Up Studies, Thiophenes, Body Weight, Heparin, Ticlopidine, Blood Pressure, Piperazines, Fibrinolytic Agents, Hirudins, Purinergic P2Y Receptor Antagonists, Stents, Percutaneous Coronary Intervention, Thrombosis, Chest Pain, Recombinant Proteins, Bundle-Branch Block, Peptide Fragments, Coronary Artery Bypass

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