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In patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI), anticoagulation with prasugrel plus bivalirudin does not reduce the excess risk of acute stent thrombosis associated with the direct thrombin inhibitor and undermines any bleeding benefit compared with heparin, according to data published online May 9, 2014, ahead of print in the European Heart Journal. However, the authors acknowledge, the study lacks sufficient power to draw firm conclusions.

Results of the BRAVE (Bavarian Reperfusion Alternatives Evaluation) 4 trial were originally presented at the American College of Cardiology/i2 Scientific Session March 29, 2014, in Washington, DC.

Investigators led by Stefanie Schulz, MD, of the Deutsches Herzzentrum München (Munich, Germany), randomized 548 STEMI patients scheduled to undergo primary PCI to prasugrel (60-mg loading dose, 10 mg daily) plus bivalirudin (IV bolus of 0.75 mg/kg of body weight; n = 271) or clopidogrel (600-mg loading dose, 75 mg daily) plus unfractionated heparin (IV bolus of 70-100 IU/kg of body weight; n = 277) at 3 German centers between September 2009 and December 2013. All patients also received 500 mg of IV aspirin. Bailout with continued bivalirudin infusion for up to 12 hours after PCI or use of a glycoprotein (GP) IIb/IIIa inhibitor was suggested in the presence of abundant thrombotic material or sustained no reflow.

Early Termination 

The trial was stopped prematurely after enrollment of less than half of the planned 1,240 patients because lack of funding resulted in slow recruitment.

Final TIMI blood flow grade was similar between the groups with more than 90% achieving TIMI 3 flow after PCI.

At 30 days, there was no difference between the prasugrel/bivalirudin and clopidogrel/heparin groups for the composite of all-cause death, recurrent MI, unplanned revascularization of the infarct-related artery, definite stent thrombosis, stroke, or HORIZONS-AMI-defined non-CABG-related major bleeding (the primary endpoint). Likewise, the composite ischemic outcome (same as the primary endpoint but without bleeding) as well as cardiac death, definite stent thrombosis, and major bleeding were also similar between the groups. The net adverse events were driven primarily by bleeding (table 1).

Table 1. Outcomes at 30 Days^a

^aP = NS for all comparisons.
^bResults of the 2-sided Fisher’s exact test with a 5% significance level.

These overall results were replicated in the 93% of patients with confirmed STEMI. In addition, the treatment effect was consistent across multiple prespecified subgroups.

“The current trial shows, for the first time, that the reduction in bleeding with bivalirudin is abrogated with the concurrent administration of prasugrel,” the authors state.

An Attempt to Eliminate Bivalirudin’s Downside

“This trial is a good first step to try to improve upon the excellent outcomes that have been seen with bivalirudin by overcoming its one major limitation, which is acute stent thrombosis,” Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), told TCTMD in a telephone interview. “Unfortunately, prasugrel doesn’t reduce acute stent thrombosis because it has a delayed onset of action, and it increases bleeding.”

However, BRAVE 4 is far from definitive, primarily due to the small numbers, Dr. Stone said, noting the rarity of adverse events and wide confidence intervals in the relative risk of the treatment arm.

In a telephone interview with TCTMD, Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), also underscored the trial’s limitations. The upshot is that “a very interesting hypothesis—that prasugrel might temper the excess stent thrombosis of bivalirudin while preserving its bleeding benefit—has been neither proven nor disproven,” he commented. Nonetheless, data from other trials such as EUROMAX support the idea that “neither prasugrel nor ticagrelor eliminates the excess stent thrombosis associated with bivalirudin because they don’t take effect in the time frame needed to prevent acute events,” he said.

Also complicating interpretation of the BRAVE 4 data is the ‘mix and match’ nature of the study treatments, he noted.

Looking to ‘Promising’ Options

To eliminate bivalirudin’s stent thrombosis signal while preserving its bleeding edge, either more data or a different strategy is needed, Dr. Bhatt contended. “I think a protracted infusion of a PCI dose of bivalirudin might do the trick,” he suggested, pointing to preliminary promising data from a EUROMAX subanalysis.  

Another “very appealing strategy” is addition of the novel P2Y12 inhibitor cangrelor, Dr. Bhatt said, which is supported by a substudy from the CHAMPION PHOENIX trial. The main hurdles to this approach are the need to gain approval of the experimental drug and determine whether the cost of the 2-agent therapy is reasonable. 

Dr. Bhatt said that findings from the HEAT PPCI trial—suggesting that heparin alone is superior to bivalirudin in STEMI patients—“came as a surprise, and I don’t have an immediate explanation for them.” But he cautioned that the only commonality between BRAVE 4 and HEAT PPCI is that they are both negative regarding bivalirudin.

“I think it’s important to look at the data from a variety of trials, especially the large multicenter trials HORIZONS-AMI and EUROMAX, which both essentially show significantly less major bleeding but an increase in stent thrombosis with bivalirudin,” Dr. Bhatt said. In addition, HORIZONS-AMI found a significant reduction in cardiovascular mortality, so the net effect of bivalirudin appears positive, he added.

Given the preponderance of evidence, “I still feel that bivalirudin trumps heparin with either planned or bailout GP IIb/IIIa inhibitors,” he concluded. However, he added, “I might consider extending the bivalirudin infusion. Or I might jump to GP IIb/IIIa inhibition a little more liberally when I’m using bivalirudin, based on the current stent thrombosis findings.”

Similarly, Dr. Stone said that although the optimal combination of antiplatelet and antithrombotic therapies for STEMI is “still up in the air, the strongest data still [favor] bivalirudin as the foundation antithrombin with provisional use of bailout GP IIb/IIIa inhibitors.” Moreover, use of cangrelor or a 4-hour high-dose infusion of bivalirudin are promising options, he added.

Study Details

Mean age was 61.4 years. Baseline and clinical characteristics were similar between the groups.

Prior to randomization, almost a quarter of both groups was administered a clopidogrel loading dose, and four-fifths also received unfractionated heparin.

Primary PCI was performed via transfemoral access in all but 1 patient.

Overall, bailout GP IIb/IIIa inhibitors were used in 4.3% of patients with a trend toward a higher rate in the clopidogrel/heparin than the prasugrel/bivalirudin arm (6.1% vs 3.0%; P = .074).

Note: Coauthor Roxana Mehran, MD, of the Mount Sinai School of Medicine (New York, NY), is a faculty member of the Cardiovascular Research Foundation, which owns and operates TCTMD.

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• Prasugrel Improves Outcomes vs Clopidogrel After Primary PCI with Bivalirudin
• Bivalirudin Shows Advantage Over GPIs—But Not Heparin Alone—in STEMI Patients