Antiplatelet Shows Promise for Secondary Prevention in PAD

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New results with the novel antiplatelet drug vorapaxar have rekindled hopes that medical therapy may be able to improve outcomes in patients with peripheral artery disease (PAD). While vorapaxar failed to definitively impact cardiovascular events, it reduced both peripheral arterial revascularization and hospitalization for acute limb ischemia. The findings, from a subanalysis of the TRA2P-TIMI 50 trial, were published online ahead of print in Circulation and presented in an American Heart Association (AHA) webinar on June 20, 2012.

Marc P. Bonaca, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), and colleagues looked at 3,787 patients with PAD who were part of the randomized, double-blind TRA2P-TIMI 50 trial, which compared the effects of 2.5 mg vorapaxar vs. placebo daily in 26,449 patients with prior MI, stroke, or PAD over a median follow-up period of 2.5 years.

Overall results from the trial, presented at the 2012 American College of Cardiology/i2 Annual Scientific Session in Chicago, IL, showed a 13% relative reduction in the primary composite (MI, stroke, and CV death) with vorapaxar (9.3% vs. 10.5% with placebo; HR 0.87; 95% CI 0.80-0.94; P < 0.001). GUSTO moderate/severe bleeding was higher, however, in the vorapaxar group than in the placebo group (4.2% vs. 2.5%; HR 1.66; 95% CI 1.43-1.93; P < 0.001).

In the newly presented data, PAD patients showed a trend toward improvement in cardiovascular efficacy as well as statistically significant decreases in secondary endpoints. Yet GUSTO moderate/severe bleeding remained an issue (table 1).

Table 1. Outcomes in PAD Cohort at 2.5-Year Follow-up

Vorapaxar inhibits PAR-1, the predominant receptor for thrombin on the surface of human platelets. PAR-1 is also expressed on endothelial and vascular smooth muscle cells. “Thrombin activation has been shown to be mitogenic in the vasculature. This has led to the hypothesis that thrombin may lead to vascular events both through activation of platelets and also adverse remodeling in the vasculature,” Dr. Bonaca explained, noting that the current findings lend support to the idea of multiple pathways.

Groups Within Groups

“It’s been so interesting to watch this drug go through various clinical trials,” said Neil Zakai, MD, of the University of Vermont (Colchester, VT), in a discussion following Dr. Bonaca’s presentation. “It has such a novel mechanism of action compared with other antiplatelet agents.” However, he questioned what the ideal patient population would be, given that prior studies have been “somewhat negative, especially with increased bleeding.”

Though Dr. Bonaca cautioned that, “[o]bviously this is an investigational therapy so thoughts about actual clinical use would be speculative,” he stressed the unique situation of PAD patients, who have few drug options. In addition, there may be subsets within that group who are at lower bleeding risk, he proposed, such as “younger patients or those that aren’t at the extremes of body weight.”

Session co-moderator Robert O. Bonow, MD, of the Northwestern University Feinberg School of Medicine (Chicago, IL), characterized the importance of the PAD analysis of TRA2P-TIMI 50 in that it highlights how secondary prevention might offer benefit in terms of softer endpoints.

A New Way of Thinking

Alan T. Hirsch, MD, of the University of Minnesota (Minneapolis, MN), meanwhile, implied that cardiologists may be in somewhat unfamiliar territory in considering PAD. “Like trialists, clinicians often focus on their end-organ of choice, and the legs are just ‘somewhere else,’” he said, asking whether the outcomes were indicative of real-world practice.

Cardiologists are mainly interested in PAD because it identifies patients at risk for MI and stroke, Dr. Bonaca acknowledged. But the current findings suggest that PAD patients “are at a higher risk than most people would anticipate of acute limb threatening events. We think of them as very rare, but at least in the population [enrolled in TRA2P-TIMI 50], they were not.”

Given the many comorbidities of this high-risk group, and that patients are likely to be on other antiplatelet agents, it may be hard for yet another antiplatelet drug to substantially reduce cardiovascular events, he added.

Co-moderator Elliott M. Antman, MD, of Brigham and Women’s Hospital (Boston, MA), pointed out, “We’re talking about different vascular beds, [yet] we lump this all under the term as atherosclerosis.” He proposed that different efficacy endpoints may be required when studying the various disease types.

Source:

Bonaca MP, Morrow DA, Braunwald E, et al. Vorapaxar for secondary prevention in patients with peripheral artery disease: Results from the peripheral artery disease cohort of the TRA2P-TIMI 50 trial. Circulation. 2012;Epub ahead of print.

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