Vorapaxar Shows Reductions in Limb Ischemia in PAD

June 22, 2012

June 20, 2012 (Dallas, Texas) — New data from the peripheral arterial disease (PAD) subgroup of the TRA 2°P TIMI 50 trial have suggested that the protease-activated receptor 1 (PAR-1) antagonist antiplatelet agent vorapaxar (Merck) appears to reduce peripheral vascular end points such as acute limb ischemia and peripheral arterial revascularizations, as well as a trend toward a reduction in cardiovascular outcomes [1].

Although vorapaxar was associated with a high bleeding rate in this trial, experts in the PAD field say the current results are encouraging, as no other therapy has been definitively shown to give such peripheral benefits.

Dr Alan T Hirsch (Lillehei Heart Institute at the University of Minnesota, Minneapolis), who was part of a panel discussion of the results, commented to heartwire : "The high rate of bleeding with vorapaxar has muted enthusiasm for the agent, but I am looking at these data not in terms of drug registration or immediate clinical use but rather as the potential for an agent with a completely new mechanism that has reduced important PAD end points in exploratory studies."

He added: "Acute limb ischemia often leads to limb amputation, and a reduction in this end point as well as in peripheral arterial revascularization in a prospective study has never been achieved before. That is a big deal. It could be a revolution for the PAD field."

Another Trial in PAD?

Hirsch is hopeful that vorapaxar at a different dose or another similar agent can be studied further in the PAD population. "We need to look at the patient population, dosing, and timing and see whether changes can be made to maximize the benefit and minimize the harms. The PAD population is enormous. This drug could have a huge impact. I would urge the sponsor to consider another trial."

The PAD data from TRA 2°P TIMI 50 was presented today by Dr Marc Bonaca (Brigham and Women's Hospital, Boston, MA) in an American Heart Association Emerging Science Series webinar.

The TRA 2°P TIMI 50 trial was conducted to investigate whether vorapaxar could reduce thrombotic events in patients with a previous MI or stroke or those with PAD. In total, 26 449 were randomized to vorapaxar 2.5 mg per day or placebo. After a median follow-up of 2.5 years, there was a significant 13% relative reduction in the primary efficacy end point (CV death/MI/stroke) for the whole patient population. But there was a significant increase in major bleeding, including intracranial hemorrhage (ICH), with vorapaxar.

There were 3787 PAD patients in the trial who had a history of symptoms of claudication and either an ankle brachial index of <0.85 or prior peripheral revascularization for limb ischemia. The primary end point of the study (cardiovascular death, MI, or stroke) was not different between the vorapaxar and placebo groups. But rates of hospitalization for acute limb ischemia and peripheral arterial revascularization were significantly lower in the vorapaxar group. Moderate or severe bleeding was increased with vorapaxar, as was ICH, but there was no increase in fatal bleeding.

TRA 2°P TIMI 50 Major Results in PAD Patients

End point Vorapaxar (%) Placebo (%) HR (95% CI) p
Primary 11.3 11.9 0.94 (0.78–1.14) 0.53
Acute limb ischemia 2.3 3.9 0.58 (0.39– 0.86) 0.006
Peripheral arterial revascularization 18.4 22.2 0.84 (0.73– 0.97) 0.017
Moderate or severe bleeding 7.4 4.5 1.62 (1.21– 2.18) 0.001
ICH 0.9 0.4 2.03 (0.82– 5.02) 0.13

Bonaca noted that PAD affects about eight million Americans and confers a doubling of cardiovascular risk, but the peripheral effects are also associated with significant morbidity, disability, and cost, with about 166 000 hospitalizations each year. There are a paucity of treatments, and no medical therapy has prospectively been shown to reduce acute limb ischemia or limb revascularization.

Noting that the reduction in acute limb ischemia with vorapaxar appeared almost immediately, while the reduction in peripheral arterial revascularization did not show up until after about two years of treatment, Bonaca suggested that the drug may be working by two different mechanisms. He explained that PAR-1 receptors exist on platelets and on endothelial and smooth-muscle cells, and it may be that the drug brings about an early antiplatelet effect and a later vascular remodeling action.

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