Merck to Pursue Approval for Vorapaxar in Prior MI Patients

August 26, 2012

August 26, 2012 (Munich, Germany) — Merck has announced that it is going to pursue approval for the antiplatelet agent vorapaxar in patients with prior MI and no history of stroke or transient ischemic attack (TIA) [1]. The company says it plans to file plans to file regulatory applications for this indication in the US and Europe in 2013.

This is based on subgroup analysis of the TRA 2°P-TIMI 50 trial, suggesting benefit in this group of patients. New data on this subgroup was presented today at the European Society of Cardiology 2012 Congress and published simultaneously in the Lancet [2].

The TRA 2°P-TIMI 50 trial was first reported at the American College of Cardiology (ACC) meeting earlier this year. The trial included 26 449 stable patients with atherosclerosis (either post-MI, a history of stroke, or peripheral arterial disease) who were randomized to vorapaxar 2.5 mg per day or placebo. Main results showed that 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 this was accompanied by a significant increase in all measures of major bleeding, including intracranial hemorrhage (ICH), which led to most experts uninvolved in the trial to conclude that the drug was too dangerous for general use.

At the time of the ACC meeting, the trial investigators said the post-MI patients in the trial were the ones most likely to see a net clinical benefit of vorapaxar, and the new data presented in Munich today are said to support that claim.

The MI subgroup was made up of 17 779 patients. In this group, vorapaxar was associated with a significant reduction in the primary efficacy end point and an increase in moderate or severe bleeding, but ICH was not different between groups.

TRA 2°P-TIMI 50 Results in Prior-MI Subgroup

Outcome Vorapaxar (n=8898), % Placebo (n=8881), % HR (95% CI) p
CV death/MI/stroke* 8.1 9.7 0.80 (0.72–0.89) <0.0001
GUSTO moderate or severe bleeding 3.4 2.1 1.61 (1.31–1.97) <0.0001
Fatal bleeding 0.2 0.1 1.56 (0.67–3.60) 0.30
ICH 0.6 0.4 1.54 (0.96–2.48) 0.076
CV death/MI/stroke/ GUSTO moderate or severe bleeding 10.2 11.0 0.91 (0.83–1.01) 0.072

*Primary end point

The TRA2°P investigators make a case for use of vorapaxar in prior-MI patients retrospectively defined as being at a low bleeding risk--those aged younger than 75 years, with no history of transient ischemic attack or stroke, and body weight over 60 kg--which they say made up 84% of the prior-MI population. They point out that the efficacy results are more favorable in this group, and although there is still an increase in GUSTO moderate or severe bleeding, the combined net clinical benefit end point of cardiovascular death, MI, stroke, urgent coronary revascularization, or GUSTO moderate or severe bleeding was significantly reduced (HR 0.86, 95% CI 0.78–0.95; p=0.003).

In contrast, they point out that for patients aged 75 or older, with a history of TIA or stroke, or weighing less than 60 kg, net clinical outcome was not significantly different with vorapaxar compared with placebo.

Dr Benjamin Scirica (Brigham and Women’s Hospital, Boston, US), who presented the prior-MI data today, commented to heartwire , "As with any new antithrombotic drug, the key is use in appropriate patients. We have provided detailed information on the benefits and risks and have shown that there are populations where the benefit/risk balance favors vorapaxar."

Noting that clopidogrel has only been proven beneficial for one year after MI, Scirica added that this is "the first study to conclusively show that prolonged antiplatelet therapy in addition to aspirin is beneficial in patients with a history of MI. As such, it is an important advance for the field of MI and secondary prevention."

Discussant: "A Difficult Path Ahead"

Designated discussant of the new data at the meeting, Dr Christoph Bode (University of Freiberg, Germany) commented: "Vorapaxar remains a viable candidate, but it is a sharp sword, and patient selection will be mandatory if it does get to the market."

To heartwire he added: "In a carefully selected subgroup of post-MI patients, vorapaxar did remarkably well. It was effective at reducing the primary end point without increasing intracranial hemorrhage. But in the prior-stroke group, it was associated with a prohibitive ICH rate of 2.4%. And any drug that has been associated with ICH makes people nervous. I predict that there will be a difficult path ahead for the drug, but I'm not saying that it is impossible that it will get to the market."

Vorapaxar remains a viable candidate, but it is a sharp sword, and patient selection will be mandatory if it does get to the market.

Bode suggested that it might have been better to study vorapaxar as an alternative to aspirin. "In this study, it was added on top of aspirin and, in many patients, clopidogrel as well. We have to think carefully about continuing to add more antithrombotic agents. Maybe we need to think about dropping aspirin. This would be difficult, as it is almost free and very active, but it does cause bleeding."

In an accompanying "comment" in the Lancet [3], Drs Stefan James and Claes Held (Uppsala University, Sweden) say that these results support the addition of long-term antithrombotic treatment for patients who have had a MI. But they ask whether doctors, patients, healthcare providers, and funding agencies will accept use of vorapaxar in view of its increased risk of severe bleeding. They write: "For patients at low or moderate risk of bleeding, the ischemic benefit seems to outweigh the risk of bleeding. But patients at low risk of bleeding are also often at low risk of ischemic events. Therefore, clinical characteristics or biomarkers to separate ischemic risk and bleeding risk should be defined."

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