The once highly-promising novel antiplatelet agent vorapaxar, widely thought to be dead on arrival after unacceptably high serious bleeding rates were found in two large clinical trials, has now returned to active duty. On Sunday the drug’s sponsor, Merck, announced that it would seek approval of the drug, with a narrower indication than originally planned, based on new data from a prespecified analysis of the TRA 2P-TIMI 50 trial presented at the ESC and published simultaneously in the Lancet.
Merck said it planned to file applications next year in the United States and Europe for an indication for the prevention of CV events in patients with a history of MI and no history or stroke or TIA.
The new hope for the drug is based on an analysis of the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events trial, which was originally presented in March at the ACC and published simultaneously in the New England Journal of Medicine. In the overall trial, which randomized 26,449 patients with a history of MI, ischemic stroke, or peripheral arterial disease to either vorapaxar or placebo in addition to standard therapy, the rate of CV death, MI, or stroke was significantly reduced by vorapaxar, but a doubling of the rate of intracranial bleeding left many convinced the drug was not commercially viable.
The new analysis, presented at the ESC by Ben Scirica, focused on the subgroup of 17,779 TRA 2P patients– a group larger than usually found in the entire population of most clinical trials, it should be noted– with a history of myocardial infarction. After 2.5 years of followup, the rate of CV death, MI, or stroke was significantly reduced in the vorapaxar group compared to the placebo group, though vorapaxar was also associated with an increased risk of bleeding, but not intracranial bleeding:
- Primary endpoint: 8.1% versus 9.7%, HR 0.80, CI 0.72-0.89, p<0.0001
- Moderate or severe bleeding:3.4% versus 2.1%, HR 1.61, CI 1.31-1.97, p<0.0001
- Intracranial hemorrhage: 0.6% versus 0.4%, p=0.076
The authors acknowledged the limitations of subgroup analysis but proposed that vorapaxar might be beneficial in a population with a history of MI but with no history of stroke or TIA, age below 75, and weight over 60 kg.
In an accompanying comment in the Lancet, Stefan James and Claes Held write that the “results support the addition of long-term antithrombotic treatment for patients who have had a myocardial infarction.” But, they ask, “will doctors, patients, health-care providers, and funding agencies accept use of an expensive drug to reduce the risk of myocardial infarction and possibly death in view of the increased risk of severe bleeding?”
Republished with permission from CardioExchange, a NEJM group publication.
Here is the press release from the Lancet:
First study to examine effects of long-term anti-platelet treatment could lead to improved outcomes for heart attack survivors
Research published in The Lancet could lead to improved long-term outcomes for heart attack survivors. The study, which is being presented at the European Society of Cardiology (ESC) 2012 Annual Congress, shows that patients who took the drug vorapaxar, alongside the standard treatment given to people who have had a heart attack, experienced a significantly reduced risk of cardiovascular death and cardiac complications from blood clots that develop in the coronary arteries.
However, like most drugs intended to reduce the risk of clots and treat heart attacks, vorapaxar also increased the risk of dangerous bleeding, leading the researchers to conclude that clinicians will need to carefully assess which groups of patients will benefit from the treatment. The drug appeared to be most effective for patients who were younger than 75 years, with no history of stroke and a body weight greater than 60kg. For this group, the researchers suggest that the cardiovascular advantages of long-term vorapaxar treatment are likely to outweigh the adverse health risks to the patient associated with a higher likelihood of bleeding.
Vorapaxar is a type of drug known as a platelet inhibitor, because it halts the reaction of platelets in the blood which can lead to blood clot formation and heart attack or stroke. While platelet inhibitors (in conjunction with aspirin) currently form part of the standard treatment in the year following a heart attack, this is the first study to demonstrate that giving an antiplatelet therapy in addition to aspirin is beneficial for longer-term secondary prevention of heart attacks.
According to lead author Dr Benjamin Scirica of the Brigham and Women’s Hospital in Boston, USA, “To our knowledge, our study is the first to show a benefit of adding intense antiplatelet treatment to aspirin for long-term secondary prevention of thrombotic events in patients who have had a heart attack.”
Dr Stefan James of Uppsala University in Sweden, author of a linked Comment accompanying the Article, adds that: “The results of this work give further support for the benefit of adding more potent long term anti thrombotic therapy for patients who have previously had a heart attack. However, the challenge – as with all strategies of this type – is to weigh the benefit against the increased bleeding risk.”*
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