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The Antiplatelet Drug Pipeline: Some Promising Candidates

November/December 2008, Vol 1, No 9 - Conference Highlights AHA
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Several antithrombotic drugs in late-stage development were featured at the 2008 Scientific Sessions of the American Heart Association (AHA).

Prasugrel. A new analysis of the antiplatelet drug prasugrel, a direct-acting P2Y12 antagonist currently under US Food and Drug Administration review, questions this agent's supposed superiority over the current standard in this class, clopidogrel (Plavix). Results of the pivotal phase 3 Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON), which compared prasugrel and clopidogrel, were released in late 2007. Among patients being considered for coronary stents, prasugrel prevented more future cardiac events than clopidogrel, but with excess bleeding. Despite this excess risk, the net benefit still favored prasugrel—23 fewer myocardial infarctions (MIs) per 1000 patients treated, at a cost of 6 extra bleeding events.

More recent analyses of TRITON have shown that much of the benefit of prasugrel in preventing ischemic events occurs early on, but the excess bleeding occurs after 30 days of use. New analyses have shown that prasugrel is better than clopidogrel at preventing stent thrombosis (blood clots forming in stents).

At the AHA, a team of investigators at Cedars-Sinai Medical Center in Los Angeles discussed its independent statistical analysis (using a Bayesian method), showing that the true superiority of prasugrel in TRITON was not as large. In their analysis, the probability of a 10% or more benefit with prasugrel over clopidogrel is less than 80%, and the chance that prasugrel is 20% better than clopidogrel in preventing cardiac events is less than 5%. If bleeding events are considered, the probability of a net benefit with prasugrel is even smaller, they argued.

Because of the risk-benefit ratio, Sanjay Kaul, MD, MPH, Director of the Vascular Physiology and Thrombosis Research Laboratory at the Burns and Allen Research Institute at Cedars-Sinai, and lead investigator of the reanalysis, proposed a strategy for using prasugrel. "One potential approach to optimizing the benefit-risk profile of prasugrel could involve giving it during the first 30 days as acute ‘induction' therapy, followed by maintenance ‘consolidation' therapy with a less potent antiplatelet agent, such as clopidogrel, in patients who receive stents," he said.

Rivaroxaban. This oral drug factor Xa inhibitor—a new class of anticlotting agents—is entering a phase 3 trial (and will enroll 16,000 patients) after the release of phase 2 data at the AHA. The data showed that rivaroxaban could reduce MI and stroke risk, with an acceptable bleeding risk at its 2 lowest doses.

That study enrolled 3491 stable patients with a recent MI who were taking aspirin and clopidogrel (if necessary). Patients were randomized to placebo or 1 of 4 doses of rivaroxaban (2.5-10 mg twice daily) for 6 months, and were followed for 1 month after stopping therapy. As expected, higher doses of rivaroxaban increased the rate of clinically significant bleeding.

Rivaroxaban reduced the risk of ischemic events by 21% relative to placebo, but this difference was not definitive, given the small number of patients enrolled, reported C. Michael Gibson, MD, Chief of Clinical Research, Beth Israel Deaconess Medical Center, Boston. "We have decided to go forward to phase 3 with the 2 lower doses—2.5 mg and 5 mg twice daily," he said. These doses reduced the risk of death, MI, and stroke by 46% compared with placebo (P = .08) and were associated with a major bleeding rate of 1.2%.

There was no drug-induced liver injury with rivaroxaban. The development of an oral direct thrombin inhibitor—ximelagatran—was derailed as a result of liver toxicity.

Other late-phase antithrombotic/antiplatelet drugs investigated for various thrombotic indications were discussed at the meeting, including:

  • Apixaban, another oral factor Xa inhibitor
  • Cangrelor, another direct-acting P2Y12 antagonist
  • Dabigatran, an oral direct thrombin inhibitor, which was recently approved in Europe (brand name, Pradaxa)
  • Idraparinux, a long-acting factor Xa inhibitor.
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Last modified: August 30, 2021