Conflicting Results with an IV Antiplatelet Drug

Cangrelor (Kengreal), the first IV P2Y12 platelet inhibitor to be approved by the FDA, will be reviewed in the next issue of The Medical Letter (1480; October 26, 2015). Its competition for use in percutaneous coronary intervention (PCI), its only approved indication, comes from three oral P2Y12 platelet inhibitors – clopidogrel (Plavix, and generics), prasugrel (Effient), and ticagrelor (Brilinta). To gain FDA approval, the manufacturer compared cangrelor with clopidogrel in 3 randomized, double-blind superiority trials.

All 3 trials used a primary endpoint that combined death, myocardial infarction, and ischemia-driven revascularization at 48 hours. The first 2 trials failed to demonstrate that the IV drug was superior to clopidogrel. The third trial, which took place after the results of the first two became available, found cangrelor to be superior to clopidogrel and, as a result of that outcome, the FDA followed the recommendation of an advisory committee and approved Kengreal for use in patients undergoing PCI.

Why did the results of the third trial outweigh the results of the other two? The answer can be found in the FDA’s Summary Review, which is cited in The Medical Letter. First, the third trial added stent thrombosis to the composite primary endpoint. Second, it enrolled a higher proportion of patients with stable angina and normal biomarker levels. Third, periprocedural MI was redefined. And fourth, patients who had been intensively pretreated with antiplatelet drugs were excluded. Taken together, these changes made it easier to detect a beneficial effect of cangrelor.

Is it acceptable to base approval of a drug on the success of a third trial that was designed specifically to avoid the failures of two earlier trials? Well, yes, if the indication limits its use to the same conditions that governed the third trial. And maybe the advantages of an IV drug (rapid onset of action, no need for hepatic activation, short half-life) would make its availability worthwhile even if there were some doubts about its superiority over its oral predecessors.

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Comments

  1. Christopher S. Conner, Pharm.D. says:

    Could the third cangrelor trial be viewed as a way to show superiority of a drug that may not be evident in the real-world setting? I haven’t seen the original third study, but it would be interesting to know how much input the manufacturer had in revamping trial design and analyzing results.

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