FDA Drug Safety Communication: FDA reviews long-term antiplatelet therapy as preliminary trial data shows benefits but a higher risk of non-cardiovascular death

The FDA has issued new information about this safety issue, see the FDA Drug Safety Communication issued 11-6-2015.

[11-16-2014] FDA is evaluating preliminary data from a clinical trial showing that treatment for 30 months with dual antiplatelet blood-thinning therapy decreased the risk of heart attacks and clot formation in stents, but there was an increased overall risk of death compared to 12 months of treatment. The clinical trial compared 30 months versus 12 months of treatment with dual antiplatelet therapy consisting of aspirin plus either clopidogrel (Plavix) or prasugrel (Effient), following implantation of drug-eluting coronary stents. These stents are small, medicine-coated tubes inserted into narrowed arteries in the heart to keep them open and maintain blood flow to the heart. Clopidogrel and prasugrel are important medicines used to prevent heart attacks, strokes, and other clot-related diseases.

FDA believes the benefits of clopidogrel (Plavix) and prasugrel (Effient) therapy continue to outweigh their potential risks when used for approved uses. Patients should not stop taking these drugs because doing so may result in an increased risk of heart attacks, blood clots, strokes, and other major cardiovascular problems. Health care professionals should not change the way they prescribe these drugs at this time.

The Dual Antiplatelet Therapy (DAPT) trial was published in the New England Journal of Medicinedisclaimer icon on November 16, 2014.1 FDA has not reviewed the trial results or reached any conclusions based on the findings from this clinical trial. We are communicating this safety information while we continue to evaluate the results from this trial and other available data. We will communicate our final conclusions and recommendations when our evaluation is complete.

The DAPT trial is a public-private collaboration to study the optimal duration of antiplatelet therapy after stent placement.1-2 The trial examined the effects of dual antiplatelet therapy for 12 months compared to 30 months in approximately 10,000 patients with an implanted drug-eluting coronary stent. The risks of stent thrombosis and heart attacks in the group receiving treatment for 30 months was reduced compared to 12 months; however, there was a higher rate of death in the 30-month treatment group. The higher rate of death was largely explained by an increase in deaths from non-cardiovascular causes, primarily cancer and trauma deaths. The increased risk of death with longer treatment was seen in the patients given clopidogrel, but not those given prasugrel. It should be noted that increases in non-cardiovascular death have not been reported in previous large trials examining clopidogrel for other cardiovascular diseases.

The DAPT trial was a randomized, placebo-controlled, double-blind clinical trial that examined the use of dual antiplatelet therapy (aspirin plus either clopidogrel or prasugrel) in patients who had undergone percutaneous coronary intervention with stent placement. The investigators selected the antiplatelet agents patients were to receive, with about 2/3 receiving clopidogrel and 1/3 receiving prasugrel. Most of the patients received drug-eluting stents (86%); 14% of patients received bare metal stents. All patients received 12 months of dual antiplatelet therapy and then were randomized to either continued treatment with dual antiplatelet therapy for an 18 additional months in the 30-month group, or to aspirin and placebo in the 12-month group. All study patients were followed for a total of 33 months.

In the drug-eluting stent patients, the trial met its two primary endpoints: a reduction in risk of stent thrombosis (1.4% risk for the 12-month group vs. 0.4% risk for the 30-month group ; HR 0.29, p<0.001) and a reduction in major cardiovascular and cerebrovascular events (combined endpoint of all-cause death, myocardial infarction, and stroke of 4.3% for the 30-month group vs. 5.9% for the 12-month group; HR 0.71, p<0.001). The reduction in risk of major cardiovascular and cerebrovascular events was driven by a decrease in the rate of non-fatal myocardial infarction, with no differences in rates of cardiovascular death or stroke.

However, in patients with a drug-eluting stent, the overall death rate was higher among those receiving 30 months of dual antiplatelet therapy compared to those receiving 12 months (2.0% vs. 1.5% respectively), explained by an increase in non-cardiovascular deaths (1% vs. 0.5%; HR 2.2, p=0.002). The most frequent causes of non-cardiovascular death were cancer (34 vs. 17 deaths) and trauma (8 vs. 2 deaths) for 30 months and 12 months of therapy, respectively. The increase in overall mortality was observed in the clopidogrel cohort (2.2% vs. 1.5%, respectively) but not the prasugrel cohort (1.6% vs. 1.6%). It should be noted that in other large clopidogrel trials, increases in risk of non-cardiovascular death have not been observed. Outcomes in patients receiving bare metal stents are still being evaluated.

FDA will continue to evaluate the information from this trial and other available data, and will communicate again when our evaluation is complete.

  1. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 Months of Dual Antiplatelet Therapy After Drug-eluting Stents. New England Journal of Medicine. Online ahead of print November 16, 2014.
  2. Mauri L, Kereiakes DJ, Normand ST, et al. Rationale and design of the dual antiplatelet therapy study, a prospective, multicenter, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy in subjects undergoing percutaneous coronary intervention with either drug-eluting stent or bare metal stent placement for the treatment of coronary artery lesions. American Heart Journal 2010; 160: 1035-1041.

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