The Dual Antiplatelet Therapy (DAPT)1 trial was a randomized, double-blind, placebo-controlled trial that compared antiplatelet treatment for 30 months vs. 12 months following percutaneous coronary intervention and placement of a drug-eluting stent. After stent placement, patients received 12 months of dual antiplatelet therapy consisting of aspirin plus either clopidogrel (Plavix) or prasugrel (Effient) and then were randomized to continued treatment for 18 additional months of dual antiplatelet therapy (aspirin plus clopidogrel or prasugrel) or to aspirin plus placebo. The investigators selected the antiplatelet agents patients received, with about two-thirds receiving clopidogrel and one-third receiving prasugrel. Acute coronary syndrome was the indication for the stent in about 46% of patients.
The DAPT trial showed that the 30-month extended antiplatelet therapy with clopidogrel or prasugrel decreased the risk of stent thrombosis and heart attacks, but increased the risk of bleeding and overall risk of death compared to the 12-month group. The higher rate of death was primarily due to a larger number of deaths from non-cardiovascular causes, principally cancer and trauma. The increased rate of death was evident in patients receiving clopidogrel but not prasugrel.
In order to investigate the signals of increased risk of death and cancer-related death from the DAPT trial, FDA evaluated the DAPT trial and performed trial-level meta-analyses of other large, long-term trials that had available data on rates of death, rates of death from cancer, or rates of cancer adverse events. Trials included in the meta-analyses had a clopidogrel plus aspirin arm (long term was 12 months or longer), a comparator arm of either aspirin alone or short-term clopidogrel plus aspirin (6 months or less), and had a planned follow-up of at least one year. We focused our investigation on clopidogrel because findings from the DAPT trial suggested an increase in the risk of death and cancer death in that group; data on prasugrel are also presented as context for the clopidogrel findings.
Investigation of the signal of increased all-cause death
In the DAPT trial, extended use of clopidogrel plus aspirin was associated with a significantly increased risk of death (2.2% for 30 months vs. 1.5% for 12 months), whereas no increased risk was observed for prasugrel plus aspirin (1.6% for 30 months vs. 1.6% for 12 months).
The FDA trial-level meta-analysis included 12 trials2-13 (56,799 patients) to explore the effect of clopidogrel on all-cause mortality. The incidence of all-cause mortality was 6.7% for the long-term clopidogrel plus aspirin arm and 6.6% for the comparator resulting in Mantel Haenszel Risk Difference (MH RD) = 0.04%, 95% confidence interval (CI) of (-0.35%-0.44%).
A similar meta-analysis that focused on the subset of 9 of these trials (45,374 patients) that enrolled patients with coronary artery disease or patients at risk of coronary artery disease also suggested no difference in the risk of all-cause mortality: [MH RD of -0.07%, 95% CI (-0.43%-0.29%)].
Investigation of the signal of increased risk of cancer death
In the DAPT trial, the risk of cancer reported as an adverse event was not different between the 30-month (2.4% ) and 12-month (2.3%) groups receiving clopidogrel when considering cancers reported after enrollment (from month 0 to 33 of the study). We performed several analyses of the cancer adverse event data, including “new” cancers in patients with no history of cancer or a history of cancer in a location different than the reported adverse event, and by cancer site. The relative risk of cancer for the 30-month vs. 12-month arm in the clopidogrel group ranged from 0.95 to 1.2, depending on the analysis. Analyses of time to first reported cancer adverse event demonstrated a hazard ratio of 1.06, 95% CI (0.80-1.41) for all cancer and 0.95, 95% CI (0.70-1.28) for new cancer. Similar analyses for the prasugrel group resulted in relative risks of cancer-related adverse events ranging from 1.4 to 1.6, and hazard ratios of 1.51, 95% CI (0.97-2.36) for all cancer and 1.51, 95% CI (0.96-2.40) for new cancer. The patterns of the reported cancer sites did not suggest site-specific effects.
Despite no increase in the risk of cancer-related adverse events for clopidogrel in the 30-month arm of the DAPT trial, the risk of cancer-related death was increased compared to the 12-month arm (0.7% for 30 months vs. 0.2% for 12 months). In contrast, for prasugrel there was a trend towards a higher risk of cancer adverse events in the 30-month arm compared to the 12-month arm (see above), but the risk of cancer death was identical in both study arms (0.4% vs. 0.4%). These findings are difficult to reconcile.
To explore the cancer signal for clopidogrel in clinical trials other than the DAPT study, FDA performed two trial-level meta-analyses. The first was an analysis of cancer-related adverse events from four trials with information on cancer adverse events2-5 (37,835 patients) that compared long-term use of clopidogrel and aspirin to use of either aspirin alone or short-term clopidogrel plus aspirin. The incidence of cancer adverse events was 4.2% for the long-term clopidogrel plus aspirin vs. 4.0% for the comparator. There was no apparent difference in the incidence of cancer adverse events between patients who received long-term clopidogrel plus aspirin and control patients across the four trials [MH RD = 0.19%, 95% CI (-0.2%-0.59%)].
The second trial-level meta-analysis was performed to assess cancer-related death and included five trials with information on cancer deaths2-6 (40,855 patients). The incidence of cancer death was 0.9% for the long-term clopidogrel plus aspirin group vs. 1.1% for the comparator. There was no apparent difference in the incidence of cancer deaths between the long-term clopidogrel plus aspirin and control groups across the five trials [MH RD = -0.14%, 95% CI (-0.33%-0.06%)].
The findings from the DAPT trial with regard to cancer-related adverse events (increased for prasugrel, but not for clopidogrel) and cancer-related death (increased for clopidogrel, but not for prasugrel) have not been observed in our analyses of other randomized-controlled clinical trials. FDA’s trial-level meta-analyses of other trials performed to evaluate the potential signal from DAPT do not suggest an increased risk of cancer adverse events or cancer-related death associated with long-term clopidogrel therapy.
Conclusion
Our reviews found no evidence of either a harmful or beneficial effect of clopidogrel on overall mortality in a population with, or at risk for, coronary artery disease, and no effect on cancer.