Author + information
- Robert W. Yeh, MD, MSc,
- Dean J. Kereiakes, MD and
- Laura Mauri, MD, MSc∗ ()
- ↵∗Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115
The DAPT (Dual Antiplatelet Therapy) study showed reduction in stent thrombosis and myocardial infarction (MI) and an increase in bleeding with continued thienopyridine therapy beyond 12 months after coronary stent treatment (1). In subgroup analysis (2), continued thienopyridine therapy provided consistent reductions in ischemic endpoints irrespective of clinical presentation (MI Group, hazard ratio: 0.27 for stent thrombosis and 0.42 for MI; No MI Group, hazard ratio: 0.30 for stent thrombosis and 0.60 for MI). Global Utilization of Streptokinase moderate or severe bleeding was increased with continued thienopyridine in both groups (hazard ratio: 2.38 and 1.53, respectively). The conclusions, that extended dual antiplatelet therapy reduced stent thrombosis and MI but increased bleeding irrespective of clinical presentation, are objectively supported by the results of this substudy.
The DAPT study was not powered to evaluate the effect of continued thienopyridine on mortality. We nevertheless published the MI subgroup data for mortality to fully acknowledge the importance of this outcome. However, emphasis on a nonsignificant, albeit underpowered, interaction for an individual component endpoint in a non-pre–specified analysis could lead to an erroneous conclusion because of either type I or type II error. Thus, the finding, although notable, should be considered hypothesis-generating, not conclusive.
Although bleeding is certainly a risk of continued dual antiplatelet therapy, the difference in mortality seen in the DAPT study was not, in fact, accounted for by a difference in antecedent bleeding (1). In addition, a secondary blinded adjudication using a sensitive definition for bleeding-related death did not support bleeding as the primary reason for the difference in mortality. Finally, a large comprehensive meta-analysis found no relationship between extended duration dual antiplatelet therapy and mortality (3). Subsequent meta-analyses focused only on drug-eluting stent populations have been driven by the DAPT study results, and have selectively excluded studies with populations for whom the relationship between antiplatelet therapy and mortality, as mediated by bleeding, are applicable (4).
Mortality is undoubtedly a critically important endpoint in the evaluation of the risks and benefits of any therapy. We believe that the mortality differences observed in the DAPT study require careful attention because of the potential for harm to the many individuals exposed to this treatment. However, the expedient explanation that bleeding explains the observed mortality differences is not currently supported by trial data. A disciplined interpretation of DAPT study results is necessary to prevent premature conclusions that, although well intentioned, may in fact jeopardize patient safety.
Please note: Dr. Mauri has received institutional research grants from Abbott, Boston Scientific, Cordis, Medtronic, Eli Lilly/Daiichi-Sankyo, and Sanofi/Bristol-Myers Squibb; and personal fees from Medtronic, Recor, St. Jude Medical, and Biotronik. Dr. Yeh is a member of the advisory board of Abbott Vascular; and has received consulting fees from Gilead Sciences, and Merck. Dr. Kereiakes has reported that he has no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation