Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents

Abstract

Background: Dual antiplatelet therapy is recommended after coronary stenting to prevent thrombotic complications, yet the benefits and risks of treatment beyond 1 year are uncertain.

Methods: Patients were enrolled after they had undergone a coronary stent procedure in which a drug-eluting stent was placed. After 12 months of treatment with a thienopyridine drug (clopidogrel or prasugrel) and aspirin, patients were randomly assigned to continue receiving thienopyridine treatment or to receive placebo for another 18 months; all patients continued receiving aspirin. The coprimary efficacy end points were stent thrombosis and major adverse cardiovascular and cerebrovascular events (a composite of death, myocardial infarction, or stroke) during the period from 12 to 30 months. The primary safety end point was moderate or severe bleeding.

Results: A total of 9961 patients were randomly assigned to continue thienopyridine treatment or to receive placebo. Continued treatment with thienopyridine, as compared with placebo, reduced the rates of stent thrombosis (0.4% vs. 1.4%; hazard ratio, 0.29 [95% confidence interval {CI}, 0.17 to 0.48]; P<0.001) and major adverse cardiovascular and cerebrovascular events (4.3% vs. 5.9%; hazard ratio, 0.71 [95% CI, 0.59 to 0.85]; P<0.001). The rate of myocardial infarction was lower with thienopyridine treatment than with placebo (2.1% vs. 4.1%; hazard ratio, 0.47; P<0.001). The rate of death from any cause was 2.0% in the group that continued thienopyridine therapy and 1.5% in the placebo group (hazard ratio, 1.36 [95% CI, 1.00 to 1.85]; P=0.05). The rate of moderate or severe bleeding was increased with continued thienopyridine treatment (2.5% vs. 1.6%, P=0.001). An elevated risk of stent thrombosis and myocardial infarction was observed in both groups during the 3 months after discontinuation of thienopyridine treatment.

Conclusions: Dual antiplatelet therapy beyond 1 year after placement of a drug-eluting stent, as compared with aspirin therapy alone, significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events but was associated with an increased risk of bleeding. (Funded by a consortium of eight device and drug manufacturers and others; DAPT ClinicalTrials.gov number, NCT00977938.).

Figure 1. Subject Randomization and Follow-Up

Subjects were enrolled within 72 hours of stent placement, followed for 12 months on open-label thienopyridine plus aspirin, then randomized to 18 months of thienopyridine or placebo (each in addition to aspirin). Randomized treatment ended at 30 months and subjects remained on aspirin only and were followed for another 3 months. While the number of subjects with clinical follow-up available is reported in each arm, the co-primary efficacy endpoints were analyzed according to the principle of intention to treat, including all randomized subjects and last available follow-up information. *Subjects may have >1 event. **Site terminated participation, randomization target met prior to subject follow-up, or subject not recognized to be eligible by site ^† Subjects moved, were incarcerated, or were prematurely exited from the study.

Figure 2. Cumulative Incidence of Stent Thrombosis, According to Treatment Group

Cumulative incidence curve is shown for the primary effectiveness outcome of stent thrombosis in the intention-to-treat analysis population. Randomization occurred at 12 months after stenting. The primary analysis period was 12-30 months after percutaneous coronary intervention, i.e. the 18 months after randomization over which subjects were treated with study drug. Subjects were followed for an observational period of an additional three months, off study drug and off open label thienopyridine treatment, to a total of 33 months, i.e. 21 months post randomization. P values were calculated with stratified log-rank test. The number at risk is defined as the number of subjects without the event of interest and available for subsequent follow-up. The numbers at risk at the start of final 33 month visit (i.e. 20 months post randomization) were 4,438 vs. 4,362 for continued thienopyridine vs. placebo, respectively. Abbreviations: ARC, Academic Research Consortium; HR, hazard ratio; MACCE, major adverse cerebral and cardiovascular events.

Figure 3. Cumulative Incidence of Major Adverse Cardiovascular and Cerebrovascular Events (MACCE) According to Treatment Group

Cumulative incidence curve is shown for the primary effectiveness outcome of MACCE in the intention-to-treat analysis population. Randomization occurred at 12 months after stenting. The primary analysis period was 12-30 months after percutaneous coronary intervention, i.e. the 18 months after randomization over which subjects were treated with study drug. Subjects were followed for an observational period of an additional three months, off study drug and off open label thienopyridine treatment, to a total of 33 months, i.e. 21 months post randomization. P values were calculated with stratified log-rank test. Error The number at risk is defined as the number of subjects without the event of interest and available for subsequent follow-up. The numbers at risk at the start of final 33-month visit (i.e. 20 months post randomization) were 4,336 vs. 4,217 for continued thienopyridine vs. placebo, respectively. Abbreviations: ARC, Academic Research Consortium; HR, hazard ratio; MACCE, major adverse cerebral and cardiovascular events.