Clopidogrel Therapy for 6 vs 12 Months After Drug-Eluting Stenting
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In this double-blind trial, researchers randomized 4000 patients who were receiving a drug-eluting stent to take clopidogrel for 6 or 12 months. No significant differences were observed between the 6- and 12-month groups.
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Researchers suggest that event rates may be lower than expected due to premature termination.
abstract
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Access this abstract nowBackground
In patients receiving aspirin, the optimal duration of clopidogrel therapy after drug-eluting stent (DES) implantation remains unclear.
Methods
This multicentre, randomized, double-blind, placebo-controlled trial tested the hypothesis that in patients undergoing DES implantation, 6 months of clopidogrel is non-inferior to 12 months in terms of clinical outcomes. At 6 months after DES implantation, patients on clopidogrel were randomly assigned to either a 6-month period of placebo or an additional 6-month period of clopidogrel. The primary endpoint was the composite of death, myocardial infarction, stent thrombosis, stroke, and thrombolysis in myocardial infarction major bleeding at 9 months after randomization.
Results
Owing to slow recruitment and low event rates, the trial was stopped prematurely after enrolment of 4005 of 6000 planned patients. Of 4000 patients included in the final analysis, 1997 received 6 months of clopidogrel and 2003 received 12 months. The primary endpoint occurred in 29 patients (1.5%) assigned to 6 months of clopidogrel and 32 patients (1.6%) assigned to 12 months, observed difference −0.1%, upper limit of one-sided 95% confidence interval (CI) 0.5%, limit of non-inferiority 2%, Pfor noninferiority <0.001. Stent thrombosis was observed in five patients (0.3%) assigned to 6 months of clopidogrel and three patients (0.2%) assigned to 12 months; hazard ratio (HR) 1.66, 95% CI: 0.40–6.96, P = 0.49. Thrombolysis in myocardial infarction major bleeding was observed in 4 patients (0.2%) assigned to 6 months clopidogrel and 5 patients (0.3%) assigned to 12 months; HR 0.80, 95% CI: 0.21–2.98, P = 0.74.
Conclusions
In the present trial, characterized by low event rates, we did not observe a significant difference in net clinical outcome between 6 and 12 months of clopidogrel therapy after DES implantation. However, the results of the trial must be considered in view of its premature termination and lower than expected event rates.
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Additional Info
Disclosure statements are available on the authors' profiles:
The optimal duration of dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation has been debated for many years. This debate was recently fueled at the last American Heart Association Scientific Session in November 2014 with a number of trials presenting contradictory results at first glance. Among these was the ISAR-SAFE trial, which was just recently published in print.
The multicenter, randomized, double-blind, placebo-controlled trial confirmed the study hypothesis that 6 months of DAPT is noninferior to 12 months of DAPT after DES in terms of the combined ischemic and bleeding endpoint. Moreover, it demonstrated a 50% lower rate of bleeding events defined by the Bleeding Academic Research Consortium.
It is interesting to note that the power calculations called for an enrollment of 6000 patients and that the protocol was amended before the completion of the study, requiring an interim analysis after enrollment of two-thirds of the patients. At that point, it was noted that the overall event rates were much lower than expected (only about 60 combined events in 4000 patients). Thus, 10 times more patients would have needed to be enrolled to meet the statistical requirements of the study, which was burdened with slow recruitment across the 40 sites to begin with. The Data Safety Monitoring Board and Steering Committee therefore recommended termination of the study at the interim stage of 4000 patients.
With this important background information, the study results are to be interpreted in a cautionary manner. Also, 40% of the patients enrolled presented with an acute coronary syndrome (ACS), and current European and US guidelines do not recommend duration of DAPT shorter than 12 months. Thus, the results do not apply to nearly half of the patients enrolled even though the study results did not differ between patients with ACS and those without. Also, nearly 50% of the patients received the everolimus-eluting XIENCE V or PRIME stent, which has already received a CE mark approval by European regulatory agencies (in May 2012) for durations of DAPT as short as 3 months. The noninferiority of 3 months of DAPT with zotarolimus-eluting Endeavor stents was demonstrated in the OPTMIZE trial in 2013. The ISAR-SAFE trial results are therefore consistent with the view that the duration of DAPT to reduce the risk of stent strut–related acute coronary thrombosis after new-generation DES does not have be 12 months as originally advised for the first-generation DES. Prolongation of DAPT beyond the complete re-endothelialization point of stents then targets the underlying disease process and might have the greatest benefit in those patients with biologically more active (ACS) or widespread (peripheral artery disease) disease, outweighing the inherent risk of bleeding.