Dual antiplatelet therapy with aspirin and clopidogrel has become the cornerstone of the treatment of acute coronary syndromes. While 12 months has become the standard treatment time for most patients, it remains unclear whether longer durations of treatment may provide additional benefit, and in particular whether it allay fears regarding the risk of late stent thrombosis associated with the use of drug eluting stents (DES).
To address some of these questions, the authors present results from two studies, REAL-LATE (Correlation of Clopidogrel Therapy Discontinuation in Real-World Patients Treated with Drug-Eluting Stent Implantation and Late Coronary Arterial Thrombotic Events) and ZEST-LATE (Evaluation of the Long-Term Safety after Zotarolimus-Eluting Stent, Sirolimus-Eluting Stent, or Paclitaxel-Eluting Stent Implantation for Coronary Lesions — Late Coronary Arterial Thrombotic Events), which were merged due to slow recruitment and similar design. In both these studies, patients had undergone implantation of a DES and successfully completed 12 months of dual antiplatelet therapy without adverse effects. Patients were subsequently randomized to either continuation of dual therapy or aspirin alone in an open label fashion. The primary end point was a composite of myocardial infarction or death from cardiac causes. Between July 2007 and September 2008, 2701 patients were enrolled at 22 centers in South Korea with 1357 assigned to clopidogrel plus aspirin and 1344 to aspirin alone. Nearly half of these patients had multivessel disease, and more than 60% had an acute coronary syndrome as the indication for their PCI (although less than half met criteria for STEMI or NSTEMI).
The median duration of follow-up was 19.2 months. The risk of the primary outcome at 2 years was 1.8% with dual antiplatelet therapy, as compared with 1.2% with aspirin monotherapy (HR, 1.65; 95% CI, 0.80 to 3.36; P = 0.17). Additionally, the individual risks of myocardial infarction, stroke, stent thrombosis, need for repeat revascularization, major bleeding, and death from any cause did not differ significantly between the two groups.
The results from the study therefore suggest that a prolongation of dual antiplatelet therapy is not beneficial and in fact there are some hints that it may be detrimental with a statistically non-significant increase in the composite of myocardial infarction, stroke, or death from any cause (HR 1.73; 95% CI, 0.99 to 3.00; P = 0.051) and in the composite of myocardial infarction, stroke, or death from cardiac causes (HR 1.84; 95% CI, 0.99 to 3.45; P = 0.06). These results in particular are counter-intuitive and are very much at odds with data from most previous studies and as such bring into play the role of chance in these findings. Unfortunately, it is difficult to glean a great deal from this study to guide clinical practice as it is an interim analysis of two ongoing, underpowered studies which, even when combined, have an event rate less than the 25% which was anticipated – raising questions of the risk profile of the enrolled patients.
In this analysis of two combined trials, no clear benefit was seen from continuing dual anti-platelet therapy for more than 12 months. Further trials on this issue are underway.