By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Dr. Zimmet reports no financial relationships relevant to this field of study.
SYNOPSIS: In this randomized trial that included more 3,000 patients, one month of dual antiplatelet therapy (DAPT) followed by single antiplatelet therapy with clopidogrel was noninferior to 12 months of DAPT following percutaneous coronary intervention with drug-eluting stents.
SOURCE: Watanabe H, Domei T, Morimoto T, et al. Effect of 1-month dual antiplatelet therapy followed by clopidogrel vs 12-month dual antiplatelet therapy on cardiovascular and bleeding events in patients receiving PCI: The STOPDAPT-2 randomized clinical trial. JAMA 2019;321:2414-2427.
The introduction of drug-eluting stents (DES) brought a promise of low restenosis rates, but at the apparent expense of delayed arterial healing with the first-generation devices. The specter of late stent thrombosis, first recognized in earnest in 2006, led to recommendations for dual antiplatelet therapy (DAPT) regimens lasting one year or longer. However, subsequent advances in stent technology have resulted in improved safety and faster endothelialization following stent deployment. Indeed, the results of multiple trials of later-generation DES have suggested that these devices carry equivalent or even lower risk of stent thrombosis vs. their bare-metal counterparts. Although current U.S. guidelines recommend a minimum of six months of DAPT following DES deployment in elective procedures, retrospective data suggest that more recent iterations of these devices heal more quickly still, and that patients who require discontinuation of DAPT as early as one month can experience favorable outcomes.
Enter the STOPDAPT-2 trial, a multicenter, randomized study of the safety of short-duration DAPT. Watanabe et al enrolled 3,045 patients at 90 centers in Japan between late 2015 and 2017. Patients were eligible for inclusion if they had undergone successful PCI with the Xience series of everolimus-eluting stents and had not experienced major in-hospital complications. Enrolled patients were, on average, 68.6 years of age; 78% were male. Most procedures were performed for stable angina, but a substantial proportion (approximately 38%) were for acute coronary syndromes (ACS). Of these ACS patients, approximately half presented with ST-elevation myocardial infarction (STEMI), with the remainder represented by non-STEMI and unstable angina.
Enrolled patients were randomized 1:1 to receive either one month of DAPT followed by 11 months of clopidogrel monotherapy or 12 months of DAPT. During the first month, all patients received aspirin in addition to a thienopyridine (either clopidogrel or prasugrel) that was chosen by the attending physician. Clopidogrel was used in 62% of patients and prasugrel was used in the remaining 38%. After the first month, patients in the short DAPT group stopped taking aspirin and were continued on clopidogrel as a single agent. The control group received aspirin and clopidogrel for 12 months; those initially managed on prasugrel were switched to clopidogrel at the one-month mark. The primary endpoint was a composite of cardiovascular death, MI, stent thrombosis, stroke, and bleeding. Cardiovascular and bleeding events were analyzed separately as major secondary endpoints.
At 12 months, the primary endpoint occurred in fewer one-month DAPT patients compared with the control group (2.36% vs. 3.70%; hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.42-0.98; P = 0.04 for superiority). Bleeding was the main driver of this difference. The major secondary cardiovascular endpoint was not significantly different between the two groups, while the major secondary bleeding endpoint (a composite of major and minor bleeding) occurred in just 0.41% of one-month DAPT patients vs. 1.54% of 12-month DAPT patients (HR, 0.26; 95% CI, 0.11-0.64; P = 0.004 for superiority). Definite or probable stent thrombosis, while numerically higher in the short DAPT group (four events vs. one event in the control group), was not statistically different between the groups. The authors concluded that in this large, randomized study of patients following successful PCI with everolimus-eluting stents, patients treated with just one month of DAPT followed by clopidogrel monotherapy experienced a net clinical benefit compared with those treated with DAPT for 12 months.
The main message of this trial is clear: Converting to a regimen of single antiplatelet therapy with clopidogrel only one month following PCI with the Xience DES platform appears to be safe regarding ischemic outcomes. Further, such a move confers a lower risk of bleeding events. But how generalizable are these results?
In most everyday clinical practice, patients completing their required DAPT regimen pare down to aspirin alone. In contrast, clopidogrel was the agent chosen for single antiplatelet therapy in this trial. Overall, clopidogrel is more effective as a single antiplatelet agent than aspirin and may be less likely to cause upper gastrointestinal bleeding. Significantly, the known variability in clopidogrel responsiveness did not hinder the Watanabe et al study, even though genetic polymorphisms resulting in reduced conversion of the clopidogrel prodrug to its active metabolite are known to be more prevalent in Asian populations.
Does it matter that all patients in the trial were treated with Xience stents? Would the same result hold for other DES? Maybe. Although the current-generation DES models are similar, we cannot exclude the possibility that the use of other platforms might have generated different results. More than half of eligible patients were not enrolled, many because the attending physician declined to participate, presumably due to a lack of clinical equipoise. Certainly, one could suggest this led to the selection of lower-risk patients for this trial. Overall, the non-enrolled patients were more complicated than the enrolled population, with older age, more STEMI and prior MI, more target vessels treated, and a greater proportion involving the left main. It is unclear that more complex patients could be treated safely with the very short DAPT duration used in STOPDAPT.
Another important point was the exceedingly high use of intravascular imaging (85% of the short DAPT group used intravascular ultrasound, and nearly the entire remainder was performed with optical coherence tomography). Using intravascular imaging to optimize stenting results has been reported to decrease ischemic outcomes in multiple prior studies. Whether the results of STOPDAPT can be extrapolated to the United States, where a minority of PCI procedures (fewer than 7% of all PCI, in one recent study) are performed with intravascular imaging, is an open question. The results of the STOPDAPT trial suggest that a one-month duration of DAPT followed by clopidogrel monotherapy is safe and may be beneficial for a subset of lower ischemic risk patients. Further studies will be required to demonstrate whether this approach may be extrapolated to the general population of post-PCI patients.