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Determining optimal duration of DAPT after coronary artery stenting
Coronary drug-eluting stents were first approved for use in the United States in 2003 after proof of efficacy for reduced target vessel failure and target vessel revascularization compared with bare-metal stents. However, in 2006, safety concerns arose after several nonrandomized papers, including an observational analysis of the BASKET-LATE trial, suggested that rates of nonfatal MI, death from cardiac causes and stent thrombosis were higher with DES than with BMS 7 to 18 months after implantation. To address safety concerns, the FDA convened an advisory panel meeting that recommended additional research to define the ideal duration of dual antiplatelet therapy after DES implantation.
The optimal duration and risk–benefit ratio for long-term DAPT after PCI with DES placement remains uncertain. Current PCI guidelines, largely rooted in observational data, recommend DAPT for at least 12 months after DES implantation. However, DAPT is associated with increased bleeding risks and costs compared with aspirin alone. In addition, endoscopic, dental and surgical procedures may be delayed because of prolonged DAPT. Therefore, determining the optimal duration of DAPT is key to preventing recurrent thrombosis while minimizing harm to the patient.
Meredith Grycki
Douglas L. Jennings
Available evidence
Several recently published studies evaluated shorter DAPT duration after results published by Park and colleagues showed that use of DAPT for longer than 12 months was not significantly more effective than aspirin monotherapy in reducing the rate of MI or death from cardiac causes (HR=1.65; 95% CI, 0.80-3.36).
PRODIGY was a randomized, multicenter, open-label clinical trial designed to assess the effect of using DAPT for 6 months (n=963) vs. 24 months (n=961) after PCI in patients receiving DES or BMS. Patients undergoing elective, urgent or emergent coronary angioplasty were randomly assigned to one of four stent types (everolimus, paclitaxel, zotarolimus or third-generation thin-strut BMS).
The Kaplan-Meier estimate of the event rate for the primary endpoint (death from any cause, MI or cerebrovascular accident) at 2 years was 10.1% in the 24-month clopidogrel group compared with 10% in the 6-month clopidogrel group (HR=0.98; 95% CI, 0.74-1.29). Of those patients randomly assigned to DES (n=1,443), the rate of definite stent thrombosis did not differ between the 6-month and 24-month treatment groups (0.42% vs. 0.56%; P>.99). However, risk for TIMI-defined major bleeding events was significantly reduced in the 6-month clopidogrel group as compared with the 24-month clopidogrel group (HR=0.38; 95% CI, 0.15-0.97).
Similarly, the EXCELLENT investigators compared 6-month DAPT (n=722) with 12-month DAPT (n=721) among patients receiving DES. The prospective, randomized trial was conducted at 19 sites in Korea. Patients received everolimus-eluting (75%) or sirolimus-eluting stents (25%).
The noninferiority of the 6-month DAPT to 12-month DAPT for the primary endpoint of target vessel failure (TVF; composite of death, MI or TVR) was confirmed (absolute risk difference, 0.5 percentage points; upper limit of 1-sided 95% CI, 2.4%; P=.001). Although this study was not powered to draw conclusions regarding the relationship between stent thrombosis and duration of DAPT, it is worth noting that there was a numerically higher rate of stent thrombosis in the 6-month DAPT group than in the 12-month group (0.9% vs. 0.1%; HR=6.02; 95% CI, 0.72-49.96). Furthermore, TVF occurred more frequently with 6-month DAPT than with 12-month DAPT among patients with diabetes (HR=3.16; 95% CI, 1.42-7.03). In contrast to the PRODIGY trial, there was no difference in bleeding events observed between the two groups (HR=0.4; 95% CI, 0.13-1.27).
The RESET trial was a prospective, open-label, randomized trial conducted at 26 sites in Korea. Researchers evaluated the safety and efficacy of DAPT for an even shorter duration (3 months). Patients with diagnosis of angina or acute MI who presented for elective PCI were randomly assigned to a zotarolimus-eluting stent (ZES; Endeavor, Medtronic) with 3-month DAPT (n=1059) or another DES, including a sirolimus-eluting stent (SES; Cypher Select, Cordis), everolimus-eluting stent (EES; Xience V, Abbott Vascular) or ZES (Resolute, Medtronic) with 12-month DAPT (n=1,058).
At 1 year, the 3-month DAPT group was noninferior to the standard therapy group for the primary composite endpoint (death from CV causes, MI, stent thrombosis, TVR or bleeding at 1-year post-procedure); the difference was 0% (95% CI, –2.5 to 2.5). The occurrence of stent thrombosis was similar between the two groups (0.2% vs. 0.3%; 95% CI, –0.5 to 0.3). Although these results suggest that 3-month DAPT may be sufficient, it should be noted that 1 year of clinical follow-up may be insufficient to assess occurrence of late thrombosis. Furthermore, use of a composite endpoint evaluating both efficacy and safety outcomes could bias the assessment of noninferiority and significantly limit the findings of this study.
Additional data are required
Given the limitations of these studies, additional data are required to define the optimal duration of DAPT after DES placement.
The DAPT randomized controlled trial is an ongoing study developed by a group of eight manufacturers (four major stent manufacturers and four manufacturers of antiplatelet medications), the FDA and the Harvard Clinical Research Institute. The trial is being conducted in response to the FDA request for postmarketing studies of DES. The DAPT trial has enrolled approximately 26,000 patients from more than 450 sites worldwide. Patients with ischemic heart disease due to stenotic or occlusive lesions in either native coronary arteries or CABGs undergoing PCI with stent placement and no contraindications to prolonged DAPT were eligible for study enrollment. The study will assess the benefits of 12 vs. 30 months of DAPT for preventing stent thrombosis and major adverse CV and cerebrovascular events in patients undergoing PCI with DES placement. Unfortunately, final results from the DAPT trial are not expected to be available until late 2014.
Current recommendations
Overall, the current body of literature does not clearly identify an ideal duration of DAPT for all patients. The PRODIGY trial suggests that 6 months of DAPT may be sufficient to prevent recurrent major adverse cardiac events and identified potential harm with respect to bleeding events associated with prolonged use of DAPT. However, this study also enrolled patients who received BMS, and therefore the results are clouded by this heterogeneity. Contrary to these findings, the EXCELLENT trial suggests that 6-month duration of DAPT may not provide adequate protection against stent thrombosis in a DES patient population. Finally, results of the RESET trial seem to support the findings of PRODIGY. However, RESET was limited by its short duration of follow-up and methodologic concerns related to the poorly chosen composite endpoint for a noninferiority study.
Pending the results of the DAPT trial, clinicians should continue to follow the current recommendations, which specify at least 12 months of DAPT after DES placement. Additionally, careful assessment of the balance between the risk for stent thrombosis and the likelihood of bleeding events at an individual patient level is required. Patients with high-risk procedures (ie, overlapping stents), lesions (ie, left-main stenting) or high-risk clinical conditions (ie, diabetes) may benefit from extended duration of DAPT. Additional large, randomized controlled trials are required to define an ideal duration of DAPT for patients after implantation of DES.