A New Strategy for Discontinuation of Dual Antiplatelet Therapy

The RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation)

Methods

The RESET trial was a prospective, open-label, randomized trial conducted at 26 sites in Korea; the complete lists and detailed information regarding participating institutes appear in the Online Appendix. The trial protocol was approved by the institutional review board at each participating center.

Patients with a diagnosis of angina or acute myocardial infarction with more than 50% diameter stenosis in a coronary artery by visual estimation, who presented to the catheterization laboratory for elective percutaneous coronary intervention, were eligible for participation. The complete inclusion and exclusion criteria are provided in the Online Appendix. All study participants provided written informed consent using documents approved by the local ethics board.

Using an interactive web-based response system, study participants were randomly assigned in a 1:1 ratio to receive either the E-ZES or another currently available DES. Randomization was stratified by participating center and 4 clinical or lesion characteristics (Fig. 1): diabetes mellitus, acute coronary syndrome, treatment of a short lesion (stent length ≤24 mm); and treatment of a long lesion (stent length ≥28 mm). Patients with diabetes mellitus or acute coronary syndrome were randomized to either the E-ZES or the Resolute zotarolimus-eluting stent (Medtronic); patients with short lesions to the E-ZES or the Cypher Select sirolimus-eluting stent (Cordis, Miami, Florida); and those with long lesions to the E-ZES or the Xience V everolimus-eluting stents (Abbott Vascular, Santa Clara, California).

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Figure 1

Diagram for Study Design and the Detailed Enrollment of Patients

DAPT = dual antiplatelet therapy; DES = drug-eluting stent; EES = everolimus-eluting stent(s); E-ZES = Endeavor zotarolimus-eluting stent(s); R-ZES = Resolute zotarolimus-eluting stent(s); SES = sirolimus-eluting stent(s).

After stent implantation, 100-mg daily aspirin was prescribed indefinitely, and the duration of clopidogrel 75-mg daily was given depending on the randomization scheme (Fig. 1). Details of study procedures and quantitative coronary angiographic analyses are provided in the Online Appendix.

Post-procedure clinical assessment was performed in-hospital, and after 1, 3, 6, and 12 months, either by clinic visit or by telephone interview. The primary endpoint was a composite of death from cardiovascular cause, myocardial infarction, stent thrombosis, ischemia-driven target-vessel revascularization, or bleeding at 1-year post-procedure. Clinical events are defined according to the Academic Research Consortium (9). Detailed definitions of study endpoints, clinical diseases, and procedural findings are provided in the Online Appendix. All clinical events were independently monitored and assessed by a clinical event committee, comprising members masked as to the assigned therapy groups.

The primary analysis was a noninferiority comparison between the 2 groups with respect to the occurrence of the primary endpoint. On the basis of the previous studies, we assumed the overall incidence of the primary endpoint after E-ZES+3-month DAPT, and after the standard therapy, would be 10% and 11%, respectively (4–6,10–12). We hypothesized that the clinical outcome of E-ZES+3-month DAPT would be noninferior to the other group, with a noninferiority margin of 4% for the absolute difference in risk at 12 months. Assuming a 10% dropout rate, this required an estimated sample size of 2,120 patients (1,060 for each group) to achieve 80% power for the noninferiority test and a 1-sided type I error of 5%. The detailed methods of statistical analysis are provided in the Online Appendix.

Results

Between April 2009 and December 2010, we enrolled and randomized 2,148 patients, of which 2,117 patients (E-ZES+3-month DAPT = 1,059; standard therapy = 1,058) comprised the analysis population. The study design and the detailed enrollment of patients are provided in Figure 1. The baseline characteristics were similar between the 2 groups (Table 1). Clinical follow-up at 1 year was completed for 2,086 of 2,117 patients (98.5%): 1,044 of 1,059 patients (98.6%) in E-ZES+3-month DAPT group, and 1,042 of 1,058 patients (98.5%) in standard therapy group (p = 0.99). Clinical outcomes through 1-year follow-up are listed in Table 2. At 1 year, the E-ZES+3-month DAPT group was noninferior to the standard therapy group for the primary endpoint (cumulative events: 40 [4.7%] vs. 41 [4.7%]; difference: 0.0%, 95% confidence interval [CI]: −2.5 to 2.5; p = 0.84; p < 0.001 for noninferiority) (Fig. 2A). The cumulative events rates of the composite of any death, myocardial infarction, or stent thrombosis were 0.8% and 1.3%, respectively (difference: −0.5%; 95% CI: −1.5 to 0.5; p = 0.48, Fig. 2B). The occurrence of stent thrombosis was similar between the 2 groups (0.2% vs. 0.3%; difference: −0.1%; 95% CI: −0.5 to 0.3; p = 0.65). From 3 months through 12 months following the index procedure, there were 3 stent thrombosis events in the standard therapy group, and none in the E-ZES+3-month DAPT group despite the cessation of clopidogrel. The rates of target-vessel revascularization were 3.9% for the E-ZES+3-month DAPT group and 3.7% for the standard therapy group. The subgroup analysis of the primary endpoint and other events at 1 year is shown in Figure 3 and Table 2.

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Figure 2

Cumulative Event Rates Using the Kaplan-Meier Method

A primary endpoint (A), and a composite of death from any cause, myocardial infarction, or stent thrombosis (B). Abbreviations as in Figure 1.

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Figure 3

Subgroup Analysis of the Primary Endpoint at 1 Year

CI = confidence interval; other abbreviations as in Figure 1.

Interruption of the DAPT regimen occurred in 62 (5.9%) of 1,059 patients who were allocated to E-ZES+3-month DAPT (mean duration of DAPT: 196 ± 63 days). Reasons for interruption of the DAPT regimen were as follows: physicians' mistake or failure of monitoring (n = 26), physicians' discretion (n = 22), patients' disagreement (n = 13), and repeat revascularization (n = 1). After censoring patients who had an interruption of DAPT duration in the E-ZES+3-month DAPT group, there were no significant differences in 1-year clinical outcomes between the 2 groups (Tables 3 and 4).⇓⇓

Discussion

This randomized study demonstrated that E-ZES+3-month DAPT is safe and noninferior to the standard therapy for the primary composite endpoint.

Regardless of DES types, current recommendations call for a minimum of 12 months of DAPT after DES implantation for the prevention of late stent thrombosis (3). However, prolonged DAPT has been associated with higher severe bleeding rates compared with treatment with aspirin alone; reported incidence of major and minor bleeding were 1.8% to 3.7% and 1.7% to 5.1%, respectively (13,14). In addition, nuisance bleeding is common in patients on prolonged DAPT post-DES implantation (28.9% of 2,948 patients) (14). The higher incidence of bleeding episodes can impact patients' compliance and result in premature discontinuation of DAPT.

A previous randomized study reported that the use of DAPT for a period longer than 12 months in patients who had received DESs was not significantly more effective than aspirin monotherapy in reducing the rate of myocardial infarction or death from cardiac causes (15). In addition, recent randomized trials showed no clinical benefits of prolonged DAPT compared with 6-month DAPT after DES implantation (16,17).

Therefore, balanced DES that can offer both safety and efficacy are desirable, especially for those who may need to stop DAPT early after DES implantation (5,6). The E-ZES comprises a cobalt alloy, thin-strut stent with a biocompatible phosphorylcholine polymer (4–6). A recent study reported that among 2,032 patients treated with E-ZES in 5 trials, Academic Research Consortium–defined definite or probable stent thrombosis rates through 3 years did not significantly differ between the 6-month and ≥12-month DAPT groups (0.3% vs. 0%, respectively) (18). These findings might be explained by better neointimal coverage in the early post-implant period compared with other DES (7).

Conclusions

E-ZES+3-month DAPT could be safe and beneficial for the selected patients with coronary artery disease who may need to stop DAPT early after DES implantation.