Comparison of Clopidogrel Monotherapy After 1 to 2 Months of Dual Antiplatelet Therapy With 12 Months of Dual Antiplatelet Therapy in Patients With Acute Coronary Syndrome: The STOPDAPT-2 ACS Randomized Clinical Trial

Abstract

Importance: Clopidogrel monotherapy after short dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) has not yet been fully investigated in patients with acute coronary syndrome (ACS).

Objective: To test the hypothesis of noninferiority of 1 to 2 months of DAPT compared with 12 months of DAPT for a composite end point of cardiovascular and bleeding events in patients with ACS.

Design, setting, and participants: This multicenter, open-label, randomized clinical trial enrolled 4169 patients with ACS who underwent successful PCI using cobalt-chromium everolimus-eluting stents at 96 centers in Japan from December 2015 through June 2020. These data were analyzed from June to July 2021.

Interventions: Patients were randomized either to 1 to 2 months of DAPT followed by clopidogrel monotherapy (n = 2078) or to 12 months of DAPT with aspirin and clopidogrel (n = 2091).

Main outcomes and measures: The primary end point was a composite of cardiovascular (cardiovascular death, myocardial infarction [MI], any stroke, or definite stent thrombosis) or bleeding (Thrombolysis in MI major or minor bleeding) events at 12 months, with a noninferiority margin of 50% on the hazard ratio (HR) scale. The major secondary end points were cardiovascular and bleeding components of the primary end point.

Results: Among 4169 randomized patients, 33 withdrew consent. Of the 4136 included patients, the mean (SD) age was 66.8 (11.9) years, and 856 (21%) were women, 2324 (56%) had ST-segment elevation MI, and 826 (20%) had non-ST-segment elevation MI. A total of 4107 patients (99.3%) completed the 1-year follow-up in June 2021. One to 2 months of DAPT was not noninferior to 12 months of DAPT for the primary end point, which occurred in 65 of 2058 patients (3.2%) in the 1- to 2-month DAPT group and in 58 of 2057 patients (2.8%) in the 12-month DAPT group (absolute difference, 0.37% [95% CI, -0.68% to 1.42%]; HR, 1.14 [95% CI, 0.80-1.62]; P for noninferiority = .06). The major secondary cardiovascular end point occurred in 56 patients (2.8%) in the 1- to 2-month DAPT group and in 38 patients (1.9%) in the 12-month DAPT group (absolute difference, 0.90% [95% CI, -0.02% to 1.82%]; HR, 1.50 [95% CI, 0.99-2.26]). The major secondary bleeding end point occurred in 11 patients (0.5%) in the 1- to 2-month DAPT group and 24 patients (1.2%) in the 12-month DAPT group (absolute difference, -0.63% [95% CI, -1.20% to -0.06%]; HR, 0.46 [95% CI, 0.23-0.94]).

Conclusions and relevance: In patients with ACS with successful PCI, clopidogrel monotherapy after 1 to 2 months of DAPT failed to attest noninferiority to standard 12 months of DAPT for the net clinical benefit with a numerical increase in cardiovascular events despite reduction in bleeding events. The directionally different efficacy and safety outcomes indicate the need for further clinical trials.

Trial registration: ClinicalTrials.gov Identifiers: NCT02619760 and NCT03462498.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Hirotoshi Watanabe reports personal fees from Abbott Medical Japan during the conduct of the study as well as personal fees from Daiichi Sankyo, Kowa, Abiomed, Bayer, Pfizer, Bristol-Myers Squibb, and Otsuka outside the submitted work. Dr Morimoto reports lecturer’s fees from Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Kyocera, Novartis, and Toray; manuscript fees from Bristol-Myers Squibb and Kowa; and is on the advisory board for Sanofi. Dr Natsuaki reports honoraria from Abbott Medical Japan. Dr Ogita reports personal fees from Daiichi Sankyo, Abbott Medical Japan, and Japan Lifeline outside the submitted work. Dr Suwa reports personal fees from Abbott Medical Japan and Daiichi Sankyo outside the submitted work. Dr Suzuki reports grants from Abbott Medical Japan during the conduct of the study. Dr Tanabe reports personal fees from Abbott Medical Japan, Boston Scientific, Terumo, Japan Lifeline, Sanofi, Daiichi Sankyo, and AstraZeneca outside the submitted work. Dr Ikari reports grants from Asahi Intech, Abbott Medical Japan, Daiichi Sankyo, Boston Scientific, and Otsuka Pharmaceutical; and personal fees from Terumo, AstraZeneca, Ono Pharmaceutical, Amgen, Bayer, and Medtronic outside the submitted work. Dr Morino reports personal fees from Abbott Medical Japan and Daiichi Sankyo during the conduct of the study; and grants from Boston Scientific, Terumo, Japan Lifeline, and personal fees from Daiichi Sankyo outside the submitted work. Dr Furukawa reports personal fees from Bayer, Daiichi Sankyo, and Sanofi outside the submitted work. Dr Nakagawa reports grants from Abbott Medical Japan and is an advisory board member of Abbott Medical Japan during the conduct of the study. Dr Kimura reports grants from Abbott Medical Japan and Boston Scientific and being an advisory board member of Abbott Medical Japan and Terumo Japan. No other disclosures were reported.

Figures

Figure 1.. Study Flowchart

In the Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt-Chromium Stent-2 (STOPDAPT-2) trial, 1161 patients with acute coronary syndrome (ACS) were enrolled and randomized at 75 centers in Japan from December 2015 to December 2017, while in the STOPDAPT-2 ACS trial, 3008 patients with ACS were enrolled and randomized at 74 centers in Japan from March 2018 to June 2020. Substantial proportions of the eligible patients were not enrolled in the study mainly by the judgment of the attending physicians or by the patients’ refusal. Excluding 33 patients who withdrew consent, 4136 patients were included in the intention-to-treat population, 2058 patients in the 1- to 2-month dual antiplatelet therapy group (DAPT) and 2078 patients in the 12-month DAPT group. Randomization was performed at a median (IQR) of 5 (2-9) days after the index percutaneous coronary intervention. CoCr-EES indicates cobalt-chromium everolimus-eluting stent and DES indicates drug-eluting stent.

Figure 2.. Time-to-Event Curves for the Primary and Secondary End Points

Time-to-event curves during 1 year after index percutaneous coronary intervention (PCI) for the primary end point (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, any stroke, or Thrombolysis in Myocardial Infarction major/minor bleeding) (A), the major secondary cardiovascular end point (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or any stroke) (B),the major secondary bleeding end point (Thrombolysis in Myocardial Infarction major or minor bleeding) (C), and definite or probable stent thrombosis (D). DAPT indicates dual antiplatelet therapy.

Figure 3.. Subgroup Analysis by Study Cohorts for Primary and Major Secondary End Points

The subgroup analysis of the effect of 1 to 2 months of dual antiplatelet therapy (DAPT) relative to 12 months of dual antiplatelet therapy for the primary and major secondary end points in the 1148 patients with acute coronary syndrome enrolled in the Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt-Chromium Stent-2 (STOPDAPT-2) trial and the additional 2988 patients enrolled in the Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt-Chromium Stent-2 trial. CV indicates cardiovascular; HR, hazard ratio.