The 4D-ACS (The effect of DAPT [dual antiplatelet therapy] in Dosage and Duration on cardiovascular events and bleeding after implantation of DCS [drug coated stent] in ACS patients) trial was a multicenter, randomized, open-label, noninferiority study (noninferiority margin 2%; one-sided α = 0.025) that compared two antiplatelet strategies in patients with either acute coronary syndrome (ACS) or unstable angina who were treated with a polymer-free biolimus-coated stent.¹ The trial investigators found that an ultrashort dual antiplatelet therapy (DAPT) regimen followed by reduced-dose (5 mg) prasugrel monotherapy significantly lowers bleeding risk without compromising ischemic safety in patients with ACS receiving polymer-free drug-coated stents.

The trial investigators enrolled 656 patients (mean age 60.9 ± 9.7 years; 82.6% male) across three South Korean tertiary centers, randomly assigning 328 individuals to each arm. Patients in the experimental arm received prasugrel-based DAPT consisting of aspirin 100 mg plus prasugrel 10 mg (or 5 mg for patients ≥75 years of age or <60 kg) for 1 month, followed by prasugrel 5 mg monotherapy through 12 months. Patients in the control arm received conventional 12-month DAPT with aspirin plus prasugrel 5 mg. The primary endpoint was net adverse clinical events (NACE) at 12 months, defined as the composite of all-cause death, nonfatal myocardial infarction (MI), stroke, ischemia-driven target-vessel revascularization (TVR), and Bleeding Academic Research Consortium (BARC) type 2-5 bleeding. Secondary endpoints included the individual ischemic and bleeding components.

At 12 months, NACE occurred in 4.9% of patients in the 1-month DAPT group and in 8.8% of patients in the 12-month DAPT group (absolute difference -3.9%; 95% confidence interval, -6.7% to -0.2%; p_{noninferiority} = 0.014; hazard ratio [HR], 0.51 [0.27-0.95]; p_superiority = 0.034). The rate of major bleeding (BARC type 3-5) was significantly lower with the shortened regimen (0.6% vs. 4.6%; HR, 0.13 [0.03-0.58]; p = 0.007). A landmark analysis beyond 30 days confirmed a sustained reduction in NACE (1.9% vs. 7.1%; HR, 0.27 [0.11-0.66]; p = 0.004). Rates of ischemic outcomes were comparable between arms.

The strategy used in this study synergizes two validated concepts—ultrashort DAPT and pharmacological de-escalation—and built on prior trials such as the STOPDAPT-2 (Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt-Chromium Stent-2) and HOST-REDUCE-POLYTECH-ACS (Harmonizing Optimal Strategy for Treatment of coronary artery diseases-comparison of REDUCtion of prasugrEl dose or POLYmer TECHnology in ACS patients) trials.^2,3 In the STOPDAPT-2 trial, participants were randomized to 1 month of DAPT followed by clopidogrel monotherapy or to 12 months of DAPT with aspirin and clopidogrel; the trial met both noninferiority and superiority for the composite of cardiovascular and bleeding events in the abbreviated arm.² The HOST-REDUCE-POLYTECH-ACS trial data showed that de-escalation to prasugrel 5 mg after 1 month of prasugrel 10 mg reduced bleeding without increasing ischemic events.³ In East Asian persons, for whom clopidogrel resistance and bleeding risk are pronounced, prasugrel de-escalation may offer particular advantages.

Limitations of this trial included:

1. The low incidence of individual ischemic events limited the statistical power to detect differences in MI, stroke, or TVR.
2. There was limited inclusion of older adults (≥75 years of age), limiting insights into this high-risk subgroup.
3. The trial was conducted exclusively in East Asian centers with polymer-free drug-coated stents; the results may not extrapolate to other stent platforms or to non–East Asian populations.

References

1. Jang Y, Park SD, Lee JP, et al. One-month dual antiplatelet therapy followed by prasugrel monotherapy at a reduced dose: the 4D-ACS randomised trial. EuroIntervention. 2025;21(14):e796-e809. Published 2025 Jul 21. doi:10.4244/EIJ-D-25-00331
2. 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(24):2414-2427. doi:10.1001/jama.2019.8145
3. Kim HS, Kang J, Hwang D, et al. Prasugrel-based de-escalation of dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (HOST-REDUCE-POLYTECH-ACS): an open-label, multicentre, non-inferiority randomised trial. Lancet. 2020;396(10257):1079-1089. doi:10.1016/S0140-6736(20)31791-8