By Jeffrey Zimmet, MD, PhD
Synopsis: In this study of acute coronary syndrome (ACS) patients, one month of dual antiplatelet therapy (DAPT) followed by reduced-dose prasugrel monotherapy led to a reduction in major bleeding events compared to 12 months of DAPT, without a corresponding increase in ischemic events.
Source: 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; May 21. doi: 10.4244/EIJ-D-25-00331. [Online ahead of print].
Current U.S. guidelines recommend 12 months of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). This recommendation is independent of the antiplatelet agents used and patient characteristics. Multiple trials have tested strategies involving early conversion to single antiplatelet therapy with P2Y12 inhibitors alone (dropping aspirin) or with de-escalation of the specific P2Y12 agent, based on the principle that balancing ischemic and bleeding risks over time is beneficial. The 4D-ACS trial takes this concept one step further by testing both early discontinuation of aspirin and de-escalation of dose using the potent thienopyridine prasugrel.
For this trial, 656 patients were enrolled at three tertiary care centers in South Korea. All patients carried a diagnosis of acute coronary syndrome, with 37% of patients classified as unstable angina, 33% of patients classified as ST-elevation myocardial infarction (STEMI), and 30% of patients classified as non-STEMI. All patients received the usual DAPT for one month with aspirin 100 mg and standard-dose prasugrel (10 mg for most patients, 5 mg for patients 75 years of age and older or with weight < 60 kg). At the one-month mark, the short DAPT group continued on prasugrel monotherapy with a reduced dose of prasugrel (5 mg), while the standard therapy arm remained on DAPT with aspirin 100 mg daily and prasugrel 5 mg. Enrolled patients averaged 61 years of age, 83% were male, and 32% had diabetes. Approximately one-quarter were taking proton pump inhibitors.
At 12 months, the primary outcome of net adverse clinical events — a composite of death, MI, stroke, ischemia-driven revascularization, and severe bleeding — occurred in 4.9% of the short DAPT group compared with 8.8% of the 12-month DAPT group, meeting criteria for both noninferiority and superiority. This outcome was driven primarily by an 87% relative risk reduction in major bleeding in the one-month DAPT group (4.6% vs. 0.6%; hazard ratio [HR], 0.13; 95% confidence interval [CI], 0.03-0.58; P = 0.007).
All categories of bleeding were lower in the short DAPT group, but the most frequent type was overt bleeding with a hemoglobin drop ≥ 5 g/dL, cardiac tamponade, bleeding requiring surgical intervention, or necessitating intravenous pressors, which occurred in 0.3% of one-month DAPT patients and in 3% of 12-month DAPT patients (P = 0.027). Other components of the primary endpoint were not significantly different between groups, including all-cause death, MI, ischemia-driven revascularization, or stroke. There were no cases of stent thrombosis in any patient during follow-up. Although the study size was relatively small, subgroup analysis showed the treatment effect of one-month DAPT followed by reduced-dose prasugrel monotherapy was consistent across all ACS subtypes, including STEMI, non-STEMI, and unstable angina.
The authors concluded that, among ACS patients treated with PCI, a strategy of one month of DAPT followed by reduced-dose prasugrel monotherapy resulted in a significant reduction in major bleeding events without an increase in ischemic outcomes.
Commentary
DAPT remains a cornerstone of post-PCI therapy. In ACS, the more-potent agents prasugrel and ticagrelor outperform clopidogrel regarding ischemic events. Multiple observers have noted that the advantages of intensive antiplatelet therapy likely are limited to the early phase after ACS and PCI, with longer periods of treatment being associated with more bleeding without clear benefit.
Strategies to reduce bleeding in the maintenance phase generally have followed one of three patterns: drop aspirin early and continue P2Y12 monotherapy, keep DAPT but change from potent P2Y12 inhibitors to clopidogrel, or reduce the dose of the P2Y12 inhibitor. Generally speaking, each of these three strategies has been effective at reducing significant bleeding after an initial period of one to three months of DAPT.
Notably, early de-escalation to clopidogrel monotherapy failed in the STOPDAPT-2 ACS trial, while STOPDAPT-3 showed that an aspirin-free strategy with prasugrel without any period of DAPT carried significantly increased risks for cardiovascular events, including stent thrombosis.
The current trial adds significantly to the body of knowledge already available by demonstrating improved outcomes with prasugrel-based regimens by both dropping aspirin and reducing the prasugrel dose at one month post-ACS.
Prasugrel dose reduction alone may have a benefit in lessening bleeding, and, indeed, a 3.75 mg dose of this drug is widely used for maintenance in other countries, including Japan and South Korea. The 5-mg dose is available in the United States, but its use to date has been limited. Low uptake of prasugrel in general in the United States may be the result, in part, of the black box warning that was released along with prasugrel’s initial approval, cautioning against use in all patients older than age 75 years, of low body weight, or with any history of stroke or transient ischemic attack.
Time will tell whether guidelines ultimately will incorporate the findings of this trial, along with others, including TWILIGHT, TOPIC, and HOST-REDUCE-POLYTECH-ACS. For now, strong consideration should be given to one of these early de-escalation strategies at least in high-bleeding-risk patients.
Jeffrey Zimmet, MD, PhD, is Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center.
In this study of acute coronary syndrome (ACS) patients, one month of dual antiplatelet therapy (DAPT) followed by reduced-dose prasugrel monotherapy led to a reduction in major bleeding events compared to 12 months of DAPT, without a corresponding increase in ischemic events.
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