The Limits of Shortened Antiplatelet Therapy in Acute Coronary Syndrome
By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
SYNOPSIS: One month of dual antiplatelet therapy (DAPT) followed by clopidogrel monotherapy did not meet criteria for noninferiority vs.12 months of DAPT for a composite endpoint of ischemic and bleeding events.
SOURCE: Watanabe H. STOPDAPT-2 ACS: One-month dual antiplatelet therapy followed by clopidogrel monotherapy in acute coronary syndrome. Presented at European Society of Cardiology Annual Congress, Aug. 30, 2021.
The authors of the original STOPDAPT-2 trial, published in 2019, investigated the use of one month of dual antiplatelet therapy (DAPT) followed by clopidogrel monotherapy in more than 3,000 patients with a mix of acute coronary syndrome (ACS) and stable presentations. That trial demonstrated a significantly lower rate of the composite of bleeding and cardiovascular events with shortened DAPT vs. 12 months of dual therapy.1 Other trials, including TWILIGHT and the recently presented MASTER DAPT, have similarly suggested shortened DAPT could reduce bleeding with no apparent cost in terms of ischemic events.2,3
STOPDAPT-2 ACS was designed to test the short DAPT hypothesis in ACS patients specifically. Researchers recruited 3,008 patients from multiple centers in Japan. An additional 1,161 patients came from the ACS subgroup of the STOPDAPT-2 trial, for a total of 4,169 patients. Among the ACS patients enrolled, ST-elevation myocardial infarction (MI) patients represented 56% of the total. Subjects were randomized 1:1 to receive either one month of DAPT followed by clopidogrel alone or standard duration 12 months of DAPT. The aspirin dose was 100 mg per day. All patients had undergone PCI with a cobalt chromium alloy everolimus-eluting stent. Importantly, enrolled subjects were not high bleeding risk. Patients requiring oral anticoagulants were specifically excluded, as were those with any history of intracranial hemorrhage or serious in-hospital bleeding.
In the composite primary endpoint of cardiovascular death, MI, stroke, stent thrombosis, and thrombosis in MI major and minor bleeding, the short DAPT group failed to meet the defined criteria for non-inferiority. Overall event rates were relatively low: 3.2% in the one-month DAPT group and 2.83% in the 12-month group, which was not statistically different (HR, 1.15; 95% CI, 0.80-1.62). Although short DAPT resulted in lower rates of bleeding (0.54% vs. 1.17%; HR, 0.46; 95% CI, 0.23-0.94), this was achieved at a cost of a significant increase in MI (1.59% vs. 0.85%; HR, 1.91; 95% CI, 1.06-3.44). The composite ischemic endpoint of cardiovascular death, MI, stroke, and stent thrombosis trended toward benefit in the standard 12-month DAPT arm (2.8% vs. 1.9%; HR, 1.50; 95% CI, 0.99-2.26).
When he presented the findings at the European Society of Cardiology Annual Congress in August, Hirotoshi Watanabe, MD, said the results were inconclusive for the benefit of one-month DAPT vs. 12 months DAPT in ACS patients.
This is an interesting trial that contributes significantly to the body of knowledge concerning the optimal type and duration of antiplatelet therapy after PCI. Comparing this trial with its direct predecessor, STOPDAPT-2, the primary lesson appears to be ACS subjects are substantially different from stable angina patients in terms of their ischemic risk over time from the event. One prior trial from 2018, SMART-DATE, similarly demonstrated a higher MI rate with six months vs. 12 months of DAPT in ACS patients, using clopidogrel as the predominant P2Y12 agent.4
STOPDAPT-2 ACS was not a high bleeding risk trial. In fact, large subsets of patients at elevated bleeding risk were specifically excluded. Short DAPT led to many fewer bleeding events, but this did not counterbalance the higher risk of MI in the composite endpoint. The balance of bleeding and ischemic risk might trend differently in a high bleeding risk population.
Another point worth noting is the choice of clopidogrel as the P2Y12 monotherapy agent. One might infer from this trial that 12 months of DAPT should remain the standard of care for ACS patients. This is true when clopidogrel is involved. But STOPDAPT-2 was performed in Japan, where there is a higher prevalence of clopidogrel resistance genotype, and clopidogrel resistance was not assessed. Other trials, such as TWILIGHT, have demonstrated fewer bleeding episodes and noninferior ischemic outcomes using shortened DAPT with ticagrelor monotherapy. More potent and predictable P2Y12 inhibitors might show different outcomes vs. clopidogrel. However, this has not been tested in an ACS population like this one.
- 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;321:2414-2427.
- Mehran R, Baber U, Sharma SK, et al. Ticagrelor with or without aspirin in high-risk patients after PCI. N Engl J Med 2019;381:2032-2042.
- Valgimigli M, Frigoli E, Heg D, et al. Dual antiplatelet therapy after PCI in patients at high bleeding risk. N Engl J Med 2021; Aug 28. doi: 10.1056/NEJMoa2108749. [Online ahead of print].
- Hahn JY, Song YB, Oh JH, et al. 6-month versus 12-month or longer dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (SMART-DATE): A randomised, open-label, non-inferiority trial. Lancet 2018;391:1274-1284.
One month of dual antiplatelet therapy (DAPT) followed by clopidogrel monotherapy did not meet criteria for noninferiority vs.12 months of DAPT for a composite endpoint of ischemic and bleeding events.
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