Seeking for the boundaries of de-escalation in antiplatelet therapy for acute coronary syndrome

De-escalation strategies of antiplatelet therapy have been shown to improve outcomes in patients with acute coronary syndrome (ACS).¹ However, not all de-escalation strategies are equivalent, and some may compromise ischaemic protection compared with a standard dual antiplatelet therapy (DAPT) (Figure 1).¹ Specifically, discontinuing the DAPT after 1–3 months in favour of aspirin or clopidogrel monotherapy reduces bleeding but increases ischaemic risk, whereas maintaining ticagrelor monotherapy lowers major bleeding while preserving ischaemic protection.^2,3 Unguided de-escalation after 1–3 months, either by switching from ticagrelor or prasugrel to clopidogrel or by dose reduction (from prasugrel 10 to 5 mg o.d. or from ticagrelor 90 to 60 mg b.i.d.), has also shown encouraging results but is supported by weaker evidence. However, because these strategies are typically implemented only after 1–3 months of the standard DAPT, they fail to mitigate bleeding during the early post-ACS period, when both ischaemic and bleeding risks are highest. At variance, guided de-escalation, which is backed by evidence and endorsed in consensus documents, though not in guidelines, may be initiated immediately after ACS, offering potential benefit from the earliest weeks compared with the standard DAPT (Figure 1).⁴ However, its implementation is currently hindered by the limited availability of platelet function or genetic testing.⁴

Figure 1.

Antiplatelet de-escalation strategies in patients with acute coronary syndromes. DAPT, dual antiplatelet therapy; P2Y₁₂ i, P2Y₁₂ inhibitor; ESC, European Society of Cardiology. Red box and * indicate de-escalation strategies to be implemented at the time of acute coronary syndrome.

The European Society of Cardiology Congress unveiled the first large-scale trial exploring a de-escalation strategy of immediate aspirin withdrawal, with potent P2Y₁₂ inhibitor monotherapy started within the first 4 days of hospitalization after successful percutaneous coronary intervention in ACS. The Percutaneous Coronary Intervention Followed by Monotherapy Instead of Dual Antiplatelet Therapy in the Setting of Acute Coronary Syndromes (NEO-MINDSET) trial randomized 3410 patients with ACS [62.1% with ST-segment elevation myocardial infarction (MI)] to stop treatment with aspirin and receive potent P2Y₁₂ inhibitor monotherapy with prasugrel (69.6%) or ticagrelor (28%) or to receive the standard DAPT for 12 months.⁵ P2Y₁₂ inhibitor monotherapy failed to demonstrate noninferiority to the DAPT for the primary endpoint of death, MI, stroke, or urgent target-vessel revascularization at 12 months.⁵ There was an absolute difference in risk of 1.47 percentage points [95% confidence interval (CI), −0.16 to 3.10], which did not meet the prespecified criteria for noninferiority (P = 0.10). Notably, Kaplan–Meier curves diverged within the first month after ACS, and there were numerically higher rates of secondary ischaemic events, including MI and cardiovascular death, in the monotherapy arm.⁵ At the same time, the primary composite endpoint did not significantly differ in the two study arms, which makes the interpretation of the study results not unequivocal. The incidence of major or clinically relevant nonmajor bleeding was 2.0% in the monotherapy group and 4.9% in the DAPT group [hazards ratio (HR) 0.40; 95% CI, 0.26–0.59], for a difference in risk of −2.97 percentage points (95% CI, −4.20 to −1.73). Net adverse clinical events occurred in 8.5% in the monotherapy group and 9.9% in the DAPT group (HR 0.86; 95% CI, 0.69–1.08).

These results emphasize once more that no single antiplatelet regimen fits all patients; therapy should be individualized, accounting for factors such as ischaemic and bleeding risks, as well as drug responsiveness, ethnicity, and sex, and adjusted dynamically over time.^6,7

Data availability

Data availability is not applicable to this article as no new data were created or analyzed in this study.