What Is the Most Appropriate Antiplatelet De-Escalation Strategy in ACS?

De-escalation of dual antiplatelet therapy (DAPT) may be the most effective acute coronary syndrome (ACS) treatment strategy, with fewer recorded bleeding events and no increase in ischemic events, according to research results published in the Journal of the American College of Cardiology.

In a systematic review and network meta-analysis, researchers evaluated randomized controlled trials to compare the efficacy and safety of DAPT strategies—including de-escalation—in patients with ACS.

Primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, and stroke. If these data were not available, the primary outcome was composites of all-cause death, myocardial infarction, and stroke; all-cause death and myocardial infarction; or cardiovascular death, myocardial infarction, stroke, and stent thrombosis.

Primary bleeding outcome was the combination of major or minor bleeding, defined as thrombolysis in myocardial infarction (TIMI) major or minor bleeding. The secondary safety outcome was major bleeding, defined as TIMI major bleeding, Bleeding Academic Research Consortium (BARC) grade ≥3 bleeding, or Platelet Inhibition and Patient Outcomes (PLATO) major bleeding.

Researchers retrieved 2250 studies, of which 15 randomized controlled trials (n=55,798) met all eligibility criteria and were included. Median follow-up period of these studies was 12 months.

Two trials compared standard-dose prasugrel vs clopidogrel (TRITON-TIMI 38 and TRILOGY-ACS). Three compared low-dose prasugrel vs clopidogrel (TRILOGY-ACS and PRASFIT-ACS), and 2 compared standard-dose prasugrel vs ticagrelor [PRAGUE-18 and ISAR-REACT5]. Six compared ticagrelor vs clopidogrel, 2 compared DAPT de-escalation vs standard dose prasugrel, and 1 compared DAPT de-escalation with ticagrelor.

A low dose of prasugrel was defined as a reduced dose—3.75 mg or 5 mg once-daily maintenance dose—compared with the standard dose of 10 mg once daily.

Most studies utilized composite of cardiovascular death, myocardial infarction, and stroke as the primary efficacy outcome; however, 2 trials used a composite of all-cause death, myocardial infarction, and stroke. Most used TIMI major or minor bleeding as the primary bleeding outcome.

No significant differences were noted between the 5 DAPT strategies in terms of the primary efficacy outcomes, nor were there significant differences in the risk of all-cause death.

De-escalation of DAPT was associated with reduced cardiovascular death compared with other treatments (hazard ratio [HR], 0.24 vs clopidogrel; HR, 0.29 vs ticagrelor; HR, 0.27 vs standard-dose prasugrel; HR, 0.26 vs low-dose prasugrel). Ticagrelor was associated with a significant reduction in cardiovascular death.

Standard dose prasugrel was associated with a significant reduction in myocardial infarction compared with clopidogrel. No significant differences in stroke risk between the 5 DAPT strategies.

Standard- and low-dose prasugrel were both associated with decreased stent thrombosis; standard-dose prasugrel was associated with decreased stent thrombosis vs ticagrelor.

DAPT de-escalation was associated with reduced risk of primary bleeding outcome vs other treatments (HR, 0.48 vs clopidogrel; HR, 0.32 vs ticagrelor; HR, 0.36 vs standard-dose prasugrel, and HR, 0.40 vs low-dose prasugrel). Clopidogrel in particular was associated with a significant reduction in both major and minor bleeding vs ticagrelor (HR, 0.67). Clopidogrel was also associated with a significant reduction in major bleeding vs ticagrelor.

Researchers conducted sensitivity analyses separating de-escalation therapies and found that de-escalation to either clopidogrel or low-dose prasugrel was associated with a reduced risk of the primary bleeding outcome with no increase in the primary efficacy outcome. Results of indirect comparisons showed no statistically significant differences in ischemic or bleeding outcomes associated with de-escalation to clopidogrel and de-escalation to low dose prasugrel.

Results of sensitivity analyses excluding patients without revascularization showed that de-escalation was associated with a reduced risk of primary bleeding outcomes without negatively impacting primary efficacy outcomes (HR, 0.46 vs clopidogrel; HR, 0.31 vs ticagrelor; HR, 0.37 vs standard-dose prasugrel; and HR, 0.33 vs low-dose prasugrel).

Among the 5 DAPT strategies, DAPT de-escalation was ranked as the most effective strategy for preventing all-cause and cardiovascular death. Low-dose prasugrel in particular was the most effective intervention for stroke and stent thrombosis, and prasugrel and clopidogrel were most effective for myocardial infarction and major bleeding.

Study limitations include the evaluation of study-level, not patient-level data, a lack of assessment of de-escalation to monotherapy, and the exclusion of trials that used genotype-guided selection of P2Y12 inhibitors or platelet function testing, among others.

“DAPT combining aspirin and de-escalation from a standard-dose potent P2Y12 inhibitor to clopidogrel or low-dose prasugrel 1 month after [percutaneous coronary intervention] is the most effective treatment strategy,” the researchers concluded. “Our study should be supported by further examination and larger RCTs examining DAPT de-escalation for a definitive conclusion.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Shoji S, Kuno T, Fujisaki T, et al. De-escalation of dual antiplatelet therapy in patients with acute coronary syndromes. J Am Coll Cardiol. Published online July 9, 2021. doi:10.1016/j.jacc.2021.06.012