Comparative effectiveness and safety of dual antiplatelet therapy with ticagrelor vs. clopidogrel in older adults with acute coronary syndrome: A population-based study using the target trial framework.

Background: Optimal P2Y12 receptor inhibition in association with aspirin as dual antiplatelet therapy (DAPT) in older adults (≥75 years) with acute coronary syndrome (ACS) is still controversial. While the POPular Age trial found fewer major/minor bleeding events for clopidogrel vs. ticagrelor, the PLATO subgroup analysis showed similar major bleeding events in both groups.

Objectives: To assess the comparative effectiveness and safety of DAPT with ticagrelor vs. clopidogrel (P2Y12 inhibitors) in older adults with ACS.

Methods: The target trial emulation framework was used to design and analyze this observational study. We performed an active-comparator new-user cohort study using data from the Stockholm CREAtinine Measurements (SCREAM) project between 2011-2021. SCREAM contains healthcare information of all residents in Stockholm region, including demographics, diagnoses from inpatient and outpatient care, pharmacy dispensations, and laboratory tests. We included older adults who initiated DAPT with ticagrelor vs. clopidogrel within 14 days from hospital discharge. The primary effectiveness outcome was major adverse cardiovascular events (MACE; composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke). The primary safety outcome was major bleeding (hemorrhagic stroke, gastrointestinal bleeding, or other bleeding). Patients were followed for 12 months. Inverse probability of treatment weighting was used to adjust for 50 baseline confounders, including demographics, comorbidities, co-medications, laboratory measurements, and healthcare use. Weighted Cox proportional hazards regression was used to estimate intention-to-treat hazard ratios (HRs) with 95% confidence intervals (CIs), and the weighted Aalen-Johansen estimator was used to estimate absolute risks (AR).

Results: Of 5,858 older adults, 47% initiated DAPT with ticagrelor and 53% with clopidogrel. Their median age was 81 years (interquartile range 77 to 86 years) and 43% were women. After weighting, all confounders were balanced, with standardized mean differences < 0.10. Ticagrelor was associated with a lower 1-year AR of MACE than clopidogrel (11.7% vs. 16.4%), corresponding to an AR difference of -4.7% (95% CI -7.4 to -1.4). The adjusted HR for ticagrelor vs. clopidogrel was 0.69 (95% CI 0.54-0.90). There was no difference in the risk of major bleeding between the two groups (HR 0.90 (95% CI 0.60-1.35)), with a similar 1-year AR of major bleeding between ticagrelor (4.6%) and clopidogrel (5.0%).

Conclusions: In older adults (≥75 years), DAPT initiation with ticagrelor was associated with a lower risk of MACE than clopidogrel and no differences in major bleeding risks, although confidence intervals were wide.