Major bleeding risk higher with ticagrelor vs clopidogrel in multiethnic ACS patients

For multiethnic Southeast Asian patients with acute coronary syndrome (ACS), bleeding outcomes including BARC type 3 bleeding appear to be less favourable with ticagrelor than with clopidogrel, as shown in a retrospective study from Singapore.

In a propensity-score matched cohort of ACS patients seen across 10 public tertiary healthcare institutions locally, ticagrelor users had a 20-percent higher risk of any clinically relevant bleeding (adjusted hazard ratio [aHR], 1.20, 95 percent confidence interval [CI], 1.02–1.40; p=0.022) compared with clopidogrel users over a median follow-up of 12 months. [JACC Asia 2025;5:1428-1438]

Specifically, ticagrelor use was associated with an increased risk of BARC type 3 (aHR, 1.33, 95 percent CI, 1.04–1.69; p=0.023), urogenital (aHR, 1.60, 95 percent CI, 1.16–2.20; p=0.004), and respiratory/nasal bleeding (aHR, 1.55, 95 percent CI, 1.03–2.33; p=0.036).

“The bleeding curves of ticagrelor and clopidogrel, particularly for any clinically relevant bleeding and BARC type 3 bleeding, diverged as early as 1-month postdischarge and continued to separate up to the 1-year mark,” according to the investigators.

Sensitivity analysis restricted to patients who underwent percutaneous coronary intervention yielded similar results.

“The overall bleeding rates in our study were lower than those reported in the predominantly Caucasian PLATO trial and East Asian studies. This discrepancy could stem from the different bleeding definitions used, as well as the inherent limitation of database studies where events were captured based on diagnosis codes, likely leading to underestimation,” the investigators noted. [N Engl J Med 2009;361:1045-1057; J Cardiovasc Pharmacol 2022;79:5:632-640; Thromb Haemost 2018;118:591-600; J Am Heart Assoc 2019;8:e012078]

“However, the rate of BARC type 3 bleeding was 3 percent in our study, which was comparable to rates reported in East Asians,” they added. [Thromb Haemost 2018;118:591-600; J Am Heart Assoc 2019;8:e012078]

Matched and unadjusted cohorts

The propensity-score matched cohort consisted of 5,387 ticagrelor users and 5,387 clopidogrel users. The average age was 59 years, 30 percent were male, 61 percent were Chinese, 15 percent were Malay, and 15 percent were Indian. The most common comorbidities were hypertension (49 percent) and hyperlipidemia (48 percent). Most patients (98 percent) had no prior bleeding.

Before matching, 14,812 patients met the eligibility criteria, with 8,502 (57 percent) receiving clopidogrel and 6,310 (43 percent) receiving ticagrelor. The overall bleeding rate was 7.4 percent, with a median index event time to bleeding of 3.8 months. The unadjusted bleeding rate was lower with ticagrelor vs clopidogrel (6.6 percent vs 8.1 percent).

“The lower unadjusted bleeding rate in ticagrelor users compared to clopidogrel users in our study reflects clinicians’ cautious selection of clopidogrel in patients with more bleeding risk factors,” the investigators said.

Predictors for bleeding

Risk factors for bleeding included ticagrelor use (vs clopidogrel: odds ratio [OR], 1.19; p=0.020), older age (≥65 years: OR, 1.51; p<0.001), increasing Charlson Comorbidity Index score (1–2 vs 0: OR, 1.33, p=0.008; 3–4: OR, 1.76, p<0.001; ≥5 vs 0: OR, 1.94, p=0.001), hyperlipidemia (OR, 1.26; p=0.014), chronic obstructive pulmonary disorder: OR, 1.95; p<0.001), severe chronic kidney disease (vs no/mild disease: OR, 1.59; p=0.001), anaemia (OR, 1.52; p<0.001), prior bleeding within 6 months (vs no prior bleeding: OR, 1.52; p=0.041), and concurrent oral anticoagulant use (OR, 3.57; p<0.001).

In terms of ethnic groups, the odds of bleeding were significantly lower among Indians relative to the Chinese (OR, 0.71; p=0.001). Additionally, the presence of diabetes mellitus (OR, 0.79; p=0.017) and a history of myocardial infarction (OR, 0.79; p=0.014) appeared to confer a protective effect on bleeding.

“If validated, these novel risk factors for bleeding would refine understanding of interethnic variations in bleeding risk and antiplatelet response, enhancing clinical practice on tailoring antiplatelet treatments for our multiethnic cohort of ACS patients,” the investigators concluded.