Abstract
IMPORTANCE: Evidence on the bleeding risk associated with low-density lipoprotein cholesterol (LDL-C) levels in patients receiving dual antiplatelet therapy (DAPT) remains sparse. OBJECTIVE: To investigate the association of LDL-C levels with bleeding risk in patients with minor ischemic stroke (MIS) or high-risk transient ischemic attack (HRTIA) receiving DAPT. DESIGN, SETTING, AND PARTICIPANTS: This cohort study was an analysis of pooled data from 2 randomized, double-blind, placebo-controlled clinical trials in China of patients with MIS or HRTIA who were receiving DAPT: the CHANCE (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) trial enrolled patients at 114 sites from October 2009 to July 2012, and the CHANCE-2 enrolled patients at 202 centers from September 2019 to March 2021. Both sets of patients were followed up for 90 days. Data analysis was performed from August 2022 to May 2023. EXPOSURES: Baseline LDL-C levels and receipt of ticagrelor-aspirin and clopidogrel-aspirin DAPT. MAIN OUTCOMES AND MEASURES: The primary outcome was any bleeding, and the secondary outcome was severe or moderate bleeding within 3 months after randomization. The association of LDL-C levels and all outcomes was assessed by using the Cox proportional hazard model. Hazard ratios (HRs) with 95% CIs were calculated on univariable (unadjusted) Cox regression models. Adjusted HRs (aHRs) and their 95% CIs were calculated on multivariable Cox regression models. RESULTS: In total, 8996 patients with acute MIS or HRTIA who were receiving DAPT were included in the 2 trials, of whom 1066 without serum specimens and 490 patients with missing baseline LDL-C value were excluded. Finally, 7440 patients with DAPT (4486 in the clopidogrel-aspirin group and 2954 in the ticagrelor-aspirin group) were included in this study. The median (IQR) age was 64.32 (56.56-71.30) years, and 2479 patients (33.32%) were women. A total of 270 (3.63%) bleeding events were reported at 3 months, and LDL-C less than 70 mg/dL was associated with an increased risk of both any bleeding (aHR, 1.48; 95% CI, 1.03-2.12), and severe or moderate bleeding (aHR, 2.78; 95% CI, 1.18-6.53). The risk of any bleeding was increased at lower LDL-C levels in the ticagrelor-aspirin group (aHR, 1.71; 95% CI, 1.08-2.72). However, an increased risk of any bleeding was not observed in the clopidogrel-aspirin group (aHR, 1.30; 95% CI, 0.73-2.30). There was no significant association between LDL-C levels and the risk of severe or moderate bleeding in either the ticagrelor-aspirin or clopidogrel-aspirin group. CONCLUSIONS AND RELEVANCE: These findings suggest that low LDL-C levels are associated with an increased bleeding risk within 3 months among patients with MIS or HRTIA receiving DAPT, especially those taking ticagrelor-aspirin. Weighing the risks and benefits is crucial when simultaneously considering the selection of LDL-C target strategies and DAPT regimens among these patients.