Key Points
Question
Are low-density lipoprotein cholesterol (LDL-C) levels associated with bleeding risk in patients with minor ischemic stroke or high-risk transient ischemic attack who are receiving dual antiplatelet therapy?
Findings
In this cohort study of 7440 patients, 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 any bleeding and severe or moderate bleeding, with risk of any bleeding risk increased at lower LDL-C levels in the ticagrelor-aspirin group. However, increased risk of any bleeding was not observed in the clopidogrel-aspirin group, and 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.
Meaning
These findings suggest that low LDL-C levels are associated with an increased bleeding risk within 3 months among patients with minor ischemic stroke or high-risk transient ischemic attack who are receiving dual antiplatelet therapy, especially those taking ticagrelor-aspirin.
This cohort study investigates the association of low-density lipoprotein cholesterol (LDL-C) levels with bleeding risk in patients taking dual antiplatelet therapy (DAPT) after minor ischemic stroke or transient ischemic attack (TIA).
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.
Low-density lipoprotein cholesterol (LDL-C) is independently associated with the risk of ischemic stroke. Both the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study1 and the Treat Stroke to Target study2,3 have demonstrated that lowering LDL-C levels can effectively reduce the risk of ischemic stroke recurrence. As a core focus of preventive therapy, evidence from accumulating clinical trials supports more intensive LDL-C lowering and treatment below lower thresholds, especially for secondary prevention.4 An LDL-C target of 70 mg/dL (to convert LDL-C to millimoles per liter, multiply by 0.0259) has been recommended to reduce the risk of long-term cardiovascular events for patients with ischemic stroke or transient ischemic attack (TIA),5 and an even more strict target value of 55 mg/dL has been recommended for patients with high cardiovascular risk.6,7 Despite the efficacy of low LDL-C levels on reducing the risk of recurrent stroke, some observational studies have found that aggressively lowering LDL-C might contribute to an increased risk of hemorrhagic events, especially hemorrhagic stroke,8,9,10 and the findings of a mendelian randomization study11 even support a possible causal relationship between LDL-C and intracranial hemorrhage (ICH).
In addition, emerging evidence implies that a potential mechanistic link between cholesterol metabolism and platelet responsiveness exist.9,12 For patients with minor ischemic stroke (MIS) or high-risk TIA (HRTIA), dual antiplatelet therapy (DAPT) with the combination of clopidogrel-aspirin13,14 or ticagrelor-aspirin15,16 has been shown to be more effective than aspirin alone for reducing recurrence events. However, the high risk of bleeding event complications due to the concomitant administration of high-intensity antiplatelet medications is a major concern,17 especially for ticagrelor-aspirin.18,19,20 For this patient population, aggressive LDL-C lowering and DAPT are often administered concomitantly, but evidence of bleeding risk associated with LDL-C levels in patients receiving DAPT is still lacking. Therefore, in this study, we sought to address the question about LDL-C levels and bleeding risk in patients taking DAPT after MIS or HRTIA by analyzing pooled individual patient-level data from the CHANCE (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) and CHANCE-2 trials.
Methods
Study Inclusion and Participants
This cohort study extracted and pooled patients’ information from the CHANCE trial and the CHANCE-2 trial and followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. Details about the design and major results of the 2 trials have been previously published.13,16 Characteristics of the 2 trials are shown in eTable 1 in Supplement 1. Briefly, both trials were randomized, double-blind, controlled, multicenter clinical trials of patients with acute MIS (National Institutes of Health Stroke Scale score ≤3) or HRTIA (age, blood pressure, clinical features, duration of TIA, and presence or absence of diabetes score ≥4) within 24 hours of symptom onset. The CHANCE trial enrolled patients at 114 sites in China from October 2009 to July 2012. Participants were randomly assigned to clopidogrel (loading dose of 300 mg followed by 75 mg per day for 3 months) plus aspirin (75 mg per day for the first 21 days) or the placebo plus aspirin (75 mg per day for 3 months). The CHANCE-2 trial enrolled patients at 202 centers in China from September 2019 to March 2021. Participants carrying CYP2C19 loss-of-function alleles were randomly assigned to ticagrelor (loading dose of 180 mg followed by 90 mg twice daily for 3 months) or clopidogrel (loading dose of 300 mg followed by 75 mg per day for 3 months), and both groups received aspirin for the first 21 days. The protocol and data collection were approved by the ethics committee at Beijing Tiantan Hospital and at each participating site. Written informed consent for participation in the trials was provided by the patients or their representatives before entering into the study. The study statisticians (A.X.W. and Q.X.) pooled individual patient level data from the 2 trials using data extracted directly from study databases.
Biochemical Measurements
Venous blood samples were drawn in serum-separation tubes within 48 hours of symptom onset of the CHANCE trial and before randomization of the CHANCE-2 trial, separately. Then the samples were sent for laboratory analysis of LDL-C concentration, which were measured using enzymatic method. For genotyping, in the CHANCE trial, the genetic substudy was prespecified. Genotyping of the 3 single-nucleotide variants for CYP2C19, including rs4244285(*2), rs4986893(*3), and rs12248560(*17), was performed using the MassARRAY iPLEX platform (Sequenom). In the CHANCE-2 trial, a novel point-of-care genetic test platform, the GMEX Point-of-Care Genotyping system,21 was used to identify the CYP2C19 genotypes. Patients with at least 1 loss-of-function allele (*2 or *3) were classified as loss-of-function carriers, those with a single *2 or *3 allele (*1/*2 or *1/*3) were classified as intermediate metabolizers, and those with at 2 or more *2 or *3 alleles (*2/*2, *2/*3, or *3/*3) were classified as poor metabolizers.22
Outcomes Assessment
The primary outcome was any bleeding, and the secondary outcome was severe or moderate bleeding within 3 months after randomization. The bleeding events, in both the CHANCE and CHANCE-2 trials, were defined by means of the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria.23 Severe bleeding was defined as fatal hemorrhage or ICH or other hemorrhage causing hemodynamic compromise that requires blood or fluid replacement, inotropic support, or surgical intervention. Moderate bleeding was defined as bleeding that required transfusion of blood but did not lead to hemodynamic compromise requiring intervention. Other secondary outcomes were net clinical outcomes, defined in 3 forms, including the composite of ischemic stroke recurrence and ICH, ischemic stroke recurrence and severe or moderate bleeding, and ischemic stroke recurrence and any bleeding. All outcomes were confirmed by an independent clinical-event adjudication committee, whose members were blinded to the study group assignments.
Statistical Analysis
Data analysis was performed from August 2022 to May 2023. All analyses adhered to the intention-to-treat principle according to the randomized treatment assignment. To compare the baseline demographic and clinical information, we divided admission LDL-C level into the following 2 categories: less than 70 mg/dL and greater than or equal to 70 mg/dL. Categorical variables are presented as counts and percentages, and continuous variables are presented as medians with IQRs. The χ2 test and nonparametric Wilcoxon test were performed for comparison of categorical variables and continuous variables between groups categorized by LDL-C levels, respectively.
The time to all outcome events of each group was presented by using the Kaplan-Meier curves, and the differences between groups were tested by the log-rank test. The association between LDL-C levels and all outcomes during the 3-month follow-up period were 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. In the first model, we adjusted for age, sex, current smoking, current drinking, history of ischemic stroke, TIA, diabetes, dyslipidemia, hypertension, systolic blood pressure at randomization, randomization group, concomitant lipid-lowering therapy, and glycemic control therapy. In the second model, on the confounding factors of the first model, we added the index trial. The interactions of LDL-C levels with randomized DAPT on the primary and secondary outcomes during the 3-month follow-up period were investigated with the use of univariable and multivariable Cox proportional-hazards models. Prespecified variables included age, sex, body mass index (calculated as weight in kilograms divided by height in meters squared), lipid-lowering therapy, history of smoking, hypertension, and diabetes. All models were adjusted for the same covariates as the first model used for the primary analyses. A 2-sided P < .05 was considered to indicate statistical significance. Statistical analyses were conducted with SAS statistical software version 9.4 (SAS Institute).
Results
Study Participants and Characteristics
In the CHANCE trial, a total of 41 561 patients with stroke or TIA were screened; 5170 patients were enrolled, with 2584 randomly assigned to the clopidogrel-aspirin group, and among them, 1518 consecutive patients with serum specimens who participated in the blood biomarker substudy were included (1066 were excluded for missing serum specimens). In the CHANCE-2 trial, a total of 11 255 patients were screened and genotyped; 6412 patients were enrolled, with 3205 randomly assigned to the ticagrelor-aspirin group and 3207 to the clopidogrel-aspirin group. Among those patients, 251 in the ticagrelor-aspirin group and 239 in the clopidogrel-aspirin group (490 total) with missing baseline LDL-C value were excluded. Finally, by pooling data from the 2 trials, 7440 consecutive patients (median [IQR] age, 64.32 [56.56-71.30] years; 2479 women [33.32%]) taking DAPT were included in this study, of whom 4486 patients were assigned to receive clopidogrel-aspirin and 2954 patients were assigned to receive ticagrelor-aspirin (eFigure 1 in Supplement 1).
Baseline characteristics stratified by baseline LDL-C (<70 mg/dL and ≥70 mg/dL) are summarized in Table 1. Patients with baseline LDL-C less than 70 mg/dL were older, were less likely to be women, were more likely to have lower systolic blood pressure, had a lower proportion of current smoking and drinking, had a higher proportion of risk factors (history of ischemic stroke, TIA, diabetes, dyslipidemia, and hypertension), and were more likely to receive discharge medications (lipid-lowering therapy or glycemic control therapy). No differences in qualifying event, randomization group, National Institutes of Health Stroke Scale score, or age, blood pressure, clinical features, duration of TIA, and presence or absence of diabetes score at admission were observed (Table 1). Baseline characteristics of the patients recruited in the CHANCE and CHANCE-2 trials are summarized in eTable 2 in Supplement 1.
Table 1. Baseline Characteristics of Patients.
| Characteristic | Patients, No. (%) | P value | ||
|---|---|---|---|---|
| Total (N = 7440) | LDL-C <70 mg/dL (n = 756) | LDL-C ≥70 mg/dL (n = 6684) | ||
| Age, median (IQR), y | 64.32 (56.56-71.30) | 65.41 (57.05-72.92) | 64.2 (56.48-71.07) | .006 |
| Sex | ||||
| Women | 2479 (33.32) | 198 (26.19) | 2281 (34.13) | <.001 |
| Men | 4961 (66.68) | 558 (73.81) | 4403 (65.87) | |
| Current smoking | 2526 (33.95) | 232 (30.69) | 2294 (34.32) | .04 |
| Current drinking | 1762 (23.68) | 150 (19.84) | 1612 (24.12) | .009 |
| Body mass index, median (IQR)a | 24.49 (22.6-26.57) | 24.24 (22.49-26.67) | 24.49 (22.66-26.57) | .31 |
| History | ||||
| Ischemic stroke | 1562 (20.99) | 259 (34.26) | 1303 (19.49) | <.001 |
| TIA | 130 (1.75) | 30 (3.97) | 100 (1.5) | <.001 |
| Myocardial infarction | 109 (1.47) | 16 (2.12) | 93 (1.39) | .15 |
| Angina | 217 (2.92) | 23 (3.04) | 194 (2.9) | .82 |
| Diabetes | 1746 (23.47) | 231 (30.56) | 1515 (22.67) | <.001 |
| Dyslipidemia | 729 (9.8) | 164 (21.69) | 565 (8.45) | <.001 |
| Hypertension | 4652 (62.53) | 516 (68.25) | 4136 (61.88) | .001 |
| Systolic blood pressure, median (IQR), mm Hg | 149 (136-162) | 144 (133-159) | 150 (136-163) | <.001 |
| Heart rate, median (IQR), beats/min | 75 (69-80) | 76 (68-80) | 75 (69-80) | .58 |
| Qualifying event | ||||
| Ischemic stroke | 5883 (79.07) | 602 (79.63) | 5281 (79.01) | .74 |
| TIA | 1557 (20.93) | 154 (20.37) | 1403 (20.99) | |
| National Institutes of Health Stroke Scale score at admission, median (IQR) | 2 (1-3) | 2 (1-3) | 2 (1-3) | .91 |
| Age, blood pressure, clinical features, duration of TIA, and presence or absence of diabetes score at admission, median (IQR) | 4 (4-5) | 5 (4-5) | 4 (4-5) | .28 |
| Randomization group | ||||
| Clopidogrel-aspirin | 4486 (60.3) | 455 (60.19) | 4031 (60.31) | .97 |
| Ticagrelor-aspirin | 2954 (39.7) | 301 (39.81) | 2653 (39.69) | |
| Concomitant medication | ||||
| Lipid-lowering therapy | 5538 (77.73) | 588 (80.88) | 4950 (77.37) | .03 |
| Antihypertensive therapy | 3111 (43.66) | 323 (44.43) | 2788 (43.58) | .66 |
| Glycemic control therapy | 1450 (20.35) | 170 (23.38) | 1280 (20.01) | .04 |
Abbreviations: LDL-C, low-density lipoprotein cholesterol; TIA, transient ischemic attack.
SI conversion factor: To convert LDL-C to millimoles per liter, multiply by 0.0259.
Body mass index is calculated as weight in kilograms divided by height in meters squared.
Association of LDL-C Level With Bleeding Events
Among 7440 patients with MIS or TIA who received DAPT, a total of 270 (3.63%) bleeding events were reported at 3 months, of which 5.16% (39 patients) occurred in the LDL-C less than 70 mg/dL group and 3.46% (231 patients) occurred in the LDL-C greater than or equal to 70 mg/dL group. Compared with LDL-C greater than or equal to 70 mg/dL, LDL-C less than 70 mg/dL was associated with an increased risk of bleeding (unadjusted HR, 1.50; 95% CI, 1.07-2.11; P = .02). Among those patients, severe or moderate bleeding, as defined by the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria, occurred in 7 patients (0.93%; 2 patients had ICH) with LDL-C less than 70 mg/dL and in 33 patients (0.49%; 11 patients had ICH) with LDL-C greater than or equal to 70 mg/dL (unadjusted HR, 1.92; 95% CI, 0.85-4.35; P = .12) (Table 2). The Figure shows that most bleeding events occurred within the first 21 days after randomization, which was the period of DAPT for both groups. After adjustment for baseline covariates and the index trials, 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; P = .03) and severe or moderate bleeding (aHR, 2.78; 95% CI, 1.18-6.53; P = .02) (Table 2). We also examined the association between LDL-C level and bleeding risk in 1526 patients who received aspirin alone from the CHANCE trial, and no statistically significant difference was found (eTable 3 in Supplement 1).
Table 2. Risk of Bleeding Events at 3 Months After a Minor Ischemic Stroke or High-Risk Transient Ischemic Attack According to LDL-C Levels.
| Variable | Event rate, No. of events/total No. (%) | HR (95% CI) | P value for adjusted modelb | ||
|---|---|---|---|---|---|
| Crude | Adjusteda | Adjustedb | |||
| Any bleeding | |||||
| LDL-C ≥70 mg/dL | 231/6684 (3.46) | 1 [Reference] | 1 [Reference] | 1 [Reference] | .03 |
| LDL-C <70 mg/dL | 39/756 (5.16) | 1.50 (1.07-2.11) | 1.49 (1.04-2.13) | 1.48 (1.03-2.12) | |
| Severe or moderate bleedingc | |||||
| LDL-C ≥70 mg/dL | 33/6684 (0.49) | 1 [Reference] | 1 [Reference] | 1 [Reference] | .02 |
| LDL-C <70 mg/dL | 7/756 (0.93) | 1.92 (0.85-4.35) | 2.59 (1.11-6.05) | 2.78 (1.18-6.53) | |
| Intracranial hemorrhage | |||||
| LDL-C ≥70 mg/dL | 11/6684 (0.16) | NA | NA | NA | NA |
| LDL-C <70 mg/dL | 2/756 (0.26) | NA | NA | NA | |
Abbreviations: HR, hazard ratio; LDL-C, low-density lipoprotein cholesterol; NA, not applicable.
SI conversion factor: To convert LDL-C to millimoles per liter, multiply by 0.0259.
Adjusted for age, sex, current smoking, current drinking, history of ischemic stroke, transient ischemic attack, diabetes, dyslipidemia, hypertension, systolic blood pressure at randomization, randomization group, concomitant lipid-lowering therapy, and glycemic control therapy.
Adjusted for age, sex, current smoking, current drinking, history of ischemic stroke, transient ischemic attack, diabetes, dyslipidemia, hypertension, systolic blood pressure at randomization, randomization group, concomitant lipid-lowering therapy, glycemic control therapy, and index trial.
Severe or moderate bleeding and mild bleeding were defined according to Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria.
Figure. Cumulative Probability of Bleeding Events by Low-Density Lipoprotein Cholesterol (LDL-C) Levels.
To convert LDL-C to millimoles per liter, multiply by 0.0259.
Sensitivity Analyses
Bleeding events occurred in 158 patients (5.35%) receiving ticagrelor-aspirin and in 112 patients (2.50%) receiving clopidogrel-aspirin within 3 months. In ticagrelor-aspirin group, the rate of any bleeding was higher in patients with LDL-C less than 70 mg/dL compared with LDL-C greater than or equal to 70 mg/dL (aHR, 1.71; 95% CI, 1.08-2.72; P = .02); in the clopidogrel-aspirin group, despite numerical increases in crude incidences for any bleeding in patients with LDL-C less than 70 mg/dL, no statistically significant difference was found compared with those with LDL-C greater than or equal to 70 mg/dL (aHR, 1.30; 95% CI, 0.73-2.30; P = .38) (Table 3). When considering LDL-C as a continuous variable in multivariable Cox analysis, we observed a statistically significant decrease in the risk of bleeding events in the ticagrelor-aspirin group (aHR, 0.79; 95% CI, 0.65-0.96; P = .02) with every 38.6 mg/dL increase in LDL-C, but not in the clopidogrel-aspirin group (aHR, 0.86; 95% CI, 0.70-1.06; P = .16) (eTable 4 in Supplement 1). However, there was no significant association between LDL-C levels and the risk of severe or moderate bleeding in either the ticagrelor-aspirin group (LDL-C <70 mg/dL vs ≥70 mg/dL: aHR, 3.33; 95% CI, 0.56-19.73; P = .19; LDL per 38.6 mg/dL increase: aHR, 1.04; 95% CI, 0.41-2.64; P = .94) or clopidogrel-aspirin group (LDL-C <70 mg/dL vs ≥70 mg/dL: aHR, 2.39; 95% CI, 0.89-6.40; P = .08; LDL per 38.6 mg/dL increase: aHR, 0.81; 95% CI, 0.54-1.22; P = .31) (Table 3 and eTable 4 in Supplement 1).
Table 3. Association of LDL-C Levels and Bleeding Events, Ischemic Stroke Recurrence, and the Net Clinical Outcomes at 3 Months After a Minor Ischemic Stroke or High-Risk Transient Ischemic Attack Stratified by Dual Antiplatelet Therapy Assignment.
| Outcome | Event rate, No. of events/total No. (%) | HR (95% CI) | P value | ||
|---|---|---|---|---|---|
| Crude | Adjusteda | Adjusted | Interaction | ||
| Any bleeding | NA | .59 | |||
| Ticagrelor-aspirin | |||||
| LDL-C ≥70 mg/dL | 134/2653 (5.05) | 1 [Reference] | 1 [Reference] | .02 | NA |
| LDL-C <70 mg/dL | 24/301 (7.97) | 1.62 (1.05-2.49) | 1.71 (1.08-2.72) | ||
| Clopidogrel-aspirin | |||||
| LDL-C ≥70 mg/dL | 97/4031 (2.41) | 1 [Reference] | 1 [Reference] | .38 | NA |
| LDL-C <70 mg/dL | 15/455 (3.30) | 1.37 (0.80-2.36) | 1.30 (0.73-2.30) | ||
| Severe or moderate bleedingb | NA | .56 | |||
| Ticagrelor-aspirin | |||||
| LDL-C ≥70 mg/dL | 7/2653 (0.26) | 1 [Reference] | 1 [Reference] | .19 | NA |
| LDL-C <70 mg/dL | 2/301 (0.66) | 2.53 (0.53-12.16) | 3.33 (0.56-19.73) | ||
| Clopidogrel-aspirin | |||||
| LDL-C ≥70 mg/dL | 26/4031 (0.65) | 1 [Reference] | 1 [Reference] | .08 | NA |
| LDL-C <70 mg/dL | 5/455 (1.10) | 1.75 (0.67-4.56) | 2.39 (0.89-6.40) | ||
| Ischemic stroke recurrence | NA | .01 | |||
| Ticagrelor-aspirin | |||||
| LDL-C ≥70 mg/dL | 160/2653 (6.03) | 1 [Reference] | 1 [Reference] | .18 | NA |
| LDL-C <70 mg/dL | 19/301 (6.31) | 1.04 (0.65-1.67) | 1.67 (0.79-3.53) | ||
| Clopidogrel-aspirin | |||||
| LDL-C ≥70 mg/dL | 307/4031 (7.62) | 1 [Reference] | 1 [Reference] | .15 | NA |
| LDL-C <70 mg/dL | 30/455 (6.59) | 0.86 (0.59-1.25) | 0.62 (0.33-1.18) | ||
| Net clinical outcome, composite of ischemic stroke recurrence and intracranial hemorrhage | NA | .02 | |||
| Ticagrelor-aspirin | |||||
| LDL-C ≥70 mg/dL | 162/2653 (6.11) | 1 [Reference] | 1 [Reference] | .20 | NA |
| LDL-C <70 mg/dL | 19/301 (6.31) | 1.03 (0.64-1.65) | 1.63 (0.77-3.43) | ||
| Clopidogrel-aspirin | |||||
| LDL-C ≥70 mg/dL | 314/4031 (7.79) | 1 [Reference] | 1 [Reference] | .29 | NA |
| LDL-C <70 mg/dL | 32/455 (7.03) | 0.89 (0.62-1.28) | 0.73 (0.40-1.32) | ||
| Net clinical outcome, composite of ischemic stroke recurrence and severe or moderate bleeding | NA | .01 | |||
| Ticagrelor-aspirin | |||||
| LDL-C ≥70 mg/dL | 165/2653 (6.22) | 1 [Reference] | 1 [Reference] | .09 | NA |
| LDL-C <70 mg/dL | 21/301 (6.98) | 1.12 (0.71-1.76) | 1.83 (0.92-3.63) | ||
| Clopidogrel-aspirin | |||||
| LDL-C ≥70 mg/dL | 332/4031 (8.24) | 1 [Reference] | 1 [Reference] | .49 | NA |
| LDL-C <70 mg/dL | 35/455 (7.69) | 0.92 (0.65-1.31) | 0.83 (0.49-1.41) | ||
| Net clinical outcome, composite of ischemic stroke recurrence and any bleeding | NA | .04 | |||
| Ticagrelor-aspirin | |||||
| LDL-C ≥70 mg/dL | 282/2653 (10.63) | 1 [Reference] | 1 [Reference] | .02 | NA |
| LDL-C <70 mg/dL | 40/301 (13.29) | 1.26 (0.91-1.76) | 1.62 (1.08-2.42) | ||
| Clopidogrel-aspirin | |||||
| LDL-C ≥70 mg/dL | 398/4031 (9.87) | 1 [Reference] | 1 [Reference] | .67 | NA |
| LDL-C <70 mg/dL | 44/455 (9.67) | 0.97 (0.71-1.32) | 0.91 (0.60-1.40) | ||
Abbreviations: HR, hazard ratio; LDL-C, low-density lipoprotein cholesterol; NA, not applicable.
SI conversion factor: To convert LDL-C to millimoles per liter, multiply by 0.0259.
Adjusted for age, sex, current smoking, current drinking, history of ischemic stroke, transient ischemic attack, diabetes, dyslipidemia, hypertension, systolic blood pressure at randomization, concomitant lipid-lowering therapy, and glycemic control therapy.
Severe or moderate bleeding and mild bleeding were defined according to Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria.
Compared with patients with LDL-C greater than or equal to 70 mg/dL, those with LDL-C less than 70 mg/dL had increased aHRs for the composite outcome of ischemic stroke recurrence and ICH (aHR, 1.63; 95% CI, 0.77-3.43; P = .20) and the composite outcome of ischemic stroke recurrence and severe or moderate bleeding in the ticagrelor-aspirin group (aHR, 1.83; 95% CI, 0.92-3.63; P = .09), and decreased aHRs in the clopidogrel-aspirin group (ischemic stroke recurrence and ICH, aHR, 0.73; 95% CI, 0.40-1.32; P = .29; ischemic stroke recurrence and severe or moderate bleeding, aHR, 0.83; 95% CI, 0.49-1.41; P = .49), but the differences were not statistically significant. For the composite outcome of ischemic stroke recurrence and any bleeding, patients with LDL-C less than 70 mg/dL in the ticagrelor-aspirin group showed a significantly increased risk (aHR, 1.62; 95% CI, 1.08-2.42; P = .02), whereas no significant association was found in clopidogrel-aspirin group (aHR, 0.91; 95% CI, 0.60-1.40; P = .67). For these 3 composite outcomes, the interaction between DAPT and LDL-C levels was statistically significant (Table 3).
We further observed the association of LDL-C with bleeding risk according to CYP2C19 genotypes in 4364 patients who receiving clopidogrel-aspirin. A total of 3779 patients (86.59%) were classified as CYP2C19 loss-of-function carriers; among them, any bleeding occurred in 15 of 414 patients (3.62%) in the LDL-C less than 70 mg/dL group, compared with 79 of 3365 patients (2.35%) in the LDL-C greater than or equal to 70 mg/dL group (aHR, 1.42; 95% CI, 0.79-2.56; P = .24) within 3 months. Among the 585 noncarriers patients, any bleeding occurred in 14 of 550 patients (2.55%) in the LDL-C greater than or equal to 70 mg/dL group, whereas no bleeding events were reported in the LDL-C less than 70 mg/dL group and no interaction was found between the LDL-C and CYP2C19 genotypes in clopidogrel-aspirin group (P for interaction = .98). LDL-C level was not found to be significantly associated with an increased risk of any bleeding in either intermediate metabolizers (aHR, 1.55; 95% CI, 0.84-2.88; P = .16) or poor metabolizers (aHR, 0.62; 95% CI, 0.08-4.92; P = .65) (Table 4).
Table 4. Association of LDL-C Levels With Any Bleeding at 3 Months in Patients Receiving Clopidogrel-Aspirin Therapy Stratified by CYP2C19 Metabolizer Status.
| CYP2C19 loss-of-function allelea | Event rates, No. of events/total No. (%) | HR (95% CI) | Adjusted P value | |
|---|---|---|---|---|
| Crude | Adjustedb | |||
| Carriers | ||||
| LDL-C ≥70 mg/dL | 79/3365 (2.35) | 1 [Reference] | 1 [Reference] | .24 |
| LDL-C <70 mg/dL | 15/414 (3.62) | 1.53 (0.88-2.66) | 1.42 (0.79-2.56) | |
| Poor | ||||
| LDL-C ≥70 mg/dL | 14/729 (1.92) | 1 [Reference] | 1 [Reference] | .65 |
| LDL-C <70 mg/dL | 1/80 (1.25) | 0.64 (0.08-4.85) | 0.62 (0.08-4.92) | |
| Intermediate | ||||
| LDL-C ≥70 mg/dL | 65/2636 (2.47) | 1 [Reference] | 1 [Reference] | .16 |
| LDL-C <70 mg/dL | 14/334 (4.19) | 1.69 (0.95-3.02) | 1.55 (0.84-2.88) | |
| Noncarriers | ||||
| LDL-C ≥70 mg/dL | 14/550 (2.55) | 1 [Reference] | 1 [Reference] | .99 |
| LDL-C <70 mg/dL | 0/35 (0) | NA | NA | |
Abbreviations: HR, hazard ratio; LDL-C, low-density lipoprotein cholesterol; NA, not applicable.
SI conversion factor: To convert LDL-C to millimoles per liter, multiply by 0.0259.
P for interaction = .98
Models were adjusted for age, sex, current smoking, current drinking, history of ischemic stroke, transient ischemic attack, diabetes, dyslipidemia, hypertension, systolic blood pressure at randomization, concomitant lipid-lowering therapy and glycemic control therapy.
Subgroup Analyses
Interactions between LDL-C levels and the predefined risk factors on any bleeding are shown in eFigure 2 in Supplement 1. LDL-C less than 70 mg/dL was associated with a higher risk of any bleeding in men (aHR, 1.63; 95% CI, 1.07-2.48) than women (aHR, 1.03; 95% CI, 0.49-2.16), in patients with hypertension (aHR, 1.86; 95% CI, 1.23-2.81) than those without hypertension (aHR, 0.81; 95% CI, 0.37-1.77), and in patients without a history of smoking (aHR, 1.69; 95% CI, 1.13-2.54) than those patients with history of smoking (aHR, 0.97; 95% CI, 0.44-2.13).
Discussion
In this cohort study using pooled data from the CHANCE and CHANCE-2 trials, we addressed the association of LDL-C levels with bleeding risk at 3 months among patients with MIS or HRTIA who were receiving DAPT. Our findings showed that lower LDL-C level (<70 mg/dL) was associated with higher bleeding risk under the background of DAPT, especially those taking ticagrelor plus aspirin. However, no similar association was found when examining the risk of severe or moderate bleeding. The bleeding events mainly occurred within the duration of DAPT (the first 21 days).
For patients with MIS or HRTIA, DAPT is associated with decreased risk of recurrent ischemic events but increased risk of bleeding. Several studies have evaluated ways to reduce the risk of bleeding by shortening the duration of DAPT, and a clear net clinical benefit was observed during the first 3 weeks of treatment.24,25 However, the identification of which patients are at increased bleeding risk is also important.
For patients with atherosclerotic cardiovascular disease, antiplatelet and LDL-C lowering are often performed at the same time, and even aggressive LDL-C lowering in addition to DAPT is given in specific clinical scenario, such as acute MIS or HRTIA and patients with acute coronary syndrome who are hospitalized following percutaneous coronary intervention. There is little evidence on the association of LDL-C level with bleeding risk in this specific clinical scenario. Yang and colleagues9 first reported an association between admission serum LDL-C and major in-hospital bleeds in a large Chinese nationwide registry involving 42 378 patients with acute coronary syndrome treated with percutaneous coronary intervention from 2014 to 2019 receiving intensive antithrombotic therapy. A threshold value of LDL-C less than 70 mg/dL for the increased risk for major bleeds was identified in that population. The current study also found that LDL-C less than 70 mg/dL was associated with an increased risk of bleeding. Consistent with the results of previous studies, we found that bleeding events occurred predominantly during the period of DAPT (the first 21 days).24,25 This finding would have important implications that low LDL-C at admission among patients with MIS or TIA may be a factor implicated in the increased susceptibility to bleeding events during the duration of DAPT, especially those taking ticagrelor-aspirin.
Nevertheless, the primary factor influencing clinical decision-making is severe or moderate bleeding and ICH. Our study demonstrated that lower LDL-C levels were associated with higher aHRs of risk of severe or moderate bleeding in both the ticagrelor-aspirin and clopidogrel-aspirin groups, but the findings were not statistically significant. This may be related to the low absolute risk of severe or moderate bleeding (including ICH) in both the CHANCE and CHANCE2 trials. In addition, clinical decision-making also requires balancing the ischemic benefit and bleeding risk. Despite a higher risk of bleeding in the ticagrelor-aspirin group compared with the clopidogrel-aspirin group when LDL level is less than 70 mg/dL, the majority of these bleeding events seem to be nonfatal extracranial bleeds. Further research is warranted to explore the underlying mechanisms and validate these findings in larger and more diverse populations.
In this pooled analysis, the bleeding risks were significantly increased at lower LDL-C levels in the ticagrelor-aspirin group, but not in the clopidogrel-aspirin group, despite a numerical increase in crude incidence of bleeding events. This result may be because ticagrelor does not require metabolic activation for its antiplatelet effect, whereas clopidogrel is a prodrug requiring hepatic conversion into its active metabolite, which is associated with CYP2C19 genetic variants.22 Therefore, ticagrelor may produce greater inhibition of platelet aggregation and higher risk of bleeding than clopidogrel.26 Because 86.59% of patients were CYP2C19 loss-of-function carriers in clopidogrel-aspirin group, the relative impact of clopidogrel would be expected to be weaker. For sensitivity analysis, we further stratified patients by CYP2C19 genotypes in the clopidogrel-aspirin group, and the results remained similar. This may imply that lower LDL-C levels may be tolerated in the clopidogrel-aspirin group than ticagrelor-aspirin. Besides the type of DAPT (ticagrelor or clopidogrel), our study also showed that men, patients without history of smoking, and patients with history of hypertension with lower LDL-C level had higher bleeding risk.
Limitations
We acknowledge several limitations of this study. First, bias may exist because of differences in the trial designs. However, both the CHANCE and CHANCE-2 studies were clinical randomized clinical trials, hosted and implemented by the same team, and the included population was all Chinese, so the bias is relatively small. For outcome assessments, we adjusted for the index trial, and the results were robust. Second, only baseline LDL-C levels were obtained in our study so far, and we look forward to further monitoring of LDL-C level to assess the cumulative average LDL-C level and bleeding risk. Third, although this study had a large sample size, the number of ICH events available for assessing associated risk factors was limited, thereby restricting the evaluation capacity. Fourth, although CHANCE and CHANCE-2 are randomized clinical trials, this post hoc exploratory analysis observationally examined the association of LDL-C levels with bleeding risk in the context of DAPT and cannot demonstrate causality; thus, further mendelian randomization studies are needed. Fifth, our patients were all from China, and because bleeding risk is acknowledged to be higher in East Asian individuals receiving antithrombotic therapies compared with White individuals,27 it may limit the generalizability of the conclusions to other populations.
Conclusions
This cohort study using pooled data from the CHANCE and CHANCE-2 trials provides evidence that low LDL-C levels (<70 mg/dL) are associated with an increased bleeding risk within 3 months among patients with MIS or HRTIA taking DAPT. Further stratified analysis showed consistent results in the ticagrelor-aspirin group, rather than the clopidogrel-aspirin group. Because of the limited number of severe or moderate bleeding events, as well as ICHs, no statistically significant results were obtained in either the ticagrelor-aspirin or clopidogrel-aspirin group. Further research is warranted to validate these findings in larger and more diverse populations.
eTable 1. Characteristics of the CHANCE and CHANCE-2 Trials
eTable 2. Characteristics of the Patients Recruited in CHANCE and CHANCE-2 Trials
eTable 3. Risk of Bleeding Events at 3 Months After a Minor Ischemic Stroke or TIA Receiving Aspirin Alone or DAPT According to LDL-C Levels
eTable 4. Association Between LDL-C Levels as a Continuous Measure and Bleeding Events at 3 Months, Stratified by DAPT Treatment Assignment
eFigure 1. The Flowchart of the Study
eFigure 2. Hazard Ratio for Any Bleeding in Prespecified Subgroups
Data Sharing Statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable 1. Characteristics of the CHANCE and CHANCE-2 Trials
eTable 2. Characteristics of the Patients Recruited in CHANCE and CHANCE-2 Trials
eTable 3. Risk of Bleeding Events at 3 Months After a Minor Ischemic Stroke or TIA Receiving Aspirin Alone or DAPT According to LDL-C Levels
eTable 4. Association Between LDL-C Levels as a Continuous Measure and Bleeding Events at 3 Months, Stratified by DAPT Treatment Assignment
eFigure 1. The Flowchart of the Study
eFigure 2. Hazard Ratio for Any Bleeding in Prespecified Subgroups
Data Sharing Statement