Clopidogrel In High-Risk Patients With Acute Nondisabling Cerebrovascular Events Research Articles

LDL-C Levels and Bleeding Risk in Patients Taking DAPT After Minor Ischemic Stroke or TIA

Evidence on the bleeding risk associated with low-density lipoprotein cholesterol (LDL-C) levels in patients receiving dual antiplatelet therapy (DAPT) remains sparse. 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. 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. Baseline LDL-C levels and receipt of ticagrelor-aspirin and clopidogrel-aspirin DAPT. 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. 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. 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.

Smokers with Elevated Glycated Albumin Could Not Benefit from Dual Antiplatelet Therapy after Minor Stroke or Transient Ischemic Attack

Introduction: The aim of this study was to investigate the impact of smoking on dual antiplatelet therapy in patients with minor stroke or transient ischemic attack (TIA) under different glycated albumin (GA) levels. Methods: We analyzed data from the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial. A subgroup of 3,044 patients with baseline GA levels was included and categorized by smoking status and GA levels. The primary efficacy outcome was a new stroke within 90 days. The safety outcome was any bleeding event at 90 days. The interaction of smoking status with antiplatelet therapy was calculated by Cox proportional hazards regression model. Results: In patients with GA levels ≤15.5%, the proportion of smokers was 37.7% (719/1,908), while in patients with GA levels >15.5%, it was 51.6% (586/1,136). During the 3-month follow-up period, 299 (9.9%) patients had a new stroke occurrence. In patients with elevated GA levels, both smokers and nonsmokers could not benefit from dual antiplatelet therapy (smokers, adjusted hazard ratio [HR] 0.70, 95% confidence interval [CI]: 0.42–1.17; nonsmokers, adjusted HR 0.82, 95% CI: 0.57–1.18). In patients with normal GA levels, dual antiplatelet therapy reduced the risk of stroke recurrence in smokers by 72% (adjusted HR 0.28, 95% CI: 0.14–0.56) and in nonsmokers by 53% (adjusted HR 0.47, 95% CI: 0.26–0.86). However, whether the GA level was elevated or normal, there was no significant interaction between smoking status and antiplatelet therapy. Conclusions: Smokers with elevated GA levels could not benefit from dual antiplatelet therapy after minor stroke or TIA.

Association Between CYP2B6 Polymorphisms and Efficacy of Clopidogrel in Minor Stroke or Transient Ischemic Attack.

CYP2B6 (cytochrome P450 subfamily IIB polypeptide 6), encoded by the CYP2B6 gene, is a critical enzyme involved in clopidogrel metabolism. However, the association between CYP2B6 polymorphisms and the efficacy of clopidogrel in minor stroke or transient ischemic attack for secondary stroke prevention remains unclear. Based on CHANCE (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) randomized clinical trial of aspirin plus clopidogrel versus aspirin alone, we investigated the role of CYP2B6 polymorphisms and the efficacy of clopidogrel in patients with minor stroke or transient ischemic attack in China from October 2009 to July 2012. A total of 2853 patients were successfully genotyped for CYP2B6-516G>T, rs3745274 and CYP2B6-1456 T>C, rs2054675. The primary efficacy and safety outcomes were new stroke and any bleeding within 90 days. Among the 2853 patients, 32.8% were identified as the carriers of the CYP2B6-516 GT/TT or -1456 TC/CC genotype. The incidences of 90-day new stroke in aspirin plus clopidogrel and aspirin alone groups were 7.1% versus 11.3% among noncarriers, respectively; and 9.7% versus 12.2% among carriers, respectively. The efficacy of aspirin plus clopidogrel versus aspirin alone was not significantly different (P interaction=0.29) in noncarriers (adjusted hazard ratio, 0.61 [95% CI, 0.45-0.83]) compared to carriers (adjusted hazard ratio, 0.80 [95% CI, 0.54-1.18]). The incidence (n=51) of 90-day any bleeding in aspirin plus clopidogrel and aspirin alone groups were 2.2% (21 bleeds) versus 1.9% (18 bleeds) among noncarriers (adjusted hazard ratio, 1.11 [95% CI, 0.59-2.09]) and 1.9% (9 bleeds) versus 0.7% (3 bleeds) among carriers (adjusted hazard ratio, 3.23 [95% CI, 0.86-12.12]). Similar findings were observed during the 1-year follow-up. In this post hoc analysis of the CHANCE trial, we did not observe a significant difference in the efficacy of aspirin plus clopidogrel compared with aspirin in carriers versus noncarriers of CYP2B6-516 GT/TT or -1456 TC/CC genotype. Our results suggest that both carriers and noncarriers suffering from a minor stroke are likely to benefit from aspirin plus clopidogrel treatment over aspirin monotherapy for secondary prevention. URL: https://www. gov; Unique identifier: NCT00979589.

Aminotransferase Level and the Effects of Dual Antiplatelet in Minor Stroke or Transient Ischemic Attack: A post hoc Analysis of a Randomized Control Trial

Introduction: This study was intended to evaluate whether the safety and efficacy of dual antiplatelet treatment in patients with minor ischemic stroke (MIS) or transient ischemic attack (TIA) could be modified by the aminotransferase level. Also, we sought to assess the interaction between aminotransferase level and CYP2C19 loss-of-function status on the efficacy of dual antiplatelet therapy. Methods: This study is a post hoc analysis of the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) study, a double-blinded randomized control trial. We included 5,133 patients with a complete workup of baseline alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. The primary outcome is stroke or TIA recurrence within 90 days. Cox proportional hazard models were used in the evaluation of the efficacy of antiplatelet treatment in patients with different aminotransferase levels and subgroups categorized by the aminotransferase level × CYP2C19 loss-of-function status. Results: The median age of all the included patients was 62 years; 66.3% of the patients were male. More recurrent stroke or TIA occurred in patients with elevated ALT and AST levels within 90 days compared to patients with normal ALT and AST levels (14.5 vs. 11.2%, p = 0.029). Dual antiplatelet treatment with aspirin and clopidogrel reduced recurrence compared with aspirin alone in patients with both normal (adjusted hazard ratio [HR], 95% confidence interval [CI]: 0.72 [0.60–0.86], p < 0.001) and elevated (adjusted HR [95% CI]: 0. 57 [0. 35–0. 92], p = 0. 020) ALT and AST levels (p = 0.64 for interaction). No significant difference in treatment efficacy on 90-day all-cause death or bleeding events was found. Conclusions: Dual antiplatelet treatment was safe for minor stroke or high-risk TIA patients with mildly elevated aminotransferase. Mild elevation of ALT or AST did not undermine the protective efficacy of the dual antiplatelet regimen in reducing recurrent stroke or TIA within 90 days after MIS or TIA. The interaction between the CYP2C19 loss-of-function allele carrier status and aminotransferase level on the efficacy of dual antiplatelet treatment was not observed.

No rebound effect after a course of clopidogrel in patients with acute TIA or minor stroke

ABSTRACT Background and Purpose Previous studies demonstrated that discontinuation of clopidogrel in patients after ACS was associated with a rebound increase in risk of recurrent events. In this study, we aimed to investigate the rebound effect after discontinuation of clopidogrel therapy in patients with TIA or stroke. Methods All patients with minor stroke or TIA were recruited from the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) trial. Patients were divided into two groups: patients who discontinued clopidogrel and switched to aspirin therapy (Clopidogrel Discontinuation Group) and patients who continued one mono-antiplatelet therapy (non-Clopidogrel Discontinuation Group) during 90-180 days. The outcomes included risks of recurrent ischemic stroke, recurrent TIA, and composite events during 90-180 days. The prevalence of each outcome was compared between two groups for every 30 days. Further subgroup analysis was conducted in patients with and without CYP2C19 loss-of-function alleles. Results Among the 3456 patients included, a total of 10 patients in the Clopidogrel Discontinuation Group and 11 patients in the non-Clopidogrel Discontinuation Group presented ischemic stroke recurrence during the 90–180-day period. The inter-group comparisons were not significant in each 30 days. Similar results were found for recurrent stroke, recurrent TIA, and composite events in these two groups, which were also found in CYP2C19 subgroup analysis. Conclusions No rebound increase in the risk of ischemic stroke and composite events was found during the 90 days after discontinuation of clopidogrel therapy in patients with TIA or minor stroke in the CHANCE trial. Trial Registration clinicaltrials.gov Identifier: NCT00979589

Analysis of Prescriptions for Dual Antiplatelet Therapy After Acute Ischemic Stroke

After the publication of the CHANCE (Clopidogrel in High Risk Patients With Acute Nondisabling Cerebrovascular Events) and POINT (Platelet-Oriented Inhibition in New Transient Ischemic Attack and Minor Ischemic Stroke) clinical trials, the American Heart Association/American Stroke Association (AHA/ASA) issued a new class 1, level of evidence A, recommendation for dual antiplatelet therapy (DAPT; aspirin plus clopidogrel) for secondary prevention in patients with minor ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤3). The extent to which variations in DAPT prescribing patterns remain and the extent to which practice patterns in the US are consistent with evidence-based guidelines are unknown. To evaluate the discharge DAPT prescribing patterns after publication of the new AHA/ASA guidelines and assess the extent of hospital-level variation in the use of DAPT for secondary prevention in patients with minor stroke (NIHSS score ≤3), as indicated by guidelines, and in patients with nonminor stroke (NIHSS score >3), for whom the risks and benefits of DAPT have not been fully established. This multicenter retrospective cohort study involved 132 817 patients from 1890 hospitals participating in the AHA/ASA Get With The Guidelines-Stroke program. Patients who were hospitalized for acute ischemic stroke and prescribed antiplatelet therapy at discharge between October 1, 2019, and June 30, 2020, were included. Minor ischemic stroke (NIHSS score ≤3) vs nonminor ischemic stroke (NIHSS score >3). The primary outcome was DAPT prescription at discharge. The extent to which variations in DAPT use were explained at the hospital level was assessed by calculating the median odds ratio (OR), which was derived using multivariable logistic regression analysis and compared the likelihood that 2 patients with identical clinical features admitted to 2 randomly selected hospitals (1 with higher propensity and 1 with lower propensity for DAPT use) would receive DAPT at discharge. Associations between hospital-level DAPT use among patients with minor vs nonminor stroke were evaluated using Pearson ρ correlation coefficients. Among 132 817 patients (median [IQR] age, 68 [59-78] years; 68 768 men [51.8%]), 4282 (3.2%) were Asian, 11 254 (8.5%) were Hispanic, 27 221 (20.5%) were non-Hispanic Black, 84 468 (63.6%) were non-Hispanic White, and 5592 (4.2%) were of other races and/or ethnicities (including American Indian or Alaska Native, Native Hawaiian or Pacific Islander, and unable to determine). Overall, 86 551 patients (65.2%) presented with minor ischemic stroke, and 46 266 patients (34.8%) presented with nonminor ischemic stroke. After the 2019 AHA/ASA guideline updates, 40 661 patients (47.0%) with minor stroke (NIHSS median [IQR] score, 1 [0-2]) and 19 703 patients (42.6%) with nonminor stroke (NIHSS median [IQR] score, 6 [5-9]) received DAPT at discharge. Despite guideline recommendations, 45 890 patients (53.0%) with minor stroke did not receive DAPT. After accounting for patient characteristics, substantial hospital-level variations were found in the use of DAPT in those with minor stroke (median [IQR] hospital-level DAPT prescription rate, 44.8% [33.7%-57.7%]; range, 0%-91.7%; median OR, 2.03 [95% CI, 1.97-2.09]) when comparing 2 patients with identical risk factors discharged from 2 randomly selected hospitals, 1 with higher propensity and 1 with lower propensity for DAPT use. The use of DAPT in patients with nonminor stroke also varied significantly (median [IQR] hospital-level DAPT prescription rate, 41.4% [30.0%-53.8%]; range, 0%-100%; median OR, 1.90 [95% CI, 1.83-1.97]). Overall, hospitals that were more likely to prescribe DAPT for minor strokes were also more likely to prescribe DAPT for nonminor strokes (Pearson ρ = 0.72; P < .001). This cohort study found that despite updated AHA/ASA guidelines, more than 50% of patients with minor acute ischemic stroke did not receive DAPT at discharge. In contrast, more than 40% of patients with nonminor stroke received DAPT despite lack of evidence in this setting. These findings suggest that enhancing adherence to evidence-based DAPT practice guidelines may be a target for quality improvement in the treatment of patients with ischemic stroke.

Predictive values of baseline matrix metalloproteinase 9 levels in peripheral blood on 3-month outcomes of high-risk patients with minor stroke or transient ischemic attack.

To explore the relationship between baseline levels of matrix metalloproteinase 9 (MMP9) in peripheral blood and the outcomes in patients with acute minor stroke and transient ischemic attack (TIA). We assessed data from patients with acute minor ischemic stroke or TIA who were included in the CHANCE (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events) trial. Baseline level of MMP9 in peripheral blood is classified into five quintiles. We assessed the relationship between the baseline MMP9 and outcomes of stroke recurrence, composite vascular events, and poor functional outcomes within 90days after stroke onset. Of the 3014 patients included, 295 (9.79%) had recurrent stroke, 289 (9.59%) had recurrent ischemic stroke, 297 (9.85%) had combined vascular events, and 199 (6.64%) had poor functional outcomes within 90days. We used MMP9 concentrations near hazard ratio (HR)=1 (Q3) in restricted cubic splines as the reference. The result showed that, compared to patients in the Q3group, patients in the highest quintile (Q5group) had an increased risk of poor functional outcomes at 90days after adjusting the risk factors and confounders (p=0.030), which may be associated with an increased risk of combined vascular events (p=0.052). Using Cox regression models or logistic regression models with restricted cubic spline, we also observed that higher MMP9 ratios were associated with an increased risk of stroke recurrence, combined events, and poor functional outcomes at a range of concentrations. For patients with acute minor stroke or TIA, higher baseline MMP9level was associated with an increased risk of poor functional outcomes, which might be related to stroke recurrence and combined vascular events.

Coexistent cerebral small vessel disease and multiple infarctions predict recurrent stroke

Background and purposeTo investigate the association of different status of cerebral small vessel disease (CSVD) and infarction number with recurrence after acute minor stroke and transient ischaemic attack (TIA).MethodsThis study was a post hoc analysis of the Clopidogrel in High-risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial, and includes 886 patients with acute minor stroke and TIA. The status of CSVD and infarction number was recorded for each individual. Infarction number were classified as multiple acute infarctions (MAIs≥2), single acute infarction (SAI =1), and non-acute infarction (NAI =0). The CSVD burden were grouped into non-CSVD (0 score) and CSVD (1–4 score). The primary outcome was a recurrent stroke at the 1-year follow-up. The secondary outcomes were recurrent ischaemic stroke, composite vascular event (CVE), and TIA. We analyzed the relationships between different status of CSVD burden and infarction pattern with the risk of outcomes using multivariable Cox regression models.ResultsAmong all 886 patients included in present analysis, recurrent stroke was occurred in 93 (10.5%) patients during 1-year follow-up. After adjusted for all potential covariates, compared with patients with non-CSVD and NAI, patients with CSVD and MAIs were associated with approximately 9.5-fold increased risk of recurrent stroke at 1 year (HR 9.560, 95% CI 1.273–71.787, p=0.028). Similar results observed in ischaemic stroke and CVE.ConclusionThe status of CSVD and infarction number predicted recurrent stroke in patients with acute minor stroke and TIA, especially for those with coexistent CSVD and MAIs.

Abstract WP194: Ldlc Levels, Lipid Lowering Treatment And Recurrent Stroke In Minor Ischemic Stroke Or Tia

Objective: To investigate the association between baseline low-density lipoprotein cholesterol (LDL-C) level, lipid lowering treatment and short-term risk of new stroke in patients with a minor ischemic stroke or transient ischemic attack (TIA). Methods: We derived data from the Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial. Patients with a minor stroke or TIA were categorized by LDL-C level at baseline (&lt;100 or ≥100 mg/dL [2.6 mmol/L]) and with or without lipid lowering treatment after symptom onset. The primary outcome was a new ischemic stroke at 3 months. The association of baseline LDL-C level and effect of lowering treatment were assessed. Results: Among 3,027 patients, 2,154(71.2%) patients had an initial LDL-C ≥100 mg/dL, of which 1,267(41.9%) received lipid lowering treatment. Elevated LDL-C level was associated with a higher risk of new ischemic stroke at 3 months in patients without lipid lowering treatment (adj.HR=1.35, 95%CI: 1.19-1.53), but not in those with lipid lowering treatment (adj.HR=0.99, 95%CI: 0.82-1.19) (p for interaction=0.007). Patients with LDL-C ≥100 mg/dL had a trend towards higher risk of ischemic stroke (11.8% vs. 8.0%, adj.HR=1.37, 95%CI: 0.96-1.96) in those without lipid lowering treatment. For patients with LDL-C ≥100 mg/dL, lipid lowering treatment was associated with reduced risk of ischemic stroke at 3 months (7.9% vs. 11.8%; adj.HR=0.54, 95%CI: 0.39-0.75). Conclusions: Elevated untreated baseline LDL-C level was associated with an increased short-term risk of ischemic stroke among patients presenting with minor ischemic stroke or TIA. There was potential benefit of lipid lowering treatment in stroke patients.

Analytical validation of GMEX rapid point-of-care CYP2C19 genotyping system for the CHANCE-2 trial

Background and purposeRapid genotyping is useful for guiding early antiplatelet therapy in patients with high-risk nondisabling ischaemic cerebrovascular events (HR-NICE). Conventional genetic testing methods used in CYP2C19 genotype-guided antiplatelet therapy...

Clopidogrel Plus Aspirin in Patients With Different Types of Single Small Subcortical Infarction.

Background: We aim to investigate the effects and safety of clopidogrel plus aspirin in patients with different types of single small subcortical infarction (SSSI) in the Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial.Methods: SSSI was defined as single DWI lesion of ≤2.0 cm. Patients with SSSI were divided into SSSI + PAD (parent artery disease) and SSSI – PAD, according to the stenosis of the parent artery. The efficacy outcome was stroke recurrence during 90-day follow-up. Cox proportional hazards models or logistic regression models were used to assess the interaction of the treatment effects of clopidogrel plus aspirin vs. aspirin alone among patients with and without PAD.Results: Among 338 patients with SSSI included in the subanalysis, 105 were with PAD and 233 without. The efficacy of clopidogrel plus aspirin compared with aspirin alone on any stroke was consistent between patients with [adjusted hazard ratio (HR) 0.84; 95% confidence interval (CI), 0.25–2.75] and without PAD (adjusted HR 1.03; 95% CI, 0.40–2.68, interaction P = 0.83). In patients with SSSI + PAD, the rate of stroke recurrence in those treated with dual antiplatelet therapy and mono antiplatelet therapy was not significantly different (10.9 vs. 13.6%, P = 0.77). The number of bleeding events was similar between the clopidogrel-aspirin group and aspirin group regardless of SSSI + PAD or SSSI – PAD.Conclusions: There was no significant difference in the efficacy of clopidogrel plus aspirin compared with aspirin alone between patients with SSSI + PAD and SSSI – PAD in the CHANCE trial. Studies in other populations and with adequate power are needed to further verify such findings.

Cerebral small vessel disease or intracranial large vessel atherosclerosis may carry different risk for future strokes

BackgroundThe effect of cerebral small vessel disease (CSVD) and intracranial arterial stenosis (ICAS) on stroke outcomes remains unclear.MethodsData of 1045 patients with minor stroke or transient ischaemic attack (TIA) were...

Higher early recurrence risk and potential benefit of dual antiplatelet therapy for minor stroke with watershed infarction: subgroup analysis of CHANCE.

The aim was to explore the risk of early stroke recurrence within 3months after watershed infarction and to investigate whether early dual antiplatelet therapy is more effective in decreasing such risk. Patients enrolled in the Clopidogrel in High-risk Patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial and who had acute infarction on diffusion-weighted imaging were included in this subgroup analysis. All magnetic resonance images were read centrally by two neurologists who were blinded to the patients' baseline and outcome information. The primary outcome was any stroke recurrence within 3months. The hazard ratios were adjusted by known predictors of stroke recurrence. Of the 1089 patients with magnetic resonance imaging data enrolled in CHANCE, 834 (76.58%) patients had acute infarcts on diffusion-weighted imaging. The median and range of duration from randomization to stroke recurrence was 1.5 (1-6) days. Patients with watershed infarction had higher risk of stroke recurrence than those without (17.20% vs. 6.34%) within the first week after initial stroke; the hazard ratio (95% confidence interval) was 2.799 (1.536-5.101) adjusted by age, sex, smoking, body mass index, medical history, time to randomization, open-label aspirin dose at first day, single or dual antiplatelet therapy, National Institutes of Health Stroke Scale score at randomization, in-hospital treatment and white matter lesions, P<0.001. There was no interaction between antiplatelet therapy and the presence of watershed infarction (P=0.544). Minor stroke with watershed infarction has high recurrent risk in the first week. Dual antiplatelet therapy may be safely implemented, yet watershed infarction mechanisms of hypoperfusion and emboli may not be addressed.

Oxidized low-density lipoprotein (LDL) and LDL cholesterol are associated with outcomes of minor stroke and TIA

Background and aimsLow-density lipoprotein (LDL) and oxidized low-density lipoprotein (oxLDL) levels are thought to be related to recurrent stroke. However, the joint association of circulating LDL and oxLDL levels with the outcomes of acute minor ischemic stroke and transient ischemic attack (TIA) remains unclear. The goal of the study was to evaluate whether LDL and oxLDL have a combined effect on outcomes of acute minor stroke and TIA. MethodsIn the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) trial, a subgroup of 3019 patients with baseline oxLDL and LDL levels were analyzed. Patients were divided into four groups according to different combinations of LDL (LDL < 3.37 mmol/L, LDL ≥ 3.37 mmol/L) and oxLDL levels (oxLDL <13.96 μg/dL, oxLDL ≥ 13.96 μg/dL). The primary outcome was any stroke within 90 days. The secondary outcomes included any stroke within 1 year and ischemic stroke and combined vascular events within 90 days and 1 year. The poor functional outcome included modified Rankin Scale (mRS) 3–6 at 90-day and 12-month follow-up. The association of LDL and oxLDL with the prognosis of patients was examined using multivariable Cox regression models. ResultsAmong 3019 patients included in this study, the medians (interquartile range) of oxLDL and LDL were 13.96 (6.65–28.81) μg/dL and 3.1 (2.5–3.8) mmol/L, respectively. The cumulative occurrence of recurrent stroke, ischemic stroke, and combined vascular events was 9.74%, 9.54%, and 9.80% within 90 days of follow-up. Compared with those with low LDL and oxLDL levels (LDL < 3.37 mmol/L with oxLDL <13.96 μg/dL), patients with high levels of LDL and oxLDL (LDL ≥3.37 mmol/L, oxLDL ≥13.96 μg/dL) had significantly increased risk of recurrent stroke at 90 days (HR,1.57; 95% CI, 1.10–2.24) and 1 year (HR,1.49; 95% CI, 1.10–2.04). Patients in groups with LDL ≥3.37 mmol/L, oxLDL <13.96 μg/dL (HR,1.35; 95% CI, 0.94–1.93) or LDL < 3.37 mmol/L with oxLDL ≥13.96 μg/dL (HR,1.11; 95% CI, 0.77–1.59) showed no statistical difference for stroke recurrence. Similar results were found for functional outcomes. ConclusionsThe presence of higher combined serum oxLDL and LDL levels was associated with increased risk of recurrent stroke and poor functional outcomes in minor stroke or high-risk TIA patients.

Outcomes Associated With Clopidogrel-Aspirin Use in Minor Stroke or Transient Ischemic Attack

Dual antiplatelet therapy with clopidogrel and aspirin is effective for secondary prevention after minor ischemic stroke or transient ischemic attack (TIA). Uncertainties remained about the optimal duration of dual antiplatelet therapy for minor stroke or TIA. To obtain precise estimates of efficacy and risk of dual antiplatelet therapy after minor ischemic stroke or TIA. This analysis pooled individual patient-level data from 2 large-scale randomized clinical trials that evaluated clopidogrel-aspirin as a treatment to prevent stroke after a minor stroke or high-risk TIA. The Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events (CHANCE) trial enrolled patients at 114 sites in China from October 1, 2009, to July 30, 2012. The Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial enrolled patients at 269 international sites from May 28, 2010, to December 19, 2017. Both were followed up for 90 days. Data analysis occurred from November 2018 to May 2019. In the 2 trials, patients with minor stroke or high-risk TIA were randomized to clopidogrel-aspirin or aspirin alone within 12 hours (POINT) or 24 hours (CHANCE) of symptom onset. The primary efficacy outcome was a major ischemic event (ischemic stroke, myocardial infarction, or death from ischemic vascular causes). The primary safety outcome was major hemorrhage. The study enrolled 5170 patients (CHANCE) and 4881 patients (POINT). Analysis included individual data from 10 051 patients (5016 in the clopidogrel-aspirin treatment group and 5035 in the control group) with a median age of 63.2 (interquartile range, 55.0-72.9) years; 6106 patients (60.8%) were male. Clopidogrel-aspirin treatment reduced the risk of major ischemic events at 90 days compared with aspirin alone (328 of 5016 [6.5%] vs 458 of 5035 [9.1%]; hazard ratio [HR], 0.70 [95% CI, 0.61-0.81]; P < .001), mainly within the first 21 days (263 of 5016 [5.2%] vs 391 of 5035 [7.8%]; HR, 0.66 [95% CI, 0.56-0.77]; P < .001), but not from day 22 to day 90. No evidence of heterogeneity of treatment outcome across trials or prespecified subgroups was observed. Major hemorrhages were more frequent in the clopidogrel-aspirin group, but the difference was nonsignificant. In this analysis of the POINT and CHANCE trials, the benefit of dual antiplatelet therapy appeared to be confined to the first 21 days after minor ischemic stroke or high-risk TIA.

Association of Body Mass Index and Risk of Stroke After Acute Minor Stroke or TIA: a Post Hoc Analysis of a Randomized Controlled Trial.

The "obesity paradox" was reported in patients with stroke. We aimed to evaluate the pattern and magnitude of association between body mass index (BMI) and prognosis of stroke in patients with minor ischemic stroke or transient ischemic attack (TIA). A total of 5163 patients with available BMI data from the Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial were included. Patients were classified into three groups according to their BMI values: normal weight (< 23.9kg/m2), overweight (24-27.9kg/m2), and obese (≥ 28.0kg/m2). The efficacy outcomes included a new stroke (ischemic or hemorrhagic), poor functional outcome defined as modified Rankin scale ≥ 2 points and death from any cause within 90days. The interaction effects were determined using multivariable Cox or logistic regression models. After 90days of follow up, there were 513 new strokes. Overweight (BMI 24-27.9kg/m2) patients had a higher risk of recurrent strokes than those with normal weight (10.8% vs 8.8%; HR = 1.24, 95% CI 1.02-1.50) after adjusting for the baseline covariates, but no significant association was observed for those who were obese (P = 0.37). No significant association was found between being overweight or obese and poor functional outcome or death. For patients with a minor ischemic stroke or TIA, being overweight was associated with an increased risk of recurrent stroke compared to being of normal weight in our study.Trial registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00979589.

Effect of dual versus mono antiplatelet therapy on recurrent stroke modulated by activated partial thromboplastin time

The efficacy of dual antiplatelet treatment may be modified by many factors. The aim was to assess whether the effect of clopidogrel plus aspirin versus aspirin alone on recurrent stroke would be affected by admission activated partial thromboplastin time (aPTT). Data were derived from the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial. A total of 5074 patients were categorized into three groups based on the aPTT distribution according to the 15th and 85th percentile. The primary outcome was any stroke within 90days. The interaction of aPTT with antiplatelet therapy on stroke risk was assessed with a Cox proportional hazards model with adjustment for covariates. In the high aPTT group (defined as ≥35.9s), stroke occurred in 6.7% of patients in the clopidogrel-aspirin arm and 11.9% in the aspirin arm [adjusted hazard ratio (HR) 0.50; 95% confidence interval (CI) 0.29-0.85]. In the medium aPTT group (24.6-35.8s), stroke occurred in 7.7% of patients in the clopidogrel-aspirin arm and 11.8% in the aspirin arm (adjusted HR 0.62; 95% CI 0.50-0.75). Furthermore, in the low aPTT group (≤24.5s), stroke occurred in 11.2% of patients in the clopidogrel-aspirin arm and 9.9% in the aspirin arm (adjusted HR 1.07; 95% CI 0.65-1.62). The interaction P value of antiplatelet therapy with aPTT level at the cut-point of approximately 25s or below was significant (P<0.05). Dual antiplatelet therapy was superior to single antiplatelet therapy in the high or medium aPTT group but not in the low aPTT group.

The influence of mean arterial pressure on the efficacy and safety of dual antiplatelet therapy in minor stroke or transient ischemic attack patients.

Mean arterial pressure (MAP) is the strongest predictor of stroke. The combination of clopidogrel and aspirin within 24hours after onset has been suggested by the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) study to be superior to aspirin alone. However, it is not clear whether poststroke blood pressure has an influence on the efficacy and safety of dual antiplatelet treatment. We have performed a post hoc analysis from the CHANCE trial. Patients were stratified into three groups based on MAP levels. Among patients with MAP <102mmHg, there was no significant difference in stroke recurrence between the clopidogrel-aspirin group and the aspirin group (7.7% vs 7.5%; hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.73-1.45). However, compared to aspirin treatment, the clopidogrel-aspirin dual treatment was more effective at reducing the risk of stroke in patients with MAP ≥113mmHg (6.9% vs 12.3%, HR, 0.55; 95% CI, 0.39-0.78) or 102-113mmHg (9.5% vs 14.9%, HR, 0.62; 95% CI, 0.48-0.81). There was a significant interaction between MAP and antiplatelet therapy as it relates to stroke recurrence (P for interaction=0.037), and a similar result was found for combined vascular events (P for interaction=0.027). In conclusion, dual antiplatelet therapy may be more effective at reducing combined vascular events in patients with higher MAP after minor stroke or transient ischemic attack.

Oxidative lipoprotein markers predict poor functional outcome in patients with minor stroke or transient ischaemic attack.

Oxidative stress plays an important role in acute ischaemic stroke. However, the association of oxidative lipoprotein markers, including oxidized low-density lipoprotein (oxLDL), oxLDL:high-density lipoprotein (HDL) and oxLDL:low-density lipoprotein (LDL), with functional outcome of minor stroke or transient ischaemic attack (TIA) remains unclear. We aimed to investigate the association between oxidative lipoprotein markers and poor functional outcome in patients with minor stroke or TIA. All patients with minor stroke or TIA were recruited from the Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events (CHANCE) trial. The poor functional outcome included modified Rankin Scale (mRS) score 2-6 and 3-6 at 90-day and 12-month follow-up. Multivariate logistic regression was used to investigate the associations of oxLDL, oxLDL:HDL and oxLDL:LDL with poor functional outcome. Among 3019 patients included in this study, the median (interquartile range) oxLDL, oxLDL:HDL and oxLDL:LDL were 13.96 (6.65-28.81), 4.52 (2.08-9.32) and 11.73 (5.27-24.85)μg/dL, respectively. After adjusted for confounding factors, patients in the highest oxLDL quartile had a higher proportion of mRS score 2-6 at 90days [hazard ratio (HR), 1.78; 95% confidence interval (CI), 1.26-2.52] and 12months (HR, 1.42; 95% CI, 1.01-1.99), and mRS score 3-6 at 90days (HR, 1.98; 95% CI, 1.29-3.04) and 12months (HR, 1.77; 95% CI, 1.09-2.89) when compared with the lowest oxLDL quartile (P<0.05). Similar results were found for oxLDL:HDL and oxLDL:LDL. Higher levels of oxidative lipoprotein markers are independent predictors of poor functional outcome in patients with minor stroke or TIA at 90days and 12months.

Association Between ABCB1 Polymorphisms and Outcomes of Clopidogrel Treatment in Patients With Minor Stroke or Transient Ischemic Attack

Genetic variants of ABCB1 may affect intestinal absorption of clopidogrel bisulfate. However, it is unclear whether ABCB1 polymorphisms are associated with clopidogrel efficacy for minor ischemic stroke or transient ischemic attack (TIA). To investigate the association between ABCB1 polymorphisms and clopidogrel efficacy for minor stroke or TIA. In this prespecified secondary analysis of the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) randomized clinical trial, 3010 patients with minor stroke or TIA at 73 sites in China with experience in conducting genetic studies were included from October 1, 2009, to July 30, 2012. The analysis was conducted on March 20, 2018. Four single-nucleotide polymorphisms (ABCB1 -154T>C [rs4148727], ABCB1 3435C>T [rs1045642], CYP2C19*2 [681G>A, rs4244285], and CYP2C19*3 [636G>A, rs4986893]) were genotyped among 2836 patients treated with clopidogrel plus aspirin (n = 1414) or aspirin alone (n = 1422). The association of ABCB1 genetic variants (-154 TC/CC and 3435 CT/TT) with clopidogrel efficacy was evaluated in the context of CYP2C19 status, another gene associated with clopidogrel efficacy. Patients in the CHANCE trial were randomized to treatment with clopidogrel combined with aspirin or to aspirin alone. Primary efficacy outcome was stroke recurrence after 3 months. The safety outcome was any bleeding risk after 3 months. Among 2836 patients, the median age was 61.8 years (interquartile range, 54.4-71.1 years) and 1887 patients (66.5%) were male. A total of 2146 (75.7%) patients were carriers of ABCB1 -154 TC/CC (570 [20.1%]) or 3435 CT/TT (1851 [65.3%]) genotype. Clopidogrel plus aspirin treatment was associated with reduced risk of new stroke in patients with ABCB1 -154 TT and 3435 CC genotype (hazard ratio [HR], 0.43; 95% CI, 0.26-0.71) but not in those with ABCB1 -154 TC/CC or 3435 CT/TT genotype (HR, 0.78; 95% CI, 0.60-1.03) compared with aspirin (P = .04 for interaction). A combined association of ABCB1 and CYP2C19 polymorphisms with new stroke was observed. The risk of bleeding for clopidogrel plus aspirin treatment was not associated with the ABCB1 genotypes (2.3% and 1.3% vs 1.9% and 2.2%; P = .25 for interaction in patients with or without ABCB1 -154 TC/CC or 3435 CT/TT genotype). The ABCB1 polymorphism was associated with the reduced efficacy of clopidogrel plus aspirin treatment compared with aspirin among patients with minor ischemic stroke or TIA. Genetic polymorphism of ABCB1 should be considered when prescribing clopidogrel for these patients. ClinicalTrials.gov identifier: NCT00979589.