Background and purpose 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 ). Methods 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 90 days. The interaction of aPTT with antiplatelet therapy on stroke risk was assessed with a Cox proportional hazards model with adjustment for covariates. Results In the high aPTT group (defined as ≥35.9 s), 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 (24.6–35.8 s), 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 (≤24.5 s), 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 25 s or below was significant ( P < 0.05). Conclusions Dual antiplatelet therapy was superior to single antiplatelet therapy in the high or medium aPTT group but not in the low aPTT group.
The study aimed to evaluate whether the benefits of dual antiplatelet therapy would be influenced by blood pressure (BP) levels, among acute minor stroke or transient ischemic attack (TIA). In CHANCE (Clopidogrel in High-Risk Patients with Acute Nondisabling cerebrovascular Events) trail, Patients were stratified by systolic BP (SBP) and diastolic BP (DBP) level measured on admission, respectively, using the supine position BP within 24 hours after symptoms onset. The primary efficacy outcome was stroke recurrence, bleeding was the safety outcome. Patients with SBP ≥ 140 mmHg, dual antiplatelet treatment could reduce the risk of stroke recurrence significantly (HR 0.654, 95% CI 0.529-0.793, p < 0.001) than mono antiplatelet therapy. And patients with DBP ≥ 90 mmHg, clopidogrel-aspirin significantly reduced the risk of recurrent stroke (HR 0.588, 95% CI 0.463-0.746, p < 0.001), compared with aspirin alone. However, in patients with SBP < 140 mmHg or DBP < 90 mmHg, no significant difference was observed between clopidogrel plus aspirin and aspirin alone. there was no difference in bleeding episodes by treatment assignment across categories of SBP or DBP. Patients with SBP ≥ 140 mmHg or DBP ≥ 90 mmHg after minor stroke or TIA got more benefits from dual antiplatelet therapy. Bleeding risk from dual antiplatelet treatment did not increase among patients with higher BP level on admission.
Body mass index (BMI) may affect the response to platelet P2Y12 receptor inhibitors. We aimed to explore whether BMI influenced the efficacy and safety of ticagrelor and clopidogrel for secondary prevention of minor ischemic stroke or transient ischemic attack (TIA) among patients enrolled in the CHANCE-2 (Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II) trial.In a multicentre, randomized, double-blind, placebo-controlled trial, conducted in China, we randomized patients with minor stroke or TIA who carried the CYP2C19 loss-of-function allele to receive either ticagrelor-acetylsalicylic acid (ASA) or clopidogrel-ASA. We classified patients into obese (BMI ≥ 28) or nonobese (BMI < 28) groups. The primary efficacy outcome was stroke within 90 days, and the primary safety outcome was severe or moderate bleeding within 90 days.Among 6412 patients, 876 were classified as obese and 5536 were classified as nonobese. Compared with clopidogrel-ASA, ticagrelor-ASA was associated with a significantly lower rate of stroke within 90 days among patients with obesity (25 [5.4%] v. 47 [11.3%]; hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.30-0.87), but not among those in the nonobese group (166 [6.0%] v. 196 [7.0%]; HR 0.84, 95% CI 0.69-1.04) The interaction of treatment and BMI group was significant (p for interaction = 0.04). We did not observe any difference by BMI group in rates of severe or moderate bleeding (9 [0.3%] v. 10 [0.4%] in the nonobese group; 0 [0.0%] v. 1 [0.2%] in the obese group; p for interaction = 0.99).In this secondary analysis of a randomized controlled trial involving patients with minor ischemic stroke or TIA, compared with clopidogrel-ASA, patients with obesity received more clinical benefit from ticagrelor-ASA therapy than those without obesity.Clinicaltrials.gov, no. NCT04078737.
Genotype data of the Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) trial showed that efficacy of clopidogrel aspirin depended on CYP2C19 genotype and risk profile. A stratification of patients who carried CYP2C19 loss-of-function (LOF) alleles according to the risk of recurrent stroke may be important for selecting optimal antiplatelet therapy. We aimed to compare the efficacy and safety of ticagrelor aspirin with clopidogrel aspirin in CYP2C19 LOF carriers with minor stroke or transient ischemic attack (TIA) stratified by risk profile.Data were obtained from Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II (CHANCE-2) trial. Low-risk and high-risk profiles were defined by Essen Stroke Risk Score (ESRS) (<3 [low risk] and ≥3 [high risk], respectively).A total of 6,412 CYP2C19 LOF carriers were enrolled; ticagrelor aspirin was associated with a reduced risk of primary outcome (new stroke within 90-day follow-up) in patients at low risk (hazard ratio [HR], 0.65; 95% CI, 0.48-0.82), but not in those at high risk (HR, 0.97; 95% CI, 0.73-1.29), compared with clopidogrel aspirin (p = 0.02 for interaction). Secondary outcomes generally went in the same direction as the primary outcome. The primary safety outcome of severe or moderate bleeding did not differ based on risk profile (p = 0.24 for interaction), although the incidence of total bleeding was greater with ticagrelor aspirin than with clopidogrel aspirin among patients at low risk (p < 0.01 for interaction). Analysis in the per-protocol population yielded similar results.This post hoc analysis of CHANCE-2 trial showed that CYP2C19 LOF carriers with minor stroke or TIA at low risk of recurrent stroke received a greater benefit from ticagrelor aspirin than from clopidogrel aspirin.This study provides Class II evidence that CYP2C19 LOF carriers with minor stroke or TIA at low risk, but not at high risk, of recurrent stroke (by the ESRS) received a greater benefit from ticagrelor aspirin than from clopidogrel aspirin.URL: www.gov. Unique identifier: NCT04078737.
Abstract Background S100A8/A9 is implicated in inflammation mechanisms related to atherosclerosis and plaque vulnerability, but it remains unclear whether S100A8/A9 is associated with the prognosis of ischemic stroke. The aim of this study was to investigate these associations in 2 independent multicenter cohorts. Methods Plasma S100A8/A9 concentrations at baseline were measured among 4785 patients with ischemic stroke from 2 independent cohorts: Infectious Factors, Inflammatory Markers, and Prognosis of Acute Ischemic Stroke (IIPAIS) and China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The primary outcome was a composite outcome of death or major disability at 3 months after ischemic stroke. Secondary outcomes were major disability, death, and a composite outcome of death or vascular events. Results Among the combined participants of IIPAIS and CATIS, the adjusted odds ratios associated with the highest quartile of plasma S100A8/A9 were 2.11 (95% CI, 1.66–2.68) for the primary outcome and 1.62 (95% CI, 1.27–2.07) for the secondary outcome of major disability; adjusted hazard ratios were 4.14 (95% CI, 2.10–8.15) for the secondary outcome of death and 2.08 (95% CI, 1.38–3.13) for the composite outcome of death or vascular events. Each SD increase of log-transformed S100A8/A9 was associated with 28% (95% CI, 18%–39%; P < 0.001) increased risk of the primary outcome. Multivariable-adjusted spline regression analyses showed a linear association between plasma S100A8/A9 concentrations and primary outcome (P < 0.001 for linearity). Subgroup analyses further confirmed these associations. Conclusions High plasma S100A8/A9 concentrations at baseline were independently associated with increased risks of adverse clinical outcomes at 3 months after ischemic stroke, suggesting that S100A8/A9 might have a role as a prognostic marker of ischemic stroke.
We aimed to assess the association between systolic blood pressure (SBP) and clinical outcome in 2,397 ischemic stroke (IS) or transient ischemic attack (TIA) patients from the Blood Pressure and Clinical Outcome in TIA or Ischemic Stroke (BOSS) study. BOSS study was a hospital-based, prospective cohort study. The SBP was defined as mean value of 90 days self-measured SBP after onset. Cox proportional hazards models were conducted to test the risk of combined vascular events (CVE) and stroke recurrence among different SBP categories. Restricted cubic splines were used to explore the shape of associations between SBP and clinical outcomes. A J-shaped association of SBP with CVE and stroke recurrence within 90 days was observed (P nonlinearity < 0.001 for both). After adjusting for age, gender, medical history, atrial fibrillation, admission NHISS score, and secondary prevention. The hazard ratios (95% confidence intervals) of SBP <115 and ⩾165 mmHg compared with 125-134 mmHg were 3.45 (1.11-10.66) and 7.20 (2.91-17.80) for CVE, 2.68 (0.75-9.53) and 9.69 (3.86-24.35) for stroke recurrence, respectively. Similar J-shaped relationships were found after 1 year of follow-up. In conclusion, both high and low SBP are associated with poor prognosis in this population.
Background: Hypoxia-inducible factor-1α (HIF-1α) plays a crucial role in both innate and adaptive immunity. Emerging evidence indicates that HIF-1α is associated with the inflammation and pathologic activities of autoimmune diseases，suggesting that HIF1α may be involved in immune dysregulation in patients with immune thrombocytopenia (ITP). Aims: The purpose of this study was to evaluate whether single nucleotide polymorphisms (SNPs) of the HIF1A gene are associated with susceptibility to ITP and its clinical prognosis including incidence of chronic immune thrombocytopenia (CITP) and glucocorticoid sensitivity. Methods: This study involved 197 Chinese ITP pediatric patients (discovery cohort) and 220 healthy controls. The Sequenom MassArray system (Sequenom, San Diego, CA) was used to detect three SNPs genotypes in the HIF1A gene: rs11549465, rs1957757 and rs2057482. We also employed another ITP cohort (N = 127) to validate the significant results of SNPs found in the discovery cohort. Results: The frequencies of the three SNPs did not show any significant differences between the ITP and healthy control groups. The CT genotype at rs11549465 was significantly higher in ITP patients sensitive to glucocorticoid-treatment than in those insensitive to glucocorticoid-treatment (P = .025). These results were validated using another ITP cohort (N =127, P = .033). Moreover, the CC genotype was a risk factor for insensitive to GT the OR (95% confidence interval) was 5.96(5.23-6.69) in standard prednisone (PDN) (P=.0069) and 6.35(5.33-7.37) in high-dose dexamethasone (HDD) (P=.04). Summary/Conclusion: Although HIF1A gene polymorphisms were not associated with susceptibility to ITP, the CT genotype at rs11549465 was associated with the sensitivity to glucocorticoid-treatment of ITP patients, suggesting that the rs11549465 SNP may contribute to the sensitivity of glucocorticoid treatment in pediatric ITP patients.
Background: Ticagrelor plus aspirin or ticagrelor alone has been demonstrated to be more effective at preventing recurrent stroke than aspirin monotherapy in patients with acute minor stroke or transient ischaemic attack (TIA) of atherosclerotic origin. However, whether ticagrelor is more efficient than clopidogrel for patients who are also carriers of CYP2C19 loss-of-function alleles remains unknown. Our aim was to investigate the efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin in patients with different intracranial artery stenosis (ICAS) statuses in Clopidogrel in High-risk patients with Acute Nondisabling Cerebrovascular Events-II (CHANCE-2) trial.Methods: CHANCE-2 was a randomized, double-blind, controlled trial exploring the use of ticagrelor-aspirin versus clopidogrel-aspirin in patients aged over 40 years with minor ischaemic stroke or high-risk TIA who were carriers of CYP2C19 loss-offunction alleles. We randomly allocated patients (1:1) within 24 hours after symptom onset to receive ticagrelor (180 mg on day 1 followed by 90 mg twice daily for days 2- 90) and placebo clopidogrel or to receive clopidogrel (300 mg on day 1 followed by 75 mg once daily for days 2-90) and placebo ticagrelor. ICAS was defined as at least 50% ipsilateral or contralateral stenosis of intracranial arteries mainly based on MR angiography and/or CT angiography, and symptomatic ICAS (sICAS) was defined as eligible ipsilateral intracranial artery stenosis according to the most recent clinical presentation. After excluding those without available imaging of the intracranial artery, all patients were classified into 3 different groups according to ICAS status: without ICAS, sICAS, or asymptomatic ICAS (asICAS). The primary efficacy outcome was new stroke, and the primary safety outcome was severe or moderate bleeding, both within 90 days. The CHANCE-2.Findings: Of the 6412 patients enrolled from September 23, 2019 to March 22, 2021, 5920 (92·3%) had available imaging of the intracranial artery, including 3535 (59·7%) without ICAS, 1639 (27·7%) with sICAS, and 746 (12·6%) with asICAS. A total of 175 (5·0%), 172 (10·5%) and 57 (7·6%) cases of new strokes occurred within 90 days in the without ICAS, with sICAS, and with asICAS groups, respectively, and the hazard ratios (HRs) of recurrence in the sICAS and asICAS groups were 2·14 (95% CI 1·72– 2·66) and 1·57 (1·15–2·14), respectively, compared to the without ICAS group. No treatment-by-ICAS status interaction was observed (p=0·14). Among patients without ICAS, new stroke within 90 days occurred in 63 (3·6%) of the 1762 patients in the ticagrelor-aspirin group and in 112 (6·3%) of the 1773 patients in the clopidogrelaspirin group (HR 0·56 [95% CI 0·41–0·77]; p<0·001). Among the patients with sICAS, new stroke occurred in 81 (9·6%) of 841 patients in the ticagrelor-aspirin group versus 91 (11·4%) of 798 patients the clopidogrel-aspirin group (0·75 [0·55–1·04]; p=0·082), and among patients in the asICAS group, new stroke occurred in 27 (7·4%) of 366 patients in the ticagrelor-aspirin group versus 30 (7·9%) of 380 patients in the clopidogrel-aspirin group (0·77 [0·43–1·38]; p=0·375). There were no significant differences in the proportion of severe or moderate bleeding events in the ticagreloraspirin group compared with the clopidogrel-aspirin group among patients with different ICAS statuses.Interpretation: In the subgroup analysis of the CHANCE-2 trial, both patients with sICAS and those with asICAS had a much higher risk of new stroke than those without ICAS. The efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin in preventing new stroke were similar between patients with and those without ICAS, which was consistent with the overall results of the CHANCE-2 intention-to-treat population. The without ICAS group may receive greater benefit.Trial Registration: Trial is registered with ClinicalTrials.gov (number NCT04078737).Funding: This trial was supported by grants from the Beijing Natural Science Foundation (Z200016), National Natural Science Foundation of China (82171270, 92046016), Ministry of Science and Technology of the People's Republic of China (National Key R&D Programme of China, 2017YFC1310901, 2016YFC0901002, 2017YFC1307905, 2015BAl12B00), Beijing Talents Project (2018000021223ZK03), Beijing Municipal Committee of Science and Technology (Z201100005620010), CAMS Innovation Fund for Medical Sciences (2019-2M-5-029).Declaration of Interests: None.Ethics Approval Statement: The trial was approved by the ethics committees at Beijing Tiantan Hospital, Capital Medical University, and at each participating site and was performed in accordance with Good Clinical Practice guidelines.
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