Acute Nondisabling Cerebrovascular Events Research Articles

Dual antiplatelet therapy in stroke and ICAS: Subgroup analysis of CHANCE.

AB OBJECTIVE: We aimed to investigate whether the efficacy and safety of clopidogrel plus aspirin vs aspirin alone were consistent between patients with and without intracranial arterial stenosis (ICAS), in the Clopidogrel in High-Risk Patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial. We assessed the interaction of the treatment effects of the 2 antiplatelet therapies among patients with and without ICAS, identified by magnetic resonance angiography (MRA) in CHANCE (ClinicalTrials.gov identifier NCT00979589). Overall, 1,089 patients with MRA images available in CHANCE were included in this subanalysis, 608 patients (55.8%) with ICAS and 481 (44.2%) without. Patients with ICAS had higher rates of recurrent stroke (12.5% vs 5.4%; p<0.0001) at 90 days than those without. But there was no statistically significant treatment by presence of ICAS interaction on either the primary outcome of any stroke (hazard ratio for clopidogrel plus aspirin vs aspirin alone: 0.79 [0.47-1.32] vs 1.12 [0.56-2.25]; interaction p=0.522) or the safety outcome of any bleeding event (interaction p=0.277). The results indicated higher rate of recurrent stroke in minor stroke or high-risk TIA patients with ICAS than in those without. However, there was no significant difference in the response to the 2 antiplatelet therapies between patients with and without ICAS in the CHANCE trial. Classification of evidence: This study provides Class II evidence that for patients with acute minor stroke or TIA with and without ICAS identified by MRA, clopidogrel plus aspirin is not significantly different than aspirin alone in preventing recurrent stroke.

Association of Lp-PLA2-A and early recurrence of vascular events after TIA and minor stroke.

To determine the association of lipoprotein-associated phospholipase A2 (Lp-PLA2) measured in the acute period and the short-term risk of recurrent vascular events in patients with TIA or minor stroke. We measured Lp-PLA2 activity (Lp-PLA2-A) in a subset of 3,201 participants enrolled in the CHANCE (Clopidogrel in High-Risk Patients with Acute Non-disabling Cerebrovascular Events) trial. Participants with TIA or minor stroke were enrolled within 24 hours of symptom onset and randomized to single or dual antiplatelet therapy. In the current analysis, the primary outcome was defined as the composite of ischemic stroke, myocardial infarction, or death within 90 days. The composite endpoint occurred in 299 of 3,021 participants (9.9%). The population average Lp-PLA2-A level was 209 ± 59 nmol/min/mL (95% confidence interval [CI] 207-211). Older age, male sex, and current smoking were associated with higher Lp-PLA2-A levels. Lp-PLA2-A was significantly associated with the primary endpoint (adjusted hazard ratio 1.07, 95% CI 1.01-1.13 for every 30 nmol/min/mL increase). Similar results were seen for ischemic stroke alone. Adjustment for low-density lipoprotein cholesterol attenuated the association between Lp-PLA2-A and the primary endpoint (adjusted hazard ratio 1.04, 95% CI 0.97-1.11 for every 30 nmol/min/mL increase). Higher levels of Lp-PLA2-A in the acute period are associated with increased short-term risk of recurrent vascular events.

Clopidogrel With Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) Trial: One-Year Outcomes.

The Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial showed that the combined treatment of clopidogrel and aspirin decreases the 90-day risk of stroke without increasing hemorrhage in comparison with aspirin alone, but provided insufficient data to establish whether the benefit persisted over a longer period of time beyond the trial termination. We report the 1-year follow-up outcomes of this trial. The trial was a randomized, double-blind, placebo-controlled trial conducted at 114 centers in China. We randomly assigned 5170 patients within 24 hours after onset of minor stroke or high-risk transient ischemic attack to clopidogrel-aspirin therapy (loading dose of 300 mg of clopidogrel on day 1, followed by 75 mg of clopidogrel per day for 90 days, plus 75 mg of aspirin per day for the first 21 days) or to the aspirin-alone group (75 mg/d for 90 days). The primary outcome was stroke event (ischemic or hemorrhagic) during 1-year follow-up. Differences in outcomes between groups were assessed by using the Cox proportional hazards model. Stroke occurred in 275 (10.6%) patients in the clopidogrel-aspirin group, in comparison with 362 (14.0%) patients in the aspirin group (hazard ratio, 0.78; 95% confidence interval, 0.65-0.93; P=0.006). Moderate or severe hemorrhage occurred in 7 (0.3%) patients in the clopidogrel-aspirin group and in 9 (0.4%) patients in the aspirin group (P=0.44). The early benefit of clopidogrel-aspirin treatment in reducing the risk of subsequent stroke persisted for the duration of 1-year of follow-up. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00979589.

Soluble CD40L Is a Useful Marker to Predict Future Strokes in Patients With Minor Stroke and Transient Ischemic Attack.

Elevated soluble CD40 ligand (sCD40L) was shown to be related to cardiovascular events, but the role of sCD40L in predicting recurrent stroke remains unclear. Baseline sCD40L levels were measured in 3044 consecutive patients with acute minor stroke and transient ischemic attack, who had previously been enrolled in the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) trial. Cox proportional-hazards model was used to assess the association of sCD40L with recurrent stroke. Patients in the top tertile of sCD40L levels had increased risk of recurrent stroke comparing with those in the bottom tertile, after adjusted for conventional confounding factors (hazard ratio, 1.49; 95% confidence interval, 1.11-2.00; P=0.008). The patients with elevated levels of both sCD40L and high-sensitive C-reactive protein also had increased risk of recurrent stroke (hazard ratio, 1.81; 95% confidence interval, 1.23-2.68; P=0.003). Elevated sCD40L levels independently predict recurrent stroke in patients with minor stroke and transient ischemic attack. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00979589.

Comment: TIA response to antiplatelets stratified by glycated albumin.

In the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) study of TIA, short-term combination therapy with clopidogrel and aspirin reduced recurrent stroke.1 Whether all TIAs benefit equally from this treatment remains unclear. Given that dual antiplatelet therapy also promotes hemorrhage, identifying which TIAs derive the greatest benefit would be clinically useful.

Glycated albumin predicts the effect of dual and single antiplatelet therapy on recurrent stroke.

To determine the relationship of glycated albumin (GA) and the recurrence of stroke in patients on either dual or single antiplatelet therapy. The Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events trial randomized minor ischemic stroke or TIA patients to antiplatelet therapy of clopidogrel plus aspirin or aspirin alone. A subgroup of 3,044 consecutive patients with baseline GA levels from 73 (64%) prespecified clinical sites was analyzed. Patients were categorized into 2 groups based on GA level of 15.5%, the cut point for development of diabetes. The primary outcome was stroke recurrence during 90-day follow-up. Cox proportional hazards models were used to assess the interaction of GA with randomized antiplatelet therapy on their risk of recurrent stroke. Significant interaction of GA levels with the 2 antiplatelet therapy groups was found after adjustment for age, sex, and other conventional confounding factors (p = 0.009). The interaction remained consistent after further adjustment for history of diabetes (p = 0.010). In patients with lower GA level, stroke occurred in 5.5% of patients in the clopidogrel-aspirin group, and 12.7% in the aspirin group (adjusted hazard ratio [HR] 0.40; 95% confidence interval [CI] 0.26-0.61; p < 0.001). Furthermore, in patients with elevated GA level, stroke occurred in 9.2% of patients in the clopidogrel-aspirin group, and 11.4% in the aspirin group (adjusted HR 0.79; 95% CI 0.60-1.05; p = 0.103). GA could be a potential biomarker to predict the effects of dual and single antiplatelet therapy in patients with minor stroke or TIA.

Recurrent stroke was associated with poor quality of life in patients with transient ischemic attack or minor stroke: finding from the CHANCE trial.

To examine the health-related quality of life (HRQOL) in patients with transient ischemic attack (TIA) or minor stroke and assess the impact of recurrent stroke on HRQOL. Health-related quality of life data on patients participated in the Clopidogrel in High-risk patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial were analyzed. The available 90-day EuroQoL data (EQ-5D) were used to calculate EQ-5D index score. Poor HRQOL was defined as an EQ-5D index score ≤0.5. The characteristics of HRQOL and factors predicting poor HRQOL in these patients were then explored. Among the total 5170 patients enrolled, 90-day HRQOL data were obtained from 5104 patients for analysis. The mean EQ-5D index score at day 90 was 0.88 ± 0.21 for all patients, but only 0.42 ± 0.35 for those with recurrent strokes. Poor 90-day HRQOL was found in 294 (5.8%) patients. Patients with poor HRQOL had more strokes during follow-up than patients with good HRQOL (94.9 vs. 4.7%, P < 0.001). Age, history of hypertension and diabetes, and NIHSS at baseline were independent risk factors for predicting poor HRQOL. Stroke recurrence, NIHSS at baseline, age, and minor stroke on admission became independent risk factors once stroke recurrence was added into the model. Stroke recurrence was associated with poor HRQOL in patients with TIA or minor strokes. Interventions focusing on controlling risk factors and prevention of worsening of neurological function may prevent poor HRQOL in these patients.

Initial 3-Weeks’ Apixaban Versus Dual-Antiplatelet Therapy (Clopidogrel and Aspirin) Followed by Clopidogrel Alone in High-Risk Patients with Acute Non-Disabling Cerebrovascular Events (ADANCE): Study Protocol for a Randomized Controlled Trial

Background Nondisabling cerebrovascular events represent the largest group of cerebrovascular disease with a high risk of recurrent stroke. A recent trial demonstrated that dual-antiplatelet therapy (clopidogrel and aspirin), compared with aspirin monotherapy, reduced the risk of recurrent stroke and was not associated with increased risk of hemorrhagic events. Apixaban, a new oral anticoagulant, has been proven to be as safe and effective as traditional anticoagulants while carrying significantly less risk of intracranial hemorrhage. Patients with transient ischemic attack (TIA)/minor stroke might benefit from apixaban treatment; therefore, an adequately powered randomized study is needed.Methods and ResultsThe ADANCE [Apixaban Versus Dual-antiplatelet Therapy (Clopidogrel and Aspirin) in Acute Non-disabling Cerebrovascular Events] study is a randomized, double-blind clinical trial with a target enrollment of 5,500 patients. A 21-day regimen of apixaban or of clopidogrel with aspirin followed by clopidogrel on days 22 through 90 will be administered to randomized participants with acute TIA or minor ischemic stroke. The primary efficacy endpoint is the percentage of patients with any new stroke (ischemic or hemorrhage), including fatal stroke, at day 21. Study visits will be performed on the day of randomization, and at days 7, 22, and 90.DiscussionThe novel oral anticoagulant apixaban has been widely used with fewer adverse effects than traditional anticoagulants. We designed the ADANCE trial to observe the effects of apixaban on recurrent stroke after TIA or minor stroke. The results should better guide the selection of anticoagulant or dual-antiplatelet therapy for patients with acute TIA or minor ischemic stroke.

CHANCE Trial

The Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial tested the effect of early dual antiplatelet treatment for the prevention of secondary stroke within the first 90 days following a qualifying transient ischemic attack (TIA) or minor stroke in 5170 Chinese patients. The trial showed a significant reduction in secondary stroke in patients treated with dual antiplatelet therapy (hazard ratio, 0.68; 95% confidence interval, 0.57–0.81; P <0.001). There was no difference in the rate of moderate or severe hemorrhages (0.3% in both groups; P =0.73).1 CHANCE is critical support for early-onset and short-term intervention of antiplatelet therapy in patients with TIAs and mild strokes. The trial builds on knowledge gained during the past decade, beginning with observations that the risks of stroke early after a TIA or minor stroke are substantial,2–4 with a 2-day risk of stroke following TIA of ≈5%.2,4 Greater attention has since been paid to early evaluation, identification, and treatment of modifiable risk factors and the initiation of antiplatelet treatment for noncardioembolic events within 48 hours of the initial event.5 Previous lysis and recanalization studies have shown the importance of immediate medical management following ischemic events. More recently, studies have addressed the use of antiplatelet agents in an earlier time window, seeking to address the period of highest stroke recurrence risk. The Fast Assessment of Stroke and Transient Ischaemic Attack to Prevent Early Recurrence (FASTER) pilot trial randomized 392 patients with TIA/stroke presenting within 24 hours to aspirin plus clopidogrel or aspirin plus placebo. There was a reduction of stroke within 90 days seen with dual therapy (absolute risk reduction, 3.8%; 95% confidence interval, −9.4 to 1.9; P =0.19) and no significant difference in bleeding events between treatment arms.5 …

Early Dual Versus Mono Antiplatelet Therapy for Acute Non-Cardioembolic Ischemic Stroke or Transient Ischemic Attack

Background— Emerging studies suggest that early administration of dual antiplatelet therapy may be better than monotherapy for prevention of early recurrent stroke and cardiovascular outcomes in acute ischemic stroke and transient ischemic attack (TIA). We performed a meta-analysis of randomized, controlled trials evaluating dual versus mono antiplatelet therapy for acute noncardioembolic ischemic stroke or TIA. Methods and Results— We assessed randomized, controlled trials investigating dual versus mono antiplatelet therapy published up to November 2012 and the CHANCE trial (Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events), for efficacy and safety outcomes in adult patients with acute noncardioembolic ischemic stroke or TIA with treatment initiated within 3 days of ictus. In total, 14 studies of 9012 patients were included in the systematic review and meta-analysis. Dual antiplatelet therapy significantly reduced risk of stroke recurrence (risk ratio, 0.69; 95% confidence interval, 0.60–0.80; P &lt;0.001) and the composite outcome of stroke, TIA, acute coronary syndrome, and all death (risk ratio, 0.71; 95% confidence interval, 0.63–0.81; P &lt;0.001) when compared with monotherapy, and nonsignificantly increased risk of major bleeding (risk ratio, 1.35; 95% confidence interval, 0.70–2.59, P =0.37). Analyses restricted to the CHANCE Trial or the 7 double-blind randomized, controlled trials showed similar results. Conclusions— For patients with acute noncardioembolic ischemic stroke or TIA, dual therapy was more effective than monotherapy in reducing risks of early recurrent stroke. The results of the CHANCE study are consistent with previous studies done in other parts of the world.

Combination Aspirin and Clopidogrel for Secondary Prevention of Ischemic Stroke

Though antiplatelet agents are the mainstay of antithrombotic therapy for secondary prevention of noncardioembolic cerebral ischemic events, the efficacy of combination aspirin and clopidogrel has yet to be clarified by clinical trials. Current evidence suggests that there is no role for long-term combination of aspirin/clopidogrel for secondary stroke prevention. Recent preliminary data from the CHANCE (Clopidogrel in High-risk Patients with Acute Non-disabling Cerebrovascular Events) trial suggests that stroke recurrence at 90days is reduced by a short course (21days) of combination aspirin/clopidogrel initiated within 24hours of minor stroke or TIA (Transient Ischemic Attack) compared with aspirin alone [1••] (Table1). Other ongoing trials, which are also investigating the role of short-term combination antiplatelet therapy initiated immediately after minor stroke and TIA, will determine if these findings will be replicated.

Rationale and design of a randomized, double-blind trial comparing the effects of a 3-month clopidogrel-aspirin regimen versus aspirin alone for the treatment of high-risk patients with acute nondisabling cerebrovascular event

Acute nondisabling cerebrovascular events are common and often portend a disabling stroke. Aspirin is the only antiplatelet agent to have been studied in patients presenting acutely with a cerebrovascular event, but the effect is modest and is reduced by a small increased risk of intracerebral hemorrhage. Treatment with the combination of clopidogrel and aspirin might be beneficial when taken soon after a transient ischemic attack (TIA) or minor stroke. The CHANCE trial is a randomized, double-blind, multicenter, placebo-controlled trial to test an aggressive antiplatelet regimen in acute minor stroke or TIA. The study will randomize 5,100 Chinese patients with acute TIA or minor stroke to receive a 3-month regimen of clopidogrel initiated with a loading dose of 300 mg followed by 75 mg/d, combined with aspirin 75 mg/d during the first 21 days, or a 3-month regimen of aspirin 75 mg/d alone. The primary efficacy end point is percentage of patients with any stroke (ischemic or hemorrhage) at 3 months. Study visits will be performed on the day of randomization, at day 21, and at day 90. CHANCE will determine whether clopidogrel combined with aspirin can prevent more strokes after acute minor stroke or TIA compared with aspirin alone-with an acceptable risk profile.

THE FUTURE OF THE ASSOCIATION

<h3>Objective</h3> Many patients receiving dual antiplatelet therapy still had recurrent strokes. We aimed to identify factors associated with recurrent stroke at 90 days in patients receiving dual antiplatelet therapy in Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events trial. <h3>Methods</h3> Patients with transient ischaemic attack or minor stroke receiving clopidogrel and aspirin in the trial were analysed in the study. The primary outcome was recurrent stroke within 90 days after the index event. Cox proportional hazard model with backward selection was used to identify factors associated with stroke. <h3>Results</h3> Among 2584 patients, 212 (8.2%) had a recurrent stroke, 216 (8.4%) had a composite of stroke, myocardial infarction, or vascular death and 204 (7.9%) had ischaemic stroke within 90 days. Multivariate analysis identified the following factors associated with stroke: history of hypertension with poor blood pressure control (HR, 1.92; 95% CI 1.22 to 3.03), the high baseline National Institute of Health Stroke Scale (NIHSS) score of 2 and 3 (2.12 (1.07 to 4.21) and 4.11 (2.05 to 8.22), respectively), time from onset to randomisation of &lt;12 hours (1.47 (1.12 to 1.94)), the lipid-lowering therapy (0.61 (0.47 to 0.83)), the open-label aspirin dose at day 1 of ≥300 mg (1.98 (1.45 to 2.69)). Intracranial arterial stenosis (ICAS) was significantly associated with stroke in the sensitivity analysis (2.17 (1.16 to 4.04)). <h3>Conclusions</h3> The high baseline NIHSS score, hypertension with poor blood pressure control, ICAS, time from onset to randomisation of less than 12 hours and no lipid-lowering therapy were associated with stroke, suggesting that patients with identified predictors still remain to be at high risk of recurrent stroke although being under the dual antiplatelet therapy. <h3>Trial registration number</h3> http://clinicaltrials.gov/show/NCT00979589. ClinicalTrials.gov number: NCT00979589