Aspirin For Secondary Stroke Prevention Research Articles

Atrial cardiopathy biomarkers and atrial fibrillation in the ARCADIA trial.

ARCADIA compared apixaban to aspirin for secondary stroke prevention in patients with cryptogenic stroke and atrial cardiopathy. One possible explanation for the neutral result is that biomarkers used did not optimally identify atrial cardiopathy. We examined the relationship between biomarker levels and subsequent detection of AF, the hallmark of atrial cardiopathy. Patients were randomized if they met criteria for atrial cardiopathy, defined as P-wave terminal force >5000 μV*ms in ECG lead V1 (PTFV1), NT-proBNP >250 pg/mL, or left atrial diameter index (LADI) ⩾3 cm/m2. For this analysis, the outcome was AF detected per routine care. Of 3745 patients who consented to screening for atrial cardiopathy, 254 were subsequently diagnosed with AF; 96 before they could be randomized and 158 after randomization. In unadjusted analyses, ln(NT-proBNP) (RR per SD, 1.99; 95% CI, 1.85-2.13), PTFV1 (RR per SD, 1.15; 95% CI, 1.03-1.28) and LADI (RR per SD, 1.34; 95% CI, 1.20-1.50) were associated with AF. In a model containing all 3 biomarkers, demographics, and AF risk factors, age (RR per 10 years, 1.24; 95% CI, 1.09-1.41), ln(NT-proBNP) (RR per SD, 1.88; 95% CI, 1.67-2.11) and LADI (RR per SD, 1.25; 95% CI, 1.14-1.37) were associated with AF. These three variables together had a c-statistic of 0.82 (95% CI, 0.79-0.85) but only modest calibration. Discrimination was attenuated in sensitivity analyses of patients eligible for randomization who may have been more closely followed for AF. Biomarkers used to identify atrial cardiopathy in ARCADIA were moderately predictive of subsequent AF.

Comparison of Aspirin and P2Y12 Inhibitors for Secondary Prevention of Ischaemic Stroke: A Systematic Review and Meta-analysis.

P2Y12 inhibitors have been widely used as an alternative to aspirin in clinical practice for secondary stroke prevention. We aimed to compare the efficiency and safety of P2Y12 inhibitors and aspirin for stroke prevention in patients with previous stroke or transient ischaemic attack (TIA). PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched. All randomized trials that compared P2Y12 inhibitors with aspirin among patients with stroke were included. The primary efficacy outcomes of our meta-analysis included stroke, vascular events, and all-cause death. The primary safety outcome was minor or major bleeding events. The search identified 4 randomized clinical trials comparing P2Y12 inhibitors with aspirin for secondary stroke prevention that collectively enrolled 24508 patients (12253 received P2Y12 inhibitor and 12255 received aspirin). Pooled results from the random-effects model showed that there were no significant differences in the risk of any stroke (OR 0.90 (0.78-1.04); I²=56.9%), vascular event (OR 0.91 (0.74-1.13); I²=78.3%), all-cause death (OR 0.98 (0.83-1.17); I²=0%), or minor or major bleeding (OR 1.13 (0.70-1.82); I²=79%) among patients who received a P2Y12 inhibitor or aspirin. P2Y12 inhibitors were associated with a significantly lower risk of recurrent ischaemic stroke (OR 0.84 (0.73- 0.96); I²=25%) than aspirin. This meta-analysis suggests that P2Y12 inhibitors are more effective than aspirin in preventing recurrent ischaemic stroke among ischaemic stroke patients despite the absence of any effect on a new ischaemic or haemorrhagic stroke, a new clinical vascular event, all-cause death, and major or minor bleeding events.

Abstract TP30: Retention And Trial Coordinator Outreach In A Multicenter Clinical Trial During Covid 19

Introduction: Human subjects research requires the retention of enrolled patients in order to provide accurate data. The COVID-19 pandemic introduced unique challenges for clinical trial coordination. AtRial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke (ARCADIA) is an NIH StrokeNet national clinical trial designed to test superiority of apixaban over aspirin for secondary stroke prevention in patients with cryptogenic stroke and atrial cardiopathy. We sought to explore the methods that allowed our site to maintain a high retention rate in our local ARCADIA population. Methods: Prior to COVID-19, our trial coordinator (JP), conducted home visits to enroll and complete study visits every 3 months for the first year. This was approved by our local institution, IRB and study sponsor. During COVID-19 precautions, phone contact was maintained and encouraged. Face-to-face visits were not possible, but our coordinator continued to deliver study drug while maintaining distancing precautions. This was followed by a phone call to remind patients of drug instructions and dosages, and inquiring about any adverse events that may have occurred since the last visit. We evaluated the number of follow up visits before and during the COVID lockdown (March through June 2020). Results: Enrollments decreased during the pandemic, in large part due to a study-wide pause in recruitment efforts. The median monthly follow-up prior to COVID-19 was 3, and increased to 5 during lockdown. Before, during and after COVID, our local retention rate has remained 100%. Conclusions: In conclusion, despite complicating factors of COVID-19, our local coordinator’s retention rate remained 100% during the COVID-19 pandemic and our median number of monthly follow up visits increased, which may be attributable to our coordinator’s efforts of socially distanced home visits and frequent communication.

Abstract TP190: Association Of Age, Sex, Race, Weight, And Height With Biomarkers Of Atrial Cardiopathy In Patients With Embolic Stroke Of Undetermined Source

Introduction: Elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) and prolonged P-wave terminal force in V1 (PTFV1) on 12-lead ECG are associated with increased risk of atrial fibrillation and stroke. Age is positively associated with NT-proBNP, men have lower levels than women, and Blacks have lower levels than Whites. Although both weight and height are positively related to risk of atrial fibrillation, both are negatively associated with NT-proBNP. We explored associations among these variables in patients with embolic stroke of undetermined source (ESUS). Methods: In an ongoing randomized trial of secondary stroke prevention, AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke (ARCADIA), as of 2021 August, 2616 ESUS patients were consented for the trial and screened for atrial cardiopathy with serum NT-proBNP and PTFV1. Baseline information on age, sex, race, weight, and height were used in sequential linear regression analyses to understand associations with ln(NT-proBNP) and ln(PTFV1). Results: In age-adjusted models of ln(NT-proBNP), significant negative associations were found for weight (beta -0.004, p=0.02) and height (beta -0.013, p<001). When sex was added to these models, significance was lost for weight and height. In a final model including all of these variables (N=2400), significant associations were found for age (beta 0.044, p<0.001), sex (men with lower levels than women, beta -0.448, p<0.001) and race (Blacks with lower levels than Whites, beta -0.141, p=0.027 and Asians with lower levels than Whites, beta -0.512, p=0.009). In similar sequential models for ln(PTFV1), only race was significant; in a final model, Blacks had higher values than Whites, beta 0.275, p<0.001. No evidence was found in these models to suggest violation of linearity. Conclusions: In a population of patients with ESUS, associations of weight and height with NT-proBNP are confounded not by age but by sex. Key associations with NT-proBNP include age, sex, and race. In ARCADIA, understanding these associations may be important in individualizing predictions about which ESUS patients with atrial cardiopathy are most likely to benefit from apixaban over aspirin for secondary stroke prevention.

Cilostazol Versus Aspirin for Secondary Stroke Prevention: Systematic Review and Meta-Analysis

ObjectivesCilostazol has promise as an alternative to aspirin for secondary stroke prevention given its vasodilatory and anti-inflammatory properties in addition to platelet aggregation inhibition. We aimed to conduct a systematic review and meta-analysis to estimate the efficacy and safety of cilostazol compared to aspirin for stroke prevention in patients with previous stroke or transient ischemic attack (TIA). Materials and methodsWe searched PubMed and the Cochrane Central Register of Controlled Trials from 1996 to 2019. Randomized clinical trials that compared cilostazol to aspirin and reported the endpoints of ischemic stroke, intracranial hemorrhage and any bleeding were included. A random-effects estimate was computed based on the Mantel-Haenszel method. The pooled risk estimates with 95% confidence intervals were compared between cilostazol and aspirin. ResultsThe search identified 5 randomized clinical trials comparing cilostazol vs. aspirin for secondary stroke prevention that collectively enrolled 7240 patients, all from Asian countries (3615 received cilostazol and 3625 received aspirin). Pooled results from the random-effects model showed that cilostazol was associated with significantly lower risk of recurrent ischemic stroke (RR 0.68; 95% CI, 0.54 to 0.87), intracranial hemorrhage (RR 0.42; 95% CI, 0.27 to 0.65) and any bleeding (RR 0.71; 95% CI, 0.55 to 0.91). ConclusionsThis meta-analysis suggests that cilostazol is more effective than aspirin in preventing recurrent ischemic stroke with lower risk of intracranial hemorrhage and other bleeding. Since all trials to date are from Asian countries, confirmatory trials of cilostazol for secondary stroke prevention in other populations are needed.

High-Sensitivity Cardiac Troponin T for Risk Stratification in Patients With Embolic Stroke of Undetermined Source.

Optimal secondary prevention for patients with embolic stroke of undetermined source (ESUS) remains unknown. We aimed to assess whether high-sensitivity cardiac troponin T (hs-cTnT) levels are associated with major vascular events and whether hs-cTnT may identify patients who benefit from anticoagulation following ESUS. Data were obtained from the biomarker substudy of the NAVIGATE ESUS trial, a randomized controlled trial testing the efficacy of rivaroxaban versus aspirin for secondary stroke prevention in ESUS. Patients were dichotomized at the hs-cTnT upper reference limit (14 ng/L, Gen V, Roche Diagnostics). Cox proportional hazard models were computed to explore the association between hs-cTnT, the combined cardiovascular end point (recurrent stroke, myocardial infarction, systemic embolism, cardiovascular death), and recurrent ischemic stroke. Among 1337 patients enrolled at 111 participating centers in 18 countries (mean age 67±9 years, 61% male), hs-cTnT was detectable in 95% and at/above the upper reference limit in 21%. During a median follow-up of 11 months, the combined cardiovascular end point occurred in 68 patients (5.0%/y, rivaroxaban 28 events, aspirin 40 events; hazard ratio, 0.67 [95% CI, 0.41-1.1]), and recurrent ischemic stroke occurred in 50 patients (4.0%/y, rivaroxaban 16 events, aspirin 34 events, hazard ratio 0.45 [95% CI, 0.25-0.81]). Annualized combined cardiovascular end point rates were 8.2% (9.5% rivaroxaban, 7.0% aspirin) for those above hs-cTnT upper reference limit and 4.8% (3.1% rivaroxaban, 6.6% aspirin) below with a significant treatment modification (P=0.04). Annualized ischemic stroke rates were 4.7% above hs-cTnT upper reference limit and 3.9% below, with no suggestion of an interaction between hs-cTnT and treatment (P=0.3). In patients with ESUS, hs-cTnT was associated with increased cardiovascular event rates. While fewer recurrent strokes occurred in patients receiving rivaroxaban, outcomes were not stratified by hs-cTn results. Our findings support using hs-cTnT for cardiovascular risk stratification but not for decision-making regarding anticoagulation therapy in patients with ESUS. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.

Abstract WMP112: Cilostazol versus Aspirin for Secondary Stroke Prevention: Systematic Review and Meta-Analysis

Introduction: Cilostazol has promise as an alternative to aspirin for secondary stroke prevention given its vasodilatory and anti-inflammatory properties in addition to platelet aggregation inhibition. We conducted a systematic review and meta-analysis to estimate the comparative effectiveness and safety of cilostazol compared to aspirin for stroke prevention in patients with previous stroke or TIA. Hypothesis: Cilostazol is more effective than aspirin in preventing recurrent ischemic stroke with lower risk of intracranial hemorrhage and bleeding. Methods: We searched PubMed and the Cochrane Central Register of Controlled Trials from inception to 2019. Randomized clinical trials that compared cilostazol vs aspirin and reported the endpoints of ischemic stroke, intracranial hemorrhage and bleeding were included. A random-effects estimate was computed based on Mantel-Haenszel methods. The pooled estimates with 95% confidence intervals were compared between cilostazol and aspirin and displayed as forest plots (Figure). Results: The search identified 5 randomized clinical trials comparing cilostazol vs aspirin for secondary stroke prevention that enrolled 7,240 patients from primarily Asian countries (3,615 received cilostazol and 3,625 received aspirin). The pooled results from the random-effects model showed that cilostazol was associated with significantly lower risk of recurrent ischemic stroke (Hazard ratio [HR] 0.70; 95%CI, 0.54-0.89), intracranial hemorrhage (HR 0.41; 95%CI, 0.25-0.65) and bleeding (HR 0.71; 95%CI, 0.55-0.91). See forest plots. Conclusion: This meta-analysis suggests cilostazol is more effective than aspirin in the prevention of recurrent ischemic stroke with lower risk of intracranial hemorrhage and bleeding. Confirmatory randomized trials of cilostazol for secondary stroke prevention to be performed in more generalizable populations are needed.

Cryptogenic Stroke: Diagnostic Workup and Management.

Cryptogenic stroke describes a subset of ischemic stroke for which no cause can be found despite a structured investigation. There are a number of putative mechanisms of cryptogenic ischemic stroke including a covert structural cardiac lesion, paroxysmal atrial fibrillation, hypercoagulable state or undiagnosed malignancy. Because many of these proposed mechanisms are embolic - and based on studies of thrombus history showing commonalities between thrombus composition between cardioembolic and cryptogenic strokes - the concept of embolic stroke of undetermined source (ESUS) (Hart et al. Lancet Neurol. 13(4):429-38, 2014; Stroke. 48(4):867-72, 2017) has been proposed to describe cryptogenic strokes that may warrant systemic anticoagulation. In this review, we discuss the phenomena of cryptogenic stroke, ESUS and a proposed management pathway. 1. The concept of ESUS was proposed in 2014 as a potentially useful therapeutic entity. Two recent trials - NAVIGATE-ESUS (Hart et al. N Engl J Med. 378(23):2191-201, 2018) and RESPECT-ESUS (Diener 2018) were proposed based on this concept. They were negative for their primary endpoint and for the secondary endpoint of ischemic stroke recurrence. Post-hoc analysis of the WARSS trial (Longstreth et al. Stroke. 44(3):714-9, 2013) suggested that people with elevated pro-BNP benefited from systemic anticoagulation whereas those with a normal pro-BNP did not. This led to the hypothesis that a subgroup of patients at higher risk for embolism from the left atrium would benefit from anticoagulation, even if the WARSS trial was negative for the primary endpoint. Thus, the ARCADIA trial (Kamel et al. Int J Stroke. 14(2):207-14, 2019) was proposed - a randomized, active-control, multi-center trial comparing apixaban with aspirin for secondary stroke prevention in patients with ESUS and biomarkers of left atrial cardiopathy. This trial is actively recruiting. 2. Carotid web - an intimal form of fibromuscular dysplasia - has come to increased prominence in the literature as a cause of embolic stroke. It is a non-stenosis, non-atherosclerotic lesion in the posterior wall of the internal carotid artery that leads to pooling with stasis of blood distal to the lesion and, as a consequence, embolic stroke. It is not usually detected by a standard stroke workup as it masquerades as non-calcified atherosclerosis and does not cause hemodynamically significant stenosis. There have been two major recent papers - a meta-analysis in Stroke (Zhang et al. Stroke. 49(12):2872-6, 2018) and narrative review in JAMA Neurology (Kim et al. JAMA Neurol. 2018) - that addressed this topic. Cryptogenic stroke describes a stroke for which no cause has been found. ESUS is a more precisely-defined entity that mandates a specific workup and implicates remote embolism as a cause of stroke. In ESUS, the options for further investigation include long-term cardiac monitoring, transesophageal echocardiography, investigation for occult malignancy or arterial hypercoagulability. Options for management include anti-platelet therapy (the current standard of care), empiric anticoagulation or enrollment in to a clinical trial examining the use of NOACs compared with aspirin for secondary prevention (such as ARCADIA or ATTICUS). In a person less than 60years old with ESUS and a patent foramen ovale the risk of a recurrent stroke is low but recent trials have suggested that percutaneous device closure reduces this risk further with an acceptable complication rate.

Aspirin better than clopidogrel on major adverse cardiovascular events reduction after ischemic stroke: A retrospective nationwide cohort study.

Several clinical trials reported that clopidogrel was superior to aspirin in secondary stroke prevention by reducing the risk of major adverse cardiovascular events (MACE). We aimed to compare the efficacy of clopidogrel with aspirin in reducing one-year risk of MACE based on real-world evidence from Taiwan Health Insurance Database. We identified ischemic stroke patients between 2000 and 2012 who took aspirin or clopidogrel within 7 days of stroke onset for 1-year follow-up. The primary outcome was one-year MACE including recurrent stroke, acute myocardial infarction, and death. Propensity score matching and conditional Cox proportional hazards regression were conducted to control the confounding factors. From 9,089 ischemic stroke patients, we found 654 patients on aspirin and 465 patients on clopidogrel who met the selective inclusion criteria. After propensity score matching, 379 patients were selected from each group. The clopidogrel group had a 1.78-fold MACE risk compared with the aspirin group at one-year follow-up (95% CI = 1.41-2.26, p<0.01). The MACE-free rate in the aspirin group was 15.74% higher than in the clopidogrel group at one-year follow-up. Sub-analysis of the three components of MACE showed that clopidogrel conferred higher risk of recurrent stroke (OR 1.43, 95% CI = 1.06-1.92, p 0.02) and acute myocardial infarction (OR 3.72, 95% CI = 1.04-13.3, p 0.04), but no different risk of death than that of aspirin. Among first-ever ischemic stroke patients, secondary stroke prevention using clopidogrel was associated with higher rates of MACE than aspirin. Aspirin might have better efficacy in secondary stroke prevention and was associated with lower risk of MACE. The real-world evidence raises the need to re-assess the current therapeutic options in secondary stroke prevention applying aspirin vs. clopidogrel.

Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial

Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial. NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy. Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22-1·36), and the risk was similar for those without known PFO (1·06; 0·84-1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51-8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69-4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24-0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity. Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted. Bayer and Janssen.

Suitability of aspirin for secondary stroke prevention pooled data reanalysis of aspirin for cerebral infarction prevention: Porcelain study

Suitability of aspirin for secondary stroke prevention pooled data reanalysis of aspirin for cerebral infarction prevention: Porcelain study

Aspirin's Benefits Were Previously Underestimated and Are Primarily Accrued in the Acute Setting.

Urgent management of transient ischemic attack (TIA) or minor stroke within 24 hours of symptom onset can reduce the 3-month risk of stroke by ≤80%.1,2 This risk had been previously estimated at 10% to 12% or more based on data from the 1990s and early 2000s,3,4 but more recent data suggest that this risk may now be <3%.1,2,5 Guidelines recommend urgent assessment and treatment, including risk factor control, carotid endarterectomy or stenting, and immediate oral anticoagulation for documented atrial fibrillation or aspirin therapy for most other cases.6–9 Because the risk of recurrent stroke is highest in the first few days,3,4 urgent TIA clinics, such as those reported in the SOS-TIA (SOS-Transient Ischemic Attack) or EXPRESS studies (Early Use of Existing Preventive Strategies for Stroke),1,2 have used dual antiplatelet therapy in the acute setting based on meta-analyses of previous trials. In SOS-TIA,1 the referring physician was instructed by telephone to immediately initiate a 300 mg loading dose of aspirin even before the initial evaluation or hospital admission and before any brain imaging. Whether this immediate empirical antiplatelet regimen partly explains the low recurrence rates observed in the SOS-TIA and EXPRESS studies is not clear because no randomized trial has yet validated this approach for TIA and minor ischemic stroke. In a recent issue of The Lancet , Rothwell et al10 report the results of a new meta-analysis of 12 randomized controlled trials of aspirin versus control for TIA or minor stroke that was focused on the time course of benefit from aspirin therapy. While the overall benefits of aspirin for secondary stroke prevention are well-established, …

Ticagrelor Found Not Superior to Aspirin for Secondary Stroke Prevention

Ticagrelor Found Not Superior to Aspirin for Secondary Stroke Prevention

Stroke of undetermined cause: workup and secondary prevention.

The purpose of this review is to update the reader on current concepts of workup and secondary prevention in patients with stroke of undetermined cause. Clinical research in patients with cryptogenic stroke has been hampered by the lack of standardized, widely accepted diagnostic criteria. The new definition of 'Embolic stroke of undetermined etiology' postulates an embolic mechanism of ischemic stroke. It is based on the exclusion of lacunar infarction by brain imaging, arterial stenosis more than 50% or dissection of the respective brain-supplying artery by computed tomography/magnetic resonance-angiography or ultrasound, atrial fibrillation by at least 24 h EKG monitoring, as well as some rare etiologies such as vasculitis, drug abuse, or coagulopathies. However, it still comprises many patients with atherosclerotic etiologies (but <50% stenosis) as well as covert paroxysmal atrial fibrillation which can be detected by repeated Holter EKG or an implantable device. A patent foramen ovale can be found in up to 58% of cryptogenic stroke patients, but causality in an individual patient remains uncertain and can only be statistically inferred. The new concept of embolic stroke of undetermined etiology enabled three ongoing randomized controlled trials which investigate oral anticoagulation versus aspirin for secondary stroke prevention.

Dual antiplatelet therapy with clopidogrel and aspirin for secondary stroke prevention.

Stroke is a major public health concern worldwide, and 25% of stroke victims would have another stroke. Although administration of antiplatelet agents has been confirmed to be one of the major approaches for secondary prevention of noncardioembolic stroke, the short-term or long-term use of aspirin plus clopidogrel for secondary stroke prevention remains to be controversial. This article aims at providing a comprehensive review of the evidence on the use of aspirin plus clopidogrel for secondary stroke prevention, with special focus on important studies that may impact clinical practice of treating patients with stroke or transient ischemic attack.

Benefit of Cilostazol in Patients with High Risk of Bleeding: Subanalysis of Cilostazol Stroke Prevention Study 2

Background: The Cilostazol Stroke Prevention Study 2 (CSPS 2) showed that cilostazol significantly reduced the risk of stroke by 25.7% relative to aspirin, with significantly fewer hemorrhagic events, in patients with prior ischemic stroke, excluding cardioembolic stroke. However, whether the benefit of cilostazol is sustained in patients with a high risk of bleeding has not been examined. Methods: We conducted a subanalysis of CSPS 2 to examine whether known risk factors for hemorrhagic stroke, such as stroke subtype and systolic blood pressure (SBP), influence the efficacy of the study drugs on hemorrhagic stroke. The relative risk reduction of hemorrhagic stroke was determined from the incidences calculated by the person-year method. The cumulative incidence rates of ischemic stroke and hemorrhagic stroke were estimated and plotted using the Kaplan-Meier method. Incidences of serious hemorrhage and hemorrhage requiring hospital admission were also evaluated in the two treatment groups. Hazard ratios (HR) and 95% confidence intervals (95% CI) calculated by the Cox proportion hazard model for cilostazol versus aspirin were assessed, and a log-rank test was used for the comparison between treatments. Results: The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group among patients with prior lacunar stroke (0.36 vs. 1.20% in person-year, HR 0.35, 95% CI 0.18-0.70, p < 0.01), but not among those with prior atherothrombotic stroke (0.31 vs. 0.59% in person-year, HR 0.53, 95% CI 0.14-2.0, p = 0.34). The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group throughout all SBP categories (Poisson regression model including time-dependent covariates, p < 0.01) including SBP above 140 mm Hg (cilostazol 0.45% vs. aspirin 1.44% in person-year; Poisson regression model including time-dependent covariates, p = 0.02). Cilostazol, compared with aspirin, significantly reduced the incidence of cerebral hemorrhage (HR 0.36, 95% CI 0.19-0.70, p < 0.01), overall hemorrhage requiring hospital admission (HR 0.53, 95% CI 0.29-0.97, p = 0.04), and gastrointestinal (GI) bleeding requiring hospital admission (HR 0.44, 95% CI 0.21-0.90, p = 0.03). Conclusions: Hemorrhagic stroke was less frequent in the cilostazol group than in the aspirin group among patients with lacunar stroke as well as those with increased blood pressure levels. As for extracranial hemorrhage requiring hospitalization, GI bleeding was also less frequent in the cilostazol than in the aspirin group. Cilostazol is supposed to be a therapeutic option to replace aspirin for secondary stroke prevention, especially in these subgroups with high risks for hemorrhagic events.

Abstract WMP104: Effect Of Addition Of Clopidogrel To Aspirin On Stroke Incidence: Meta-analysis Of Randomized Trials

Introduction: Current guidelines do not support the use of aspirin and clopidogrel for secondary stroke prevention due to a nonsignificant reduction in stroke and a significant increase in life-threatening bleeding. Hypothesis: We assessed the hypothesis that the effect of dual antiplatelet therapy on stroke prevention would be different depending on the trial cohort. Methods: We conducted a meta-analysis of published randomized trials comparing the combination of clopidogrel and aspirin versus aspirin alone that reported stroke incidence. Statistical heterogeneity across trials was evaluated using the I2 index and the Chi-square test for heterogeneity. Results: Thirteen randomized trials were included with a total of 90,433 participants (mean age 63 years; 63% male) with a mean follow up of 1.0 years and 2011 strokes. Stroke was reduced 19% by dual antiplatelet therapy (OR=0.81; 95% CI 0.74-0.89) with no evidence of heterogeneity of effect across different trial populations (I2 index = 5%, p = 0.4 for heterogeneity). Dual antiplatelet therapy reduced ischemic stroke by 23% (OR=0.77; 95% CI 0.70-0.85). The risk of major bleeding was increased by 40% (OR 1.40, 95% CI 1.26-1.55) by dual antiplatelet therapy; there was a nonsignificant 2% increase in intracerebral hemorrhage (OR=1.12, 95% CI 0.86-1.46). Conclusions: Contrary to our hypothesis, this meta-analysis demonstrates a substantial relative risk reduction in stroke by clopidogrel plus aspirin vs. aspirin alone that is consistent across different trial cohorts. Given this findings the strong proscription against the use of clopidogrel plus aspirin for secondary stroke prevention advocated by most current guidelines may warrant reconsideration.

Abstract 2559: Subgroup analysis of the Cilostazol Stroke Prevention Study 2 (CSPS 2)

Background: Cilostazol has been suggested to be superior to aspirin in secondary stroke prevention in patients with non-cardioembolic ischemic stroke from the results of the CSPS 2 and meta-analysis of the Cochrane Collaboration. The purpose of this study was to investigate the efficacy and safety of cilostazol and aspirin in the various subgroups of the study population. Methods: Recurrence of stroke was studied in the subgroup analysis according to patient's characteristics, concomitant use of drugs, and ischemic stroke subtypes. Heterogeneity of stroke risk between subgroups classified by each variable was analyzed using Log-rank test. Results: A total of 2672 Japanese patients enrolled in the CSPS 2 (Lancet Neurol 2010;9:959-68) were analyzed. A tendency of interaction was observed in alcohol drinking (p=0.0782) and dyslipidemia (p=0.0873). Stroke rates in alcohol drinkers (HR 0.574, 95% CI 0.386-0.855) and non-dyslipidemic patients (HR 0.608, 95% CI 0.426-0.869) were lower in the cilostazol group than in the aspirin group. A significant interaction was demonstrated in the use of angiotensin receptor blocker (ARB) (p=0.0267). Stroke rate in non-users of ARB was lower in the cilostazol group than in the aspirin group (HR 0.542, 95% CI 0.370-0.793), while it was not different between both groups in users of ARB (HR 1.016, 95% CI 0.677-1.524). There was no significant difference in the rate of ischemic stroke between both treatment groups in patients with atherothrombotic stroke (cilostazol 1.77%/year, aspirin 2.45%/year, p=0.2808) and lacunar stroke (cilostazol 2.68%, aspirin 2.88%/year, p=0.7198). The rate of hemorrhagic stroke was not different between both groupsin patients with atherothrombotic stroke (cilostazol 0.31%/year, aspirin 0.59%/year, p=0.3444), while it was significantly much lower in the cilostazol group (0.36%/year) than in the aspirin group (1.20%/year) (RRR 65.0%, p=0.0030) among patients with lacunar stroke. Conclusion: Superiority of cilostazol over aspirin in secondary stroke prevention tended to be more obvious in alcohol drinkers and non-dyslipidemics. A significant interaction was observed in the concomitant use of ARB, which might be related to pleiotropic effects of cilostazol and ARB. Cilostazol has an advantage over aspirin in lower risk of cerebral hemorrhage especially in Japanese patients with lacunar stroke.

Abstract 2455: Cilostazol For Men, But Aspirin For Women In Stroke Prevention For Patients With Cerebral Infarction - Pooled Analysis Of CSPS 2 And CASISP -

Objectives It has been reported that aspirin is effective for primary stroke prevention in women, but not men. Here, we conducted subgroup analysis of pooled results of Cilostazol versus Aspirin for Secondary Ischemic Stroke Prevention [CASISP] in China (Lancet Neurol 7: 494 - 499, 2008) and Cilostazol Stroke Prevention Study 2 [CSPS 2] in Japan (Lancet Neurol 9: 959 - 968, 2010) to evaluate gender differences in the effects of cilostazol and aspirin in secondary stroke prevention. Methods The analysis included 2410 men (cilostazol 1200, aspirin 1210) and 981 women (cilostazol 497, aspirin 484) from the two independent studies. Incidences of stroke as well as baseline patient characteristics, were compared between men and women in each group. Subgroup analysis, with stroke as an endpoint, was also conducted regarding age (≥60 yrs vs &lt;60 yrs), smoking and drinking habit, complications, stroke subtypes etc. in both genders. Results At baseline, the rates of patients with smoking and drinking habits and with diabetes mellitus were higher in men versus women, and the rates of older (≥60 yrs) patients and those with hypertension and dyslipidemia were higher in women versus men in both the cilostazol group and aspirin group. However, there was no significant difference in the baseline characteristics of men or of women between the cilostazol and aspirin groups. In men, stroke was significantly reduced by cilostazol versus aspirin (cilostazol 2.89%/person·year, aspirin 4.50%/person·year; p=0.0032). But, in women, aspirin was slightly, though not significantly, more effective than cilostazol (2.40% vs. 2.66%; p=0.7498). Intracranial hemorrhage was also significantly reduced in men by cilostazol versus aspirin (p&lt;0.001, 0.25% vs 1.22%), but not in women (p=0.8813, 0.53% vs 0.48%). Cilostazol was significantly more effective than aspirin in men with older age (≥60 yrs), drinking habit or lacunar infarction. But these differences were not observed in women. Furthermore, hemorrhagic side effects such as gastrointestinal hemorrhage were not different in women in the aspirin group compared with the cilostazol group. Conclusions Gender differences in efficacy of antiplatelet agents appear to exist for secondary stroke prevention. Cilostazol was more effective in men, but aspirin may be the first choice drug for women.

Cilostazol combined with aspirin prevents early neurological deterioration in patients with acute ischemic stroke: A pilot study

Recent randomized trials have shown that cilostazol is superior to aspirin for secondary stroke prevention. We hypothesized that combining cilostazol with aspirin is more effective than aspirin alone in patients with acute ischemic stroke. This randomized study compared the effects of oral aspirin alone to aspirin plus cilostazol in patients with non-cardioembolic ischemic stroke within 48 h of stroke onset. NIH Stroke Scale (NIHSS) and modified Rankin Scale (mRS) scores were checked before and after 14 days and 6 months of drug administration. The primary and secondary endpoints were neurological deterioration or stroke recurrence (NIHSS score ≥ 1) within 14 days and 6 months, respectively. For statistical analysis, on-treatment analysis was conducted. Seventy-six patients were enrolled in the study. The primary endpoint was significantly higher in the aspirin group than in the aspirin plus cilostazol group (28% vs. 6%, relative risk (RR): 0.21, 95% confidence intervals (CI): 0.05–0.87, p = 0.013). Among the patients who did not reach these endpoints, the mean improvement in the NIHSS score at day 14 tended to be better (− 1.8 ± 1.2 vs. − 1.2 ± 1.0, p = 0.078) and the frequency of the favorable functional status of mRS 0–1 at month 6 was significantly higher (RR: 1.48, 95% CI: 1.07–2.06, p = 0.0048) in the aspirin plus cilostazol group than in the aspirin group. Patients treated with aspirin plus cilostazol during the acute phase of stroke had less neurological deterioration and more favorable functional status than those treated with aspirin alone.