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Original Paper

Cerebrovasc Dis 2008;25:344–347 DOI: 10.1159/000118380

Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Stroke in Patients with a History of Atrial Fibrillation: Subgroup Analysis of the CHARISMA Randomized Trial

Robert G. Hart a Deepak L. Bhatt b Werner Hacke e Keith A.A. Fox f

Graeme J. Hankey g Peter B. Berger c Tingfei Hu b Eric J. Topol d

for the CHARISMA Investigators

a University of Texas Health Science Center at San Antonio, San Antonio, Tex. , b Cleveland Clinic, Cleveland, Ohio , c Geisinger Center for Health Research, Danville, Pa. , d Scripps Clinic, La Jolla, Calif. , USA; e University of Heidelberg, Heidelberg , Germany; f University and Royal Infirmary of Edinburgh, Edinburgh , UK; g University of Western Australia, Perth, W.A. , Australia

the composite of stroke, myocardial infarction, or vascular death (HR = 1.2, 95% CI 0.7–2.0). Severe/fatal extracranial hemorrhage occurred in 6 patients with combination vs. 3 with aspirin alone. Conclusions: This post-hoc subgroup analysis does not support the use of this combination over aspirin alone in patients with a history of atrial fibrillation pending results of ongoing larger randomized trials.

Copyright © 2008 S. Karger AG, Basel

Introduction

Aspirin offers only modest protection against stroke in patients with nonvalvular atrial fibrillation: about a 20% reduction, which is much less than that afforded by anticoagulants (about 60%) [1] . The main protectiveeffect of aspirin in atrial fibrillation patients is presumed to be on smaller, noncardioembolic strokes [2] . However, aspirin appears to protect against pulmonary embolism in some settings [3] , and an effect on stasis-precipitated left atrial appendage thrombi has been hypothesized [4] . Consequently, there has been interest in whether a com-bination of two antiplatelet agents, particularly of aspi-

Key Words

Atrial fibrillation � Clopidogrel � Aspirin � Antiplatelet � Stroke

Abstract

Background: Aspirin offers modest reduction in stroke in patients with atrial fibrillation. Whether combination of as-pirin with clopidogrel offers additional protection is unclear. Methods: Post-hoc subgroup analysis of 593 participants with a history of atrial fibrillation in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Manage-ment, and Avoidance (CHARISMA) randomized trial testing clopidogrel 75 mg per day plus aspirin (75–162 mg per day) vs. aspirin alone in patients with stable cardiovascular dis-ease or multiple cardiovascular risk factors. Results: Mean patient age was 70 years, 78% were men, and hypertension, heart failure and diabetes were present in 78, 20 and 44%, respectively. During a median follow-up of 2.3 years, stroke (ischemic and hemorrhagic) occurred in 15 of 298 assigned to clopidogrel plus aspirin and in 14 of 285 given aspirin alone (hazard ratio, HR, 1.03, 95% CI 0.49–2.1). There was no difference in all-cause mortality (HR 1.1, 95% CI 0.6–1.9) or in

Received: October 15, 2007 Accepted: October 17, 2007 Published online: February 27, 2008

Robert G. Hart, MD Department of Neurology, University of Texas Health Science Center 7703 Floyd Curl Drive MC# 7883 San Antonio, TX 78229-3900 (USA) Tel. +1 210 592 0404, Fax +1 210 592 0552, E-Mail hartr@uthscsa.edu

© 2008 S. Karger AG, Basel1015–9770/08/0254–0344$24.50/0

Accessible online at:www.karger.com/ced

Atrial Fibrillation Patients in CHARISMA

Cerebrovasc Dis 2008;25:344–347 345

rin with clopidogrel, would offer additional protection against stroke with acceptable bleeding risks for elderly patients with atrial fibrillation. The large ACTIVE-A trial involving about 7,600 atrial fibrillation patients ran-domized to aspirin plus clopidogrel vs. aspirin plus pla-cebo is currently ongoing and should eventually provide a definitive comparison [4] .

Recently, the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) randomized trial showed no statistically significant benefit of adding clopidogrel 75 mg per day to aspirin (dosages ranging from 75 to 162 mg per day) in the overall population of 15,603 patients with stable cardiovascular disease or multiple cardiovascular risk factors [5] . Included in the CHARISMA trial was a subset of participants with a history of atrial fibrillation who were not treated with anticoagulation at study entry. Here, subgroup analysis of the effect of clopidogrel plus aspirin vs. aspirin alone is presented for these 593 par-ticipants with a history of atrial fibrillation.

Methods

The design, baseline participant features, and main results of CHARISMA have been published [5–7] . In brief, it was a double-blind randomized trial run by the Cleveland Clinic Cardiovascu-lar Coordinating Center and sponsored by Sanofi-Aventis and Bristol-Myers Squibb comparing clopidogrel (75 mg per day) plus low-dose aspirin (75–162 mg per day) with low-dose aspirin alone in 15,603 patients with clinically evident vascular disease or mul-tiple vascular risk factors, carried out between 2002 and 2005 at 768 sites in 32 countries. Overall, the combination of clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the primary efficacy composite outcome of myocardial infarction, stroke or vascular death [5] . This is a post-hoc subgroup analysis of patients identified as having a history of atrial fibrillation at study entry.

Eligible patients were 6 45 years old and had one of the follow-ing: multiple atherothrombotic risk factors or clinically docu-mented coronary artery, cerebrovascular, or peripheral arterial disease. Patients receiving oral anticoagulants were ineligible. Randomization was performed centrally using voice-response system on the basis of a pre-established scheme with the sequence blocked from previewing. Participants were followed in clinic at 1, 3 and 6 months after entry and then every 6 months. Atrial fi-brillation was defined at study entry as a history consistent with atrial fibrillation; no ECG evidence was required, nor was infor-mation collected on the duration or pattern of atrial fibrillation or reason not to treat with oral anticoagulation.

Endpoints were adjudicated by a central events committee whose members were unaware of treatment assignment. Stroke was defined as an acute neurological vascular event with focal signs lasting more than 24 h. All strokes included ischemic stroke, primary intracranial hemorrhage (including nontraumatic sub-

dural hematomas), and those classified as uncertain in the ab-sence of neuroimaging or autopsy.

Data are analyzed on an intention to treat basis. � 2 or Fisher’s test was used to analyze differences in categorical variables. Dif-ferences in continuous variables were evaluated by Wilcoxon rank-sum tests. A p value of ! 0.05 was required as statistical sig-nificance. The endpoints for clopidogrel plus aspirin versus pla-cebo plus aspirin were assessed using a two-sided log-rank test. Treatment effect, as measured by the hazard ratio and its associ-ated 95% confidence interval (CI), was estimated using Cox’s pro-portional hazards model. All analyses were performed using SAS version 8.2 (SAS Institute, Inc., Cary, N.C., USA).

Results

For atrial fibrillation participants, the mean age was 70 years old, 78% were men, and hypertension, heart fail-ure and diabetes at baseline were present in 78, 20 and 44%, respectively ( table 1 ). Randomization resulted in relatively equal distribution of patient features and asso-ciated vascular disease, excepting more assigned to clo-pidogrel plus aspirin vs. aspirin alone had previously un-

Table 1. CHARISMA participants with atrial fibrillation

Clopidogrel+ aspirin(n = 298)

Aspirin(n = 285)

pvalue

Median age, years 70.0 70.0 NSFemale sex 19% 24% NSWhite race 93% 95% NSInclusion group NS

Documented vascular disease 78% 83%Multiple risk factors 43% 39%Neither subgroup 1% 1%

Smoking status NSCurrent smoker 11% 11%Former smoker 60% 55%

Hypertension 76% 80% NSMean blood pressure at entry, mm Hg 137/76 136/77 NSCongestive heart failure1 20% 20% NSDiabetes 44% 44% NSPrior stroke 15% 15% NSPrior TIA 13% 12% NSPeripheral artery disease 29% 24% NSPrior carotid endarterectomy 9% 5% 0.05Prior CABG 43% 53% 0.02Prior percutaneous coronary intervention 24% 31% NSOral vitamin K antagonists during

follow-up 15% 15% NS

NS = Not significant; TIA = transient ischemic attack; CABG = coronary artery bypass grafting.

1 Requiring hospital admission.

Hart/Bhatt/Hacke/Fox/Hankey/Berger/Hu/Topol

Cerebrovasc Dis 2008;25:344–347346

dergone carotid endarterectomy (9 vs. 5%, p = 0.05), while fewer had prior coronary artery bypass grafting (43 vs. 53%, p = 0.02). Blood pressure at baseline averaged 136/76 mm Hg. During follow-up, 15% of participants in both treatment arms received oral vitamin K antagonists. Two patients (0.3%), one in each treatment arm, were lost to follow-up. Neuroimaging (computed tomography or magnetic resonance imaging) was available for 97% of stroke events. Of patients with confirmed ischemic strokes, 14% died within 1 month.

During a median follow-up of 2.3 years, stroke (isch-emic and hemorrhagic) occurred in 15 of 298 patients as-signed to clopidogrel plus aspirin (2.2% per year) and in 14 of 285 patients given aspirin alone (2.1% per year; haz-ard ratio 1.03, 95% CI 0.49–2.13). There was no difference in all-cause mortality (29 patients given combination vs. 25 patients given aspirin alone) or the composite of stroke, myocardial infarction, or vascular death (35 patients giv-en combination vs. 27 patients given aspirin alone). Se-vere or fatal extracranial hemorrhage occurred in 6 pa-tients given the combination vs. 3 with aspirin alone, while intracranial bleeding occurred in 3 patients vs. 1 patient, respectively ( table 2 ).

One hundred and forty-two patients (24%) had either a prior history of stroke or transient ischemic attack (time between the most recent cerebral ischemic event and tri-al entry averaged 1.1 years). Their ischemic stroke rate was 3.7% per year during antiplatelet therapy, signifi-

cantly (unadjusted relative increase = 2.8, 95% CI 1.3–6.0, p = 0.005) higher than atrial fibrillation patients without prior cerebral ischemia (1.5% per year).

Discussion

These results are not definitive due to small sample size (i.e. a clinically meaningful benefit or hazard of up to twofold cannot be excluded with certainty) and the post-hoc comparison, but they do not suggest that ad-dition of clopidogrel to aspirin in AF patients reduces stroke and major vascular events. Given the increased risk of moderate bleeding associated with this combina-tion compared with the use of either alone demonstrated in the larger CHARISMA trial [5] , the results of this sub-group analysis do not favor the addition of clopidogrel to aspirin chronically to prevent stroke in atrial fibrillation patients, pending the definitive results of the ongoing ACTIVE-A trial [4] .

Atrial fibrillation patients included in CHARISMA were similar in age, gender distribution and frequency of hypertension to those in other recent randomized trials testing antithrombotic therapies for this dysrhythmia [8–10] . However, the frequency of diabetes was higher, and a greater fraction of CHARISMA participants with a his-tory atrial fibrillation had clinically evident coronary ar-tery and peripheral vascular disease. The observed stroke

Table 2. Vascular events according to assigned treatment

Outcome Clopidogrel + aspirin(n = 298)

Aspirin(n = 285)

Hazard ratio p value

All stroke 15 (2.2%/year) 14 (2.1%/year) 1.03 (0.49–2.13) 0.94Ischemic stroke1 14 (2.0%/year) 14 (2.1%/year) 0.96 (0.46–2.01) 0.91Primary intracerebral hemorrhage2 1 0 –Intracranial bleeds3 3 1 – 0.62Severe/fatal extracranial hemorrhage 6 3 – 0.51MI 9 6 1.43 (0.51–4.01) 0.50Vascular death 21 12 1.68 (0.83–3.42) 0.15All-cause mortality 29 25 1.12 (0.65–1.90) 0.69Stroke, MI, or vascular death 35 27 1.24 (0.75–2.05) 0.40Rehospitalization 41 43 0.89 (0.58–1.37) 0.60Stroke, MI, vascular death or rehospitalization 70 66 0.99 (0.70–1.38) 0.93

Total patient-years of observation was 682 years for those assigned to clopidogrel plus aspirin and 655 years for those given aspirin alone. MI = Myocardial infarction.

1 Includes one classified as uncertain assigned to dual therapy due to absence of neuroimaging.2 Including nontraumatic subdural hematomas and subarachnoid.3 Including traumatic subdural hematomas.

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Cerebrovasc Dis 2008;25:344–347 347

rate (2.2% per year) and all-cause mortality rate (4.0% per year) during antiplatelet therapy were similar to those seen for presumed high-risk atrial fibrillation patients re-ceiving clopidogrel plus aspirin in the recent ACTIVE-W trial (2.4% per year for all stroke, 3.8% per year for death) [8] .

The main strength of this study is that it is the first published double-blind, randomized comparison of clo-pidogrel plus aspirin with aspirin alone in the long-term prevention of stroke among patients with a history of atri-al fibrillation. Important limitations include its post-hoc subgroup design. The presence of atrial fibrillation, its duration and pattern, and the absence of valve disease were not recorded on data collection forms; a history of atrial fibrillation was based on evaluation by cardiovas-cular researchers, but the presence of atrial fibrillation was not documented by EKG. Furthermore, patients re-ceiving chronic anticoagulation for atrial fibrillation or those who were perceived to be at high risk of bleeding

were excluded from the CHARISMA trial (although 15% were anticoagulated during follow-up). Finally, the small number of major outcome events, and consequent wide 95% CIs surrounding the estimates of treatment effect, enhance the possibility of random error in the point es-timates of treatment effect. Given the sample size, the study has only 13% power to detect a 20% reduction in stroke (i.e. false-negative results are likely for this degree of benefit). Nevertheless, these results contribute usefully to the totality of randomized evidence concerning the value of this combination of antiplatelet therapy to pa-tients with atrial fibrillation.

Addition of clopidogrel to aspirin may reduce stroke over aspirin alone in certain specific settings [11–13] . However, with the caveat of methodological limitations described above, we found no evidence that this combi-nation adds benefit to treatment with aspirin alone in pa-tients with a history of atrial fibrillation.

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