Aspirin and Clopidogrel Combination Effective for Stroke Prevention in Atrial Fibrillation: Review #2
Aspirin and Clopidogrel Combination Effective for Stroke Prevention in Atrial Fibrillation: Review #2
Abstract & Commentary
By Alan Z. Segal, MD, Associate Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Segal reports no financial relationships relevant to this field of study. This article originally appeared in the July 2009 issue of Neurology Alert. It was edited by Matthew Fink, MD, and peer reviewed by M. Flint Beal, MD. Dr. Fink is Vice Chairman, Professor of Neurology, Weill Cornell Medical College; Chief, Division of Stroke and Critical Care Neurology, NewYork-Presbyterian Hospital, and Dr. Beal is Professor and Chairman, Department of Neurology, Cornell University Medical College. Drs. Fink and Beal report no financial relationships relevant to this field of study.
Synopsis: The combination of aspirin with clopidogrel is better than aspirin alone in reducing the risk of stroke in patients with atrial fibrillation.
Source: The ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360:2066-2078.
Patients with atrial fibrillation (AF) are at increased risk of stroke, especially if they are older than age 75 or have risk factors such as coronary artery disease or diabetes. Warfarin has been shown to be the drug of choice for stroke prevention in this setting, but it is underutilized, with as few as 50% of eligible patients on this therapy in some surveys. Warfarin may be withheld due to many factors including, among others, a narrow therapeutic window and poor compliance with monitoring. Bleeding risks of warfarin due to falls, for example, or medical comorbidities often are difficult to quantify.
In the absence of AF, aspirin and clopidogrel (ASA/C) is not considered an effective regimen for stroke prevention, as the combination has not been shown to be superior to either drug alone. In the MATCH trial, not only was ASA/C ineffective in stroke prevention, but it also produced an increase in brain hemorrhage rates.1 In contrast, ASA/C has demonstrated proven efficacy and safety in patients with acute coronary syndromes, and is frequently prescribed for patients with cardiac stents. While clopidogrel has historically been prescribed for short periods of time after coronary stent placement (e.g., six weeks to three months), many patients, especially those with drug-eluting stents, now require this therapy indefinitely. Because a subset of these patients with coronary artery disease also have AF (prompting a need for warfarin), it is not uncommon that, despite bleeding risks, patients may be considered for treatment with all three drugs simultaneously.
The role of ASA/C in comparison to warfarin for patients with AF was investigated in the Clopidogrel -Aspirin in Atrial Fibrillation (CLAAF) pilot study, with data suggesting that these regimens might have comparable efficacy.2 A larger, definitive trial, however - the Active-W Study - had to be stopped prematurely due to a clear superiority for warfarin.3 Active-W showed a 42% benefit of warfarin over ASA/C, about as comparable to the superiority of warfarin over ASA alone (approximately 38% in meta-analyses). This indirect comparison suggested that an ASA/C regimen provided no added benefit in AF patients over ASA alone, a contention now refuted with the present study.
Active-A (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) compared ASA/C with ASA alone in patients with AF who were at increased risk for stroke and who were considered unsuitable for warfarin therapy. Out of 7,554 patients enrolled, the primary outcome (composite of stroke, MI, non-brain systemic embolism, or death from vascular causes) was found in 832 patients on ASA/C (6.8%) compared with 924 patients (7.6%) on ASA alone. The majority of this difference was due to a decrease in the rate of stroke, which was 296 (2.4%) with ASA/C compared to 408 (3.3%) with ASA alone. This benefit included non-disabling strokes, as well as fatal strokes, and was only marginally mitigated by a small increase in hemorrhagic strokes (total of three fatal hemorrhagic strokes in the entire population, which was statistically insignificant). ASA/C did produce significantly more non-brain major bleeds - 251 (2%) - compared to 162 (1.3%) with ASA alone.
As the authors note, the relative benefit of ASA/C (28%) in stroke prevention was not as potent as warfarin (38% from meta-analyses, as noted above), but ASA/C also produced lower rates of major hemorrhage when compared to oral anticoagulation. Warfarin has been shown to produce a 70% increased risk of systemic hemorrhage (a 128% increase in brain bleeding) when compared to ASA, while ASA/C increased these risks by 51% and 87%, respectively.
Commentary
As the authors emphasize, warfarin remains the preferred and recommended therapy for the prevention of ischemic stroke in patients with AF. These data do, however, provide useful support for an ASA/C regimen in certain patients - perhaps those who already require this combination for treatment of their coronary artery disease. For other patients who may be reluctant to take warfarin, ASA/C presents a compromise, unquestionably inferior to full anticoagulation, but a better option than aspirin alone.
References
1. Diener HC, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): Randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:331-337.
2. The Active Steering Committee, et al. Rationale and design of ACTIVE: The atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events. Am Heart J. 2006;151:1187-1193.
3. ACTIVE Writing Group of the ACTIVE Investigators, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE-W): A randomised controlled trial. Lancet. 2006;367:1903-1912.
The combination of aspirin with clopidogrel is better than aspirin alone in reducing the risk of stroke in patients with atrial fibrillation.Subscribe Now for Access
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