Is Clopidogrel Plus Aspirin Superior to Aspirin Alone for Atrial Fibrillation?
Is Clopidogrel Plus Aspirin Superior to Aspirin Alone for Atrial Fibrillation?
Abstract & Commentary
By John P. DiMarco, MD, PhD, Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville. Dr. DiMarco is a consultant for Novartis, and does research for Medtronic and Guidant.
Source: The ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360:2066-2078.
The role of intensive antiplatelet therapy for prevention of vascular events in patients with atrial fibrillation remains controversial. The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) trio of studies is an attempt to clarify this issue. The first trial, ACTIVE-W, compared anticoagulation with a vitamin K antagonist to antiplatelet therapy with aspirin plus clopidogrel in patients with atrial fibrillation. This trial was stopped by its Data Safety Monitoring Board before its scheduled completion when warfarin proved to be clearly superior to the clopidogrel-aspirin combination. Patients were eligible for the ACTIVE trials if they had either persistent, permanent, or at least two recent episodes of intermittent atrial fibrillation. Patients also had to have one or more of the following risk factors for stroke: age 75 or greater, systemic hypertension, prior stroke, TIA or systemic embolism, a left ventricular ejection fraction less than 45%, peripheral vascular disease, or an age between 50 and 75 with associated diabetes mellitus or coronary artery disease. ACTIVE-A enrolled those patients who were thought to be unsuitable for vitamin K antagonist therapy. Patients who underwent cardioversion at any point in the trial were treated with open-label vitamin K antagonists for four weeks before and after cardioversion and, thus, could resume antiplatelet therapy. The primary study outcome was any major vascular event, including stroke, non-central nervous system systemic embolism, myocardial infarction, or vascular death. Secondary outcomes included the individual components of the primary outcome, as well as a composite of the primary outcome and major hemorrhage. In this study, major hemorrhage was defined as overt bleeding requiring transfusion of at least 2 units of blood, a drop in total hemoglobin of 5 grams per deciliter, intraocular bleeding resulting in loss of vision, bleeding-related hypotension requiring inotropic agents, symptomatic intracranial hemorrhage, or a total transfusion requirement of 4 units or more.
A total of 7,554 patients were enrolled in ACTIVE-A over a three-year period. The median duration of follow-up was 3.6 years. The mean age was 71 years, and 58% of the patients were male. Atrial fibrillation was permanent in 64%, persistent in 14%, and paroxysmal in 22%. The mean CHADS2 score was 2.0. The reasons for enrollment in ACTIVE-A, as opposed to ACTIVE-W, were a specific risk of bleeding in 22.9% of patients, a physician judgment that a vitamin K antagonist would be inappropriate in 49.7%, and a patient's reluctance to take a vitamin K antagonist in 26%. Major vascular events, the primary endpoint, occurred in 832 patients in the clopidogrel group (6.8% per year) compared to 925 patients in the aspirin-only group (7.6% per year). The relative risk was 0.89, with a 95% confidence interval of 0.81 to 0.98; p = 0.01. Stroke occurred in 296 patients who received clopidogrel plus aspirin (2.4% per year), compared to 480 patients who received aspirin only (3.3% per year). Myocardial infarction was also reduced, with 90 patients in the clopidogrel plus aspirin group (0.7% per year) experiencing a myocardial infarction, compared to 115 patients in the aspirin-only group (0.9% per year). However, the total number of deaths from vascular causes was similar in the two groups: 600 in the clopidogrel-aspirin group and 599 in the aspirin group. Total mortality was also similar, with 825 deaths in the clopidogrel plus aspirin group and 841 deaths in the aspirin-only group. The total number of days of hospitalization for cardiovascular cause was also slightly reduced by clopidogrel plus aspirin therapy.
Strokes were analyzed for mechanism and severity. The rate for ischemic stroke was lower in the clopidogrel plus aspirin group compared to the aspirin-only group (1.9% per year vs. 2.8% per year). Hemorrhagic stroke rates were 0.17% per year in the aspirin-only group compared to 0.23% per year in the clopidogrel plus aspirin group.
Major bleeding was increased by clopidogrel plus aspirin therapy. There were 251 patients on clopidogrel who experienced major bleeding, compared to 162 patients on aspirin only. When the secondary outcome of a combination of major vascular events and major hemorrhage was combined, there was no significant difference in the total rates between the two groups (986 vs. 966 events; relative risk 0.97). The effects of clopidogrel plus aspirin were fairly consistent across major subgroups.
The authors concluded that treatment with clopidogrel plus aspirin is superior to aspirin therapy alone in patients with atrial fibrillation and risk factors for stroke or death who are unable or unwilling to take a vitamin K antagonist. The reduction in the risk of vascular events, in particular stroke, however, is at the cost of a significant increase in the risk of a major hemorrhage.
Commentary
It is well recognized that carefully monitored anticoagulation with vitamin K antagonist can reduce the risk of stroke by approximately two-thirds in patients with atrial fibrillation and risk factors for stroke. However, these trials have consistently shown a bleeding risk during chronic warfarin therapy at least 2% per year. This is probably an underestimation of risk since many of the patients had already tolerated warfarin for some time before trial entry. The risk of bleeding during initiation of warfarin therapy is considerably higher. Aspirin is frequently used as an alternative to warfarin in low-risk patients or in those with contraindications to warfarin therapy. The benefits of aspirin are largely based on the results of the first SPAF trial. Other trials have not shown a similar benefit with aspirin alone. The ACTIVE trials provide important data about the role of antiplatelet therapy in patients with atrial fibrillation. In ACTIVE-W, vitamin K antagonist therapy was shown to be clearly superior to clopidogrel plus aspirin, and that trial was terminated prematurely. However, it was noted in that trial that many patients who had not previously been exposed to a vitamin K antagonist had to discontinue therapy. In the warfarin-naive subgroup, clopidogrel plus aspirin performed almost as well. In ACTIVE-A, clopidogrel plus aspirin was compared to aspirin only in patients who were thought unsuitable for warfarin therapy. The definition of this group, however, is vague in the report. Only about one-quarter of the patients had a documented history of bleeding as their contraindication to warfarin. Almost half were judged unsuitable by their physicians for unspecified reasons, probably concerns about compliance or bleeding risk. An additional one-quarter were unwilling to take warfarin by personal choice, even though they had no bleeding history. It is likely that many of these patients could have been appropriately treated with warfarin, and the lesson from the ACTIVE trials is that vitamin K antagonist therapy remains the gold standard for stroke prevention in patients with atrial fibrillation and risk factors. Only if there is a clear contraindication to vitamin K antagonist therapy should an antiplatelet strategy be considered in moderate- to high-risk patients.
The dose of aspirin used in ACTIVE A (75-100 mg daily) is also of concern since the maximally effective dose of aspirin has never been defined. It, therefore, remains a possibility that lower stroke rates seen with clopidogrel plus aspirin in ACTIVE A might have been achievable at a lower cost with a higher dose of aspirin alone.
The final trial in the ACTIVE series is ACTIVE I. Patients from the other two ACTIVE trials have been randomized in a factorial design to the addition of irbesartan to their standard therapy. This trial will test the hypothesis that agents that block the renin-angiotensin system have added benefits in patients with atrial fibrillation.
The role of intensive antiplatelet therapy for prevention of vascular events in patients with atrial fibrillation remains controversial.Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.