A 70-year-old man presents for an initial visit. He is healthy, lives independently, and takes only blood pressure and cholesterol medication. On examination, his pulse is irregular. Electrocardiography (ECG) confirms atrial fibrillation.
For patients with nonvalvular atrial fibrillation and no history of stroke or transient ischemic attack (TIA), how effective at preventing stroke is oral anticoagulation therapy compared with antiplatelet therapy? Who benefits most, and what are the associated risks?
Compared with antiplatelet therapy, oral anticoagulation significantly reduces stroke at an average follow-up of one to three years, but does not reduce mortality. Intracranial or extracranial hemorrhage is more common with anticoagulation and must be weighed against its therapeutic benefit.1
Cardioembolic stroke afflicts 60,000 Americans annually and is most often caused by atrial fibrillation,2 which affects 5 percent of adults older than 65 years and 10 percent older than 80 years.1 Patients with atrial fibrillation who receive antiplatelet therapy alone have a 4 percent annual risk of stroke, although the more recent AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) study puts the estimate closer to 2.5 percent.1,3 Since the Stroke Prevention in Atrial Fibrillation (SPAF) trials were launched in 1987, more than a dozen studies have looked at anticoagulation in atrial fibrillation. Applied to all-comers with atrial fibrillation, aspirin reduces stroke by 20 percent, whereas warfarin (Coumadin) reduces it by 65 percent.4 The SPAF III trial showed that the combination of aspirin and warfarin is a harmful treatment strategy.4 Despite its proven superiority in preventing stroke, warfarin increases the risk of severe hemorrhage. The mortality benefits of warfarin over aspirin are less clear in certain subgroups, including patients with no history of stroke or TIA.
The authors of this Cochrane review chose studies pertaining to the primary prevention of stroke in patients with atrial fibrillation. Included were eight randomized trials comparing oral anticoagulation with antiplatelet therapy. Six of the eight trials used aspirin as the antiplatelet agent, and six of the eight trials used warfarin as the anticoagulant. Two of the eight trials had populations with poorly controlled international normalized ratios. The size of the studies varied greatly and ranged from a small cohort of 31 participants with poorly matched treatment groups to the more robust ACTIVE trial, where 6,706 patients (70 percent of the total meta-analysis population) were randomized to aspirin plus clopidogrel (Plavix; a treatment strategy that is no longer the standard of care) versus warfarin alone. About 10 percent of the meta-analysis population actually had a history of stroke or TIA, but their data could not be separated from the rest of the population.
Despite the above limitations, some notable outcomes emerged. Overall mortality did not vary between treatment groups. If 1,000 patients were treated for a year with anticoagulation (versus antiplatelet therapy), 19 fewer patients would have an ischemic stroke (number needed to treat [NNT] = 53) and 13 fewer would have any type of stroke (NNT = 77). However, 10 more would have a major extracranial hemorrhage (number needed to harm [NNH] = 96) and four more would have an intracranial hemorrhage (NNH = 231) over one to three years. The authors excluded data on extracranial hemorrhage—but not intracranial hemorrhage—from the ACTIVE trial in their meta-analysis calculations.
Background: Nonvalvular atrial fibrillation carries an increased risk of stroke mediated by embolism of stasis-precipitated thrombi originating in the left atrial appendage. Oral anticoagulants and antiplatelet agents have proven effective for stroke prevention in most patients at a high risk for vascular events, but primary stroke prevention in patients with nonvalvular atrial fibrillation potentially merits separate consideration because of the suspected cardioembolic mechanism of most strokes in patients with atrial fibrillation.
Objective: To characterize the relative effect of long-term oral anticoagulant treatment compared with antiplatelet therapy on major vascular events in patients with nonvalvular atrial fibrillation and no history of stroke or transient ischemic attack (TIA).
Search strategy: The authors searched the Cochrane Stroke Group Trials Register (June 2006). They also searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2006), Medline (1966 to June 2006) and Embase (1980 to June 2006). The Atrial Fibrillation Collaboration and experts working in the field were contacted to identify unpublished and ongoing trials.
Selection criteria: All non-confounded, randomized trials in which long-term (more than four weeks) adjusted-dose oral anticoagulant treatment was compared with antiplatelet therapy in patients with chronic nonvalvular atrial fibrillation.
Data collection and analysis: Two reviewers independently selected trials for inclusion, assessed quality, and extracted data. The Peto method was used for combining odds ratios after assessing for heterogeneity.
Main results: Eight randomized trials, including 9,598 patients, tested adjusted-dose warfarin versus aspirin (in dosages ranging from 75 to 325 mg per day) in patients with atrial fibrillation without prior stroke or TIA. The mean overall follow-up was 1.9 years per participant. Oral anticoagulants were associated with a lower risk of all stroke (odds ratio [OR] = 0.68; 95% confidence interval [CI], 0.54 to 0.85), ischemic stroke (OR = 0.53; 95% CI, 0.41 to 0.68) and systemic emboli (OR = 0.48; 95% CI, 0.25 to 0.90). All disabling or fatal strokes (OR = 0.71; 95% CI, 0.59 to 1.04) and myocardial infarction (OR = 0.69; 95% CI, 0.47 to 1.01) were substantially, but not significantly, reduced by oral anticoagulants.
Vascular death (OR = 0.93; 95% CI, 0.75 to 1.15) and all-cause mortality (OR = 0.99; 95% CI, 0.83 to 1.18) were similar with these treatments. Intracranial hemorrhages (OR = 1.98; 95% CI, 1.20 to 3.28) were increased by oral anticoagulant therapy.
Authors' conclusions: Adjusted-dose warfarin and related oral anticoagulants reduce stroke, disabling stroke, and other major vascular events for those with nonvalvular atrial fibrillation by about one third when compared with antiplatelet therapy.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of SystematicReviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the originalreviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minorediting changes have been made to the text (http://www.cochrane.org).
How, then, is the family physician to decide who will receive the most benefit from anticoagulation? The CHADS2 criteria can help determine a patient's risk for cardioembolic stroke.5 A point of risk is assigned for each of the following items: history of Congestive heart failure; Hypertension; Age older than 75; and Diabetes mellitus. A history of Stroke or TIA counts as 2 points. If a patient has a CHADS2 score of 2 points or higher, anticoagulation should be strongly considered. An online CHADS2 risk calculator, based on the 2001 ATRIA study, can be accessed at http://www.mdcalc.com/chads2.6
Although the CHADS2 criteria estimate cardioembolic risk, physicians should keep in mind the increased risk of hemorrhage from anticoagulation in older patients. In a recent cohort study of 472 patients older than 65 years and with newly diagnosed atrial fibrillation, 7.2 percent had major hemorrhage during their first year on warfarin, and 2.5 percent had intracranial hemorrhage.7 A subset of patients 80 years and older had a 13.1 percent incidence of major hemorrhage.
Family physicians should, above all, use common sense and share decision-making with their patients. Whether or not to choose warfarin in place of aspirin will depend on patient preference, availability of anticoagulation monitoring, and weighing stroke risk against bleeding risk. For patients choosing anticoagulation therapy, a consistent diet and restriction in alcohol intake are important factors. Patient information on anticoagulation, including dietary considerations, can be found through the National Institutes of Health at http://www.ods.od.nih.gov/factsheets/cc/coumadin1.pdf.