Am Fam Physician. 2008;77(7):1018-1019
Background: An estimated 12 percent of persons older than 75 years have atrial fibrillation, which is associated with a fivefold increase in risk of stroke. Older patients often have additional cardiovascular and cerebrovascular risks for stroke, making atrial fibrillation particularly dangerous in this population. Although anticoagulation is effective for reducing stroke risk, it is associated with hemorrhagic consequences and requires diligent monitoring that can be difficult and inconvenient for older patients.
Alternative therapies, such as aspirin and antiplatelet drugs, are easier to manage but are less effective than warfarin (Coumadin). Comparative studies of anticoagulants and antiplatelets have not focused on older patients; however, subgroup analyses have raised doubts about the potential benefit versus harm in older participants. Mant and colleagues directly compared warfarin and aspirin for stroke prevention in older patients with atrial fibrillation.
The Study: Patients 75 years or older with atrial fibrillation or flutter were recruited from 260 general practices in England and Wales. Diagnosis was demonstrated on electrocardiography and confirmed through examination by a consultant cardiologist. Exclusions were: rheumatic heart disease, major nontraumatic hemorrhage within five years, peptic ulcer, recent surgery, elevated blood pressure (180/110 mm Hg or higher), and concern about the potential safety of the study drugs in certain patients.
After screening by baseline data and physical assessment, 485 patients were randomly assigned to treatment with 75 mg aspirin daily, and 488 were assigned to treatment with warfarin to a target International Normalized Ratio (INR) of 2.5 (range 2 to 3). Patients were followed by their physicians according to usual care practices and were formally evaluated every six months. The primary outcome was the first occurrence of any fatal or disabling stroke, intracranial hemorrhage, or significant embolism. Secondary outcomes included major extracranial hemorrhage, hospital admission for any vascular event, and mortality from any cause. All potential secondary outcomes were reviewed for inclusion by a blinded, independent geriatrician. In addition to follow-up by the physicians, hospital and death certificate databases identified any events involving study participants. The mean follow-up was 2.7 years.
Results: Patients in the warfarin group had more risk factors for stroke than those in the aspirin group, but were otherwise comparable in all major variables. In the warfarin group, 67 percent of patients remained on therapy throughout the study. They also had INRs in the target range 67 percent of the time (mean INR 2.4). In the aspirin group, 76 percent of patients remained on therapy throughout the study.
Primary outcomes were documented 24 times in the warfarin group and 48 times in the aspirin group (see accompanying table). The statistically significant benefit found with warfarin was primarily because of the large reduction in ischemic stroke for patients in the warfarin group compared with those in the aspirin group (annual risk of 0.8 versus 2.5 percent). The number needed to treat for one year to prevent one primary event was 50.
| Warfarin (n = 488) | Aspirin (n = 485) | Warfarin vs. aspirin | ||||||
|---|---|---|---|---|---|---|---|---|
| Number of patients | Risk per year (%) | Number of patients | Risk per year (%) | Relative risk (95% confidence interval) | P value | |||
| Stroke | 21 | 1.6 | 44 | 3.4 | 0.46 (0.26 to 0.79) | .003 | ||
| By severity | ||||||||
| Fatal | 13 | 1.0 | 21 | 1.6 | 0.59 (0.27 to 1.24) | .14 | ||
| Disabling nonfatal | 8 | 0.6 | 23 | 1.8 | 0.33 (0.13 to 0.77) | .005 | ||
| Type of stroke* | ||||||||
| Ischemic | 10 | 0.8 | 32 | 2.5 | 0.30 (0.13 to 0.63) | .0004 | ||
| Hemorrhagic | 6 | 0.5 | 5 | 0.4 | 1.15 (0.29 to 4.77) | .83 | ||
| Unknown | 5 | 0.4 | 7 | 0.5 | 0.69 (0.17 to 2.51) | .53 | ||
| Other intracranial hemorrhage† | 2 | 0.2 | 1 | 0.1 | 1.92 (0.10 to 113.3) | .65 | ||
| Systemic embolism‡ | 1 | 0.1 | 3 | 0.2 | 0.32 (0.01 to 3.99) | .36 | ||
| Total number of events | 24 | 1.8 | 48 | 3.8 | 0.48 (0.28 to 0.80) | .0027 | ||
Subgroup analysis showed warfarin benefit applied even to patients older than 85 years. Warfarin also provided better outcomes for most of the secondary measures compared with aspirin, but the benefit was only statistically significant for all strokes (2.5 versus 4.9 percent) and all strokes plus transient ischemic attacks (3.1 versus 5.7 percent). Warfarin also was not associated with an increased risk of major hemorrhage compared with aspirin (1.9 versus 2.0 percent). Conversely, the annual risk of major vascular events, including myocardial infarction, embolism, or any vascular death, was significantly reduced in the warfarin group compared with the aspirin group (5.9 versus 8.1 percent; P = .03). A composite outcome of all primary events plus hemorrhage showed a significant reduction in annual risk for patients allocated to warfarin (3.0 versus 5.1 percent; P = .008).
Conclusion: The authors conclude that treatment with warfarin to a target INR range of 2 to 3 offers benefit to older patients with atrial fibrillation and may be used safely in older age groups. They stress the need to consider contraindications, potential complications, and the increased burden of managing anticoagulation therapy when making decisions for individual patients.