At baseline, the median age of our cohort of 13559 persons with atrial fibrillation was 73 years, with an interquartile range of 66 to 80 years. Overall, 20.2% had no major risk factors for ischemic stroke with atrial fibrillation, including age 75 years or older, previous ischemic stroke, diabetes mellitus, hypertension, or congestive heart failure (8
). We recorded the events of the patients’ clinical course over a median of 6 years, accumulating more than 66000 person-years of observation in aggregate. During follow-up, 30% of patients developed at least 1 more stroke risk factor.
At entry to the cohort, 53% of patients were receiving warfarin treatment. At baseline, compared with those patients not taking warfarin, patients taking warfarin were less likely to be aged 75 years or older or to be women (). Overall, patients receiving warfarin tended to have a higher prevalence of other stroke risk factors and were less likely to have had a previous bleeding event (). During the study period, an additional 15.5% received warfarin for at least 30 days. Fourteen percent of INR tests for specific patients were separated by more than 8 weeks, thereby precluding interpolations to estimate time in various INR ranges for that 14% of tests. Excluding these noninterpolatable INR test intervals, the percentage of time in the therapeutic INR range (INR, 2.0 to 3.0) in patients receiving warfarin was 65.4%, with 24.2% below an INR of 2.0 and 10.4% above an INR of 3.0.
ATRIA cohort baseline characteristics stratified by warfarin status
During follow-up, we identified 1092 valid thromboembolic events in the ATRIA cohort (1017 ischemic strokes and 75 systemic emboli), 407 in patients receiving warfarin and 685 in patients not receiving warfarin at the time of their event. We also identified 299 valid intracranial hemorrhagic events, including 139 intracerebral hemorrhages, 101 subdural hemorrhages, 45 subarachnoid or other hemorrhages, and 14 intracranial hemorrhages of unknown type. Among patients taking warfarin, 193 intracranial hemorrhage events occurred (98 intracerebral, 63 subdural, 24 subarachnoid or other intracranial, and 8 of unknown type).
The overall unadjusted annual rate of ischemic stroke or systemic embolism was 2.10% (95% CI, 1.96% to 2.28%) in patients not receiving warfarin therapy versus 1.27% (CI, 1.19% 1.44%) in patients receiving warfarin therapy. The overall unadjusted annual rate of intracranial hemorrhage was 0.58% (CI, 0.51% to 0.68%) in patients receiving warfarin therapy versus 0.32% (CI, 0.27% to 0.39%) in patients not receiving warfarin therapy. After adjustment for age, sex, previous stroke, diagnosed hypertension, diagnosed heart failure, diagnosed diabetes, and coronary artery disease, and incorporation of a weighting factor of 1.5 for intracranial hemorrhages (our base case), the overall adjusted net clinical benefit of warfarin was 0.68 (CI, 0.34 to 0.87) adverse events prevented per 100 patients per year (Tables and ).
Adjusted rates* and rate differences for thromboembolism (TE) and intracranial hemorrhage (ICH) by warfarin status
The net clinical benefit of warfarin therapy overall and by individual risk factors using different weights for ICH
The benefits of warfarin increased as the absolute risk for thromboembolism increased, whereas the harms increased only moderately. Rates of thromboembolism in patients not receiving warfarin were clearly higher in the presence of any risk factor, with age 85 years or older and previous stroke conferring the greatest risk for subsequent ischemic stroke (). Also, the rates of thromboembolism were lower in patients receiving warfarin than in patients not receiving warfarin in the presence of any risk factor. However, the absolute reduction in rates of thromboembolism attributable to warfarin therapy in any risk factor category decreased as the absolute risk while not receiving warfarin therapy decreased. Although the adjusted rate of intracranial hemorrhage while not receiving warfarin was substantially higher among older persons and among those with a history of ischemic stroke, the absolute increase in the rate of intracranial hemorrhage associated with warfarin use stayed within a narrow range across the subgroups.
A history of ischemic stroke was the strongest risk factor for future ischemic stroke and also a strong risk factor for future intracranial hemorrhage in patients receiving warfarin. Nonetheless, using the base-case weighting factor of 1.5 for intracranial hemorrhage, the impact of warfarin on thromboembolism risk was much larger than its effect on intracranial hemorrhage risk, such that the adjusted net clinical benefit was 2.48% per year (CI, 0.75% to 4.22%) among patients with a history of stroke as opposed to 0.56% per year (CI, 0.22% to 0.72%) among those without a history of stroke (). The adjusted point estimates of net clinical benefit of warfarin therapy were higher in all other risk factor—positive categories (that is, older age, female sex, diagnosed heart failure, and diagnosed diabetes) except for diagnosed hypertension, in which the net clinical benefit was similar for patients with and without hypertension. These differences in estimates of net clinical benefit largely reflect the increased absolute benefit of warfarin therapy in reducing the rate of thromboembolism in the risk factor—positive groups.
Net clinical benefit increased monotonically with age, regardless of the weighting factor for intracranial hemorrhage ( and ). The benefit was near zero for patients younger than 75 years. Indeed, the point estimate suggests a small net harm in patients younger than 65 years, although the accompanying CI includes zero effect. The net clinical benefit of warfarin also increased substantially as the CHADS2 risk score increased ( and ). Using impact weights of 1.0 or 2.0 for the difference in rates of intracranial hemorrhage between patients receiving and not receiving warfarin, our estimates of net clinical benefit were changed in the expected direction. The overall pattern of results was largely preserved, reflecting the greater importance of the effect of warfarin on thromboembolism rates relative to its effect on intracranial hemorrhage rates ().
Figure The net clinical benefit of warfarin by age group (top) and CHADS2 score (bottom). Net clinical benefit is plotted as the adjusted, weighted adverse events prevented per 100 person-years by warfarin treatment, according to age group and CHADS2 score, (more ...)