The Net Clinical Benefit of Warfarin Anticoagulation in Atrial Fibrillation

Context Guidelines for prescribing anticoagulants in atrial fibrillation do not use contemporary stroke rates or account for intracranial bleeding risk. Contribution The authors studied 6-year rates of ischemic stroke and intracranial hemorrhage in 13559 adults with nonvalvular atrial fibrillation. They calculated ischemic stroke rates in patients receiving and not receiving warfarin (treatment benefit) and intracranial hemorrhage rates (treatment harm). Benefit minus harm (net treatment benefit) was highest in patients with previous stroke, age older than 84 years, and others with high stroke risk. Caution Patients received warfarin according to clinical judgment, not randomly. Implication Age and other stroke risk factors should drive the decision to use warfarin in atrial fibrillation. The Editors Warfarin anticoagulation is very efficacious in preventing thromboembolism (primarily ischemic stroke but also systemic thromboembolism) in patients with atrial fibrillation and is highly effective in practice (1, 2). Nonetheless, warfarin therapy increases the risk for major hemorrhage and is burdensome for both physicians and patients. Therefore, clinical guidelines (3, 4) recommend warfarin only for patients with atrial fibrillation who are considered to be at intermediate or high risk for ischemic stroke. However, these risk-based anticoagulation guidelines have substantial limitations. First, they do not explicitly account for the risk for fatal and disabling hemorrhage due to warfarin. Second, they are primarily based on studies conducted more than 15 years ago. Recent studies (2, 5, 6) of patients with atrial fibrillation suggest a lower absolute risk for stroke while not receiving warfarin therapy, perhaps reflecting better treatment of hypertension or other risk factors. Finally, the net clinical benefit of risk-based recommendations for anticoagulation in patients with atrial fibrillation has not been demonstrated in large populations followed for long periods. In our observational study, we quantify the net clinical benefit of warfarin anticoagulation, defined as the estimated reduction in rate of thromboembolism, mainly ischemic stroke, minus 1.5 times the estimated increase in rate of intracranial hemorrhage attributable to warfarin therapy in standard stroke risk subgroups in the community-based cohort of patients in the ATRIA (AnTicoagulation and Risk Factors In Atrial Fibrillation) Study. Methods Study Population The ATRIA Study cohort consists of 13559 adults with diagnosed nonvalvular atrial fibrillation who received care within Kaiser Permanente of Northern California, a large integrated health care delivery system. Cohort assembly is described in detail elsewhere (2, 7). In brief, we identified patients with a diagnosis of atrial fibrillation between 1 July 1996 and 31 December 1997 by searching outpatient databases for internal medicine or cardiology visits in which an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), diagnosis of atrial fibrillation (427.31) was assigned and by searching electrocardiographic databases for a diagnosis of atrial fibrillation. The date of the first diagnosis of atrial fibrillation during the period of cohort assembly was considered the patient's index date. Cohort assembly was finalized by November 1998, and the cohort was followed through 30 September 2003 with a combination of retrospective (back to July 1996) and prospective (through September 2003) review of health plan databases and medical records. Patients who died or withdrew from the health plan during follow-up were censored at their date of death or on the last day of the month in which they terminated their membership. Date of death was ascertained from health plan clinical or administrative files, the California Automated Mortality Linkage System, or the Social Security Administration Death Master File. The institutional review boards at Massachusetts General Hospital and the Kaiser Foundation Research Institute approved the research. Patient Characteristics We searched databases of clinical inpatient and ambulatory visits (outpatient clinic and emergency department) during the 5 years before each patient's index date to identify previously diagnosed ischemic stroke, heart failure, coronary heart disease, and hypertension by using relevant ICD-9-CM codes (2). We used a validated, comprehensive health plan diabetes registry to identify patients with diabetes mellitus. Ascertainment of these stroke risk factors was validated against review of samples of outpatient medical records; crude agreement was high (78% to 96%), and corresponding statistics ranged from 0.51 to 0.89. Of note, stroke risk prediction based on risk factors ascertained in the ATRIA Study was in good agreement with risk schemes generated by pooled randomized trial and chart-based cohort study data (2, 810). Information from medical care received at both health plan and nonhealth plan facilities was obtained through these databases. Data on age and sex were obtained from administrative databases. Warfarin Exposure We determined warfarin exposure on the basis of information from automated clinical, pharmacy, and laboratory databases by using methods described elsewhere (2). We validated this computerized approach in 1207 patients by comparing it with warfarin status documented in their medical record at the time of an outcome event; the resulting statistic was 0.84. Nearly all discrepancies were due to transient discontinuation of warfarin treatment. If medical chart review of an outcome event showed that the patient stopped receiving warfarin within 5 days before the event, the event was considered to take place while the patient was receiving warfarin. For patients considered to be receiving warfarin, an adapted linear interpolation method was used to determine the person-time spent in the therapeutic international normalized ratio (INR) range of 2.0 to 3.0 (11). If the interval between consecutive INR measurements was greater than 8 weeks, the INR person-time for this period was considered not available. Outcome Assessment Thromboembolic Events We searched hospitalization and billing claims databases through 30 September 2003 for primary ICD-9-CM discharge diagnoses that indicated potential thromboembolism, including ischemic stroke and other systemic embolism (ICD-9-CM codes available on request) (2). For both potential thromboembolic events and hemorrhagic events, medical record analysts obtained the relevant medical records by using a structured protocol. We did not investigate hospitalizations with the selected discharge diagnosis codes in a secondary position, because such hospitalizations rarely were prompted by new thromboembolic events. We estimate that our rates of ischemic stroke would have been increased relatively by 6% had we reviewed all such hospitalizations (2). We defined a validated ischemic stroke as a sudden neurologic deficit lasting more than 24 hours, corresponding to a vascular territory in the absence of primary hemorrhage, that was not explained by other causes (for example, trauma or infection). We defined a valid peripheral embolism as being identified by radiographic imaging, intraoperative examination, or pathologic findings (with no atherosclerotic disease in the affected artery). Thromboembolic events occurring after hospital admission, generally as a complication of medical care, were not included as outcome events. Two members of the physician outcomes review committee reviewed all potential thromboembolic events by using a formal protocol. Disagreements were resolved by a third committee member or by a consulting neurologist, if needed. Intracranial Hemorrhage We searched hospitalization and billing databases for primary and secondary discharge diagnoses of intracranial hemorrhage, including intraparenchymal, subdural, subarachnoid, and other hemorrhage (ICD-9-CM codes available on request). We excluded intracranial hemorrhage associated with a concomitant discharge diagnosis of major trauma (ICD-9-CM codes 852.1, 852.3, 852.5, and 853.1) and events not leading to hospitalization or those that occurred as a complication of a hospitalization for another problem. Net Clinical Benefit We defined the core net clinical benefit of warfarin therapy in atrial fibrillation as the annualized rate of thromboembolic events (TE rate) prevented minus the annualized rate of intracranial hemorrhages (ICH rate) induced, multiplied by a weighting factor. The following equation illustrates this definition: The weighting factor reflects the relative impact, in terms of death and disability, of an intracranial hemorrhage (including intracerebral, subdural, subarachnoid, and other hemorrhages) while receiving warfarin versus experiencing an ischemic stroke while not receiving warfarin (12). We assigned our base case a weighting factor of 1.5, reflecting outcomes in the ATRIA Study cohort (13, 14). We also provide additional sensitivity analyses by using weighting factors of 1.0 and 2.0. For 10% of potential thromboembolic events and intracranial hemorrhages identified by ICD-9-CM codes, the patients' medical records were unavailable or contained insufficient information to determine whether a valid event had occurred. We did not include these events. For events with missing clinical information, the ratio of patients receiving warfarin to those not receiving warfarin was similar to the ratio for validated events. Making the improbable assumption that all such potential events met our validity criteria increased our estimate of unadjusted overall net clinical benefit by only 0.07% per year. Statistical Analysis We calculated incidence rates of thromboembolism and intracranial hemorrhage as the number of events per 100 person-years of follow-up. Because individual participants in the ATRIA Study cohort could have alternating periods of receiving and not receiving warfarin, we use