The decision to use anticoagulants for atrial fibrillation depends on comparing a patient’s estimated risk of stroke to their bleeding risk. Several of the risk factors in the stroke risk schemes overlap with hemorrhage risk. We compared how well 2 stroke risk scores (CHADS 2 and CHA 2 DS 2 -VASc) and 2 hemorrhage risk scores (the ATRIA bleeding score and the HAS-BLED score) predicted major hemorrhage on and off warfarin in a cohort of 13,559 community-dwelling adults with AF. Over a cumulative 64,741 person-years of follow-up, we identified a total of 777 incident major hemorrhage events. The ATRIA bleeding score had the highest predictive ability of all the scores in patients on warfarin (c-index of 0.74 [0.72 to 0.76] compared with 0.65 [0.62 to 0.67] for CHADS 2 , 0.65 [0.62 to 0.67] for CHA 2 DS 2 -VASc, and 0.64 [0.61 to 0.66] for HAS-BLED) and in those off warfarin (0.77 [0.74 to 0.79] compared with 0.67 [0.64 to 0.71] for CHADS 2 , 0.67 [0.64 to 0.70] for CHA 2 DS 2 -VASc, and 0.68 [0.65 to 0.71] for HAS-BLED). In conclusion, although CHADS 2 and CHA 2 DS 2 -VASc stroke scores were better at predicting hemorrhage than chance alone, they were inferior to the ATRIA bleeding score. Our study supports the use of dedicated hemorrhage risk stratification tools to predict major hemorrhage in atrial fibrillation.
Anticoagulant therapy significantly reduces the risk of ischemic stroke from atrial fibrillation, and guidelines recommend using stroke risk stratification schemes to estimate the risk of stroke and determine the need for anticoagulation. However, the bleeding complications associated with anticoagulation deter many clinicians from prescribing such therapy. Stroke risk schemes, while developed to predict ischemic stroke, contain variables that are also risk factors for anticoagulant-associated hemorrhage, leading to suggestions that stroke risk schemes can be used as proxies for hemorrhage risk. The objective of our study was to test whether 2 widely used stroke risk stratification schemes based on individual risk factors, the CHADS 2 and CHA 2 DS 2 -VASc scores, could effectively predict major hemorrhage in anticoagulated patients and compared their predictive ability with 2 validated hemorrhage risk scores also based on individual risk factors (ATRIA and HAS-BLED).
Methods
The ATRIA study is a cohort of 13,559 adults enrolled in Kaiser Permanente Northern California diagnosed with nonvalvular atrial fibrillation. Subjects were enrolled in the cohort from July 1, 1996, to December 31, 1997, and followed until September 30, 2003. Patients were included if they had serial outpatient diagnoses of atrial fibrillation, with the large majority having electrocardiographic evidence of atrial fibrillation. Demographic data and dates of hospitalization were available from health plan administrative databases.
We compared the CHADS 2 and CHA 2 DS 2 -VASc stroke risk scores with the ATRIA bleeding score and the HAS-BLED scores. The individual components of the risk scores are presented in Table 1 . The presence of specific medical conditions included in the risk scores was identified by searching for relevant International Classification of Diseases, Ninth Edition ( ICD-9 ), codes as previously described. Diabetes mellitus diagnoses were obtained from a validated diabetes registry. Laboratory data on hemoglobin, estimated glomerular filtration rate, and international normalized ratio (INR), were obtained from outpatient laboratory databases. Exposure to warfarin was determined using a combination of information from prescriptions and INR measurements in pharmacy and laboratory databases using a previously developed and validated algorithm. Longitudinal warfarin exposure was based on number of days of supply per prescription and intervening INRs. Data on prescription antiplatelet medications were obtained from outpatient pharmacy databases, but use of over-the-counter medications (e.g., aspirin and nonsteroidal anti-inflammatory drugs) was not available.
| Variables | Points |
|---|---|
| CHADS 2 | |
| Congestive heart failure | 1 |
| Hypertension | 1 |
| Age ≥ 75 years | 1 |
| Diabetes mellitus | 1 |
| Stroke/TIA | 2 |
| Scoring: Continuous or Low (0 points), Intermediate (1 point), and High (2-6 points) | |
| CHA 2 DS 2 -VASc | |
| Congestive heart failure | 1 |
| Hypertension | 1 |
| Age ≥ 75 years | 2 |
| Diabetes mellitus | 1 |
| Stroke/TIA | 2 |
| Vascular disease | 1 |
| Age 65-74 years | 1 |
| Female sex | 1 |
| Scoring: Continuous or Low (0 points), Intermediate (1 point), and High (2-10 points) | |
| ATRIA Bleeding Score | |
| Anemia | 3 |
| Severe renal disease | 3 |
| Age ≥ 75 years | 2 |
| Prior bleeding | 1 |
| Hypertension | 1 |
| Scoring: Continuous or Low (0-3 points), Intermediate (4 points), and High (5-10 points) | |
| HAS-BLED | |
| Hypertension | 1 |
| Abnormal renal/liver function | 1-2 |
| Stroke history | 1 |
| Bleeding history or predisposition | 1 |
| Labile INR | 1 |
| Age > 65 yrs | 1 |
| Drugs/alcohol concomitantly | 1-2 |
| Scoring: Continuous | |
The primary outcome of the study was major hemorrhage, defined as fatal, requiring transfusion of ≥2 units of packed red blood cells or hemorrhage into a critical anatomic site (such as intracranial or retroperitoneal). Potential events in the cohort were identified from clinical databases by searching for hospitalizations with a primary discharge diagnosis of extracranial hemorrhage those with a primary or secondary diagnosis of intracranial hemorrhage. Medical charts from potential hemorrhagic events were reviewed by a physician-led clinical outcomes committee using a formal study protocol to determine whether the events were valid and met major hemorrhage criteria.
The cohort was divided into on- and off-warfarin periods based on the warfarin algorithm. Exposure to individual clinical risk factors was assessed using a time-varying approach where the presence of risk factors was allowed to change over time based on changes in clinical factors (such as increasing age or new medical diagnoses). Major hemorrhage rates were calculated for on- and off-warfarin periods as events per 100 person-years. The predictive ability of each risk score was measured by calculating a c-index from a logistic regression model, using risk scores in their continuous form. We also divided risk scores into low-, intermediate-, and high-risk categories to calculate the net reclassification improvement between risk scores, a measure of the proportion of patients correctly moved from 1 risk category to another based on outcomes.
Results
A total of 13,559 patients contributed 32,611 person-years on warfarin and 32,130 off warfarin. There were 777 major hemorrhages in the cohort. The CHADS 2 and CHA 2 DS 2 -VASc stroke risk scores performed better than chance alone in predicting major hemorrhage in patients on and off warfarin, although the difference in hemorrhage rates between low- and high-risk categories was small ( Table 2 ). However, stroke risk scores did not perform and the ATRIA bleeding score as well, which predicted hemorrhage better than CHADS 2 , CHA 2 DS 2 -VASc, and HAS-BLED ( Table 2 ).
