Class of 2010 Abstract / OBJECTIVES: The purpose of this study was to demonstrate that an increase in INR is associated with a hemorrhagic event in patients taking the oral anticoagulant warfarin. METHODS: A retrospective review of data from 18 patients previously stable on warfarin therapy with an elevation in INR at the time of a hemorrhagic event. Patients were receiving warfarin treatment in the anticoagulation clinic at the Southern Arizona VA Healthcare system from April 2008 to December 2009. Primary outcome measures included a comparison of INR, warfarin dose, and hematocrit at baseline, within 7 days of the event, and during follow-­‐up. RESULTS: A significant increase in INR was observed from baseline to the event (2.5 +/-­‐ 0.36 vs 6.2 +/-­‐ 3.2; p = 0.0002) but differences in INR during all periods of follow-­‐up did not differ from baseline (p = 0.35 – 0.99). When compared with baseline, differences in warfarin dose reached statistical significance when all 12 weeks of follow-­‐up were included (34.4 +/-­‐ 13.8 mg vs 32.4+/-­‐ 15.5 mg; p = 0.01) but were not significant when only the last 8 weeks (p = 0.06) or 4 weeks (p = 0.16) were included. Hematocrit values decreased significantly following hemorrhage (39.8 +/-­‐ 3.63 vs 33.5 +/-­‐ 5.72; p = 0.0002) before trending toward baseline (39.85 +/-­‐ 3.63 vs 37.13 +/-­‐ 4.72; p = 0.007). CONCLUSIONS: Hemorrhagic events were associated with an increased INR in previously stable warfarin patients. The mean weekly warfarin dose required to maintain a therapeutic INR returned to baseline within 8 weeks of the hemorrhagic event.

Patients with atrial fibrillation (AF) are at increased risk of stroke. Warfarin anticoagulation therapy reduces the incidence of stroke and increases the incidence of hemorrhagic events. This dissertation further informs the decision to use anticoagulation therapy in AF patients by examining outcomes in patients with major hemorrhages, further examination of stroke risk in diabetic patients with AF, and by evaluating the association between warfarin and stroke while accounting for competing risk events. These studies utilized data from the AnTicoagulation and Risk Factors In Atrial Fibrillation (ATRIA) and ATRIA-CVRN (Cardiovascular Research Network) (Study 1 only) studies which consist of patients from Kaiser Permanente Northern and Southern California. Study 1 examined short and long-term mortality in patients who experienced major gastrointestinal (GI) hemorrhages. In the ATRIA cohort, patients using and not using warfarin at the time of GI hemorrhage were equally likely to die within 30-days, while in ATRIA-CVRN, patients using warfarin were much less likely to die within 30-days (adjusted mortality rate ratio (aMRR): 0.33, 95% CI: 0.16-0.70). For longer-term mortality, both cohorts were consistent with a reduced mortality rate among patients whose GI hemorrhage occurred while using warfarin. Study 2 assessed the association between diabetes characteristics (duration of diabetes and glycemic control) and incidence of ischemic stroke among patients with AF and diabetes. Duration ≥ 3 years was associated with a large increase in rate of stroke (adjusted hazard ratio (aHR): 2.04, 95% CI: 1.27-3.26) compared to patients with duration < 3 years. Patients with the poorest glycemic control (hemoglobin A1c (HbA1c) values ≥ 9.0%) did not have an increased rate of ischemic stroke compared to patients with HbA1c < 7.0%. Study 3 evaluated the association between warfarin and thromboembolism in analyses that did and did not account for competing death events. In analyses not accounting for competing events, the adjusted HR was 0.61 (95% CI: 0.54-0.69), and after accounting for competing death events this association was attenuated (aHR: 0.87, 95% CI: 0.77-0.99). In summary, these studies add to the literature about the benefits of warfarin therapy and risk of stroke in patients with AF, findings that can improve decisions about use of anticoagulants in patients with AF.