Prediction of rates of thromboembolic and major bleeding outcomes with dabigatran or warfarin among patients with atrial fibrillation: new initiator cohort study

Abstract

Objectives: To compare stratified event rates from randomized controlled trials with predicted event rates from models developed in observational data, and assess their ability to accurately capture observed rates of thromboembolism and major bleeding for patients treated with dabigatran or warfarin as part of routine care.

Design: New initiator cohort study.

Setting: Data from United Health (October 2009 to June 2013), a commercial healthcare claims database in the United States.

Participants: 21 934 adults with atrial fibrillation initiating dabigatran (150 mg dose only) or warfarin treatment as part of routine care.

Main outcome measures: Predicted annual rates of thromboembolism or major bleeding, based on estimates from randomized controlled trials, models developed in routine care patients, and baseline risk scores (CHADS2, CHA2DS2-VASc, and HAS-BLED). Thromboembolism was a composite outcome, including primary inpatient diagnosis codes for ischemic or ill defined stroke, transient ischemic attack, pulmonary embolism, deep vein thrombosis, and systemic embolism. Major bleeding was a composite outcome including codes occurring in an inpatient setting for hemorrhagic stroke; major upper, lower, or unspecified gastrointestinal bleed; and major urogenital or other bleed.

Results: 6516 (30%) and 15 418 (70%) of patients initiated dabigatran and warfarin, respectively. Annual event rates per 100 patients were 1.7 for thromboembolism and 4.6 for major bleeding. For thromboembolism, calibration of estimates from randomized controlled trials was similar to calibration for model based predictions; however, trial estimates for major bleeding consistently underestimated the rate of bleeding among patients in routine care. Underestimation of bleeding rates was particularly pronounced in warfarin initiators with high HAS-BLED scores, where event rates were underestimated by up to 4.0 per 100 patient years. Harrell's c indices for discrimination for thromboembolism or major bleeding in dabigatran and warfarin initiators ranged between 0.59 and 0.66 for randomized controlled trial predictions, and between 0.52 and 0.70 for cross validated model based predictions.

Conclusion: Estimated rates of thromboembolism under dabigatran or warfarin treatment in randomized controlled trials were close to observed rates in routine care patients. However, rates of major bleeding were underestimated. Models developed in routine care patients can provide accurate, tailored estimates of risk and benefit under alternative treatment to enhance patient centered care.

Fig 1 Steps for obtaining predicted annual rates per 100 patient years of thromboembolism and major bleeding outcomes from randomized controlled trial participants and routine care patients. *Risk score=estimated baseline rate of outcome from relevant external risk score developed in patients not on oral anticoagulation therapy (or mix of treated and untreated). Risk score factors are CHADS₂ (congestive heart failure, hypertension, age≥75 years, diabetes mellitus, previous stroke/transient ischaemic attack/thromboembolism (doubled risk weight)), CHA₂DS₂-VASc (CHADS₂ plus vascular disease, age 65-74 years, and female sex (age≥75 years and previous stroke carry doubled risk weight)), and HAS-BLED (age>65 years, hypertension, abnormal renal function, abnormal liver function, prior stroke, bleeding history (or predisposition), drugs predisposing to bleed, alcohol use disorders, and labile international normalized ratio). †Estimated rate of outcomes in trial participants randomized to warfarin or dabigatran. ‡Estimated rate of outcomes from models fit separately in initiators of warfarin and dabigatran in routine care, using risk factors in relevant risk score. Performance evaluated for average estimate from repeated 10-fold cross validation

Fig 2 Calibration of predicted rates per 100 patient years of thromboembolism or major bleeding in initiators of dabigatran or warfarin. Difference between rates calculated as observed rates minus predicted rates. RCT=estimated rate of outcomes in trial participants randomized to warfarin or dabigatran; model=estimated rate of outcomes from models fit separately in initiators of warfarin and dabigatran in routine care, using risk factors in relevant risk score; score=estimated baseline rate of outcome from relevant external risk score developed in patients not on oral anticoagulation therapy (or mix of treated and untreated patients). Performance evaluated for average estimate from repeated 10-fold cross validation. Risk score factors: CHADS₂=congestive heart failure, hypertension, age (≥75 years), diabetes mellitus, and previous stroke/transient ischaemic attack/thromboembolism (doubled risk weight); CHA₂DS₂-VASc=factors in CHADS₂ plus vascular disease, age 65-74 years, and female sex (age≥75 years and previous stroke carry doubled risk weight); HAS-BLED=age>65 years, hypertension, abnormal renal and liver function, prior stroke, bleeding history (or predisposition), drugs predisposing to bleed, alcohol use disorders, and labile international normalized ratio. Criteria for ascertaining major bleeding in clinical trials: ISTH=International Society on Thrombosis and Haemostasis; TIMI=thrombolysis in myocardial infarction; GUSTO=global use of strategies to open occluded arteries