Abstract and Introduction
Abstract
Objectives To determine the real world safety of dabigatran or rivaroxaban compared with warfarin in terms of gastrointestinal bleeding.
Design Retrospective cohort study.
Setting Large administrative database of commercially insured people in United States from 1 October 2010 through 31 March 2012.
Participants Enrollees with a prescription of warfarin, dabigatran, or rivaroxaban between 1 October 2010 and 31 March 2012, who were aged 18 years or older, had continuous enrollment and no oral anticoagulant use during the six months before the entry date, with known age and sex, and with no gastrointestinal bleeding for at least six months before the cohort entry date. The final study sample of 46 163 patients included 4907 using dabigatran, 1649 using rivaroxaban, and 39 607 using warfarin.
Main outcome measure Time to gastrointestinal bleeding. Hazard ratios were derived from Cox proportional hazard models with propensity score weighting and robust estimates of errors.
Results Dabigatran users tended to be older (dabigatran v rivaroxaban v warfarin: 62.0 v 57.6 v 57.4 years) and more likely to be male (69% v 49% v 53%). The rate of gastrointestinal bleeding was highest among dabigatran users and lowest among rivaroxaban users (dabigatran v rivaroxaban v warfarin: 9.01 v 3.41 v 7.02 cases per 100 person years). After adjustment for potentially confounding covariates, there was no evidence of a statistically significant difference in the risk of gastrointestinal bleeding between dabigatran and warfarin users (adjusted hazard ratio 1.21, 95% confidence interval 0.96 to 1.53) or between rivaroxaban and warfarin users (0.98, 0.36 to 2.69).
Conclusions Although rates of gastrointestinal bleeding seem to be similar in this commercially insured sample of adults in the United States, we cannot rule out as much as a 50% increase in the risk of gastrointestinal bleeding with dabigatran compared with warfarin or a more than twofold higher risk of bleeding with rivaroxaban compared with warfarin.
Introduction
Anticoagulants are widely prescribed in the United States, the United Kingdom, and around the world for various conditions including atrial fibrillation. Dabigatran and rivaroxaban are available as alternatives to warfarin for the prevention of stroke in atrial fibrillation. These drugs offer several advantages over warfarin, including simplified dosing, fewer drug interactions, and no requirement for monitoring. As the pharmacokinetic half life of novel anticoagulants is relatively brief, their pharmacologic effects are transient and disappear within a week.
Clinical trials have established the relative efficacy or non-inferiority of these agents compared with warfarin in selected patients. For example, in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial, dabigatran administered at a dose of 150 mg was associated with lower rates of stroke and systemic embolism (1.11% v 1.71%; P<0.001) compared with warfarin. In this trial, both drugs had similar rates of major hemorrhage (annual major bleeding risk 3.32% v 3.57% for dabigatran v warfarin; P=0.32). However, the rates of gastrointestinal bleeding were higher with dabigatran. The Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation (ROCKET-AF) trial showed that rivaroxaban at a 10 mg dose was non-inferior to warfarin for the outcome of stroke and systemic embolism. As with the RE-LY trial, no differences were seen in rates of major bleeding between warfarin and rivaroxaban in the ROCKET-AF trial, although rates of fatal bleeding were lower in the rivaroxaban arm.
Despite the insights that these trials provide, the real world safety of these novel oral anticoagulants compared with warfarin from limited observational studies is less clear. Such safety may diverge from the trial results for several reasons, including trials' selective inclusion criteria as well as the limited duration of these investigations. Information on findings on gastrointestinal safety will allow clinicians to weigh the risks and benefits of these agents. Gastrointestinal bleeding carries substantial morbidity and mortality. In the United States in 2009, an estimated 140 000 or more hospital admissions had the principal diagnoses of gastrointestinal bleeding and their aggregate costs reached $1.15bn (£0.77bn; €1.06bn). The incidence of upper gastrointestinal bleeding in the United Kingdom was 103 cases per 100 000 adults per year. Among patients admitted to hospital with acute upper gastrointestinal bleeding in the United Kingdom in 2007, the overall mortality rate was 10%; among UK patients with atrial fibrillation with warfarin induced gastrointestinal bleeding, 6% of such bleeds are fatal.
Post-marketing reports have noted reports of major bleeding associated with dabigatran among older patients, those at the extremes of body weight, and those with impaired renal function. Such patients have been largely excluded from the trials. Approximately 25% of the bleeding events in post-marketing reports were associated with prescribing and dosing error. Concomitant use of antiplatelet drugs with dabigatran increases the risk of bleeding. The proportion of patients taking antiplatelet drugs is higher in the real world, making such patients susceptible to bleeding complications. Furthermore, in contrast to warfarin, no specific antidote for dabigatran exists and it is not dialyzable.
We did a retrospective cohort study using a large administrative claims database of commercially insured people to quantify the comparative safety of these novel anticoagulants relative to warfarin with respect to major gastrointestinal bleeding. We focused on gastrointestinal bleeding because of earlier signals in pivotal clinical trials suggesting an increase in gastrointestinal bleeding with dabigatran relative to warfarin. Additionally, these novel agents have been approved only recently and assessing the efficacy of long term outcomes such as stroke without incurring adequate follow-up would be premature.