Research
Risk of gastrointestinal bleeding associated with oral anticoagulants: population based retrospective cohort study
(Published 24 April 2015)
Cite this as: BMJ 2015;350:h1585

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.

Commentary.
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.

What is already known on this topic
Most evidence on the increased risk of gastrointestinal bleeding for novel oral anticoagulants compared with warfarin comes from clinical trials providing limited duration of follow-up and selective inclusion criteria
Observational studies have been inconsistent on the association with gastrointestinal bleeding of dabigatran compared with warfarin.

What this study adds
A 50% increase in the risk of gastrointestinal bleeding associated with dabigatran compared with warfarin cannot be ruled out
A more than twofold increased risk of bleeding with rivaroxaban compared with warfarin cannot be ruled out.

G Mohan.