Mixed findings on GI bleeding risk with new oral anticoagulants

Last Updated: 2015-05-06

By Will Boggs MD

NEW YORK (Reuters Health) - New oral anticoagulants may be associated with a higher risk of gastrointestinal bleeding than warfarin in patients over 75 years, but two new studies yield conflicting results.

"Our finding that a patient's age influences the gastrointestinal safety of the drug is an important new finding," Dr. Neena S. Abraham from Mayo Clinic in Scottsdale, Arizona, told Reuters Health.

"Patients <65 years had fewer gastrointestinal bleeds when treated with dabigatran and rivaroxaban, compared to warfarin. But this risk increased after the age of 65 such that by age 76, the risk of gastrointestinal bleed associated with either agent exceeded that with warfarin," she said in an email.

Yet Dr. Hsien-Yen Chang from Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, and colleagues found no significant difference in bleeding.

He told Reuters Health by email, "Our inability to detect a significant difference between dabigatran and warfarin may have been a result of a low number of events resulting in inadequate statistical power. In addition, most patients exited the cohort due to loss of continuous exposure."

Both studies were published online April 24 in the BMJ.

Earlier research has been inconsistent on the risk of GI bleeding with the newer drugs relative to warfarin, according to the reports, though meta-analyses have found more bleeds with dabigatran and rivaroxaban.

Dr. Abraham's team used data from Optum Labs Data Warehouse to compare GI bleeding risks associated with dabigatran, rivaroxaban, and warfarin in nearly 93,000 patients taking one of these anticoagulants.

Overall, dabigatran and rivaroxaban patients had GI bleeding rates comparable to those of matched patients taking warfarin, they found.

When patients with atrial fibrillation were grouped by age, though, the GI bleeding risk for patients aged 76 and older was 2.49 times higher with dabigatran and 2.91 times higher with rivaroxaban than with warfarin.

For patients without atrial fibrillation, the rate of GI bleeding was 56% higher for dabigatran and 4.58 times higher for rivaroxaban than for warfarin.

"Physicians need to carefully consider the patient's age when prescribing these new anticoagulants," Dr. Abraham concluded. "There is up to a five-fold increase in gastrointestinal bleeding associated with these agents when used in the elderly."

"But," she conceded, "these drugs may be a convenient and safe choice for patients under the age of 65."

In the other study, Dr. Chang's team found no significant difference in the risk of GI bleeding between dabigatran and warfarin or between rivaroxaban and warfarin using the IMS Health LifeLink Health Plan Claims Database with more than 46,000 patients.

They also found no difference when they compared patients over and under age 65 years, though there was a borderline increase in the hazard ratio for patients over 65 who used dabigatran.

"However, these findings are not inconsistent with previous studies and do not rule out a greater than 50% increased risk with dabigatran and more than twofold increased risk with rivaroxaban," the researchers say.

A related editorial calls for better ways to predict which patients are at highest risk of GI bleeding.

"Monitoring of drug concentrations in patients taking newer agents, combined with a range of possible dose options, may hold the key to optimizing the safety and effectiveness of these unfamiliar drugs," Dr. Mary S. Vaughan Sarrazin from University of Iowa in Iowa City and Dr. Adam Rose from Boston University write.

"While one of the advantages of novel oral anticoagulants is that routine monitoring is not required, some monitoring at drug initiation to verify appropriate dosing may be warranted, and would still be less burdensome than warfarin which requires routine monitoring," Dr. Sarrazin added in an email to Reuters Health.

"Stroke prevention is the driving factor for choosing anticoagulants," she said. "While GI and other bleeding associated with oral anticoagulants can be dangerous, most bleeding events are not nearly as devastating as stroke. Nevertheless, oral anticoagulants should be tolerable to the patients who take them, as failure to adhere limits their effectiveness in preventing stroke."

Dr. Mark Crowther, head of thromboembolism research at McMaster University in Hamilton, Ontario, Canada, sees no surprises in the new results.

"They should reassure clinicians that despite a lack of reversal agents, new anticoagulants are likely as safe as warfarin, reduce intracerebral bleeding (the worst kind), are easier to use than warfarin, and are at least as effective as warfarin," Dr. Crowther, who was not involved in the studies, told Reuters Health by email.

"Bleeding is a fact in patients taking anticoagulants," Dr. Crowther said. "Other data suggests fatal bleeding is reduced with new agents compared with warfarin. Clinicians should not assume that warfarin (as the 'standby') is either safer or more effective than new agents."

Dr. Martin Ellis, head of the hematology institute and blood bank at Meir Medical Center in Kfar Saba, Israel, agreed, though he felt caution was still warranted.

"These claims-based studies studied GI bleeding overall, and we are not informed regarding serious GI bleeding leading to hospitalization, blood transfusion, etc., nor is there an analysis of fatal bleeding," he told Reuters Health by email.

"In appropriately chosen patients (particularly regarding age), dabigatran and rivaroxaban may not be as problematic as previously thought with regard to GI bleeding," Dr. Ellis concluded. "Screening for risk factors is important."

Neither of the new studies had commercial funding.

SOURCE: http://bit.ly/1zAw6qX, http://bit.ly/1KgWXc2 and http://bit.ly/1F5AQHJ

BMJ 2015.