Greater bleeding risk with dabigatran than warfarin in Medicare patients, 2 studies find

Two studies of Medicare data released last week added to existing evidence that older dabigatran users have higher bleeding risks than warfarin users.

In the first study, researchers retrospectively analyzed medical and pharmacy claims from a random sample of Medicare patients who were newly diagnosed with atrial fibrillation between Oct.1, 2010, and Oct. 31, 2011. All patients started dabigatran (n=1,302) or warfarin (n=8,102) within 60 days of their diagnosis and were followed until Dec. 31, 2011, or until they discontinued anticoagulant use, switched drugs, or died. Results were published online Nov. 3 by JAMA Internal Medicine.

For any bleeding event (after adjustment for patient characteristics), dabigatran was associated with a higher bleeding risk than warfarin (hazard ratio [HR], 1.30; 95% CI, 1.20 to 1.41); it was also associated with greater risk for gastrointestinal (GI) bleeding (HR, 1.85; 95% CI, 1.64 to 2.07) and major bleeding (incidence, 9% vs. 5.9%; HR, 1.58; 95% CI, 1.36 to 1.83).

In subgroup analysis of high-risk patients, major and GI bleeding risk remained higher for dabigatran users in the following groups: African-Americans, patients with chronic kidney disease, older patients (≥75 years), and patients with more than 7 comorbidities. Major bleeding risk in dabigatran users was especially high in the first 2 subgroups. However, intracranial hemorrhage risk was lower among dabigatran users compared to warfarin users (HR, 0.32; 95% CI, 0.20 to 0.50).

An editorialist remarked that the study highlights the importance of gathering postmarketing data on drugs recently approved by the FDA, in order to learn about “risks associated with real-world use. [The study authors] give us cause for concern because it appears that the bleeding risk for dabigatran is higher than for warfarin, and significantly greater than originally appeared at the time of FDA approval,” she wrote.

The study authors noted the FDA's investigation of dabigatran didn't adjust for differences in patient characteristics between treatment groups. “Dabigatran and warfarin users are very different in several factors that directly affect the risk of bleeding, and failing to adjust would bias the results, as our unadjusted estimates indicate,” they wrote. Physicians should use caution in prescribing dabigatran, especially to African-Americans and those with renal impairment, they wrote, and should counsel dabigatran patients on how to detect potential GI bleeding. Dabigatran may make the most sense for patients at high risk of intracranial bleeding, they added.

A second study of 134,414 Medicare patients (age ≥65 years) with nonvalvular atrial fibrillation also found elevated risk of GI bleeding, and lower risk of intracranial hemorrhage, in dabigatran users compared to warfarin users. Researchers analyzed claims data on patients who first began taking either dabigatran (n=67,494) or warfarin (n=273,920) between October 2010 and December 2012. Results were published Oct. 30 by Circulation.

Patients taking dabigatran, either 150 mg or 75 mg twice daily, had more GI bleeding (HR, 1.28; 95% CI, 1.14 to 1.44), fewer intracranial hemorrhages (HR, 0.34; 95% CI, 0.26 to 0.46), fewer ischemic strokes (HR, 0.80; 95% CI, 0.67 to 0.96), fewer acute myocardial infarctions (HR,0.92; 95% CI, 0.78 to 1.08), and fewer deaths (HR,0.86; 95% CI, 0.77 to 0.96) than those taking warfarin. A subgroup of 75-mg, twice-daily dabigatran users had no differences in risk compared to warfarin users, except for lower intracranial hemorrhage risk. Most people who took the lower dabigatran dose “appeared not to have severe renal impairment, the intended population for this dose,” the researchers noted. The subgroup of patients who took the higher dabigatran dose had a greater magnitude of effect for each outcome compared to the combined-dose group of dabigatran users.

Subgroup analyses found that the higher GI bleeding risk with dabigatran occurred in women age 75 years or older and men age 85 years or older; below these thresholds, the GI bleeding risks of dabigatran and warfarin were comparable. Also, the beneficial effect of dabigatran on mortality relative to warfarin wasn't evident in women older than 85 years.

“The benefit-risk profile of dabigatran may be less favorable in women age 85 years and older than in other age-gender groups,” the researchers wrote. The results also suggest many patients were treated with the 75-mg dose off-label, meaning they may have been underdosed, which “could explain why we found no difference in ischemic stroke, major gastrointestinal bleeding, or mortality between warfarin and the lower dose of dabigatran,” the researchers wrote.