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One particular macrolide antibiotic was tied to higher bleeding risk in people taking direct oral anticoagulants (DOACs), a study found.

Compared with azithromycin, patients prescribed a course of clarithromycin had a greater risk of 30-day hospital admission or emergency department visit with major hemorrhage (0.77% vs 0.43%, adjusted HR 1.71, 95% CI 1.20-2.45), according to Manish Sood, MD, of The Ottawa Hospital in Ontario, and colleagues reporting online in .

"These findings were consistent when a more broad-based definition for hemorrhage was used that included receipt of a blood transfusion, after excluding individuals with a history of H. pylori infection, using alternative methods of controlling for confounding (inverse probability of treatment weighting), and limited to patients with known kidney function," the authors noted.

A self-controlled case series analysis -- comparing periods of exposure and non-exposure to antibiotics in people who had a hemorrhage -- also found that these bleeds were associated with periods of clarithromycin use (RR 1.44, 95% CI 1.08-1.92).

"Thus, the concurrent use of clarithromycin and DOACs poses a significant drug-drug interaction. Clinicians need to consider the risk of hemorrhage, the indication and microbial susceptibility of the infection being treated, and whether viable alternatives (either anticoagulant or antimicrobial) are readily available," Sood's group concluded.

Monitoring of DOAC levels may be necessary when patients use these drugs with clarithromycin, they suggested.

Clarithromycin is similar to azithromycin as commonly used macrolide class antibiotics, except that the former is a more potent CYP3A4 and P-glycoprotein inhibitor, which increases risk of adverse bleeding events, and has also been shown to .

The findings affirm a clinically relevant impact of what pharmacokinetic studies had suggested, in that clarithromycin increases serum levels of DOACs by 20% to 100% and prolongs coagulation time.

Taking azithromycin has its own risks, however, as the antibiotic has been linked to dangerous arrhythmias and sudden cardiac death.

The population-based study included people in Ontario age 66 and older (half of them women, mean age 77.6 years). All were on DOAC therapy: 28.1% dabigatran (Pradaxa), 31.9% apixaban (Eliquis), and 40.0% rivaroxaban (Xarelto).

The group was split between those who had been newly prescribed clarithromycin (n=6,592) or azithromycin (n=18,351) in 2009-2016. The two cohorts had few differences at baseline, among them proton pump inhibitor use and DOAC type.

Chief among the study's limitations were the potential for unmeasured confounding, the small number of bleeding events, selection for an older population, and the lack of information on whether patients actually adhered to their prescribed medications.

"We specifically examined for effect modification in our models and did not detect any difference in bleeding risk by DOAC. The inability to detect differences by DOAC types suggests that either there is no increased risk of hemorrhage with all 3 DOACs examined or, alternatively, there was an inability to detect differences owing to limited sample sizes," the investigators noted.

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