‘Small but Important’ Bleeding Risk With Concurrent Clarithromycin/DOAC Use

Concurrent use of clarithromycin and a direct oral anticoagulant (DOAC) raises the risk of bleeding in older adults, according to a retrospective study from Canada.

This risk is “likely underrecognized,” corresponding author Dr. Manish Sood, Ottawa Hospital Research Institute, told Reuters Health by email. “Our study is the largest and most thorough examining and quantifying the small but important increased risk of bleeding with this combination of medications.”

In a report in JAMA Internal Medicine, the researchers say anticoagulant-associated hemorrhage is one of the most common adverse drug reactions requiring hospital admission. DOACs have become the anticoagulant drugs of choice for many patients, but their safety and drug interaction profile are not completely understood.

Clarithromycin, a commonly prescribed macrolide antibiotic, is associated with higher levels of direct oral anticoagulants (DOACs) in the blood. “Multiple pharmacokinetic studies have demonstrated that concomitant use of apixaban, rivaroxaban, or dabigatran with clarithromycin increases serum levels of DOACs by 20% to 100% and prolongs coagulation time,” the researchers point out. This is not the case with azithromycin. Yet, knowledge on the bleeding risk with concurrent DOAC and clarithromycin therapy is “limited.”

To investigate, they took a look back at 24,943 older adults (mean age, 77.6) who were newly coprescribed clarithromycin (26%) or azithromycin (74%) while taking a DOAC.

Rivaroxaban was the most commonly prescribed DOAC (40%), followed by apixaban (32%) and dabigatran (28%).

Hospital admission with major hemorrhage (primary outcome) occurred in 51 of 6592 patients (0.77%) taking clarithromycin and 79 of 18,351 patients (0.43%) taking azithromycin.

The crude incident rate for major hemorrhage was higher in patients taking clarithromycin than azithromycin (95.9 vs 53.1 per 1000 person-years).

After adjusting for proton pump inhibitor use, DOAC type, and DOAC mean daily dose, clarithromycin users had a 1.71-fold higher rate of hospital admission within 30 days for major hemorrhage (absolute risk difference, 0.34%). Results were consistent in multiple additional analyses.

DOACs are still “relatively new to the market having been widely available for just over a decade. As such, there is little information regarding rare drug interactions, such as the clarithromycin-DOAC interaction in our study,” Dr. Sood told Reuters Health.

“As clarithromycin and DOACs are commonly prescribed by a wide array of different types of physicians, there may not be broad awareness of the risks. Furthermore other important health professionals, such as pharmacists, may be unaware,” he noted.

To help reduce the risk, Dr. Sood suggests the following steps:

– Determine if the patient is at high risk for bleeding (for example previous bleeding episodes, on other blood thinning medications such as aspirin, advanced age)

– If high risk, is there another suitable antibiotic that can be prescribed instead of clarithromycin; can clarithromycin be given for the shortest time possible or can an alternative blood thinning medication be prescribed (such as low molecular weight heparin)?

– If they require clarithromycin and DOAC with no suitable alternatives, can the bleeding risk be reduced by stopping aspirin or prescribing a gastric acid lowering medication (reduces the risk of an ulcer-related stomach bleeding)?

– Lastly, carefully follow the patient and empower them to self-monitor and seek medical attention immediately if any signs or symptoms of bleeding develop while on clarithromycin-DOAC combination.

Support for the study was provided by the Heart and Stroke Foundation of Canada and the Institute for Clinical Sciences (ICES). Dr. Sood has received grants from the Heart and Stroke Foundation of Canada during the conduct of the study and speaker fees from AstraZeneca.