Diltiazem may increase bleeding risk when coadministered with DOACs in afib

Patients with atrial fibrillation who take diltiazem and direct-acting oral anticoagulants (DOACs) concurrently may be at increased bleeding risk, according to a recent study.

Researchers used data from a large U.S. health system to evaluate the association between concomitant use of diltiazem with DOACs and bleeding in patients with atrial fibrillation and varying levels of kidney function. Patients were eligible if they were adults with a diagnosis of atrial fibrillation who began taking rivaroxaban, apixaban, or dabigatran between Jan. 1, 2010, and Feb. 1, 2019, had been seen in the health system for at least one year previously, and had at least one outpatient serum creatinine measurement available in the year before the index date, which was defined as the date of first DOAC prescription. Patients were considered exposed to both diltiazem and DOACs when they had prescriptions for both and were considered unexposed when they were using only DOACs. Bleeding was defined as hospitalization (an ED visit or inpatient stay) with a primary diagnosis of any bleeding, regardless of site. The study results were published July 5 by the Journal of the American Heart Association.

Overall, 4,544 patients with atrial fibrillation who began taking rivaroxaban (n=1,583), apixaban (n=2,373), or dabigatran (n=588) were included in the study. The mean age was 72 years, and the estimated glomerular filtration rate was 70 mL/min per 1.73 m². Fifteen percent of patients who began taking DOACs were also taking diltiazem at the time of DOAC initiation, and another 5% began taking diltiazem during follow-up. Among patients taking DOACs, concurrent use of diltiazem was associated with an increased risk of any bleeding-related hospitalization (unadjusted risk difference, 2.4 [95% CI, 0.6 to 4.2] events per 100 person-years; adjusted hazard ratio, 1.56 [95% CI, 1.15 to 2.12]) and major bleeding (unadjusted risk difference, 1.4 [95% CI, 0.1 to 2.6] events per 100 person-years; adjusted hazard ratio, 1.84 [95% CI, 1.18 to 2.85]) versus use of a DOAC alone. The increased risk of any or major bleeding with diltiazem was seen in patients with and without chronic kidney disease (P=0.524 and 0.629, respectively, for the interaction). In a negative control group of 13,179 patients taking warfarin, no association was seen between bleeding and concomitant diltiazem use.

The researchers noted that their study took place in a single health system, that most of their study population was White, and that medication use was determined by prescription, among other limitations. They also noted that they had limited power to detect associations in patients taking dabigatran, since this group made up only approximately 12% of the study population. The authors concluded that in this study of real-world data, concomitant use of diltiazem with rivaroxaban or apixaban was associated with a higher bleeding risk in patients with atrial fibrillation and was similar in those with and without chronic kidney disease. “These findings support current FDA labeling for rivaroxaban, which recommends avoidance of concurrent use of diltiazem with rivaroxaban. This study also provides important safety information for apixaban users, given that the FDA's guidance for concurrent use of diltiazem with apixaban is lacking,” the authors wrote. “Alternative drugs to diltiazem may be a safer choice to reduce the risk of bleeding for patients taking rivaroxaban or apixaban.”