Concomitant azole use may influence bleeding risk in AF patients on NOACs

In a study evaluating azole use in patients with atrial fibrillation (AF) on non-vitamin K antagonist oral anticoagulants (NOACs), systemic exposure to the antifungal agent fluconazole was associated with an elevated risk of bleeding, particularly among those on apixaban. Conversely, no association was seen between NOACs and topical azoles*.

Fluconazole, the most commonly used systemic antifungal agent, is reportedly associated with increased bleeding risk in patients on apixaban or rivaroxaban. [Int J Antimicrob Agents 2013;42:466-470; Br J Clin Pharmacol 2013;76:455-466; JAMA 2017;318:1250-1259; Pharmacol Res Perspect 2020;8:e00647]

Other studies have also shown the potential of topical azoles to interfere with anticoagulant treatment. [J Clin Pharm Ther 2011;36:642-650; Proc Singapore Healthc 2015;24:121-122; Am J Med 2021;134:e308-e312] “[This] begs the question whether topical azoles could also be associated with elevated bleeding risk in patients on NOACs,” said the researchers.

However, these associations have not been adequately explored, the researchers pointed out, hence the need for further investigation. “[A]nd with azoles for topical use being available over the counter (OTC), it is warranted to investigate any potential association,” they added.

Using nationwide Danish registers, the researchers evaluated AF patients initiated on apixaban (n=32,340), rivaroxaban (n=32,409), or dabigatran (n=24,940) from 2012 through 2018. Of these, 1,990, 2,403, and 2,277 individuals in the respective arms were hospitalized due to bleeding. [Am J Med 2022;135:595-602]

 

Systemic fluconazole

Following exposure (30-day window) to systemic fluconazole, a significantly increased bleeding risk was found among individuals on apixaban (odds ratio [OR], 3.5) but not rivaroxaban (OR, 1.1) or dabigatran (OR, 2.0). The gastrointestinal tract was the most predominant bleeding site among apixaban, rivaroxaban, and dabigatran recipients (39, 40, and 50 percent, respectively).

According to the researchers, the effect with apixaban could have been driven by the patients’ age and comorbidities. “[Apixaban users] were older and more comorbid – thus more fragile – compared with patients on rivaroxaban, resulting in a bigger risk of hospitalization.”

With dabigatran, the lack of association may be expected owing to the absence of CYP3A4 involvement, they said. “[However,] due to the shared elimination pathway with apixaban, it was surprising that no association was found among patients on rivaroxaban either.”

It should be noted that systemic fluconazole use was low**, the researchers pointed out, resulting in large confidence intervals (CIs) that may confound interpretation of data. “We would need very narrow CIs to conclude that no association exists. But on the contrary, statistically significant findings can probably be trusted – despite large CIs.”

 

Topical azoles

The three NOACs evaluated were not associated with increased bleeding risk among those who were on topical azoles (ORs for 30-day exposure windows, 0.8, 1.3, and 1.2 for apixaban, rivaroxaban, and dabigatran, respectively). As such, based on these data, it appears safe to administer topical azoles concurrently with these NOACs, they said.

This finding was furthered by the nonsignificant association seen in a supplementary analysis evaluating topical azoles applied to mucosal tissue (ORs for 30-day exposure windows, 1.8, 1.9, and 1.8 for apixaban, rivaroxaban, and dabigatran, respectively). “This suggests that topical azoles are not absorbed sufficiently for the interaction to be clinically relevant,” said the researchers.

“[Despite the lack of power to interpret this outcome,] this could mean, at least in a Danish context, that the prevalence of co-exposure in relation to a bleeding incident was extremely low … This is reassuring due to the widespread use, as well as the OTC availability, of topical azoles,” they added.

Takeaways

“Added to available knowledge, [the association between NOAC and systemic fluconazole use] should encourage physicians to apply close monitoring or other risk mitigation strategies if co-administration is necessary,” the researchers said. “[I]t could be time to review official recommendations.”

The effect with topical azoles should be explored further to ascertain their safety when used alongside NOACs, they added.