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Interaction between newer anticoagulants, certain drugs increases major bleeding in AF
In patients with atrial fibrillation taking non-vitamin K oral anticoagulants, some concurrently prescribed drugs increased the risk for major bleeding compared with oral anticoagulants alone, study data show.
“Non-vitamin K oral anticoagulants (NOACs) are being used more frequently because of their ease of administration and comparative efficacy compared with warfarin in reducing thromboembolism and major bleeding,” Shang-Hung Chang, MD, PhD, of the cardiovascular department at the Chang Gung Memorial Hospital, Taiwan, and colleagues wrote. “However, for patients with atrial fibrillation, NOACs still pose a major bleeding risk, which is particularly problematic when multiple morbidities, high-risk medications, polypharmacy or drug-drug interactions are present.”
Chang and colleagues used data from the National Health Insurance database in Taiwan and included 91,330 patients with nonvalvular AF (mean age, 75 years; 56% men) who were prescribed dabigatran (n = 45,347; Pradaxa, Boehringer Ingelheim), rivaroxaban (n = 54,006; Xarelto, Janssen) or apixaban (n = 12,886; Eliquis, Bristol-Myers Squibb/Pfizer) from 2012 to 2016.
The most common medications coprescribed with NOACs were atorvastatin (27.6%), diltiazem (22.7%), digoxin (22.5%) and amiodarone (21.1%).
The primary endpoint was major bleeding, defined as hospitalization or ED visit with diagnosis of intracranial hemorrhage or gastrointestinal, urogenital or other bleeding.
During 447,037 person-quarters, 4,770 major bleeding events occurred.
Compared with NOAC use alone, there was an increased adjusted incidence rate per 1,000 person-years of major bleeding with concurrent use of NOACs and amiodarone (38.09 vs. 52.04; difference, 13.94; 99% CI, 9.76-18.13), NOACs and fluconazole (102.77 vs. 241.92; difference, 138.46; 99% CI, 80.96-195.97), NOACs and rifampin (65.66 vs. 103.14; difference, 36.9; 99% CI, 1.59-72.22) and NOACs and phenytoin (56.07 vs. 108.52; difference, 52.31; 99% CI, 32.18-72.44).
The adjusted incidence rate for major bleeding was significantly lower for concurrent use of NOACs and atorvastatin, digoxin, and erythromycin or clarithromycin compared with NOAC use alone. There was no significant difference in major bleeding for concurrent use of NOACS and verapamil; diltiazem; cyclosporine; ketoconazole, itraconazole, voriconazole or parconazole; and dronedarone.
“Some specific medications advised to be avoided in NOAC users, including diltiazem and amiodarone, were frequently prescribed to patients with nonvalvular atrial fibrillation in the clinical settings. ... [A]miodarone, fluconazole, rifampin and phenytoin were associated with a significantly increased risk of major bleeding, whereas some combinations not recommended by guidelines were not associated with major bleeding,” the researchers wrote.
“Physicians prescribing NOAC medications should consider the potential risks associated with concomitant use of other drugs,” Chang and colleagues wrote. by Cassie Homer
Disclosures: The authors report no relevant financial disclosures.
Perspective
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These results were interesting, even though it’s hard to reconcile the pharmacological principles at play with the results the authors actually saw. Many of the pharmaco-interaction concerns that are expressed in the paper are not entirely surprising. In other words, we know that these medications are metabolized by CYP3a4 system, so one would expect there to be drug-drug interactions. But we don’t really see any major risks for increased adverse events or CV events with these medications and concomitant medications in carefully conducted randomized controlled clinical trials where patients have very close follow-up. Some of these medications were excluded in those studies. For example, in ROCKET-AF, patients couldn’t receive phenytoin or rifampin because those were known strong inducers of CYP3a4.
What is interesting is the authors reported a significantly increased risk for major bleeding in patients who received these medications with phenytoin and with rifampin, which really doesn’t make any sense because if you’re going to see an interaction, what you should see is lower risk for major bleeding because those medications are strong inducers of the enzyme. So, you actually see lower amounts of NOAC drug concentration, and therefore you should see lower rates of major bleeding. What those associations are likely reflecting is that the patients on the additional medications are sicker and have more comorbidities, and therefore may be more susceptible to adverse events like bleeding.
Despite the interesting results, I’m not sure there are specific messages for the clinical community. In general, it’s very important to pay attention to drug-drug interactions and to be very mindful when we’re prescribing a new medication to a patient that they’re not taking any medications that would potentially interact. However, that’s true all the time. We should always be paying attention to those things. It’s reassuring that increased major bleeding with verapamil, diltiazem, dronedarone, etc., was not observed in clinical practice. In the case of amiodarone, multiple studies have shown that people taking it are at very high risk, so the observed high rate of bleeding in the patients taking amiodarone likely highlights that there are high-risk patients that we should pay special attention to.
It may be easier to say what we should not take away from the analysis and I think we certainly should not take away from the analysis that patients with amiodarone should not be treated with a NOAC, it’s just that we need to be cognizant of the fact that they may be at increased risk for bleeding events and we should do everything we can to minimize risk factors for bleeding, like use of non-steroidal anti-inflammatories or concurrent aspirin when it’s not needed.