NOAC-Drug Interactions Linked to Increased Bleeding

October 06, 2017

Bleeding risk with the new oral anticoagulant drugs (NOACs) is increased when they are used with some other medications, including amiodarone, often co-prescribed with these agents, a new study warns.

The study, published in the October 3 issue of JAMA, found that among patients taking NOACs for nonvalvular atrial fibrillation, concurrent use of amiodarone, fluconazole, rifampin, and phenytoin was associated with increased risk for major bleeding compared with the use of NOACs alone.

But atorvastatin, which like the other drugs studied shares key metabolic pathways with NOACs, did not show an increased bleeding risk when combined with a NOAC and was actually associated with a lower risk than a NOAC alone.

"This is the first...nationwide population-based cohort study to quantify the major bleeding risk associated with drug-drug interaction with NOACs," the researchers report.

"Physicians prescribing NOAC medications should consider the potential risks associated with concomitant use of other drugs," they conclude. 

The current study used a nationwide cohort of patients with nonvalvular atrial fibrillation to estimate the bleeding risk in NOAC users associated with the concurrent use of 12 commonly prescribed medications that share metabolic pathways with NOACs.

The researchers analyzed data from the Taiwan National Health Insurance database on 91,330 patients with nonvalvular atrial fibrillation (mean age, 75 years) who received at least one NOAC prescription of dabigatran, rivaroxaban, or apixaban between 2012 and 2016.

The major bleeding risks associated with NOACs alone and when prescribed with the 12 concurrent medications were assessed.  The other medications selected were P-glycoprotein competitors (digoxin, verapamil, diltiazem, amiodarone, and cyclosporine), CYP3A4 inhibitors (fluconazole and ketoconazole, itraconazole, voriconazole, or posaconazole), or both (atorvastatin, erythromycin or clarithromycin, dronedarone, rifampin, and phenytoin), which may have a potential drug-drug interaction with NOACs.

The main outcome of the study was major bleeding, defined as hospitalization or emergency department visit with a primary diagnosis of intracranial hemorrhage or gastrointestinal, urogenital, or other bleeding.

For the analysis, each calendar year was partitioned into 4 quarters for each patient, and the analytic unit was 1 person-quarter. This was done because medications for chronic illnesses were refilled with a maximum length of 3 months (per the Taiwanese reimbursement policy), and this design simplified the assessment of the complex prescription pattern of NOACs and multiple drugs, the researchers explain.

After adjustment for patient demographics, comorbidities, relevant medications, and healthcare utilization, 4770 major bleeding events occurred during 447,037 person-quarters with NOAC prescriptions.

The most common medications co-prescribed with NOACs were atorvastatin (27.6%), diltiazem (22.7%), digoxin (22.5%), and amiodarone (21.1%).

Concurrent use of amiodarone, fluconazole, rifampin, and phenytoin with NOACs was associated with a significant increase in adjusted incidence rates per 1000 person-years of major bleeding than NOACs alone — an increase of 13.94 for amiodarone, 138.46 for fluconazole, 36.90 for rifampin, and 52.31 for phenytoin.

Compared with NOAC use alone, the adjusted incidence rate for major bleeding was significantly lower for concurrent use of atorvastatin, digoxin, and erythromycin or clarithromycin and was not significantly different for concurrent use of verapamil; diltiazem; cyclosporine; ketoconazole, itraconazole, voriconazole, or posaconazole; and dronedarone.

Interactions and patterns were similar for all three NOACs studied.

The authors point out that although the 12 concurrent medications evaluated in this study are not recommended by the updated guidelines, they are often required for NOAC users in many clinical scenarios, with digoxin, diltiazem, amiodarone, and atorvastatin used in more than 20% of NOAC-exposed person-quarters in this study cohort.

The researchers note that amiodarone plus a NOAC was associated with significantly more major bleeding events in all primary and secondary analyses, with an overall adjusted incidence rate difference for major bleeding of 13.94 events per 1000 person-years, which they say "probably exceeds any benefit that such a combination could deliver."

The highest bleeding risk was found in the combination of fluconazole and a NOAC, with an adjusted incidence rate difference of 138.46 events per 1000 person-years. "Therefore, fluconazole should be avoided in NOAC users," the authors stress.

Reassuringly, atorvastatin plus a NOAC was associated with lower bleeding risk than a NOAC alone. Atorvastatin was also reported to reduce all stroke and not to increase intracranial hemorrhage, leading the researchers to suggest it may prevent hemorrhagic transformation after ischemic stroke.

"Considering the cardiovascular benefit of atorvastatin and a lack of increased bleeding risk, clinicians should not avoid using atorvastatin with a NOAC in patients with nonvalvular atrial fibrillation," they say.

This study was funded by grants from Chang Gung Memorial Hospital and the Taiwan Ministry of Science and Technology.

JAMA.  2017;318(13):1250-1259. Abstract

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