Case Challenge

NOACs for Atrial Fibrillation: Important Drug/Drug Interactions

Douglas S. Paauw, MD


January 03, 2018

The correct answer is amiodarone, because there is a significant drug interaction between rivaroxaban and amiodarone.

Let's begin with examining the known drug interactions associated with non-vitamin K oral anticoagulants, also known as "novel oral anticoagulants" (NOACs). This drug class is divided into direct Xa inhibitors and direct thrombin inhibitors.

Direct Xa inhibitors. These agents work by inhibiting factor Xa in the coagulation cascade. The two Xa inhibitors that are used most commonly in the United States are rivaroxaban (Xarelto®) and apixaban (Eliquis®). The drugs that have been shown to have the greatest impact on area under the plasma drug concentration/time curve for both rivaroxaban and apixaban are ketoconazole and protease inhibitors, specifically ritonavir.[1] Both ketoconazole and ritonavir can increase the area under the curve for these drugs by more than twofold. Both approximately double the risk for bleeding.

Drugs that can in theory increase metabolism of the Xa inhibitors include carbamazepine, phenytoin, St John's wort, and rifampin.[1] In principle, the use of these drugs with the Xa inhibitors could decrease efficacy of the NOAC.

Direct thrombin inhibitors. These agents work by directly inhibiting the enzyme thrombin. Dabigatran (Pradaxa®) is the only direct thrombin inhibitor currently marketed in the United States. One study found that coadministration of dabigatran with verapamil increased the area under the curve by 54%.[2] Of note, diltiazem does not have the same effect. There is no increase in the steady-state level of dabigatran in patients treated with diltiazem.

Amiodarone increases the area under the curve for dabigatran by 60%. Drugs that are formally contraindicated for use with dabigatran include cyclosporine, ketoconazole, itraconazole, and dronedarone.[1] As is the case with Xa inhibitors, direct thrombin inhibitors are also associated with drug interactions that can reduce efficacy. Drugs that are inducers and may increase the metabolism of dabigatran, such as carbamazepine, phenytoin, and rifampin as well as the herb St John's wort, could in theory reduce the efficacy of dabigatran.

Real-World Experience With NOACs

But beyond theoretical concerns, what is the real-world experience with NOACs? A recent retrospective population-based cohort study examined data from the Taiwan National Health Insurance database involving over 91,000 patients with nonvalvular atrial fibrillation who received at least one NOAC prescription over a 5-year period.[3] A total of 4770 major bleeding events occurred. Atorvastatin, digoxin, and diltiazem had a non-statistically significant lower risk for bleeding when they were used with the NOACs. Amiodarone had a relative risk (RR) for bleeding of 1.37 (P = .01) and was associated with significantly more bleeding events, with the study authors concluding that the risk "probably exceeds any benefit that such a combination could deliver." Fluconazole had an RR of 2.35 (P < .01).

Of note, in this study, some of the drugs that would be anticipated to lower the effect of the NOACs actually increased the likelihood of bleeding. Those drugs were rifampin (RR, 1.57) and phenytoin (RR, 1.54). Rifampin and phenytoin should in theory increase metabolism of the NOACs, which should lead to lower levels, more rapid clearance, and decreased efficacy. That finding needs to be further studied.

Take-Home Messages

What is the take-home message from drug interactions with NOACs? I think the most important thing to remember is the drug amiodarone. Amiodarone is often used in patients with atrial fibrillation, the condition that is the most common indication for a NOAC. If possible, use of amiodarone in patients who are on NOACs should be avoided.

It is important to remember that warfarin also has a potentially significant interaction with amiodarone as well. The difference is that it is easier to measure the drug interaction with warfarin—that is, you can serially measure the international normalized ratio and adjust the dose of warfarin as needed. This is much harder to do with NOACs. There may be a role for continued use of warfarin in patients who must be on amiodarone or dronedarone.


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