Drug Interactions Affecting Oral Anticoagulant Use

Abstract

Oral anticoagulants (OACs) are medications commonly used in patients with atrial fibrillation and other cardiovascular conditions. Both warfarin and direct oral anticoagulants are susceptible to drug-drug interactions (DDIs). DDIs are an important cause of adverse drug reactions and exact a large toll on the health care system. DDI for warfarin mainly involve moderate to strong inhibitors/inducers of cytochrome P450 (CYP) 2C9, which is responsible for the elimination of the more potent S-isomer of warfarin. However, inhibitor/inducers of CYP3A4 and CYP1A2 may also cause DDI with warfarin. Recognition of these precipitating agents along with increased frequency of monitoring when these agents are initiated or discontinued will minimize the impact of warfarin DDI. Direct oral anticoagulants are mainly affected by medications strongly affecting the permeability glycoprotein (P-gp), and to a lesser extent, strong CYP3A4 inhibitors/inducers. Dabigatran and edoxaban are affected by P-gp modulation. Strong inducers of CYP3A4 or P-gp should be avoided in all patients taking direct oral anticoagulant unless previously proven to be otherwise safe. Simultaneous strong CYP3A4 and P-gp inhibitors should be avoided in patients taking apixaban and rivaroxaban. Concomitant antiplatelet/anticoagulant use confers additive risk for bleeding, but their combination is unavoidable in many cases. Minimizing duration of concomitant anticoagulant/antiplatelet therapy as indicated by evidence-based clinical guidelines is the best way to reduce the risk of bleeding.

Keywords: anticoagulants; apixaban; atrial fibrillation; glycoprotein; warfarin.

Figure 1:

Schematic of major vitamin K antagonist and direct oral anticoagulant sites of drug interactions. Tan panel depicts simplified coagulation cascade and yellow lightning bolts indicate sites of inhibition by anticoagulants (blue rectangles – vitamin K antagonist; purple hexagons – direct oral anticoagulant). Gray rectangle encompass coagulation factors affected by vitamin K antagonism. Red arrowed boxes indicate interactions that inhibit anticoagulation. Green arrowed boxes indicate interactions that potentiate anticoagulation. CYP – Cytochrome P-450; DOAC – Direct oral anticoagulant; R-Warf – R-warfarin; S-Warf – S-warfarin; P-gp – P-glycoprotein; VKA – Vitamin K Antagonist; I – Fibrinogen; II – Prothrombin; IIa – Thrombin; VII – Factor 7; VIIa – Activated Factor 7; X – Factor 10; Xa – Activated Factor 10; IX – Factor 9; IXa – Activated Factor 9

Figure 2:

Algorithm to manage warfarin drug-drug interactions during warfarin initiation as well as adding a potentially interacting drug on chronic warfarin therapy. AP – Anti-platelet; CYP – cytochrome P450; DDI – drug-drug interaction; INR – International normalized ratio; NSAID – Non-steroidal anti-inflammatory drugs; VKA - warfarin

Figure 3:

Algorithm to screen for significant direct oral anticoagulant drug-drug interactions. AP – Anti-platelet; DDI – drug-drug interaction; DOAC – direct oral anticoagulant drug-drug; CYP – Cytochrome P450; NSAID – Non-steroidal anti-inflammatory drugs; P-gp – P-glycoprotein; PK – Pharmacokinetic *List is not exhaustive ^†Although clarithromycin is both a strong CYP3A4 and P-gp inhibitor, pharmacokinetic analyses show that it is safe to use with apixaban and rivaroxaban ‡Refers to additive P-gp inhibition from the same interacting agent, or another agent that the patient is taking with either CYP3A4 or P-gp inhibition