Systematic review of drug–drug interactions between rifamycins and anticoagulant and antiplatelet agents and considerations for management

Abstract

Rifamycins (rifampin, rifabutin, and rifapentine) play an essential role in the treatment of mycobacterial and some nonmycobacterial infections. They also induce the activity of various drug transporting and metabolizing enzymes, which can impact the concentrations and efficacy of substrates. Many anticoagulant and antiplatelet (AC/AP) agents are substrates of these enzymes and have narrow therapeutic indices, leading to risks of thrombosis or bleeding when coadministered with rifamycins. The objective of this systematic review was to evaluate the effects on AC/AP pharmacokinetics, laboratory markers, and clinical safety and efficacy of combined use with rifamycins. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta‐analyses guidance was performed. The PubMed, Embase, and Web of Science databases were queried for English‐language reports on combination use of rifamycins and AC/AP agents from database inception through August 2021. The 29 studies identified examined warfarin (n = 17), direct oral anticoagulants (DOACs) (n = 8), and antiplatelet agents (n = 4) combined with rifampin (n = 28) or rifabutin (n = 1). Eleven studies were case reports or small case series; 14 reported on pharmacokinetic or laboratory markers in healthy volunteers. Rifampin‐warfarin combinations led to reductions in warfarin area under the curve (AUC) of 15%–74%, with variability by warfarin isomer and study. Warfarin dose increases of up to 3–5 times prerifampin doses were required to maintain coagulation parameters in the therapeutic range. DOAC AUCs were decreased by 20%–67%, with variability by individual agent and with rifampin versus rifabutin. The active metabolite of clopidogrel increased substantially with rifampin coadministration, whereas prasugrel was largely unaffected and ticagrelor saw decreases. Our review suggests most combinations of AC/AP agents and rifampin are problematic. Further studies are required to determine whether rifabutin or rifapentine could be safe alternatives for coadministration with AC/AP drugs.

A Case of Tuberculosis-related Cerebral Venous Sinus Thrombosis and Pulmonary Thromboembolism Successfully Treated with Edoxaban

“…The use of oral anticoagulants for patients with TB is often a major concern for clinicians. Rifampicin, a key drug for TB, decreases the effect of anticoagulants by inducing the activity of various drug transporting and metabolizing enzymes [ 3 ]. Clinicians frequently experience difficulties in achieving therapeutic PT-INR levels, even with significant increases in warfarin doses [ 17 ].…”

“…However, DOACs should also be used with caution because rifampicin reduces the area under the curve (AUC) of DOACs. We decided to use edoxaban because the degree of AUC decrease of edoxaban (34%) by rifampicin could be smaller than that of apixaban (53%), dabigatran (67%), and rivaroxaban (49%) [ 3 ]. Indeed, edoxaban showed sufficient thrombolytic effect in our patient.…”

“…Indeed, edoxaban showed sufficient thrombolytic effect in our patient. Rifabutin, an alternative of rifamycin, seems to have fewer interactions with edoxaban; however, sufficient pharmacokinetic data are still lacking [ 3 ]. Further clinical trials are required to evaluate the safety and efficacy of DOACs in the management of TB-associated thrombosis.…”

“…These are relatively uncommon but potentially lethal complications. Additionally, treatment for thrombosis can be challenging because of interactions between anticoagulants and rifampicin [ 3 ]. This report describes the case of a young woman who developed acute PTE and CVST as complications with pulmonary TB and was successfully treated with anti-tuberculosis agents and edoxaban, a direct oral anticoagulant (DOAC).…”

Safety and effectiveness of anticoagulation with non-vitamin K antagonist oral anticoagulants and warfarin in patients on tuberculosis treatment

“…Rifampin is a potent inducer of multiple pathways affecting drug metabolism including the hepatic cytochrome P450 (CYP) and P-glycoprotein (P-gp) efflux transporter system 5 . Warfarin is mainly metabolized in the liver via the CYP 2C9, 1A2, and 3A4 6 , and induction of the CYP enzymes leads to a significant decrease (about 15–74%) in warfarin area under the concentration–time curve (AUC) 7 . A three- to five-fold increase in warfarin dosage is usually required to attain sufficient warfarin levels measured by prothrombin time international normalized ratio (INR) testing 7 , 8 .…”