NOACs
NOACs can directly inhibit thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban and edoxaban) and are prescribed more commonly for stroke prevention in AF.52NOACs have been recommended as the first-line medications unless contraindications are present.36Different from warfarin, NOACs have less drug-drug or drug-food interactions and are prescribed at a fixed dose following individual dosage criteria without routine monitorof the drug concentrations or anticoagulation activities.53However, NOACs still have drug-drug interactions with some medications. An important interaction mechanism for all NOACs is significant gastrointestinal re-secretion over a P-gp transporter after absorption in the gut. Competitive inhibition of this pathway will result in increased plasma levels.53Besides, CYP3A4-dependent elimination is relevantly involved in the hepatic clearance of rivaroxaban and apixaban. Strong CYP3A4 inhibition or induction may affect plasma concentrations.53Based on these concepts, COVID-19 medications which could compete or inhibit P-gp or CYP3A4 would result in increased plasma levels of NOACs.
As Table 2 shows, HCLQ is a substrate of CYP3A4, and therefore, may pontentially increase the plasma concentrations of NOACs. Generally, NOACs could be co-administered with HCLQ with either usual dosages (apixaban or rivaroxaban) or dosage adjustments (dabigatran or edoxaban). However, marcolides (e.x. erythromycin or clarithromycin or azithromycin) are moderate P-gp competitors and strong CYP3A4 inhibitors, and may increase the exposures of NOACs by 15-20% for dabigatran, 60% for apixaban, 90% for edoxaban and 34% (erythromycin)/54% (clarithromycin) for rivaroxaban.53Therefore, if HCLQ plus azithromycin regimen is adopted to AF patients with COVID-19 , the NOACs should be co-administered with cautions.
Remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, provides a great hope for the treatment of COVID-19 infection.9Remdesivir is expected to have no significant effects on the metabolisms or eliminations of all four NOACs, and could be co-administrated with NOACs.