Apixaban × Diltiazem

Diltiazem is a moderate inhibitor of the CYP3A4 enzyme and a weak inhibitor of the P-glycoprotein transporter (diltiazem and apixaban SmPCs), and apixaban is cleared through both routes. Diltiazem 360 mg once daily raised the apixaban area under the curve (AUC) 1.4-fold and peak concentration 1.3-fold (apixaban SmPC of the European Medicines Agency, EMA). Higher apixaban levels mean a higher bleeding risk.

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools, haematuria. Higher risk in older patients, prior peptic ulcer disease, and chronic kidney disease.

The combination is allowed with caution. Do not change the apixaban dose because of diltiazem: the apixaban SmPC of the European Medicines Agency (EMA) requires no dose adjustment with inhibitors that are not strong and names diltiazem among them (apixaban SmPC, EMA). The diltiazem SmPC asks for caution and monitoring with direct oral anticoagulants, especially in patients at high bleeding risk (diltiazem SmPC). In atrial fibrillation, reduce apixaban to 2.5 mg twice daily only by its own criteria: two of three (age 80 years or older, body weight 60 kg or less, serum creatinine 133 µmol/L or higher) or creatinine clearance 15–29 mL/min (apixaban SmPC, EMA). The European Heart Rhythm Association (EHRA) advises caution, especially with polypharmacy. If at least one more risk factor is present (age 75 years or older, body weight 60 kg or less, chronic kidney disease, antiplatelet drugs, non-steroidal anti-inflammatory drugs, systemic steroids, previous bleeding, anaemia or low platelets, frailty or falls), EHRA suggests considering an anticoagulant with fewer interactions or replacing the other drug (EHRA 2021).