The product information for Cardizem® (diltiazem) has recently been updated to include the potential for an interaction with direct-acting oral anticoagulants (DOACs). Diltiazem is a moderate inhibitor of cytochrome P450 3A4 and a weak inhibitor of the P‐glycoprotein efflux transporter. It is thought that diltiazem may potentiate the bleeding risk of DOACs.

The DOAC class of medications includes:

  • Dabigatran etexilate (a substrate for P-glycoprotein);
  • Apixaban (metabolised by CYP3A4 and a substrate of P-glycoprotein); and
  • Rivaroxaban (metabolised by CYP3A4 and a substrate of P-glycoprotein).

The impact of these potential drug interactions was investigated in a study of patients with atrial fibrillation who were initiated on one of the above DOACs. At the time of initiation, 15% of patients were taking diltiazem and a further 5% were started on diltiazem during the study. The concomitant use of diltiazem plus a DOAC was associated with a higher risk of any bleeding-related hospitalisation (adjusted hazard ratio 1.56, 95% CI: 1.15–2.12) and major bleeding (adjusted hazard ratio 1.84, 95% CI: 1.18–2.85). This increased risk occurred in patients with and without renal impairment. However, findings were inconsistent for dabigatran which was only taken by around 12% of the cohort. The authors concluded that diltiazem should only be used with a DOAC when the benefit outweighs the risk and the patient is closely monitored for signs of bleeding.

A larger and more recent study looking at only apixaban and rivaroxaban had similar findings. This study found that patients taking a DOAC with diltiazem had a higher risk of serious bleeding compared to patients taking a DOAC with metoprolol. The risk was noted to be particularly high in patients receiving diltiazem doses greater than 120mg per day.

References:

  1. Cardizem® (Diltiazem) Australian approved product information. Macquarie Park: Sanofi-Aventis. Approved August 2024.
  2. Ray WA, Chung CP, Stein CM, et al. Serious bleeding in patients with atrial fibrillation using diltiazem with apixaban or rivaroxaban. JAMA. 2024; 331(18): 1565–1575.
  3. Xu Y, Chang AR, Inker LA, et al. Concomitant use of diltiazem with direct oral anticoagulants and bleeding risk in atrial fibrillation. J Am Heart Assoc. 2022; 11(14): e025723.

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