Drug interactions between direct-acting oral anticoagulants and calcineurin inhibitors during solid organ transplantation: considerations for therapy

ABSTRACT

Introduction: There is a high incidence of venous thromboembolism (VTE) in solid organ transplant recipients. The safety and efficacy of direct-acting oral anticoagulants (DOAC) have been well established in clinical practice for the prevention and treatment of VTE in broad populations. However, the management of VTE in the setting of solid organ transplantation remains a challenge to clinicians due to limited evidence of DOAC usage with calcineurin inhibitors.

Areas covered: The current literature available on the pharmacokinetic–pharmacodynamic interaction between DOACs and calcineurin inhibitors is presented. A comprehensive review was undertaken using PubMed, Embase, drug product labeling, and drug product review conducted by the US Food and Drug Administration using Drugs@FDA. The potential for mitigation strategies and clinical management using extant knowledge is explored.

Expert opinion: Immunosuppression therapy is necessary to prevent graft rejection by the host. The sparsity of data together with the lack of well-designed prospective studies of DOAC use in solid organ transplant recipients presents a unique challenge to clinicians in determining the clinical relevance of possible drug interactions. Existing evidence suggests that with attention to concomitant drug use and renal function, the co-administration of DOACs and calcineurin inhibitors is safe and effective.

KEYWORDS:

• Direct oral anticoagulants
• DOAC
• cyclosporine
• tacrolimus
• solid organ transplant
• anticoagulation
• venous thromboembolism
• apixaban
• rivaroxaban
• dabigatran
• warfarin

Article Highlights

• The calcineurin inhibitors, cyclosporine, and tacrolimus are commonly used in maintenance immunosuppression regimens to prevent graft rejection following solid organ transplant. Cyclosporine may have a higher likelihood of inhibiting drug metabolizing enzymes and transporters compared to tacrolimus.

• Direct oral anticoagulant (DOAC) clinical trials often excluded those on either cyclosporine or tacrolimus.

• Identifying intrinsic and extrinsic variabilities in the pharmacokinetics-pharmacodynamics in solid organ transplant recipients may balance the risks of bleeding while maintaining adequate anticoagulation.

• The Cockcroft-Gault formula using ideal body weight is used for dosing adjustments for apixaban and edoxaban while actual body weight is used to adjust dabigatran and rivaroxaban. While limited, pharmacokinetic-pharmacodynamic and outcomes evidence suggests safe and effective use of DOACs together with calcineurin inhibitors.

• Anti-Factor Xa monitoring is not standardized and is not helpful in dose selection.

• Direct oral anticoagulant use should be avoided in the immediate post-operative period and considered only after there is stability of renal and hepatic function and when bleeding risk has stabilized.

• Dose adjustment should not be made in the setting of acute thrombosis. After at least three months of therapy, intrinsic and extrinsic factors may inform the use of switching to attenuated dose for secondary thromboprophylaxis.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Supported by a National Institute of General Medical Sciences of the National Institutes of Health training grant T32GM008562.