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Warfarin resistance.

P Sinxadi¹, M Blockman

¹Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory. phumla.sinxadi@uct.ac.za

Cardiovascular Journal of Africa

|September 9, 2008

Summary

Warfarin dosing shows significant variability. True warfarin resistance is rare, necessitating exclusion of other factors like non-adherence before considering higher doses for patients with persistent sub-therapeutic INR levels.

Area of Science:

Pharmacology
Genetics
Internal Medicine

Background:

Warfarin is a critical oral anticoagulant for thrombo-embolism in South Africa.
It exhibits a narrow therapeutic index and high inter-individual dose variability.
Known genetic and clinical factors explain less than 55% of this variability.

Purpose of the Study:

To investigate the challenges in warfarin dosing and the definition and management of warfarin resistance.
To highlight the limitations of current pharmacogenetic models in predicting warfarin dose requirements.
To provide guidance on managing patients with presumed warfarin resistance.

Main Methods:

Review of existing literature on warfarin pharmacogenetics and clinical factors influencing dose.
Definition and prevalence of true warfarin resistance (<0.1%).

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Analysis of factors contributing to persistent sub-therapeutic international normalised ratio (INR) levels.

Main Results:

Genetic (VKORC1, CYP2C9) and clinical factors account for <55% of warfarin dose variability.
True warfarin resistance is rare, defined by weekly doses >70 mg for therapeutic INR.
Non-adherence, lab errors, and drug interactions are common causes of apparent resistance.

Conclusions:

Current pharmacogenetic models do not incorporate mutations causing warfarin resistance.
In cases of presumed warfarin resistance, higher warfarin doses should be administered under close INR monitoring.
Exclusion of non-adherence, laboratory errors, and interactions is crucial before escalating warfarin dosage.