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Warfarin in the Secondary Prevention of Thromboembolism in Atrial Fibrillation

Impact of Bioavailability on Costs and Outcomes

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Abstract

Background: The bioavailability of warfarin is an important factor affecting the achievement of therapeutic anticoagulation. It is uncertain whether less expensive generic preparations of warfarin would compromise prevention of thromboembolism or increase bleeding risk in patients with atrial fibrillation.

Objective: To compare the cost effectiveness of strategies using warfarin products with variable bioavailability in patients with a prior stroke or transient ischaemic attack related to atrial fibrillation.

Results: In our institution, warfarin F = 1 was similar in cost to the other three strategies ($Can1361 vs $Can1334–1613) and may be more effective than switching between generic preparations which have bioavailabilities at the extremes of acceptable limits (thromboembolism and bleeds 7. 1% vs 9.3%).

Conclusions: In patients with atrial fibrillation and a prior ischaemic stroke or transient ischaemic attack, the use of one warfarin agent within the range of acceptable bioavailability can be considered economically attractive from the healthcare perspective.

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Fig. 1
Table I
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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgements

This study was investigator driven. Investigators had full publication rights. This study was conducted with an unrestricted research grant from Dupont Pharma (Canada). Dupont was the manufacturer of brand-name warfarin (Coumadin®). The authors do not have any financial interest in the company. Mr Walker and Dr Bartle had a consulting agreement with Dupont. Dupont Pharma is now part of BristolMyers Squibb. BristolMyers Squibb had 30 days to review the document prior to the submission of the manuscript.

Dr Mittmann received the New Investigator Award from the International Society of Pharmacoeconomic and Outcomes Research in Washington 2000 for this research.

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Authors and Affiliations

  1. Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada

    Nicole Mittmann

  2. Division of Clinical Pharmacology, HOPE Research Centre, Sunnybrook and Women’s College Health Sciences Centre, Toronto, Ontario, Canada

    Nicole Mittmann & Paul I. Oh

  3. Department of Medicine, University of Toronto, Toronto, Ontario, Canada

    Paul I. Oh

  4. Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

    Scott E. Walker & William R. Bartle

  5. Department of Pharmacy, Sunnybrook and Women’s College Health Sciences Centre, Toronto, Ontario, Canada

    Scott E. Walker & William R. Bartle

Authors
  1. Nicole Mittmann
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  2. Paul I. Oh
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  3. Scott E. Walker
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  4. William R. Bartle
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Corresponding author

Correspondence to Nicole Mittmann.

Appendix

Appendix

In order to derive the INR distributions (i.e. the proportion of patients with low, therapeutic and high INR levels) for the generic products with a range of bioavailabilities, the following calculations were conducted. It was assumed that the warfarin dose was related to log of the prothrombin ratio (PR) multiplied by a constant (K). Dose C was equal to the milligram dose of warfarin F = 1 before switching and PR C is the PR of warfarin F = 1 (equation 2):

$${\rm{Dose\;C}} = {\rm{K}} \bullet {\rm{log(PRC)}}$$

Dose W was equal to the dose of warfarin based on different bioavailabilities after switching to a new generic product and PR W was the PR of the new warfarin (equation 3).

$${\rm{Dose\;W}} = {\rm{K}} \bullet {\rm{log(PRW)}}$$

The two equations were combined in order to determine a new PR for a product with a different dose (equation 4):

$${\rm{K}} = {{{\rm{dose\;C}}} \over {{\rm{log(PRC)}}}} = {{{\rm{dose\;W}}} \over {\log ({\rm{PRW}})}}$$

In order to determine the new PR for warfarin, the equation was as follows (equation 5):

$$\log ({\rm{PRW}}) = {{{\rm{dose\;W}} \bullet \log ({\rm{PRC}})} \over {{\rm{dose\;C}}}}$$

The PR ratio is related to the INR, in that the INR = PRn and n is a factor unique to the thromboplastin used or International Sensitivity Index (ISI) value. The ISI is dependent on the assay used to determine the PR. We assumed an ISI value of 1; therefore, the INR is equivalent to the PR.

Bioavailability scores were converted to INR values using the following equation (equation 6):

$$\matrix{ {{\rm{logIN}}{{\rm{R}}_{{\rm{F = 1}}}}{\rm{ = bioavailabilit}}{{\rm{y}}_{{\rm{F = 1}}}}} \cr {{\rm{logIN}}{{\rm{R}}_{{\rm{F = x}}}}{\rm{ = bioavailabilit}}{{\rm{y}}_{{\rm{F = x}}}}} \cr } $$

where x equalled the various bioavailability values used as generic comparator agents, namely 0.80 and 1.25. Table I lists the proportion of the atrial fibrillation population stratified into low, therapeutic and high INR values according to the different bioavailabilities examined in this analysis and using the formulae outlined above.

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Mittmann, N., Oh, P.I., Walker, S.E. et al. Warfarin in the Secondary Prevention of Thromboembolism in Atrial Fibrillation. PharmacoEconomics 22, 671–683 (2004). https://doi.org/10.2165/00019053-200422100-00005

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