Warfarin Dosing Algorithms Underpredict Dose Requirements in Patients Requiring ≥7 mg Daily: A Systematic Review and Meta‐analysis

Saffian, Shamin Mohd; Duffull, Stephen B.; Wright, Daniel F. B.

doi:10.1002/cpt.649

Cited by 21 publications

(10 citation statements)

References 47 publications

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“…5 mg) . Our results are consistent with a recent meta‐analysis, where it was reported that with daily warfarin doses of over 7 mg, the dose prediction algorithms underestimated the maintenance dose . In our study, the patients with more than one admission criterion had significantly higher warfarin dose requirement than those with only one admission criterion, highlighting the increased thrombogenic potential.…”

Section: Discussionsupporting

confidence: 92%

Warfarin dose requirement in patients having severe thrombosis or thrombophilia

Helin

Joutsi‐Korhonen

Asmundela

et al. 2019

Brit J Clinical Pharma

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Aims: Warfarin dose requirement varies significantly. We compared the clinically established doses based on international normalized ratio (INR) among patients with severe thrombosis and/or thrombophilia with estimates from genetic dosing algorithms. Methods: Fifty patients with severe thrombosis and/or thrombophilia requiring permanent anticoagulation, referred to the Helsinki University Hospital Coagulation Center, were screened for thrombophilias and genotyped for CYP2C9*2 (c.430C>T, rs1799853), CYP2C9*3 (c.1075A>C, rs1057910) and VKORC1 c.-1639G>A (rs9923231) variants. The warfarin maintenance doses (target INR 2.0-3.0 in 94%, 2.5-3.5 in 6%) were estimated by the Gage and the International Warfarin Pharmacogenetics Consortium (IWPC) algorithms. The individual warfarin maintenance dose was tailored, supplementing estimates with comprehensive clinical evaluation and INR data.Results: Mean patient age was 47 years (range 20-76), and BMI 27 (SD 6), 68% being women. Forty-six (92%) had previous venous or arterial thrombosis, and 26 (52%) had a thrombophilia, with 22% having concurrent aspirin. A total of 40% carried the CYP2C9*2 or *3 allele and 54% carried the VKORC1-1639A allele. The daily mean maintenance dose of warfarin estimated by the Gage algorithm was 5.4 mg (95% CI 4.9-5.9 mg), and by the IWPC algorithm was 5.2 mg (95% CI 4.7-5.7 mg). The daily warfarin maintenance dose after clinical visits and follow-up was higher than the estimates, mean 6.9 mg (95% CI 5.6-8.2 mg, P < 0.006), with highest dose in patients having multiple thrombophilic factors (P < 0.03). Conclusions:In severe thrombosis and/or thrombophilia, variation in thrombin generation and pharmacodynamics influences warfarin response. Pharmacogenetic dosing algorithms seem to underestimate dose requirement.

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Section: Discussionsupporting

confidence: 92%

Warfarin dose requirement in patients having severe thrombosis or thrombophilia

Helin

Joutsi‐Korhonen

Asmundela

et al. 2019

Brit J Clinical Pharma

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“…Comparison of the warfarindosing.com and IWPC algorithms suggests that both predict comparable warfarin doses [ 193 ]. A recent study found that in patients requiring 7 mg or greater per day, a range of algorithms including those from warfarindosing.org and IWPC under-predicted maintenance dose requirement [ 195 ]. The underlying reason for this issue remains unclear, but it has been suggested that it could reflect the complexity of the blood clotting cascade.…”

Section: Warfarin Dosing Algorithmsmentioning

confidence: 99%

Pharmacogenomics of CYP2C9: Functional and Clinical Considerations

Daly

Rettie

Fowler

et al. 2017

JPM

162

123

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CYP2C9 is the most abundant CYP2C subfamily enzyme in human liver and the most important contributor from this subfamily to drug metabolism. Polymorphisms resulting in decreased enzyme activity are common in the CYP2C9 gene and this, combined with narrow therapeutic indices for several key drug substrates, results in some important issues relating to drug safety and efficacy. CYP2C9 substrate selectivity is detailed and, based on crystal structures for the enzyme, we describe how CYP2C9 catalyzes these reactions. Factors relevant to clinical response to CYP2C9 substrates including inhibition, induction and genetic polymorphism are discussed in detail. In particular, we consider the issue of ethnic variation in pattern and frequency of genetic polymorphisms and clinical implications. Warfarin is the most well studied CYP2C9 substrate; recent work on use of dosing algorithms that include CYP2C9 genotype to improve patient safety during initiation of warfarin dosing are reviewed and prospects for their clinical implementation considered. Finally, we discuss a novel approach to cataloging the functional capabilities of rare ‘variants of uncertain significance’, which are increasingly detected as more exome and genome sequencing of diverse populations is conducted.

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“…It is also fair to state that no algorithm is perfect, because not all factors that determine warfarin dosing have been identified [ 10 ]. The algorithms also predict extreme doses less efficiently (i.e., low or high daily warfarin doses) [ 15 , 24 ]. Algorithms designed for African-American, Indian, and Chinese patients have been developed but have not been tested in clinical trials [ 25 , 26 , 27 ].…”

Section: Warfarin Pharmacology and Pharmacogeneticsmentioning

confidence: 99%

Warfarin: The End or the End of One Size Fits All Therapy?

Pirmohamed

2018

JPM

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Oral anticoagulants are required for both treatment and prophylaxis in many different diseases. Clinicians and patients now have a choice of oral anticoagulants, including the vitamin K antagonists (of which warfarin is the most widely used and is used as the exemplar in this paper), and direct oral anticoagulants (DOACs: dabigatran, apixaban, rivaroxaban, and edoxaban). This paper explores the recent advances and controversies in oral anticoagulation. While some commentators may favour a complete switchover to DOACs, this paper argues that warfarin still has a place in therapy, and a stratified approach that enables the correct choice of both drug and dose would improve both patient outcomes and affordability.

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Warfarin Dosing Algorithms Underpredict Dose Requirements in Patients Requiring ≥7 mg Daily: A Systematic Review and Meta‐analysis

Cited by 21 publications

References 47 publications

Warfarin dose requirement in patients having severe thrombosis or thrombophilia

Warfarin dose requirement in patients having severe thrombosis or thrombophilia

Pharmacogenomics of CYP2C9: Functional and Clinical Considerations

Warfarin: The End or the End of One Size Fits All Therapy?

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