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On the Prediction of Warfarin Dose
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Warfarin is one of the most widely used anticoagulants in the world. Treatment is complicated by a large inter-individual variation in the dose needed to reach adequate levels of anticoagulation i.e. INR 2.0 – 3.0. The objective of this thesis was to evaluate which factors, mainly genetic but also non-genetic, that affect the response to warfarin in terms of required maintenance dose, efficacy and safety with special focus on warfarin dose prediction.

Through candidate gene and genome-wide studies, we have shown that the genes CYP2C9 and VKORC1 are the major determinants of warfarin maintenance dose. By combining the SNPs CYP2C9 *2, CYP2C9 *3 and VKORC1 rs9923231 with the clinical factors age, height, weight, ethnicity, amiodarone and use of inducers (carbamazepine, phenytoin or rifampicin) into a prediction model (the IWPC model) we can explain 43 % to 51 % of the variation in warfarin maintenance dose. Patients requiring doses < 29 mg/week and doses ≥ 49 mg/week benefitted the most from pharmacogenetic dosing. Further, we have shown that the difference across ethnicities in percent variance explained by VKORC1 was largely accounted for by the allele frequency of rs9923231. Other novel genes affecting maintenance dose (NEDD4 and DDHD1), as well as the replicated CYP4F2 gene, have small effects on dose predictions and are not likely to be cost-effective, unless inexpensive genotyping is available.

Three types of prediction models for warfarin dosing exist: maintenance dose models, loading dose models and dose revision models. The combination of these three models is currently being used in the warfarin treatment arm of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) study. Other clinical trials aiming to prove the clinical validity and utility of pharmacogenetic dosing are also underway.

The future of pharmacogenetic warfarin dosing relies on results from these ongoing studies, the availability of inexpensive genotyping and the cost-effectiveness of pharmacogenetic driven warfarin dosing compared with new oral anticoagulant drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. , 79 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 773
Keyword [en]
Warfarin, pharmacogenetics, prediction models, Dosing algorithm, GWAS, VKORC1, CYP2C9
National Category
Pharmacology and Toxicology
Research subject
Clinical Pharmacology
Identifiers
URN: urn:nbn:se:uu:diva-172864ISBN: 978-91-554-8359-3 (print)OAI: oai:DiVA.org:uu-172864DiVA: diva2:516480
Public defence
2012-06-05, Enghoffsalen, Akademiska sjukhuset, ingång 50, bv, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2012-05-14 Created: 2012-04-16 Last updated: 2012-08-01Bibliographically approved
List of papers
1. The largest prospective warfarin-treated cohort supports genetic forecasting
Open this publication in new window or tab >>The largest prospective warfarin-treated cohort supports genetic forecasting
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2009 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 113, no 4, 784-792 p.Article in journal (Refereed) Published
Abstract [en]

Genetic variants of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) are known to influence warfarin dose, but the effect of other genes has not been fully elucidated. We genotyped 183 polymorphisms in 29 candidate genes in 1496 Swedish patients starting warfarin treatment, and tested for association with response. CYP2C9*2 and *3 explained 12% (P = 6.63 x 10(-34)) of the variation in warfarin dose, while a single VKORC1 SNP explained 30% (P = 9.82 x 10(-100)). No SNP outside the CYP2C gene cluster and VKORC1 regions was significantly associated with dose after correction for multiple testing. During initiation of therapy, homozygosity for CYP2C9 and VKORC1 variant alleles increased the risk of over-anticoagulation, hazard ratios 21.84 (95% CI 9.46; 50.42) and 4.56 (95% CI 2.85; 7.30), respectively. One of 8 patients with CYP2C9*3/*3 (12.5%) experienced severe bleeding during the first month compared with 0.27% of other patients (P = .066). A multiple regression model using the predictors CYP2C9, VKORC1, age, sex, and druginteractions explained 59% of the variance in warfarin dose, and 53% in an independent sample of 181 Swedish individuals. In conclusion, CYP2C9 and VKORC1 significantly influenced warfarin dose and predicted individuals predisposed to unstable anticoagulation. Our results strongly support that initiation of warfarin guided by pharmacogenetics would improve clinical outcome.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-98487 (URN)10.1182/blood-2008-04-149070 (DOI)000262646200006 ()18574025 (PubMedID)
Available from: 2009-02-24 Created: 2009-02-24 Last updated: 2017-12-13
2. Estimation of the warfarin dose with clinical and pharmacogenetic data
Open this publication in new window or tab >>Estimation of the warfarin dose with clinical and pharmacogenetic data
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2009 (English)In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 360, no 8, 753-764 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Genetic variability among patients plays an important role in determining the dose of warfarin that should be used when oral anticoagulation is initiated, but practical methods of using genetic information have not been evaluated in a diverse and large population. We developed and used an algorithm for estimating the appropriate warfarin dose that is based on both clinical and genetic data from a broad population base.

METHODS: Clinical and genetic data from 4043 patients were used to create a dose algorithm that was based on clinical variables only and an algorithm in which genetic information was added to the clinical variables. In a validation cohort of 1009 subjects, we evaluated the potential clinical value of each algorithm by calculating the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable therapeutic dose; we also evaluated other clinically relevant indicators.

RESULTS: In the validation cohort, the pharmacogenetic algorithm accurately identified larger proportions of patients who required 21 mg of warfarin or less per week and of those who required 49 mg or more per week to achieve the target international normalized ratio than did the clinical algorithm (49.4% vs. 33.3%, P<0.001, among patients requiring < or = 21 mg per week; and 24.8% vs. 7.2%, P<0.001, among those requiring > or = 49 mg per week).

CONCLUSIONS: The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation.

Keyword
Pharmacogenetics
National Category
Medical and Health Sciences
Research subject
Clinical Pharmacology
Identifiers
urn:nbn:se:uu:diva-98505 (URN)10.1056/NEJMoa0809329 (DOI)000263411300005 ()19228618 (PubMedID)
Note

Co-author: Mia Wadelius, Uppsala universitet, Institutionen för medicinska vetenskaper, forskargrupp Clinical pharmacogenetics and osteoporosis, ingår i the International Warfarin Pharmacogenetics Consortium.

Available from: 2009-02-24 Created: 2009-02-24 Last updated: 2017-12-13Bibliographically approved
3. Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across three racial groups
Open this publication in new window or tab >>Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across three racial groups
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2010 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 115, no 18, 3827-3834 p.Article in journal (Refereed) Published
Abstract [en]

Warfarin dosing algorithms incorporating CYP2C9 and VKORC1-1639G>A improve dose prediction compared to algorithms based solely on clinical and demographic factors. However these algorithms better capture dose variability among Whites compared to Asians or Blacks. Herein we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1-1639G>A among Asians (n=1103), Blacks (n=670) and Whites (n=3113). Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 SNPs and haplotypes on warfarin dose employed both univariate and multivariable linear regression. VKORC1-1639G>A and 1173C>T individually explained the greatest variance in dose in all three racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction. VKORC1 explained greater variability in dose among Whites as compared to Blacks and Asians. Differences in the percent variance in dose explained by VKORC1 across race was largely accounted for by the frequency of the -1639 A (or 1173 T) allele. Thus, clinicians should recognize that although at a population level, the contribution of VKORC1 towards dose requirements is higher in Whites compared to non-whites; genotype predicts similar dose requirements across racial groups.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-124680 (URN)10.1182/blood-2009-12-255992 (DOI)000277335900027 ()20203262 (PubMedID)
Available from: 2010-05-05 Created: 2010-05-05 Last updated: 2017-12-12
4. Genetic determinants of warfarin response, efficacy and safety: a RE-LY genomics substudy
Open this publication in new window or tab >>Genetic determinants of warfarin response, efficacy and safety: a RE-LY genomics substudy
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(English)Manuscript (preprint) (Other academic)
Keyword
Warfarin, GWAS, Prediction
National Category
Cardiac and Cardiovascular Systems
Research subject
Clinical Pharmacology
Identifiers
urn:nbn:se:uu:diva-172004 (URN)
Available from: 2012-04-16 Created: 2012-03-31 Last updated: 2012-06-08
5. Prediction of warfarin dose: why, when and how?
Open this publication in new window or tab >>Prediction of warfarin dose: why, when and how?
2012 (English)In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 13, no 4, 429-440 p.Article, review/survey (Refereed) Published
Abstract [en]

Prediction models are the key to individualized drug therapy. Warfarin is a typical example of where pharmacogenetics could help the individual patient by modeling the dose, based on clinical factors and genetic variation in CYP2C9 and VKORC1. Clinical studies aiming to show whether pharmacogenetic warfarin dose predictions are superior to conventional initiation of warfarin are now underway. This review provides a broad view over the field of warfarin pharmacogenetics from basic knowledge about the drug, how it is monitored, factors affecting dose requirement, prediction models in general and different types of prediction models for warfarin dosing.

Keyword
dosing algorithm, human CYP2C9 protein, human VKORC1 protein, pharmacogenetics models, statistical regression analysis, warfarin
National Category
Medical and Health Sciences
Research subject
Clinical Pharmacology
Identifiers
urn:nbn:se:uu:diva-170013 (URN)10.2217/pgs.11.184 (DOI)000301098000018 ()22379999 (PubMedID)
Funder
Swedish Research Council, K2012-66X-22105-01-3
Available from: 2012-03-07 Created: 2012-03-07 Last updated: 2017-12-07Bibliographically approved

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