A pharmacogenetic versus a clinical algorithm for warfarin dosing

Stephen E. Kimmel, Benjamin French, Scott E. Kasner, Julie A. Johnson, Jeffrey L. Anderson, Brian F. Gage, Yves D. Rosenberg, Charles S. Eby, Rosemary A. Madigan, Robert B. McBane, Sherif Z. Abdel-Rahman, Scott M. Stevens, Steven Yale, Emile R. Mohler, Margaret C. Fang, Vinay Shah, Richard B. Horenstein, Nita A. Limdi, James A S Muldowney, Jaspal GujralPatrice Delafontaine, Robert J. Desnick, Thomas L. Ortel, Henny H. Billett, Robert C. Pendleton, Nancy L. Geller, Jonathan L. Halperin, Samuel Z. Goldhaber, Michael D. Caldwell, Robert M. Califf, Jonas H. Ellenberg

Research output: Contribution to journalArticle

483 Citations (Scopus)

Abstract

BACKGROUND: The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. METHODS: We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. RESULTS: At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], -0.2; 95% confidence interval, -3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy. CONCLUSIONS: Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy.

Original languageEnglish (US)
Pages (from-to)2283-2293
Number of pages11
JournalNew England Journal of Medicine
Volume369
Issue number24
DOIs
StatePublished - 2013

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Pharmacogenetics
Warfarin
Genotype
International Normalized Ratio
Therapeutics
Thromboembolism
Observational Studies
Clinical Trials
Confidence Intervals
Hemorrhage

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kimmel, S. E., French, B., Kasner, S. E., Johnson, J. A., Anderson, J. L., Gage, B. F., ... Ellenberg, J. H. (2013). A pharmacogenetic versus a clinical algorithm for warfarin dosing. New England Journal of Medicine, 369(24), 2283-2293. https://doi.org/10.1056/NEJMoa1310669

A pharmacogenetic versus a clinical algorithm for warfarin dosing. / Kimmel, Stephen E.; French, Benjamin; Kasner, Scott E.; Johnson, Julie A.; Anderson, Jeffrey L.; Gage, Brian F.; Rosenberg, Yves D.; Eby, Charles S.; Madigan, Rosemary A.; McBane, Robert B.; Abdel-Rahman, Sherif Z.; Stevens, Scott M.; Yale, Steven; Mohler, Emile R.; Fang, Margaret C.; Shah, Vinay; Horenstein, Richard B.; Limdi, Nita A.; Muldowney, James A S; Gujral, Jaspal; Delafontaine, Patrice; Desnick, Robert J.; Ortel, Thomas L.; Billett, Henny H.; Pendleton, Robert C.; Geller, Nancy L.; Halperin, Jonathan L.; Goldhaber, Samuel Z.; Caldwell, Michael D.; Califf, Robert M.; Ellenberg, Jonas H.

In: New England Journal of Medicine, Vol. 369, No. 24, 2013, p. 2283-2293.

Research output: Contribution to journalArticle

Kimmel, SE, French, B, Kasner, SE, Johnson, JA, Anderson, JL, Gage, BF, Rosenberg, YD, Eby, CS, Madigan, RA, McBane, RB, Abdel-Rahman, SZ, Stevens, SM, Yale, S, Mohler, ER, Fang, MC, Shah, V, Horenstein, RB, Limdi, NA, Muldowney, JAS, Gujral, J, Delafontaine, P, Desnick, RJ, Ortel, TL, Billett, HH, Pendleton, RC, Geller, NL, Halperin, JL, Goldhaber, SZ, Caldwell, MD, Califf, RM & Ellenberg, JH 2013, 'A pharmacogenetic versus a clinical algorithm for warfarin dosing', New England Journal of Medicine, vol. 369, no. 24, pp. 2283-2293. https://doi.org/10.1056/NEJMoa1310669
Kimmel SE, French B, Kasner SE, Johnson JA, Anderson JL, Gage BF et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. New England Journal of Medicine. 2013;369(24):2283-2293. https://doi.org/10.1056/NEJMoa1310669
Kimmel, Stephen E. ; French, Benjamin ; Kasner, Scott E. ; Johnson, Julie A. ; Anderson, Jeffrey L. ; Gage, Brian F. ; Rosenberg, Yves D. ; Eby, Charles S. ; Madigan, Rosemary A. ; McBane, Robert B. ; Abdel-Rahman, Sherif Z. ; Stevens, Scott M. ; Yale, Steven ; Mohler, Emile R. ; Fang, Margaret C. ; Shah, Vinay ; Horenstein, Richard B. ; Limdi, Nita A. ; Muldowney, James A S ; Gujral, Jaspal ; Delafontaine, Patrice ; Desnick, Robert J. ; Ortel, Thomas L. ; Billett, Henny H. ; Pendleton, Robert C. ; Geller, Nancy L. ; Halperin, Jonathan L. ; Goldhaber, Samuel Z. ; Caldwell, Michael D. ; Califf, Robert M. ; Ellenberg, Jonas H. / A pharmacogenetic versus a clinical algorithm for warfarin dosing. In: New England Journal of Medicine. 2013 ; Vol. 369, No. 24. pp. 2283-2293.
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abstract = "BACKGROUND: The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. METHODS: We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. RESULTS: At 4 weeks, the mean percentage of time in the therapeutic range was 45.2{\%} in the genotype-guided group and 45.4{\%} in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], -0.2; 95{\%} confidence interval, -3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy. CONCLUSIONS: Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy.",
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T1 - A pharmacogenetic versus a clinical algorithm for warfarin dosing

AU - Kimmel, Stephen E.

AU - French, Benjamin

AU - Kasner, Scott E.

AU - Johnson, Julie A.

AU - Anderson, Jeffrey L.

AU - Gage, Brian F.

AU - Rosenberg, Yves D.

AU - Eby, Charles S.

AU - Madigan, Rosemary A.

AU - McBane, Robert B.

AU - Abdel-Rahman, Sherif Z.

AU - Stevens, Scott M.

AU - Yale, Steven

AU - Mohler, Emile R.

AU - Fang, Margaret C.

AU - Shah, Vinay

AU - Horenstein, Richard B.

AU - Limdi, Nita A.

AU - Muldowney, James A S

AU - Gujral, Jaspal

AU - Delafontaine, Patrice

AU - Desnick, Robert J.

AU - Ortel, Thomas L.

AU - Billett, Henny H.

AU - Pendleton, Robert C.

AU - Geller, Nancy L.

AU - Halperin, Jonathan L.

AU - Goldhaber, Samuel Z.

AU - Caldwell, Michael D.

AU - Califf, Robert M.

AU - Ellenberg, Jonas H.

PY - 2013

Y1 - 2013

N2 - BACKGROUND: The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. METHODS: We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. RESULTS: At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], -0.2; 95% confidence interval, -3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy. CONCLUSIONS: Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy.

AB - BACKGROUND: The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. METHODS: We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. RESULTS: At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], -0.2; 95% confidence interval, -3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy. CONCLUSIONS: Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy.

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