Is Pharmacogenetic-based Dosing of Warfarin Superior for Anticoagulation Control?
Reporter: Aviva Lev-Ari, PhD, RN
UPDATED on 4/28/2014
A pharmacogenetic versus a clinical algorithm for warfarin dosing.
Kimmel SE1, 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 3rd, Fang MC, Shah V, Horenstein RB, Limdi NA, Muldowney JA 3rd, Gujral J, Delafontaine P, Desnick RJ, Ortel TL, Billett HH, Pendleton RC, Geller NL, Halperin JL, Goldhaber SZ, Caldwell MD, Califf RM, Ellenberg JH; COAG Investigators.
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.
(Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657.).
Comment in
- Pharmacogenetics and coumarin dosing–recalibrating expectations. [N Engl J Med. 2013]
- Anticoagulation therapy: genotype-guided anticoagulation therapy-the jury is still out. [Nat Rev Cardiol. 2014]
- Do pharmacogenetics have a role in the dosing of vitamin K antagonists? [N Engl J Med. 2013]
SOURCE
http://www.ncbi.nlm.nih.gov/pubmed/24251361
What is the clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin?
“Anticoagulation Control” defined: higher percentage of time in the therapeutic INR range than was standard dosing. It was achieved in an European Study and not conferred in an American Study, see below the two studies.
A Randomized Trial of Genotype-Guided Dosing of Warfarin
Munir Pirmohamed, Ph.D., F.R.C.P., Girvan Burnside, Ph.D., Niclas Eriksson, Ph.D., Andrea L. Jorgensen, Ph.D., Cheng Hock Toh, M.D., Toby Nicholson, F.R.C.Path., Patrick Kesteven, M.D., Christina Christersson, M.D., Ph.D., Bengt Wahlström, M.D., Christina Stafberg, M.D., J. Eunice Zhang, Ph.D., Julian B. Leathart, M.Phil., Hugo Kohnke, M.Sc., Anke H. Maitland-van der Zee, Pharm.D., Ph.D., Paula R. Williamson, Ph.D., Ann K. Daly, Ph.D., Peter Avery, Ph.D., Farhad Kamali, Ph.D., and Mia Wadelius, M.D., Ph.D. for the EU-PACT Group
N Engl J Med 2013; 369:2294-2303 December 12, 2013DOI: 10.1056/NEJMoa1311386
BACKGROUND
The level of anticoagulation in response to a fixed-dose regimen of warfarin is difficult to predict during the initiation of therapy. We prospectively compared the effect of genotype-guided dosing with that of standard dosing on anticoagulation control in patients starting warfarin therapy.
METHODS
We conducted a multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism. Genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 (−1639G→A) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days. Patients in the control (standard dosing) group received a 3-day loading-dose regimen. After the initiation period, the treatment of all patients was managed according to routine clinical practice. The primary outcome measure was the percentage of time in the therapeutic range of 2.0 to 3.0 for the international normalized ratio (INR) during the first 12 weeks after warfarin initiation.
RESULTS
A total of 455 patients were recruited, with 227 randomly assigned to the genotype-guided group and 228 assigned to the control group. The mean percentage of time in the therapeutic range was 67.4% in the genotype-guided group as compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% confidence interval, 3.3 to 10.6; P<0.001). There were significantly fewer incidences of excessive anticoagulation (INR ≥4.0) in the genotype-guided group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (P<0.001).
CONCLUSIONS
Pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy.
(Funded by the European Commission Seventh Framework Programme and others; ClinicalTrials.gov number, NCT01119300.)
A Pharmacogenetic versus a Clinical Algorithm for Warfarin Dosing
Stephen E. Kimmel, M.D., Benjamin French, Ph.D., Scott E. Kasner, M.D., Julie A. Johnson, Pharm.D., Jeffrey L. Anderson, M.D., Brian F. Gage, M.D., Yves D. Rosenberg, M.D., Charles S. Eby, M.D., Rosemary A. Madigan, R.N., M.P.H., Robert B. McBane, M.D., Sherif Z. Abdel-Rahman, Ph.D., Scott M. Stevens, M.D., Steven Yale, M.D., Emile R. Mohler, III, M.D., Margaret C. Fang, M.D., Vinay Shah, M.D., Richard B. Horenstein, M.D., Nita A. Limdi, Pharm.D., Ph.D., James A.S. Muldowney, III, M.D., Jaspal Gujral, M.B., B.S., Patrice Delafontaine, M.D., Robert J. Desnick, M.D., Ph.D., Thomas L. Ortel, M.D., Ph.D., Henny H. Billett, M.D., Robert C. Pendleton, M.D., Nancy L. Geller, Ph.D., Jonathan L. Halperin, M.D., Samuel Z. Goldhaber, M.D., Michael D. Caldwell, M.D., Ph.D., Robert M. Califf, M.D., and Jonas H. Ellenberg, Ph.D. for the COAG Investigators
N Engl J Med 2013; 369:2283-2293 December 12, 2013DOI: 10.1056/NEJMoa1310669
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.
(Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657.)
Other related articles published in this Open Access Online Scientific Journal include the following:
Pharmocogenomics is a Multidirectional Street
Demet Sag, PhD
http://pharmaceuticalintelligence.com/2014/04/28/pharmocogenomics-is-a-multidirectional-street/
Pharmacogenomics – A New Method for Druggability
Demet Sag, PhD
http://pharmaceuticalintelligence.com/2014/04/28/pharmacogenomics-a-new-method-for-druggability/
Is Pharmacogenetic-based Dosing of Warfarin Superior for Anticoagulation Control?
Aviva Lev-Ari, PhD, RN
Clinical Trials on Bivalirudin: Questions on Bleeding and Outcomes
Aviva Lev-Ari, PhD, RN
2012pharmaceutical
Amandeep Kaur
Aashir Awan, Phd
Abhisar Anand
Adina Hazan
Alan F. Kaul, PharmD., MS, MBA, FCCP
alexcrystal6
anamikasarkar
apreconasia
aptubman
Arav Gandhi
aviralvatsa
David Orchard-Webb, PhD
danutdaagmailcom
Demet Sag, Ph.D., CRA, GCP
Dror Nir
dsmolyar
Ethan Coomber
evelinacohn
FrasonKalapurackal
Gail S Thornton
Irina Robu
jayzmit48
jdpmd
jshertok
kellyperlman
Ed Kislauskis
larryhbern
Madison Davis
marzankhan
megbaker58
ofermar2020
Dr. Pati
pkandala
ritusaxena
Rick Mandahl
sjwilliamspa
Srinivas Sriram
stuartlpbi
Dr. Sudipta Saha
tildabarliya
zraviv06
zs22
Leave a Reply