Update (12/17/2013):
New perspective piece from the New England Journal of Medicine
The December 12 issue of the New England Journal of Medicine
includes a perspective piece discussing the recent trial results on coumarin
dosing. This article, Pharmacogenetics and Coumarin Dosing — Recalibrating
Expectations, by Zineh et al from the Food and Drug Administration, discusses the different results from three
randomized controlled trials published in the same issue of the journal and the
implications for public expectations for pharmacogenetics testing. They
highlight the importance of including “uncommon but clinically meaningful
outcomes” “in addition to intermediate end points (e.g., percentage of time in the therapeutic range) in a totality-of-evidence
approach to assessing the usefulness of pharmacogenetic approaches”. They also
add that “Many observers have called for randomized, controlled trials to
address the translation lag….Randomization, in and of itself, does not
accomplish this end. Rather, the choice of control, the treatment setting,
characteristics of the population tested, the analytic approach, and end-point
definition are likely to be the key considerations that determine the public
health relevance of pharmacogenetic trials in the future. Future trials should
use various methods to assess the clinical usefulness of pharmacogenetic
interventions; these may include designs focused on assessing efficacy
(emphasis on internal validity), effectiveness (emphasis on generalizability),
and implementation effectiveness (emphasis on adoption and uptake). These
approaches are not mutually exclusive and, if combined, may expedite assessment
of the effects of pharmacogenetic interventions on patients, providers, and
health systems.”
Issam Zineh, Pharm.D., M.P.H., Michael Pacanowski, Pharm.D.,
M.P.H., and Janet Woodcock, M.D.
From the Center for Drug Evaluation and Research, Food and
Drug Administration, Silver Spring, MD.
N Engl J Med 2013; 369:2273-2275December 12, 2013DOI:
10.1056/NEJMp1314529
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Warfarin is a widely used blood thinning agent to prevent strokes, heart attacks, and
dangerous blood clots. Though highly efficacious, warfarin use has been
challenging due to its narrow therapeutic window and high degree of
inter-individual variability. Overdose and underdose of warfarin are both
dangerous. Taking too much warfarin could result in bleeding and taking too
little may not be able to stop clotting. Many studies have attempted to
explain the factors that influence warfarin response and define the optimal
dosing algorithm. Clinical factors (eg. race, age, height, body weight,
smoking, interacting drugs, comorbidities etc.) as well as genetic factors are
all established determinants of variable warfarin response. In particular,
genetic variations in two genes, CYP2C9 and VKORC1, have been repeatedly associated with warfarin dosing in
various populations. The US FDA had revised the warfarin drug label twice (2007
and 2010) to indicate that CYP2C9 and
VKORC1 genotypes may be useful in
determining the optimal initial dose of warfarin and provided the recommended
initial dosing ranges for patients with different combinations of CYP2C9 and VKORC1 genotypes.
Despite the large body of literature documenting the
significant association between CYP2C9/VKORC1
genotypes and warfarin dose, there is still debate surrounding the clinical
utility of this knowledge. A few large, randomized clinical trials are
currently underway to determine if using
genetic information in warfarin dosing improves clinical outcomes
(both efficacy and safety). The results of three studies have
just been published online in the New England Journal of Medicine.
• Kimmel et al, 2013,
COAG Trial: This trial included 1,015 patients (27% black) who were randomized
at 18 centers in the U.S. to compare the efficacy of a warfarin-dosing
algorithm based on genotype and clinical data with a dosing algorithm based on
clinical data only. The authors showed that using a warfarin dosing algorithm
based on both clinical and genetic information did NOT increase the percentage
of time spent within the therapeutic range as compared to an algorithm based on
clinical factors alone at 4 weeks (45.2% versus 45.4%, P=0.91), suggesting that
genotype-guided dosing of warfarin did not improve anticoagulation control
during the first 4 weeks of therapy. This study also found no difference in the
rate of having an INR of 4 or higher, thromboembolism, or major bleeding
between the groups (20% versus 21%, P=0.93).
• Pirmohamed et al, 2013, EU-PACT Warfarin Trial: This
trial included 455 patients (98.5% white) recruited from centers in the U.K.
and Sweden to compare the effect of genotype-guided dosing with that of
standard dosing on anticoagulation control. The authors found that
genotype-guided group had higher mean percentage of time in the therapeutic
range for the genotype-guided group as compared with the standard dosing group
(67.4% versus 60.3%, P<0.001). There were also significantly fewer
incidences of excessive anticoagulation (INR ≥4.0) in the genotype-guided group.
• Verhoef et al, 2013,
EU-PACT Acenocoumarol and Phenprocoumon Trial: This trial included 548 patients
(>96% white) with atrial fibrillation or venous thromboembolism treated with
acenocoumarol or phenprocoumon to compare the effect of a genotype-guided
dosing algorithm with the effect of a dosing algorithm based solely on clinical
factors (control). Similar to the study by Kimmel et al, this study also found
that genotype-guided dosing did not increase the time spent within the
therapeutic range through 12 weeks as compared to the control (61.6% versus
60.2%, P=0.52).
All three studies are large, multi-center randomized trials
and they all measure the same primary endpoint, the percentage of time that a
patient is within the therapeutic range during the initial phase of treatment.
Two studies (Kimmel et al, Verhoef et al) suggested no significant difference
between the genotype-guided group vs. control in terms of the primary outcome,
while one study (Pirmohamed et al) suggested
positive improvement (though modest) with added genetic information. The
different findings from the three studies might partly be due to factors
besides genetics that determine warfarin dose, eg. race, age, weight,
smoking, concomitant drugs or comorbidities. Additionally, these
studies examined if genotyping improves the initial time in therapeutic range, and yet, they were not powered to examine
the effect on the secondary clinical outcome (eg. the rate of bleeding and
thrombotic complications) and neither were they designed to address whether a
longer duration of genotype-guided dosing would have improved INR control. We
eagerly await publications of trials focusing on these aspects. The
genetics-informatics trial of warfarin (GIFT Trial) is one of such trials that
evaluates whether the addition of genotyping will reduce the risk of venous
thromboembolism (VTE) and severe bleeding associated with warfarin management
(PMID: 21606949). Even though the current clinical utility studies showed mixed results, the results of these trials are
highly valuable. Given that preemptive genotyping is occurring on a more
frequent basis, when genotypes are already available, it is in the best
interest of the patient to use that information along with their clinical information
to achieve a more optimum starting dose of therapy (PMID:19228618).
Read the articles:
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., Ph.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
New England Journal of Medicine November 19, 2013, DOI:
10.1056/NEJMoa1310669
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
New England Journal of Medicine November 19, 2013 DOI:
10.1056/NEJMoa1311386 .
Talitha I. Verhoef, M.Sc., Georgia Ragia, Ph.D., Anthonius
de Boer, M.D., Ph.D., Rita Barallon, Ph.D., Genovefa Kolovou, M.D., Ph.D., Vana
Kolovou, M.Sc., Stavros Konstantinides, M.D., Ph.D., Saskia Le Cessie, Ph.D.,
Efstratios Maltezos, M.D., Ph.D., Felix J.M. van der Meer, M.D., Ph.D., William
K. Redekop, Ph.D., Mary Remkes, M.D., Frits R. Rosendaal, M.D., Ph.D., Rianne
M.F. van Schie, Ph.D., Anna Tavridou, Ph.D., Dimitrios Tziakas, M.D., Ph.D., Mia
Wadelius, M.D., Ph.D., Vangelis G. Manolopoulos, Ph.D., and Anke H.
Maitland-van der Zee, Pharm.D., Ph.D. for the EU-PACT Group
New England Journal of
Medicine November 19, 2013DOI: 10.1056/NEJMoa1311388
Also read the editorial:
Bruce Furie, M.D.
New England Journal of
Medicine November 19, 2013DOI: 10.1056/NEJMe1313682
