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
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