The inter-individual variation in warfarin dosing requirements and narrow therapeutic index for anticoagulation necessitates a personalized dosing regimen. Variation in dosing requirements are in part explained by genetic polymorphism in CYP (involved in warfarin metabolism) and VKOR (a warfarin target) genes. A dosing strategy informed by these polymorphism may hold promise to improve anticoagulation control. In three large randomized trials of similar design, a sophisticated pharmacogenetic approach to warfarin initiation was compared with standard care. All three studies used the percentage of time in therapeutic range as the primary end-point. None of the studies were powered to assess bleeding complications. A genotype-guided dosing approach failed to demonstrate improvements in anticoagulation control for the two largest studies. In the smallest of the three studies, pharmacogenomic-based dosing resulted in a statistically significant benefit (mean percentage of time in therapeutic 67.4% vs. 60.3%, p<0.001). Given the lack of benefit in the larger trials, and the modest effect size observed in the single trial demonstrating benefit, genotype-guided therapy does not appear justified in current practice.
These studies highlight the challenges care guided by pharmacogenomics. First, genotype currently explains less than half of the variability in response to warfarin. Thus, the potential to predict response to warfarin based on genotype is far from perfect. Further, individual response to warfarin is readily apparent through INR monitoring. When phenotypic responses to therapy (INR for warfarin or blood pressure for antihypertensive therapies) are readily available, it may be difficult for genomic guided therapies to improve on standard care.
Summarized by Steven M. Bradley and Hussain Contractor
- 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 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 and Ellenberg JH. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med. 2013 Dec 12;369(24):2283-93.
- Pirmohamed M, Burnside G, Eriksson N, Jorgensen AL, Toh CH, Nicholson T, Kesteven P, Christersson C, Wahlström B, Stafberg C, Zhang JE, Leathart JB, Kohnke H, Maitland-van der Zee AH, Williamson PR, Daly AK, Avery P, Kamali F and Wadelius M. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med. 2013 Dec 12;369(24):2294-303.
- Verhoef TI, Ragia G, de Boer A, Barallon R, Kolovou G, Kolovou V, Konstantinides S, Le Cessie S, Maltezos E, van der Meer FJ, Redekop WK, Remkes M, Rosendaal FR, van Schie RM, Tavridou A, Tziakas D, Wadelius M, Manolopoulos VG and Maitland-van der Zee AH. A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon. N Engl J Med. 2013 Dec 12;369(24):2304-12.