Author(s): Joyce HS You [*] aff1
atrial fibrillation; cost-effectiveness analysis; CYP2C9; direct oral anticoagulant; genotype-guided therapy; VKORC1; warfarin
Warfarin is the most commonly prescribed oral anticoagulant in the USA and its anticoagulation effect is measured by international normalized ratio (INR). Warfarin therapy with good INR control, indicated by time-in-therapeutic range (TTR) of 75% or above, is associated with lower bleeding and thromboembolic event rates [1 ]. Warfarin dosage requirement is subjected to wide variability [2 ]. A number of factors have been identified to influence the warfarin dosage, including age, body weight, comorbidities, concurrent medications, dietary intake, patient compliance level and genetic factors [3,4 ]. Genetic variations of CYP2C9 and VKORC1 are highly associated with the change in metabolism of warfarin and receptor sensitivity to warfarin, respectively [3 ]. The polymorphisms CYP2C9 and VKORC1 genes, patient age, body weight and the use of amiodarone together explain over 50% of warfarin dose variation [4,5 ]. Recently, a number of multicenter randomized trials evaluating the effect of genotype-guided warfarin dosing on TTR showed diverging results (TTR ranged from 45 to 71%), possibly explained by the difference in ethnical diversity of subjects (and therefore frequencies of polymorphisms of CYP2C9 and VKORC1 ) between studies [6-8 ].
Direct oral anticoagulants (DOACs), including direct thrombin inhibitor (dabigatran) and direct factor Xa inhibitors (rivaroxaban and apixaban), are either associated with lower rates of stroke and systemic embolism, or noninferior to warfarin for stroke prevention in AF patients [9-11 ]. Risk of DOACs for major bleeding was similar to warfarin therapy [ 12 ]. Multiple cost-effectiveness analyses found DOACs to be more costly and effective when comparing to standard warfarin therapy with average TTR of 60% or genotype-guided warfarin dosing [13-15 ], and the incremental cost per additional quality-adjusted life-year (QALY) gained (ICER) by DOACs was lower than the willingness-to-pay (WTP) threshold. Majority of the health economic studies used USD50,000 per additional QALY gain as the WTP threshold. Despite DOAC therapy fulfilled the cost-effective threshold in health economic research, the high drug cost of DOAC is nevertheless a heavy economic burden for many healthcare systems and patients in clinical settings.
Besides personalization of warfarin dosing, another potential application of the CYP2C9 and VKORC1 genotype data is to guide the use of DOAC and warfarin for balancing the higher clinical benefit of universal use of DOAC and lower cost of universal use of warfarin. Patients with normal warfarin sensitivity as indicated by CYP2C9 and VKORC1 genotypes could receive warfarin, whereas patients with high or low warfarin sensitivity could receive a DOAC. A prior cost-effectiveness analysis found genotype-guided selection of oral anticoagulant therapy to be highly cost-effective comparing to universal warfarin therapy [16 ]. In this analysis, the potential clinical and economic outcomes of genotype-guided use of DOAC versus universal DOAC therapy for stroke prevention in AF patients were compared from the perspective of US healthcare payers.
A life-long Markov model (Figure 1) was used to simulate the outcomes of two anticoagulation treatment strategies in a hypothetical cohort of 65-year-old newly...