Should we test for CYP2C9 before initiating anticoagulant therapy in patients with atrial fibrillation?

Abstract

Background: Genetic variants of the warfarin sensitivity gene CYP2C9 have been associated with increased bleeding risk during warfarin initiation. Studies also suggest that such patients remain at risk throughout treatment.

Objective: Would testing patients with non-valvular atrial fibrillation (AF) for CYP2C9 before initiating warfarin improve outcomes?

Design: Markov state transition decision model.

Setting: Ambulatory or inpatient settings necessitating new initiation of anticoagulation.

Patients: The base case was a 69-year-old man with newly diagnosed non-valvular AF. Interventions included: (1) warfarin, (2) aspirin, or (3) no antithrombotic therapy without genetic testing; and genetic testing followed by (4) aspirin or (5) no antithrombotic therapy in those with culprit CYP2C9 alleles.

Measures: Quality-adjusted life years (QALYs).

Results: In the base case, testing and treating patients with CYP2C9*2 and/or CYP2C9*3 with aspirin rather than warfarin was best (8.97 QALYs). However, warfarin without genetic testing was a close second (8.96 QALYs), a difference of roughly 5 days. Sensitivity analyses demonstrated that genetic testing followed by aspirin was best for patients at lower risk of embolic events. Warfarin without testing was preferred if the rate of embolic events was greater than 5% per year, or the risk of major bleeding while receiving warfarin was lower.

Conclusion: For patients at average risk for ischemic stroke due to AF and at average risk for major hemorrhage, treatment based on genetic testing offers no benefit compared to warfarin initiation without testing. The gain from testing may be larger in patients at lower risk of embolic events or at greater risk of bleeding.

Figure 1

Strategies examined for prevention of thromboembolism in a 69-year-old man with newly diagnosed non-valvular atrial fibrillation. In the top panel treatment is initiated without knowledge of CYP2C9 genotype. In the lower panel treatment is based on the results of CYP2C9 genotyping. Those who are negative for the variant alleles receive warfarin, whereas in those who test positive, we examine treatment with either aspirin or no antithrombotic therapy.

Figure 2

Quality-adjusted life expectancy (y-axis) predicted for three of the five strategies as a function of the estimated annual risk of thromboembolism (x-axis). At the base case value (4.5% annual rate of thromboembolism) for “average risk” patients with atrial fibrillation, testing and treating those found to possess the culprit alleles of CYP29C with aspirin is best. For patients having less than a 1.3% per year risk of embolic events, no antithrombotic therapy is best, while for those having greater than a 5% per year risk anticoagulation without prior testing is best. Thus, for individuals judged to have an annual risk of thromboembolism between 1.3% and 5% per year, testing and treating those found to possess culprit alleles of CYP29C with aspirin yields best outcomes, although by a very small margin.

Figure 3

Quality-adjusted life expectancy (y-axis) predicted as a function of varying the hazard of major bleeding on warfarin (x-axis). Hazard of major bleeding on warfarin is relative to the baseline hazard estimate drawn from prior published reports. Thus, a hazard of 1.0 on the x-axis indicates relative hazards of 5.7, 4.0, and 2.4, respectively, for intracerebral, subdural, and extracranial bleeding while receiving warfarin. For patients in whom this hazard is judged to be less than 0.9, anticoagulation without prior testing yields superior outcomes. Aspirin without prior testing is best if the relative hazard exceeds 4.7, while genetic testing followed by aspirin for those possessing culprit alleles is favored in the range between these two values.

Figure 4

Two-way sensitivity analysis examining the effect of varying the annual risk of embolic events (x-axis) and the relative hazard of major bleeding associated with culprit alleles of CYP2C9 during the maintenance phase of anticoagulant therapy (y-axis). Hypothetical patients can therefore be assigned risk estimates for each of these two parameters. The area on the graph where they fall then allows assignment of a strategy either of (1) “Do not anticoagulate,” (2) genetic testing followed by aspirin for those individuals found to possess CYP2C9*2 and/or CYP2C9*3 culprit alleles, or (3) anticoagulation without genetic testing. Patients whose risk for thromboembolism is judged to be high are placed in the region to the right. For these patients, if the relative hazard for bleeding conferred by CYP2C9 is low, anticoagulation without prior testing is favored. For patients in whom the rate of embolic events is judged to be low (but not less than 1% per year) and the relative hazard conferred by CYP2C9 is high, genetic testing followed by aspirin in those found to possess the culprit genetic variants is best. For our base case 69-year-old man with nonvalvular AF, estimates for these two parameters place him just within the genetic testing region.