Abstract
Objectives To determine the incremental net health benefits of dabigatran etexilate 110 mg and 150 mg twice daily and warfarin in patients with non-valvular atrial fibrillation and to estimate the cost effectiveness of dabigatran in the United Kingdom.
Design Quantitative benefit-harm and economic analyses using a discrete event simulation model to extrapolate the findings of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study to a lifetime horizon.
Setting UK National Health Service.
Population Cohorts of 50 000 simulated patients at moderate to high risk of stroke with a mean baseline CHADS2 (Congestive heart failure, Hypertension, Age≥75 years, Diabetes mellitus, previous Stroke/transient ischaemic attack) score of 2.1.
Main outcome measures Quality adjusted life years (QALYs) gained and incremental cost per QALY of dabigatran compared with warfarin.
Results Compared with warfarin, low dose and high dose dabigatran were associated with positive incremental net benefits of 0.094 (95% central range −0.083 to 0.267) and 0.146 (−0.029 to 0.322) QALYs. Positive incremental net benefits resulted for high dose dabigatran in 94% of simulations versus warfarin and in 76% of those versus low dose dabigatran. In the economic analysis, high dose dabigatran dominated the low dose, had an incremental cost effectiveness ratio of £23 082 (€26 700; $35 800) per QALY gained versus warfarin, and was more cost effective in patients with a baseline CHADS2 score of 3 or above. However, at centres that achieved good control of international normalised ratio, such as those in the UK, dabigatran 150 mg was not cost effective, at £42 386 per QALY gained.
Conclusions This analysis supports regulatory decisions that dabigatran offers a positive benefit to harm ratio when compared with warfarin. However, no subgroup for which dabigatran 110 mg offered any clinical or economic advantage over 150 mg was identified. High dose dabigatran will be cost effective only forpatients at increased risk of stroke or for whom international normalised ratio is likely to be less well controlled.
Introduction
Atrial fibrillation is the most common sustained cardiac arrhythmia, with an estimated prevalence in the United Kingdom of 10% in patients aged 75 or over and an associated fivefold increase in the risk of ischaemic stroke.1 2 Bed days for patients with a primary or secondary diagnosis of atrial fibrillation cost the National Health Service (NHS) £1.9bn (€2.2bn; $2.9bn) in 2008, with outpatient and other inpatient costs totalling £329m.3
Warfarin is the mainstay of oral thromboprophylactic anticoagulation treatment.4 However, patients show considerable variability in their response to warfarin, which, coupled with a narrow therapeutic range, necessitates frequent monitoring and adjustment of dosage to ensure optimal anticoagulation. Deviations outside the therapeutic range (international normalised ratio (INR) 2.0-3.0) increase the risk of both strokes and haemorrhagic events.5
Dabigatran etexilate is a new oral direct thrombin inhibitor that may provide an alternative to warfarin; it has the advantage of not requiring regular monitoring. In the multinational, Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study, 18 113 patients with non-valvular atrial fibrillation and at least one risk factor for stroke were randomised to one of two doses of dabigatran (110 mg or 150 mg, twice daily) or dose adjusted warfarin.6 After a median follow-up of two years, the rates of the primary outcome (stroke or systemic embolism) were similar to those for warfarin among patients assigned the lower dose but were lower among patients assigned the higher dose (1.11% v 1.71% per year; relative risk 0.66, 95% confidence interval 0.53 to 0.82; P=0.0001). Compared with warfarin, the annual rate of major bleeding was lower among patients assigned dabigatran 110 mg (2.71% v 3.36%; relative risk 0.80, 0.69 to 0.93; P=0.003) but similar among those assigned 150 mg. Dabigatran was associated with higher rates of myocardial infarction, but these were not statistically significant.7
The US Food and Drug Administration (FDA) was satisfied of the positive benefit to harm balance of dabigatran but failed to identify a subgroup of patients in which the benefit-harm profile was superior for the 110 mg dose compared with the 150 mg dose and consequently approved only the higher dose.8 However, both doses have been approved by other regulatory authorities, including the European Medicines Agency, which specifies 150 mg twice daily for patients under 80 years of age and 110 mg twice daily for those aged 80 and over or as an option when the thromboembolic risk is considered to be low and the risk of bleeding is high.9
Against this background, we describe a quantitative analysis of the trade-off between thrombotic and bleeding risks—events that have differential effects on life expectancy and quality of life—as a basis to guide clinicians’ prescribing. We also develop a health economic evaluation to estimate the cost effectiveness of dabigatran in patients with non-valvular atrial fibrillation, given the considerable uncertainty about its cost effectiveness in the UK healthcare setting.
