Efficacy and cost-effectiveness of new oral anticoagulants compared to warfarin for the prevention of stroke in patients with atrial fibrillation
Health technology assessment
|Updated
Warfarin has been used as the only oral anticoagulant for over 50 years in patients with atrial fibrillation.
Key message
Warfarin has been used as the only oral anticoagulant for over 50 years in patients with atrial fibrillation. Recently new oral anticoagulants like dabigatran, rivaroxaban and apixaban have been developed for this indication. We compared these new oral anticoagulants with each other and with warfarin with respect to efficacy and cost-effectiveness for patients with atrial fibrillation and moderate or high risk of stroke. The new oral anticoagulants reported statistically significant reductions of intracranial bleeding compared to warfarin. For the outcomes all-cause mortality, ischemic stroke, gastrointestinal bleeding and myocardial infarction, results were inconclusive. The quality of evidence for the outcomes was generally regarded as low or very low. Only one large randomised controlled trial presently exists for each of these three new oral anticoagulants, all compared to warfarin. This necessitated modelling through indirect comparisons. Apixaban 5 mg x 2, dabigatran 150 mg x 2 and rivaroxaban 20 mg x 1 all seems to be cost-effective when each are compared to warfarin for patients with atrial fibrillation at medium and high risk of stroke. When all drugs are compared to each other, dabigatran 150 mg x 2 seems to be the most cost-effective in 28 of 30 individual risk groups and apixaban in the remaining three risk groups based on an assumed threshold cost-effectivness of NOK 588 000 per QALY. The conclusions regarding efficacy and cost-effectiveness are highly uncertain. The conclusions may change if the assumptions in the model change. New research directly comparing the new oral anticoagulants with each other and with warfarin is likely to be useful and would reduce decision uncertainty.
Summary
Background Atrial fibrillation is an abnormality of the heart rhythm that leads to increased risk of stroke and other cardiovascular events, which in turn may lead to disability or premature death. The oral anticoagulant warfarin has been used for atrial fibrillation for more than five decades and is still widely used. Use of warfarin requires close monitoring and leads to numerous visits to the doctor. New oral anticoagulants dabigatran, rivaroxaban and apixaban probably require less intensive monitoring, but are more expensive drugs than warfarin. It is uncertain whether the new drugs are effective, safe and cost-effective in a Norwegian setting. Objective To calculate the cost-effectiveness of the new oral anticoagulants, apixaban, dabigatran and rivaroxaban, relative to each other and to warfarin for the prevention of stroke in patients with atrial fibrillation at different levels of risk. Method We performed a systematic literature search for systematic reviews and randomised controlled trials to inform us regarding efficacy and safety. Quality of efficacy documentation was assessed with GRADE. We developed a decision analytic model for patients with atrial fibrillation. In the model, patients are assumed to be at elevated risk of stroke, myocardial infarction, bleeding and death. Epidemiological input data was gathered from mainly Scandinavian registries. Data on Quality of Life was based on EQ-5D data and costs were mainly based on Norwegian fees and schedules. Results We found one Canadian HTA report with a systematic review of clinical studies. The main efficacy data were based on three large randomized controlled trials comparing each of the new oral anticoagulants with warfarin. All three randomized controlled trials reported statistically significant reductions of intracranial bleeding compared to warfarin. For the outcomes all-cause mortality, ischemic stroke, gastrointestinal bleeding and myocardial infarction, results were inconclusive. The quality of evidence for the outcomes was generally regarded as low or very low. Model analyses indicated that the new drugs are likely to lead to some increase in remaining quality-adjusted life expectancy, but also increased costs. All three new anticoagulants are likely to be cost-effective compared to warfarin, but this conclusion is highly uncertain and depends heavily on model assumptions. For atrial fibrillation patients with moderate stroke risk, apixaban seems to be effective compared to the other anticoagulants, while the cost-effectiveness depends heavily on risk of bleeding. For high risk patients, dabigatran is likely to be cost-effective compared to the alternatives. Discussion Limited efficacy data is the major source of uncertainty in the analyses. Only one major trial compared each new drug to warfarin and no trials have compared any of the new oral anticoagulants with each other. Currently, prices of the three new drugs are in a state of flux because of competition among the pharmaceutical companies. Because changes in drug prices affect cost-effectiveness estimates, the conclusions of this report may well need to be revised after the report is released. Conclusion Which of the oral anticoagulants is the most effective, the safest and the most cost-effective is highly uncertain. Decision uncertainty could be reduced through large, independent, randomized controlled trials. The trials should ideally be done in different countries and directly compare the new drugs with each other and warfarin. This would also benefit patients.