James V. Freeman, MD, MPH; Ruo P. Zhu, BA; Douglas K. Owens, MD, MSc; Alan M. Garber, MD, PhD; David W. Hutton, PhD; Alan S. Go, MD; Paul J. Wang, MD; Mintu P. Turakhia, MD, MAS
Warfarin reduces the risk for ischemic stroke in patients with atrial fibrillation (AF) but increases the risk for hemorrhage. Dabigatran is a fixed-dose, oral direct thrombin inhibitor with similar or reduced rates of ischemic stroke and intracranial hemorrhage in patients with AF compared with those of warfarin.
To estimate the quality-adjusted survival, costs, and cost-effectiveness of dabigatran compared with adjusted-dose warfarin for preventing ischemic stroke in patients 65 years or older with nonvalvular AF.
Markov decision model.
The RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial and other published studies of anticoagulation. The cost of dabigatran was estimated on the basis of pricing in the United Kingdom.
Patients aged 65 years or older with nonvalvular AF and risk factors for stroke (CHADS2 score ≥1 or equivalent) and no contraindications to anticoagulation.
Warfarin anticoagulation (target international normalized ratio, 2.0 to 3.0); dabigatran, 110 mg twice daily (low dose); and dabigatran, 150 mg twice daily (high dose).
Quality-adjusted life-years (QALYs), costs (in 2008 U.S. dollars), and incremental cost-effectiveness ratios.
The quality-adjusted life expectancy was 10.28 QALYs with warfarin, 10.70 QALYs with low-dose dabigatran, and 10.84 QALYs with high-dose dabigatran. Total costs were $143 193 for warfarin, $164 576 for low-dose dabigatran, and $168 398 for high-dose dabigatran. The incremental cost-effectiveness ratios compared with warfarin were $51 229 per QALY for low-dose dabigatran and $45 372 per QALY for high-dose dabigatran.
The model was sensitive to the cost of dabigatran but was relatively insensitive to other model inputs. The incremental cost-effectiveness ratio increased to $50 000 per QALY at a cost of $13.70 per day for high-dose dabigatran but remained less than $85 000 per QALY over the full range of model inputs evaluated. The cost-effectiveness of high-dose dabigatran improved with increasing risk for stroke and intracranial hemorrhage.
Event rates were largely derived from a single randomized clinical trial and extrapolated to a 35-year time frame from clinical trials with approximately 2-year follow-up.
In patients aged 65 years or older with nonvalvular AF at increased risk for stroke (CHADS2 score ≥1 or equivalent), dabigatran may be a cost-effective alternative to warfarin depending on pricing in the United States.
American Heart Association and Veterans Affairs Health Services Research & Development Service.
Dabigatran is a direct thrombin inhibitor shown to be about as safe and effective as warfarin for preventing thromboembolism in patients aged 65 years or older with nonvalvular atrial fibrillation.
This analysis suggests that dabigatran is generally cost-effective as an alternative to warfarin. Treatment seems to become less cost-effective when daily costs exceed $9.36 for low-dose therapy and $13.70 for high-dose therapy.
Much of the analysis relies on data from the single available manufacturer-sponsored study of dabigatran.
Depending on how it is priced, dabigatran could be a cost-effective alternative to warfarin for treating atrial fibrillation.
Appendix Table 1.
“M” represents a Markov process with 9 health states for each of the 3 treatment options. These potential health states are identical for each treatment option. All patients remain in the “Well” state until 1 of 6 events occurs: TIA, stroke, ICH, extracranial hemorrhage, myocardial infarction, or death. The probabilities of these events occurring depend on the prescribed therapy. Triangles indicate which health state the patient enters after an event. A “RIND” is the health state that patients enter after a TIA or stroke without residual neurologic deficit. “Mild” represents a neurologic event that results in neurologic deficit but no limitation in performing activities of daily living; “moderate to severe” represents a neurologic event that results in loss of independence for at least 1 activity of daily living. ICH = intracranial hemorrhage; RIND = reversible ischemic neurologic event; TIA = transient ischemic attack.
Appendix Table 2.
Bars indicate the range of cost per additional QALY of dabigatran compared with warfarin as determined in 1-way sensitivity analyses over plausible ranges for variables. Upper and lower limits of values evaluated in sensitivity analysis are indicated next to the bars. One-way sensitivity analysis was performed on all model variables, and the cost-effectiveness of dabigatran relative to warfarin varied the most with the variables shown. The incremental cost-effectiveness ratio remained <$85 000 per QALY over the full range of assumptions evaluated. The dotted line represents the cost-effectiveness threshold of $50 000 per QALY. ICH = intracranial hemorrhage; QALY = quality-adjusted life-year.
The slope of the cost-effectiveness line for high-dose dabigatran was lower than for low-dose dabigatran, so that at a pricing ratio ≥1.66 ($9.50 per day for low-dose and $15.73 per day for high-dose dabigatran), high-dose dabigatran no longer achieved extended dominance over low-dose dabigatran. The dotted line represents the cost-effectiveness threshold of $50 000 per QALY. At a cost >$9.36 for low-dose dabigatran, the ICER compared with warfarin exceeded $50 000 per QALY, and at a cost >$13.70 for high-dose dabigatran, the ICER compared with warfarin exceeded $50 000 per QALY. ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year.
The ICER for high-dose dabigatran compared with warfarin remained <$64 455 per QALY for the full range of stroke rates tested and <$60 120 per QALY for the full range of ICH rates tested. ICER = incremental cost-effectiveness ratio; ICH = intracranial hemorrhage; QALY = quality-adjusted life-year.
The base-case rate of ischemic stroke and ICH for each therapy is multiplied by the same ratio, and the varying rate of events on warfarin is used as the reference. Dabigatran, 150 mg twice daily (high dose), was favored for the base case (asterisk) and for patients with a higher risk for both ischemic stroke and ICH. For patients with a low absolute risk for ischemic stroke, low-dose dabigatran was the preferred therapy, especially if the concurrent ICH risk was relatively high. For patients with a low absolute risk for ICH, warfarin was the preferred therapy. The annual rate of ischemic stroke for patients receiving warfarin with a CHADS2 score of 1 is 0.72%, CHADS2 score of 1–2 is 1.2%, and CHADS2 score of 4 is 2.35%. ICH = intracranial hemorrhage.
This graph is based on 10 000 Monte Carlo simulations of the model, drawing parameters for each input simultaneously from probability distributions. Warfarin is most likely to be cost-effective at a willingness-to-pay threshold ≤$30 000 per QALY. At thresholds ≥$35 000 per QALY, high-dose dabigatran is most likely to be cost-effective. High-dose dabigatran is 53%, 68%, and 70% likely to be cost-effective at willingness-to-pay thresholds of $50 000, $100 000, and $150 000 per QALY, respectively. Either high-dose or low-dose dabigatran was preferred to warfarin in more than 80% of simulations using a willingness-to-pay threshold of $50 000 per QALY. QALY = quality-adjusted life-year.
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James V. Freeman, Ruo P. Zhu, Douglas K. Owens, Alan M. Garber, David W. Hutton, Alan S. Go, et al. Cost-Effectiveness of Dabigatran Compared With Warfarin for Stroke Prevention in Atrial Fibrillation. Ann Intern Med. 2011;154:1–11. doi: 10.7326/0003-4819-154-1-201101040-00289
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Published: Ann Intern Med. 2011;154(1):1-11.
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