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Original Research |

Cost-Effectiveness of Dabigatran Compared With Warfarin for Stroke Prevention in Atrial Fibrillation FREE

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; and Mintu P. Turakhia, MD, MAS
[+] Article and Author Information

From Stanford University School of Medicine, Stanford, California; Veterans Affairs Palo Alto Health Care System, Palo Alto, California; University of Michigan, Ann Arbor, Michigan; Kaiser Permanente of Northern California, Oakland, California; and University of California, San Francisco, San Francisco, California.


Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Veterans Affairs.

Grant Support: By an American Heart Association Pharmaceutical Round Table Outcomes Research Postdoctoral Fellowship (0875162N; Dr. Freeman), a Veterans Affairs Health Services Research & Development Career Development Award (CDA09027-1; Dr. Turakhia), and an American Heart Association National Scientist Development Grant (09SDG2250647; Dr. Turakhia).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-1416.

Reproducible Research Statement:Study protocol and statistical code: Not available. Data set: Selected data elements are available to approved individuals with written agreement from Dr. Turakhia (e-mail, mintu@stanford.edu).

Requests for Single Reprints: Mintu P. Turakhia, MD, MAS, Veterans Affairs Palo Alto Health Care System, Stanford University, 3801 Miranda Avenue, 111C, Palo Alto, CA 94304; e-mail, mintu@stanford.edu.

Current Author Addresses: Dr. Freeman: Stanford University School of Medicine, 300 Pasteur Drive, Falk Building, CVRC 5406, Stanford, CA 94305-5406.

Mr. Zhu: Stanford University School of Medicine, 300 Pasteur Drive, Medical School Office Building, Stanford, CA 94305-5404.

Drs. Owens and Garber: Center for Health Policy/Center for Primary Care and Outcomes Research, 117 Encina Commons, Stanford, CA 94305-6019.

Dr. Hutton: Department of Health Management and Policy, University of Michigan School of Public Health, 1415 Washington Heights, M3525 SPH II, Ann Arbor, MI 48109.

Dr. Go: Division of Research, Kaiser Permanente of Northern California, 2000 Broadway Street, Oakland, CA 94612-2304.

Dr. Wang: Stanford University School of Medicine, 300 Pasteur Drive, H2146, Stanford, CA 94305-5319.

Dr. Turakhia: Veterans Affairs Palo Alto Health Care System, Cardiology 111C, 3801 Miranda Avenue, Palo Alto, CA 94304.

Author Contributions: Conception and design: J.V. Freeman, R.P. Zhu, D.K. Owens, A.M. Garber, M.P. Turakhia.

Analysis and interpretation of the data: J.V. Freeman, R.P. Zhu, D.K. Owens, A.M. Garber, D.W. Hutton, A.S. Go, P.J. Wang, M.P. Turakhia.

Drafting of the article: J.V. Freeman, M.P. Turakhia.

Critical revision of the article for important intellectual content: J.V. Freeman, R.P. Zhu, D.K. Owens, A.M. Garber, D.W. Hutton, A.S. Go, P.J. Wang, M.P. Turakhia.

Final approval of the article: J.V. Freeman, D.K. Owens, A.M. Garber, D.W. Hutton, A.S. Go, P.J. Wang, M.P. Turakhia.

Statistical expertise: J.V. Freeman, R.P. Zhu, D.K. Owens, A.M. Garber, D.W. Hutton, M.P. Turakhia.

Obtaining of funding: A.S. Go.

Administrative, technical, or logistic support: J.V. Freeman, M.P. Turakhia.

Collection and assembly of data: J.V. Freeman, R.P. Zhu, M.P. Turakhia.


Ann Intern Med. 2011;154(1):1-11. doi:10.7326/0003-4819-154-1-201101040-00289
Text Size: A A A

Background: 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.

Objective: 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.

Design: Markov decision model.

Data Sources: 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.

Target Population: Patients aged 65 years or older with nonvalvular AF and risk factors for stroke (CHADS2 score ≥1 or equivalent) and no contraindications to anticoagulation.

Time Horizon: Lifetime.

Perspective: Societal.

Intervention: 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).

Outcome Measures: Quality-adjusted life-years (QALYs), costs (in 2008 U.S. dollars), and incremental cost-effectiveness ratios.

Results of Base-Case Analysis: 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.

Results of Sensitivity Analysis: 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.

Limitation: 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.

Conclusion: 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.

Primary Funding Source: American Heart Association and Veterans Affairs Health Services Research & Development Service.

Editors' Notes
Context

  • 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.

Contribution

  • 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.

Caution

  • Much of the analysis relies on data from the single available manufacturer-sponsored study of dabigatran.

Implication

  • Depending on how it is priced, dabigatran could be a cost-effective alternative to warfarin for treating atrial fibrillation.

—The Editors

Atrial fibrillation (AF) is the second most common cardiovascular condition in the United States, affecting at least 2.3 million Americans (1) and 10% of adults older than 80 years. The age-adjusted prevalence is increasing; by 2030, AF will affect an estimated 4 million Americans (23). The morbidity and mortality of AF are largely due to the 5-fold increased risk for ischemic stroke. The annual incidence of stroke in patients with AF who are not receiving antithrombotic therapy is 4.5% (45). Atrial fibrillation is responsible for 15% of the 700 000 strokes in the United States each year (6), resulting in $57.9 billion in annual direct and indirect costs (7).

Randomized trials have shown that anticoagulation with warfarin and other vitamin K antagonists can reduce the relative risk for stroke by two thirds (8). However, warfarin has a narrow therapeutic window and may fail to prevent stroke if anticoagulation is inadequate. Overanticoagulation can lead to serious or fatal hemorrhage (911). As a result, warfarin therapy requires frequent and long-term laboratory monitoring and dose adjustment.

Oral direct thrombin inhibitors can modulate the coagulation cascade with a predictable pharmacokinetic profile and do not require laboratory testing or dose adjustment (12). Ximelagatran was the first such drug evaluated for stroke prevention in AF and had similar effectiveness as warfarin (13), but it was not approved in the United States because of hepatotoxicity. Dabigatran etexilate is a newer direct thrombin inhibitor that does not cause liver dysfunction (1416). The RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial was an international, multicenter randomized noninferiority trial in which 18 113 patients with AF at increased risk for stroke (CHADS2 score ≥1 or equivalent [Appendix Table 1] [17]) were randomly assigned to receive dabigatran, 110 mg twice daily (low dose); dabigatran, 150 mg twice daily (high dose); or adjusted-dose warfarin (18). After a median 2-year follow-up, the rates of stroke and systemic embolism were similar in the low-dose dabigatran and warfarin groups, but the low-dose dabigatran group had lower rates of intracranial hemorrhage (ICH) and major hemorrhage. Patients in the high-dose dabigatran group had lower rates of stroke, systemic embolism, and ICH compared with warfarin recipients, although rates of any major hemorrhage were similar. In October 2010, the U.S. Food and Drug Administration (19) approved high-dose dabigatran (150 mg twice daily) for prevention of stroke and systemic embolism in AF, with reduced dosing (75 mg twice daily) available for patients with severe renal impairment. Low-dose dabigatran (110 mg twice daily) was not approved.

Table Jump PlaceholderAppendix Table 1.  CHADS2 Score Components

In this study, we compared the quality-adjusted survival, costs, and cost-effectiveness of warfarin, low-dose dabigatran, and high-dose dabigatran in patients with nonvalvular AF.

Decision Model

Using a Markov model (20), we performed a decision analysis comparing 3 treatment strategies for the prevention of stroke in patients with AF: adjusted-dose warfarin with a target international normalized ratio (INR) of 2.0 to 3.0, twice-daily dabigatran at 110 mg (low dose), and twice-daily dabigatran at 150 mg (high dose). Our base case was a hypothetical cohort of patients 65 years or older with AF who were at increased risk for stroke (on the basis of a CHADS2 score ≥1 or equivalent) and had no contraindications to anticoagulation. We expressed our results in quality-adjusted life expectancy, 2008 U.S. dollars, and incremental cost-effectiveness ratios (ICERs).

The health states in the model included healthy with AF, transient ischemic attack, ischemic stroke (fatal, moderate to severe, mild, or reversible), hemorrhage (fatal, moderate to severe intracranial, mild intracranial, major noncerebral, or minor noncerebral), myocardial infarction, recurrent or combined events, and death (Appendix Figure 1). Appendix Table 2 provides definitions of ischemic stroke, ICH, and myocardial infarction (2122). We applied utilities and costs to each outcome over its expected duration in 2-week increments, and we discounted costs and benefits at 3% annually (23). The risks for the adverse events included in our model were generally derived from the event rates published in the RE-LY trial unless stated otherwise (18). We assumed that event rates for other conditions not included in our model were similar across all treatments. For all treatments, we quantified quality-adjusted life expectancy, risk for adverse events, and net cost over 35 years or until death (if that occurred earlier). Model creation and analyses were performed by using TreeAge Pro Suite 2009 (TreeAge Software, Williamstown, Massachusetts) and Microsoft Excel 2007 (Microsoft, Redmond, Washington).

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Appendix Figure 1.
Decision model.

“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.

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Table Jump PlaceholderAppendix Table 2.  Definitions of Ischemic Stroke, Intracranial Hemorrhage, and Myocardial Infarction
Probability of Adverse Outcomes in the Decision Model

Mortality rates were adjusted for age (beginning at age 65 years). The presence of AF and antithrombotic therapy are accounted for in our model by the clinical event rates derived from the RE-LY trial (8, 18, 2429).

Ischemic Stroke

In the base case, the annual rates of ischemic stroke were 1.20% for warfarin, 1.34% for low-dose dabigatran, and 0.92% for high-dose dabigatran (Table 1) (18). The rate of stroke and transient ischemic attack increased by a factor of 1.4 per decade of life (multiplicative adjustment) (8). We defined the annual risk for ischemic stroke at 3.20% with aspirin. We assumed that 28% of ischemic neurologic events were transient ischemic attacks (3437).

Table Jump PlaceholderTable 1.  Base-Case Values and Ranges Used in Sensitivity Analyses
Hemorrhage

For the base case, the annual rate of ICH was estimated at 0.74% for warfarin, 0.23% for low-dose dabigatran, and 0.30% for high-dose dabigatran (Table 1) (18). The rate of ICH increased by a factor of 1.97 per decade of life (multiplicative adjustment) (63). The annual rate of major hemorrhage was estimated at 3.36% with warfarin, 2.71% with low-dose dabigatran, and 3.11% with high-dose dabigatran (18, 28). We assumed that a major hemorrhage (intracranial or major noncerebral) resulted in discontinuation of anticoagulation and replacement with aspirin. The relative risk for hemorrhage with aspirin compared with warfarin was estimated at 0.87 (3032).

Stroke and Hemorrhage Severity

We classified initial ischemic stroke into 4 categories: fatal, moderate to severe neurologic sequelae, mild neurologic sequelae, and no residual neurologic deficit (Table 1) (28, 31, 3341). We assumed that a second mild ischemic stroke resulted in a moderate to severe ischemic stroke and that a second moderate to severe ischemic stroke resulted in death or a utility of 0. We classified hemorrhage into 6 categories: fatal, ICH with moderate to severe neurologic sequelae, ICH with mild neurologic sequelae, ICH with no residual neurologic deficit, nonfatal extracerebral major hemorrhage, and nonfatal extracerebral minor hemorrhage (Table 1) (13, 18, 32, 4247). We assigned temporary decrements in quality of life (utility) for 2 days for nonfatal extracerebral minor hemorrhage and 2 weeks for nonfatal extracerebral major hemorrhage. We considered ICH either fatal or with a permanent decrement in utility due to neurologic sequelae.

Myocardial Infarction Risk

For the base case, the annual risk for myocardial infarction was 0.53% for warfarin, 0.72% for low-dose dabigatran, and 0.74% for high-dose dabigatran (Table 1) (18). The risk for myocardial infarction increased by a factor of 1.3 per decade on the basis of Framingham risk score mortality estimates for a person with the average risk factor profile of the RE-LY trial population (64).

Quality-of-Life Estimates

To calculate quality-adjusted survival, we multiplied the probabilities of adverse events by quality-of-life estimates (utilities) (49). We adjusted baseline quality of life by age to reflect the disutility associated with aging. We obtained the utility for warfarin without complications from published data on patients with AF that were based on patient ratings of their quality of life while receiving warfarin, including prothrombin time monitoring and changes in diet or lifestyle. The mean utility was 0.987 for warfarin (22, 65) and 0.998 for aspirin (22, 49) (Table 1).

To estimate the utility for dabigatran, we used published estimates of utility for ximelagatran, an older direct thrombin inhibitor with similar dosing and mechanism of action. We used a utility of 0.994 for both doses of dabigatran, which was the utility for ximelagatran estimated from a survey of anticoagulation physicians (28). This estimate was based on the disutility of taking a medication with potential adverse effects, such as bleeding, as well as the need for regular hepatic function testing required for ximelagatran. Although dabigatran does not require hepatic function testing, it is a twice-daily medication and is associated with substantial rates of dyspepsia (approximately 11%).

Costs

Costs, expressed in 2008 U.S. dollars, reflected the perspective of an ideal insurer that covered inpatient and outpatient medical care and prescription costs. This analysis excluded indirect costs. We projected costs over 35 years; future costs and life-years were discounted at 3% per year. We included age-adjusted average health care expenditures for each patient and then added the costs associated with each of the 3 treatment strategies.

Drug Treatment Costs

For warfarin, we combined the annual medication cost with the cost for 14 INR tests and the Center for Medicare & Medicaid Services (CMS) reimbursement for 90-day anticoagulation management (Current Procedural Terminology [CPT] code 99363). In sensitivity analysis, we allowed patients initiating warfarin anticoagulation to have up to 8 additional INR tests and CMS reimbursement to be at the higher rate allowed for anticoagulation initiation for 90 days (CPT code 99364) (6667).

Pricing for dabigatran has not yet been established in the United States. Dabigatran is approved in the United Kingdom, Canada, and other countries for the prevention of venous thromboembolism. The price for low-dose dabigatran in the United Kingdom National Health Service is £4.20 per day (equal to $6.35 in 2008 U.S. dollars at time of analysis) (54). On the basis of historical cost ratios for other on-patent cardiovascular medications, we projected that the retail price in the United States would be 1.5 times higher than that in the United Kingdom (53, 6870). We estimated a price of $9.50 per day for low-dose dabigatran and $13.00 per day for high-dose dabigatran, on the basis of the dosing ratio (150:110 mg) (53, 70). We also included the costs of established care patient visits at 1 and 3 months, then every 3 months through the first year and every 4 months thereafter (18).

Complications and Adverse Events

We estimated the 1-time costs of ischemic stroke, transient ischemic attack, ICH, and myocardial infarction on the basis of the costs of a hospitalization for the diagnosis-related group published by the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project (59). We estimated monthly costs of care for each complication on the basis of previously published cost estimates by using CMS reimbursement for the diagnosis-related group, adjusted to 2008 U.S. dollars, and the gross domestic product deflator (22, 5662). Costs of a minor hemorrhage were based on reimbursement for an expanded problem-focused patient visit (71). We estimated the 1-time cost of a major extracranial hemorrhage on the basis of the CMS payment for the diagnosis-related group associated with gastrointestinal hemorrhage (22).

Sensitivity Analyses

We performed 1-way sensitivity analyses of all variables included in the decision model over their plausible ranges (Table 1). Ranges for clinical events were derived from CIs for event rates from the RE-LY trial and from the published literature (18). Medication costs for aspirin and warfarin included the range of discount and retail costs (53). For dabigatran, we evaluated a cost range from below the price of the medication in the United Kingdom to more than twice the cost in the United Kingdom. We derived nonmedication costs and utilities from the published literature. In 2-way sensitivity analysis, we calculated cost-effectiveness ratios of dabigatran over combinations of stroke and ICH risk.

We also conducted a sensitivity analysis in which we varied the baseline risk for stroke for all 3 treatment strategies by the same ratio to simulate the ICERs for patients with AF at lower stroke risk (CHADS2 score, 1) and higher stroke risk (CHADS2 score, 4). The risk ratios used were based on the published annual rate of stroke for patients with AF who were receiving warfarin with CHADS2 scores of 1 (0.72%) and CHADS2 scores of 4 (2.35%) relative to our base case, which was derived from the RE-LY trial with an annual stroke rate of 1.2%.

Probabilistic Sensitivity Analysis

We performed first-order Monte Carlo simulations (72), randomly sampling (with replacement) a distribution of all variables 10 000 times and then simulating outcomes. For event rates, we generally used a normal distribution, except for the mutually exclusive subcategorization of stroke, for which we used a Dirichlet distribution. We used a β distribution for utilities and [ggr ] and log-normal distributions for cost.

Role of the Funding Source

The investigators were supported by grants from the American Heart Association and the Veterans Affairs Health Services Research & Development Service. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; or decision to submit the manuscript for publication.

Base-Case Analysis

Under base-case conditions, 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 (Table 2). Total costs were $143 193 for warfarin, $164 576 for low-dose dabigatran, and $168 398 for high-dose dabigatran. The ICERs compared with warfarin were $51 229 per QALY for low-dose dabigatran and $45 372 per QALY for high-dose dabigatran. Thus, at our base-case prices, high-dose dabigatran was more cost-effective than low-dose dabigatran (extended dominance).

Table Jump PlaceholderTable 2.  Projected Costs and QALYs for Patients With Nonvalvular Atrial Fibrillation, by Varying Risk for Stroke and ICH

In a hypothetical cohort of 10 000 patients with AF followed over their lifetime starting at age 65 years, low-dose dabigatran averted 1300 ICHs compared with warfarin but resulted in an additional 400 ischemic strokes (including reversible events) and 400 myocardial infarctions. High-dose dabigatran averted 1000 ICHs and 600 ischemic strokes (including reversible events) compared with warfarin but resulted in 400 additional myocardial infarctions.

Sensitivity Analyses

One-way sensitivity analyses showed that several key variables influenced the cost-effectiveness of dabigatran (Appendix Figure 2), including drug cost, stroke and ICH risk for dabigatran and warfarin, age, utility of dabigatran and warfarin, costs after ICH, and utility after myocardial infarction. When we varied other model variables across plausible ranges, the ICER for high-dose dabigatran versus warfarin varied by less than $15 000 per QALY and remained less than $85 000 per QALY.

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Appendix Figure 2.
One-way sensitivity analyses on variables that most influenced the incremental cost-effectiveness of high-dose dabigatran compared with warfarin.

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.

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Costs

The cost of dabigatran had the greatest effect on its cost-effectiveness. At a cost greater than $9.36 per day for low-dose dabigatran, the ICER compared with warfarin exceeded $50 000 per QALY. At a cost greater than $13.70 per day for high-dose dabigatran, the ICER compared with warfarin exceeded $50 000 per QALY. When all 3 therapies were compared and the cost of high-dose dabigatran was increased from the base-case estimate of $13.00 to greater than $15.73 per day (ratio of 1.66 compared with low-dose dabigatran at its base-case cost of $9.50 per day), it no longer achieved extended dominance over low-dose dabigatran (Figure 1).

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Figure 1.
Cost-effectiveness of fixed-dose dabigatran, 110 mg (low dose) and 150 mg (high dose) twice daily, compared with adjusted-dose warfarin anticoagulation at varying daily costs of dabigatran.

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.

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The model was also moderately sensitive to the monthly costs of medical care for patients after ICH (Appendix Figure 2). However, the ICER for high-dose dabigatran compared with warfarin for the full range of these costs evaluated was less than $53 880 per QALY.

Ischemic Stroke

The cost-effectiveness of high-dose dabigatran was moderately sensitive to changes in ischemic stroke rates. In a 1-way sensitivity analysis of the relative risk for stroke for high-dose dabigatran compared with warfarin, the ICER was less than $64 455 per QALY over the full range of values tested (Appendix Figure 3).

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Appendix Figure 3.
ICERs for high-dose dabigatran compared with warfarin with varying relative risk for ischemic stroke and ICH.

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.

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In a secondary analysis, we performed sensitivity analyses varying the stroke rates for the 3 therapies to simulate patients with AF at low risk (CHADS2 score, 1) or high risk (CHADS2 score, 4) for ischemic stroke (0.72% to 2.35% per year with warfarin) (Table 2). We adjusted untreated baseline stroke rates for all interventions by the same factors and held ICH rates constant at the base-case rate (0.74% per year with warfarin). For the patients at low risk for stroke (0.72% per year with warfarin), low-dose dabigatran was more cost-effective than high-dose dabigatran and cost $40 355 per QALY compared with warfarin. For patients at high risk for stroke (2.35% per year with warfarin), high-dose dabigatran was more cost-effective and cost $39 680 per QALY compared with warfarin.

Intracranial Hemorrhage

The ICER for high-dose dabigatran was moderately sensitive to changes in ICH rates in our analysis. High-dose dabigatran was more cost-effective than low-dose dabigatran over the range of ICH rates tested. In a 1-way sensitivity analysis for the relative risk for ICH for high-dose dabigatran compared with warfarin, the ICER was less than $60 120 per QALY over the full range tested (Appendix Figure 3).

We also varied the ICH rates for the 3 therapies to simulate patients with AF at low risk to high risk for ICH (0.44% to 1.48% per year with warfarin) (Table 2). We adjusted the ICH rates for all interventions by the same factors and held stroke rates constant at the base-case rate (1.2% per year with warfarin). For patients at low risk for ICH (0.44% per year with warfarin), high-dose dabigatran was more cost-effective than low-dose dabigatran and cost $69 574 per QALY compared with warfarin. For patients at high risk for ICH (1.48% per year with warfarin), low-dose dabigatran was more cost-effective than high-dose dabigatran and cost $16 147 per QALY compared with warfarin.

Myocardial Infarction

In 1-way sensitivity analysis over the plausible range of myocardial infarction risk, the ICER for high-dose dabigatran versus warfarin varied by less than $11 000 per QALY and remained less than $51 000 per QALY over the entire range evaluated.

Utility

We evaluated the sensitivity of our model to changes in the utility weights of included health states. The model was most sensitive to the utility for patients receiving warfarin and the utility for patients receiving dabigatran. The ICER for dabigatran compared with warfarin remained less than $55 730 per QALY over the full range of utilities evaluated for warfarin and less than $63 360 per QALY over the full range of utilities evaluated for dabigatran (0.975 to 1.0).

Age

Using an 80-year-old patient for the base case, the quality-adjusted survival was 5.87 QALYs with warfarin, 6.24 QALYs with low-dose dabigatran, and 6.31 QALYs with high-dose dabigatran. The ICER was $27 308 per QALY for low-dose dabigatran versus warfarin, $31 168 per QALY for high-dose dabigatran versus warfarin, and $52 613 per QALY for high-dose dabigatran versus low-dose dabigatran. The ICER decreased with age because older patients had higher rates of ischemic stroke and ICH and had a larger absolute risk reduction when dabigatran was used rather than warfarin.

Two-Way Sensitivity Analyses

We performed 2-way sensitivity analyses of key variables, including one demonstrating which therapy would be preferred for varying risks for ischemic stroke and ICH. We first performed this analysis without consideration of cost and demonstrated that purely on the basis of effectiveness, high-dose dabigatran was the preferred therapy for all combinations of risk except when a patient had a very low risk for stroke and a very high risk for ICH. Using a willingness-to-pay threshold of $50 000 per QALY (Figure 2), high-dose dabigatran was favored for the base case and for patients with a higher risk for both ischemic stroke and ICH. For patients with a low absolute risk for ischemic stroke (for example, CHADS2 score of 0 or 1), 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.

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Figure 2.
Two-way sensitivity analysis demonstrating which therapy would be preferred for varying risks for ischemic stroke and ICH, using a willingness-to-pay threshold of $50 000 per 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.

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Probabilistic Sensitivity Analysis

In the Monte Carlo simulation varying all variables simultaneously, high-dose dabigatran was cost-effective in 53% of the simulations using a willingness-to-pay threshold of $50 000 per QALY and in 68% of the simulations using a willingness-to-pay threshold of $100 000 per QALY. Although low-dose dabigatran was cost-effective in fewer than 30% of the simulations at any willingness-to-pay threshold, it had more QALYs than high-dose dabigatran in 26% of simulations. 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 and in more than 95% of simulations using a willingness-to-pay threshold of $100 000 per QALY (Figure 3).

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Figure 3.
Cost-effectiveness acceptability curves representing the probability that each treatment strategy is cost-effective for a given maximum willingness-to-pay threshold per QALY gained.

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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We demonstrated that in patients aged 65 years or older with AF who are at increased risk for stroke (CHADS2 score ≥1 or equivalent), dabigatran could be a cost-effective alternative to warfarin. Our base-case analysis estimated a cost of $45 372 per QALY gained with high-dose dabigatran compared with warfarin, which was within a range generally considered to be cost-effective (73). High-dose dabigatran was also the most effective treatment option we evaluated, yielding an additional 0.56 QALY compared with warfarin. The cost-effectiveness of dabigatran was sensitive to drug costs and relative differences in cost between the high- and low-dose formulations, but it was relatively insensitive to other model inputs. In addition, for patients at higher risk for ischemic stroke or ICH, including those with CHADS2 scores of 2 or greater, the ICER for high-dose dabigatran compared with warfarin improved.

Our analysis suggests that at a willingness-to-pay threshold of $50 000 per QALY, low-dose dabigatran may be the preferred therapy for patients with a low absolute risk for ischemic stroke (for example, CHADS2 score of 0 or 1), especially if their concurrent risk for ICH is high. For patients with low absolute risk for ICH, warfarin may be the preferred therapy. However, for some low-risk patients, antiplatelet therapy rather than anticoagulation may be a reasonable alternative, but further clinical study is needed to determine optimal treatment for patients who are at low risk for stroke and ICH.

Dabigatran is the first direct thrombin inhibitor to show similar safety and efficacy to warfarin for stroke prevention in AF. Warfarin is a generic medication and prescription costs are low, but the costs of laboratory monitoring and complications due to over- and underanticoagulation are substantial. Multiple strategies to reduce costs and improve effectiveness in warfarin-treated patients, including genotype-guided warfarin dosing and patient self-testing of INR, have been evaluated. Results to date suggest that these strategies are not cost-effective for the typical patient with nonvalvular AF (7477). Therefore, cost-effective alternatives to current methods of delivering warfarin anticoagulation are needed.

Several caveats apply to our results. First, the therapeutic efficacies and adverse event rates used in our analysis were derived mostly from the open-label RE-LY randomized, controlled trial. Follow-up of this trial cohort is ongoing (ClinicalTrials.gov registration number: NCT00808067), and clinical event rates may change with longer term follow-up. Although additional phase 3 or 4 randomized trial results are desirable, we do not know that a replication trial to confirm safety and efficacy will be performed. However, a randomized trial comparing high-dose dabigatran with adjusted-dose warfarin for the treatment of acute venous thromboembolism in 2539 patients had hemorrhage rates that were very similar to those in the RE-LY trial, demonstrating a consistent risk for adverse events (78). The results of our analysis would change if future effectiveness studies provide alternative estimates for bleeding risk and stroke reduction. Second, a treatment administered in clinical practice may not be as effective as one administered in randomized trials, which generally enroll healthier patients, achieve high levels of adherence, and monitor patients more intensively (79). Finally, although dabigatran in a reduced dose of 75 mg twice daily was approved by the U.S. Food and Drug Administration for patients with creatinine clearance of 15 to 30 mL/min (19), the RE-LY trial excluded patients with creatinine clearance less than 30 mL/min (18), so our results do not apply to that patient population.

In conclusion, we found that treatment with dabigatran could be a cost-effective alternative to adjusted-dose warfarin for stroke prevention in patients older than 65 years with nonvalvular AF at increased risk for stroke (CHADS2 score ≥1 or equivalent). High-dose dabigatran was the most cost-effective and most effective therapy we evaluated, providing an additional 0.56 QALY over warfarin in our base-case analysis. For patients at higher risk for ischemic stroke and ICH, the ICER of dabigatran compared with warfarin improved. These results were robust over a wide range of model assumptions but were sensitive to dabigatran costs.

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Figures

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Appendix Figure 1.
Decision model.

“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.

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Appendix Figure 2.
One-way sensitivity analyses on variables that most influenced the incremental cost-effectiveness of high-dose dabigatran compared with warfarin.

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.

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Figure 1.
Cost-effectiveness of fixed-dose dabigatran, 110 mg (low dose) and 150 mg (high dose) twice daily, compared with adjusted-dose warfarin anticoagulation at varying daily costs of dabigatran.

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.

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Appendix Figure 3.
ICERs for high-dose dabigatran compared with warfarin with varying relative risk for ischemic stroke and ICH.

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.

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Figure 2.
Two-way sensitivity analysis demonstrating which therapy would be preferred for varying risks for ischemic stroke and ICH, using a willingness-to-pay threshold of $50 000 per 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.

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Figure 3.
Cost-effectiveness acceptability curves representing the probability that each treatment strategy is cost-effective for a given maximum willingness-to-pay threshold per QALY gained.

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.

Grahic Jump Location

Tables

Table Jump PlaceholderAppendix Table 1.  CHADS2 Score Components
Table Jump PlaceholderAppendix Table 2.  Definitions of Ischemic Stroke, Intracranial Hemorrhage, and Myocardial Infarction
Table Jump PlaceholderTable 1.  Base-Case Values and Ranges Used in Sensitivity Analyses
Table Jump PlaceholderTable 2.  Projected Costs and QALYs for Patients With Nonvalvular Atrial Fibrillation, by Varying Risk for Stroke and ICH

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