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W1987556610 abstract "This study aims to estimate the cost-effectiveness of dabigatran 150 mg twice daily versus warfarin for stroke and systemic embolism risk reduction in patients with nonvalvular atrial fibrillation initiating treatment before age 75 (<75), at or after age 75 (≥75), and the overall population (All) from a US Medicare payer perspective. Clinical event rates by age cohort with dabigatran or warfarin for safety-on-treatment and intent-to-treat populations were estimated from Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY). An economic model was adapted using these data to evaluate the impact of starting age on clinical and economic outcomes. Costs were obtained from Medicare payment schedules and utilities from publications. Model outputs included event rates, costs, quality-adjusted life-years, and incremental cost-effectiveness ratios. The RE-LY analysis shows that the <75 cohort has lower rates of all events than the ≥75 cohort; versus warfarin, dabigatran performed better in main efficacy and safety in all age cohorts with the exception of extracranial hemorrhage in the ≥75 cohort. The clinical event costs avoided per patient for dabigatran were $1,100, $135, and $713 for cohorts <75, ≥75, and All, respectively. Extrapolating over a lifetime horizon, the model found that dabigatran resulted in lower rates of stroke and intracranial hemorrhage and higher rates for extracranial hemorrhage versus warfarin for all age cohorts. Lifetime quality-adjusted life-years and costs were higher for dabigatran than warfarin, resulting in incremental cost-effectiveness ratios of $52,773, $65,946, and $56,131 for cohorts <75, ≥75, and All, respectively. In conclusion, dabigatran was cost-effective versus warfarin in US patients with atrial fibrillation regardless of age of treatment initiation. This study aims to estimate the cost-effectiveness of dabigatran 150 mg twice daily versus warfarin for stroke and systemic embolism risk reduction in patients with nonvalvular atrial fibrillation initiating treatment before age 75 (<75), at or after age 75 (≥75), and the overall population (All) from a US Medicare payer perspective. Clinical event rates by age cohort with dabigatran or warfarin for safety-on-treatment and intent-to-treat populations were estimated from Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY). An economic model was adapted using these data to evaluate the impact of starting age on clinical and economic outcomes. Costs were obtained from Medicare payment schedules and utilities from publications. Model outputs included event rates, costs, quality-adjusted life-years, and incremental cost-effectiveness ratios. The RE-LY analysis shows that the <75 cohort has lower rates of all events than the ≥75 cohort; versus warfarin, dabigatran performed better in main efficacy and safety in all age cohorts with the exception of extracranial hemorrhage in the ≥75 cohort. The clinical event costs avoided per patient for dabigatran were $1,100, $135, and $713 for cohorts <75, ≥75, and All, respectively. Extrapolating over a lifetime horizon, the model found that dabigatran resulted in lower rates of stroke and intracranial hemorrhage and higher rates for extracranial hemorrhage versus warfarin for all age cohorts. Lifetime quality-adjusted life-years and costs were higher for dabigatran than warfarin, resulting in incremental cost-effectiveness ratios of $52,773, $65,946, and $56,131 for cohorts <75, ≥75, and All, respectively. In conclusion, dabigatran was cost-effective versus warfarin in US patients with atrial fibrillation regardless of age of treatment initiation. Atrial fibrillation (AF) is a common arrhythmia and the leading cause of stroke, which is associated with a high humanistic and economic burden.1Roger V.L. Go A.S. Lloyd-Jones D.M. Benjamin E.J. Berry J.D. Borden W.B. Bravata D.M. Dai S. Ford E.S. Fox C.S. Fullerton H.J. Gillespie C. Hailpern S.M. Heit J.A. Howard V.J. Kissela B.M. Kittner S.J. Lackland D.T. Lichtman J.H. Lisabeth L.D. Makuc D.M. Marcus G.M. Marelli A. Matchar D.B. Moy C.S. Mozaffarian D. Mussolino M.E. Nichol G. Paynter N.P. Soliman E.Z. Sorlie P.D. Sotoodehnia N. Turan T.N. Virani S.S. Wong N.D. Woo D. Turner M.B. American Heart Association Statistics CommitteeStroke Statistics SubcommitteeHeart disease and stroke statistics—2012 update: a report from the American Heart Association.Circulation. 2012; 125: e2-e220Crossref PubMed Scopus (0) Google Scholar The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial demonstrated the safety and efficacy of dabigatran versus warfarin for the prevention of stroke and systemic embolism, and in additional analyses, the efficacy and safety by age cohorts in patients with AF at moderate to high risk of stroke.2Connolly S.J. Ezekowitz M.D. Yusuf S. Eikelboom J. Oldgren J. Parekh A. Pogue J. Reilly P.A. Themeles E. Varrone J. Wang S. Alings M. Xavier D. Zhu J. Diaz R. Lewis B.S. Darius H. Diener H.C. Joyner C.D. Wallentin L. Re-LY Steering Committee InvestigatorsDabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (8994) Google Scholar, 3Eikelboom J.W. Wallentin L. Connolly S.J. Ezekowitz M. Healey J.S. Oldgren J. Yang S. Alings M. Kaatz S. Hohnloser S.H. Diener H.C. Franzosi M.G. Huber K. Reilly P. Varrone J. Yusuf S. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial.Circulation. 2011; 123: 2363-2372Crossref PubMed Scopus (995) Google Scholar The effects of dabigatran compared with warfarin on stroke or systemic embolism were consistent across age cohorts, but a significant treatment-by-age interaction was seen in major bleeding outcomes. In the dabigatran 150 mg twice daily dose arm, the dose approved by the FDA, patients <75 years had lower rates of intracranial hemorrhage (ICH) and extracranial hemorrhage (ECH) than those treated with warfarin, whereas patients ≥75 years had a lower risk of ICH but higher rates of ECH than warfarin-treated patients.3Eikelboom J.W. Wallentin L. Connolly S.J. Ezekowitz M. Healey J.S. Oldgren J. Yang S. Alings M. Kaatz S. Hohnloser S.H. Diener H.C. Franzosi M.G. Huber K. Reilly P. Varrone J. Yusuf S. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial.Circulation. 2011; 123: 2363-2372Crossref PubMed Scopus (995) Google Scholar, 4Hart R.G. Diener H.C. Yang S. Connolly S.J. Wallentin L. Reilly P.A. Ezekowitz M.D. Yusuf S. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial.Stroke. 2012; 43: 1511-1517Crossref PubMed Scopus (361) Google Scholar In addition, the overall risk of stroke increases with age, as indicated by the CHADS2 scoring increasing by a point at age 75. Given the different safety results by age group and the increasing risk of stroke with age, there is a need to understand the cost-effectiveness for each age group. The objective of this study is to investigate the cost-effectiveness of dabigatran etexilate 150 mg twice daily versus warfarin in patients with AF in whom anticoagulation is appropriate, in cohorts initiating treatment before age 75 (<75), those initiating at or after age 75 (≥75), and all RE-LY trial patients (All) from a US payer perspective. The analysis uses efficacy and safety data of the RE-LY trial by age cohorts specifically generated from individual patient data for this analysis. A previously published Markov model was adapted to simulate anticoagulation treatment in individual age cohorts and the resulting clinical events in the United States.5Kansal A.R. Sharma M. Bradley-Kennedy C. Clemens A. Monz B.U. Peng S. Roskell N. Sorensen S.V. Dabigatran versus rivaroxaban for the prevention of stroke and systemic embolism in atrial fibrillation in Canada. Comparative efficacy and cost-effectiveness.Thromb Haemost. 2012; 108: 672-682Crossref PubMed Scopus (53) Google Scholar, 6Kansal A.R. Sorensen S.V. Gani R. Robinson P. Pan F. Plumb J.M. Cowie M.R. Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in UK patients with atrial fibrillation.Heart. 2012; 98: 573-578Crossref PubMed Scopus (99) Google Scholar, 7Sorensen S.V. Kansal A.R. Connolly S. Peng S. Linnehan J. Bradley-Kennedy C. Plumb J.M. Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation: a Canadian payer perspective.Thromb Haemost. 2011; 105: 908-919Crossref PubMed Scopus (177) Google Scholar The model followed patients with nonvalvular AF at risk of relevant clinical events through the natural course of the disease until the end of their lives. Using a US Medicare payer perspective, a lifetime horizon was considered in the base case. The clinical events included were primary and recurrent ischemic stroke, transient ischemic attack, systemic embolism, acute myocardial infarction, ICH (including hemorrhagic stroke), ECH, and death. Patients could experience no clinical event, 1 of the events, and/or death during any 3-month model cycle. The key consequences of the clinical events were a change in treatment status (switching treatment to aspirin or permanent discontinuation of treatment), a change in functional disability after a stroke or ICH (defined by modified Rankin Score [strokes] or Glasgow Outcomes Scale [ICH]), and/or a reduction in quality of life and death. Patients could also switch treatment for reasons not related to a clinical event. Patients were also subject to mortality from other causes at every cycle using age-, gender-, and event-adjusted all-cause mortality data. Three patient cohorts were defined: those initiating anticoagulation treatment <75 years, ≥75 years, and all patients (All). Gender distribution and acute myocardial infarction history were assigned at baseline. Each cohort included subcohorts for each year of age at baseline with specific CHADS2 and previous stroke distribution for that baseline age obtained from a RE-LY analysis by starting age. Also obtained from the age analysis were the baseline risks of each event while on warfarin and the relative risks of dabigatran versus warfarin. In addition to the bleeding events in the intent-to-treat population reported by Eikelboom et al,3Eikelboom J.W. Wallentin L. Connolly S.J. Ezekowitz M. Healey J.S. Oldgren J. Yang S. Alings M. Kaatz S. Hohnloser S.H. Diener H.C. Franzosi M.G. Huber K. Reilly P. Varrone J. Yusuf S. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial.Circulation. 2011; 123: 2363-2372Crossref PubMed Scopus (995) Google Scholar the new analysis reported all clinical events for patients in each cohort for both the safety-on-treatment and the intent-to-treat populations. The safety-on-treatment population data (based only on patients who received at least 1 dose of a study drug and were followed for events from first to last dose plus 6 days, regardless of adherence to the protocol or temporary discontinuations2Connolly S.J. Ezekowitz M.D. Yusuf S. Eikelboom J. Oldgren J. Parekh A. Pogue J. Reilly P.A. Themeles E. Varrone J. Wang S. Alings M. Xavier D. Zhu J. Diaz R. Lewis B.S. Darius H. Diener H.C. Joyner C.D. Wallentin L. Re-LY Steering Committee InvestigatorsDabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (8994) Google Scholar) were used for the “on-treatment” health states in the model, whereas the treatment efficacy of aspirin and no treatment were applied for patients who switched or discontinued treatment. The use of the safety-on-treatment population for the clinical outcomes avoided double counting of the effects of treatment discontinuation. The baseline risks of clinical events were based on rates in the warfarin arm for patients aged <75. Relative risks of the age (≥75 vs <75) and treatment (dabigatran vs warfarin) were calculated using age-stratified data from RE-LY. Relative risks of aspirin and no treatment versus warfarin were obtained from a network meta-analysis.8Roskell N.S. Lip G.Y. Noack H. Clemens A. Plumb J.M. Treatments for stroke prevention in atrial fibrillation: a network meta-analysis and indirect comparisons versus dabigatran etexilate.Thromb Haemost. 2010; 104: 1106-1115Crossref PubMed Scopus (101) Google Scholar Postevent disability was based on analysis of the RE-LY trial.9Sorensen S.V. Peng S. Walker D. Sander S. Kansal A.R. Cost-Effectiveness of dabigatran etexilate versus rivaroxaban for stroke and systemic embolism risk reduction in atrial fibrillation: a US third party payer perspective.Circulation. 2012; 126 (Abstract A14964)Google Scholar For patients receiving warfarin, 22.1% of ischemic stroke events were fatal; and 4.3%, 19.7%, and 53.9% were completely dependent, moderately dependent, and independent functioning after ischemic stroke events, respectively. This distribution was 25.1%, 1.6%, 15.6%, and 57.7%, respectively, in the dabigatran arm. After ICH events, 51.6% of the events were fatal, 31.8% of the patients were completely dependent, 8.8% were moderately dependent, and 7.8% were independent functioning regardless of current anticoagulation treatment. The proportions of ECH that are gastrointestinal bleeding were obtained from RE-LY and estimated to be 48.7% and 35.7% in the dabigatran and warfarin arms, respectively. Event and disability costs were calculated using Medicare reimbursement data (Table 1). The acute event costs and long-term follow-up costs were obtained from a database analysis on the long-term costs of stroke and major bleeding events in patients with nonvalvular AF.10Mercaldi C.J. Ciarametaro M. Hahn B. Chalissery G. Reynolds M.W. Sander S.D. Samsa G.P. Matchar D.B. Cost efficiency of anticoagulation with warfarin to prevent stroke in Medicare beneficiaries with nonvalvular atrial fibrillation.Stroke. 2011; 42: 112-118Crossref PubMed Scopus (71) Google Scholar, 11Mercaldi C.J. Siu K. Sander S.D. Walker D.R. Wu Y. Li Q. Wu N. Long-Term Costs of Ischemic Stroke and Major Bleeding Events among Medicare Patients with Nonvalvular Atrial Fibrillation. Cardiol Res Pract 2012, 2012Google Scholar The study analyzed cost data of nondisabled Medicare patients. In contrast to commercial claims data sources, Medicare has a large number of patients older than 65 years, which fits the model population well. The cost components included in the analysis are inpatient hospital, outpatient hospital, skilled nursing facility, hospice, home health agency, and durable medical equipment. The study captured costs up to 3 years after stroke or bleeding events. Acute event costs were based on costs of the first 3 months postevent. Long-term follow-up costs were based on average costs from the fourth month through 3 years postevent, prorated to fit the model cycles. Stratification of the long-term follow-up costs by disability level was not available from the study by Mercaldi et al.11Mercaldi C.J. Siu K. Sander S.D. Walker D.R. Wu Y. Li Q. Wu N. Long-Term Costs of Ischemic Stroke and Major Bleeding Events among Medicare Patients with Nonvalvular Atrial Fibrillation. Cardiol Res Pract 2012, 2012Google Scholar To differentiate the cost consequences of stroke and bleeding events resulting in different disability levels, the unstratified follow-up costs were adjusted to reflect the dependence of costs on disability level according to a population-based study on long-term care cost of patients with AF in the United Kingdom.12Luengo-Fernandez R. Yiin G.S. Gray A.M. Rothwell P.M. Population-based study of acute- and long-term care costs after stroke in patients with AF.Int J Stroke. 2013; 8: 308-314Crossref PubMed Scopus (48) Google Scholar All costs were adjusted to 2013 values using the medical component of the consumer price index.8Roskell N.S. Lip G.Y. Noack H. Clemens A. Plumb J.M. Treatments for stroke prevention in atrial fibrillation: a network meta-analysis and indirect comparisons versus dabigatran etexilate.Thromb Haemost. 2010; 104: 1106-1115Crossref PubMed Scopus (101) Google Scholar Acute event costs not available from the study by Mercaldi et al10Mercaldi C.J. Ciarametaro M. Hahn B. Chalissery G. Reynolds M.W. Sander S.D. Samsa G.P. Matchar D.B. Cost efficiency of anticoagulation with warfarin to prevent stroke in Medicare beneficiaries with nonvalvular atrial fibrillation.Stroke. 2011; 42: 112-118Crossref PubMed Scopus (71) Google Scholar, 11Mercaldi C.J. Siu K. Sander S.D. Walker D.R. Wu Y. Li Q. Wu N. Long-Term Costs of Ischemic Stroke and Major Bleeding Events among Medicare Patients with Nonvalvular Atrial Fibrillation. Cardiol Res Pract 2012, 2012Google Scholar were based on the US diagnosis-related group data.13Holden K. DRG Expert 2012, a Comprehensive Guidebook to the DRG Classification System. OptumInsight™ (INGENIX), 2011: 74-75Google Scholar Health-related quality of life was calculated for each health state using published utility data.7Sorensen S.V. Kansal A.R. Connolly S. Peng S. Linnehan J. Bradley-Kennedy C. Plumb J.M. Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation: a Canadian payer perspective.Thromb Haemost. 2011; 105: 908-919Crossref PubMed Scopus (177) Google Scholar, 14Sullivan P.W. Arant T.W. Ellis S.L. Ulrich H. The cost effectiveness of anticoagulation management services for patients with atrial fibrillation and at high risk of stroke in the US.Pharmacoeconomics. 2006; 24: 1021-1033Crossref PubMed Scopus (120) Google Scholar, 15Tengs T.O. Lin T.H. A meta-analysis of quality-of-life estimates for stroke.Pharmacoeconomics. 2003; 21: 191-200Crossref PubMed Scopus (169) Google ScholarTable 1Model costsDrug CostsPer DaySource∗Drug costs were obtained January 2014. All the other costs were inflated to 2013 value.Dabigatran 150 mg twice daily$8.84Red Book™20Thomson Reuters. RED BOOK Online® via MicroMedex Gateway. New York, NY: Thomson Reuters/Truven Health Analytics, 2013. Available at: http://www.micromedexsolutions.com/micromedex2/librarian/ND_T/evidencexpert/ND_PR/evidencexpert/CS/D1626C/ND_AppProduct/evidencexpert/DUPLICATIONSHIELDSYNC/86DBB2/ND_PG/evidencexpert/ND_B/evidencexpert/ND_P/evidencexpert/PFActionId/pf.Logout.Google ScholarWarfarin$0.16Red Book™20Thomson Reuters. RED BOOK Online® via MicroMedex Gateway. New York, NY: Thomson Reuters/Truven Health Analytics, 2013. Available at: http://www.micromedexsolutions.com/micromedex2/librarian/ND_T/evidencexpert/ND_PR/evidencexpert/CS/D1626C/ND_AppProduct/evidencexpert/DUPLICATIONSHIELDSYNC/86DBB2/ND_PG/evidencexpert/ND_B/evidencexpert/ND_P/evidencexpert/PFActionId/pf.Logout.Google ScholarAspirin$0.01Red Book™20Thomson Reuters. RED BOOK Online® via MicroMedex Gateway. New York, NY: Thomson Reuters/Truven Health Analytics, 2013. Available at: http://www.micromedexsolutions.com/micromedex2/librarian/ND_T/evidencexpert/ND_PR/evidencexpert/CS/D1626C/ND_AppProduct/evidencexpert/DUPLICATIONSHIELDSYNC/86DBB2/ND_PG/evidencexpert/ND_B/evidencexpert/ND_P/evidencexpert/PFActionId/pf.Logout.Google ScholarTreatment Monitoring CostAnnualSourceWarfarin$285.10Assume 14 international normalized ratio tests Shah et al19Shah S.V. Gage B.F. Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillation.Circulation. 2011; 123: 2562-2570Crossref PubMed Scopus (287) Google Scholar Physicians fee and Coding Guide 2012 (CPT 99211)21Physicians Fee & Coding Guide 2012. Chicago, IL: MAG Mutual HealthCare Solutions Inc., 2011:58.Google ScholarEvent CostsPer Acute EventSourceIschemic stroke, fatal and non-fatal$22,653.16Mercaldi et al 201211Mercaldi C.J. Siu K. Sander S.D. Walker D.R. Wu Y. Li Q. Wu N. Long-Term Costs of Ischemic Stroke and Major Bleeding Events among Medicare Patients with Nonvalvular Atrial Fibrillation. Cardiol Res Pract 2012, 2012Google ScholarSystemic embolism, fatal and non-fatal$7,291.83Mercaldi et al 201110Mercaldi C.J. Ciarametaro M. Hahn B. Chalissery G. Reynolds M.W. Sander S.D. Samsa G.P. Matchar D.B. Cost efficiency of anticoagulation with warfarin to prevent stroke in Medicare beneficiaries with nonvalvular atrial fibrillation.Stroke. 2011; 42: 112-118Crossref PubMed Scopus (71) Google ScholarTransient ischemic attack$3,905.03Mercaldi et al 201110Mercaldi C.J. Ciarametaro M. Hahn B. Chalissery G. Reynolds M.W. Sander S.D. Samsa G.P. Matchar D.B. Cost efficiency of anticoagulation with warfarin to prevent stroke in Medicare beneficiaries with nonvalvular atrial fibrillation.Stroke. 2011; 42: 112-118Crossref PubMed Scopus (71) Google ScholarIntracranial hemorrhage and hemorrhagic stroke$34,572.50Mercaldi et al 201211Mercaldi C.J. Siu K. Sander S.D. Walker D.R. Wu Y. Li Q. Wu N. Long-Term Costs of Ischemic Stroke and Major Bleeding Events among Medicare Patients with Nonvalvular Atrial Fibrillation. Cardiol Res Pract 2012, 2012Google ScholarExtracranial hemorrhage (non-brain), fatal and non-fatal$16,769.55Mercaldi et al 201211Mercaldi C.J. Siu K. Sander S.D. Walker D.R. Wu Y. Li Q. Wu N. Long-Term Costs of Ischemic Stroke and Major Bleeding Events among Medicare Patients with Nonvalvular Atrial Fibrillation. Cardiol Res Pract 2012, 2012Google ScholarMinor bleed$211.05Physicians fee and Coding Guide 2012 (CPT 99215)21Physicians Fee & Coding Guide 2012. Chicago, IL: MAG Mutual HealthCare Solutions Inc., 2011:58.Google ScholarAcute myocardial infarction, fatal$5,447.99DRG 283, 284, 285Acute myocardial infarction, non-fatal$6,560.89DRG 280, 281, 282Follow-up CostsPer QuarterSourceIndependent with stroke history$203.67Mercaldi et al 2012; Luengo-Fernandez et al 201211Mercaldi C.J. Siu K. Sander S.D. Walker D.R. Wu Y. Li Q. Wu N. Long-Term Costs of Ischemic Stroke and Major Bleeding Events among Medicare Patients with Nonvalvular Atrial Fibrillation. Cardiol Res Pract 2012, 2012Google Scholar, 12Luengo-Fernandez R. Yiin G.S. Gray A.M. Rothwell P.M. Population-based study of acute- and long-term care costs after stroke in patients with AF.Int J Stroke. 2013; 8: 308-314Crossref PubMed Scopus (48) Google ScholarModerate disability$1,764.56Dependent disability$3,746.33∗ Drug costs were obtained January 2014. All the other costs were inflated to 2013 value. Open table in a new tab Model outcomes presented in this analysis include the number of clinical events per 100 patient-years, total costs, breakdown by cost type, and quality-adjusted life-years (QALYs). Incremental cost-effectiveness ratios (ICERs) were also computed as incremental cost in the dabigatran arm versus the warfarin arm divided by incremental QALYs. These analyses were conducted for each of the 3 age cohorts. All costs and outcomes were discounted by 3% annually.16Gold M.R. Siegel J.E. Russell L.B. Weinstein M.C. Cost-effectiveness in Health and Medicine. Oxford University Press, New York, NY1996: 232Google Scholar The model was validated by comparing the results of the model output over a 2-year time horizon for dabigatran and warfarin with the intent-to-treat results of the RE-LY trial. One-way sensitivity analyses were performed by varying time horizon and discount rates, and clinical inputs such as relative risks (upper and lower 95% confidence interval [CI]), event rates, treatment discontinuation, and event and long-term follow-up costs. Because starting age determines the length of a lifetime analysis, a limited time horizon of 10 years was examined to create a similar follow-up time for the 3 cohorts. Relative risks were varied based on the 95% CI. A scenario with event rates based on the intent-to-treat population and excluding treatment discontinuation was also explored. Scenario analyses were also conducted to investigate the impact of aging and stroke events on ischemic stroke risk. A probabilistic sensitivity analysis characterized the uncertainty surrounding the cost-effectiveness results. All model parameters were simultaneously varied based on statistical distribution and their 95% CI. Beta distributions were assumed for baseline event probabilities and utility estimates, log-normal distributions for relative risks, and gamma distributions for event and health state costs. The results of the RE-LY analysis by initiating age cohort for the safety-on-treatment and intent-to-treat populations are presented in Table 2. Rates of all events were higher in the older cohort at treatment initiation versus the younger cohort. In the intent-to-treat population, the annual risks of ischemic stroke in the warfarin arm increased steadily with the baseline CHADS2 score in both age cohorts. Dabigatran treatment was associated with a lower risk of stroke across all CHADS2 scores for both age cohorts. However, because of small sample sizes, no trends in the relative risks of dabigatran versus warfarin were seen in terms of increasing CHADS2 risk. In the <75 age cohort, the risks of all other events were also lower for dabigatran-treated patients, except a numerical increase in acute myocardial infarction. In the older cohort, dabigatran had lower risk of all events except acute myocardial infarction, minor bleeds, and ECH. The distributions of baseline CHADS2 scores by age are presented in Figure 1. In the group of patients between 65 and 75 years, there was a greater proportion of patients in lower CHADS2 categories than in older patients.Table 2Annual probability and relative risk of clinical events, safety-on-treatment, and intent-to-treat populationsSource: RE-LY age cohort analysis.VariableWarfarinDabigatran 150 mg Twice DailyAnnual Rate Per 100 Patient-years, Age <75Annual Rate Per 100 Patient-years, Age ≥75Relative Risk, Age <75 vs. WarfarinRelative Risk, Age 75≥ vs. WarfarinSafety-on-treatment Ischemic stroke, CHADS2 = 0–1∗Used in model.0.610.820.75 (0.37, 1.55)0.95 (0.27, 3.28) Ischemic stroke, CHADS2 = 2∗Used in model.0.791.060.64 (0.29, 1.40)0.58 (0.27, 1.24) Ischemic stroke, CHADS2 = 3–4∗Used in model.1.511.360.64 (0.33, 1.24)0.80 (0.41, 1.55) Ischemic stroke, CHADS2 = 5–6∗Used in model.2.283.470.93 (0.13, 6.63)0.43 (0.13, 1.43) Systemic embolism∗Used in model.0.140.190.57 (0.19, 1.69)0.40 (0.11, 1.51) Stroke/systemic embolism1.311.870.56 (0.39, 0.80)0.56 (0.38, 0.82) Transient ischemic attack∗Used in model.0.711.100.80 (0.52, 1.23)0.78 (0.50, 1.22) Intracranial hemorrhage (including hemorrhagic stroke)∗Used in model.0.601.030.34 (0.18, 0.63)0.30 (0.16, 0.56) Extracranial hemorrhage∗Used in model.2.363.470.80 (0.63, 1.02)1.50 (1.21, 1.86) Acute myocardial infarction∗Used in model.0.490.741.40 (0.89, 2.21)1.20 (0.74, 1.95) Minor bleeds∗Used in model.16.7619.150.80 (0.74, 0.88)1.09 (0.99, 1.20) Disabling or fatal stroke0.761.030.48 (0.29, 0.78)0.54 (0.33, 0.91) Death from any cause2.472.920.69 (0.54, 0.89)1.01 (0.79, 1.31)Intent-to-treat Ischemic stroke, CHADS2 0–10.720.910.65 (0.34, 1.25)0.74 (0.23, 2.43) Ischemic stroke, CHADS2 20.771.290.77 (0.38, 1.57)0.59 (0.31, 1.11) Ischemic stroke, CHADS2 3–41.741.760.79 (0.45, 1.37)0.87 (0.52, 1.46) Ischemic stroke, CHADS2 5–62.053.820.98 (0.14, 6.96)0.90 (0.38, 2.12) Systemic embolism0.160.210.72 (0.29, 1.78)0.49 (0.17, 1.43) Stroke/systemic embolism1.422.150.63 (0.46, 0.86)0.67 (0.49, 0.90) Transient ischemic attack0.701.040.83 (0.55, 1.25)0.90 (0.60, 1.35) Intracranial hemorrhage (including hemorrhagic stroke)0.611.000.43 (0.25, 0.74)0.39 (0.23, 0.67) Extracranial hemorrhage2.443.450.78 (0.62, 0.97)1.39 (1.14, 1.71) Acute myocardial infarction0.540.791.34 (0.88, 2.03)1.20 (0.77, 1.85) Minor bleeds15.7017.390.81 (0.74, 0.88)1.06 (0.97, 1.17) Disabling or fatal stroke0.801.320.59 (0.38, 0.90)0.73 (0.50, 1.06) Death from any cause3.475.130.77 (0.63, 0.92)0.99 (0.83, 1.19)∗ Used in model. Open table in a new tab The validation analysis showed that the event rates predicted in the model largely matched the event rates in the intent-to-treat population from the RE-LY trial, with all model outcomes within 5% of the trial intent-to-treat population except ECH (overestimated for dabigatran by 9%) and transient ischemic attack (overestimated in both arms by 10%). This validation demonstrates that the model replicated the clinical trial with on-treatment clinical inputs based on safety-on-treatment data and simulated effects of treatment switching and discontinuation. The model calculated overall and specific clinical events per 100 patient-years (Table 3). In all age subgroups, the model found that in comparison with warfarin-treated patients, dabigatran-treated patients experienced fewer instances of ischemic stroke and ICH and more instances of ECH and acute myocardial infarction over the lifetime horizons. The differences in the number of events experienced per 100 patient-years by dabigatran versus warfarin-treated patients were the greatest in the age ≥75 cohort, with the exception of acute myocardial infarction for which the age <75 cohort showed the greatest difference.Table 3Model results: events per 100 patient-years by age, lifetime analysisDabigatranAge <75Age ≥75All PatientsAll events (excluding minor bleed)∗All events (excluding minor bleed) include ischemic stroke, systemic embolism, transient ischemic attack, intracranial hemorrhage & hemorrhagic stroke, extracranial hemorrhage and acute myocardial infarction.9.319.869.47 Ischemic stroke (overall)1.841.601.77 Ischemic stroke (disabling and fatal)0.880.740.84 Intracranial hemorrhage and hemorrhagic stroke0.410.410.41 Extracranial hemorrhage4.555.454.80 Acute myocardial infarction1.161.101.14 Systemic embolism and transient ischemic attack1.351.301.34 Minor bleed20.3121.0420.51WarfarinAge <75Age ≥75All PatientsAll events (excluding minor bleed)∗All events (excluding minor bleed) include ischemic stroke, systemic embolism, transient ischemic attack, intracranial hemorrhage & hemorrhagic stroke, extracranial hemorrhage and acute myocardial infarction.9.459.509.47 Ischemic stroke (overall)2.131.962.09 Ischemic stroke (disabling and fatal)1.171.051.14 Intracranial hemorrhage and hemorrhagic stroke0.961.070.99 Extracranial hemorrhage3.863.963.88 Acute myocardial infarction0.930.930.93 Systemic embolism and transient ischemic attack1.571.591.57 Minor bleed21.1220.0320.81∗ All events (excluding minor bleed) include ischemic stroke, systemic embolism, transient ischemic attack, intracranial hemorrhage & hemorrhagic stroke, extracranial hemorrhage and acute myocardial infarction. Open table in a new tab The use of dabigatran resulted in lower total event costs and lower long-term follow-up costs per patient than warfarin in all age subgroups (Table 4). Compared with warfarin, dabigatran reduced the per-patient costs of ischemic stroke and ICH and the follow-up costs of the resulting long-term disability and increased the per-patient costs of ECH and acute myocardial infarction over the lifetime horizon, consistent with the clinical efficacy for each event. The total costs avoided per patient because of event for dabigatran were $1,100, $135, and $713, and the total costs avoided per patient in the long-term follow-up to disability outcomes resulting from clinical events were $3,450, $1,297, and $2,589 for patient cohorts <75, ≥75, and All, respectively. The differences in total medical costs were the greatest in the age <75 cohort.Table 4Model results: event and long-term follow-up costs per patient by age, lifetime analysisDabigatranAge <75Age ≥75All PatientsAll Events∗All events include IS, SE, TIA, ICH & HS, ECH, minor bleed and AMI.13,2429,56011,771 Ischemic stroke (overall)3,6272,1463,035 Ischemic stroke (disabling and fatal)3,2571,9482,813 Intracranial hemorrhage and hemorrhagic stroke1,2898461,112 Extracranial hemorrhage6,7235,5326,247 Acute myocardial infarction678431579 Systemic embolism and transient ischemic attack849558752 Minor bleed764746Long-term follow-up5,6792,4574,391WarfarinAge <75Age ≥75All PatientsAll Events∗All events include IS, SE, TIA, ICH & HS, ECH, minor bleed and AMI.14,3429,69312,484 Ischemic stroke (overall)4,1292,5813,510 Ischemic stroke (disabling and fatal)3,7582,3773,288 Intracranial hemorrhage and hemorrhagic stroke2,9282,1822,630 Extracranial hemorrhage5,7323,9095,004 Acute myocardial infarction532357462 Systemic embolism and transient ischemic attack938620828 Minor bleed834450Long-term follow-up8,0293,6216,267∗ All events include IS, SE, TIA, ICH & HS, ECH, minor bleed and AMI. Open table in a new tab Table 5 presents mean total costs, total QALYs, and incremental cost per QALY gained (i.e., ICER) per patient comparing dabigatran with warfarin. Dabigatran-treated patients accrued more QALYs than warfarin-treated patients in all the cohorts. Dabigatran-treated patients also had a higher cost versus warfarin-treated patients in all the cohorts. The lowest (most favorable to dabigatran) ICER was seen in the cohort initiating anticoagulation treatment before age 75.Table 5Model results: total and incremental costs and quality-adjusted life-years over a lifetime analysisAge <75Age ≥75All PatientsTotal costs ($) Dabigatran46,44428,64539,331 Warfarin25,48515,17821,366Total QALYs Dabigatran9.695.628.07 Warfarin9.305.427.75Incremental results—dabigatran vs. warfarin Costs ($)20,96013,46717.965 QALYs0.400.200.32 ICER ($/QALY)52,77365,94656,131 Open table in a new tab Sensitivity analyses showed that dabigatran remained a <$100,000/QALY willingness-to-pay threshold for all variations in model input parameters, except for relative risk of ischemic stroke and time horizon. The most significant driver of cost-effectiveness was the relative risk of ischemic stroke (ICER range $42,062 to $213,652 for all patients cohort). Other important drivers were the relative risks of ICH, ECH, and acute myocardial infarction in all age cohorts (ICER range $48,175 to $83,582). An analysis time horizon shorter than lifetime also affected results, especially for the age <75 cohort (time horizon of 10 years ICER of $115,256). Similarly, the variations of both health and cost discount rates showed greater impact in the age <75 cohort than in the age ≥75 cohort, as this younger cohort remained in the model gaining QALYs and costs over a longer time. Varying the cost of event and long-term follow-up by ±20% results in <5% change in the ICER. The probabilistic sensitivity analysis also found relatively stable predicted ICERs of dabigatran. In the probabilistic sensitivity analysis, dabigatran was cost effective relative to warfarin in 95%, 79%, and 95% of simulations at a willingness-to-pay threshold of $100,000, for age <75, ≥75, and overall cohorts, respectively. The base-case and sensitivity analyses used safety-on-treatment data from the RE-LY trial to inform the clinical inputs with treatment discontinuation because of nonclinical reason incorporated explicitly to reproduce the intent-to-treat results. A scenario analysis was conducted using intent-to-treat estimates to inform the clinical inputs and assuming the treatment benefit continued until treatment switch because of clinical reason. This analysis yielded ICER estimates approximately 14% greater than the base-case estimates in all age cohorts. This greater ICER reflects that in this scenario, clinical efficacy is estimated based on the average of those that remain on treatment and those that have discontinued, but all patients, except those discontinuing for clinical reasons, accrue the full drug costs. This study used age-adjusted estimates of clinical event risks to evaluate the cost-effectiveness of 150 mg twice daily dabigatran versus warfarin in different age cohorts in the US Medicare payer setting. The base-case lifetime analysis showed that the <75 cohort, on average, experienced more ischemic strokes per 100 patient-years than the ≥75 cohort. As expected, the weighted average ischemic stroke risk for warfarin was initially lower in the <75 cohort (0.897 and 1.292 for the age <75 and age ≥75 cohorts, respectively). As the entire younger cohort aged beyond 75 years, however, their CHADS2 scores increased by 1 point for all patients, raising the weighted average ischemic stroke risk to 1.361. Thus, the <75 cohort spends a significant fraction of time at a higher risk than the baseline risk of the older cohort. Additionally, the <75 cohort has more time to experience a stroke (which raises CHADS2 score by 2 points in the cohort resulting in a weighted average ischemic stroke risk of 2.253 for the <75 cohort). Because of these increases in risk over time, a cohort with a younger starting age experienced more ischemic strokes per 100 patient-years than a cohort with an older starting age with the same CHADS2 score at baseline. The effect of aging was also reflected in ECH results. Although in the age <75 cohort, dabigatran-treated patients have lower ECH risk than warfarin-treated patients (relative risk 0.80), in the age ≥75 cohort, dabigatran-treated patients have higher ECH risk (relative risk 1.50). Because of the effect of aging, over a lifetime horizon, the dabigatran-treated patients with starting age <75 and initial ECH risk lower than warfarin-treated patients experienced more ECH per 100 patient-years than warfarin-treated patients. The key model drivers for determining cost-effectiveness were ischemic stroke risk and time horizon. These 2 drivers have opposing effects when comparing the cost-effectiveness of dabigatran in the 2 age cohorts. Dabigatran is more cost-effective in the ≥75 cohort than the <75 cohort over shorter time horizons because the baseline risk of ischemic stroke (and bleeding) is higher in the ≥75 cohort, magnifying the clinical benefit of dabigatran. This can be seen in the analyses using a 10-year time horizon in which the ICER for the ≥75 cohort is lower (more favorable for dabigatran) than the ICER for the <75 cohort. In the lifetime analyses, however, the opposite is true, reflecting the longer remaining life expectancy of the <75 cohort and their correspondingly greater opportunity to avoid events and benefit from events avoided. Overall, these 2 effects counterbalance each other resulting in relatively similar lifetime ICERs for the <75 and ≥75 cohorts. The cost-effectiveness findings of the present study were broadly in line with findings from the recent literature on these drugs in the US setting. Until now, no study had examined the cost-effectiveness of 150 mg twice daily dabigatran versus warfarin in specific age cohorts. In the published comparisons of dabigatran 150 mg twice daily versus dose-adjusted warfarin over an all-ages cohort in the US setting, the ICERs were within the $100,000 cost per QALY willingness to pay threshold (ranged from $12,386/QALY in Freeman and Turakhia17Freeman J. Turakhia M. Dabigatran compared with warfarin for stroke prevention in atrial fibrillation.Ann Intern Med. 2011; 154 ([Author reply]): 570-571Crossref Scopus (5) Google Scholar, 18Freeman J.V. Zhu R.P. Owens D.K. Garber A.M. Hutton D.W. Go A.S. Wang P.J. Turakhia M.P. Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation.Ann Intern Med. 2011; 154: 1-11Crossref PubMed Scopus (362) Google Scholar and Freeman et al17Freeman J. Turakhia M. Dabigatran compared with warfarin for stroke prevention in atrial fibrillation.Ann Intern Med. 2011; 154 ([Author reply]): 570-571Crossref Scopus (5) Google Scholar, 18Freeman J.V. Zhu R.P. Owens D.K. Garber A.M. Hutton D.W. Go A.S. Wang P.J. Turakhia M.P. Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation.Ann Intern Med. 2011; 154: 1-11Crossref PubMed Scopus (362) Google Scholar to approximately $86,000/QALY in Shah and Gage19Shah S.V. Gage B.F. Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillation.Circulation. 2011; 123: 2562-2570Crossref PubMed Scopus (287) Google Scholar). The ICERs found in our study ($58,962 to $73,694/QALY) fell well within that range, which provides evidence that our model was neither overly optimistic nor conservative regarding cost and effectiveness outcomes of 150 mg twice daily dabigatran versus warfarin. This study has a number of strengths. The baseline CHADS2 distributions of single-year age cohorts were modeled explicitly based on new analyses of the RE-LY trial data. This ensured that the efficacy and safety data comparing dabigatran with warfarin were based on a direct head-to-head comparison. The model also incorporated safety-on-treatment data for clinical efficacy and treatment discontinuation and was able to closely reproduce the intent-to-treat estimates from RE-LY, avoiding confounding the clinical inputs because of the rates of use and efficacy of subsequent treatment. The present analysis focused on the Medicare cost perspective, which is an important payer for the AF population in the United States. However, because Medicare does not pay for long-term costs associated with a nursing home facility, this analysis does not capture the full cost impact associated with the long-term disability that is common with stroke and ICH. Sensitivity analysis showed that the variation around long-term follow-up cost minimally affects the results. The model adapted for this study has undergone extensive review and validation. The model was peer-reviewed through publications, including the application of the model to compare dabigatran with warfarin in Canada and the United Kingdom6Kansal A.R. Sorensen S.V. Gani R. Robinson P. Pan F. Plumb J.M. Cowie M.R. Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in UK patients with atrial fibrillation.Heart. 2012; 98: 573-578Crossref PubMed Scopus (99) Google Scholar, 7Sorensen S.V. Kansal A.R. Connolly S. Peng S. Linnehan J. Bradley-Kennedy C. Plumb J.M. Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation: a Canadian payer perspective.Thromb Haemost. 2011; 105: 908-919Crossref PubMed Scopus (177) Google Scholar and underwent a comprehensive review through the assessment process of a number of health authorities, including but not limited to health technology assessment bodies in the United Kingdom, Canada, and Australia. As described in the validation analysis, the model simulation over a 2-year time horizon was able to closely reproduce the clinical event rates for dabigatran and warfarin for the intent-to-treat populations in RE-LY, providing evidence that the model was well calibrated. As with all models that are based on clinical trial data, assumptions must be made to extend the trial findings to longer (lifetime) time horizons. In this model, we applied the age-related relative risks of events found at the completion of the trial to subsequent years beyond the trial period. In comparison with some previous models, this adjustment of the baseline risks over time as the population ages would lead to more precise projection. It was also assumed that the international normalized ratio control for warfarin was the same across all age cohorts. The analysis incorporated Medicare costs and, therefore, did not reflect the full costs of long-term care, which are limited under the Medicare program. Thus, severe disability resulting from events had lower costs in the model than would exist in real-world practice, which yields a conservative estimate of ICER for the treatment with fewer events. We would like to thank Dr. Cheng Wang (from Boehringer Ingelheim) for reviewing the manuscript and providing valuable comments. This research was funded by Boehringer Ingelheim Pharma GmbH & Co KG. All authors are in agreement with the content of the manuscript and are aware of this submission. All authors contributed to the study design, data interpretation, and writing of the manuscript. In addition, Anuraag Kansal, Sarah Brand, Siyang Peng, and Sonja Sorensen were responsible for the model design and implementation. Anuraag Kansal, Sarah Brand, Siyang Peng, and Sonja Sorensen are employees of Evidera, which received funding from Boehringer Ingelheim Pharma GmbH & Co KG for this project. Andreas Clemens, Martina Brueckmann, Herbert Noack, Jonathan Lim, and Stephen Sander are employees of Boehringer Ingelheim, the manufacturer of dabigatran etexilate." @default.
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W1987556610 title "Efficacy and Cost-Effectiveness of Dabigatran Etexilate Versus Warfarin in Atrial Fibrillation in Different Age Subgroups" @default.
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