Economic Analysis of Apixaban Therapy for Patients With Atrial Fibrillation From a US Perspective: Results From the ARISTOTLE Randomized Clinical Trial

Key Points

Question  Is apixaban therapy cost-effective relative to warfarin therapy from a US perspective in patients with atrial fibrillation and at least 1 additional risk factor for stroke?

Findings  This patient-level analysis of the ARISTOTLE trial found no difference between treatments in health care costs (excluding anticoagulation costs) but significantly longer expected survival with apixaban therapy compared with warfarin therapy. Over a lifetime, apixaban treatment cost an additional $53 925 per quality-adjusted life-year gained.

Meaning  In patients with atrial fibrillation, lifetime anticoagulation with apixaban therapy rather than warfarin therapy meets current US norms for reasonable value in health care.

Importance  The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial reported that apixaban therapy was superior to warfarin therapy in preventing stroke and all-cause death while causing significantly fewer major bleeds. To establish the value proposition of substituting apixiban therapy for warfarin therapy in patients with atrial fibrillation, we performed a cost-effectiveness analysis using patient-level data from the ARISTOTLE trial.

Objective  To assess the cost and cost-effectiveness of apixaban therapy compared with warfarin therapy in patients with atrial fibrillation from the perspective of the US health care system.

Design, Setting, and Participants  This economic analysis uses patient-level resource use and clinical data collected in the ARISTOTLE trial, a multinational randomized clinical trial that observed 18 201 patients (3417 US patients) for a median of 1.8 years between 2006 and 2011.

Interventions  Apixaban therapy vs warfarin therapy.

Main Outcomes and Measures  Within-trial resource use and cost were compared between treatments, using externally derived US cost weights. Life expectancies for US patients were estimated according to their baseline risk and treatment using time-based and age-based survival models developed using the overall ARISTOTLE population. Quality-of-life adjustment factors were obtained from external sources. Cost-effectiveness (incremental cost per quality-adjusted life-year gained) was evaluated from a US perspective, and extensive sensitivity analyses were performed.

Results  Of the 3417 US patients enrolled in ARISTOTLE, the mean (SD) age was 71 (10) years; 2329 (68.2%) were male and 3264 (95.5%) were white. After 2 years of anticoagulation therapy, health care costs (excluding the study drug) of patients treated with apixaban therapy and warfarin therapy were not statistically different (difference, −$60; 95% CI, −$2728 to $2608). Life expectancy, modeled from ARISTOTLE outcomes, was significantly longer with apixaban therapy vs warfarin therapy (7.94 vs 7.54 quality-adjusted life years). The incremental cost, including cost of anticoagulant and monitoring, of achieving these benefits was within accepted US norms ($53 925 per quality-adjusted life year, with 98% likelihood of meeting a $100 000 willingness-to-pay threshold). Results were generally consistent when model assumptions were varied, with lifetime cost-effectiveness most affected by the price of apixaban and the time horizon.

Conclusions and Relevance  Apixaban therapy for ARISTOTLE-eligible patients with atrial fibrillation provides clinical benefits at an incremental cost that represents reasonable value for money judged using US benchmarks for cost-effectiveness.

Trial Registration  clinicaltrials.gov Identifier: NCT00412984

Patients with atrial fibrillation (AF) face an increased risk of ischemic cerebrovascular events and systemic embolism, and daily oral anticoagulation therapy is recommended for at-risk patients.¹ Until recently, warfarin has been the anticoagulant of choice, reducing thromboembolic risk by two-thirds at minimal expense.² However, benefits of warfarin therapy come at a price: patients must undergo regular monitoring owing to the drug’s narrow therapeutic range, deal with potential interactions of warfarin with food and other medications, and accept an elevated risk of bleeding.³ Adoption of warfarin therapy in the community has been less than optimal, reaching about half to two-thirds of eligible patients.⁴

In an effort to improve the quality of anticoagulation therapy, several non–vitamin K oral anticoagulants (NOACs) have been developed. The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial reported that apixaban therapy, an oral direct factor Xa inhibitor, was superior to warfarin therapy in preventing stroke and all-cause death while at the same time causing significantly fewer major bleeds.^5,6 However, this superiority in both efficacy and safety domains does not by itself establish the value of apixaban therapy to society. To make a persuasive case for investment of societal resources to provide this therapy, the efficiency of producing these benefits must compare favorably with well-accepted benchmarks of good value for money in health care.

In this study, we used patient-level resource use and clinical data collected in the ARISTOTLE trial to assess the cost and cost-effectiveness of treating patients with AF with apixaban therapy compared with warfarin therapy from the perspective of the US health care system.

In the ARISTOTLE trial, 18 201 patients with AF and 1 or more additional risk factors for stroke were randomized to apixaban therapy or warfarin therapy in 39 countries between 2006 and 2010. The trial protocol can be found in Supplement 1. Approval of appropriate ethics committees was obtained at all sites. All patients provided written informed consent.

Compared with warfarin therapy, apixaban therapy significantly reduced the primary end point of stroke or systemic embolism (1.27% vs 1.60%; hazard ratio, 0.79; 95% CI, 0.66-0.95) and reduced all-cause death (3.52% vs 3.94%; hazard ratio, 0.89; 95% CI, 0.80-0.998) and major bleeding (2.13% vs 3.09%; hazard ratio, 0.69; 95% CI, 0.60-0.80). For the US economic evaluation, a patient-level survival model was developed using the overall cohort and applied to the 3417 US patients. Costs were based on resource use in the US cohort. This approach assumes that effectiveness is independent of geographic region, as found in the ARISTOTLE trial, but accounts for observed regional variation in resource use and patient risk.

Resource use data collected in the ARISTOTLE trial included dates of inpatient and outpatient care for clinical events; number of nights in intensive care, stepdown unit, or ward; dates of invasive cardiac procedures; and days receiving treatment. Procedures were assigned to reported hospital encounters using dates. Encounters were classified hierarchically as bleeding-related, cardiovascular (without bleeding), noncardiovascular, or unknown. Patients receiving warfarin therapy were assumed to have 8 prothrombin time measurements with clinical follow-up in the first 3 months and monthly monitoring visits thereafter.^7,8 Patients receiving apixaban were assumed to have semiannual follow-up. Although nonacute health care services were not tracked in the ARISTOTLE trial, use of such services can be affected by occurrence of stroke.^9-11 To value nonacute care, a longitudinal record of stroke status was created for each patient using dates of disabling and nondisabling stroke.

External cost weights were developed to value resource use collected in the ARISTOTLE trial. Weights for hospital-based services were estimated using encounter-level cost data from the Premier Research Database (2008-2010) for patients with a diagnosis of AF.¹² Using a generalized linear model with an identity link and gamma distribution function, weights for major components of inpatient and observation encounters were estimated and used to predict a cost weight and associated standard error for each ARISTOTLE hospitalization.¹³ Weights for major procedures without a corresponding hospital encounter, outpatient procedures, emergency department visits, and outpatient visits were based on a random sample of corresponding encounter costs from the Premier subset. The costs of physician services, including daily hospital care, procedures, visits, and office-based anticoagulant monitoring, were based on the 2014 Medicare Fee Schedule.¹⁴ Anticoagulant costs were based on the 2014 National Average Drug Acquisition Cost.¹⁵ Cost weight distributions for nursing home care, home health services, medications, and supplies were derived for disabling and nondisabling stroke status using the 2004 National Nursing Home Survey and the 2008 Medical Expenditure Panel Survey data for respondents reporting coronary heart disease or stroke risk factors.^16,17

Patient-level costs were calculated by applying cost weights to resource use during trial follow-up. Mean costs were estimated in 3-month intervals using inverse probability weighting methods that accounted for administrative (noninformative) censoring.¹⁸

We assumed anticoagulation as observed in the trial would continue over a lifetime. A 2-stage approach was used to model life expectancy.¹⁹ Survival through 2 years was estimated with within-trial data (overall cohort) using a standard time-based Cox proportional hazards model, with adjustment for baseline covariates and treatment. Survival beyond 2 years was estimated using an age-based model, which treats the hazard of death as a function of age rather than time to fully exploit the patient-years of follow-up in the overall ARISTOTLE cohort. Cox proportional hazards methods for left-truncated and right-censored data were used, with adjustment for baseline prognostic factors and stratified by treatment. The time-based and age-based survival models were combined to estimate each patient’s survival curve. Life expectancies, calculated from the area under survival curves, were averaged to obtain the mean predicted life expectancy in each treatment group.

Age-based quality-of-life adjustment factors for patients with AF were based on previously developed preference weights for chronic conditions.^20,21 Expected survival was reduced by a factor of 0.81 at age 67 years, and an age-related adjustment of −0.0003 per year was applied.

Health care costs beyond trial follow-up were based on experience in years 2 and 3 of follow-up. Apixaban was valued using proprietary rates for the estimated patent-life of 10 years, after which time we assumed generic apixaban would be prescribed. Projected costs of inpatient, outpatient, home health, and nursing home care beyond the study were based on inverse probability-weighted cost estimates for years 2 and 3, estimated as described above (eFigure 1 in Supplement 2).

Baseline characteristics of the US cohort were compared with those of patients enrolled elsewhere, and within-trial resource use and cumulative costs through 2 years were compared between treatment groups. Incremental cost-effectiveness ratios were calculated as the between-group difference in mean lifetime cost divided by the between-group difference in mean quality-adjusted life expectancy. The base case included US patients and assumed (1) a lifetime horizon with projected cost and effectiveness mirroring trial experience, (2) a comprehensive definition of cost (including nonacute care and all procedures), (3) 10 years of proprietary apixaban therapy ($9.47 per day) followed by generic apixaban therapy at 20% of proprietary cost in the treatment group, (4) a warfarin therapy cost of $0.09 per day, and (5) an annual discount rate of 3% for cost and survival. In sensitivity analyses, we excluded estimates of nonacute care costs associated with stroke, excluded proxy costs for major procedures without associated encounters in the case report form, removed the substitution of generic for proprietary apixaban, removed the quality-of-life adjustment, restricted the time horizon over which benefits and costs could accrue, varied the discount rate, and estimated cost and effectiveness for the overall trial population. We also explored the cost-effectiveness of treatment in subgroups of interest (CHA₂DS₂-VASc status and prior vitamin K antagonist [VKA] use).

In each scenario, sampling uncertainty was characterized using nonparametric bootstrap techniques, resampling patients with replacement 1000 times. Uncertainty regarding input costs was incorporated by drawing a value at random for each cost from its respective distribution within each bootstrap iteration. Confidence intervals were calculated for differences using the normal approximation, with standard errors estimated from the bootstrap. Incremental cost-effectiveness was displayed on the cost-effectiveness plane and summarized using cost-effectiveness acceptability curves.²² All costs were expressed in 2014 US dollars.²³ Analyses were performed using SAS version 9.4 (SAS Institute).

Compared with patients enrolled elsewhere, US patients were slightly older and were more likely to have histories of diabetes and myocardial infarction (eTable 1 in Supplement 2). Risk factors less common in the US cohort included heart failure and prior stroke, transient ischemic attack, or systemic embolism. Prior VKA use was more common in the United States. Baseline characteristics in the US cohort were balanced between treatment groups (eTable 2 in Supplement 2).

Over a median follow-up of 1.8 years, one-fourth of patients were hospitalized (Table 1). Almost half of hospitalizations were cardiovascular (excluding bleeding). Although the likelihood of hospitalization overall did not differ significantly between treatments, admissions for bleeding appeared slightly less likely with apixaban therapy compared with warfarin therapy (apixaban: 8.2%; 95% CI, 6.9-9.5; vs warfarin: 10.0%; 95% CI, 8.5-11.4; P = .07). The number of hospitalizations followed a similar pattern. Underlying these averages are high hospitalization rates of patients experiencing stroke, which are difficult to discern in treatment-level comparisons owing to the low absolute incidence of stroke (apixaban: 1.2 admissions per patient with stroke vs 0.38 without stroke; warfarin: 1.5 admissions per patient with stroke vs 0.43 without stroke).

Overall, time in the hospital with apixaban therapy was marginally lower, but not statistically different, than with warfarin therapy (mean, 2.03 vs 2.17 days; difference, −0.14; 95% CI for difference, −0.60 to 0.33). The cost of hospitalizations during follow-up averaged $4757 with apixban therapy compared with $5122 with warfarin therapy (eTable 3 in Supplement 2). Emergency department visits for bleeding were less frequent with apixaban therapy than warfarin therapy (mean, 0.04 vs 0.06; difference, −0.02; 95% CI for difference, −0.03 to 0.0), as were outpatient visits for clinical events (mean, 0.34 vs 0.39; difference, −0.04; 95% CI for difference, −0.10 to 0.0). Major procedures were fairly infrequent and similar between treatments (Table 1). Consistent with patterns of resource use, mean cumulative cost of inpatient, outpatient, and emergency department care (excluding unlinked procedures) at 2 years was marginally lower, but not statistically different, with apixaban therapy compared with warfarin therapy (difference, −$172; 95% CI, −$1440 to $1097) (Table 2). The cost of procedures without an associated hospital encounter in the case report form was slightly higher in the apixaban group compared with the warfarin group but again was not statistically different (difference, $376; 95% CI, −$1172 to $2463). Mean estimated nursing home and home health care costs, which reflect stroke care, were slightly lower with apixaban therapy (difference, −$214; 95% CI, −$604 to $177). Overall, there was little evidence of a reduction through 2 years that would offset the incremental cost of apixaban therapy itself, which approached $6000 (difference in health care costs, −$60; 95% CI, −$2728 to $2608).

Projected health care costs beyond 2 years (excluding anticoagulant therapy) did not differ between groups (mean difference, −$45; 95% CI, −$1635 to $1544 annually before discounting). After discounting, comprehensive health care costs over a lifetime averaged $73 663 with apixaban therapy compared with $70 465 with warfarin therapy. Lifetime anticoagulant monitoring cost was $2980 lower with apixaban therapy ($1164 vs $4144); when combined with lifetime anticoagulant drug cost ($21 769 vs $247), total anticoagulant therapy cost was $18 542 higher with apixaban therapy than warfarin therapy ($22 934 vs $4392). In total, the incremental cost of apixaban therapy compared with warfarin therapy was estimated to be $21 740 ($96 596 vs $74 856; difference, $21 740; 95% CI for difference, $7342 to $36 139).

Projected life expectancy of US patients postrandomization was significantly longer with apixaban therapy than warfarin therapy (12.13 vs 11.40 life-years; difference, 0.73; 95% CI, 0.47 to 0.99). These gains in life-years compounded over time, with a difference of just 0.01 apparent after 2 years (eFigure 2 in Supplement 2). After discounting survival at 3%, projected life expectancy with apixaban therapy was 0.50 years greater (9.83 vs 9.33 years; 95% CI for difference, 0.32 to 0.68) (Table 3). Quality-adjusted life-years (QALYs) were 0.40 greater with apixaban therapy compared with warfarin therapy (7.94 vs 7.54 QALYs; 95% CI for difference, 0.26 to 0.55).

Under base case assumptions, the additional cost of anticoagulation therapy for a patient using apixaban rather than warfarin was $53 925 per QALY gained, with a 98% likelihood of meeting a $100 000 willingness-to-pay threshold (Figure 1) (Table 3). The ratio was fairly stable when assumptions regarding cost were varied (Table 3). Excluding unlinked procedures improved the ratio slightly to $49 250, while excluding nonacute health care costs associated with stroke along with unlinked procedures moved the ratio back toward the base case ($52 171) (Figure 2A). Of cost parameters examined, apixaban price was the most influential; reducing the proprietary price to 75%, 50%, and 25% of the 2014 value reduced the incremental cost-effectiveness ratio to $40 426, $26 927, and $13 427 per QALY gained, respectively, and dramatically increased the likelihood of cost-effectiveness at a $50 000 threshold (Figure 2A). Conversely, continued use of proprietary drug after generic availability increased the cost per QALY gained to $68 125. Ratios exceeded contemporary norms for cost-effectiveness when the time horizon was changed from a lifetime perspective to 5 years ($282 468 per QALY gained) or to the median trial period of 2 years ($670 589 per QALY gained) (Figure 2B).

Exploratory analyses stratified by CHA₂DS₂-VASc scores suggest that while absolute life expectancy declines with increased risk of thromboembolism, cost-effectiveness is relatively stable (Figure 2C) (eTable 4 in Supplement 2). History of VKA use had no discernable effect on results.

Estimated life expectancy for the US cohort was slightly longer than for non-US patients, owing to differences in baseline demographic and clinical risk factors. Basing life expectancy estimates on the overall cohort resulted in a slightly lower, though more precise, estimate of QALYs gained with apixaban therapy (Table 3). When combined with an estimate of cost for the overall cohort based on US cost weights, the cost-effectiveness ratio rose slightly to $66 366 per QALY gained (Figure 2B) (Table 3).

Our analysis suggests that anticoagulation therapy for patients with AF using apixaban rather than warfarin increases average quality-adjusted life expectancy at an additional cost that falls within current US norms for reasonable value in health care. This result stems primarily from gains in life-years accumulated over a lifetime of therapy, as we did not find convincing evidence of a meaningful reduction in health care costs to offset the additional ongoing cost of apixaban therapy. Contributing factors may include the low underlying stroke rate, which muted stroke-related savings, and costs incurred in years of life gained with apixaban therapy.

Estimates of cost-effectiveness were not greatly affected by changes in comprehensiveness of health care cost estimates, quality-of-life adjustment, or discount rates. The most influential determinant of incremental cost was the price of apixaban itself. Reductions in proprietary price and substitution of generic alternatives when available would improve the cost-effectiveness profile of apixaban therapy. Restricting the time horizon of the analysis reduced the incremental QALYs and cost-effectiveness dramatically, clearly demonstrating that the absolute benefits of lowering chronic risk build over a lifetime. Although exploratory in nature, analyses of cost-effectiveness stratified by thromboembolism risk and prior VKA use found no major differences. Assessing the value of a long-term therapy can be challenging when cost and benefits must be projected beyond available evidence. We relied primarily on trial experience to support estimation of ongoing resource use and overall mortality risk for patients with AF as they age. This holistic approach differs from the decision analytic frameworks of previous studies examining the cost-effectiveness of apixaban therapy, which incorporated estimates of risks of individual clinical events and their associated costs that were derived from multiple sources. These modeling studies varied considerably with respect to model assumptions, risk of underlying population, and perspective, as did their estimates of incremental cost and benefit.^8,24,25 However, a common finding was that apixaban therapy meets currently accepted thresholds for cost-effectiveness.

When considering alternatives to warfarin, patients and physicians have a choice of 3 NOACs in addition to apixaban: rivaroxaban, edoxaban, and dabigatran.³ All are as effective as warfarin in preventing stroke, none require regular monitoring of clotting time, and all have been judged cost-effective relative to warfarin, although only apixaban has the joint advantage of significantly reducing the risks of both stroke and major bleeding. However, unlike warfarin, none has an available test for anticoagulation level, and only dabigatran has an approved antidote for use in emergencies, although a universal Factor Xa reversal agent is currently under US Food and Drug Administration review.^26-28 Perhaps more important to payers, health systems, and patients, all NOACs cost considerably more than warfarin. The additional monthly out-of-pocket expense for NOACs varies dramatically with insurance coverage, averaging $2 for dual Medicare/Medicaid enrollees, $30 for those commercially insured, $70 for Medicare patients with initial Part D coverage, and $130 for Medicare patients in the Part D coverage gap.^29,30 Clearly, while NOACs meet current thresholds for cost-effectiveness (relative to warfarin) from the perspective of the health care system, medication choice when starting or continuing anticoagulation must depend on the clinical and economic risk profiles of individual patients.³¹ An additional consideration is the distribution of the financial burden of NOACs relative to their clinical benefit across the health care sector, as responsibility for affected service areas, such as formularies, anticoagulation clinics, and stroke rehabilitation, may be spread across multiple entities.

This analysis had some limitations. First, because cost data were not collected in the ARISTOTLE trial, health services were valued with externally derived unit costs. However, unit cost estimates were based on costs of patients with AF treated at geographically diverse US hospitals, uncertainty of estimates was incorporated in analyses, and estimated costs reflect intensity of care as reported in the trial. Second, some procedures reported on the case report form did not link to health care encounters. However, these procedures occurred infrequently and at similar rates between groups, and their inclusion, while increasing the imprecision of estimates, did not affect results appreciably. Third, nonacute care services commonly provided to patients following a stroke were not captured in the ARISTOTLE trial. Because the absolute rate of stroke in the study was low, including external estimates of these costs had little effect on results. Fourth, productivity losses and informal care were not collected in the ARISTOTLE trial and were excluded. A broader analytical perspective that included patient and caregiver time associated with warfarin monitoring would likely improve the cost-effectiveness of apixaban therapy.³² Fifth, quality-of-life adjustments did not reflect effects of nonfatal stroke, yielding a conservative estimate of the cost of effectiveness apixaban therapy. Sixth, most ARISTOTLE patients had prior exposure to VKAs, and results reflect this patient mix. However, no interaction between prior VKA use and outcomes was found in the ARISTOTLE trial, nor were costs appreciably affected by prior VKA status. Seventh, consistent with study objectives, cost-effectiveness was estimated for US patients. While estimates lack precision, they capture clinical risk and resource use of the US cohort. Consistency with overall study outcomes was maintained by using the total cohort to estimate effects of clinical risk and treatment on survival. The consistency of results was confirmed in a sensitivity analysis that estimated cost-effectiveness for the overall cohort using US cost weights. Eighth, limited survival data were available for the uppermost tail of the age distribution. However, the contribution of life-years in this range to life expectancy was minor. Our estimates of life expectancy are comparable to recent estimates for patients with AF with similar baseline risk treated with warfarin therapy.³³ Finally, as with all lifetime cost-effectiveness analyses, assumptions were required regarding long-term treatment and its effects. We based extrapolations on trial experience, assuming that effectiveness and adherence observed over time would reflect the chronic state. Large-scale, long-term follow-up of patients in the community could provide data with which to validate results in the future.

Apixaban therapy for ARISTOTLE-eligible patients achieves clinical benefits at an incremental cost that is within a range considered acceptable in the US health care system.

Corresponding Author: Patricia A. Cowper, PhD, Duke Clinical Research Institute, Duke University Medical Center, PO Box 17969, Durham, NC 27715 (patricia.cowper@dm.duke.edu).

Accepted for Publication: January 2, 2017.

Published Online: March 29, 2017. doi:10.1001/jamacardio.2017.0065

Author Contributions: Dr Cowper had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Cowper, Lopes, Al-Khatib, Dorian, Steg, Wallentin, Granger, Mark.

Acquisition, analysis, or interpretation of data: Cowper, Sheng, Lopes, Anstrom, Stafford, Davidson-Ray, Al-Khatib, Ansell, Dorian, McMurray, Steg, Alexander, Mark.

Drafting of the manuscript: Cowper.

Critical revision of the manuscript for important intellectual content: Cowper, Sheng, Lopes, Anstrom, Stafford, Davidson-Ray, Al-Khatib, Ansell, Dorian, McMurray, Steg, Alexander, Wallentin, Granger, Mark.

Statistical analysis: Cowper, Sheng, Anstrom, Stafford.

Obtained funding: Granger, Mark.

Administrative, technical, or material support: Davidson-Ray, Dorian, Alexander.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Cowper has received research support from Bristol-Myers Squibb, Pfizer, Eli Lilly, Tenax Therapeutics, Gilead Sciences, AGA Medical Corporation, AstraZeneca, and General Electric. Dr Lopes has received research grants from Bristol-Myers Squibb, Pfizer, GlaxoSmithKline and consulting fees from Bayer Corporation, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, Pfizer, and Portola. Dr Anstrom has received research grants from Bristol-Myers Squibb and Pfizer. Dr Ansell served as an advisor or consultant for Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Daiichi Sankyo, Janssen Pharmaceuticals, and Pfizer. Dr Dorian has received grants for clinical research from as well as served as a consultant and a speaker for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, and Pfizer. Dr Husted has received research grants from Boehringer Ingelheim and Bristol-Myers Squibb, honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, and Pfizer, and consultant board fees from AstraZeneca, Bayer, Boehringer Ingelheim, and Bristol-Myers Squibb. Dr McMurray has received support from Novartis, Cardiorentis, Amgen, Oxford University/Bayer, GlaxoSmithKline, Theracos, Abbvie, DalCor, Pfizer, Merck, AstraZeneca, Bristol-Myers Squibb, and Kidney Research UK/Kings College Hospital/Vifor-Fresenius. Dr Steg has received research grants from Merck, Sanofi, and Servier and consulting fees from Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CSL-Behring, Daiichi-Sankyo, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Sanofi, Servier, and The Medicines Company. Dr Alexander has received institutional research grants from Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Pfizer, Tenax Therapeutics, Regado Biosciences, Sanofi, and Vivus Pharmaceuticals and consulting fees from Bristol-Myers Squibb, Portola, and Somahlution. Dr Wallentin has received research grants from AstraZeneca, Merck, Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer, GlaxoSmithKline, and Roche and consulting fees or honoraria from Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, Abbott, and Bristol-Myers Squibb, and Pfizer. Dr Granger has received research grants from Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic Foundation, Merck & Co, Pfizer, Sanofi Aventis, Takeda, The Medicines Company, AstraZeneca, Daiichi Sankyo, Janssen Pharmaceuticals, Bayer, and Armetheon and consulting fees from Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Hoffmann-LaRoche, Eli Lilly, Pfizer, Sanofi Aventis, Takeda, The Medicines Company, AstraZeneca, Daiichi Sankyo, Ross Medical Corporation, Janssen Pharmaceuticals, Salix Pharmaceuticals, Gilead, and Medtronic Inc. Dr Mark has consulted for Medtronic, CardioDx, and St Jude Medical and received research grants from Eli Lilly, Medtronic, Bristol-Myers Squibb, Pfizer, AstraZeneca, Merck & Company, Oxygen Therapeutics, and Gilead. No other disclosures were reported.

Funding/Support: This economic substudy was supported by Bristol-Myers Squibb and Pfizer through a research grant to Duke Clinical Research Institute.

Role of the Funder/Sponsor: The sponsor was asked to provide feedback regarding the economic substudy design, was involved in the collection and management of data and was asked to provide feedback regarding analysis and interpretation of data, was asked to review and provide feedback regarding the manuscript, and was informed of the decision to submit the manuscript for publication. All final decisions regarding this article and its contents were made independently of the sponsor by the coauthors.

Meeting Presentation: A preliminary analysis of resource use was presented as a poster at the 2013 American College of Cardiology scientific sessions; March 10, 2013; San Francisco, California. A preliminary analysis of cost-effectiveness was presented as a poster at the 2014 American Heart Association scientific sessions; November 17, 2014; Chicago, Illinois.

Additional Contributions: We thank Jerome J. Federspiel, MD, PhD (Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, Maryland), for his valuable statistical input. Dr Federspiel received no compensation for his contribution.