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ORIGINAL RESEARCH ARTICLE

Am J Cardiovasc Drugs 2010; 10 (1): 55-63 1175-3277/10/0001-0055/$49.95/0

2010 Adis Data Information BV. All rights reserved.

Cost Effectiveness of Eplerenone in Patients with Heart Failure after Acute Myocardial Infarction Who were Taking Both ACE Inhibitors and b-Blockers
Subanalysis of the EPHESUS
Zefeng Zhang,1,2 Elizabeth M. Mahoney,3 Paul Kolm,4 John Spertus,3 Jaime Caro,5 Richard Willke6 and William S. Weintraub4
1 2 3 4 5 6 School of Public Health, Nantong University, Nantong, P.R. China Emory University School of Medicine, Atlanta, Georgia, USA Mid America Heart Institute, Kansas City, Missouri, USA Christiana Care Health System, Newark, Delaware, USA Caro Research, Inc., Boston, Massachusetts, USA Pfizer, Inc., New York, New York, USA

Abstract

Background: The EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure and Survival Study) showed that the use of aldosterone blockade with eplerenone decreased mortality in patients with heart failure after acute myocardial infarction, and a subsequent analysis showed eplerenone to be highly cost effective in this population. Objective: To assess the cost effectiveness of eplerenone in an EPHESUS subgroup population who were taking both ACE inhibitors and b-blockers (b-adrenoceptor antagonists) at baseline. Intervention: In the EPHESUS, a total of 6632 patients were randomized to receive eplerenone 2550 mg/day (n = 3319) or placebo (n = 3313) concurrently with standard therapy and were followed for up to 2.5 years. Of these, 4265 (64.3%) patients (eplerenone: n = 2113; placebo: n = 2152) were taking both ACE inhibitors and b-blockers at baseline. Methods and Main Outcome Measures: Resource use after the initial hospitalization included additional hospitalizations, outpatient services, emergency room visits, and medications. Eplerenone was priced at an average wholesale price of $US3.60 per day (year 2004 value). Bootstrap methods were used to estimate the fraction of the joint distribution of the cost and effectiveness. A net-benefit regression model was used to derive the propensity score-adjusted cost-effectiveness curve. The incremental cost effectiveness of eplerenone in cost per life-year gained (LYG) and cost per quality-adjusted life-year (QALY) gained beyond the trial period was estimated using data from the Framingham Heart Study, the Saskatchewan Health database, and the Worcester Heart Attack Registry. Both costs and effectiveness were discounted at 3%. Allthough not all resource use could be accounted for, the overall perspective was societal. Results: As in the overall EPHESUS population, the total direct treatment costs were higher in the eplerenone arm than the placebo arm for patients who were taking both ACE inhibitors and b-blockers ($US14 563 vs $US12 850, difference = $US1713; 95% CI 721, 2684). The number of LYGs with eplerenone compared with placebo was 0.1665 based on the Framingham data, 0.0979 using the Saskatchewan data, and 0.2172 using the Worcester data. The incremental cost-effectiveness ratio (ICER) was $US10 288/LYG with the Framingham data, $US17 506/LYG with the Saskatchewan data, and $US7888/LYG with the Worcester data (99% <$US50 000/LYG for all three sources). The ICERs were systematically higher when calculated as the cost per QALY gained ($US14 926, $US25 447, and $US11 393, respectively) as the utilities were below 1 with no difference between the treatment arms.

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Conclusions: As for the overall EPHESUS population, aldosterone blockade with eplerenone is effective in reducing mortality and is cost effective in increasing years of life for the EPHESUS subgroup of patients who were taking both ACE inhibitors and b-blockers.

Background Heart failure is one of the most frequent complications of myocardial infarction[1] and significantly worsens the prognosis of patients with ischemic heart disease.[2] The presence of heart failure in patients with acute myocardial infarction is associated with a 1.55-fold greater risk of dying and a 2.15-fold greater risk of death or recurrent myocardial infarction at 30 days.[3] Data from an international registry showed that patients with heart failure and left ventricular systolic dysfunction (LVSD) carried a hazard ratio (HR) for in-hospital mortality of 4.12.[4] ACE inhibitors and b-blockers (b-adrenoceptor antagonists) are considered to represent the current standard of care in patients with LVSD after acute myocardial infarction. Nonselective aldosterone blockade has been shown to reduce the rate of death due to progressive heart failure and the rate of sudden death from cardiac causes in patients with severe heart failure when used with ACE inhibitors, diuretics, and sometimes digoxin.[5] The EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) demonstrated that selective aldosterone blockade with eplerenone significantly reduced mortality and morbidity in patients with LVSD and heart failure post-myocardial infarction who were receiving optimal medical therapies,[6] and a subsequent analysis showed eplerenone to be highly cost effective in this population.[7] The EPHESUS trial also demonstrated that eplerenone was beneficial in terms of death from any cause and death from cardiovascular causes or hospitalizations from cardiovascular events in patients who were receiving both ACE inhibitors and b-blockers at baseline.[6] This finding is important because other treatments, including endothelin-receptor antagonists, antibodies against tumor necrosis factor-a, and angiotensinreceptor antagonists, have not been found to reduce mortality among patients with LVSD and heart failure who are being treated with an ACE inhibitor and a b-blocker. Whether the use of eplerenone in this patient population is cost effective has been unknown. The aim of this economic analysis was to assess the cost effectiveness of eplerenone in the patient population who were taking both ACE inhibitors and b-blockers at baseline in the EPHESUS from the societal perspective.
2010 Adis Data Information BV. All rights reserved.

Methods

The EPHESUS Trial and Study Population

The EPHESUS, a large, multicenter, international, randomized, double-blind, placebo-controlled trial, has been reported previously in detail.[6] In summary, 6632 patients at 671 centers from 37 countries were randomly assigned to receive either eplerenone (n = 3319) or placebo (n = 3313) between 27 December 1999 and 31 December 2001; the follow-up period ranged from 0 to 2.5 years. Patients were randomized 314 days after acute myocardial infarction. Inclusion criteria included LVSD (documented ejection fraction of 40% or lower on echocardiography, radionuclide angiography, or angiography of the left ventricle) and heart failure (documented by pulmonary rales, venous congestion on chest x-ray, or the presence of a third heart sound). In patients with diabetes mellitus who met the criteria for LVSD, signs of heart failure did not have to be demonstrated. Patients were assigned randomly to receive eplerenone (25 mg/day) or placebo for 4 weeks, after which the dosage of eplerenone was increased to a maximum of 50 mg/day in the epleronone group. All patients received standard optimal medical therapy, which could include ACE inhibitors, angiotensin receptor antagonists, diuretics, b-blockers, statin therapy, and coronary reperfusion. The two primary endpoints were time to death from any cause and time to death from cardiovascular causes or first hospitalization for a cardiovascular event, including heart failure, recurrent acute myocardial infarction, stroke, or ventricular arrhythmia. The major secondary endpoints included death from cardiovascular causes and death from any cause or any hospitalization. The EPHESUS trial was approved by the institutional review board at all sites and complied with the Declaration of Helsinki for protection of human subjects. The majority of EPHESUS patients were receiving standard therapies for acute myocardial infarction complicated by LVSD and heart failure, including ACE inhibitors/angiotensin receptor antagonists (87%), b-blockers (75%), aspirin (88%), and diuretics (60%). Of the 6632 EPHESUS patients, 4265 (64.3%) of them (eplerenone: n = 2113; placebo: n = 2152) were taking both ACE inhibitors and b-blockers at baseline, and were included in the current economic analysis.
Am J Cardiovasc Drugs 2010; 10 (1)

Cost Effectiveness of Eplerenone in an EPHESUS Subgroup

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Healthcare Resource Use and Costs

Direct medical care costs associated with subsequent hospitalizations, outpatient procedures, emergency room visits, concomitant medications, and eplerenone use were considered in this analysis. The initial hospitalization costs were not included in the base-case analysis because administration of the study drug was initiated towards the end of this hospitalization. No data were available from EPHESUS to calculate indirect costs such as costs due to lost productivity. Subsequent hospitalizations were assigned a diagnosisrelated group (DRG) code as used in the Medicare Program in the US.[8] Costs for each DRG were estimated using the average Medicare reimbursement rates obtained from the Medicare Part A (MEDPAR) data file,[9] and professional costs were calculated as the percentage share by DRG according to the method of Mitchell and colleagues.[10] Outpatient procedures were coded using the Current Procedural Terminology (CPT)[11] and assigned a cost based on the Medicare fee schedule. Medication costs were based on the Red Book average wholesale price (AWP).[12] The cost of eplerenone was assigned using an AWP of $US3.60 a day. All medications were assumed to continue for the duration of time that each patient was followed. As in the original economic analysis of EPHESUS,[7] all costs were calculated using 2001 as the base year, except for the cost of eplerenone, for which the 2004 AWP was used (this drug was not marketed until 2004). While the analysis used US unit costs, resource use information and clinical outcomes were utilized for all 4265 patients.

hazards models derived from the same data. For patients who died during the trial, life-years lost were obtained by subtracting the in-trial survival times from estimated age- and sexspecific life expectancy estimates.[18] Patients were considered to have zero life-years lost if they survived during the trial period. Average life-years lost for each treatment group were calculated across all patients who died and all who survived in each arm of the trial. The difference in average life-years lost due to deaths (values for those in the placebo group minus values for those in the eplerenone group) yielded an estimate of the life-years gained (LYGs) with eplerenone.
Utility

For this subset population of the EPHESUS trial, utility was measured in 1279 patients at baseline, 1130 patients at 6 months, and 832 patients at 12 months using a well recognized qualityof-life (QOL) instrument (EQ-5D).[19] Quality-adjusted lifeyears (QALYs) were calculated by multiplying survival life expectancy values by utility. For patients with a missing utility score, the average utility for all patients with available scores by treatment arm was used to estimate utility. Utility after 12 months was carried forward using the 12-month value. Because utility was only measured in a minority of patients, the primary outcome of the cost-effectiveness analysis was the cost per LYG, with the cost per QALY gained assessed in a sensitivity analysis.
Cost-Effectiveness and Statistical Analyses

Life Expectancy Estimation

The estimates of lost life expectancy associated with the intrial deaths were obtained from three independent sources: the Framingham Heart Study,[13] the Saskatchewan Health database,[14] and the Worcester Heart Attack Registry.[15,16] The ideal data source from which to estimate lost life expectancy for this study would include longitudinal data, a large cohort of patients, and patients with similar characteristics to those in the EPHESUS, and would be widely known and acknowledged as credible. The three different sources mentioned above were used to estimate survival because no single source perfectly met these criteria. For the Saskatchewan and Worcester databases, data on 2543 and 1094 patients, respectively, with heart failure after an acute myocardial infarction were analyzed using fractional polynomials and piecewise regression to obtain death hazard functions over time.[17] These were adjusted according to patient characteristics using separate Cox proportional
2010 Adis Data Information BV. All rights reserved.

Continuous variables are expressed as mean SD and were compared using the Wilcoxon rank-sum test. The chi-squared (w2) or Fishers exact test were used for categorical data comparison. Costs and life expectancy differences were discounted by 3% annually. The economic analytic plan was to compare the overall treatment costs of the two treatment arms and, if the eplerenone arm was more costly as well as more effective, to perform an incremental cost-effectiveness analysis. The lifetime cost effectiveness of eplerenone was expressed as the incremental costeffectiveness ratio (ICER), i.e. the added cost in the eplerenone group divided by the life-years or QALYs gained. Bootstrap methods (5000 replicates) were used to estimate the fraction of the joint distribution of the cost and effectiveness differences lying in different regions of the cost-effectiveness plane. Because the studied population was not directly randomized to receive eplerenone versus placebo, there is the possibility of selection bias with respect to patients within each treatment
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group in the EPHESUS subgroup of patients who were taking both ACE inhibitors and b-blockers at baseline. A propensity score-adjusted cost-effectiveness analysis was carried out in the current study using a net-benefit regression model from which a propensity score-adjusted cost-effectiveness acceptability curve was derived.[20] Results There were no significant differences in baseline characteristics between patients who were and were not taking both ACE inhibitors and b-blockers at baseline (data not shown). For patients who were taking both ACE inhibitors and b-blockers at baseline, the two treatment groups were well balanced with respect to age, gender, White race, prior myocardial infarction, diabetes mellitus, hypertension, prior history of heart failure, ejection fraction (mean = 33%), BP, hemoglobin level, creatinine clearance, height, and weight at baseline (table I). There was a 27% decrease in the death rate from any cause with eplerenone compared with placebo (10.9% vs 14.6%; HR: 0.730; 95% CI 0.617, 0.863; p < 0.001) and a 16% decrease in the other primary endpoint of death from cardiovascular causes or first hospitalization for a cardiovascular event (24.6% vs 28.4%; HR: 0.841; 95% CI 0.749, 0.944; p = 0.004). The average followup was 16 months. Healthcare resource utilization is presented in table II. There were no significant differences between the eplerenone and

placebo recipients in the number of rehospitalizations, or the percentage of patients with 1 rehospitalizations, outpatient procedures, or emergency room visits. Table III shows the life-years and QALYs lost due to early mortality and the gains with eplerenone versus placebo using data from the Framingham Heart Study, Saskatchewan Health database, and Worcester Heart Attack Registry (see Utility section in the Methods). The average utility scores with eplerenone and placebo, respectively, were 0.645 (n = 630) and 0.657 (n = 649) at baseline, 0.768 (n = 558) and 0.775 (n = 572) at 6 months, and 0.799 (n = 405) and 0.780 (n = 427) at 1 year (all p > 0.30). Using the Framingham database, there were 0.4107 life-years lost and 0.3026 QALYs lost in the eplerenone arm and 0.5772 life-years lost and 0.4174 QALYs lost in the placebo arm; these between-group differences were statistically significant. Estimated life-years and QALYs lost with eplerenone versus placebo using the Saskatchewan database were slightly lower than those using the Framingham data (life-years lost: 0.2386 vs 0.3364; QALYs lost: 0.1748 vs 0.2421), whereas these estimates were slightly greater with the Worcester data (lifeyears lost: 0.4909 vs 0.7081; QALYs lost: 0.3618 vs 0.5122) [table III]. There was a significant gain in life-years and QALYs with eplerenone versus placebo for each of the long-term projections. The gain in QALYs was systematically smaller than the gain in life-years because the utility score was <1 and there was no significant difference in utility found between the treatment arms. Compared with the overall population,[7] both

Table I. Baseline characteristics between treatment groups for patients who were taking both ACE inhibitors and b-blockers (b-adrenoceptor antagonists)a Characteristic Age (y) Male [n (%)] White race [n (%)] BP: systolic (mmHg) BP: diastolic (mmHg) Heart rate History of acute myocardial infarction [n/N (%)] History of diabetes mellitus [n/N (%)] History of heart failure [n/N (%)] History of hypertension [n/N (%)] Ejection fraction (%) Hemoglobin (g/dL) Creatinine clearance (mg/dL) Height (cm) Weight (kg) Eplerenone (n = 2113) 63.3 11.5 1534 (72.6) 1944 (92.0) 121.1 18.0 (n = 2110) 73.0 11.8 (n = 2110) 76.4 13.7 (n = 2107) 569/2105 (27.0) 700/2102 (33.3) 257/2105 (12.2) 1290/2102 (61.4) 33.1 5.9 (n = 2110) 13.4 1.7 (n = 2096) 98.2 28.1 (n = 2106) 169.2 9.4 (n = 2108) 79.7 15.4 (n = 2112) Placebo (n = 2152) 63.8 11.7 1553 (72.2) 1959 (91.0) 121.2 18.2 (n = 2149) 72.7 11.6 (n = 2149) 76.0 13.2 (n = 2149) 540/2145 (25.2) 693/2144 (32.3) 291/2144 (13.6) 1313/2144 (61.2) 32.9 6.2 (n = 2148) 13.4 1.7 (n = 2136) 98.0 27.8 (n = 2144) 169.2 9.2 (n = 2147) 78.9 15.1 (n = 2151) p-Value 0.095 0.752 0.630 0.775 0.498 0.434 0.168 0.497 0.187 0.931 0.534 0.505 0.803 0.892 0.141

a Values are presented as mean SD, unless otherwise indicated.


2010 Adis Data Information BV. All rights reserved. Am J Cardiovasc Drugs 2010; 10 (1)

Cost Effectiveness of Eplerenone in an EPHESUS Subgroup

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Table II. Healthcare resource utilization by treatment group Parameter Mean number of rehospitalizations per patient Patients with 1 rehospitalizations (%) Mean number of outpatient procedures per patient Patients with 1 outpatient procedures (%) Mean number of emergency room visits per patient Patients with 1 emergency room visit (%) Eplerenone (n = 2113) 0.90 49.20 1.85 51.30 0.31 19.20 Placebo (n = 2152) 0.94 49.30 1.77 49.40 0.34 19.60 p-Value 0.80 0.58 0.16 0.20 0.72 0.62

the life-years lost and QALYs lost were less for both treatment arms, and the gains in life-years and QALYs with eplerenone versus placebo were greater in this subset population who received both ACE inhibitors and b-blockers. Table IV shows the direct treatment costs per patient in the eplerenone and placebo groups, the between-group differences in costs, and the 95% confidence intervals. There were no significant differences between the two treatment groups in costs for subsequent hospitalizations, medications other than eplerenone, outpatient procedures, or emergency room visits. The cost of eplerenone itself was $US1538. Overall, total follow-up costs were $US1713 higher in the eplerenone group ($US14 563 vs $US12 850; 95% CI of the difference 721, 2684), which is higher than the cost difference between the eplerenone and placebo groups for the overall EPHESUS population ($US1391).[7] The per patient costs of cardiovascular hospitalizations are shown in table V. Cardiovascular hospitalizations were divided into three categories: (i) heart failure hospitalizations, (ii) narrowly defined cardiovascular hospitalizations using the definition from the clinical study[6] (i.e. hospitalizations for heart failure, myocardial infarction, ventricular arrhythmia, or stroke), and (iii) all cardiovascular hospitalizations (i.e. hospitalizations for progression of heart failure, myocardial infarction, ventricular arrhythmia, stroke, unstable angina, stable angina, peripheral vascular disease, hypotension, hypertension, atrial flutter/fibrillation, elective cardiovascular surgery, and other cardiovascular events). Overall, there were significantly lower costs for heart failure ($US925 vs $US1183; difference: $US258.50; 95% CI -471.3, -60.4) and narrowly defined cardiovascular hospitalizations ($US1537 vs $US1780.50; difference: $US243; 95% CI -485.1, -5.0) with eplerenone compared with placebo. For all cardiovascular hospitalizations, there was a trend toward lower costs with eplerenone ($US7760 vs $US7980; difference: $US219.50; 95% CI -912.5, 417.6). The ICERs (cost per LYG) for eplerenone were $US10 288 with the Framingham data, $US17 506 with the Saskatchewan data, and $US7888 with the Worcester data, with 99% of
2010 Adis Data Information BV. All rights reserved.

the estimates falling below the $US50 000 per LYG threshold for each of the three data sources (table VI). The ICERs were systematically higher when calculated as cost per QALY gained ($US14 926, $US25 447, and $US11 393 per QALY gained with the Framingham, Saskatchewan, and Worcester data, respectively). The ICERs were systematically higher if the costs after the trial period were included (table VI). A plot of the bootstrap-derived joint distribution of cost and effectiveness differences on the basis of the Framingham estimates for lost life expectancy is shown in figure 1. Almost all estimates are in quadrant 1 of the cost-effectiveness plane, meaning that there was greater efficacy at increased cost with eplerenone. The majority of the distribution (99%) lies below and to the right of the diagonal line that represents the commonly used societal willingness-to-pay threshold of $US50 000 per LYG.
Table III. Life-years and quality-adjusted life-years (QALYs) by treatment group and data source Parameter Life-years lost Framinghama Saskatchewanb Worcesterc QALYs lost Framinghama Saskatchewanb Worcesterc 0.3026 0.1748 0.3618 0.4174 0.2421 0.5122 0.1148 0.0673 0.1504 0.0485, 0.1705 0.0341, 0.1045 0.0760, 0.2340 0.4107 0.2386 0.4909 0.5772 0.3364 0.7081 0.1665 0.0979 0.2172 0.0877, 0.2551 0.0519, 0.1497 0.1110, 0.3305 Eplerenone (n = 2113) Placebo (n = 2152) Gain with eplerenone 95% CI

a Framingham Heart Study.[13] b Saskatchewan Health database.[14] c Worcester Heart Attack Registry.[15,16]

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Table IV. Per patient direct treatment costs ($US)a by treatment group Cost component Re-hospitalization Medication costs other than eplerenone Outpatient diagnostic procedure costs Emergency room visit costs Eplerenone costs ($US3.6/day) Total follow-up costs Eplerenone (n = 2113) 8 699 3 689 594 43 1 538 14 563 Placebo (n = 2152) 8 755 3 494 554 46 0 12 850 1 713 721, 2 684 D (eplerenone - placebo) -56 195 39 -3 95% CI -951, 919 44, 344 -52, 125 -11, 3

a Year 2001 costs were used for subsequent hospitalizations, outpatient visits, emergency room visits, and concomitant medication, and year 2004 costs for eplerenone. D = difference in cost.

Cost-effectiveness acceptability curves derived from bootstrap resampling as well as propensity score-adjusted net benefit regression models are presented in figure 2. LYGs based on the Framingham data were used as the measure of efficacy. There were no significant differences between the two methods in the percentage of estimates considered cost effective at any ceiling ratio, although there was a slight trend toward more favorable ICERs using the adjusted net benefit regression method. After adjusting for the propensity score, at a ceiling ratio of $US10 000, eplerenone is cost effective in over 49% of estimates (vs 46% from the bootstrap method); at a ceiling ratio of $US20 000, eplerenone is cost effective in over 95% of estimates (vs 94% from the bootstrap method); and at a ceiling ratio of $US50 000, eplerenone is cost effective in over 99.8% of estimates (vs 99.0% from the bootstrap method). Discussion Eplerenone was proven to be a life-saving and highly costeffective medication in the setting of heart failure after an acute myocardial infarction in the overall EPHESUS population.[6,7] Results from this post hoc cost-effectiveness analysis using data

from EPHESUS also demonstrated that, for patients who were taking both ACE inhibitors and b-blockers, aldosterone blockade with eplerenone is highly cost effective compared with placebo. These results were robust to application of three different external sources for estimates of lost life expectancy resulting from in-trial deaths. The ICERs for all three external sources for this subset population were more favorable compared with those from the overall EPHESUS population. The ICERs were $US10 288, $US17 506, and $US7888 per LYG with eplerenone using the Framingham, Saskatchewan, and Worcester data, respectively, and 99% of the estimates were below the $US50 000 benchmark ceiling ratio for all three sources; the corresponding ICERs were $US13 178, $US21 876, and $US10 402, respectively, for the overall EPHESUS population. These ICERs are relevant to recent changes in US cost levels, since the cost difference between the arms is principally due to the cost of eplerenone, and the unit cost of eplerenone was midway between 2008 AWP and wholesale acquisition cost levels. Although ACE inhibitors and b-blockers have been proven to reduce mortality in patients with heart failure complicating acute myocardial infarction, morbidity and mortality remain high despite the use of these standard-of-care therapies.[3,21]

Table V. Costs ($US)a of heart failure and cardiovascular hospitalizations by treatment group Cost component Cardiovascular hospitalizationsb Cardiovascular hospitalizations
c

Eplerenone (n = 2113) 1537.1 7760.3 924.7

Placebo (n = 2152) 1780.5 7979.8 1183.2

D (eplerenone - placebo) -243.4 -219.5 -258.5

95% CI -485.1, -5.0 -912.5, 417.6 -471.3, -60.4

Congestive heart failure hospitalizations

a Year 2001 costs were used for subsequent hospitalizations, outpatient visits, emergency room visits, and concomitant medication, and year 2004 costs for eplerenone. b Including heart failure, myocardial infarction, ventricular arrhythmia, or stroke. c Including progression of heart failure, myocardial infarction, ventricular arrhythmia, stroke, unstable angina, stable angina, peripheral vascular disease, hypotension, hypertension, atrial flutter/fibrillation, elective cardiovascular surgery, and other cardiovascular events. D = difference in cost.
2010 Adis Data Information BV. All rights reserved. Am J Cardiovasc Drugs 2010; 10 (1)

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Table VI. Cost-effectiveness analysis by data source Parameter D Cost ($US)a D Effectiveness ICER Dominated (%) Dominant (%) % <$50 000 LYG/QALYs gained

Costs resulting from life-years saved excluded Life-years Framinghamb Saskatchewan Worcesterd QALYs Framinghamb Saskatchewanc Worcester
d c

1 713 1 713 1 713

0.1665 0.0979 0.2172

10 288 17 506 7 888

0.04 0 0.02

0.02 0 0.02

99.0 99.0 99.0

1 713 1 713 1 713

0.1148 0.0673 0.1504

14 926 25 447 11 393

0.04 0.08 0.04

0.02 0.02 0.02

99.0 95.0 99.0

Costs resulting from life-years saved included Life-years Framinghamb Saskatchewan Worcesterd QALYs Framinghamb Saskatchewan Worcesterd
c c

2 915 2 536 3 207

0.1665 0.0979 0.2172

17 507 25 912 14 765

0 0 0

0 0 0

99.0 98.0 99.0

2 915 2 536 3 207

0.1148 0.0673 0.1504

25 398 37 664 21 326

0 0 0

0 0.02 0

98.0 85.0 99.0

a Year 2001 costs were used for subsequent hospitalizations, outpatient visits, emergency room visits, and concomitant medication, and year 2004 costs for eplerenone. b Framingham Heart Study.[13] c Saskatchewan Health database.[14] d Worcester Heart Attack Registry.[15,16] D = difference between eplerenone and placebo; ICER = incremental cost-effectiveness ratio; LYG = life-year gained; QALYs = quality-adjusted life-years.

The estimated direct and indirect health expenditures for heart failure are nearing $US26 billion annually in the US. As such, it is necessary to develop new strategies to better improve outcomes and potentially lower the costs of patient care in this setting. Previous experience with regard to the effectiveness of aldosterone blockade in patients with LVSD and heart failure who are receiving both ACE inhibitors and b-blockers is limited. In the RALES (Randomized ALdactone [spironolactone] Evaluation Study for congestive heart failure),[5] the proportion of patients who were treated with a b-blocker was only 11%. The EPHESUS was the first study to show improved clinical outcomes and high cost effectiveness with the use of eplerenone in patients with heart failure post-acute myocardial infarction in addition to standard treatment (with ACE inhibitors and b-blockers). EPHESUS, however, cannot be used to compare the clinical outcomes or cost effectiveness of eplerenone with those of spironolactone. In addition, spironolactone has never been shown to be effective in reducing mortality in patients with congestive heart failure after myocardial infarction.
2010 Adis Data Information BV. All rights reserved.

A major strength of this analysis is that it was performed with patient-level data directly from the EPHESUS subset population who were taking both ACE inhibitors and b-blockers at baseline. However, some limitations in the present analysis should be considered. First, the EPHESUS was a multinational study; the application of US DRG-based costs to trial-wide resource utilization does not fully account for possible differences in treatment practices across countries or health systems. If a large proportion of patients come from countries for which the threshold for resource use differs considerably from that in the US, the difference in costs between treatment arms may be under- or overestimated. However, unless within a DRG the costs are higher in one treatment arm (which was not the case in this study), this approach to costing should yield unbiased overall cost estimates and, in fact, should reduce unwanted variability in the evaluation of cost differences attributable to treatment. Second, life expectancy was estimated using data from three external sources; the extent to which the survival experience of patients from these
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3000

2000

1000

1000 0.1 0.0 0.1 0.2 0.3

Mean difference in lost life-years

Fig. 1. Scatterplot of the joint distribution of cost and effectiveness differences in the cost-effectiveness plane based on Medicare costs and Framingham life expectancy estimates.

observational studies yields accurate estimates of life expectancy for this EPHESUS subgroup population is uncertain. The 1-year mortality rate from both the Saskatchewan and Worcester databases was higher than that from EPHESUS, which would translate into a shorter projected life expectancy, and render the results conservative. The Worcester and Saskatchewan databases were used because they included a more contemporary population, and because patients were similar to those in EPHESUS and also underwent long-term follow-up. The Framingham heart study was used because it is a well known,
Bootstrap Net benefit 1.0 Probability of being cost effective 0.8 0.6 0.4 0.2 0 0 10 000 20 000 30 000 40 000 Ceiling ratio 50 000 60 000

epidemiological database with long-term follow-up. Third, the costing methodology was based on Medicare payments for hospitalization, the Medicare fee schedule for outpatient procedures, and the AWP for medications. The extent to which these costs reflect resource utilization from a societal point of view is somewhat uncertain because there is no single source for costs that unequivocally represents societal costs. Thus, Medicare payments may be suitable for costs for the Centers for Medicare and Medicaid Services, but may not adequately represent resource consumption by hospitals and physicians because Medicare costs tend to be lower than managed care costs. Furthermore, indirect costs were not captured. These costs might be higher in the placebo group given the trend towards a higher rate of subsequent hospitalizations or death, which would yield even more favorable cost-effectiveness estimates for eplerenone. Finally, the length of follow-up in EPHESUS varied (range, 033 months). Thus, cost effectiveness was calculated for the average follow-up period of 16 months. Treatment was assumed to last for an average of 16 months only, and survival curves were assumed to remain parallel after the trial period. This study cannot address the issue of how long eplerenone should be taken. Conclusions Eplerenone, a selective aldosterone antagonist, has been clearly shown to reduce overall mortality and the composite of cardiovascular deaths and hospitalizations for cardiovascular causes, and to be highly cost effective in patients with heart failure after acute myocardial infarction. Results presented here show that, as for the overall EPHESUS population, eplerenone is cost effective in increasing LYGs for the EPHESUS subgroup of patients who were taking both ACE inhibitors and b-blockers.

Mean cost difference ($US)

Acknowledgments
This analysis was financially supported by Pfizer, Inc. The sponsor of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The writing committee had final responsibility for the decision to submit for publication. Dr Weintraub has received grants from Pfizer, Inc. Dr Willke is an employee of Pfizer, Inc.; his compensation includes stock options. The other authors have no conflicts of interest that are directly relevant to the content of this study.

Fig. 2. Cost-effectiveness acceptability curves from bootstrap and net benefit regression (propensity score-adjusted) methods based on Medicare costs and Framingham life expectancy estimates.
2010 Adis Data Information BV. All rights reserved.

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Correspondence: Dr Zefeng Zhang, Emory Program in Cardiovascular Outcomes Research and Epidemiology, Emory University School of Medicine, 1256 Briarcliff Road, Suite 1 North, Atlanta, GA 30306, USA. E-mail: zefengzh@yahoo.com

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