Search

Background: Acne is common, can cause significant impact on quality of life and is a frequent reason for long-term antibiotic use. Spironolactone has been prescribed for acne in women for many years, but robust evidence is lacking., Objective: To evaluate whether spironolactone is clinically effective and cost-effective in treating acne in women., Design: Pragmatic, parallel, double-blind, randomised superiority trial., Setting: Primary and secondary healthcare and community settings (community and social media advertising)., Participants: Women aged 18 years and older with facial acne persisting for at least 6 months, judged to potentially warrant oral antibiotic treatment., Interventions: Participants were randomised 1 : 1, using an independent web-based procedure, to either 50 mg/day spironolactone or matched placebo until week 6, increasing to 100 mg/day spironolactone or matched placebo until week 24. Participants continued usual topical treatment., Main Outcome Measures: Primary outcome was the adjusted mean difference in Acne-Specific Quality of Life symptom subscale score at 12 weeks. Secondary outcomes included Acne-Specific Quality of Life total and subscales; participant self-assessed improvement; Investigator's Global Assessment; Participant's Global Assessment; satisfaction; adverse effects and cost-effectiveness., Results: Of 1267 women assessed for eligibility, 410 were randomised (201 intervention, 209 control), 342 in the primary analysis (176 intervention, 166 control). Mean age was 29.2 years (standard deviation 7.2) and 7.9% (28/356) were from non-white backgrounds. At baseline, Investigator's Global Assessment classified acne as mild in 46%, moderate in 40% and severe in 13%. At baseline, 82.9% were using topical treatments. Over 95% of participants in both groups tolerated the treatment and increased their dose. Mean baseline Acne-Specific Quality of Life symptom subscale was 13.0 (standard deviation 4.7) across both groups. Mean scores at week 12 were 19.2 (standard deviation 6.1) for spironolactone and 17.8 (standard deviation 5.6) for placebo [difference favouring spironolactone 1.27 (95% confidence interval 0.07 to 2.46) adjusting for baseline variables]. Mean scores at week 24 were 21.2 (standard deviation 5.9) in spironolactone group and 17.4 (standard deviation 5.8) in placebo group [adjusted difference 3.77 (95% confidence interval 2.50 to 5.03) adjusted]. Secondary outcomes also favoured spironolactone at 12 weeks with greater differences at 24 weeks. Participants taking spironolactone were more likely than those taking placebo to report overall acne improvement at 12 weeks {72.2% vs. 67.9% [adjusted odds ratio 1.16 (95% confidence interval 0.70 to 1.91)]} and at 24 weeks {81.9% vs. 63.3% [adjusted odds ratio 2.72 (95% confidence interval 1.50 to 4.93)]}. Investigator's Global Assessment was judged successful at week 12 for 31/201 (18.5%) taking spironolactone and 9/209 (5.6%) taking placebo [adjusted odds ratio 5.18 (95% confidence interval 2.18 to 12.28)]. Satisfaction with treatment improved in 70.6% of participants taking spironolactone compared with 43.1% taking placebo [adjusted odds ratio 3.12 (95% confidence interval 1.80 to 5.41)]. Adverse reactions were similar between groups, but headaches were reported more commonly on spironolactone (20.4% vs. 12.0%). No serious adverse reactions were reported. Taking account for missing data through multiple imputation gave an incremental cost per quality-adjusted life-year of £27,879 (adjusted) compared to placebo or £2683 per quality-adjusted life-year compared to oral antibiotics., Conclusions: Spironolactone resulted in better participant-reported and investigator-reported outcomes than placebo, with greater differences at week 24 than week 12., Trial Registration: This trial is registered as ISRCTN12892056 and EudraCT (2018-003630-33)., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/13/02) and is published in full in Health Technology Assessment ; Vol. 28, No. 56. See the NIHR Funding and Awards website for further award information.

Background and Objective: Certain patients with heart failure (HF) are unable to tolerate spironolactone therapy due to hyperkalemia. Patiromer is a novel agent used to treat hyperkalemia and has been shown to be efficacious, safe, and well-tolerated. The potential clinical outcomes and economic value of using patiromer and spironolactone in patients with HF unable to otherwise tolerate spironolactone due to hyperkalemia are unclear. The objective of this analysis was to model the potential pharmacoeconomic value of using patiromer and spironolactone in patients with a history of hyperkalemia that prevents them from utilizing spironolactone., Methods: We performed a cost-effectiveness analysis of treatment with patiromer, spironolactone, and an angiotensin-converting enzyme inhibitor (ACEI) in patients with New York Heart Association (NYHA) class III-IV HF compared with ACEI alone. A Markov model was constructed to simulate a cohort of 65-year-old patients diagnosed with HF from the payer perspective across the lifetime horizon. Clinical inputs were derived from the RALES and OPAL-HK randomized trials of spironolactone and patiromer, respectively. Utility estimates and costs were derived from the literature and list prices. Outcomes assessed included hospitalization, life expectancy, and quality-adjusted life-years (QALYs), costs, and the incremental cost-effectiveness ratio (ICER). One-way and probability sensitivity analyses were performed to test the robustness of the model findings., Results: Treatment with patiromer-spironolactone-ACEI was projected to increase longevity compared with ACEI alone (5.29 vs. 4.62 life-years gained, respectively), greater QALYs (2.79 vs. 2.60), and costs (US$28,200 vs. US$18,200), giving an ICER of US$52,700 per QALY gained. The ICERs ranged from US$40,000 to US$85,800 per QALY gained in 1-way sensitivity analyses., Conclusion: Our results suggest that the use of spironolactone-patiromer-ACEI may provide clinical benefit and good economic value in patients with NYHA class III-IV HF unable to tolerate spironolactone due to hyperkalemia.

Background: Eplerenone has been demonstrated as being cost effective for the treatment of patients with systolic heart failure (HF) and mild symptoms in several jurisdictions; however, its cost effectiveness is unknown in the context of Alberta, Canada., Methods: We used a discrete-event simulation model to compare costs and outcomes between standard care and standard care plus eplerenone for the treatment of HF with mild symptoms. We used Alberta data (whenever possible) together with a healthcare perspective, a lifetime horizon, and 3 % annual discount rate for analyses., Results: Clinically, eplerenone prevented HF hospitalizations, atrial fibrillations, and cardiovascular (CV) deaths, but incurred more adverse events and device implantations than standard care. The remaining life of patients receiving eplerenone was 7.08 versus 5.83 years for those receiving standard care. Eplerenone gained 1.25 life-years and 1.18 quality-adjusted life-years (QALYs), with an incremental cost of $Can7200. Therefore, the incremental cost-effectiveness ratio (ICER) was $Can5700 per life-year gained and $Can6100 per QALY gained., Conclusions: Given the most cited ICER threshold is $Can50,000, the use of eplerenone as an adjunct to standard care for treating patients with systolic HF and mild symptoms is cost effective in the context of Alberta. Eplerenone would cost the Alberta health system about $Can4.6 million a year in drug costs. Incorporating reductions in health services utilization associated with eplerenone, the budget impact is smaller. For the first year, the use of eplerenone is cost saving and for 5 years the cost is approximately $Can6 million.

The objective of this study was to determine the cost-effectiveness of eplerenone compared with usual care in patients with chronic heart failure and New York Heart Association (NYHA) Class II symptoms.A Markov model was constructed with 5 health states to reflect NYHA symptom status (Classes I-IV) and death. All subjects began in the "Class II" health state and then moved to other symptom health states or died. Subjects could also be hospitalized for HF in any cycle. Transition probabilities were derived from the Eplerenone in Mild Patients Hospitalization And Survival Study in Heart Failure (EMPHASIS-HF) study. Decision analysis was applied to compare an Eplerenone Group with a Usual Care Group (UCG). In the UCG, 47.3% of subjects in Class II and 93.7% of subjects in Classes III and IV were assumed to be taking spironolactone (as per published data). In the Eplerenone Group, all subjects in Classes II, III, and IV were assumed to be taking eplerenone. The efficacy of spironolactone was assumed to be the same as eplerenone. Cost and utility data were derived from published sources. A discount rate of 5.0% was applied to future costs and benefits. The outcome of interest was incremental cost-effectiveness ratio (ICER) (cost per year of live saved (YoLS) and quality-adjusted life years (QALY) gained).Over 10 years the model predicted that for each patient compared with usual care, eplerenone would lead to 0.26 YoLS (discounted) and 0.19 QALYs gained (discounted), at a net cost of AUD $6961 (discounted). These equate to ICERs of AUD 28,001 per YoLS and AUD 37,452 per QALY gained. Sensitivity analyses indicated a 99.0% likelihood of eplerenone being cost-effective compared with usual care at a willingness to pay threshold of AUD 50,000 per QALY gained.From an Australian healthcare perspective, the addition of eplerenone in management of patients with chronic heart failure and NYHA Class II symptoms represents a cost-effective strategy compared with usual care.

Aim: In the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF), aldosterone blockade with eplerenone decreased mortality and hospitalisation in patients with mild symptoms (New York Heart Association class II) and chronic systolic heart failure (HF). The present study evaluated the cost-effectiveness of eplerenone in the treatment of these patients in the UK and Spain., Methods and Results: Results from the EMPHASIS-HF trial were used to develop a discrete-event simulation model estimating lifetime direct costs and effects (life years and quality-adjusted life years (QALYs) gained) of the addition of eplerenone to standard care among patients with chronic systolic HF and mild symptoms. Eplerenone plus standard care compared with standard care alone increased lifetime direct costs per patient by £4284 for the UK and €7358 for Spain, with additional quality-adjusted life expectancy of 1.22 QALYs for the UK and 1.33 QALYs for Spain. Mean lifetime costs were £3520 per QALY in the UK and €5532 per QALY in Spain. Probabilistic sensitivity analysis suggested a 100% likelihood of eplerenone being regarded as cost-effective at a willingness-to-pay threshold of £20 000 per QALY (UK) or €30 000 per QALY (Spain)., Conclusions: By currently accepted standards of value for money, the addition of eplerenone to optimal medical therapy for patients with chronic systolic HF and mild symptoms is likely to be cost-effective., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Chronic heart failure (CHF) remains an important cause of morbidity and mortality worldwide. Currently, there are no cost-effectiveness studies of eplerenone use in patients with New York Heart Association (NYHA) class II CHF., Objective: We sought to evaluate the cost effectiveness of eplerenone compared with placebo in patients with chronic systolic heart failure and NYHA class II symptoms., Methods and Results: A 10-year Markov model with yearly cycles was constructed to evaluate the cost effectiveness of eplerenone compared with placebo, based on data from the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And Survival Study in Heart Failure) study. The model classified subjects into two health states: 'Alive with CHF' and 'Dead'. Information about the cost of disease was derived from Australian Refined Diagnosis-Related Groups (AR-DRG) data. The cost of eplerenone was taken from the Australian Pharmaceutical Benefit Scheme. Utility data were derived from published sources, and a 5 % annual discount rate was applied to future costs and benefits. Over 10 years, and compared with placebo, the model predicted that eplerenone would lead to a saving of 0.5 life-years (discounted) and 0.4 quality-adjusted life-years (QALYs) per person. The net cost was (in Australian dollars [$A]) $A6,117 (discounted) per person. These equated to incremental cost-effectiveness ratios of $A12,024 per life-year saved and $A16,700 per QALY saved. Sensitivity analyses indicated that these results were robust., Conclusion: Eplerenone may represent a cost-effective strategy for preventing morbidity and mortality among patients with chronic systolic heart failure and NYHA class II symptoms.

The use of a placebo arm in clinical trials is unethical if there is an active comparator that is acceptably safe and effective. We argue that reasonable evidence of effectiveness and safety of an inexpensive alternative to an expensive therapy is sufficient to require that the inexpensive therapy be included as a comparator when the expensive therapy is tested, and that use of an inactive placebo comparator only is not ethical. For example, studies of the expensive drug eplerenone for congestive heart failure have not included a spironolactone arm, although there is reasonable evidence that spironolactone would be safe and effective, and spironolactone is inexpensive. The requirement to study inexpensive therapies is based on avoidance of unnecessary cost in medical care as an example of non-maleficence. Several ethical actors in the design, conduct, and publication of clinical trials and their results bear responsibility for the appropriate conduct of clinical trials. That responsibility includes protecting study subjects from being asked to participate in clinical trials that serve primarily to promote the use of new and expensive therapies.

Background: Socioeconomic deprivation is associated with increased heart failure (HF) incidence, hospitalization rates, and mortality. However, whether the delivery of survival-enhancing medical therapy is equitable remains uncertain. We examined secular trends in the uptake of key medical therapies (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, β-blockers, spironolactone) stratified by socioeconomic circumstances in patients with HF. Secondary analyses examined trends in HF incidence, prevalence, and survival., Methods and Results: This study was a cross-sectional observational analysis of nationally representative primary care data from England. Treatments for patients with HF in 1999 and 2007 (n=13 330) were extracted from the General Practice Research Database. Socioeconomic circumstances were defined with the Index of Multiple Deprivation 2007, a weighted composite of 7 area-level deprivation domains. Treatment uptake estimates were age standardized. The incidence and prevalence of HF decreased year to year. Although clear socioeconomic gradients in both the incidence and prevalence of HF were apparent, the absolute difference between most and least deprived reduced over time. Uptake of therapies improved over time in both men and women. Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker uptake increased from 46% to 64%, β-blocker uptake from 12% to 41%, and spironolactone uptake from 3% to 20%. Modest age and sex inequalities were apparent. However, no consistent socioeconomic gradients were observed in either treatment or case fatality., Conclusions: Socioeconomic gradients in the incidence and prevalence of HF are reducing. Treatment is generally equitable and independent of socioeconomic circumstances. Most important, no significant inequality in outcomes was apparent. Future strategies should continue to address inequalities in the underlying causes of HF and to increase overall treatment levels further.

Introduction: Eplerenone is publicized to be extremely effective in reducing mortality from heart failure, with a reasonable side-effect profile. However, it is much more expensive compared with older aldosterone antagonists. We reviewed available evidence to assess whether increased expense was justified with outcomes data., Methods and Results: The authors searched the PubMed, CENTRAL, CINAHL, and EMBASE databases for randomized controlled trials from 1966 through July 2011. Interventions included aldosterone antagonists (Aldactone [Pfizer, NY, NY], canrenone, eplerenone) in systolic heart failure. The comparator included standard medical therapy or placebo, or both. Outcomes assessed were mortality in the intervention versus the comparator groups, and rates of adverse events at the end of at least 8 weeks of follow-up. Event rates were compared using a forest plot of relative risk (RR) (95% confidence interval [CI]) using a random-effects model (Mantel-Haenszel) between the aldosterone antagonists and controls. We included 13 studies for aldosterone antagonists other than eplerenone, and 3 studies for eplerenone. There was significant reduction of mortality with all aldosterone antagonists, but eplerenone (15% mortality relative reduction; RR 0.85; 95% CI, 0.77-0.93; P=.0007) was outperformed by other aldosterone antagonists, namely, spironolactone and canrenone (26% mortality relative reduction; RR 0.74; 95% CI, 0.66-0.83; P <.0001). Reduction in cardiovascular mortality with eplerenone was 17% (RR 0.83; 95% CI, 0.75-0.92; P=.0005), while that with other aldosterone antagonists was 25% (RR 0.75; 95% CI, 0.67-0.84, P <.0001), without contributing significantly to an improved side-effect profile., Conclusion: Eplerenone does not appear to be more effective in reducing clinical events compared with older, less expensive aldosterone antagonists., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Two aldosterone inhibitors are currently licensed for heart failure (HF) in the UK: spironolactone and eplerenone. Recent clinical guidelines recommend eplerenone after an acute myocardial infarction (MI) for patients with symptoms and/or signs of HF and left ventricular dysfunction., Objectives: The primary objective was to evaluate relative clinical effectiveness and cost-effectiveness of spironolactone and eplerenone in patients with postMI HF and explore the possibility of conducting an indirect comparison of spironolactone and eplerenone. A second objective was to undertake value-of-information (VOI) analyses to determine the need for further research to identify research questions critical to decision-making and to help inform the design of future studies., Data Sources: Relevant databases including MEDLINE, EMBASE and CENTRAL were searched between September and December 2008. Randomised controlled trials (RCTs) of spironolactone, eplerenone, canrenone or potassium canrenoate were included if conducted in a postMI HF population. Trials of general HF patients with a subgroup of postMI HF patients were considered if they had at least 100 ischaemic participants per arm and the authors provided subgroup data when contacted. Adverse events summary data were sought from recognised reference sources and RCTs or observational studies in any population that recruited more than 100 participants., Review Methods: The comparative clinical effectiveness and cost-effectiveness of spironolactone and eplerenone was derived using Bayesian meta-regression drawing on a wider 'network' of aldosterone trials to those considered in the main clinical effectiveness review. An alternative scenario was also considered assuming a 'class effect' for the aldosterone antagonists in terms of major clinical events, but allowing for potential differences in side effect profiles. Cost-effectiveness was assessed using incremental cost-effectiveness ratios (ICERs) where appropriate. Uncertainty in cost-effectiveness results was also presented and used to inform future research priorities using VOI analyses based on expected value of perfect information (EVPI). A probabilistic decision analytic model was developed to estimate cost-effectiveness of spironolactone, eplerenone and standard care for management of postMI HF, provide estimates relevant to the NHS and explore alternative approaches to an indirect comparison between spironolactone and eplerenone. The model incorporated a lifetime horizon to estimate outcomes in terms of quality-adjusted life-years (QALYs) and costs from the NHS persepctive. In the base-case analysis, 2-year treatment duration was assumed, consistent with the follow-up in the main RCTs. Other scenarios were explored to examine the robustness of alternative assumptions including impact of different treatment durations., Results: Searches yielded five RCTs: two spironolactone trials of poor methodological quality and three trials of which only one (of eplerenone) specifically examined postMI HF (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study, EPHESUS). One trial of spironolactone (Randomised Aldactone Evaluation Study, RALES) and one of canrenone (Antiremodelling Effect of Aldosterone receptors blockade with canrenone In mild Chronic Heart Failure, AREA IN-CHF) comprised general HF, but data were available for an ischaemic subgroup. Structural similarity of spironolactone and eplerenone suggests that they may be interchangeable, but formal indirect comparison between the three trials was severely limited by trial differences. Relative safety data were limited from RCTs and observational sources. Hyperkalaemia rates varied, but were generally higher than for placebo; data were insufficient to assess discontinuation because of hyperkalaemia.Gynaecomastia rates were higher with spironolactone. Adverse event data were sparse. Systematic review of economic evidence identified three main published studies but none used a UK perspective or attempted to compare cost-effectiveness in postMI HF. The new decision model indicated that eplerenone was the most cost-effective strategy for postMI HF (ICER of eplerenone compared with standard care was 4457 pounds per QALY, increasing to 7893 pounds per QALY if treatment continued over the patient's lifetime); in neither scenario did spironolactone appear cost-effective. The ICER of eplerenone was consistently under the 20,000-30,000 pounds per QALY threshold used to establish value for money in the NHS. Uncertainty resulted in EVPI estimates between 820M pounds (base-case) and 1265M pounds (lifetime treatment duration scenario). When class effect for mortality and hospitalisations was assumed spironolactone emerged as the most cost-effective treatment and EVPI estimates were negligible. If class effect is considered more plausible than the results of the evidence synthesis model then there would be limited value in additional research., Limitations: Exchangeability between trials was poor and there was a lack of robust data in RCTs., Conclusions: Only two good-quality trials of aldosterone inhibitors in the postMI HF population were found, but lack of exchangeability with respect to study populations, meant that a comparison between these drugs could not be done. It consistently emerged that, compared with usual care, use of an aldosterone antagonist appears to be a highly cost-effective strategy for the management of postMI HF patients in the NHS. An adequately powered, well-conducted RCT that directly compares spironolactone and eplerenone is required to provide more robust evidence on the optimal management of postMI HF patients.

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 beta-blockers (beta-adrenoceptor antagonists) at baseline. In the EPHESUS, a total of 6632 patients were randomized to receive eplerenone 25-50 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 beta-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 $US3.60 per day (year 2004 value). Bootstrap methods were used to estimate the fraction of the joint distribution of the cost and effectiveness. A net-benefit regression model was used to derive the propensity score-adjusted cost-effectiveness curve. The incremental cost effectiveness of eplerenone in cost per life-year gained (LYG) and cost per quality-adjusted life-year (QALY) gained beyond the trial period was estimated using data from the Framingham Heart Study, the Saskatchewan Health database, and the Worcester Heart Attack Registry. Both costs and effectiveness were discounted at 3%. Although not all resource use could be accounted for, the overall perspective was societal., Results: As in the overall EPHESUS population, the total direct treatment costs were higher in the eplerenone arm than the placebo arm for patients who were taking both ACE inhibitors and beta-blockers ($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., Conclusion: 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 beta-blockers.

Background: Although a variety of prognostic tools have been shown to predict rehospitalization and mortality in heart failure patients, their utility in assessing future costs is less clear. We assessed whether health status assessment with the Kansas City Cardiomyopathy Questionnaire (KCCQ) predicts future costs in stable heart failure outpatients with left ventricular dysfunction after myocardial infarction., Methods and Results: We evaluated 12-month cost utilization data from 1516 heart failure outpatients enrolled in the Quality-of-Life Substudy of the Eplerenone Post-Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Multivariable hierarchical models assessed whether the KCCQ (categorized as 0 to <25, 25 to <50, 50 to <75, and 75 to 100) was an independent predictor of future resource use. At baseline, 685 patients (45.2%) had good health status (KCCQ scores > or =75), whereas 510 (33.6%), 262 (17.3%), and 59 (3.9%) had fair (KCCQ, 50 to 74), poor (KCCQ, 25 to 49), and the worst (KCCQ <25) health status, respectively. After multivariable adjustment, compared with patients with good health status, patients with fair health status incurred incremental 1-year costs of $1520 (cost ratio, 1.23; 95% confidence interval, 1.05 to 1.43), whereas patients with poor and the worst health status incurred incremental 1-year costs of $4265 (cost ratio, 1.63; 95% confidence interval, 1.34 to 1.99) and $8999 (cost ratio, 2.34; 95% confidence interval, 1.62 to 3.38), respectively (P<0.0001 for association with KCCQ). Further adjustment for New York Heart Association class led to only partial attenuation of this relationship (P=0.0002)., Conclusions: Health status assessment predicts resource use and costs over the next year in stable heart failure outpatients with left ventricular dysfunction after myocardial infarction.

Background: The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) randomized clinical trial demonstrated the efficacy of eplerenone, a new aldosterone antagonist diuretic, with standard treatment versus standard treatment alone in the reduction of cardiovascular mortality and cardiovascular-related hospital readmissions for patients with heart failure after an acute myocardial infarction., Aim: We assessed the incremental cost per life-year saved of eplerenone in the French context versus standard treatment., Methods: A within-trial study was designed. A piecewise regression model yielded death rates and survival gains adjusted for patients' characteristics, based on the extraction of comparable patients from the Saskatchewan Health database. Resource use was collected alongside the clinical trial data. Only direct medical costs were considered. All costs were in 2003 euros. Costs and outcomes were discounted at 5%., Results: The overall mortality rate was 14.4% in the treatment group versus 16.7% in the placebo group (p=0.008). Combined cardiovascular deaths and hospitalization rates were 26.7% in the treatment group versus 30.3% in the placebo group (p=0.002). The discounted survival gain was 3.2 weeks. The incremental cost per life-year saved was euro15,382 (95% confidence interval 8274-42,723). Seventy-four per cent of the values of the incremental cost-effectiveness ratio fell under a euro15,000 per life-year saved threshold., Conclusion: The cost of eplerenone leads to an acceptable level of incremental cost per life-year saved when compared with existing treatments in the cardiovascular domain for the prevention of cardiovascular death and morbidity in patients with heart failure after an acute myocardial infarction.

In order to allocate health care resources more efficiently, it is necessary to relate health improvements provided by new medicines to their cost. It is necessary to ascertain when the additional cost of introducing a new health technology is justified by the additional health gain produced. Eplerenone is a new medicine that reduces the risk of death after myocardial infarction (MI) but produces additional cost to the health system. The contingent valuation approach can be used to measure the monetary value of this risk reduction and to estimate society's willingness to pay (WTP) for a new medicine that reduces the risk of death after MI by 2% points. We used a contingent valuation approach to evaluate WTP amongst members of the general population. We used the ex-ante and the ex-post approach. In the ex-ante approach, subjects are asked if they would accept an increase in their taxes in order to have access to eplerenone should they need it in the future. In the ex-post approach, subjects are asked if they would pay a certain amount of money as co-payment per month during 5 years if they suffered an MI. We used the dichotomous choice method, using five bids in each approach. The WTP was estimated using both single-bound and double-bound dichotomous choice (SBDC, DBDC). Extensive piloting (n = 187) preceded the final survey (n = 350). The WTP in the ex-ante case was euro 58 per year under both SBDC and DBDC. In the ex-post case, monthly WTP was euro 141 for the SBDC and euro 85 for the DBDC. Subjects with higher income and subjects with a higher perception of risk showed a higher WTP (P 0.05). Society is willing to pay an additional amount of money in order to give eplerenone to present and future patients. We estimate that euro 85 per month is a conservative estimate of the monetary value of a 2% risk reduction in mortality after MI and to spend this additional amount of money in Eplerenone can be considered an efficient policy.

Each year in the UK, an estimated 50,000 patients develop major left ventricular systolic dysfunction (LVSD) and heart failure following a myocardial infarct.1 Such patients have a particularly poor prognosis. Eplerenone (Inspra - Pfizer) is an aldosterone-receptor antagonist for patients who have LVSD and heart failure following a recent myocardial infarct. Here, we discuss whether such patients should receive this drug.

Multiple studies now demonstrate that autism is medically characterized, in part, by immune system dysregulation, including evidence of neuroglial activation and gastrointestinal inflammation. This neuroglial process has further been characterized as neuroinflammation. In addition, a subset of autistic children exhibit higher than average levels of androgens. Spironolactone is an aldosterone antagonist and potassium-sparing diuretic with a desirable safety profile. It possesses potent anti-inflammatory and immune modifying properties that might make it an excellent medical intervention for autism spectrum disorders. Furthermore, spironolactone demonstrates substantial anti-androgen properties that might further enhance its appeal in autism, particularly in a definable subset of hyperandrogenic autistic children. One case report is briefly reviewed demonstrating objective clinical improvements in an autistic child after spironolactone administration. Additional research in controlled trials is now needed to further define the risks and benefits of spironolactone use in children with autism.

Development of heart failure (HF) or left ventricular systolic dysfunction (LVSD) significantly increases mortality post acute myocardial infarction (AMI). Aldosterone contributes to the development and progression of HF post AMI, and major guidelines now recommend aldosterone blockade in this setting. However, lack of practical experience with aldosterone blockade may make clinicians hesitant to use these therapies. This review is based on a consensus cardiology conference that occurred in May 2005 (New York City) concerning these topics. Potential barriers to the use of aldosterone blockade are discussed and an algorithm for appropriate in-hospital pharmacologic management of AMI with LVSD and/or HF is presented.

Objective: The EPHESUS study demonstrated that aldosterone blockade with eplerenone decreased mortality in patients with left ventricular systolic dysfunction (LVSD) and heart failure after acute myocardial infarction (AMI). The EPHESUS pharmacoeconomic analysis was performed to evaluate the cost-effectiveness of eplerenone in the Swiss setting., Materials and Methods: A total of 6,632 patients with LVSD and heart failure after AMI were randomized to eplerenone or placebo and followed for a mean of 16 months. The co-primary endpoints were all-cause death and the composite of cardiovascular death/cardiovascular hospitalization. The evaluation of resource use included hospitalizations, outpatient services, and medications. Survival beyond the trial period was estimated using data from the Framingham Heart Study, the Saskatchewan Health database, and the Worcester Heart Attack Registry. The incremental cost-effectiveness of eplerenone in cost per life-year and quality-adjusted life-year gained was estimated. The perspective of the Swiss third party payers was used. Daily treatment costs of eplerenone were set at CHF 3.88. All other resources were valued on the basis of official tariffs. Discounting of the results was performed at a rate of 3%., Results: The number of life-years gained with eplerenone was 0.1083 based on Framingham, 0.0661 with Saskatchewan and 0.1518 with Worcester survival estimates. Total costs were CHF 1,028 higher over the trial period in the eplerenone arm, due to drug cost. The incremental cost-effectiveness ratio was CHF 10,145 per life-year gained with Framingham, CHF 16,178 with Saskatchewan, and CHF 7,693 with Worcester survival estimates. The corresponding costs per QALY were CHF 15,219, CHF 23,965 and CHF 11,337, respectively., Conclusion: Eplerenone is effective in reducing mortality and, in Switzerland, is also cost-effective in increasing years of life for patients with LVSD after AMI.

[reaction: see text] Whereas ozonization of furan 3a affords little or no carboxylic acid 5, ozonization of the corresponding trans-enedione 6 afforded carboxylic acid 5 in 82.4% yield (cryst., overall from furan, 100 g scale; after workup with dimethyl sulfide, followed by mildly basic hydrogen peroxide). This new approach to furan degradation is showcased in a cost-effective synthesis of eplerenone, an important new medicine for cardiovascular indications.

Congestive heart failure (CHF) is the most common cause of cardiovascular hospital admission. A significant proportion of the costs of CHF is due to hospitalizations. The present study evaluated the economic impact of a modest increase in the use of angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, spironolactone and digoxin on CHF hospitalizations. Patients with CHF were identified through the Canadian Institute for Health Information (CIHI) database. The efficacy of ACE inhibitors, beta-blockers, spironolactone and digoxin in the first year of treatment were retrieved from the Survival and Ventricular Enlargement (SAVE) trial, a meta-analysis, the Randomized Aldactone Evaluation Study (RALES) and the Digitalis Investigation Group (DIG) trial, respectively. Cost of CHF hospitalization was based on the National List of Provincial Costs. Costs of drug treatment were based on the 2002 Alberta Health and Wellness Drug Benefit list. Physician visits for drug titration were also included in the model. A total of 85,679 patients with CHF were identified with a total of 106,130 hospital discharges. A 10% increase in use of ACE inhibitors, beta-blockers, spironolactone and digoxin would incur in a total cost due to avoidable hospital admissions of 0.4 million dollars, 1.3 million dollars, 3.7 million dollars and 1.2 million dollars, respectively. Similarly, the costs of drug treatment would be 2.2 million dollars, 1.3 million dollars, 0.3 million dollars and 0.5 million dollars, respectively. An increase in the use of the above medications would save 6.6 million dollars due to avoidable hospital admissions. The total cost of drug treatment was 4.3 million dollars, giving a net savings of 2.3 million dollars in the first year. The implementation of evidence-based therapy for CHF treatment is not only clinically efficacious, but also economically attractive.

Background: In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), aldosterone blockade with eplerenone decreased mortality in patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction. The present study was performed to evaluate the cost-effectiveness of eplerenone compared with placebo in these patients., Methods and Results: A total of 6632 patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction were randomized to eplerenone or placebo and followed up for a mean of 16 months. The coprimary end points were all-cause mortality and the composite of cardiovascular mortality/cardiovascular hospitalization. The evaluation of resource use included hospitalizations, outpatient services, and medications. Eplerenone was priced at the average wholesale price, 3.60 dollars per day. Survival beyond the trial period was estimated from data from the Framingham Heart Study, the Saskatchewan Health database, and the Worcester Heart Attack Registry. The incremental cost-effectiveness of eplerenone in cost per life-year and quality-adjusted life-year gained compared with placebo was estimated. The number of life-years gained with eplerenone was 0.1014 based on Framingham (95% CI, 0.0306 to 0.1740), 0.0636 with Saskatchewan (95% CI, 0.0229 to 0.1038), and 0.1337 with Worcester (95% CI, 0.0438 to 0.2252) data. Cost was 1391 dollars higher over the trial period in the eplerenone arm (95% CI, 656 to 2165) because of drug cost. The incremental cost-effectiveness ratio was 13,718 dollars per life-year gained with Framingham (96.7% under 50,000 dollars per life-year gained), 21,876 dollars with Saskatchewan, and 10,402 dollars with Worcester., Conclusions: Eplerenone compared with placebo in the treatment of heart failure after acute myocardial infarction is effective in reducing mortality and is cost-effective in increasing years of life by commonly used criteria.

Eplerenone (Inspra) is a selective aldosterone blocker. When added to standard medical therapy, eplerenone significantly improved morbidity and mortality in patients with left ventricular (LV) systolic dysfunction and clinical evidence of heart failure following acute myocardial infarction (MI), in a well designed, placebo-controlled trial known as EPHESUS (Eplerenone Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study). Although eplerenone was generally well tolerated, it was associated with a higher incidence of hyperkalaemia than placebo.Cost-effectiveness analyses based on this trial have been performed in the US, The Netherlands, Germany, France and Spain. Direct medical costs were analysed based on prospectively collected resource-use data with local costs applied; modelling was conducted to calculate incremental costs per life-year or QALY gained, with survival curves assumed to remain parallel after treatment ended. Eplerenone was associated with a gain of 0.0304 life-years (approximately 11 days) compared with placebo during the study period. Based on these analyses, eplerenone was cost effective compared with placebo in patients with LV systolic dysfunction and heart failure after an MI when added to standard therapy for 16 months. The incremental cost per life-year gained for eplerenone versus placebo (for a range of three different life-expectancy projections) was 10,402-21,876 US dollars in the US (year 2001 costs, except for eplerenone [2004]) [equivalent to 12,274-25,814 euro; mid-2001 exchange rate], 5,365-12,795 euro for The Netherlands (year 2003 costs), 6,956-14,628 euro for Germany, 5,432-11,423 euro for France and 8,626-18,141 euro for Spain (year of costing not reported). The US, Dutch, French and Spanish analyses estimated that >90% of observations for incremental cost per life-year gained were below a threshold of 50,000 US dollars or 50,000 euro. Incremental costs per QALY gained for eplerenone versus placebo in the US, Dutch, French and Spanish analyses were 15,330-32,405 US dollars (18,089-38,238 euro), 12,148, 8,005-16,922 euro and 12,713-26, 873 euro, respectively. Clinical and pharmacoeconomic data comparing eplerenone with another active drug, such as spironolactone, in this patient population are not available. In conclusion, when added to standard therapy in patients with LV systolic dysfunction and heart failure after an acute MI, eplerenone was associated with significant reductions in mortality and morbidity compared with placebo. Despite some inherent limitations, available pharmacoeconomic data from Europe and the US indicate that eplerenone is a cost-effective treatment compared with placebo in terms of incremental cost per life-year gained in this patient population.

Objective: To evaluate the pharmacology, pharmacokinetics, safety, and clinical use of eplerenone in heart failure (HF)., Data Sources: English-language MEDLINE searches were performed from 1966 to May 2004. Key words included eplerenone, aldosterone receptor antagonist, heart failure, myocardial infarction, left-ventricular dysfunction, and cost-effectiveness. Additional references were identified from bibliographies of selected articles., Study Selection and Data Extraction: Human trials evaluating the efficacy, safety, and cost-effectiveness of aldosterone receptor antagonists in HF were evaluated., Data Synthesis: Eplerenone is the first selective aldosterone receptor antagonist. The drug is indicated to improve the survival of stable patients with left-ventricular systolic dysfunction (ejection fraction <40%) and clinical evidence of HF following acute myocardial infarction. Efficacy and safety in this population have been demonstrated in a large, randomized clinical trial. Eplerenone is associated with severe and sometimes life-threatening hyperkalemia. Patients with reduced renal function and diabetes, as well as those on other drugs that increase potassium levels, are at highest risk. Eplerenone is metabolized by the cytochrome P450 system and may interact with drugs that interfere with this system. A major advantage of eplerenone over the nonselective aldosterone receptor antagonist spironolactone is lack of binding to progesterone and androgen receptors, which is associated with drug-induced gynecomastia, breast pain, and impotence., Conclusions: The addition of eplerenone to traditional HF therapy has been shown to reduce morbidity and mortality in patients who develop left-ventricular dysfunction after acute myocardial infarction. Eplerenone's selectivity reduces sex hormone-related adverse effects. Despite these benefits, the overall cost-effectiveness has yet to be determined.

Background: Management of heart failure is estimated to consume between 1% and 2% of total healthcare resources with hospital admissions accounting for up to 70% of this. The ability of the aldosterone antagonist spironolactone to reduce hospital admission rates by 35% would be expected to prove cost-effective., Aim: To determine the cost-effectiveness of spironolactone when added to standard therapy in patients with severe chronic heart failure., Methods: A Markov model of chronic heart failure was constructed using Treeage software. Irish cost data were incorporated into the model., Results: The incremental cost-effectiveness ratio (ICER) for spironolactone therapy was Euro 466 per life year gained (LYG). Sensitivity analysis demonstrated an ICER range of Euro 75 to Euro 1,136 per LYG., Conclusion: This economic evaluation suggests that the addition of spironolactone to standard therapy for patients with severe chronic heart failure is not only safe and effective, but is highly cost-effective in the Irish healthcare setting.

Purpose: To use data from the Randomized Aldactone Evaluation Study (RALES) to compare clinical outcomes and costs as part of the assessment of the economic implications of spironolactone treatment of advanced heart failure., Methods: RALES was a randomized, double-blinded, placebo-controlled trial that enrolled participants who had severe heart failure and a left ventricular ejection fraction of no more than 35% and who were receiving standard therapy, including an angiotensin-converting enzyme inhibitor, a loop diuretic, and, in some cases, digoxin. We used a decision analytic model that incorporated data from participants in RALES as well as cost data from five countries that participated in the study. Costs were calculated for nonfatal hospitalizations, ambulatory care, spironolactone therapy, and death. The primary health outcome was quality-adjusted life-years saved (QALYS). Outcomes were evaluated for the first 35 months of observation in RALES., Results: Spironolactone therapy during the first 35 months of follow-up in RALES increased quality-adjusted survival time (0.13 QALYS, 95% CI, 0.07 to 0.18) without increasing costs ($713 savings, 95% CI, $2,123 savings to $783 in costs). Spironolactone therapy either dominated placebo or had a ratio of cost per QALYS that was unlikely to exceed $20,300. These results were robust in both one-way and multiway sensitivity analyses., Conclusions: Even after implementation of current clinical guidelines, addition of spironolactone therapy provides an opportunity to further reduce the large clinical and economic burden of patients with heart failure.

The familiar diuretic spironolactone has taken on new life as a treatment for left-sided congestive heart failure. Spironolactone has been shown to decrease mortality in such patients who are New York Heart Association class IV. It can be used in addition to agents such as angiotensin-converting enzyme inhibitors and beta blockers, which also decrease mortality, and diuretics and digoxin, which are useful in treating symptoms. Spironolactone is safe, easy to use and reasonably priced. More research is necessary to determine the order and combinations of these medications in slowing the progression of this disease.

Background: Chronic heart failure (CHF) is the first cause of hospitalization in elderly patients. The use of spironolactone in patients with CHF (degree III-IV) reduces their mortality and the rate of hospitalization. The aim of this study has been to assess the efficiency of using spironolactone in the treatment of CHF when compared with the use of conventional treatment alone., Material and Methods: The study has been performed through the design of a decision analytic model. A cost-effectiveness analysis was carried out by doing a simulation of 2 hypothetic cohorts of 1000 patients with CHF. It was evaluated the costs of each extra life year gained with each alternative under study. Data included have been obtained from Rales and the mean survival time for these patients has been considered of 4.3 years. Only direct medical costs have been included into this analysis. The chosen perspective has been the society and the time horizon included has been of 4.3 years., Results: The cost/effectiveness ratio has been better in the spironolactone group (1,961,214) than in the standard treatment alone (2,242,912) and each extra life year gained when adding spironolactone to the conventional treatment yielded an additional cost of 591,457 ptas. The sensitivity analysis performed has shown that the option of using spironolactone presents always a better cost/effectiveness ratio even in the worst scenarios., Conclusions: The association of 25 mg/day of spironolactone to the conventional treatment of CHF is going to get more life years gained for these patients with a reasonable cost and clearly affordable by our National Health Service.

Introduction and Objectives: Chronic heart failure (CHF) is a disease with a high morbidity and mortality. The addition of spironolactone (25 mg/day) in the treatment of CHF has demonstrated a reduction in the mortality rate by 30% and in the hospitalization rate by 35%. The aim of this study was to perform a cost-benefit analysis of the association of spironolactone with the standard therapy for heart failure., Methods: This analysis was carried out by assessing all the direct benefits and costs, derived from the association of either spironolactone or placebo with the standard therapy for heart failure in patients with functional degree III and IV. Data of costs and benefits were obtained from RALES. The following costs were included: hospitalisation, complementary tests and medication given. Benefit included avoided hospitalisations, complementary tests not performed and medication saved. The chosen perspective was the National Health Service and the time span chosen was of two years., Results: The cost/patient in the spironolactone group (293,653 pts.) was lower than in placebo group (402,353 pts.). The benefit/patient in the former group (615,690 pts.) was higher than in the latter group (542,014 pts.). The net benefit (benefit-cost) of the spironolactone group (322,037 pts.) was higher than that observed in the placebo group (139,661 pts.)., Conclusions: The association with spironolactone (25 mg/day) with the standard therapy for heart failure produces a remarkable net benefit in monetary terms. This fact will probably generate some resource saving for the National Health Service.