Aims Evidence has accumulated that elevated aldosterone levels are associated with increased risks of fatal cardiovascular (CV) events. With the present analysis, we aimed at evaluating prospectively whether plasma aldosterone correlates with all-cause and CV disease (CVD) mortality in a large cohort of patients.

Methods and results Median plasma aldosterone concentration (PAC) was 79.0 (48.0–124.0) pg/mL (normal range: 30–160) in 3153 patients [median age: 63.5 (56.3–70.6) years; 30.1% women] who had undergone coronary angiography. After a median follow-up of 7.7 (7.2–8.5) years, a total of 716 participants died [22.7%; 454 (14.4%) due to CV causes and 262 (8.3%) due to non-CV causes]. In multivariable Cox proportional hazard analysis, adjusted for age, gender, antihypertensive treatment, and established CV risk factors, PAC levels stratified in quartiles were significantly associated with all-cause and CVD mortality. Compared with the reference (first) PAC quartile, hazard ratios (confidence interval 95%) for the fourth, third, and second PAC quartiles were 1.30 (1.02–1.65, P = 0.033), 1.32 (1.04–1.68, P = 0.021), and 1.20 (0.93–1.54, P = 0.155) for total mortality and 1.58 (1.15–2.16, P = 0.004), 1.39 (1.01–1.90, P = 0.041), and 1.63 (1.20–2.20, P = 0.002) for CVD mortality, respectively. Analyses for specific causes of CV death revealed strong associations between PAC levels and higher risk for fatal stroke and sudden cardiac death.

Conclusion In a large cohort of patients scheduled for coronary angiography, variation in PAC levels within the normal range is associated with increased all-cause and CVD mortality independent of major established CV risk factors.

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Plasma aldosterone levels are associated with increased cardiovascular mortality: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

Aims Myocardial infarction (MI) is a common cause of heart failure (HF), which may develop early and persist or resolve, or develop late. The cumulative incidence, persistence, and resolution of HF after MI are poorly described. The aim of this study is to describe the natural history and prognosis of HF after an MI.

Methods and results Patients with a death or discharge diagnosis of MI in 1998 were identified from records of hospitals providing services to a local community of 600 000 people. Records were scrutinized to identify the development of HF, defined as signs and symptoms consistent with that diagnosis and treated with loop diuretics. HF was considered to have resolved if diuretics could be stopped without recurrent symptoms. Totally, 896 patients were identified of whom 54% had died by December 2005. During the index admission, 199 (22.2%) patients died, many with HF, and a further 182 (20.3%) patients developed HF that persisted until discharge, of whom 121 died subsequent to discharge. Of 74 patients with transient HF that resolved before discharge, 41 had recurrent HF and 38 died during follow-up. After discharge, 145 (33%) patients developed HF for the first time, of whom 76 died during follow-up. Overall, of 281 deaths occurring after discharge, 235 (83.6%) were amongst inpatients who first developed HF.

Conclusion The development of HF precedes death in most patients who die in the short- or long-term following an MI. Prevention of HF, predominantly by reducing the extent of myocardial damage and recurrent MI, and subsequent management could have a substantial impact on prognosis.

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The timing of development and subsequent clinical course of heart failure after a myocardial infarction

The autonomic nervous system plays an important role in the genesis of ventricular arrhythmias and sudden cardiac death. Evidence is substantial for a neural component in sudden cardiac death. Sympathetic nerve sprouting and regional myocardial hyperinnervation following myocardial injury promote cardiac arrhythmia and sudden cardiac death through several potential mechanisms. Modulating autonomic tone is a potential method to reduce the risk of ventricular arrhythmias. Thoracic spinal cord stimulation is showing promise as a treatment for refractory angina. In addition, spinal cord stimulation has protected against ventricular tachycardia/ventricular fibrillation in animal models of postinfarction heart failure.

https://www.ccjm.org/content/ccjom/75/3_suppl_2/S94.full.pdf

Heart-brain interactions in cardiac arrhythmias: role of the autonomic nervous system.

The renin-angiotensin system (RAS) is a hormonal system that controls body fluid volume, blood pressure, and cardiovascular function in both health and disease. Various tissues, including the heart and kidneys, possess individual locally regulated RASs. In each RAS, the substrate protein angiotensinogen is cleaved by the peptidases renin and angiotensin-converting enzyme to form the biologically active product angiotensin II, which acts as an intracrine cardiac and renal hormone. The components of each RAS, including aldosterone (ALDO), may be produced locally and/or may be delivered by or sequestered from the circulation. Overactivity of the cardiac RAS has been associated with cardiac diseases, including cardiac hypertrophy due to volume and/or pressure overload, heart failure, coronary artery disease with myocardial infarction, and hypertension. Overactivity of the renal RAS has been associated with various kidney diseases, including nephropathies and renal artery stenosis. The principal effects of an overactive RAS include the generation of reactive oxygen species, which leads to "oxidative stress," activation of the nuclear transcription factor kappaB, and stimulation of pathways and genes that promote vasoconstriction, endothelial dysfunction, cell hypertrophy, fibroblast proliferation, inflammation, excess extracellular matrix deposition, atherosclerosis, and thrombosis. It has been suggested that oxidative stress is the central mechanism underlying the pathogenesis of RAS-related and ALDO-related chronic cardiovascular and renal tissue injury and of cardiac arrhythmias and conduction disturbances.

https://jim.bmj.com/content/jim/55/7/341.full.pdf

Intracardiac and Intrarenal Renin-Angiotensin Systems: Mechanisms of Cardiovascular and Renal Effects

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.

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A systematic review and economic evaluation of the clinical effectiveness and cost-effectiveness of aldosterone antagonists for postmyocardial infarction heart failure

Aims: Because of the prognostic importance of LV dysfunction following an AMI and the increasing use of electrical and/or mechanical interventions in patients with LV systolic dysfunction, this retrospective analysis of EPHESUS patients with LVEF 30% at baseline was conducted to determine the value of eplerenone in this setting. Methods and results: In EPHESUS, 6632 patients with LVEF 40% and clinical heart failure (HF) post-AMI who were receiving standard therapy were randomized to eplerenone 25 mg/day titrated to 50 mg/day or placebo for a mean follow-up of 16 months. Treatment with eplerenone in the subgroup of patients with LVEF 30% (N=2106) resulted in relative risk reductions of 21% versus placebo in both allcause mortality (P=0.012) and cardiovascular (CV) mortality/CV hospitalization (P=0.001), and 23% for CV mortality (P=0.008). The relative risk of sudden cardiac death (SCD) was reduced 33% (P=0.01) and HF mortality/HF hospitalization was reduced 25% (P=0.005) with eplerenone compared with placebo. Within 30 days of randomization, eplerenone resulted in relative risk reductions of 43% for all-cause mortality (P=0.002), 29% for CV mortality/CV hospitalization (P=0.006), and 58% for SCD (P=0.008). Conclusions: Treatment with eplerenone plus standard therapy in patients with post-AMI HF and LVEF 30% provided significant incremental benefits in reducing both early and late mortality and morbidity.

https://onlinelibrary.wiley.com/doi/pdf/10.1016/j.ejheart.2005.11.008

Eric Q. Klug

Papers

Evaluation of eplerenone in the subgroup of EPHESUS patients with baseline left ventricular ejection fraction 30