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In this trial, 2737 patients with heart failure and LV systolic dysfunction were given eplerenone or placebo in addition to recommended therapy. Eplerenone significantly reduced the risk of the primary outcome, a composite of death or hospitalization. The activation of mineralocorticoid receptors by aldosterone and cortisol has deleterious effects in patients with cardiovascular disease. 1 In the placebo-controlled Randomized Aldactone Evaluation Study (RALES), 2 adding the mineralocorticoid-receptor antagonist spironolactone to recommended therapy in patients with systolic heart failure and moderate-to-severe symptoms (i.e., New York Heart Association [NYHA] functional class III or IV symptoms) decreased the rate of death from any cause and the risk of hospitalization for cardiovascular reasons. In the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), 3 the selective mineralocorticoid-receptor antagonist eplerenone, added to recommended medical therapy, reduced the rates of death from any . . .

Chronic kidney disease (CKD) is associated with a substantial risk of progression to end-stage renal disease and vascular events. The nonsteroidal mineralocorticoid receptor antagonist (MRA), finerenone, offers cardiorenal protection for people with CKD and diabetes, but there is uncertainty if the steroidal MRA, spironolactone, provides the same protection. In this prospective, randomized, open, blinded endpoint trial, we assessed the effectiveness of 25 mg spironolactone in addition to usual care or usual care alone for reducing cardiovascular outcomes in stage 3b CKD among an older community cohort (mean age = 74.8 years and s.d. = 8.1). We recruited 1,434 adults from English primary care, of whom 1,372 (96%) were included in the primary analysis. The primary outcome was time from randomization until the first occurrence of death, hospitalization for heart disease, stroke, heart failure, transient ischemic attack or peripheral arterial disease, or first onset of any condition listed not present at baseline. Across 3 years of follow-up, the primary endpoint occurred in 113 of 677 participants randomized to spironolactone (16.7%) and 111 of 695 participants randomized to usual care (16.0%) with no significant difference between groups (hazard ratio = 1.05, 95% confidence interval: 0.81–1.37). Two-thirds of participants randomized to spironolactone stopped treatment within 6 months, predominantly because they met prespecified safety stop criteria. The most common reason for stopping spironolactone was a decrease in the estimated glomerular filtration rate that met prespecified stop criteria ( n  = 239, 35.4%), followed by participants being withdrawn due to treatment side effects ( n  = 128, 18.9%) and hyperkalemia ( n  = 54, 8.0%). In conclusion, we found that spironolactone was frequently discontinued due to safety concerns, with no evidence that it reduced cardiovascular outcomes in people with stage 3b CKD. Spironolactone should not be used for people with stage 3b CKD without another explicit treatment indication. ClinicalTrials.gov registration: ISRCTN44522369 . A randomized controlled trial involving patients with stage 3b chronic kidney disease from primary care reported that in contrast to reported cardiorenal protective effects of nonsteroidal mineralocorticoid receptor antagonists (MRA), the steroidal MRA spironolactone did not reduce mortality or cardiovascular disease hospitalization compared to usual care.

Inflammation is associated with adverse cardiovascular events. Data from recent trials suggest that colchicine reduces the risk of cardiovascular events. In this multicenter trial with a 2-by-2 factorial design, we randomly assigned patients who had myocardial infarction to receive either colchicine or placebo and either spironolactone or placebo. The results of the colchicine trial are reported here. The primary efficacy outcome was a composite of death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia-driven coronary revascularization, evaluated in a time-to-event analysis. C-reactive protein was measured at 3 months in a subgroup of patients, and safety was also assessed. A total of 7062 patients at 104 centers in 14 countries underwent randomization; at the time of analysis, the vital status was unknown for 45 patients (0.6%), and this information was most likely missing at random. A primary-outcome event occurred in 322 of 3528 patients (9.1%) in the colchicine group and 327 of 3534 patients (9.3%) in the placebo group over a median follow-up period of 3 years (hazard ratio, 0.99; 95% confidence interval [CI], 0.85 to 1.16; P = 0.93). The incidence of individual components of the primary outcome appeared to be similar in the two groups. The least-squares mean difference in C-reactive protein levels between the colchicine group and the placebo group at 3 months, adjusted according to the baseline values, was -1.28 mg per liter (95% CI, -1.81 to -0.75). Diarrhea occurred in a higher percentage of patients with colchicine than with placebo (10.2% vs. 6.6%; P<0.001), but the incidence of serious infections did not differ between groups. Among patients who had myocardial infarction, treatment with colchicine, when started soon after myocardial infarction and continued for a median of 3 years, did not reduce the incidence of the composite primary outcome (death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia-driven coronary revascularization). (Funded by the Canadian Institutes of Health Research and others; CLEAR ClinicalTrials.gov number, NCT03048825.).

Spironolactone is effective at reducing blood pressure in patients with uncontrolled resistant hypertension. However, the use of spironolactone in patients with chronic kidney disease can be restricted by hyperkalaemia. We evaluated use of the potassium binder patiromer to allow more persistent use of spironolactone in patients with chronic kidney disease and resistant hypertension. In this phase 2 multicentre, randomised, double-blind, placebo-controlled study, we enrolled participants aged 18 years and older with chronic kidney disease (estimated glomerular filtration rate 25 to ≤45 mL/min per 1·73 m2) and uncontrolled resistant hypertension from 62 outpatient centres in ten countries (Bulgaria, Croatia, Georgia, Hungary, Ukraine, France, Germany, South Africa, the UK, and the USA). Patients meeting all eligibility criteria at the final screening visit were stratified by local serum potassium measurement (4·3 to <4·7 mmol/L vs 4·7 to 5·1 mmol/L) and history of diabetes. Participants were randomly assigned (1:1) with an interactive web response system to receive either placebo or patiromer (8·4 g once daily), in addition to open-label spironolactone (starting at 25 mg once daily) and their baseline blood pressure medications. Participants, the study team that administered treatments and measured blood pressure, and the investigators were masked to assigned treatment groups. Dose titrations were permitted after 1 week (patiromer) and 3 weeks (spironolactone). The primary endpoint was the between-group difference at week 12 in the proportion of patients on spironolactone. Efficacy endpoints and safety were assessed in all randomised patients (intention to treat). The study was registered with Clinicaltrials.gov, NCT03071263. Between Feb 13, 2017, and Aug 20, 2018, we screened 574 patients. 295 (51%) of 574 patients met all inclusion criteria and were randomly assigned to spironolactone in addition to double-blind treatment with either placebo (n=148) or patiromer (n=147). At week 12, 98 (66%) of 148 patients in the placebo group and 126 (86%) of 147 patients in the patiromer group remained on spironolactone (between-group difference 19·5%, 95% CI 10·0–29·0; p<0·0001). Adverse events were mostly mild or moderate in severity and occurred in 79 (53%) of 148 patients in the placebo group and 82 (56%) of 147 patients in the patiromer group. In patients with resistant hypertension and chronic kidney disease, patiromer enabled more patients to continue treatment with spironolactone with less hyperkalaemia. Persistent spironolactone enablement in this population of patients has clinical relevance for the treatment of resistant hypertension. Relypsa, a Vifor Pharma Group Company.

Patients undergoing maintenance dialysis for kidney failure are at substantial risk of cardiovascular morbidity and mortality. We aimed to establish if spironolactone reduces heart failure and cardiovascular deaths in these patients. ACHIEVE was an international, parallel-group, randomised controlled trial done in 143 dialysis programmes in 12 countries. Patients were aged 45 years or older, or aged 18 years or older with a history of diabetes, and were receiving maintenance dialysis for kidney failure for at least 3 months at the time of recruitment. Patients who were able to tolerate and adhere to spironolactone 25 mg daily orally during an open-label run-in were randomly assigned (1:1) to continue spironolactone or matching placebo, using a central computerised block randomisation system (block sizes of 4) stratified by centre. Participants, health-care providers, and those assessing outcomes were masked to group assignment. The primary outcome was a composite of cardiovascular mortality or hospitalisation for heart failure analysed as time-to-event in all randomly assigned participants. The trial was registered at ClinicalTrials.gov, NCT03020303. After a planned interim analysis of 75% of the expected primary outcome events, the external safety and efficacy monitoring committee recommended the trial be stopped early for futility. From Sept 19, 2017, to Oct 31, 2024, 3689 patients were screened for inclusion, 3565 of whom were enrolled in the open-label run-in phase, and 2538 were randomly assigned to spironolactone (n=1260) or placebo (n=1278). 931 (36·7%) participants were female and 1607 (63·3%) were male. Median follow-up was 1·8 years (IQR 0·85–3·35). The composite primary outcome occurred in 258 participants (10·46 events per 100 patient-years) in the spironolactone group and in 276 participants (11·33 per 100 patient-years) in the placebo group (hazard ratio [HR] 0·92 [95% CI 0·78–1·09]; p=0·35). Death from any cause was similar between groups (HR 0·95 [0·83–1·09]) as was hospitalisation for any cause (HR 0·96 [0·87–1·06]). Among patients receiving maintenance dialysis, spironolactone 25 mg daily orally did not reduce the composite outcome of cardiovascular mortality and hospitalisation due to heart failure compared with placebo. This trial did not identify a benefit of initiating spironolactone in patients receiving maintenance dialysis. Future research should consider alternatives to steroidal mineralocorticoid receptor antagonism to reduce cardiovascular morbidity and mortality in patients receiving maintenance haemodialysis. The Canadian Institutes of Health Research, The Medical Research Future Fund, The Health Research Council, The British Heart Foundation, Population Health Research Institute/Hamilton Health Sciences Research Institute, St Joseph's Healthcare Hamilton Division of Nephrology, Accelerating Clinical Trials Consortium, Can-SOLVE CKD Network, and the Dalhousie Department of Medicine.

In this trial, 3445 patients with heart failure and a preserved ejection fraction were assigned to spironolactone or placebo. At a mean of 3.3 years, there was no significant difference in death from cardiovascular causes, aborted cardiac arrest, or hospitalization for heart failure. Many patients with heart failure have a normal or near-normal left ventricular ejection fraction. 1 – 4 Such patients share common signs and symptoms, as well as an impaired quality of life and a poor prognosis, with patients who have heart failure and a reduced ejection fraction. 5 – 8 However, the benefit of most medical therapies for heart failure is limited to those with a reduced ejection fraction, generally 40% or less. 1 , 2 , 9 The lack of favorable evidence from clinical-outcome trials involving patients with heart failure and a preserved left ventricular ejection fraction is reflected in current guidelines, which offer no specific . . .

No pharmacological therapy has been shown with certainty to improve the cardiovascular prognosis in patients with kidney failure on chronic haemodialysis. We aimed to investigate the effects of the steroidal mineralocorticoid receptor antagonist spironolactone on cardiovascular outcomes in patients on haemodialysis who are at high risk of cardiovascular events. ALCHEMIST was an investigator-initiated, multicentre, double-blind, randomised, placebo-controlled, event-driven trial conducted at 64 university hospitals, general hospitals, and non-profit or private practice dialysis centres in France, Belgium, and Monaco. Adult patients aged 18 years and older with kidney failure on chronic haemodialysis with at least one cardiovascular comorbidity or risk factor were enrolled into a 4-week run-in period on open-label oral spironolactone 25 mg every other day. Participants were randomly assigned (1:1) to oral spironolactone titrated to 25 mg per day or placebo. The randomisation sequence was computer generated and stratified by centre in blocks of 4 or 6, and permutation of treatments within each block. The random assignment was double-blinded. The primary endpoint was time to first major adverse cardiovascular event (cardiovascular death, non-fatal myocardial infarction, acute coronary syndrome, stroke, or hospitalisation for heart failure) and was analysed in the intention-to-treat population. We also performed an updated meta-analysis of double-blind, randomised controlled trials of mineralocorticoid receptor antagonists in patients on haemodialysis incorporating data from ALCHEMIST. The study was registered with ClinicalTrials.gov, NCT01848639. Between June 13, 2013, and Nov 24, 2020, 1442 patients were locally screened for eligibility. 823 patients were included in the trial and 794 entered the run-in period. 644 patients were randomly assigned to spironolactone (n=320) or placebo (n=324). 444 (69%) patients were men and 200 (31%) were women. The trial was stopped prematurely due to lack of funding from the sponsor. Median follow-up was 32·6 months (IQR 17·3–48·4). The primary endpoint occurred in 78 (24%) of 320 patients in the spironolactone group (10·66 per 100 patient-years [95% CI 8·54–13·31]) and 79 (24%) of 324 patients in the placebo group (10·70 per 100 patient-years [8·59–13·35]; hazard ratio [HR] 1·00 [95% CI 0·73–1·36]; p=0·98). Hyperkalaemia above 6 mmol/L was reported in 135 (42%) patients in the spironolactone group and 134 (41%) in the placebo group (HR 1·12 [95% CI 0·88–1·43]). In the meta-analysis, mineralocorticoid receptor antagonists did not reduce all-cause or cardiovascular mortality or non-fatal cardiovascular events and did not increase the odds of hyperkalaemia events (serum potassium concentration >6 mmol/L). In patients with kidney failure on haemodialysis and with high risk of adverse cardiovascular outcomes, spironolactone did not reduce the incidence of major cardiovascular events. The updated meta-analysis shows that mineralocorticoid receptor antagonists did not reduce all-cause or cardiovascular mortality. Therefore, off-label use of spironolactone in this setting is not supported by available evidence. French Ministry of Health.

Cardiomyopathy is a leading cause of death in patients with Duchenne muscular dystrophy and myocardial damage precedes decline in left ventricular systolic function. We tested the efficacy of eplerenone on top of background therapy in patients with Duchenne muscular dystrophy with early myocardial disease. In this randomised, double-blind, placebo-controlled trial, boys from three centres in the USA aged 7 years or older with Duchenne muscular dystrophy, myocardial damage by late gadolinium enhancement cardiac MRI and preserved ejection fraction received either eplerenone 25 mg or placebo orally, every other day for the first month and once daily thereafter, in addition to background clinician-directed therapy with either angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Computer-generated randomisation was done centrally using block sizes of four and six, and only the study statistician and the investigational pharmacy had the preset randomisation assignments. The primary outcome was change in left ventricular circumferential strain (Ecc) at 12 months, a measure of contractile dysfunction. Safety was established through serial serum potassium levels and measurement of cystatin C, a non-creatinine measure of kidney function. This trial is registered with ClinicalTrials.gov, number NCT01521546. Between Jan 26, 2012, and July 3, 2013, 188 boys were screened and 42 were enrolled. 20 were randomly assigned to receive eplerenone and 22 to receive placebo, of whom 20 in the eplerenone group and 20 in the placebo group completed baseline, 6-month, and 12-month visits. After 12 months, decline in left ventricular circumferential strain was less in those who received eplerenone than in those who received placebo (median ΔEcc 1·0 [IQR 0·3–2·2] vs 2·2 [1·3–3·1]; p=0·020). Cystatin C concentrations remained normal in both groups, and all non-haemolysed blood samples showed normal potassium concentrations. One 23-year-old patient in the placebo group died of fat embolism, and another patient in the placebo group withdrew from the trial to address long-standing digestive issues. All other adverse events were mild: short-lived headaches coincident with seasonal allergies occurred in one patient given eplerenone, flushing occurred in one patient given placebo, and anxiety occurred in another patient given placebo. In boys with Duchenne muscular dystrophy and preserved ejection fraction, addition of eplerenone to background ACEI or ARB therapy attenuates the progressive decline in left ventricular systolic function. Early use of available drugs warrants consideration in this population at high risk of cardiac death, but further studies are needed to determine the effect of combination cardioprotective therapy on event-free survival in Duchenne muscular dystrophy. BallouSkies, Parent Project for Muscular Dystrophy, US National Center for Advancing Translational Sciences, and US National Institutes of Health.

Blockade of aldosterone receptors with spironolactone is beneficial in patients with chronic heart failure. This study evaluated eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction and heart failure after myocardial infarction. Eplerenone reduced overall and cardiovascular mortality by about 15 percent. Eplerenone reduced mortality in patients with chronic heart failure. Aldosterone blockade reduces the rate of death due to progressive heart failure and the rate of sudden death from cardiac causes, as well as the rate of hospitalizations for heart failure, among patients with severe heart failure due to systolic left ventricular dysfunction who are being treated with an angiotensin-converting–enzyme (ACE) inhibitor. 1 Aldosterone blockade also prevents ventricular remodeling and collagen formation in patients with left ventricular dysfunction after acute myocardial infarction 2 and affects a number of pathophysiological mechanisms that are thought to be important in the prognosis of patients with acute myocardial infarction. 3 – 12 Its role in reducing mortality and . . .

Mineralocorticoid receptor antagonists have been shown to reduce mortality in patients after myocardial infarction with congestive heart failure. Whether routine use of spironolactone is beneficial after myocardial infarction is uncertain. In this multicenter trial with a 2-by-2 factorial design, we randomly assigned patients with myocardial infarction who had undergone percutaneous coronary intervention to receive either spironolactone or placebo and either colchicine or placebo. The results of the spironolactone trial are reported here. The two primary outcomes were a composite of death from cardiovascular causes or new or worsening heart failure, evaluated as the total number of events; and a composite of the first occurrence of myocardial infarction, stroke, new or worsening heart failure, or death from cardiovascular causes. Safety was also assessed. We enrolled 7062 patients at 104 centers in 14 countries; 3537 patients were assigned to receive spironolactone and 3525 to receive placebo. At the time of our analyses, the vital status was unknown for 45 patients (0.6%). For the first primary outcome, there were 183 events (1.7 per 100 patient-years) in the spironolactone group as compared with 220 events (2.1 per 100 patient-years) in the placebo group over a median follow-up period of 3 years (hazard ratio adjusted for competing risk of death from noncardiovascular causes, 0.91; 95% confidence interval [CI], 0.69 to 1.21; P = 0.51). With respect to the second primary outcome, an event occurred in 280 of 3537 patients (7.9%) in the spironolactone group and 294 of 3525 patients (8.3%) in the placebo group (hazard ratio adjusted for competing risk, 0.96; 95% CI, 0.81 to 1.13; P = 0.60). Serious adverse events were reported in 255 patients (7.2%) in the spironolactone group and 241 (6.8%) in the placebo group. Among patients with myocardial infarction, spironolactone did not reduce the incidence of death from cardiovascular causes or new or worsening heart failure or the incidence of a composite of death from cardiovascular causes, myocardial infarction, stroke, or new or worsening heart failure. (Funded by the Canadian Institutes of Health Research and others; CLEAR ClinicalTrials.gov number, NCT03048825.).