The effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure: the heart 'OMics' in AGEing (HOMAGE) randomized clinical trial.
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ABSTRACT: Aims
To investigate the effects of spironolactone on fibrosis and cardiac function in people at increased risk of developing heart failure.Methods and results
Randomized, open-label, blinded-endpoint trial comparing spironolactone (50 mg/day) or control for up to 9 months in people with, or at high risk of, coronary disease and raised plasma B-type natriuretic peptides. The primary endpoint was the interaction between baseline serum galectin-3 and changes in serum procollagen type-III N-terminal pro-peptide (PIIINP) in participants assigned to spironolactone or control. Procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP), reflecting synthesis and degradation of type-I collagen, were also measured. In 527 participants (median age 73 years, 26% women), changes in PIIINP were similar for spironolactone and control [mean difference (mdiff): -0.15; 95% confidence interval (CI) -0.44 to 0.15 μg/L; P = 0.32] but those receiving spironolactone had greater reductions in PICP (mdiff: -8.1; 95% CI -11.9 to -4.3 μg/L; P < 0.0001) and PICP/CITP ratio (mdiff: -2.9; 95% CI -4.3 to -1.5; <0.0001). No interactions with serum galectin were observed. Systolic blood pressure (mdiff: -10; 95% CI -13 to -7 mmHg; P < 0.0001), left atrial volume (mdiff: -1; 95% CI -2 to 0 mL/m2; P = 0.010), and NT-proBNP (mdiff: -57; 95% CI -81 to -33 ng/L; P < 0.0001) were reduced in those assigned spironolactone.Conclusions
Galectin-3 did not identify greater reductions in serum concentrations of collagen biomarkers in response to spironolactone. However, spironolactone may influence type-I collagen metabolism. Whether spironolactone can delay or prevent progression to symptomatic heart failure should be investigated.
SUBMITTER: Cleland JGF
PROVIDER: S-EPMC7878013 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AimsIn people at risk of heart failure (HF) enrolled in the Heart 'OMics' in AGEing (HOMAGE) trial, spironolactone reduced circulating markers of collagen synthesis, natriuretic peptides, and blood pressure and improved cardiac structure and function. In the present report, we explored factors associated with dyskalaemia.Methods and resultsThe HOMAGE trial was an open-label study comparing spironolactone (up to 50 mg/day) versus standard care in people at risk for HF. After randomization, serum potassium was assessed at 1 and 9 months and was defined as low when ≤3.5 mmol/L (hypokalaemia) and high when ≥5.5 mmol/L (hyperkalaemia). Multivariable logistic regression models were constructed to identify clinical predictors of dyskalaemia. A total of 513 participants (median age 74 years, 75% men, median estimated glomerular filtration rate 71 mL/min/1.73 m2 ) had serum potassium available and were included in this analysis. At randomization, 88 had potassium < 4.0 mmol/L, 367 had potassium 4.0-5.0 mmol/L, and 58 had potassium > 5.0 mmol/L. During follow-up, on at least one occasion, a serum potassium < 3.5 mmol/L was observed in 6 (1.2%) and <4.0 mmol/L in 46 (9%) participants, while a potassium > 5.0 mmol/L was observed in 38 (8%) and >5.5 mmol/L in 5 (1.0%) participants. The median (percentile25-75 ) increase in serum potassium with spironolactone during the study was 0.23 (0.16; 0.29) mmol/L. Because of the low incidence of dyskalaemia, for regression analysis, hypokalaemia and hyperkalaemia thresholds were set at <4.0 and >5.0 mmol/L, respectively. The occurrence of a serum potassium > 5.0 mmol/L during follow-up was positively associated with the presence of diabetes mellitus {odds ratio [OR]: 1.21 [95% confidence interval (CI) 2.14; 3.79]} and randomization to spironolactone (OR: 2.83 [95% CI 1.49; 5.37]). Conversely, the occurrence of a potassium concentration < 4.0 mmol/L was positively associated with the use of thiazides (OR: 2.39 [95% CI 1.32; 4.34]), blood urea concentration (OR: 2.15 [95% CI 1.34; 3.39] per 10 mg/dL), and history of hypertension (OR: 2.32 [95% CI 1.02; 5.29]) and negatively associated with randomization to spironolactone (OR: 0.30 [95% CI 0.18; 0.52]).ConclusionsIn people at risk for developing HF and with relatively normal renal function, spironolactone reduced the risk of hypokalaemia and, at the doses used, was not associated with the occurrence of clinically meaningful hyperkalaemia.
| S-EPMC9773649 | biostudies-literature
Project description:To address the need for personalized prevention, we conducted a subject-level meta-analysis within the framework of the Heart "OMics" in AGEing (HOMAGE) study to develop a risk prediction model for heart failure (HF) based on routinely available clinical measurements. Three studies with elderly persons (Health Aging and Body Composition [Health ABC], Valutazione della PREvalenza di DIsfunzione Cardiaca asinTOmatica e di scompenso cardiaco [PREDICTOR], and Prospective Study of Pravastatin in the Elderly at Risk [PROSPER]) were included to develop the HF risk function, while a fourth study (Anglo-Scandinavian Cardiac Outcomes Trial [ASCOT]) was used as a validation cohort. Time-to-event analysis was conducted using the Cox proportional hazard model. Incident HF was defined as HF hospitalization. The Cox regression model was evaluated for its discriminatory performance (area under the receiver operating characteristic curve) and calibration (Grønnesby-Borgan χ2 statistic). During a follow-up of 3.5 years, 470 of 10 236 elderly persons (mean age, 74.5 years; 51.3% women) developed HF. Higher age, BMI, systolic blood pressure, heart rate, serum creatinine, smoking, diabetes mellitus, history of coronary artery disease, and use of antihypertensive medication were associated with increased HF risk. The area under the receiver operating characteristic curve of the model was 0.71, with a good calibration (χ2 7.9, P=0.54). A web-based calculator was developed to allow easy calculations of the HF risk. Simple measurements allow reliable estimation of the short-term HF risk in populations and patients. The risk model may aid in risk stratification and future HF prevention strategies.
| S-EPMC5524083 | biostudies-literature
Project description:AimsWe aim to characterize the clinical and proteomic profiles of patients at risk of developing heart failure (HF), with and without coronary artery disease (CAD) or prior myocardial infarction (MI).Methods and resultsHOMAGE evaluated the effect of spironolactone on plasma and serum markers of fibrosis over 9 months of follow-up in participants with (or at risk of having) CAD, and raised natriuretic peptides. In this post hoc analysis, patients were classified as (i) neither CAD nor MI; (ii) CAD; or (iii) MI. Proteomic between-group differences were evaluated through logistic regression and narrowed using backward stepwise selection and bootstrapping. Among the 527 participants, 28% had neither CAD or MI, 31% had CAD, and 41% had prior MI. Compared with people with neither CAD nor MI, those with CAD had higher baseline plasma concentrations of matrix metalloproteinase-7 (MMP-7), galectin-4 (GAL4), plasminogen activator inhibitor 1 (PAI-1), and lower plasma peptidoglycan recognition protein 1 (PGLYRP1), whilst those with a history of MI had higher plasma MMP-7, neurotrophin-3 (NT3), pulmonary surfactant-associated protein D (PSPD), and lower plasma tumour necrosis factor-related activation-induced cytokine (TRANCE). Proteomic signatures were similar for patients with CAD or prior MI. Treatment with spironolactone was associated with an increase of MMP7, NT3, and PGLYRP1 at 9 months.ConclusionsIn patients at risk of developing HF, those with CAD or MI had a different proteomic profile regarding inflammatory, immunological, and collagen catabolic processes.
| S-EPMC10804163 | biostudies-literature
Project description:BackgroundPatients with diabetes mellitus (DM) are at increased risk of developing heart failure (HF). The "Heart OMics in AGEing" (HOMAGE) trial suggested that spironolactone had beneficial effect on fibrosis and cardiac remodelling in an at risk population, potentially slowing the progression towards HF. We compared the proteomic profile of patients with and without diabetes among patients at risk for HF in the HOMAGE trial.MethodsProtein biomarkers (n = 276) from the Olink®Proseek-Multiplex cardiovascular and inflammation panels were measured in plasma collected at baseline and 9 months (or last visit) from HOMAGE trial participants including 217 patients with, and 310 without, diabetes.ResultsTwenty-one biomarkers were increased and five decreased in patients with diabetes compared to non-diabetics at baseline. The markers clustered mainly within inflammatory and proteolytic pathways, with granulin as the key-hub, as revealed by knowledge-induced network and subsequent gene enrichment analysis. Treatment with spironolactone in diabetic patients did not lead to large changes in biomarkers. The effects of spironolactone on NTproBNP, fibrosis biomarkers and echocardiographic measures of diastolic function were similar in patients with and without diabetes (all interaction analyses p > 0.05).ConclusionsAmongst patients at risk for HF, those with diabetes have higher plasma concentrations of proteins involved in inflammation and proteolysis. Diabetes does not influence the effects of spironolactone on the proteomic profile, and spironolactone produced anti-fibrotic, anti-remodelling, blood pressure and natriuretic peptide lowering effects regardless of diabetes status. Trial registration NCT02556450.
| S-EPMC8351439 | biostudies-literature
Project description:BACKGROUND:Recent evidence suggests that the mineralocorticoid receptor antagonist spironolactone should be the preferred fourth-line antihypertensive treatment in resistant hypertension (RHTN). Whether spironolactone improves blood pressure (BP) control in heart failure with preserved ejection fraction (HFpEF) and RHTN is unknown. METHODS:We identified patients with RHTN, defined as baseline systolic blood pressure (SBP) between 140 and 160 mm Hg on 3 or more medications, in the Americas cohort of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial, in which patients with HFpEF were randomized to spironolactone vs. placebo. We evaluated the effects of spironolactone vs. placebo on BP reduction in this group and related this to the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for heart failure. RESULTS:We identified 403 participants in the Americas with RHTN. Compared to people without RHTN, those with RHTN were more frequently women, non-White, diabetics, with a higher left ventricular ejection fraction and body mass index, and a lower hemoglobin concentration. In the RHTN group, spironolactone resulted in a decrease of SBP: -6.1 (-8.9, -3.3); P < 0.001 and diastolic BP: -2.9 (-4.6, -1.2); P = 0.001 mm Hg during the first 8 months. BP became controlled after 4 weeks in 63% of patients receiving spironolactone vs. 46% receiving placebo (P = 0.003), with similar responses at 8 weeks, 4 and 8 months. Patients with RHTN derived similar overall benefit from spironolactone on the primary outcomes as those without. CONCLUSIONS:In HFpEF patients with RHTN, spironolactone lowered BP substantially and was associated with similar benefit as those without RHTN. CLINICAL TRIALS REGISTRATION:Trial Number NCT00094302 (ClinicalTrials.gov identifier).
| S-EPMC5861580 | biostudies-literature
Project description:BackgroundHyponatremia, a marker of disease severity and prognosis, has been associated with various clinical factors and drug use, especially diuretics.MethodsThis observational prospective cohort study enrolled patients hospitalized at the University Hospital Center Split because of heart failure (HF). We investigated the association of clinical variables and cardiovascular drugs, including furosemide, hydrochlorothiazide, spironolactone, and their doses, with the presence of hyponatremia at admission.ResultsOf the 565 included patients, 32.4% were hyponatremic, 62.6% were males, and the mean age was 73.1 ± 10.6 years. In the univariate analysis, hyponatremic patients were more often current smokers (p = 0.01), alcohol consumers (p = 0.01), receiving spironolactone (p = 0.004) or combination of furosemide and spironolactone (p = 0.003). Patients who received 50 and 100 mg of spironolactone, compared to those receiving 25 mg (p < 0.0001), as well as patients who received 250 to 500 mg of furosemide compared to ≤240 mg (p = 0.001), were significantly more often hyponatremic. In the multivariate analysis, when diuretic doses were accounted for, furosemide doses of 250 to 500 mg (p = 0.009), spironolactone doses of 50 to 100 mg (p = 0.0003), increasing age (p = 0.03), diabetes mellitus (p = 0.02) and alcohol consumption (p = 0.04) were independently associated with hyponatremia.ConclusionHigh doses of furosemide and spironolactone, or concomitant use of these diuretics, seem to be an important cause of hyponatremia in HF patients, particularly in combination with advanced age, diabetes and alcohol consumption. Diuretic dose reduction may help avoid hyponatremia and improve clinical status and prognosis in such patients.
| S-EPMC7397681 | biostudies-literature
Project description:Background Although aldosterone antagonists improve outcomes in select individuals with heart failure and reduced ejection fraction, studies in the United States have raised concerns about underuse and overuse. Variations in the prescription of aldosterone antagonist in China are unknown. Methods and Results In the multicenter, hospital-based, retrospective China PEACE (China Patient-Centered Evaluative Assessment of Cardiac Events) study, we identified a nationally representative cohort of admissions for heart failure in a nationally representative sample of Chinese hospitals in 2015. Patients were classified into 1 of 3 groups according to their eligibility for spironolactone-"ideal" (left ventricular ejection fraction <40% and without contraindications), "contraindicated" (a documented contraindication, irrespective of left ventricular ejection fraction), and "uncertain-benefit" (all others). We measured hospital variation of spironolactone prescriptions at discharge in the "ideal" and "contraindicated" group and calculated the median odds ratio (MOR), a measure of institution-level variation for 2 individuals with similar characteristics discharged at 2 randomly selected hospitals. Hospital characteristics associated with spironolactone use were identified using multivariable linear regression model. Among 1222 ideal patients from 97 hospitals, the median rate of spironolactone prescription was 78.6% (interquartile range [IQR], 42.8%-89.6% [range, 0%-100%], MOR, 3.4 [95% CI, 2.7-4.0]) at discharge. Among 900 contraindicated patients from 83 hospitals, the median rate of spironolactone prescription was 30.0% (IQR, 9.1%-50.0% [range, 0%-100%], MOR, 3.1 [95% CI, 2.4-3.9]) at discharge. Hospitals with independent departments of cardiology and located in Eastern China were associated with a 38.0% (95% CI, 18.7-57.3; P<0.001) and a 14.6% (95% CI, 2.3%-26.9%; P=0.020) higher rate of spironolactone use for ideal patients. Conclusions In this national study of hospitals in China, the use of spironolactone among ideal patients and the inappropriate use of spironolactone among patients with contraindications was substantial, with rates that varied markedly by institution. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02877914.
| S-EPMC9673705 | biostudies-literature
Project description:BACKGROUND:The efficacy of mineralocorticoid receptor antagonists or aldosterone antagonists in heart failure with reduced ejection fraction (HFrEF) is well known. Less is known about their effectiveness in real-world older patients with HFrEF. METHODS:Of the 8206 patients with heart failure and ejection fraction ?35% without prior spironolactone use in the Medicare-linked OPTIMIZE-HF registry, 6986 were eligible for spironolactone therapy based on serum creatinine criteria (men ?2.5 mg/dL, women ?2.0 mg/dL) and 865 received a discharge prescription for spironolactone. Using propensity scores for spironolactone use, we assembled a matched cohort of 1724 (862 pairs) patients receiving and not receiving spironolactone, balanced on 58 baseline characteristics (Creatinine Cohort: mean age, 75 years, 42% women, 17% African American). We repeated the above process to assemble a secondary matched cohort of 1638 (819 pairs) patients with estimated glomerular filtration rate (eGFR) ?30 mL/min/1.73 m2 (eGFR Cohort: mean age, 75 years, 42% women, 17% African American). RESULTS:In the matched Creatinine Cohort, spironolactone-associated hazard ratios (95% confidence intervals) for all-cause mortality, heart failure readmission, and combined endpoint of heart failure readmission or all-cause mortality were 0.92 (0.81-1.03), 0.87 (0.77-0.99), and 0.87 (0.79-0.97), respectively. Respective hazard ratios (95% confidence intervals) in the matched eGFR Cohort were 0.87 (0.77-0.98), 0.92 (0.80-1.05), and 0.91 (0.82-1.02). CONCLUSIONS:These findings provide evidence of consistent, albeit modest, clinical effectiveness of spironolactone in older patients with HFrEF regardless of renal eligibility criteria used. Additional strategies are needed to improve the effectiveness of aldosterone antagonists in clinical practice.
| S-EPMC6511886 | biostudies-literature
Project description:AimsIn Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA-HF), high-dose spironolactone (100 mg daily) did not improve efficacy endpoints over usual care [placebo or continued low-dose spironolactone (25 mg daily) in patients already receiving spironolactone] in the treatment of acute heart failure (HF). We hypothesized that low concentrations of the long-acting active metabolites of spironolactone [canrenone and 7α-thiomethylspironolactone (7α-TMS)] in the high-dose group could have contributed to these neutral results.Methods and resultsIn patients randomized to high-dose spironolactone not previously treated with spironolactone (high-dose-naïve, n = 112), concentrations of canrenone and 7α-TMS increased at 48 and 96 h compared to baseline, and between 48 and 96 h (all P < 0.005), indicating that steady-state concentrations had not been reached by 48 h. In patients previously on low-dose, high-dose spironolactone (high-dose-previous, n = 37), concentrations of canrenone increased at 48 and 96 h compared to baseline (both P < 0.0005), with a marginal increase between 48 and 96 h (P = 0.0507). At 48 h, both high-dose groups had higher concentrations of both metabolites than the low-dose spironolactone group (P < 0.0001). Moreover, concentrations of both metabolites were higher in high-dose-previous vs. high-dose-naïve patients (P < 0.01), indicating that previous spironolactone use was significant, and that steady-state has not been reached in high-dose-naïve patients at 48 h. We found limited and inconsistent evidence of correlation between metabolite concentrations and endpoints.ConclusionsLower-than-anticipated concentrations of spironolactone active metabolites were observed for at least 48 h in the high-dose spironolactone group and may have contributed to the absence of pharmacological effects of spironolactone in the ATHENA-HF trial.
| S-EPMC7958586 | biostudies-literature
Project description:ObjectiveTo quantify the risk of hyperkalemia and acute kidney injury (AKI) when spironolactone use is added on to loop diuretic use among patients with heart failure, and to evaluate whether the risk is modified by level of kidney function.MethodsWe identified 17,110 patients with heart failure treated with loop diuretics between January 1, 2004, and December 31, 2016 within the Geisinger Health System. We estimated the incidence of hyperkalemia and AKI associated with spironolactone initiation, and used target trial emulation methods to minimize confounding by indication.ResultsDuring a mean follow-up of 134 mo, 3229 of 17,110 patients (18.9%) initiated spironolactone. Incidence rates of hyperkalemia and AKI in patients using spironolactone with a loop diuretic were 2.9 and 10.1 events per 1000 person-months, respectively. In propensity score-matched analyses, spironolactone initiation was associated with higher hyperkalemia and AKI risk compared with loop alone (hazard ratio, 1.69; 95% CI, 1.35 to 2.10; P<.001, and hazard ratio, 1.12; 95% CI, 1.00 to 1.26; P=.04, respectively). There were no differences in the relative risk of either outcome associated with spironolactone by level of kidney function.ConclusionThe addition of spironolactone to loop diuretics in patients with heart failure was associated with higher risk of hyperkalemia and AKI; these risks must be weighed against the potential benefits of spironolactone.
| S-EPMC8005315 | biostudies-literature