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Spironolactone Use and Improved Outcomes in Patients With Heart Failure With Preserved Ejection Fraction With Resistant Hypertension.
Tsujimoto, T, Kajio, H
Journal of the American Heart Association. 2020;(23):e018827
Abstract
Background Resistant hypertension is a salt-retaining condition possibly attributable to inappropriate aldosterone secretion. Methods and Results This study was a secondary analysis of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial. Patients with heart failure with preserved ejection fraction (HFpEF) with (n=1004) and without (n=2437) resistant hypertension were included. Resistant hypertension was defined as systolic blood pressure ≥130 mm Hg and/or diastolic blood pressure ≥80 mm Hg in a patient with hypertension, despite the concurrent use of a renin-angiotensin system blocker (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker), a calcium channel blocker, and a diuretic; or as those patients using ≥4 classes of antihypertensive medication. The primary outcome was a composite of cardiovascular death, aborted cardiac arrest, or heart failure hospitalization. We analyzed hazard ratios (HRs) for outcomes with 95% CIs in the spironolactone group and compared them with the placebo group using Cox proportional hazard models. The risk of primary outcome events in patients with HFpEF with resistant hypertension was significantly lower in the spironolactone group than in the placebo group (HR, 0.70; 95% CI, 0.53-0.91; P=0.009), whereas the risk of primary outcome events in patients with HFpEF without resistant hypertension was not significantly different between the 2 groups (HR, 1.00; 95% CI, 0.83-1.20; P=0.97). There was a significant interaction between spironolactone use and resistant hypertension (P=0.03). Similar associations were also observed in patients with HFpEF from the Americas (United States, Canada, Brazil, and Argentina) only. Conclusions Spironolactone may be an effective add-on medication for patients with HFpEF with resistant hypertension taking angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, calcium channel blockers, and diuretics.
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[Effectiveness of spirolactone on the treatment of laryngeal edema and complications after H-uvulopalatopharyngoplasty for patients with obstructive sleep apnea].
Tang, ZP, Wu, ZM, Li, WB, Wu, YJ, Zheng, T
Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology, head, and neck surgery. 2020;(1):49-52
Abstract
Objective:To determine whether taking spirolactone orally after H-UPPP may relieve laryngeal edema and complications for patients with obstructive sleep apnea(OSA). Method:Fifty patients with OSA to undergo H-UPPP operation were randomly divided equally to the intervention group(taking spirolactone 20 mg orally twice a day for 7 days after H-UPPP) or the control group, all patients received conventional therapy after H-UPPP including anti-infection, hemostatic treatment, fluid replacement and expectorant by fogged absorption. The pharyngeal wound, diet, sleep and speaking pronunciation of all patients in each group were evaluated every other day in 7 days postoperation. The minimum oxygen saturation of blood(SaO2) during sleep at night each day and the period needed for staphyledema resolution of all patients were recorded and compared between each group. Result:Postoperatively, the intervention group had significantly slighter bleeding at wound site, better sleep and more legible speaking pronunciation than the control group after 3 days to 5 days(P<0.05). The wound dehiscence of the intervention group was significantly slighter than the control group within 7 days after operation(P<0.05). During 3 days to 7days after operation, the intervention group had a significantly better diet than the control group(P<0.05). The average minimum SaO2during sleep at night in the intervention group was significantly higher than that in the control group from 3 days to 5 days post operation(P<0.05). Period needed for staphyledema resolution in the intervention group(4.1±1.5) days was significantly shorter than that in the control group(5.9±1.8) days (P<0.05). Conclusion:Taking spirolactone orally after H-UPPP may relieve laryngeal edema and complications for OSA patients, and it will also shorten the period needed for staphyledema resolution.
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Reduced circulating levels of chemokine CXCL14 in adolescent girls with polycystic ovary syndrome: normalization after insulin sensitization.
García-Beltran, C, Cereijo, R, Quesada-López, T, Malpique, R, López-Bermejo, A, de Zegher, F, Ibáñez, L, Villarroya, F
BMJ open diabetes research & care. 2020;(1)
Abstract
OBJECTIVE CXCL14 (C-X-C motif chemokine ligand-14) is a chemokine released by active brown fat, showing protective effects against insulin resistance in experimental models. Polycystic ovary syndrome (PCOS) in adolescent girls is usually related to hepato-visceral fat excess and insulin resistance, and associates with comorbidities such as type 2 diabetes. Treatment with a low-dose combination of one antiandrogen and antimineralocorticoid drug (spironolactone) and two insulin sensitizers (pioglitazone/metformin) (SPIOMET) is particularly effective in improving these metabolic derangements. Adipose tissue may be involved in the metabolic alterations of PCOS, and it is a likely target of therapeutic action. We investigated the alterations in CXCL14 levels and the effects of drugs composing SPIOMET treatment on CXCL14 in human adipocytes. RESEARCH DESIGN AND METHODS We studied 51 adolescent patients with PCOS and 21 age-matched healthy controls. Thirty-one adolescent patients with PCOS under SPIOMET or oral contraception-based treatment were also studied. For studies in vitro, Simpson Golabi Behmel Syndrome (SGBS) adipose cells were used. Gene expression for CXCL14 and other genes was quantified using quantitative real-time PCR. The levels of CXCL14 and adipokines in serum and cell culture media were determined by ELISA. RESULTS Serum CXCL14 levels are reduced in patients with PCOS. One-year SPIOMET treatment normalized CXCL14 concentrations and improved the metabolic status of patients with PCOS. Pioglitazone induced CXCL14 expression in differentiating human SGBS adipocytes, in parallel with the induction of marker genes of brown adipogenesis. Spironolactone induced CXCL14 expression and release in differentiated human adipocytes. CONCLUSION Insulin sensitization with SPIOMET normalizes the abnormally low levels of CXCL14 in girls with PCOS. This is consistent with the effects of pioglitazone and spironolactone inducing CXCL14 expression and promoting a brown-like phenotype in adipocytes. CXCL14 may be a novel biomarker for PCOS as well as a potential mediator of the beneficial effects of the SPIOMET combination and may hold promise as a therapeutic modulator of the disorder. TRIAL REGISTRATION NUMBERS ISRCTN29234515 and ISCRCTN11062950.
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Early detection of diabetic kidney disease by urinary proteomics and subsequent intervention with spironolactone to delay progression (PRIORITY): a prospective observational study and embedded randomised placebo-controlled trial.
Tofte, N, Lindhardt, M, Adamova, K, Bakker, SJL, Beige, J, Beulens, JWJ, Birkenfeld, AL, Currie, G, Delles, C, Dimos, I, et al
The lancet. Diabetes & endocrinology. 2020;(4):301-312
Abstract
BACKGROUND Microalbuminuria is an early sign of kidney disease in people with diabetes and indicates increased risk of cardiovascular disease. We tested whether a urinary proteomic risk classifier (CKD273) score was associated with development of microalbuminuria and whether progression to microalbuminuria could be prevented with the mineralocorticoid receptor antagonist spironolactone. METHODS In this multicentre, prospective, observational study with embedded randomised controlled trial (PRIORITY), we recruited people with type 2 diabetes, normal urinary albumin excretion, and preserved renal function from 15 specialist centres in ten European countries. All participants (observational cohort) were tested with the CKD273 classifier and classified as high risk (CKD273 classifier score >0·154) or low risk (≤0·154). Participants who were classified as high risk were entered into a randomised controlled trial and randomly assigned (1:1), by use of an interactive web-response system, to receive spironolactone 25 mg once daily or matched placebo (trial cohort). The primary endpoint was development of confirmed microalbuminuria in all individuals with available data (observational cohort). Secondary endpoints included reduction in incidence of microalbuminuria with spironolactone (trial cohort, intention-to-treat population) and association between CKD273 risk score and measures of impaired renal function based on estimated glomerular filtration rate (eGFR; observational cohort). Adverse events (particularly gynaecomastia and hyperkalaemia) and serious adverse events were recorded for the intention-to-treat population (trial cohort). This study is registered with the EU Clinical Trials Register (EudraCT 20120-004523-4) and ClinicalTrials.gov (NCT02040441) and is completed. FINDINGS Between March 25, 2014, and Sept 30, 2018, we enrolled and followed-up 1775 participants (observational cohort), 1559 (88%) of 1775 participants had a low-risk urinary proteomic pattern and 216 (12%) had a high-risk pattern, of whom 209 were included in the trial cohort and assigned to spironolactone (n=102) or placebo (n=107). The overall median follow-up time was 2·51 years (IQR 2·0-3·0). Progression to microalbuminuria was seen in 61 (28%) of 216 high-risk participants and 139 (9%) of 1559 low-risk participants (hazard ratio [HR] 2·48, 95% CI 1·80-3·42; p<0·0001, after adjustment for baseline variables of age, sex, HbA1c, systolic blood pressure, retinopathy, urine albumin-to-creatinine ratio [UACR], and eGFR). Development of impaired renal function (eGFR <60 mL/min per 1·73 m2) was seen in 48 (26%) of 184 high-risk participants and 119 (8%) of 1423 low-risk participants (HR 3·50; 95% CI 2·50-4·90, after adjustment for baseline variables). A 30% decrease in eGFR from baseline (post-hoc endpoint) was seen in 42 (19%) of 216 high-risk participants and 62 (4%) of 1559 low-risk participants (HR 5·15, 95% CI 3·41-7·76; p<0·0001, after adjustment for basline eGFR and UACR). In the intention-to-treat trial cohort, development of microalbuminuria was seen in 35 (33%) of 107 in the placebo group and 26 (25%) of 102 in the spironolactone group (HR 0·81, 95% CI 0·49-1·34; p=0·41). In the safety analysis (intention-to-treat trial cohort), events of plasma potassium concentrations of more than 5·5 mmol/L were seen in 13 (13%) of 102 participants in the spironolactone group and four (4%) of 107 participants in the placebo group, and gynaecomastia was seen in three (3%) participants in the spironolactone group and none in the placebo group. One patient died in the placebo group due to a cardiac event (considered possibly related to study drug) and one patient died in the spironolactone group due to cancer, deemed unrelated to study drug. INTERPRETATION In people with type 2 diabetes and normoalbuminuria, a high-risk score from the urinary proteomic classifier CKD273 was associated with an increased risk of progression to microalbuminuria over a median of 2·5 years, independent of clinical characteristics. However, spironolactone did not prevent progression to microalbuminuria in high-risk patients. FUNDING European Union Seventh Framework Programme.
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Clinical Phenogroups in Heart Failure With Preserved Ejection Fraction: Detailed Phenotypes, Prognosis, and Response to Spironolactone.
Cohen, JB, Schrauben, SJ, Zhao, L, Basso, MD, Cvijic, ME, Li, Z, Yarde, M, Wang, Z, Bhattacharya, PT, Chirinos, DA, et al
JACC. Heart failure. 2020;(3):172-184
Abstract
OBJECTIVES This study sought to assess if clinical phenogroups differ in comprehensive biomarker profiles, cardiac and arterial structure/function, and responses to spironolactone therapy. BACKGROUND Previous studies identified distinct subgroups (phenogroups) of patients with heart failure with preserved ejection fraction (HFpEF). METHODS Among TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial) participants, we performed latent-class analysis to identify HFpEF phenogroups based on standard clinical features and assessed differences in multiple biomarkers measured from frozen plasma; cardiac and arterial structure/function measured with echocardiography and arterial tonometry; prognosis; and response to spironolactone. RESULTS Three HFpEF phenogroups were identified. Phenogroup 1 (n = 1,214) exhibited younger age, higher prevalence of smoking, preserved functional class, and the least evidence of left ventricular (LV) hypertrophy and arterial stiffness. Phenogroup 2 (n = 1,329) was older, with normotrophic concentric LV remodeling, atrial fibrillation, left atrial enlargement, large-artery stiffening, and biomarkers of innate immunity and vascular calcification. Phenogroup 3 (n = 899) demonstrated more functional impairment, obesity, diabetes, chronic kidney disease, concentric LV hypertrophy, high renin, and biomarkers of tumor necrosis factor-alpha-mediated inflammation, liver fibrosis, and tissue remodeling. Compared with phenogroup 1, phenogroup 3 exhibited the highest risk of the primary endpoint of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest (hazard ratio [HR]: 3.44; 95% confidence interval [CI]: 2.79 to 4.24); phenogroups 2 and 3 demonstrated similar all-cause mortality (phenotype 2 HR: 2.36; 95% CI: 1.89 to 2.95; phenotype 3 HR: 2.26, 95% CI: 1.77 to 2.87). Spironolactone randomized therapy was associated with a more pronounced reduction in the risk of the primary endpoint in phenogroup 3 (HR: 0.75; 95% CI: 0.59 to 0.95; p for interaction = 0.016). Results were similar after excluding participants from Eastern Europe. CONCLUSIONS We identified important differences in circulating biomarkers, cardiac/arterial characteristics, prognosis, and response to spironolactone across clinical HFpEF phenogroups. These findings suggest distinct underlying mechanisms across clinically identifiable phenogroups of HFpEF that may benefit from different targeted interventions.
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Spironolactone in Acute Heart Failure Patients With Renal Dysfunction and Risk Factors for Diuretic Resistance: From the ATHENA-HF Trial.
Greene, SJ, Felker, GM, Giczewska, A, Kalogeropoulos, AP, Ambrosy, AP, Chakraborty, H, DeVore, AD, Fudim, M, McNulty, SE, Mentz, RJ, et al
The Canadian journal of cardiology. 2019;(9):1097-1105
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Abstract
BACKGROUND Acute heart failure (HF) patients with renal insufficiency and risk factors for diuretic resistance may be most likely to derive incremental improvement in congestion with the addition of spironolactone. METHODS The Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA-HF) trial randomized 360 acute HF patients with reduced or preserved ejection fraction to spironolactone 100 mg daily or usual care for 96 hours. The current analysis assessed the effects of study therapy within tertiles of baseline estimated glomerular filtration rate (eGFR) and subgroups at heightened risk for diuretic resistance. RESULTS Across eGFR tertiles, there was no incremental benefit of high-dose spironolactone on any efficacy endpoint, including changes in log N-terminal pro-B-type natriuretic peptide and signs and symptoms of congestion (all P for interaction ≥ 0.06). High-dose spironolactone had no significant effect on N-terminal pro-B-type natriuretic peptide reduction regardless of blood pressure, diabetes mellitus status, and loop diuretic dose (all P for interaction ≥ 0.38). In-hospital changes in serum potassium and creatinine were similar between treatment groups for all GFR tertiles (all P for interaction ≥ 0.18). Rates of inpatient worsening HF, 30-day worsening HF, and 60-day all-cause mortality were numerically higher among patients with lower baseline eGFR, but relative effects of study treatment did not differ with renal function (all P for interaction ≥ 0.27). CONCLUSIONS High-dose spironolactone did not improve congestion over usual care among patients with acute HF, irrespective of renal function and risk factors for diuretic resistance. In-hospital initiation or continuation of spironolactone was safe during the inpatient stay, even when administered at high doses to patients with moderate renal dysfunction.
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Spironolactone to increase natriuresis in congestive heart failure with cardiorenal syndrome.
Verbrugge, FH, Martens, P, Ameloot, K, Haemels, V, Penders, J, Dupont, M, Tang, WHW, Droogné, W, Mullens, W
Acta cardiologica. 2019;(2):100-107
Abstract
BACKGROUND Signs and symptoms of volume overload are the most frequent reason for hospital admission in acute heart failure (AHF). Diuretics are mainstay treatment, but their optimal type and dose regimen remain unclear, especially in patients with cardiorenal syndrome. METHODS This prospective study aimed to include 80 AHF patients with volume overload and cardiorenal syndrome. Through a 2 × 2 factorial design, patients were randomised towards (1) combinational treatment with acetazolamide and low-dose loop diuretics versus high-dose loop diuretics; and (2) open-label oral spironolactone 25 mg OD given upfront versus at discharge. Here reported are the results of the spironolactone treatment arm after complete follow-up of 34/80 patients (since the study was stopped because of slow recruitment). The primary study end-point was incident hypokalaemia (<3.5 mmol/L) or hyperkalaemia (>5.5 mmol/L). RESULTS Serum potassium derangements were numerically less frequent in the upfront versus discharge spironolactone group, yet this result was underpowered due to incomplete study recruitment (hyperkalaemia: 6% vs. 11%; hypokalaemia: 13% vs. 28%, respectively; p-value = .270). Natriuresis after 24 h was higher in the upfront vs. discharge spironolactone group (314 ± 142 vs. 200 ± 91 mmol/L, respectively; p-value = .010). Relative change in plasma NT-proBNP level after 72 h was similar among both groups (-16 ± 29% vs. -5 ± 45%, respectively; p value = .393), with no difference in all-cause mortality (p-value = .682) or the combination of all-cause mortality and heart failure readmission (p-value = .799). DISCUSSION Spironolactone use upfront in AHF patients at high risk for cardiorenal syndrome is safe and increases natriuresis.
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Mineralocorticoid receptor antagonist pre-treatment and early post-treatment to minimize reperfusion injury after ST-elevation myocardial infarction: The MINIMIZE STEMI trial.
Bulluck, H, Fröhlich, GM, Nicholas, JM, Mohdnazri, S, Gamma, R, Davies, J, Sirker, A, Mathur, A, Blackman, D, Garg, P, et al
American heart journal. 2019;:60-67
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BACKGROUND Mineralocorticoid receptor antagonist (MRA) therapy has been shown to prevent adverse left ventricular (LV) remodeling in ST-segment elevation myocardial infarction (STEMI) patients with heart failure. Whether initiating MRA therapy prior to primary percutaneous coronary intervention (PPCI) accrues additional benefit of reducing myocardial infarct size and preventing adverse LV remodeling is not known. We aimed to investigate whether MRA therapy initiated prior to reperfusion reduces myocardial infarct (MI) size and prevents adverse LV remodeling in STEMI patients. METHODS STEMI patients presenting within 12 hours and with a proximal coronary artery occlusion with Thrombolysis In Myocardial Infarction flow grade 0 were consented and randomized to either an intravenous bolus of potassium canrenoate, followed by oral spironolactone for 3 months or matching placebo. The primary endpoint was MI size by cardiovascular magnetic resonance at 3 months. RESULTS Sixty-seven patients completed the study. There was no significant difference in the final MI size at 3 months between the 2 groups (placebo: 17 ± 11%, MRA: 16 ± 10%, P = .574). There was also no difference in acute MI size (26 ± 16% versus 23 ± 14%, P = .425) or myocardial salvage (26 ± 12% versus 24 ± 8%, P = .456). At follow-up, there was a trend towards an improvement in LVEF (placebo: 49 ± 8%, MRA: 54 ± 11%, P = .053), and the MRA group had significantly greater percentage decrease in LVEDV (mean difference: -12.2 (95% CI -20.3 to -4.4)%, P = .003) and LVESV (mean difference: -18.2 (95% CI -30.1 to -6.3)%, P = .003). CONCLUSION This pilot study showed no benefit of MRA therapy in reducing MI size in STEMI patients when initiated prior to reperfusion, but there was an improvement in LV remodeling at 3 months. Adequately powered studies are warranted to confirm these findings.
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Cardiac effects of 6 months' dietary nitrate and spironolactone in patients with hypertension and with/at risk of type 2 diabetes, in the factorial design, double-blind, randomized controlled VaSera trial.
Faconti, L, Mills, CE, Govoni, V, Gu, H, Morant, S, Jiang, B, Cruickshank, JK, Webb, AJ
British journal of clinical pharmacology. 2019;(1):169-180
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AIMS: The aims of the present study were to explore whether a long-term intervention with dietary nitrate [(NO3- ), a potential tolerance-free source of beneficial vasoactive nitric oxide] and spironolactone (to oppose aldosterone's potential deleterious cardiovascular effects) improve cardiac structure/function, independently of blood pressure (BP), in patients with/at risk of type 2 diabetes (a population at risk of heart failure). METHODS A subsample of participants in our double-blind, randomized, factorial-design intervention (VaSera) trial of active beetroot juice as a nitrate source (≤11.2 mmol) or placebo (nitrate depleted) beetroot juice, and either ≤50 mg spironolactone or ≤16 mg doxazosin (control), had transthoracic cardiac ultrasounds at baseline (n = 105), and at 3 months and 6 months (n = 87) after the start of the intervention. Analysis was by modified intent-to-treat. RESULTS Nitrate-containing juice (n = 40) decreased left ventricular (LV) end-diastolic volume {-6.3 [95% confidence interval (CI) -11.1, -1.6] ml} and end-systolic volume [-3.2 (95% CI -5.9, -0.5) ml], and increased end-diastolic mass/volume ratio [+0.04 (95% CI 0.00, 0.07)], relative to placebo juice (n = 47). Spironolactone (n = 44) reduced relative wall thickness compared with doxazosin (n = 43) [-0.01 (95% CI -0.02, -0.00)]. Although spironolactone reduced LV mass index relative to baseline [-1.48 (95% CI -2.08, -0.88) g m-2.7 ], there was no difference vs. doxazosin [-0.85 (95% CI -1.76, 0.05) g m-2.7 ]. Spironolactone also decreased the E/A ratio [-0.12 (95% CI -0.19, -0.04)] and increased S' (a tissue-Doppler systolic function index) by 0.52 (95% CI 0.05, 1.0) cm s-1 . BP did not differ between the juices, or between the drugs. CONCLUSIONS Six months' dietary nitrate decreased LV volumes ~5%, representing new, sustained, BP-independent benefits on cardiac structure, extending mechanisms characterized in preclinical models of heart failure. Spironolactone's effects on cardiac remodelling and systolic-diastolic function, although confirmatory, were independent of BP.
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Perturbations in serum chloride homeostasis in heart failure with preserved ejection fraction: insights from TOPCAT.
Grodin, JL, Testani, JM, Pandey, A, Sambandam, K, Drazner, MH, Fang, JC, Tang, WHW
European journal of heart failure. 2018;(10):1436-1443
Abstract
AIMS: Prior cohorts demonstrating the importance of serum chloride levels in heart failure either excluded or had partial representation of patients with heart failure with preserved ejection fraction (HFpEF). We aimed to examine the relationship between serum chloride concentration and outcomes in HFpEF. METHODS AND RESULTS We included participants from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT) who met the following criteria: met inclusion by the natriuretic peptide stratum, had recorded serum chloride levels, and were from the Americas (n = 942). Multivariable Cox proportional hazards models tested the association of serum chloride with clinical outcomes, and mixed effects modelling tested the association of spironolactone or loop diuretic on serial serum chloride levels. The median serum chloride level was 102 [25th-75th percentile 100-105 mmol/L (range 84-114 mmol/L)]. After multivariable adjustment, every standard deviation decrease in serum chloride (4.05 mmol/L) was associated with ∼50% increased risk for cardiovascular death [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.11-2.06, P = 0.008] and ∼30% increased risk for all-cause death (HR 1.29, 95% CI 1.02-1.62, P = 0.04), but not with the primary composite endpoint or heart failure hospitalization (P > 0.3 for both). There were no significant interactions between spironolactone use and the serum chloride-risk relationship (P > 0.1) for each endpoint. Spironolactone was not (P = 0.33) but loop diuretic use was associated with lower serial serum chloride levels (P < 0.001). CONCLUSION Lower serum chloride was independently associated with increased risk of cardiovascular and all-cause death in HFpEF. Loop diuretic use, but not spironolactone, lead to a decrease in serum chloride levels over time.