Effect Of Spironolactone Research Articles

RF04 Oral spironolactone for adult female acne (SAFA): a multicentre, double-blind, randomized trial

Abstract Acne is common and results in significant burden and patients with acne frequently receive prolonged oral antibiotics leading to antimicrobial resistance. Oral spironolactone is prescribed for acne, although there is a paucity of evidence on its effectiveness. The aim of this pragmatic parallel, double-blind, superiority trial was to assess the effectiveness of systemic spironolactone for acne in adult women. Participants were identified through primary and secondary health care and through community and social media advertising. Women aged ≥ 18 years with facial acne for at least 6 months, judged to warrant oral antibiotics, were invited to participate. Consented recruits were randomized 1 : 1 to either 50 mg daily spironolactone or matched placebo until week 6, increasing to 100 mg daily spironolactone or placebo until week 24. Topical treatment could be continued. The primary outcome was Acne-Specific Quality of Life (Acne-QoL) symptom subscale score at week 12. Secondary outcomes included Acne-QoL at week 24, participant self-assessed improvement, Investigator’s Global Assessment (IGA) and adverse effects. Of 1267 women assessed, 410 were randomized (201 intervention, 209 control) and 342 were included in the primary analysis. Baseline mean (SD) age was 29.2 (7.2) years, 7.9% (n = 28/356) were of a non-White background, 46% had mild acne, 40% moderate acne and 13% severe acne (IGA classified). Eighty-three per cent used topical treatments. Over 95% of patients in both groups tolerated treatment and increased dosage. Mean (SD) Acne-QoL symptom scores at baseline and week 12 were 13.2 (4.9) and 19.2 (6.1) for spironolactone and 12.9 (4.5) and 17.8 (5.6) for placebo, respectively {difference favouring spironolactone 1.27 [95% confidence interval (CI) 0.07–2.46]}. Scores at week 24 were 21.2 (5.9) for spironolactone and 17.4 (5.8) for placebo [difference 3.45 (95% CI 2.16–4.75)]. Secondary outcomes also favoured spironolactone at week 12, with greater differences at week 24. More participants on spironolactone reported acne improvement than those on placebo. At week 12, this difference was not statistically significant [72.2% vs. 67.9%; odds ratio (OR) 1.16, 95% CI 0.70–1.91], but at week 24, it was significant (81.9% vs. 63.3%; OR 2.72, 95% CI 1.50–4.93). Treatment success (IGA classified) at week 12 was 31/201 on spironolactone and 9/209 on placebo (OR 5.18, 95% CI 2.18–12.28). Adverse reactions were not serious and were similar between groups, although more headaches were reported by those on spironolactone (20.4% vs. 12.0%; P = 0.02). Spironolactone improved outcomes vs. placebo, with greater differences at week 24 than at week 12. This study supports spironolactone as a potential alternative to oral antibiotics for acne in adult women.

Combination of spironolactone and sitagliptin improves clinical outcomes of outpatients with COVID-19: a prospective cohort study.

There are evidences showing that sitagliptin and spironolactone can potentially improve the clinical outcomes of COVID-19 cases. In this observational study on acutely symptomatic outpatient COVID-19 cases, we investigated the effects of spironolactone and sitagliptin on the outcomes of the disease. This is a prospective, naturally randomized cohort study. We followed mild to moderate symptomatic COVID-19 patients, who were treated with either combination (spironolactone 100mg daily and sitagliptin 100mg daily) or standard (steroid, antiviral and/or supportive care) therapy up to 30days. The primary outcome was hospitalization rate. The secondary outcomes included ER visit, duration of disease, and complications, such as hypoglycemia, low blood pressure or altered mental status. Of the 206 patients referred to clinics randomly, 103 received standard therapy and 103 treated with combination therapy. There were no significant differences in baseline characteristics, except for slightly higher clinical score in control group (6.92 ± 4.01 control, 4.87 ± 2.92 combination; P < 0.0001). Treatment with combination therapy was associated with lower admission rate (5.8% combination, 22.3% control; P = 0.0011), ER visits (7.8% combination, 23.3% control; P = 0.0021) and average duration of symptoms (6.67 ± 2.30days combination, 18.71 ± 6.49days control; P ≤ 0.0001). The combination of sitagliptin and spironolactone reduced duration of COVID infection and hospital visits better than standard therapeutic approaches in outpatients with COVID-19. The effects of combination of sitagliptin and spironolactone in COVID-19 patients should be further verified in a double-blind, randomized, placebo-controlled trial.

#5482 CIRCULATING BIOMARKERS OF COLLAGEN REMODELING AS MARKERS FOR DEVELOPMENT OF MICROALBUMINURIA IN TYPE 2 DIABETES: THE PRIORITY TRIAL

Abstract Background and Aims Kidney disease progression is characterized by extensive deposition of extracellular matrix components such as collagen. Therefore, we assessed the effect of spironolactone on collagen remodeling biomarkers and investigated the association between the markers and development of microalbuminuria in serum of persons with type 2 diabetes and normoalbuminuria. Method We measured collagen type III (PRO-C3), VI (PRO-C6; endotrophin), VII (PRO-C7), and XXVIII (PRO-C28) formation, and a fragment of degraded crosslinked collagen type III (CTX-III) in serum of persons with high-risk (stratified by a urinary proteomics classifier, CKD273) for development of microalbuminuria, randomized to either spironolactone 25 mg or placebo. Crude and adjusted Cox models were applied to investigate the association between baseline biomarker levels and development of the primary outcome, persistent microalbuminuria, and development of microalbuminuria in at least one morning void sample, used as a secondary outcome. Results In the PRIORITY trial, spironolactone treatment did not prevent progression to microalbuminuria compared to placebo. All biomarkers were measured in 154 participants at baseline and 117 at end-of-study (week 208). Treatment with spironolactone did not affect serum levels of any of the investigated collagen remodeling biomarkers compared to placebo, and there were no differences in delta-biomarker levels between baseline and end-of-study (p ranging 0.277-0.875). In crude analyses, serum endotrophin was associated with both the primary (n = 44) and secondary outcome (n = 74) (HR per two-fold higher level: 1.58, 95% CI: 1.03-2.44, p = 0.037 and 1.62, 1.12-2.35, p = 0.010), whereas serum PRO-C3 was only associated with the secondary outcome (1.89, 1.19-2.99, p = 0.007). After adjustment for sex, baseline age, systolic blood pressure, estimated glomerular filtration rate, urinary albumin-creatinine ratio, and HbA1c, serum endotrophin and PRO-C3 remained significantly associated with the secondary outcome (1.52, 1.03-2.24, p = 0.036 and 1.73, 1.08-2.78, p = 0.022). Levels of PRO-C7, PRO-C28, and CTX-III were not associated with the specified outcomes. Neither baseline levels of serum endotrophin nor PRO-C3 correlated with baseline CKD273 levels (R: 0.00-0.06, p&amp;gt;0.47). Conclusion Treatment with spironolactone did not change serum levels of collagen remodeling biomarkers. Serum endotrophin, reflecting collagen type VI formation and the pro-fibrotic molecule endotrophin, and PRO-C3, a marker of collagen type III formation, were associated with development of microalbuminuria in at least one urine sample, suggesting that these biomarkers are relevant risk markers for kidney disease development in type 2 diabetes.

#3068 POTASSIUM LEVELS AND EGFR DO NOT PREDICT SEVERE HYPERKALEMIA FOLLOWING SPIRONOLACTONE INTRODUCTION IN PATIENTS WITH CKD AT HIGH RISK OF HYPERKALEMIA

Abstract Background and Aims Mineralocorticoid receptor antagonists (MRA) reduce blood pressure, albuminuria and the rate of disease progression in patients with chronic kidney disease (CKD) and albuminuria. Despite these apparent benefits, only a very small fraction of patients with CKD are treated with an MRA. This may in part be due to the fear of hyperkalemia (HK), which in the most severe cases can cause life-threatening arrythmias. Indeed, international guidelines and previous studies have excluded patients believed to be at high risk of severe HK from treatment with MRA including patients with pre-existing high serum potassium. To examine if the risk of HK can in fact be predicted by baseline potassium levels or eGFR, we performed a clinical study testing the effect of introducing spironolactone on plasma potassium (P-K) levels in closely monitored, high-risk patients excluded from other studies. Secondly, we analyzed the effect of spironolactone on eGFR and albuminuria. Method We included patients with eGFR 25-60 ml/min/1.73 m2 on maximal tolerated RAAS-blockade (ACEi or ARB) and a history of at least two HK-episodes (P-K &amp;gt; 4.5mmol/l) within 24 months prior to inclusion. Following dietary counselling on avoidance of potassium-rich foods, spironolactone was initiated at 25 mg daily. If tolerated as defined by a decline in eGFR &amp;lt; 30%, a P-K ≤ 5.5mmol/l and the absence of severe hypotension, the dose was increased to 50 mg after two weeks. Total follow-up was four weeks measuring P-K, eGFR, blood pressure and spot urine albumin creatinine ratio. Results from maximal tolerated dose were compared to baseline using paired t-test. In a post-hoc analysis, patients were grouped based on the occurrence of severe HK (P-K &amp;gt; 5.5mmol/l) or not, and baseline characteristics and the change from baseline to maximal dose were compared using unpaired t-test. Linear regression model was used to test the association between baseline P-K vs. P-K at maximal dose of spironolactone and the change in P-K from baseline to maximal dose of spironolactone vs. baseline eGFR. Results Fifty-eight patients were included with a mean age of 65 years. Forty-seven were males and 23 had diabetes. Forty-eight patients reached a spironolactone dose of 50 mg. Following spironolactone introduction, mean eGFR declined from 39 at baseline to 34ml/min/1.73 m2 (p&amp;lt;0.001) and albuminuria was reduced from a median of 1276mg/g to 654 mg/g (49%; 95%CI: 44 – 54%) with no significant change in blood pressure. Mean P-K increased 0.5mmol/l (95% CI 0.3 - 0.7mmol/l) from 4.7mmol/l to 5.2mmol/l. Seventeen patients developed severe HK with a P-K &amp;gt; 5.5mmol/l and four were briefly admitted with a P-K &amp;gt; 6.2mmol/l. Importantly, there was no difference in baseline P-K nor eGFR in patients that developed severe HK when compared with those that did not (4.70 vs 4.67 mmol/L, p = 0.83 and 36.2 vs. 40.1 ml/min/1.73 m2, p = 0,13). Furthermore, baseline P-K did not correlate with P-K at maximum spironolactone dose (Figure 1) and the change in P-K did not significantly correlate with baseline eGFR (Figure 2). Conclusion Short-term treatment with spironolactone in patients with CKD at high risk of HK leads to similar reductions in albuminuria and eGFR when compared with low-risk cohorts. With dietary counseling, 30% of patients will develop severe HK within 4 weeks. Importantly and contrary to common belief, neither baseline P-K levels nor baseline eGFR were associated with the development of severe HK. Thus, excluding patients from MRA treatment based solely on eGFR and P-K levels is not appropriate. Instead, we believe an empirical approach based on dietary counseling and close monitoring of P-K should be used.

Usefulness of urinary potassium to creatinine ratio to predict diuretic response in patients with acute heart failure and preserved ejection fraction.

Patients with acute heart failure (AHF) require intensification in the diuretic strategy. However, the optimal diuretic strategy remains unclear. In this work, we aimed to evaluate the role of urinary potassium to creatinine ratio (K/Cr) to predict diuretic and natriuretic response to thiazide or mineralocorticoid receptor antagonists (MRAs) in a cohort of patients with AHF and preserved ejection fraction (AHF-pEF). Patients with a high urinary K/Cr ratio will have a better diuretic and natriuretic response with spironolactone versus chlorthalidone. This is a study of 44 patients with AHF-pEF with suboptimal loop diuretic response. The primary endpoint was the baseline K/Crassociated with natriuretic and diuretic effect of chlorthalidone versus spironolactone at 24and 72 h. Mixed linear regression models were used to analyze the endpoints. Estimates were reported as least squares meanwith their respective 95% confidence interval(CIs). The median age of the study population was 85 years (82.5-88.5), and 30 (68.2%) were women. The inferential multivariate analysis suggested a greater natriuretic and diuretic effect of chlorthalidone across K/Cr levels. In the upper category, chlorthalidone translated into a statistically increase in natriuresis at 24and 72 h. Chlorthalidone versus spironolactone showed ∆uNa of 25.7 mmol/L at 24 h (95%CI = -3.7 to 55.4, p = .098) and ∆uNa of 24.8 mmol/L at 72 h (95%CI = -4 to 53.6, p = .0106). The omnibus p value is .027. Multivariate analyses revealed a significant increase in 72 hcumulative diuresis irrespective of K/Cr status in those on chlorthalidone. In patients with AHF-pEF and suboptimal diuretic response, diuresis and natriuresis are higher with the administration of chlorthalidone over spironolactone. These data don't support the hypothesis that the K/Cr ratio can help guide the choice of thiazide diuretic versus MRA in AHF-pEF patients on loop diuretic.

Effectiveness of spironolactone for women with acne vulgaris (SAFA) in England and Wales: pragmatic, multicentre, phase 3, double blind, randomised controlled trial

ObjectiveTo assess the effectiveness of oral spironolactone for acne vulgaris in adult women.DesignPragmatic, multicentre, phase 3, double blind, randomised controlled trial.SettingPrimary and secondary healthcare, and advertising in the community and...

Phase 2 randomised placebo-controlled trial of spironolactone and dexamethasone versus dexamethasone in COVID-19 hospitalised patients in Delhi

BackgroundIn this phase 2 randomised placebo-controlled clinical trial in patients with COVID-19, we hypothesised that blocking mineralocorticoid receptors using a combination of dexamethasone to suppress cortisol secretion and spironolactone is safe and may reduce illness severity.MethodsHospitalised patients with confirmed COVID-19 were randomly allocated to low dose oral spironolactone (50 mg day 1, then 25 mg once daily for 21 days) or standard of care in a 2:1 ratio. Both groups received dexamethasone 6 mg daily for 10 days. Group allocation was blinded to the patient and research team. Primary outcomes were time to recovery, defined as the number of days until patients achieved WHO Ordinal Scale (OS) category ≤ 3, and the effect of spironolactone on aldosterone, D-dimer, angiotensin II and Von Willebrand Factor (VWF).ResultsOne hundred twenty patients with PCR confirmed COVID were recruited in Delhi from 01 February to 30 April 2021. 74 were randomly assigned to spironolactone and dexamethasone (SpiroDex), and 46 to dexamethasone alone (Dex). There was no significant difference in the time to recovery between SpiroDex and Dex groups (SpiroDex median 4.5 days, Dex median 5.5 days, p = 0.055). SpiroDex patients had significantly lower D-dimer levels on days 4 and 7 (day 7 mean D-dimer: SpiroDex 1.15 µg/mL, Dex 3.15 µg/mL, p = 0.0004) and aldosterone at day 7 (SpiroDex 6.8 ng/dL, Dex 14.52 ng/dL, p = 0.0075). There was no difference in VWF or angiotensin II levels between groups. For secondary outcomes, SpiroDex patients had a significantly greater number of oxygen free days and reached oxygen freedom sooner than the Dex group. Cough scores were no different during the acute illness, however the SpiroDex group had lower scores at day 28. There was no difference in corticosteroid levels between groups. There was no increase in adverse events in patients receiving SpiroDex.ConclusionLow dose oral spironolactone in addition to dexamethasone was safe and reduced D-dimer and aldosterone. Time to recovery was not significantly reduced. Phase 3 randomised controlled trials with spironolactone and dexamethasone should be considered.Trial registrationThe trial was registered on the Clinical Trials Registry of India TRI: CTRI/2021/03/031721, reference: REF/2021/03/041472. Registered on 04/03/2021.

Do Pleiotropic Effects of Spironolactone in Women with PCOS Make it More than an Anti-androgen? Evidence from a Systematic Review and Meta-analysis.

Spironolactone use as a treatment for hirsutism and other dermatological conditions among polycystic ovary syndrome (PCOS) and idiopathic hirsutism shows varied results. This study thus summarizes the entire evidence to better define its impact on Ferriman-Gallwey (FG) score in addition to other derangements associated with PCOS. PubMed, Embase, Scopus and bibliographies of relevant articles were searched. Randomized controlled trails (RCTs) investigating the efficacy of spironolactone in PCOS and idiopathic hirsutism were included. Pooled mean difference (MD) was calculated using random effects model and relevant subgroup analysis was done. Potential heterogeneity and publication bias was assessed. Of 1041 retrieved studies, 24 RCTs were included. Spironolactone (100 mg/daily) exhibited a significant reduction in FG score in idiopathic hirsutism compared to finasteride (MD: -2.43; 95% C.I: -3.29, -1.57) and cyproterone acetate (MD: -1.18; 95% C.I: -2.10, -0.26), however, no significant difference was found among PCOS subjects in comparison to flutamide and finasteride. A lower dose of spironolactone (50 mg/day) exhibited no significant difference relative to metformin on FG Score (MD: -0.61; 95% C.I: -1.76, 0.54, I2 = 57%), serum total testosterone (MD: -0.61; 95% C.I: -1.76, 0.54), I2 = 57% and HOMA-IR (MD: 1.03; 95% C.I: -1.22, 3.29), I2 = 60% among PCOS women. The main side effects reported by the studies were menstrual irregularity, mild nausea, vomiting and diarrhea. Spironolactone is well tolerated among idiopathic hirsute and PCOS women. The drug significantly improved hirsutism in the former group and shows a positive trend in the latter women, however, displays no effect on FSH, LH, menstrual cyclicity, BMI, and HOMA-IR in PCOS women.

A machine learning-derived echocardiographic algorithm identifies people at risk of heart failure with distinct cardiac structure, function, and response to spironolactone: Findings from the HOMAGE trial.

An echocardiographic algorithm derived by machine learning (e'VM) characterizes pre-clinical individuals with different cardiac structure and function, biomarkers, and long-term risk of heart failure (HF). Our aim was the external validation of the e'VM algorithm and to explore whether it may identify subgroups who benefit from spironolactone. The HOMAGE (Heart OMics in AGEing) trial enrolled participants at high risk of developing HF randomly assigned to spironolactone or placebo over 9 months. The e'VM algorithm was applied to 416 participants (mean age 74 ± 7 years, 25% women) with available echocardiographic variables (i.e. e' mean, left ventricular end-diastolic volume and mass indexed by body surface area [LVMi]). The effects of spironolactone on changes in echocardiographic and biomarker variables were assessed across e'VM phenotypes. A majority (>80%) had either a 'diastolic changes' (D), or 'diastolic changes with structural remodelling' (D/S) phenotype. The D/S phenotype had the highest LVMi, left atrial volume, E/e', natriuretic peptide and troponin levels (all p < 0.05). Spironolactone significantly reduced E/e' and B-type natriuretic peptide (BNP) levels in the D/S phenotype (p < 0.01), but not in other phenotypes (p > 0.10; pinteraction <0.05 for both). These interactions were not observed when considering guideline-recommended echocardiographic structural and functional abnormalities. The magnitude of effects of spironolactone on LVMi, left atrial volume and a type I collagen marker was numerically higher in the D/S phenotype than the D phenotype but the interaction test did not reach significance. In the HOMAGE trial, the e'VM algorithm identified echocardiographic phenotypes with distinct responses to spironolactone as assessed by changes in E/e' and BNP.

Effects of Spironolactone on Arrhythmias in Hemodialysis Patients: Secondary Results of the SPin-D Randomized Controlled Trial.

Background Patients receiving maintenance hemodialysis (HD) have a high incidence of cardiovascular events, including arrhythmia and sudden death. Spironolactone reduces the risk of cardiovascular events and sudden death in patients with heart failure, but the effects of spironolactone on arrhythmic events in patients treated with maintenance HD are unclear. Methods The Safety and Cardiovascular Efficacy of Spironolactone in Dialysis-Dependent ESRD (SPin-D) trial, was a 36-week randomized, placebo-controlled, double-blind trial comparing 3 different doses of spironolactone with placebo in maintenance HD patients. We performed a post-hoc analysis in a subset (n=57) who underwent extended electrocardiographic monitoring using a wearable device at baseline and follow-up. Generalized estimating equations models were fit to determine the associations of spironolactone (individual doses and combined) versus placebo on the incidence rate of predefined categories of arrhythmic events. Results The average age of participants was 55 ±12 years; 61% were male; and 77% were Black. The overall proportion of patients with at least one arrhythmia event was 43% (15/35) at baseline and 81% (43/53) at the end of follow-up. At the end of follow-up, the rate of bradycardic events or conduction blocks was higher in the combined spironolactone group, compared with placebo, (82.4 versus 38.7 events/100 patient days; P<0.001). Similar findings were noted in adjusted models, but did not meet statistical significance (adjusted rate ratio of 2.04; 95%CI 0.83 - 5.05). Conclusions In a 36-week trial of patients receiving maintenance hemodialysis, a higher frequency of bradycardia and conduction blocks was observed among those treated with spironolactone treatment compared with placebo. Larger studies are required to investigate the longer-term effects of spironolactone on cardiac conduction in patients receiving hemodialysis.

Spironolactone effect on circulating procollagen type I carboxy-terminal propeptide: Pooled analysis of three randomized trials

BackgroundSpironolactone might improve the prognosis of patients with heart failure with preserved left ventricular ejection fraction (HFpEF), but the mechanisms by which it acts are uncertain. Serum concentrations of procollagen type I carboxy-terminal propeptide (PICP) reflect the synthesis of type I collagen and correlate well with histologically proven cardiac fibrosis. AimsTo investigate the effect of spironolactone on serum PICP concentration in patients with stage B and C HFpEF across three trials (HOMAGE, ALDO-DHF, and TOPCAT) for which measurements of serum PICP were available. MethodsRandom-effects meta-analysis. ResultsA total of 1038 patients with PICP measurements available both at baseline and 9–12 months were included in this analysis: 488 (47.0%) from HOMAGE, 386 (37.2%) from ALDO-DHF, and 164 (15.8%) from TOPCAT. The median (percentile25–75) serum PICP was 98 (76–128) ng/mL. Compared to placebo or usual care, administration of spironolactone for 9 to 12 months reduced serum PICP by −7.4 ng/mL, 95%CI -13.9 to −0.9, P-value =0.02. The effect was moderately heterogeneous (I2 = 64%) with the most pronounced effect seen in TOPCAT where PICP was reduced by −27.0 ng/mL, followed by HOMAGE where PICP was reduced by −8.1 ng/mL, and was least marked in ALDO-DHF where PICP changed by −2.9 ng/mL. The association between spironolactone and serum PICP was not mediated substantially by blood pressure. ConclusionsSpironolactone reduced serum concentrations of PICP in patients with HFpEF with different severity and stages of disease. These findings are consistent with spironolactone having an anti-fibrotic effect.

Long-Lasting Effects of Spironolactone after its Withdrawal in Patients with Hyperandrogenic Skin Disorders.

Hyperandrogenic skin disorders, such as hirsutism, acne and alopecia, affect approximately 10-20% of women of reproductive age, reducing quality of life and causing psychological impairment. Spironolactone is a commonly used antiandrogen, especially in women who are not sexually active or have contraindications to hormonal contraceptives. The aim of this study was to evaluate the effects of spironolactone, especially after its withdrawal, in patients with hyperandrogenic skin disorders. Retrospective analysis of 63 women with hyperandrogenic skin symptoms due to polycystic ovary syndrome (PCOS), treated with spironolactone for at least 6 months as first-line treatment. After a mean time of treatment of 25.7 months, all patients reported a significant improvement in hyperandrogenic skin disorders; only 5 patients were dissatisfied and required the addition of an oral contraceptive. The therapy was well tolerated and the most frequent side-effect was intermestrual bleeding in 68.2% of cases, affecting mainly classic PCOS phenotype. Thirthyeight patients showed prolonged effects 33.7 months after spironolactone withdrawal, whereas 20 relapsed 17.5 months after discontinuation. No significant difference in clinical and biochemical parameters was observed between these two groups both at baseline and after spironolactone treatment. Ovulatory PCOS patients were treated for a shorter time and reported earlier relapse than classic PCOS patients. Spironolactone is an effective and safe treatment for hyperandrogenic skin disorders, showing long-lasting effects even several months after its discontinuation.

Effectiveness of Spironolactone in Terms of Galectin-3 Levels in Patients with Heart Failure with a Reduced Ejection Fraction in the Vietnamese Population.

Background: Galectin-3 is a biomarker that has been demonstrated to play a significant role in myocardial fibrosis and remodeling in the pathogenesis of heart failure. Furthermore, spironolactone has the ability to control galectin-3 levels in heart failure patients. Objectives: The aim of our study was to determine the factors associated with the increase in galectin-3 and the alteration of galectin-3 concentration in patients with heart failure with a reduced ejection fraction after 12 weeks of treatment with spironolactone. Materials and methods: A cross-sectional descriptive study was conducted on 122 patients with heart failure with a reduced ejection fraction. Those patients were nonusers of spironolactone and presented for examination or had been hospitalized at the Can Tho Cardiovascular Hospital in Vietnam. The demographic and cardiovascular risk factor details were obtained at baseline, and galectin-3 levels were measured at baseline and also 12 weeks after taking spironolactone 25 mg once daily vs. 50 mg once daily. Results: The median baseline galectin-3 was 54.82 ± 26.06. Galectin-3 levels were positively correlated with age, NT-proBNP, and negatively correlated between EF and galectin-3 levels (p < 0.05). After 12 weeks of treatment with spironolactone, the galectin-3 concentration decreased from 54.82 ± 26.06 to 44.20 ± 24.36 (p < 0.05). According to the subgroup analysis, the average concentration of galectin-3 decreased the most in the group of patients with grade 3 hypertension and NYHA class III heart failure. The 50 mg once-daily dose of spironolactone significantly improved galectin-3 concentrations compared with the 25 mg once-daily group, at 17.11 ± 20.81 (p < 0.05) (reduced 29.05%) and 3.46 ± 6.81 ng/mL (p < 0.05) (reduced 6.87%), respectively. Conclusion: Treatment with spironolactone played an essential role in reducing galectin-3 concentrations, especially spironolactone 50 mg once daily, which showed a significant effect on reducing galectin-3 compared with a 25 mg once-daily dose.

Effect of Spironolactone on QRS Duration in Patients at Risk for Heart Failure (from the HOMAGE Trial)

The QRS duration can be easily obtained from a 12-lead electrocardiogram. Increased QRS duration reflects greater ventricular activation times and often ventricular dyssynchrony. Dyssynchrony causes an impairment of the global cardiac function and adversely affects the prognosis of patients with heart failure (HF). Little is known about the impact of pharmacologic therapies on the QRS duration, particularly for patients with presymptomatic HF with a preserved left ventricular (LV) ejection fraction (i.e., stage B HF with preserved ejection fraction [HFpEF]). The HOMAGE (Heart OMics in AGEing) trial enrolled patients at risk factors for developing HF and assigned them to receive either spironolactone or the usual care for approximately 9months in a randomized manner. This analysis reports the effect of spironolactone on the QRS duration. A total of 525 patients was included in the analysis. The median (percentile25-75) QRS duration at baseline was 92 (84 to 106) ms. Spironolactone reduced the QRS duration at month 9 by -2.8, 95% confidence interval -4.6 to -1.0 ms, p=0.003. No significant associations were found between month 9 changes in the QRS duration and corresponding changes in the LV ejection fraction, LV mass, LV end-diastolic volume, blood pressure, N-terminal pro-brain natriuretic peptide, and procollagen type I carboxy-terminal propeptide (all p >0.05). This analysis shows that for patients with stage B HFpEF, therapy with spironolactone for 9months shortened the QRS duration, an effect that was not associated with reductions in LV mass or volume, supporting the hypothesis that spironolactone has direct beneficial effects to improve myocardial electrical activation in patients with stage B HFpEF.

PS-BPC11-5: INCIDENCE OF CLINICAL HYPERTENSION IN YOUNG TRANSGENDER PEOPLE AFTER A FIVE-YEAR FOLLOW-UP: ASSOCIATION WITH GENDER-AFFIRMING HORMONAL THERAPY

Introduction and Objective: There is a paucity of data on the long-term cardiovascular side effects of hormonal therapy in transgender people. The most overlooked issue is the cardiovascular risk associated with the use of androgen blockers. While some short-term data on blood pressure effects of gender-affirming hormonal therapy are available, the risk of hypertension development is unknown. We sought to assess this risk in our transgender patients. Design and Methods: Retrospective analysis of the clinical records of consecutive transgender patients who began hormonal therapy in our Outpatient Gender Identity Clinic with &lt; 30 years of age and have a follow-up of at least 5 years. Patients who had office sitting BP &gt; 140/90 mmHg at least twice, had an ABPM or systematic HBPM register with &gt; 135/85 mmHg or were taking antihypertensive medication were diagnosed with hypertension. Mediation analyses with weight increase as mediator were performed post-hoc to quantify its relative contribution to the increase in blood pressure. Patients who were already living with hypertension at the onset of hormonal therapy, withdrew from it or switched androgen blockers were excluded. All subjects gave informed consent. Results: 129 transgender women treated with estradiol and 153 transgender men treated with testosterone were included. Their onset and 5-year follow-up age, blood pressure and body weight are shown in the Table (women are stratified by type of androgen blocker) along with the incidence of hypertension. The increase in body weight was strongly correlated with the SBP increase (Spearman's r: 0.361, p &lt; 0.001). Mediation analyses showed that 31.2% - 42.3% (95% CI) of the SBP increase was mediated by body weight increase but the rest was body weight-independent. Conclusions: The annual incidence of hypertension in young transgender men (1.17%) seems comparable to that of the general population, but in young transgender women the choice of androgen blocker has a remarkable effect on the incidence of hypertension, with apparent protective effect of spironolactone but a striking risk increase with cyproterone acetate (close to 5% yearly). Taken together with the known risks of this drug (meningioma, depression, low libido, liver toxicity, thrombosis…), the use of cyproterone acetate for this indication should be reconsidered. Body weight increase is undoubtedly related to the increase of BP transgender people on gender-affirming hormone therapy but is probably not the main factor.

PS-BPC07-2: EFFECTS OF MINERALOCORTICOID RECEPTOR ANTAGONISTS ON SEX HORMONES AND BODY COMPOSITION IN PATIENTS WITH PRIMARY ALDOSTERONISM

Objective: Mineralocorticoid receptor antagonists are frequently used for the treatment of primary aldosteronism. Steroidal mineralocorticoid receptor antagonists may have antagonistic actions on androgen receptors, agonistic actions on progesterone receptors, and antagonistic actions on mineralocorticoid receptors. Because anti-androgen effects may cause body fat accumulation and skeletal muscle atrophy, there are concerns that this drug may have adverse effects on body composition. Design and method: Therefore, in this randomized prospective study, we compared the adverse effects of spironolactone, a steroidal mineralocorticoid receptor antagonist, and esaxerenone, a nonsteroidal mineralocorticoid receptor antagonist, on sex hormone levels and body composition in patients with primary aldosteronism without severe renal dysfunction. Results: The serum concentration of free testosterone was significantly higher in the spironolactone group than in the esaxerenone group in both males and females. However, the levels of estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone did not significantly increase. Changes in body fat percentage and muscle mass rate were not significantly different between the two groups. No patient showed a serum potassium level &gt; 6.0 mEq/L; however, serum potassium levels were significantly higher in the spironolactone group than in the esaxerenone group. Conclusions: These data indicate that spironolactone may have antagonistic effects on androgen receptors. Esaxerenone did not show any apparent adverse effects, suggesting that it can be safely used in patients with primary aldosteronism.

The impact of different diuretics on regression of myocardial reperfusion injury in spontaneously hypertensive rats.

The study's objective was to ascertain the results of sub-chronic therapy of various diuretics on the ischemia/reperfusion dysfunction of the heart in hypertensive rats by a global ischemia in an isolated rat heart model. The research included 40 spontaneously hypertensive male rats (Wistar Kyoto strain, body mass 250 ± 30g, 8weeks old) grouped into four groups. The animals were treated for 4weeks with 10mg/kg of hydrochlorothiazide, indapamide, or spironolactone per os. After a period of sub-chronic treatment, we analyzed hemodynamic measurements, echocardiography, and myocardial function according to the Langendorff retrograde perfusion method. The hearts were subjected to 20min of global ischemia and then reperfused for 30min (I20:R30). Cardiovascular parameters that depict the left ventricle functions were continuously monitored, while flowmetry was used to determine coronary flow values. Markers of oxidative stress were estimated from coronary venous effluent using spectrophotometry. All three examined diuretics (hydrochlorothiazide, spironolactone, indapamide) lowered the production of the majority of the detected prooxidants, reducing myocardial oxidative damage. The cardiological examination of heart function in vivo demonstrated that treatment with indapamide and spironolactone mitigates left ventricular hypertrophy but without significant lowering of blood pressure or increment in ejection fraction. Additionally, monitoring of cardiac function ex vivo indicated the cardiodepressant effect of spironolactone in spontaneously hypertensive rats.

Spironolactone effect on cardiac structure and function of patients with heart failure and preserved ejection fraction: a pooled analysis of three randomized trials.

Spironolactone is currently used in a large proportion of patients with heart failure and preserved ejection fraction (HFpEF), yet its effect on cardiac structure and function in a large population has not been well established. The aim of this study was to evaluate the impact of spironolactone on key echocardiographic parameters in HFpEF. An individual-patient-data meta-analysis of three randomized trials (HOMAGE, Aldo-DHF, and TOPCAT) was performed comparing spironolactone (9-12 month exposure) to placebo (or control) for the changes in left atrial volume index (LAVi), left ventricular mass index (LVMi), interventricular septum (IVS) thickness, E/e' ratio, and left ventricular ejection fraction (LVEF) among patients with stage B (HOMAGE) or C (Aldo-DHF and TOPCAT) HFpEF. Analysis of covariance was used to test the effect of spironolactone on echocardiographic changes. A total of 984 patients were included in this analysis: 452 (45.9%) from HOMAGE, 398 (40.4%) from Aldo-DHF, and 134 (13.6%) from TOPCAT. The pooled-cohort patient's median age was 71 (66-77) years and 39% were women. Median LAVi was 29 (24-35)ml/m2 , LVMi 100 (84-118) g/m2 , IVS thickness 12 (10-13)mm, E/e' ratio 11 (9-13), and LVEF 64 (59-69)%. Spironolactone reduced LAVi by -1.1 (-2.0 to -0.1) ml/m2 (p=0.03); LVMi by -3.6 (-6.4 to -0.8)g/m2 (p=0.01); IVS thickness by -0.2 (-0.3 to -0.1)mm (p=0.01); E/e' ratio by -1.3 (-2.4 to -0.2) (p=0.02); and increased LVEF by 1.7 (0.8-2.6)% (p < 0.01). No treatment-by-study heterogeneity was found except for E/e' ratio with a larger effect in Aldo-DHF and TOPCAT (interaction p < 0.01). Spironolactone improved cardiac structure and function of patients with HFpEF.

Abstract 11691: Self-Reported Sodium Intake Identifies a Sodium Vulnerable State With Increased Response to Spironolactone in HFpEF

Introduction: Asking patients about sodium intake is standard practice in heart failure (HF). Hypothesis: Self-reported sodium intake in HF with preserved ejection fraction (HFpEF) reflects a vulnerability to sodium intake driven by aldosterone. Methods: The TOPCAT trial registered self-reported sodium intake at baseline. Cox-regression and linear-mixed models were used to assess the relationship between self-reported sodium intake and outcome. Interaction analysis between self-reported sodium intake and the treatment effect of spironolactone on HF-outcome, blood pressure (BP), dyspnea and edema at follow-up were used to assess sodium vulnerability mediated by an aldosterone effect. Results: Self-reported sodium intake of 1748 HFpEF patients included in TOPCAT were divided according to tertiles of sodium intake (47% low, 35% moderate and 18% reported high sodium intake). After covariate adjustment lower self-reported sodium intake associated with higher risk for HF-admission (p=0.009). Patients with a lower sodium intake demonstrated higher E-wave and LV-end diastolic volume and higher estimated plasma volume (p&lt;0.001). Lower sodium intake was associated with a larger treatment effect of spironolactone on HF-admission (HR=0.69, 95%CI 0.53-0.91 vs highest tertile HR=1.37 95%CI 0.79-2.38, p-interaction=0.030). Additionally, linear-mixed models indicated larger BP-reduction (Figure) and larger reduction in dyspnea and edema (p-interaction all&lt;0.001) in patients with lower sodium intake receiving spironolactone. Conclusions: Low self-reported sodium in HFpEF is associated with volume status and higher risk of HFH. The more pronounced treatment effect with spironolactone on HF-outcome, BP and volume status in patients with the lowest self-reported sodium intake potentially suggests that low self-reported sodium intake is an indicator of a sodium vulnerable, potentially aldosterone driven, state.

Effect of spironolactone therapy on the activity of the matrix metalloproteinase system in patients with heart failure after COVID-19

Aim. To assess the change in the activity of the matrix metalloproteinase (MMP) system after 6-month spironolactone therapy in patients with heart failure (HF) with preserved (HFpEF) and mildly reduced ejection fraction (HFmrEF) after coronavirus disease 2019 (COVID-19).Material and methods. The study included 90 patients treated at the University Clinical Hospital № 4 of the I.M. Sechenov First Moscow State Medical University with a laboratory-confirmed COVID-19. There were following inclusion criteria: age of 18-85 years; the presence of HFpEF and HFmrEF. The patients were randomized into two groups: group I (n=60) — patients with 6-month spironolactone therapy (25 mg/day) in addition to the standard therapy for HF, spironolactone was taken at a dose of 25 mg/day; Group II (comparison group, n=30) — patients who received standard therapy without spironolactone. All patients were determined plasma MMP concentrations.Results. There were no significant differences in the levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) between the groups when included in the study. A repeated investigation revealed a significant decrease in the concentrations of MMP-9 and TIMP-1 only in group I. In patients of group II, there were no significant changes in the plasma concentrations of MMP-9 and TIMP-1. The MMP-9/TIMP-1 ratio during the initial examination of patients did not have significant differences. After 6-months therapy, a significant decrease in the ratio of MMP-9/TIMP-1 was observed only in patients taking spironolactone.Conclusion. The results obtained confirm a significant decrease in MMP system activity after 6-month spironolactone therapy in patients with HFpEF and HFmrEF after COVID-19. The described antifibrotic effects of spironolactone make it possible to recommend the use of this drug in this category of patients to reduce the negative effect of MMPs on cardiovascular system.