Association of spironolactone use with risk of urinary tract cancer in the general population: A matched population-based cohort study.

PURPOSE: The correlation between spironolactone usage and cancer risk has sparked interest. The objective of this study is to examine the association between spironolactone use and the incidence of urinary tract cancer in the general population. METHODS: We conducted a matched population-based cohort study. The study population was obtained from the Taiwan National Health Insurance Research Database (TNHIRD) during the period from 2000 to 2016. The multivariate Cox proportional hazard model was performed to examine the impact of spironolactone use on the risk of urinary tract cancer. A total of 8,608 individuals exposed to spironolactone were exact matched by 1:1 ratio with unexposed controls on factors including age, gender, comorbidities, CCI scores and socioeconomic status. The incidences of urinary tract cancer, including prostate, renal and bladder cancer, were estimated in both spironolactone exposed and non-exposed cohorts. RESULTS: After adjusting for confounding variables, the multivariate Cox regression analysis showed no significant association between spironolactone exposure and urinary tract cancer incidence, including bladder (adjusted hazard ratio [aHR] = 1.19, 95% confidence interval [CI] = 0.72-1.96, p = 0.50), renal (aHR = 1.75, 95% CI = 0.99-3.07, p = 0.053), and prostate cancer (aHR = 0.67, 95% CI = 0.43-1.04, p = 0.07). When the population was stratified into low (cumulative dose < = 29,300 mg) and high (cumulative dose >29,300 mg) dose of spironolactone, only high dose of spironolactone use was significantly associated with a reduced risk of prostate cancer (aHR = 0.45, 95% CI = 0.23-0.89, p = 0.02), while being associated with an elevated risk of renal cancer (aHR = 2.09, 95% CI = 1.07-4.08, p = 0.03). However, no clear cumulative dose-response relationship was observed in theses associations. CONCLUSIONS: High cumulative dose of spironolactone may be potentially associated with a decreased incidence of prostate cancer and an increased incidence of renal cancer, while no significant association was observed with bladder cancer incidence. However, given the lack of support from the dose-response pattern, the available evidence is inconclusive to establish a definitive association between spironolactone use and urinary tract cancer.

Effectiveness and safety of early treatment with spironolactone for new-onset acute heart failure.

BACKGROUND: The effectiveness and safety of mineralocorticoid receptor antagonists (MRA) in acute heart failure (HF) is uncertain. We sought to describe the prescription of spironolactone during acute HF and whether early treatment is effective and safe in a real-world setting. METHODS: We performed a retrospective cohort study of adult (≥18 years) nonpregnant patients hospitalized with new-onset HF with reduced ejection fraction (HFrEF, defined by ejection fraction ≤40%) within 15 Kaiser Permanente Southern California medical centers between 2016 and 2021. Early treatment was defined by spironolactone prescription at discharge. The primary effectiveness outcome was a composite of HF readmission or all-cause mortality at 180 days. Safety outcomes were hypotension and hyperkalemia at 90 days. RESULTS: Among 2318 HFrEF patients, 368 (15.9%) were treated with spironolactone at discharge. After 1:2 propensity score matching, 354 early treatment and 708 delayed/no treatment patients were included in the analysis. The median age was 63 (IQR: 52-74) years; 61.6% were male, and 38.6% were White. By 90 days, ~20% had crossed over in the two groups. Early treatment was not associated with the composite outcome at 180 days (HR [95% CI]: 0.81 [0.56-1.17]), but a trend towards benefit by 365 days that did not reach statistical significance (0.78 [0.58-1.06]). Early treatment was also associated with hyperkalemia (subdistribution HR [95% CI]: 2.33 [1.30-4.18]) but not hypotension (0.93 [0.51-1.72]). CONCLUSIONS: Early treatment with spironolactone at discharge for new-onset HFrEF in a real-world setting did not reduce the risk of HF readmission or mortality in the first year after discharge. The risk of hyperkalemia was increased.

Efficacy of Spironolactone Compared with Doxycycline in Moderate Acne in Adult Females: Results of the Multicentre, Controlled, Randomized, Double-blind Prospective and Parallel Female Acne Spironolactone vs doxyCycline Efficacy (FASCE) Study.

Acne in adult females is triggered mainly by hormones. Doxycycline is a reference treatment in acne. Spironolactone targets the androgen receptor of sebaceous glands and is prescribed off-label for female adult acne. This multicentre, controlled, randomized, double-blind prospective and parallel study assessed the efficacy of spironolactone compared with doxycycline in adult female acne. A total of 133 women with moderate acne were randomized to receive treatment with: (i) doxycycline and benzoyl peroxide for 3 months followed by a 3-month treatment with its placebo and benzoyl peroxide, or (ii) spironolactone and benzoyl peroxide for 6 months. Successfully treated patients continued with benzoyl peroxide or spironolactone alone for a further 6 months. Primary endpoints were treatment success at month 4 and month 6 with the AFAST score. At all visits, the ECLA score, lesion counts, local and systemic safety and quality of life were assessed. Spironolactone performed better at month 4 and showed a statistically significant better treatment success after 6 months than doxycycline (p = 0.007). Spironolactone was 1.37-times and 2.87-times more successful compared with doxycycline at respective time-points. AFAST and ECLA scores, as well as lesion counts always improved more with spironolactone. Patients' quality of life was better with spironolactone at month 4 and month 6. Spironolactone was very well tolerated. This is the first study to show that, in female adults with moderate acne, treatment with spironolactone is significantly more successful than doxycycline and very well tolerated.

The efficacy of the combination of topical minoxidil and oral spironolactone compared with the combination of topical minoxidil and oral finasteride in women with androgenic alopecia, female and male hair loss patterns: A blinded randomized clinical trial.

INTRODUCTION: Androgenic alopecia (AGA) is the most common cause of hair loss in women, affecting their quality of life. The present study was conducted with the aim of comparing the combined effect of topical minoxidil and oral spironolactone with the combined effect of topical minoxidil and oral finasteride in women with AGA, female and male hair loss patterns. METHOD: This clinical study was performed on 60 women suffering from AGA. The patients were divided into two groups receiving spironolactone 100 mg/day and finasteride 5 mg/day. In addition, a 2% minoxidil solution was used in all patients in addition to treatment with finasteride or spironolactone. At 2 months after initiation and at the end of treatment, patients were evaluated using the Ludwig/Norwood-Hamilton scale and the degree of physician and patient satisfaction. RESULTS: After 2 months, hair density, hair thickness, and hair loss had improved in both groups; however, statistically, there was no significant difference between the two groups with respect to these parameters (p > 0.05). After 4 months, a significant difference was found between the two groups in terms of treatment response (physician satisfaction), hair density, and hair loss severity. So that, the drugs used were ineffective in 6.7% of cases in the minoxidil-spironolactone group and in 16.7% of cases in the minoxidil-finasteride group. In addition, 43.3% of cases in the minoxidil-spironolactone group and 53% in the minoxidil-finasteride group responded well to treatment. The treatment effect was excellent in 56.7% and 0% of the mentioned groups, respectively, and the mentioned difference was statistically significant (p: 0.01). The response to treatment in female pattern hair loss (FPHL) was not statistically significant (p: 0.52), but there was a significant difference in the response to both treatments in male pattern hair loss (MPHL; p: 0.007). In terms of patient satisfaction, minoxidil-spironolactone treatment was significantly better than minoxidil-finasteride regarding hair density and severity of hair loss (p: 0.01). Finally, in terms of treatment complications, the patients in two groups did not have any serious adverse effects. CONCLUSION: The combination of minoxidil and spironolactone could be considered a more effective treatment than the combination of minoxidil and finasteride in women with AGA, FPHL, and MPHL.

Spironolactone improves left atrial function and atrioventricular coupling in patients with resistant hypertension.

To determine the blood pressure independent effects of spironolactone on left atrial (LA) size and function in patients with resistant hypertension (RHTN). Patients with RHTN (n = 36, mean age 55 ± 7) were prospectively recruited. Spironolactone was initiated at 25 mg/day and increased to 50 mg/day after 4 weeks. Other antihypertensives were withdrawn to maintain constant blood pressure. Cardiac magnetic resonance imaging was performed at baseline and after 6 months of spironolactone treatment and changes in LA functional metrics were assessed. LA size and function parameters were improved (p < 0.05) from baseline to month-6: LA volumes indexed to body surface area (LAVI) were reduced (LAVImaximum 41.4 ± 12 vs. 33.2±9.7 mL/m2; LAVIpre-A 32.6 ± 9.8 vs. 25.6 ± 8.1 mL/m2; median LAVIminimum 18.5 [13.9-24.8] vs. 14.1 [10.9-19.2] mL/m2); left atrioventricular coupling index was reduced (28.2 ± 11.5 vs. 22.7 ± 9.2%); LA emptying fractions (LAEF) were increased (median total LAEF 52.4 [48.7-60.3] vs. 55.9 [50.3-61.1] %; active LAEF 40.2 ± 8.6 vs. 43.1 ± 7.8%). LA global longitudinal strain in the active phase was increased (16.3 ± 4.1 vs. 17.8 ± 4.2%). The effect of spironolactone was similar in patients with high (N = 18) and normal (N = 18) aldosterone status (defined by plasma renin activity and 24-h urine aldosterone). Treatment of RHTN with spironolactone is associated with improvements in LA size and function, and atrioventricular coupling, regardless of whether aldosterone levels were normal or high at baseline. This study suggests the need for larger prospective studies examining effects of mineralocorticoid receptor antagonists on atrial function and atrioventricular coupling.

Potassium levels in women with polycystic ovary syndrome using spironolactone for long-term.

OBJECTIVE: Spironolactone (SPL) has been used to manage hyperandrogenic manifestations in women with polycystic ovary syndrome (PCOS), but data on the risk of hyperkalemia in this population are scarce. The aim of this study was to evaluate the incidence of hyperkalemia in women with PCOS using SPL in the long term. DESIGN: Single-centre retrospective study. PATIENTS: Inclusion and analysis of 98 treatment periods in 78 women with PCOS (20 of whom were duplicates, returning after treatment interruption for a mean of 38 months) who received SPL for a minimum of 12 months and had at least three measurements of potassium levels over time. MEASUREMENTS: Clinical and hormonal profiles before and during SPL treatment. RESULTS: Mean age was 29.1 (SD: 9.6) years, and body mass index was 32.2 (SD: 8.1) kg/m². Nine patients had diabetes, and 22 had prediabetes. SPL was used in combination with combined oral contraceptive pills in 55 participants and progestin-only pills/long-acting reversible contraception in 28; metformin was added in 35, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in 15. Median SPL dose was 100 (range: 50-150) mg. A total of 327 serum potassium measurements were obtained (84 pre-exposure and 243 postexposure). Four potassium measurements were above the reference range before exposure and 19 during exposure. All potassium measurements above the reference range during follow-up were classified as mild hyperkalemia (5.1-5.5 mEq/L). CONCLUSIONS: The present findings suggest that women with PCOS, without kidney or heart disease, using SPL combined with hormonal contraception for managing clinical hyperandrogenism have a low incidence of hyperkalemia and well-tolerated minor adverse effects.

Efficacy and safety of iodized lecithin tablets versus spironolactone in alleviating central serous retinopathy among Chinese patients with uncontrolled diabetes.

To compare the effectiveness and safety of spironolactone versus lecithin-bound iodine in patients with central serous retinopathy (CSR). Chinese diabetes patients aged>18 years with CSR with persistent increased level of subretinal fluid (SRF) were enrolled. Subjects were randomized to receive either oral lecithin-bound iodine (390µg/kg/day) or oral spironolactone (50mg/day) for 6 months. A total of 200 patients were randomized and completed the study. Compared to spironolactone group, patients treated with lecithin-bound iodine had greater proportion of eye with complete resolution (87% vs 81%, p>0.005). Higher improvement in height of SRF was observed in lecithin-bound iodine-treated patients as compared with Spironolactone-treated patients (91.2[87.5] vs 142.5 [121.1]; p>0.005). However, no statistically significant difference was observed on none of comparisons. Compared to Spironolactone, the patients treated with lecithin-bound iodine had greater improvement in lesion size, central macular thickness and best-corrected visual acuity. However, no statistically significant difference was observed in any of parameter assessed. (p>0.005). The results of the present study suggested that the lecithin-bound iodine was found more effective (nnumerically) than spironolactone in Chinese diabetes patients with CSR.

Spironolactone for acne in women.

Overview of: Santer M, Lawrence M, Renz S, et al. Effectiveness of spironolactone for women with acne vulgaris (SAFA) in England and Wales: pragmatic, multicentre, phase 3, double blind, randomised controlled trial. BMJ. 2023;381:e074349.

Initiation of eplerenone or spironolactone, treatment adherence, and associated outcomes in patients with new-onset heart failure with reduced ejection fraction: a nationwide cohort study.

BACKGROUND: The mineralocorticoid receptor antagonists (MRAs) eplerenone and spironolactone are beneficial in heart failure with reduced ejection fraction (HFrEF), but have not been prospectively compared. We compared clinical outcomes, daily dosages, and discontinuation rates for the two drugs in a nationwide cohort. METHODS: We identified all patients with HFrEF in the period 2016-2020, who were alive and had initiated MRA treatment at study start, 180 days after HF diagnosis. We estimated the 2-year risk of a composite of death and HF hospitalization, as well as each component separately, using Kaplan-Meier, cumulative incidence functions, and Cox proportional hazards models adjusted for age, sex, and comorbidities. Secondly, we assessed treatment withdrawal, cross-over, and daily drug dosage. RESULTS: We included 7479 patients; 653 (9%) on eplerenone and 6840 (91%) on spironolactone. Patients in the eplerenone group were younger (median age 65 vs. 69 years), and more often men (91% vs. 68%), both P < 0.001. In adjusted analyses, with spironolactone as reference, there were no differences in the risk of the composite of all-cause death and HF hospitalization (HR 1.02, 95% CI 0.82-1.27), all-cause death (HR 0.93, 95% CI 0.67-1.30), or HF hospitalization (HR 1.10, 95% CI 0.84-1.42). Treatment withdrawal occurred in 34% in the eplerenone group and 53% in the spironolactone group (P < 0.001), treatment cross-over in 3%, and 10%, respectively. Daily dose >25 mg at 12 months, was observed in 230 patients (37%) in the eplerenone group and 771 patients (12%) in the spironolactone (P < 0.001). CONCLUSIONS: In a contemporary nationwide cohort of patients with new-onset HFrEF who initiated MRA, we found no differences in clinical outcomes associated with initiation of eplerenone vs. spironolactone. Treatment was more frequently withdrawn, and daily drug dosage was lower among patients treated with spironolactone.

Hypertension in chronic kidney disease-treatment standard 2023.

Hypertension is very common and remains often poorly controlled in patients with chronic kidney disease (CKD). Accurate blood pressure (BP) measurement is the essential first step in the diagnosis and management of hypertension. Dietary sodium restriction is often overlooked, but can improve BP control, especially among patients treated with an agent to block the renin-angiotensin system. In the presence of very high albuminuria, international guidelines consistently and strongly recommend the use of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker as the antihypertensive agent of first choice. Long-acting dihydropyridine calcium channel blockers and diuretics are reasonable second- and third-line therapeutic options. For patients with treatment-resistant hypertension, guidelines recommend the addition of spironolactone to the baseline antihypertensive regimen. However, the associated risk of hyperkalemia restricts the broad utilization of spironolactone in patients with moderate-to-advanced CKD. Evidence from the CLICK (Chlorthalidone in Chronic Kidney Disease) trial indicates that the thiazide-like diuretic chlorthalidone is effective and serves as an alternative therapeutic opportunity for patients with stage 4 CKD and uncontrolled hypertension, including those with treatment-resistant hypertension. Chlorthalidone can also mitigate the risk of hyperkalemia to enable the concomitant use of spironolactone, but this combination requires careful monitoring of BP and kidney function for the prevention of adverse events. Emerging agents, such as the non-steroidal mineralocorticoid receptor antagonist ocedurenone, dual endothelin receptor antagonist aprocitentan and the aldosterone synthase inhibitor baxdrostat offer novel targets and strategies to control BP better. Larger and longer term clinical trials are needed to demonstrate the safety and efficacy of these novel therapies in the future. In this article, we review the current standards of treatment and discuss novel developments in pathophysiology, diagnosis, outcome prediction and management of hypertension in patients with CKD.

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

OBJECTIVE: To assess the effectiveness of oral spironolactone for acne vulgaris in adult women. DESIGN: Pragmatic, multicentre, phase 3, double blind, randomised controlled trial. SETTING: Primary and secondary healthcare, and advertising in the community and on social media in England and Wales. PARTICIPANTS: Women (≥18 years) with facial acne for at least six months, judged to warrant oral antibiotics. INTERVENTIONS: Participants were randomly assigned (1:1) to either 50 mg/day spironolactone or matched placebo until week six, increasing to 100 mg/day spironolactone or placebo until week 24. Participants could continue using topical treatment. MAIN OUTCOME MEASURES: Primary outcome was Acne-Specific Quality of Life (Acne-QoL) symptom subscale score at week 12 (range 0-30, where higher scores reflect improved QoL). Secondary outcomes were Acne-QoL at week 24, participant self-assessed improvement; investigator's global assessment (IGA) for treatment success; and adverse reactions. RESULTS: From 5 June 2019 to 31 August 2021, 1267 women were assessed for eligibility, 410 were randomly assigned to the intervention (n=201) or control group (n=209) and 342 were included in the primary analysis (n=176 in the intervention group and n=166 in the control group). Baseline mean age was 29.2 years (standard deviation 7.2), 28 (7%) of 389 were from ethnicities other than white, with 46% mild, 40% moderate, and 13% severe acne. Mean Acne-QoL symptom scores at baseline were 13.2 (standard deviation 4.9) and at week 12 were 19.2 (6.1) for spironolactone and 12.9 (4.5) and 17.8 (5.6) for placebo (difference favouring spironolactone 1.27 (95% confidence interval 0.07 to 2.46), adjusted for baseline variables). Scores at week 24 were 21.2 (5.9) for spironolactone and 17.4 (5.8) for placebo (difference 3.45 (95% confidence interval 2.16 to 4.75), adjusted). More participants in the spironolactone group reported acne improvement than in the placebo group: no significant difference was reported at week 12 (72% v 68%, odds ratio 1.16 (95% confidence interval 0.70 to 1.91)) but significant difference was noted at week 24 (82% v 63%, 2.72 (1.50 to 4.93)). Treatment success (IGA classified) at week 12 was 31 (19%) of 168 given spironolactone and nine (6%) of 160 given placebo (5.18 (2.18 to 12.28)). Adverse reactions were slightly more common in the spironolactone group with more headaches reported (20% v 12%; p=0.02). No serious adverse reactions were reported. CONCLUSIONS: Spironolactone improved outcomes compared with placebo, with greater differences at week 24 than week 12. Spironolactone is a useful alternative to oral antibiotics for women with acne. TRIAL REGISTRATION: ISRCTN12892056.

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

BACKGROUND: In 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. METHODS: Hospitalised 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). RESULTS: One 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. CONCLUSION: Low 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 REGISTRATION: The 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.

Efficacy and Safety of Low-dose Spironolactone for Chronic Kidney Disease in Type 2 Diabetes.

CONTEXT: Although adding spironolactone to renin-angiotensin system blockers reduces albuminuria in adults with chronic kidney disease and type 2 diabetes, it increases the risk of hyperkalemia. OBJECTIVE: To assess whether a lower dose of spironolactone (12.5 mg/d) reduces the risk of hyperkalemia while maintaining its effect on reducing albuminemia. DESIGN: Multicenter, open-label, randomized controlled trial. SETTING: This study was conducted from July 2016 to November 2020 in ambulatory care at 3 diabetes medical institutions in Japan. PATIENTS: We enrolled 130 Japanese adults with type 2 diabetes and albuminuria (≥30 mg/gCre), estimated glomerular filtration rate ≥30 mL/min/1.73 m2, and serum potassium level <5.0 mEq/L. INTERVENTIONS: The participants were randomly assigned to the spironolactone-administered and control groups. MAIN OUTCOME MEASURES: Changes in urine albumin-to-creatinine ratio (UACR) from baseline over the 24-week interventional period. RESULTS: The spironolactone group showed a significant reduction in UACR from baseline (mean decrease, 103.47 ± 340.80 mg/gCre) compared with the control group, which showed an increased UACR (mean increase, 63.93 ± 310.14 mg/gCre; P = .0007, Wilcoxon rank-sum test and t test). Although the spironolactone group had a statistically significant increase in serum potassium levels, none of the participants had a potassium level ≥5.5 mEq/L at 24 weeks. Further, participants with a higher initial serum potassium level tended to have a smaller increase (estimate, -0.37, analysis of covariance). CONCLUSIONS: Low-dose spironolactone administration reduced albuminuria without causing hyperkalemia. Spironolactone administration, the oldest known and most cost-effective mineralocorticoid receptor antagonist, at lower doses should be reconsidered.

Research Progress on the Efficacy and Safety of Spironolactone in Reversing Left Ventricular Hypertrophy in Hemodialysis Patients.

The mineralocorticoid receptor antagonist spironolactone has been shown to improve cardiac function and reverse left ventricular hypertrophy in heart failure patients, but there are no consistent findings on the efficacy and safety in hemodialysis patients. Abnormal aldosterone secretion plays a critical role in the formation of left ventricular hypertrophy. Because of the existence of "aldosterone escape", the routine use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers does not completely inhibit aldosterone secretion. Low-dose spironolactone (25 mg/d) has been found in small-sample clinical studies to have a significant positive impact with respect to decreasing left ventricular mass index, increasing left ventricular ejection fraction, reversing left ventricular hypertrophy, and improving cardiovascular function while still being safe. More prospective multicenter clinical trials with large sample sizes are needed, however, to provide convincing evidence.