Spironolactone

BackgroundOptimal drug treatment for patients with resistant hypertension is undefined. We aimed to test the hypotheses that resistant hypertension is most often caused by excessive sodium retention, and that spironolactone would therefore be superior to non-diuretic add-on drugs at lowering blood pressure.MethodsIn this double-blind, placebo-controlled, crossover trial, we enrolled patients aged 18-79 years with seated clinic systolic blood pressure 140 mm Hg or greater (or ≥135 mm Hg for patients with diabetes) and home systolic blood pressure (18 readings over 4 days) 130 mm Hg or greater, despite treatment for at least 3 months with maximally tolerated doses of three drugs, from 12 secondary and two primary care sites in the UK. Patients rotated, in a preassigned, randomised order, through 12 weeks of once daily treatment with each of spironolactone (25-50 mg), bisoprolol (5-10 mg), doxazosin modified release (4-8 mg), and placebo, in addition to their baseline blood pressure drugs. Random assignment was done via a central computer system. Investigators and patients were masked to the identity of drugs, and to their sequence allocation. The dose was doubled after 6 weeks of each cycle. The hierarchical primary endpoints were the difference in averaged home systolic blood pressure between spironolactone and placebo, followed (if significant) by the difference in home systolic blood pressure between spironolactone and the average of the other two active drugs, followed by the difference in home systolic blood pressure between spironolactone and each of the other two drugs. Analysis was by intention to treat. The trial is registered with EudraCT number 2008-007149-30, and ClinicalTrials.gov number, NCT02369081.FindingsBetween May 15, 2009, and July 8, 2014, we screened 436 patients, of whom 335 were randomly assigned. After 21 were excluded, 285 patients received spironolactone, 282 doxazosin, 285 bisoprolol, and 274 placebo; 230 patients completed all treatment cycles. The average reduction in home systolic blood pressure by spironolactone was superior to placebo (-8·70 mm Hg [95% CI -9·72 to -7·69]; pInterpretationSpironolactone was the most effective add-on drug for the treatment of resistant hypertension. The superiority of spironolactone supports a primary role of sodium retention in this condition.FundingThe British Heart Foundation and National Institute for Health Research.

BackgroundIn the PATHWAY-2 study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. We did three substudies to assess the mechanisms underlying this superiority and the pathogenesis of resistant hypertension.MethodsPATHWAY-2 was a randomised, double-blind crossover trial done at 14 UK primary and secondary care sites in 314 patients with resistant hypertension. Patients were given 12 weeks of once daily treatment with each of placebo, spironolactone 25-50 mg, bisoprolol 5-10 mg, and doxazosin 4-8 mg and the change in home systolic blood pressure was assessed as the primary outcome. In our three substudies, we assessed plasma aldosterone, renin, and aldosterone-to-renin ratio (ARR) as predictors of home systolic blood pressure, and estimated prevalence of primary aldosteronism (substudy 1); assessed the effects of each drug in terms of thoracic fluid index, cardiac index, stroke index, and systemic vascular resistance at seven sites with haemodynamic monitoring facilities (substudy 2); and assessed the effect of amiloride 10-20 mg once daily on clinic systolic blood pressure during an optional 6-12 week open-label runout phase (substudy 3). The PATHWAY-2 trial is registered with EudraCT, number 2008-007149-30, and ClinicalTrials.gov, number NCT02369081.FindingsOf the 314 patients in PATHWAY-2, 269 participated in one or more of the three substudies: 126 in substudy 1, 226 in substudy 2, and 146 in substudy 3. Home systolic blood pressure reduction by spironolactone was predicted by ARR (r2=0·13, p2=0·11, p=0·00024). 42 patients had low renin concentrations (predefined as the lowest tertile of plasma renin), of which 31 had a plasma aldosterone concentration greater than the mean value for all 126 patients (250 pmol/L). Thus, 31 (25% [95% CI 17-33]) of 126 patients were deemed to have inappropriately high aldosterone concentrations. Thoracic fluid content was reduced by 6·8% from baseline (95% CI 4·0 to 8·8; pInterpretationOur results suggest that resistant hypertension is commonly a salt-retaining state, most likely due to inappropriate aldosterone secretion. Mineralocorticoid receptor blockade by spironolactone overcomes the salt retention and resistance of hypertension to treatment. Amiloride seems to be as effective an antihypertensive as spironolactone, offering a substitute treatment for resistant hypertension.FundingBritish Heart Foundation and UK National Institute for Health Research.

ObjectivesThe purpose of this study was to investigate the effects of mineralocorticoid receptor antagonists (MRAs) on systolic blood pressure (SBP) and outcomes according to baseline SBP in patients with heart failure with reduced ejection fraction (HFrEF).BackgroundMRAs are greatly underused in patients with HFrEF, often because of fear of adverse events. Concern about hypotension has been raised by the demonstration that MRAs are particularly effective treatment for resistant hypertension.MethodsThe effect of MRA therapy was studied in 4,396 patients with HFrEF randomized in the RALES (Randomized Aldactone Evaluation Study) and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trials.ResultsMean SBP change from baseline to 6 months was +1.4 ± 18.1 mm Hg in the placebo group and -1.2 ± 17.9 mm Hg in the MRA group. The between-treatment difference was 2.6 mm Hg (95% confidence interval [CI]: 1.5 to 3.6; p 105 to ≤115 mm Hg; HR: 0.78; 95% CI: 0.60 to 1.02; SBP >115 to ≤125 mm Hg; HR: 0.71; 95% CI: 0.53 to 0.94; SBP >125 to ≤135 mm Hg; HR: 0.79; 95% CI: 0.57 to 1.10; and SBP > 135 mm Hg; HR: 0.67; 95% CI: 0.50 to 0.90; p for interaction = 0.95). Hypotension was infrequent and not more common with MRA therapy than with placebo, overall (4.6% vs. 3.9%; p = 0.25) or in any SBP category.ConclusionsMRA treatment had little effect on SBP in patients with HFrEF, and the clinical benefits were not modified by baseline SBP. MRA treatment infrequently caused hypotension, even when the baseline SBP was low. The treatment discontinuation rates between MRA and placebo therapy were similar. Low SBP is not a reason to withhold MRA therapy in patients with HFrEF.

ImportanceCirrhosis is a significant global health burden, with serious liver-related complications leading to high morbidity and mortality. Effective therapeutic options to mitigate these complications remain limited. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors, primarily used in diabetes and heart failure management, may offer additional liver-related benefits.ObjectiveTo evaluate the association between SGLT-2 inhibitor use and the risk of serious liver events in patients with cirrhosis receiving furosemide and spironolactone.Design, setting, and participantsThis cohort study used data from over 120 health care organizations within the TriNetX platform. Adult patients with cirrhosis who were receiving furosemide and spironolactone from January 2013 to July 2021 were included. Patients who were receiving SGLT-2 inhibitors plus furosemide and spironolactone were matched with a control group of patients who were receiving furosemide and spironolactone alone according to age, demographics, and comorbidities using 1:1 propensity matching. Each patient was followed up for 3 years; follow-up ended on July 11, 2024.ExposureUse of SGLT-2 inhibitors.Main outcomes and measuresThe primary outcome was a composite of serious liver events defined as incidence of ascites, variceal development, hyponatremia, or all-cause mortality. Secondary outcomes included incidence of variceal bleeding, paracentesis, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome, hepatocellular carcinoma, hypoglycemia, and all-cause hospitalizations. Continuous variables were compared using an independent-samples t test; categorical variables were compared using the Pearson χ2 test.ResultsAmong 10 660 propensity-matched patients (mean [SD] age, 63.8 [10.7] years; 57.8% male), those receiving SGLT-2 inhibitors had a lower incidence of serious liver events compared with control patients (hazard ratio [HR], 0.68 [95% CI, 0.66-0.71]; P Conclusions and relevanceIn this cohort study of adults with cirrhosis who were receiving diuretic therapy, the findings suggest that SGLT-2 inhibitor use was associated with a lower incidence of serious liver events. These findings further suggest a potential role for SGLT-2 inhibitors in cirrhosis management.