The Safety and Cardiovascular Efficacy of Spironolactone in Dialysis-Dependent End-Stage Renal Disease (SPin-D) Trial was a randomized, blinded, placebo-controlled 4-arm trial that compared placebo with three doses of spironolactone for patients with end-stage renal disease (ESRD) receiving treatment with hemodialysis. Participants were randomized in a 2:1:1:1 fashion to placebo or spironolactone, with equal proportions randomized to each of three spironolactone doses: 12.5, 25, or 50 mg once daily. The study was conducted in two phases ‒ a dose escalation phase and a treatment phase.

All participants randomized to spironolactone initiated treatment at 12.5 mg daily. Participants were evaluated weekly for tolerability, hypotension, and hyperkalemia. At 2 weeks, if the initial dose had been tolerated, participants randomized to the 25 or 50 mg spironolactone arm increased the dose to 25 mg for 2 weeks with weekly evaluation for tolerability, hypotension, and hyperkalemia. Participants randomized to 12.5 mg spironolactone or placebo arm continued on the same dose with weekly evaluation for tolerability, hypotension, and hyperkalemia. At 4 weeks, participants randomized to the 50 mg spironolactone arm increased the dose to 50 mg if the 25 mg dose was tolerated with weekly evaluations for tolerability, hypotension, and hyperkalemia until 6 weeks. Participants randomized to 12.5 mg, 25 mg, or placebo continued on the same dose with weekly evaluation for tolerability, hypotension, and hyperkalemia until 6 weeks. In order to maintain the blind, during the dose escalation phase, all study participants regardless of randomized assignment, received new study drug kits every 2 weeks and were evaluated weekly. At the end of the dose escalation phase, participants continued treatment based on the randomized dose assignment for an additional 30 weeks (treatment phase) such that the total duration of study medication was 36 weeks. The dose of spironolactone or placebo was decreased during the dose-escalation and follow-up phases for hypotension, hyperkalemia, or other dose limiting side effects.

The primary objectives of the trial were to evaluate the safety of chronic spironolactone therapy in individuals with ESRD receiving treatment with hemodialysis, tolerability of chronic spironolactone therapy, test the hypothesis that chronic blockade of aldosterone with spironolactone improves diastolic function, and assess feasibility of conducting a full-scale mortality-powered trial. For efficacy, the change in E′ on TDI echocardiography of the left ventricle from baseline to end of study was used in the primary endpoint assessment of diastolic function. Feasibility was assessed based on recruitment rate and dropout rates.

The secondary objectives were designed to expand understanding of cardiovascular structure and function and their association with spironolactone therapy in ESRD.

Safety was evaluated by examining potassium level > 6.5 mEq/L; serious hypotension or hyperkalemia; treatment-emergent events defined as the combined incidence of death, myocardial infarction, stroke, hospitalizations, and potassium level > 6.5 mEq/L; the individual components of the treatment-emergent endpoint; cardiovascular death; proportion of dialysis sessions utilizing 1 mEq/L potassium dialysis solution bath; and within-patient variability in serum potassium concentration. Tolerability events included reduction in dose of study medication during the course of the treatment period and discontinuation of study drug.

Secondary objectives of expanding understanding cardiovascular structure and function and their association with spironolactone therapy by analysis of change between baseline and 36 weeks in left ventricular mass index (LVMI), ejection fraction, myocardial strain and strain rate; circulating indices of tissue fibrosis, systemic inflammation, and oxidative stress; coronary flow reserve; and association between change in coronary flow reserve (CFR) and change in heart rate variability and arrhythmia.

• Maintenance hemodialysis therapy for end-stage renal disease
• Age 18-85 years
• ≥ 3 calendar months since dialysis initiation
• For participants on dialysis for ≥ 3 but less than 6 calendar months, there must be no hospitalizations during the 6 weeks prior to screening and no change in EDW within 2 weeks of the screening date
• For women of childbearing potential, willingness to use a highly effective method of birth control for up to 4 weeks after the last dose of study drug
• Ability to provide informed consent

• Serum potassium ≥ 6.5 mEq/L within 3 months prior to screening
• Serum potassium level ≥ 6.0 mEq/L within 2 weeks prior to the baseline visit
• Unscheduled dialysis for hyperkalemia within 3 months prior to screening
• Pre-dialysis systolic blood pressure < 100 mm Hg within 2 weeks prior to screening or at the baseline visit
• Two or more dialysis sessions within the month prior to screening with either two intradialytic measurements of systolic blood pressure < 80 mm Hg
• Current dual use of ACEI or ARB
• Current use of digoxin, spironolactone, or epleronone
• Allergy to spironolactone
• Inability to maintain dialysis machine blood flow ≥ 300 mL/min during any of the most recent three dialysis sessions prior to the screening visit as an indicator of vascular access dysfunction
• Mitral valve repair or replacement; or severe mitral valve disease by echocardiography, coronary angiography, or cardiac magnetic resonance imaging
• Anticipated kidney transplant, change to peritoneal dialysis, or transfer to another dialysis unit within 9 months
• Expected survival < 9 months
• Pregnancy, anticipated pregnancy, or breastfeeding
• Incarceration
• Participation in another intervention study

There were 125 of the 129 participants (97%) that completed dose escalation, with no significant differences in permanent study drug discontinuation between the groups (27.5% in placebo versus 16.7% in the combined spironolactone groups, and 28% in the 50 mg group). Hyperkalemia frequency was similar between spironolactone and placebo (0.49 versus 0.50 events per patient-year), but demonstrated a significant linear trend due primarily to an increased event rate at the 50 mg dose (0.89 events per patient-year). The primary hypotension outcome was infrequent and similar with spironolactone and placebo (0.11 versus 0 events per patient-year). Gynecomastia was rare and did not differ significantly between groups. Change in diastolic function was similar with spironolactone and placebo. The overall conclusions were that spironolactone appears safe in carefully monitored maintenance hemodialysis patients, but did not affect cardiovascular parameters in this study, and that hyperkalemia occurs more frequently as dosage increases to 50 mg daily.