Low-dose spironolactone and cardiovascular outcomes in moderate stage chronic kidney disease: a randomized controlled trial

Abstract

Chronic kidney disease (CKD) is associated with a substantial risk of progression to end-stage renal disease and vascular events. The nonsteroidal mineralocorticoid receptor antagonist (MRA), finerenone, offers cardiorenal protection for people with CKD and diabetes, but there is uncertainty if the steroidal MRA, spironolactone, provides the same protection. In this prospective, randomized, open, blinded endpoint trial, we assessed the effectiveness of 25 mg spironolactone in addition to usual care or usual care alone for reducing cardiovascular outcomes in stage 3b CKD among an older community cohort (mean age = 74.8 years and s.d. = 8.1). We recruited 1,434 adults from English primary care, of whom 1,372 (96%) were included in the primary analysis. The primary outcome was time from randomization until the first occurrence of death, hospitalization for heart disease, stroke, heart failure, transient ischemic attack or peripheral arterial disease, or first onset of any condition listed not present at baseline. Across 3 years of follow-up, the primary endpoint occurred in 113 of 677 participants randomized to spironolactone (16.7%) and 111 of 695 participants randomized to usual care (16.0%) with no significant difference between groups (hazard ratio = 1.05, 95% confidence interval: 0.81-1.37). Two-thirds of participants randomized to spironolactone stopped treatment within 6 months, predominantly because they met prespecified safety stop criteria. The most common reason for stopping spironolactone was a decrease in the estimated glomerular filtration rate that met prespecified stop criteria (n = 239, 35.4%), followed by participants being withdrawn due to treatment side effects (n = 128, 18.9%) and hyperkalemia (n = 54, 8.0%). In conclusion, we found that spironolactone was frequently discontinued due to safety concerns, with no evidence that it reduced cardiovascular outcomes in people with stage 3b CKD. Spironolactone should not be used for people with stage 3b CKD without another explicit treatment indication. ClinicalTrials.gov registration: ISRCTN44522369 .

Fig. 1. CONSORT flow diagram.

The CONSORT flow diagram reports the flow of participants through the study. Note that participants who stopped taking treatment but who continued with the study follow-up remain in their allocated treatment arm. *Participants found to be ineligible after randomisation, excluded from the analysis population.

Fig. 2. Kaplan–Meier curve for the time (in months) from randomization to the first primary endpoint event.

Kaplan–Meier curve for the composite primary outcome comparing those randomized to spironolactone versus usual care (two-sided test).

Extended Data Fig. 1. Cost-effectiveness plane for spironolactone in addition to usual care versus usual care alone under complete case analysis using EQ-5D-5L weights for the quality-adjusted life years (QALY).

The cost-effectiveness plane presents the results from 1,000 bootstrap replications, each represented by an individual circle.

Extended Data Fig. 2. Cost-effectiveness acceptability curve for spironolactone in addition to usual care versus usual care alone under complete case analysis with EQ-5D-5L weights for the quality-adjusted life years (QALY).

The cost-effectiveness acceptability curve presents the probability of spironolactone in addition to usual care being cost-effective compared to usual care alone at different cost-effectiveness thresholds.

Extended Data Fig. 3. Forest plot of the hazard ratio and 95% confidence interval from the subgroup analyses compared to the main trial result (dotted vertical line).

†Spironolactone versus standard care among sub-groups of participants with type 2 diabetes, coronary artery disease or blood pressure above or below the NICE target at baseline. Cox proportional hazards model adjusted for randomized arm, an indicator variable for the subgroup and an interaction between randomized arm and the subgroup indicator variable. A hazard ratio of less than 1 indicates improvement in favor of spironolactone. ‡Two-sided P-value. Level of significance = 0.05.

Extended Data Fig. 4. Kaplan–Meier curve for the time (in months) from randomization to the first primary endpoint for the post hoc analysis based on a per-protocol principle and an on-treatment population.

Spironolactone versus usual care. Cox proportional hazards model adjusted for randomized arm. A hazard ratio of less than 1 indicates improvement in favor of spironolactone. Two-sided P-value. Level of significance = 0.05.

Extended Data Fig. 5. Kaplan–Meier curve for the time (in months) from randomization to the first primary endpoint, excluding PAD from the composite primary outcome definition.

Spironolactone versus usual care (two-sided test), excluding PAD from the composite primary outcome. P-value level of significance = 0.05. PAD: peripheral arterial disease.