Authors' objectives: Chronic kidney disease affects around 10% of the global population and is associated with significant risk of progression to end-stage renal disease and vascular events. Aldosterone receptor antagonists such as spironolactone have shown prognostic benefits in patients with heart failure, but effects on patients with chronic kidney disease are uncertain. To determine the effect of low-dose spironolactone on mortality and cardiovascular outcomes in people with chronic kidney disease stage 3b. Chronic kidney disease (CKD) is a major cause of increased mortality and morbidity through increased vascular events and progression to end-stage renal failure (ESRF). These increased events result in CKD having high cost to healthcare systems, with the dialysis required in ESRF benchmarked as at the maximum acceptable cost-effectiveness threshold for an intervention by most healthcare systems. However, the most important component of CKD in terms of mortality and morbidity is cardiovascular disease (CVD). While the cardiovascular risk of end-stage CKD is extreme, in public health terms the burden resides in early-stage (CKD stages 1–3) disease, which is more prevalent, affecting around 40% of those over 70 years. When added to conventional risk factors, renal markers substantially improve risk stratification and CKD is therefore an important and under-recognised risk factor for CVD in the general population. Although the risks of myocardial infarction and other manifestations of coronary artery disease are increased in CKD, the pattern of CVD is atypical, with a much greater incidence of heart failure and sudden cardiac death than in the general CVD population. Few therapies have proved effective in modifying the increased CVD risk or the rate of renal decline in CKD. There are accumulating data that aldosterone receptor antagonists (ARAs) may offer cardio-protection and delay renal impairment in patients with the cardiovascular (CV) phenotype in CKD. The use of ARA in CKD has therefore been increasingly advocated and even termed the ‘renal aspirin’. Prior to the initiation of benefits of aldosterone receptor antagonism in chronic kidney disease (BARACK-D), no large study of ARAs with renal or CVD outcomes was underway. This trial evaluates the benefits of an ARA, spironolactone, in patients with stage 3b CKD. The primary objective was to determine the effect of aldosterone receptor antagonism with spironolactone on mortality and cardiovascular outcomes in people with CKD stage 3b. Secondary objectives included determining the effect on renal function and blood pressure control, cost-effectiveness and the safety of this treatment approach.

Authors' results and conclusions: One thousand four hundred and thirty-four participants were randomised of the 3022 planned. We found no evidence of differences between the intervention and control groups in terms of effectiveness with the primary combined vascular end points, nor with the secondary clinical outcomes, including progression in renal decline. These results were similar for the total treatment periods or a 3-year follow-up period as originally planned. More adverse events were experienced and more participants discontinued treatment in the intervention group. Two-thirds of participants randomised to spironolactone stopped treatment within six months because they met pre-specified safety stop criteria. The addition of low-dose spironolactone was estimated to have a cost per quality-adjusted life-year gained value above the National Institute for Health and Care Excellence’s threshold of £30,000. The benefits of aldosterone receptor antagonism in chronic kidney disease trial found no evidence to support adding low-dose spironolactone (25 mg daily) in patients with chronic kidney disease stage 3b: there were no changes to cardiovascular events during the trial follow-up, either for the combined primary or individual components. There was also no evidence of benefit observed in rates of renal function decline over the trial, but much higher initial creatinine rise and estimated glomerular filtration rate decline, and to a higher percentage rate, in the intervention arm in the first few weeks of spironolactone treatment, which resulted in a high proportion of participants discontinuing spironolactone treatment at an early stage. These higher rates of negative renal change reduced in scale over the study but did not equalise between arms. The addition of 25 mg of spironolactone therefore provided no reno- or cardio-protection and was associated with an increase in adverse events. One thousand four hundred and thirty-four participants were randomised of the 3022 we planned. One thousand three hundred and seventy-two (96%) were included in the analysis. Of the participants, 113/677 (16.7%) in the spironolactone arm and 111/695 (16.0%) in the standard care arm had a primary combined vascular event. We found no evidence of differences between the intervention and control groups in terms of effectiveness with the primary outcome [hazard ratio 1.05, 95% confidence interval (0.81 to 1.37); p = 0.70], nor with the secondary clinical outcomes, including progression in renal decline. These findings were consistent whether analysing the total treatment periods or a 3-year follow-up period as was originally planned. Adverse events were experienced more often, and participants were more likely to discontinue treatment in the intervention group. Two-thirds of participants randomised to spironolactone discontinued taking treatment within six months, with the most frequenst reasons being a decrease in the estimated glomerular filtration rate that met pre-specified stop criteria (n = 239, 35.4%), treatment side-effects (n = 128, 18.9%) and hyperkalaemia (n = 54, 8.0%). The addition of low-dose spironolactone was unlikely to be cost-effective The BARACK-D trial found no evidence of benefit with the addition of low-dose spironolactone at 25 mg daily in patients with CKD 3b on the high rates of cardiovascular events seen in the trial follow-up, either for the combined primary or for individual components. There was also no benefit observed in rates of renal function decline over the trial with much higher initial creatinine rise and eGFR decline, and to a higher percentage rate, in the first few weeks of spironolactone treatment. These higher rates of negative renal change reduced in scale over the study but did not equalise between arms. The addition of 25 mg of spironolactone therefore provided no reno- or cardio-protection but was associated with more adverse events.

Authors' methods: Prospective randomised open blinded end-point trial. Three hundred and twenty-nine general practitioner practices throughout the United Kingdom. Patients meeting the criteria for chronic kidney disease stage 3b (estimated glomerular filtration rate 30–44 ml/minute/1.73 m2) according to National Institute for Health and Care Excellence guidelines were recruited. Due to the higher than anticipated measurement error/fluctuations, the eligible range was extended to 30–50 ml/minute/1.73 m2 following the initial recruitment period. Main limitations were difficulties in recruiting eligible participants resulting in an underpowered trial with poor ethnic diversity taking twice as long as planned to complete. We have explored the data in secondary analyses that indicate that, despite these difficulties, the findings were reliable.

Project Status: Completed

URL for project: https://www.journalslibrary.nihr.ac.uk/programmes/hta/12/01/52

Year Published: 2025

URL for published report: https://www.journalslibrary.nihr.ac.uk/hta/PYFT6977

URL for additional information: English

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: England, United Kingdom

DOI: 10.3310/PYFT6977

Organisation Name: NIHR Health Technology Assessment programme

Contact Address: NIHR Journals Library, National Institute for Health and Care Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK

Contact Name: journals.library@nihr.ac.uk

Contact Email: journals.library@nihr.ac.uk