Benefits of aldosterone receptor antagonism in chronic kidney disease: the BARACK-D RCT.

Background: 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.

Objectives: To determine the effect of low-dose spironolactone on mortality and cardiovascular outcomes in people with chronic kidney disease stage 3b.

Design: Prospective randomised open blinded end-point trial.

Settings: Three hundred and twenty-nine general practitioner practices throughout the United Kingdom.

Participants: 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.

Intervention: Participants were randomised 1 : 1 to receive either spironolactone 25 mg once daily in addition to standard care, or standard care only.

Outcome measures: Primary outcome was the first occurring of all-cause mortality, first hospitalisation for heart disease (coronary heart disease, arrhythmia, atrial fibrillation, sudden death, failed sudden death), stroke, heart failure, transient ischaemic attack or peripheral arterial disease, or first occurrence of any condition not listed at baseline. Secondary outcome measures included changes in blood pressure, renal function, B-type natriuretic peptide, incidence of hyperkalaemia and treatment costs and benefits.

Results: 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.

Limitations: 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.

Conclusions: 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.

Future work: These findings might not be applicable to different mineralocorticoid receptor antagonists.

Study registration: Current Controlled Trials ISRCTN44522369.

Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/01/52) and is published in full in Health Technology Assessment; Vol. 29, No. 5. See the NIHR Funding and Awards website for further award information.