Title: Benefits of Aldosterone Receptor Antagonism in Chronic Kidney Disease (BARACK D) Trial
Funder: Department of Health and Social Care

Abstract: CKD is common and increasing in prevalence. Cardiovascular disease is a major cause of morbidity and death in CKD, though of a different phenotype to the general CVD population. Few therapies have proved effective in modifying the increased CVD risk or rate of renal decline in CKD. There are accumulating data that aldosterone receptor blockers (ARAs) may offer cardio-protection and delay renal impairment in patients with the CV phenotype in CKD. The use of ARA in CKD has therefore been increasingly advocated and even termed the ‘renal aspirin’. However, no large study of ARAs with renal or CVD outcomes is underway. There are recent data indicating beneficial effects of ARA therapy on surrogate markers for CV disease risk in patients with CKD. This is important because there are limited therapeutic options to reduce overall CV risk in CKD, with modest effects of LDL reduction shown in the recent SHARP study and sub-studies of large ACE inhibitor and statin trials only suggesting limited CV benefits in patients with early stage CKD. The Birmingham CRIB-2 study (involving co-applicants Ferro & Townend), showed that spironolactone provided significant beneficial effects on validated intermediate CV end points of prognostic value. In a placebo controlled double blind trial 112 patients with stage 2 and 3 CKD with good blood pressure control on established treatment with ACE inhibitors or ARBs were treated in an active run-in phase with spironolactone 25mg once daily and then randomised to continue spironolactone or to receive a matching placebo. LV mass and arterial stiffness were measured before run in and after 40 weeks of treatment. Compared with placebo, the use of spironolactone resulted in highly significant reductions in LV mass and arterial stiffness, improved myocardial diastolic function and collagen turnover. These findings were attributed to a reduction in arterial and myocardial inflammation and fibrosis but may also be a function of the considerable evidence base that aldosterone receptor antagonism improves endothelial dependent vasodilatation and vascular nitric oxide bioactivity. Further data have shown that ARA therapy in early CKD prevented progression of carotid intima-media thickness in haemodialysis patients. These data on the effect of ARA on intermediate vascular outcomes have resulted in calls for definitive trials. In a recent review, the RALES Chief Investigator Bertram Pitt was cautiously optimistic that use of an ARA ‘…will reduce the mortality and morbidity associated with CKD, as well as prevent its progression to end-stage renal disease with all of its health-care and health-cost consequences”. ARA therapy might therefore be an effective candidate for improved CV outcomes, through the prevention of aldosterone mediated vascular endothelial dysfunction as well as widespread CV inflammation, fibrosis, hypertrophy. Since spironolactone is well recognised as an effective anti-hypertensive agent, even when this is resistant to other drugs, the intensive phenotyping of blood pressure, LV function and arterial stiffness in BARACK D will enable modelling of the extent to which positive results may be explained by blood pressure differences between study arms. The dose of spironolactone used in BARACK D, and most clinical trials in which it has been involved, is similar to that used in hypertension and heart failure cases – states characterised by excess CV risk and with high probability of co-morbid CKD.

Lay abstract: Chronic kidney disease (CKD) affects around 10% of the UK population. It is a disease associated with increasing age and accelerated with other illnesses such as hypertension, diabetes mellitus, obesity and primary renal disorders. It is therefore of increasing burden in terms of morbidity, mortality and high healthcare costs. Of interest to this study, CKD is a major contributor to cardiovascular disease, with CKD patients showing a greater incidence of heart failure and sudden cardiac death due to the high prevalence of both left ventricular hypertrophy and arterial wall stiffening. Conventional treatments for cardiovascular disease as used in the non-CKD population have been disappointing in CKD patients. To date there have also been limited treatment options to prevent further decline in kidney function. Previous studies have shown that targeting aldosterone receptors by using aldosterone receptor antagonist drugs has reduced mortality in patients with heart disease. There are also increasing evidence that these drugs may reduce kidney damage attributed to circulating aldosterone. We will conduct a prospective randomised open blinded endpoint (PROBE) trial using the aldosterone receptor antagonist, spironolactone. Patients with stage 3b CKD meeting the inclusion criteria will be randomly allocated into two groups. One group will be given the standard care currently offered to patients with CKD in the UK. The other group will receive this same care, but in addition be given spironolactone to take daily throughout the trial period. Eligible patients will be chosen from 120 General Practice (GP) Surgeries. They will be randomised into the two groups and followed up for 156 weeks and then again at 5 years. From the data collected we aim to establish whether the group receiving the spironolactone experience reduced incidence of hospitalisation for cardiovascular disease and death, and whether there are other beneficial cardiovascular and kidney function markers identified in clinical tests taken over the trial period. An important aspect of these tests will include the safety of spironolactone as a drug used by this patient group. There will be no increased risks for patients in the group not prescribed spironolactone, as they will receive the same care they would be entitled to if they were not in the trial. For the group receiving the drug, there is the potential risk that spironolactone will result in adverse events. All patients will be monitored in order to identify any safety concerns throughout the trial. Conversely, the group receiving spironolactone may benefit from this treatment, if it is found to be of value in cardiovascular and kidney function outcomes.

Research activity codes: 6.1 PHARMACEUTICALS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: RENAL AND UROGENITAL