Benefits of Aldosterone Receptor Antagonism in Chronic Kidney Disease (BARACK D) Trial

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.