Dual Blockade of the Renin-Angiotensin-Aldosterone System: Beyond the ACE Inhibitor and Angiotensin-II Receptor Blocker Combination

Since the introduction of angiotensin-converting enzyme inhibitors (ACEIs) in the early 1980s and angiotensin-II (ANG-II) receptor blockers (ARBs) in the mid-1990s as antihypertensive therapies, pharmacologic blockade of the renin-angiotensin-aldosterone system (RAAS) has become one of the most effective and widespread therapeutic approaches in the management of cardiovascular and kidney disease. Blockade of the RAAS lowers blood pressure, decreases morbidity and mortality in patients with chronic heart failure, 1 and decreases proteinuria and slows the rate of decline in glomerular filtration rate in patients with chronic kidney disease. 2-5 However, significant numbers of patients with chronic heart and kidney disease progress despite this standard therapy. For example, current treatment regimens that include an ACEI or ARB still have not been proven to halt kidney disease progression in most patients over the long term. 2,6-8 Indeed, a recent 5-year study found that early blockade of the RAAS with either an ACEI or ARB in patients with type 1 diabetes, while slowing the progression of retinopathy, did not protect against the progression of nephropathy on biopsy findings and measurements of urinary albumin excretion. ncomplete blockade of the RAAS at recommended doses may be one explanation for this observation. Accordingly, one strategy to improve the efficacy of RAAS blockade is to combine ACEIs and ARBs. Furthermore, increased appreciation of the role of aldosterone in the pathogenesis of cardiovascular and renal disease, This review examines what is presently known about ACEI/ARB combination therapy and explores alternative combination RAAS-blocking strategies that include DRIs and mineralocorticoid receptor blockers (MRBs).