Effects of renin-angiotensin system inhibition on end-organ protection: can we do better?

The renin-angiotensin system (RAS) is a major regulator of blood pressure (BP) and vascular response to injury. There is increasing evidence that RAS inhibition may provide end-organ protection independent of BP lowering. Two drug classes directly target angiotensin II through complementary mechanisms. Angiotensin-converting enzyme (ACE) inhibitors block the conversion of angiotensin I to the active peptide angiotensin II and increase the availability of bradykinin. Angiotensin receptor blockers (ARBs) selectively antagonize angiotensin II at AT 1 receptors and may also increase activation of the AT 2 receptor and modulate the effects of angiotensin II breakdown products. This paper presents an overview of clinical data supporting the use of RAS inhibitors (ACE inhibitors and ARBs) as monotherapy or combination therapy based on the known role of the RAS in BP regulation and the vascular response to injury, and considers the implications of the data for future treatment. Relevant experimental and clinical studies were identified by searching MEDLINE (1969-June 30, 2007) using the primary search terms renin-angiotensin system, angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, and dual RAS blockade. Trials included in the review were large (>200 patients), prospective, randomized controlled studies evaluating the effect of RAS inhibition on end-organ protection in various high-risk populations. Eleven clinical trials each were identified that evaluated the effect of ACE-inhibitor and ARB monotherapy on end-organ protection. Five trials were identified that evaluated the effects of combination therapy with an ACE inhibitor and an ARB compared with treatment with either agent alone in different patient populations using different end points. In hypertensive patients with type 2 diabetes and microalbuminuria, combination ACE-inhibitor/ARB therapy resulted in better BP control than either agent alone (mean difference, 11.2 mm Hg systolic [P = 0.002], 5.9 mm Hg diastolic [P = 0.003]), as well as greater reductions in microalbuminuria (mean difference in albumin:creatinine ratio, 34%; P = 0.04). Compared with monotherapy, dual RAS inhibition reduced the occurrence of a doubling of the serum creatinine concentration or end-stage renal disease by 60% to 62% in patients with nondiabetic renal disease (P = 0.018 vs ACE inhibitor alone; P = 0.016 vs ARB alone). A recently published study reported a nonsignificant benefit for combination therapy over monotherapy only in a subset of hypertensive patients with high levels of microalbuminuria at baseline (58.1% vs 43.4% reduction, respectively). In patients with heart failure and left ventricular ejection fraction