Systematic Review of Combined Angiotensin-Converting Enzyme Inhibition and Angiotensin Receptor Blockade in Hypertension

Abstract

Abstract-Some evidence suggests that long-term angiotensin-converting enzyme (ACE) inhibition may become less effective, thereby increasing angiotensin II levels, which could be inhibited by the addition of an angiotensin receptor blocker. We conducted a meta-analysis of randomized trials with searches of MEDLINE, EMBASE, and Cochrane databases. Overall, the combination of an ACE inhibitor and an angiotensin receptor blocker reduced ambulatory blood pressure by 4.7/3.0 mm Hg (95% confidence interval [CI], 2.9 to 6.5/1.6 to 4.3) compared with ACE inhibitor monotherapy and 3.8/2.9 mm Hg (2.4 to 5.3/0.4 to 5.4) compared with angiotensin receptor blocker monotherapy. Clinic blood pressure was reduced by 3.8/2.7 mm Hg (0.9 to 6.7/0.8 to 4.6) and 3.7/2.3 mm Hg (0.4 to 6.9/0.2 to 4.4) compared with ACE inhibitor and angiotensin receptor blocker, respectively. However, the majority of these studies used submaximal doses or once-daily dosing of shorter-acting ACE inhibitors and, when a larger dose of shorter-acting ACE inhibitor was given or a longer-acting ACE inhibitor was used, there was generally no additive effect of the angiotensin receptor blocker on blood pressure. Proteinuria was reduced by the combination compared with ACE inhibitor and angiotensin receptor blocker monotherapy, an effect that was independent of blood pressure in several studies, suggesting that the combination could have benefits in proteinuric nephropathies. None of the studies was of sufficient size and duration to determine whether there may be safety concerns. In conclusion, although there is a small additive effect on blood pressure with an ACE inhibitor-angiotensin receptor blocker combination, the routine use of this combination in uncomplicated hypertension is not recommended until more carefully controlled studies are performed. Key Words: angiotensin-converting enzyme Ⅲ hypertension Ⅲ meta-analysis Ⅲ proteinuria Ⅲ receptors, angiotensin Ⅲ renin-angiotensin system T he renin-angiotensin system (RAS) plays an important role in regulating blood pressure (BP). 1,2 Both angiotensinconverting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) inhibit the RAS and have been shown to be effective treatments for increased BP. 3 At the same time, they have other beneficial effects that may be independent of their ability to lower BP, for example, reductions in the progression of nephropathy in diabetes mellitus (DM) and chronic renal failure (CRF). 4 -6 Administration of ACEI causes plasma levels of angiotensin II (Ang II) to become undetectable, whereas there is some evidence that chronic administration of ACEI results in partial escape, ie, there is incomplete suppression of Ang II levels at peak, which may reduce the effectiveness of ACEI as BP-lowering agents. [7][8][9] Several studies have suggested that combining an ARB with an ACEI may provide a more complete blockade of the RAS in the treatment of diabetic and nondiabetic nephropathy and essential hypertension; in particular, it may lower BP and proteinuria furt...

Lessons Learned from Recent Hypertension Trials about Kidney Disease

“…Moreover, a substudy of the main trial using 24-h ambulatory monitoring demonstrated that those with the greatest reductions in proteinuria at 6 mo had the slowest declines in GFR, an effect independent of BP level achieved (14). The notion that the combination of an ACE inhibitor and an ARB should be used only for proteinuric renal disease and not for BP reduction is supported further by the results of a clinical trial and by a meta-analysis of studies that used the combination (33,34).…”

Management of Hypertension in Diabetes

“…46,47 Combination therapy may, however, reduce albuminuria by 30-40% compared to monotherapy with either drug. 47 Pending the results of additional clinical trials, combination therapy with an ACE inhibitor and ARB is not currently recommended.…”

Rationale and design of a study to evaluate management of proteinuria in patients at high risk for vascular events: the IMPROVE trial

“…22,23 Currently, it is unclear whether the combination of an ACE inhibitor with an ARB, provides greater renoprotection than the use of either approach alone. 24 The COOPERATE trial combined an ACE inhibitor and an ARB and demonstrated an additional 30% reduction in proteinuria over either agent alone, an effect independent of blood pressure. 25,26 This implies an additive effect of these agents that is specific to the intrarenal RAAS.…”