ArticlesEffect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis
Introduction
National and international guidelines endorse the view that inhibition of the renin-angiotensin system with angiotensin-converting-enzyme (ACE) inhibitors should be first-line antihypertensive therapy in patients with diabetic and non-diabetic nephropathy. In the UK, the Renal Association, British Diabetic Association, British Hypertension Society, and National Institute of Clinical Excellence all encourage use of these drugs as first-line treatment to reduce proteinuria and retard the progression of renal disease.1, 2, 3, 4 The recommendation in diabetes has been formalised in the new General Medical Services Contract for primary care in the UK, with remuneration linked to the prescription of these drugs for this indication.4 Similar advice is included in other European and US guidelines, which advocate that either ACE inhibitors or angiotensin-II receptor blockers (ARB) be used to delay the progression of renal disease.5, 6
Implicit in this advice is the assumption that inhibition of the renin-angiotensin system with ACE inhibitors (and, more recently, ARBs) has specific renoprotective effects beyond those resulting from lowering blood pressure alone.7, 8, 9 Blood-pressure-independent effects of ACE inhibitors on cardiovascular outcomes have also been proposed, based on the results of several large multicentre trials, especially the HOPE, PROGRESS, and EUROPA studies,10, 11, 12 and similar claims have been made for ARBs.13 However, these placebo-controlled trials have been difficult to interpret because use of the active drug reduced blood pressure compared with the control group. The log-linear association between blood pressure and the incidence of cardiovascular events14 means that a reduction in systolic blood pressure of as little as 5 mm Hg reduces the incidence of stroke by about 40% and myocardial infarction by 20%.15 The reduction in the occurrence of cardiovascular endpoints seen in placebo-controlled trials of ACE inhibitors or ARBs is in the range expected from the blood-pressure-lowering effect, arguing against pleiotropic effects of inhibition of the renin-angiotensin system on cardiovascular endpoints.2, 15, 16 Indeed, when the cardiovascular effects in patients randomly assigned ACE inhibitors were assessed in trials with an active comparator rather than placebo, no particular advantage of ACE inhibitors was seen over other classes of blood-pressure-lowering drugs.15
Blood pressure is also an important risk factor for the progression of renal disease.17, 18, 19 However, the guidelines that advocate use of ACE inhibitors and ARBs in renal disease base their recommendations largely on the results of placebo-controlled trials, often using surrogate markers rather than clinically relevant endpoints.20, 21, 22 To assess blood-pressure-independent renoprotection due to inhibition of the renin-angiotensin system, we undertook a systematic review and meta-analysis of randomised controlled trials investigating the effect of different classes of antihypertensive drugs on progression of renal disease. In particular, we compared the effects on renal outcomes of inhibition of the renin-angiotensin system in trials using placebo controls versus trials with active comparator drugs.
Section snippets
Methods
Three electronic databases (MEDLINE, EMBASE, and the Cochrane Library) were searched from 1960 to Jan 31, 2005, for randomised controlled trials investigating any antihypertensive drug and progression of human renal disease, with MeSH headings and text words (discussed in detail in search strategies, webappendix). We searched for any additional studies in the references of all identified publications, including previous relevant meta-analyses and narrative reviews.
Results
Figure 1 summarises the identification process for eligible clinical trials. We found 127 eligible studies corresponding to 150 group comparisons with a weighted mean follow-up of 4·2 years. 99 group comparisons used trials including only patients with diabetes (weighted mean GFR 84·5 mL/min), 36 included only patients without diabetes (73·4 mL/min), ten included both types of patient (75·0 mL/min), and five did not report information on the presence of diabetes (96 mL/min). The study sample
Discussion
This analysis confirms the importance of blood-pressure control per se in the prevention of renal disease, in view of the larger renoprotective effect of ACE inhibitors or ARBs in placebo-controlled trials than in active comparator studies. Indeed, when blood-pressure differences were reduced substantially by antihypertensive treatment in control groups, there was no evidence of a significant salutary effect of ACE inhibitors or ARBs on renal outcomes in patients with diabetes. By contrast,
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