Elsevier

The Lancet

Volume 366, Issue 9502, 10–16 December 2005, Pages 2026-2033
The Lancet

Articles
Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis

https://doi.org/10.1016/S0140-6736(05)67814-2Get rights and content

Summary

Background

A consensus has emerged that angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-II receptor blockers (ARBs) have specific renoprotective effects. Guidelines specify that these are the drugs of choice for the treatment of hypertension in patients with renal disease. We sought to determine to what extent this consensus is supported by the available evidence.

Methods

Electronic databases were searched up to January, 2005, for randomised trials assessing antihypertensive drugs and progression of renal disease. Effects on primary discrete endpoints (doubling of creatinine and end-stage renal disease) and secondary continuous markers of renal outcomes (creatinine, albuminuria, and glomerular filtration rate) were calculated with random-effect models. The effects of ACE inhibitors or ARBs in placebo-controlled trials were compared with the effects seen in trials that used an active comparator drug.

Findings

Comparisons of ACE inhibitors or ARBs with other antihypertensive drugs yielded a relative risk of 0·71 (95% CI 0·49–1·04) for doubling of creatinine and a small benefit on end-stage renal disease (relative risk 0·87, 0·75–0·99). Analyses of the results by study size showed a smaller benefit in large studies. In patients with diabetic nephropathy, no benefit was seen in comparative trials of ACE inhibitors or ARBs on the doubling of creatinine (1·09, 0·55–2·15), end-stage renal disease (0·89, 0·74–1·07), glomerular filtration rate, or creatinine amounts. Placebo-controlled trials of ACE inhibitors or ARBs showed greater benefits than comparative trials on all renal outcomes, but were accompanied by substantial reductions in blood pressure in favour of ACE inhibitors or ARBs.

Interpretation

The benefits of ACE inhibitors or ARBs on renal outcomes in placebo-controlled trials probably result from a blood-pressure-lowering effect. In patients with diabetes, additional renoprotective actions of these substances beyond lowering blood pressure remain unproven, and there is uncertainty about the greater renoprotection seen in non-diabetic renal disease.

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,

References (34)

  • WeberMA et al.

    Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial

    Lancet

    (2004)
  • SterneJA et al.

    Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature

    J Clin Epidemiol

    (2000)
  • Treatment of adults and children with renal failure: standards and audit measures

    (2002)
  • B Williams et al.

    Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004-BHS IV

    J Hum Hypertens

    (2004)
  • A McIntosh et al.

    Clinical guidelines and evidence review for type 2 diabetes. Renal disease: prevention and early management

    (2002)
  • Royal College of General Practitioners

  • Standards of medical care in diabetes, 2005

    Diabetes Care

    (2005)
  • AV Chobanian et al.

    The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report

    JAMA

    (2003)
  • Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy

    Lancet

    (2000)
  • LewisEJ et al.

    The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group

    N Engl J Med

    (1993)
  • LewisEJ et al.

    Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes

    N Engl J Med

    (2001)
  • Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study)

    Lancet

    (2003)
  • Effects of an angiotensin converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients

    N Engl J Med

    (2000)
  • Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack

    Lancet

    (2001)
  • Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies

    Lancet

    (2002)
  • Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials

    Lancet

    (2003)
  • LawM et al.

    Lowering blood pressure to prevent myocardial infarction and stroke: a new preventive strategy

    Health Technol Assess

    (2003)
  • Cited by (630)

    • Pharmacology of angiotensin in renovascular diseases

      2023, Angiotensin: From the Kidney to Coronavirus
    View all citing articles on Scopus
    View full text