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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Antiproteinuric response to dual blockade of the renin-angiotensin system in primary glomerulonephritis: meta-analysis and metaregression

F Catapano, P Chiodini, L De Nicola, R Minutolo, P Zamboli, C Gallo, and G Conte.

Review published: 2008.

Link to full article: [Journal publisher]

CRD summary

The review concluded that the antiproteinuric response to angiotensin-converting enzyme inhibitor plus angiotensin receptor blocker combination therapy was consistently greater and strictly related to baseline proteinuria compared with monotherapy of either drug in primary glomerulonephritis patients. Given the small number of participants in the meta-analysis and the possibility of publication bias, the authors' conclusions should be interpreted with some caution.

Authors' objectives

To determine the antiproteinuric efficacy and safety of combination or monotherapy with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker in patients with primary glomerulonephritis (kidney disease).

Searching

MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from January 1996 to April 2007 for studies published in any language; search terms were reported. Reference lists were checked for any additional relevant articles.

Study selection

Randomised controlled trials (RCTs) that compared combined therapy of an angiotensin-converting enzyme inhibitor plus an angiotensin receptor blocker versus monotherapy with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker were eligible for inclusion in the review. Trials were excluded if data for levels of proteinuria were not available or if participants had kidney disease other than primary glomerulonephritis or end-stage renal disease.

The primary outcome was absolute change in urinary excretion. Secondary outcomes included office blood pressure, glomerular filtration rate, and serum potassium levels. Withdrawal rate and adverse side effects were also of interest.

In almost 40% of included trials, patients had been previously treated with an angiotensin-converting enzyme inhibitor. A number of trials recruited only patients with immunoglobulin A nephropathy. In four trials an angiotensin-converting enzyme inhibitor and angiotensin receptor blocker were co-administered at a dose that was half that used in monotherapy. In all trials, the primary end-point was decrease in proteinuria. Included trials reported the following exclusion criteria: treatment with steroid/immunosuppressive agent at enrolment or in the previous three months (ten trials), severe cardiovascular disease (seven trials), severe hepatic disease (five trials), cancer (four trials), secondary hypertension (three trials), hyperkalaemia (two trials), and hypertension (two trials). Concomitant drugs were reported in the review, but use of non-steroidal anti-inflammatory drugs and anti-aldosterone drugs were not reported in any of the trials. For included participants, mean age was 44 years (range 25 to 60 years, where reported), mean baseline proteinuria was protein of 3.0g/d (range 0.8 to 7.9g/d), mean glomerular filtration rate was 71mL/min/1.73m2 (range 73 to 11071mL/min/1.73m2), urinary sodium excretion ranged from 170mmol/d to 219mmol/d (where reported), and the mean length of intervention was four months (range 1.5 to 12 months).

Two reviewers independently selected trials for inclusion in the review.

Assessment of study quality

Two reviewers independently assessed the quality of the included trials using the Jadad score (which measured reported randomisation, blinding and treatment of withdrawals and drop-outs), complemented with assessment of the intention-to-treat analysis and industry sponsorship. A maximum score of 8 points could be awarded. Disagreements were resolved by consensus and inter-rater agreement assessed by means of K test.

Data extraction

The mean difference and standard deviation (SD) were extracted for all outcomes of interest from each trial. Where standard deviations were not reported, they were estimated on the basis of P (probability) values or confidence intervals (CIs), if available, or of the difference assuming a 0.5 correlation between the initial and final period (with sensitivity analysis assuming alternative values 0.25 and 0.75).

The authors did not state how many reviewers extracted data.

Methods of synthesis

For each outcome, pooled weighted mean differences were calculated separately for cross-over and parallel design trials using a fixed-effect model. Meta-analysis was also performed (according to Curtin et al) to allow the combination of cross-over and parallel design trials. Heterogeneity was assessed using the Q statistic (p<0.10 was considered significant). If significant heterogeneity was found, a random-effects model was performed. Subgroup and sensitivity analyses were performed. Meta-regression was used to explore heterogeneity.

Results of the review

Thirteen RCTs were included in the review (n=425 patients). Five trials were parallel group design and eight were cross-over trials. Medium score for trial quality was 6 (range 5 to 8).

Proteinuria: Combination therapy (angiotensin-converting enzyme inhibitor plus angiotensin receptor blocker) reduced proteinuria by 060g/day (95% CI 0.40 to 0.80; 13 RCTs) compared with angiotensin-converting enzyme inhibitor monotherapy. Combination therapy educed proteinuria by 0.54g/day (95% CI 0.30 to 0.78; eight RCTs) compared with angiotensin receptor blocker monotherapy. Significant heterogeneity was found, so the results were based on random-effects models. The effect on proteinuria induced by dual blockade of the renin-angiotensin system versus angiotensin-converting enzyme inhibitors or angiotensin receptor blocker monotherapy did not differ substantially. No significant difference was found between antiproteinuric effects observed in trials in which participants had previously been treated with an angiotensin-converting enzyme inhibitor and that obtained in untreated patients.

Blood pressure: Combination therapy significantly decreased systolic (-4.76mmHg, 95% CI -6.55 to -2.98; 10 RCTs) and diastolic blood pressure (2.48, 95% CI -3.73 to -1.22; 10 RCTs) compared with angiotensin-converting enzyme inhibitor monotherapy. Combination therapy significantly decreased systolic (-5.28mmHg, 95% CI -7.14 to -3.4; eight RCTs) and and diastolic blood pressure (1.88mmHg, 95% CI -3.58 to -0.17, 8 RCTs) compared with angiotensin receptor blocker monotherapy. There was evidence of significant heterogeneity.

Safety: A significant increase in serum potassium levels was found with combination therapy versus angiotensin-converting enzyme inhibitors (11 RCTs) or angiotensin receptor blockers (seven RCTs). No significant effect of combination therapy was found for glomerular filtration rate. Patient withdrawal during follow-up was rare; no difference was found between therapies.

In meta-regression, differences in average baseline proteinuria were found to be associated with antiproteinuric response.

Authors' conclusions

The antiproteinuric response to combination angiotensin-converting enzyme inhibitor plus angiotensin receptor blocker therapy was consistently greater and strictly related to baseline proteinuria when compared with monotherapy of either drug.

CRD commentary

The review question and inclusion criteria were clearly defined. Attempts were made to identify relevant evidence from a number of databases. However, the search was restricted to English language publications and no specific attempt was made to locate unpublished trials, so language and publication bias was possible. Steps were taken to minimise error or bias in the selection of studies and the assessment of study quality. It was not clear if similar steps were taken during data extraction.

The quality of the trials was formally assessed and the results clearly reported. Appropriate methods appeared to have been used to pool studies. Attempts were made to explore heterogeneity. It should be borne in mind that a significant association in a meta-regression does not prove causality. This, along with the small number of participants included in the meta-analysis and the possibility of publication bias, mean that the authors' conclusions should be interpreted with some caution.

Implications of the review for practice and research

Practice: The authors stated that the extent of proteinuria decrease in the short term appears predictive of long-term nephroprotection, so combination therapy with an angiotensin-converting enzyme inhibitor and angiotensin receptor blocker can be considered as an adjuvant to immunosuppression or even first-line therapy in the presence of mild disease. The use of this intervention in patients with advanced chronic kidney disease and elderly patients is not advised.

Research: The authors stated that the use of individual patient data would enhance the strength of the analysis.

Funding

None.

Bibliographic details

Catapano F, Chiodini P, De Nicola L, Minutolo R, Zamboli P, Gallo C, Conte G. Antiproteinuric response to dual blockade of the renin-angiotensin system in primary glomerulonephritis: meta-analysis and metaregression. American Journal of Kidney Diseases 2008; 52(3): 475-485. [PubMed: 18468748]

Indexing Status

Subject indexing assigned by NLM

MeSH

Angiotensin II Type 1 Receptor Blockers /therapeutic use; Angiotensin-Converting Enzyme Inhibitors /therapeutic use; Blood Pressure /drug effects; Drug Therapy, Combination; Glomerulonephritis /physiopathology /urine; Humans; Potassium /blood; Proteinuria /drug therapy /etiology; Randomized Controlled Trials as Topic; Renin-Angiotensin System /drug effects

AccessionNumber

12008105844

Database entry date

02/03/2011

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 18468748

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