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

Safety and efficacy of rennin-angiotensin system inhibitors in heart failure with preserved ejection fraction

M Singh, T Shah, S Adigopula, S Khosla, R Arora, and E Jawad.

Review published: 2011.

Link to full article: [Journal publisher]

CRD summary

The review reported that rennin-angiotensin system inhibitors in heart failure with preserved ejection fraction significantly improved exercise tolerance, quality of life and significantly reduced the risk of worsening heart failure, but failed to reduce total and cardiovascular mortality. Potential bias in the review process, unclear reporting and limitations in the evidence base make the reliability of the conclusions unclear.

Authors' objectives

To assess the efficacy and safety of rennin-angiotensin system inhibitors (RASIs) in heart failure patients with preserved ejection fraction (HF-PEF).

Searching

PubMed, EMBASE, CINAHL and The Cochrane Library were searched up to July 2010 for relevant studies; search terms were reported. Reference lists of retrieved studies and related links were searched.

Study selection

Randomised controlled trials (RCTs) of patients with HF-PEF that compared RASI therapy with placebo were eligible for inclusion in the review. Eligible studies were required to report at least one of the outcomes of all-cause mortality, cardiovascular mortality, worsening of heart failure, hospitalisations for heart failure, worsening of renal function, incidence of hyperkalaemia, exercise tolerance on six-minute walk test and quality of life index.

Most participants were classified as white, The proportion with moderate to severe heart failure ranged from 25% to 80%. Mean left ventricular ejection fraction ranged from 54% to 72%. The proportion of participants with hypertension ranged from 23% to 89%. The proportion who were ischaemic ranged from 18% to 57%. RASI interventions included perindopril, candesartan, enalapril, irbesartan, ramipril and valsartan. Outcome endpoints were defined differently in the included studies. HF-PEP was defined as either left ventricular ejection fraction at least 45%, at least 40% or more than 40%. Worsening of heart failure was defined based on clinical criteria and/or echocardiographic criteria. Worsening of renal function was defined as doubling serum creatinine from baseline. A cut-off value of potassium more than 6mmol/L was used to define presence of hyperkalaemia. Quality of life was assessed using the Minnesota Heart Failure Symptom Questionnaire. Exercise tolerance was measured using the six-minute walk distance test. Follow-up ranged from 3.5 months to 49.5 months.

At least two reviewers selected studies for the review.

Assessment of study quality

Studies were assessed for quality using two criteria: allocation concealment and completeness of follow-up.

The authors did not state how many reviewers performed the quality assessment.

Data extraction

Data were extracted on outcomes. Odds ratios (ORs) were calculated for dichotomous data and mean differences were calculated for continuous data, together with 95% confidence intervals (CIs). The definitions of the outcomes at endpoints were those used in the individual trials.

Two reviewers independently extracted data. Disagreements were resolved by consensus.

Methods of synthesis

Studies were pooled in meta-analyses and summary effect measures (ORs and standardised mean differences (SMDs)), together with 95% CIs were calculated using a Mantel-Haenszel fixed-effect model for efficacy outcomes and a random-effects model for safety outcomes. Heterogeneity was assessed with the X2 statistic.

Results of the review

Six RCTs (8,425 participants, range 71 to 4,128) were included in the review. One study was classified as two substudies and considered separately in the meta-analysis. All studies had adequate allocation concealment and follow-up that was more than 90% complete.

There was no evidence of significant differences between groups in the risk of total or cardiovascular mortality (five studies, 8,273 participants).

Compared to placebo, in three studies (8,001 participants) RASI therapy was associated with a significant reduction in worsening of heart failure (OR 1.16, 95% CI 1.03 to 1.31). There was a non-significant trend favouring reduced hospitalisations for heart failure in the RASI group (OR 1.11, 95% CI 0.99 to 1.24).

Compared to placebo, in four studies (424 participants) RASI therapy was associated with a significant improvement in-six minute walking distance (SMD 0.34, 95% CI 0.18 to 0.50) and in quality of life scores (SMD -0.31, 95% CI -0.50 to -0.11).

Compared to placebo, in two studies (7,151 participants) RASI therapy was associated with significantly more hyperkalaemic events (OR 0.53, 95% CI 0.30 to 0.95) and worsening of renal failure (OR 0.65, 95% CI 0.50 to 0.85).

Authors' conclusions

RASI treatment in patients with heart failure and preserved ejection fraction showed significant improvement in six-minute walking distance, quality of life and significant reduction in worsening heart failure, but it failed to reduce total and cardiovascular mortality.

CRD commentary

The review addressed a clear research question and inclusion criteria were appropriately specified. A range of relevant sources was used to search for eligible studies. No attempts were made to identify unpublished studies, so publication bias could not be ruled out. Appropriate methods were used for the selection of studies and data extraction. The authors did not state how many reviewers undertook quality assessment, so reviewer error and bias during this process could not be ruled out. Limited quality criteria were used to assess studies and more than half had small sample sizes, so the overall quality of the included studies was unclear.

There was a discrepancy in the reporting of summary effect measures; odds ratios were reported in the results, but the authors stated that they computed relative risks in their descriptions of methods used in the review. There was a discrepancy in the table of study characteristics; numbers of subjects in each trial were listed under placebo and control separately, but it appeared that the numbers listed under control were the participants who took RASI. The synthesis of studies and assessment of heterogeneity were appropriate, but the results of heterogeneity assessment were not reported. Outcome endpoints were defined differently in the included studies and this may have contributed to heterogeneity. The presentation of all pooled outcomes in a forest plot appeared misleading. Although worsening of renal function and hyperkalaemia were reportedly increased with RASI therapy, the graph label indicated that the result favoured RASI and although worsening of heart failure was reduced with RASI therapy, the graph label indicated that the result favoured placebo.

Potential for bias in the review process and publication bias, unclear reporting and limitations in the evidence base make the reliability of the conclusions unclear.

Implications of the review for practice and research

Practice: The authors stated that close monitoring of HF-PEF patients on RASI therapy may result in a reduction in hospitalisations and improvement in quality of life.

Research: The authors stated that the effect of RASI therapy on long-term mortality needed to be investigated.

Funding

Not stated.

Bibliographic details

Singh M, Shah T, Adigopula S, Khosla S, Arora R, Jawad E. Safety and efficacy of rennin-angiotensin system inhibitors in heart failure with preserved ejection fraction. International Journal of Collaborative Research on Internal Medicine and Public Health 2011; 3(4): 295-310.

Indexing Status

Subject indexing assigned by CRD

MeSH

Angiotensin-Converting Enzyme Inhibitors; Heart Failure; Humans

AccessionNumber

12011003848

Database entry date

29/01/2012

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.

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