Current evidence supporting the role of diuretics in heart failure: a meta analysis of randomised controlled trials

https://doi.org/10.1016/S0167-5273(01)00600-3Get rights and content

Abstract

Objective: To summarise the current evidence from randomised controlled trials for diuretics in patients with congestive heart failure (CHF). Data sources: English-language randomised controlled trials and review papers referenced in Medline, Embase between 1966 and 1999. General literature review of pertinent journals was carried out and reference lists of papers were inspected. Review method: study design: Meta-analysis of randomised controlled trials of diuretic therapy in patients with CHF. Study selection: Studies were included if they were randomised comparisons of loop or thiazide diuretics and control, or one diuretic and another active agent (e.g. ACE inhibitors, ibopamine and digoxin). Data abstraction: Using a standardised protocol, two reviewers independently abstracted the data and assessed the methodological quality of each paper. Data synthesis: The odds ratio (OR) of treated group compared with control was estimated for each end-point outcome and plotted against each other using the fixed-effects model. The main outcome measures: The primary outcomes of our analysis were effects of diuretics on mortality and morbidity. Results: Eighteen trials met our criteria and were eligible for analysis, involving 928 patients. Eight trials were placebo-controlled. We analysed the data for mortality and for worsening heart failure. A further ten trials compared diuretics against other agents such as ACE inhibitors, ibopamine, and digoxin. Mortality data were available in three of the placebo-controlled trials (n=221); the mortality rate was lower for patients treated with diuretics than for control [the odds ratio for death, 0.25; 95% confidence intervals (CI), 0.07–0.84; P=0.03]. Admissions for worsening heart failure in the four small trials (n=448) showed an odds ratio of 0.31 (95% CI 0.15–0.62; P=0.001). In six studies of diuretics compared to active control, diuretics significantly improved exercise capacity in patients with CHF [OR: 0.37; CI: 0.10–0.64, P=0.007]. Conclusion: Compared to active control, diuretics appear to reduce the risk of worsening disease and improve exercise capacity. The available data from small studies show that in CHF conventional diuretics reduce the risk of death and worsening heart failure compared to placebo.

Introduction

Congestive heart failure (CHF) is a major cause of morbidity and mortality worldwide. During the last 2 decades clinical trials have shown that use of angiotensin-converting enzyme (ACE) inhibitors [1], [2], [3], and more recently β-blockers [4], [5] reduce mortality and morbidity in CHF.

Diuretics are regarded as the first-line treatment for patients with CHF since they provide symptomatic relief [6], [7], [8]. Despite widespread clinical acceptance of the use of diuretics, there is uncertainty about their precise therapeutic efficacy because there are no large trials comparable to those of ACE inhibitors [1], [2], [3] and β-blockers [4], [5]. Diuretics reduce pulmonary congestion in patients with heart failure, but their effects on disease progression and survival remain unclear [9], [10]. We conducted a meta-analysis to summarise the current evidence for conventional diuretic therapy in patients with heart failure based on data from published randomised controlled trials to determine whether there were any effects on clinical outcomes.

Section snippets

Methods

Randomised trials of loop or thiazide diuretic therapy in patients with CHF were identified by performing a Medline and Embase search referenced between 1966 and 1999. The search was carried out using the following keywords: heart failure; congestive heart failure; cardiac failure; diuretics; treatment; trials; randomised controlled trials; controlled trials; observational studies and reviews. Hand searching of pertinent journals was carried out and reference lists of papers were inspected. The

Results

Eighteen randomised controlled trials carried out from 1966 to 1999 met our criteria [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33] (Table 1, Table 2). Four studies which did not fulfil our criteria were excluded [12], [13], [14], [15] (Fig. 1). One of these studies was the large RALES trial [15]. This was a double-blind study of the effect of spironolactone vs. placebo on morbidity and mortality in patients with severe heart failure.

Discussion

The principal finding of this systematic overview was that treatment with diuretic therapy produced a relative reduction in mortality of about 70% (absolute reduction of 8%) with wide confidence intervals compared to control in patients with heart failure. If this estimate is correct about 80 deaths could be avoided for every 1000 patients treated. We also demonstrate that diuretic therapy compared to placebo produced a similar reduction in the risk of worsening heart failure. Compared to other

Limitations

This analysis has several limitations. All randomised trials were small with inadequate statistical power to demonstrate clearly the effectiveness of the intervention in terms of reduction in morbidity and mortality rates. There was also great variability in the type of intervention, clinical characteristics of patients, assessment of severity, aetiology of heart failure, study duration, concomitant medications, outcome measures, and drop out rates. The methods of masking and assessment of

Conclusion

Our study provides evidence of the benefits of diuretics on mortality, progression of heart failure and exercise capacity in patients with heart failure. This evidence from trials done is not sufficient by current standards to justify widespread use of diuretics to influence clinical outcomes. On the other hand, clinical experience with diuretics in heart failure following the seminal work of Slater and Nabarro in 1958 [40], provides clinicians with the evidences of experience for continuing to

Acknowledgements

The authors would like to thank Duolao Wang (London School of Hygiene and Tropical Medicine) and Andrew Wright (Clinical Trials and Evaluation Unit) for statistical support.

References (40)

  • J. Baylsis et al.

    Untreated heart failure: clinical and endocrine effects of introducing diuretics

    Br. Heart J.

    (1987)
  • Robson AO, Ashcoft R, Kerr DN, Teasdale G. The diuretic response to furosemide, Lancet,...
  • G.S. Francis et al.

    Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without heart failure

    Circulation

    (1990)
  • Hollifield JW, Slaton PE. Cardiac arrhythmias associated with diuretic-induced hypokalaemia and hypomagnasemia. Proc...
  • N. Mantel et al.

    Statistical aspects of the analysis of data from retrospective studies of diseases. Statistical methods for rates and proportion

    (1981)
  • Edhago, Furhoff AK, Gertz I. et al. Ethacyrnic acid in pulmonary oedema. Lakartindingen, 64 (1967) (Suppl 4)...
  • W. Haerer et al.

    Acute and chronic effects of a diuretic monotherapy with piretanide in congestive heart failure: a placebo-controlled trial

    Cardiovasc. Drugs Ther.

    (1990)
  • W.C. Grinstead et al.

    Discontinuation of chronic diuretic therapy in stable congestive heart failure

    Am J Cardiol

    (1994)
  • Effect of spironolactone on morbidity and mortality in patients with severe heart failure

    New Eng J Med

    (1999)
  • M.L. Burr et al.

    The effects of discontinuing long-term diuretic therapy in elderly

    Age Ageing

    (1977)
  • Cited by (199)

    • Heart failure: pathophysiology and the emergence of novel therapies

      2023, Cardiovascular Endocrinology and Metabolism: Theory and Practice of Cardiometabolic Medicine
    • Mechanism of action of diuretic and anti-diuretic drugs

      2023, How Synthetic Drugs Work: Insights into Molecular Pharmacology of Classic and New Pharmaceuticals
    View all citing articles on Scopus
    View full text