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The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure: a meta-regression analysis |
Thackray S, Easthaugh J, Freemantle N, Cleland J G |
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Authors' objectives To review systematically and evaluate the effectiveness and relative effectiveness of intravenous (IV) inotropic agents acting through the adrenergic signalling pathway, compared with placebo or an active agent, in patients with heart failure.
Searching MEDLINE (from 1966 to 2000), EMBASE (from 1974 to 2000) and the Cochrane Controlled Trials Register were searched. The search terms were not given. The reference list of each identified study was reviewed, and existing bibliographies and reviews were also examined for relevant studies.
Study selection Study designs of evaluations included in the reviewOnly randomised controlled trials (RCTs) were eligible for inclusion. Where crossover trials were identified, the first period of therapy was treated as a simple RCT and data from that period were included if the trial otherwise met the inclusion criteria. The trials were single-blind, double-blind or open.
Specific interventions included in the reviewDrugs of the following classes were included: the beta-agonists; dobutamine, high-dose (greater than 2.5 microg/kg per minute), dopamine, dopexamine and the phosphodiesterase inhibitors; amrinone, milrinone, enoximone and toborinone. The drugs were administered intravenously at doses that varied across the included studies (details given in the paper). Cardiac glycosides and calcium sensitisers were excluded unless these agents also had important effects on the adrenergic pathway. The control groups received placebo or alternative therapy. More specifically, three studies compared amrinone and dobutamine; two compared dobutamine with milrinone; six compared dobutamine with control; one compared dobutamine with dopamine; three compared dobutamine with enoximone; two compared dopexamine with placebo; one compared toborinone with placebo; one compared toborinone with dobutamine; and one compared milrinone with placebo.
Participants included in the reviewParticipants with heart failure were eligible for inclusion. The specific inclusion and exclusion criteria varied between the studies. The included studies included patients with severe acute or exacerbation of chronic heart failure, heart failure post acute myocardial infarction, severe end-stage heart failure, and idiopathic or alcoholic cardiomyopathy or valvular disease. Some of the included studies excluded patients with severe concomitant disease such as renal or obstructive airways disease, angina or previous myocardial infarction, serious arrhythmia and uncontrolled ventricular tachycardia. Detailed inclusion and exclusion criteria were provided for each included study. The age, where given, ranged from 40 to 75 years or older. Male and female participants were included. Trials conducted in the immediate post-operative period were excluded.
Outcomes assessed in the reviewThe stated primary outcome was all-cause mortality. Where possible, data were also abstracted on the length of hospital stay admissions/follow-up time, days alive and out of hospital, and major morbidity (worsening heart failure, change of NYHA class, nonfatal myocardial infarction). Additional outcomes in the included studies were heart rate, mean arterial pressure, systemic vascular resistance, cardiac index, stroke index, pulmonary capillary wedge pressure and discontinuation of treatment. Data on adverse events, such as hypotension and arrhythmias, were also abstracted where possible. The follow-up period for the included studies ranged from 90 minutes to 32 months.
How were decisions on the relevance of primary studies made?The authors do not state how the papers were selected for the review, or how many of the reviewers performed the selection.
Assessment of study quality Information on trial validity, such as losses to follow-up, level of blinding and concealment of allocation (see Other Publications of Related Interest no.1), was extracted and reported. The authors did not report the method used to assess validity, or how the validity assessment was performed.
Data extraction Two researchers abstracted the data independently. No further details were given. The following information was abstracted where possible: the total number of participants randomised, participant inclusion and exclusion criteria, dose, length of treatment, deaths, re-infarction, symptom severity (NYHA class, exercise testing and haemodynamic measures), quality of life, all-cause hospitalisation, hospitalisations for worsening heart failure (including length of stay/days alive and out of hospital), other patient symptom data, and adverse effects such as hypotension and arrhythmias.
Methods of synthesis How were the studies combined?Pooled estimates of effect were calculated for each drug. Pooled odds ratios (OR), together with their 95% confidence intervals (95% CI), were also calculated using both a fixed-effect model and a random-effects model (allowing for heterogeneity). A Bayesian approach was adopted since the data were sparse (see Other Publications of Related Interest nos.2-6). Convergence was assessed statistically (see Other Publications of Related Interest no.7) and by visual inspection of convergence plots. Drug classes (the main protocol-defined, treatment-related covariates) were examined using nested random-effects logistic regression models. Risk differences were calculated using standard random-effects methods (see Other Publications of Related Interest no.3). A pooled incidence risk difference was also estimated (see Other Publications of Related Interest nos.8-9).
How were differences between studies investigated?The authors do not state how differences between the studies were investigated. Since heterogeneity was anticipated a priori, a random- effects model was used to estimate the pooled ORs.
Results of the review Twenty-one RCTs (632 participants) were included. Not all of the studies reported the primary outcome.
The trials were small and often failed to report clinical outcomes. Twelve of the included trials were double-blind, two were single-blind, five were open, one was defined as rater-blind, and one was unclear.
Eleven studies contributed to the main analysis in which, compared to placebo, intravenous inotropic agents tended to increase mortality (OR 1.50, 95% CI: 0.51, 3.92). However, this did not reach significance and insufficient data were available to determine whether the symptoms improved. No differences on mortality were identified between dobutamine and alternative inotropic agents (OR 1.37, 95% CI: 0.23, 8.46). There was a non significant increase in the discontinuation of allocated treatment associated with not receiving intravenous inotropic drugs (OR 0.52, 95% CI: 0.11, 2.3). In active-comparator studies, discontinuation was slightly greater in dobutamine-treated patients (OR 0.46, 95% CI: 0.083, 2.29). Data from two trials showed that treatment with intravenous inotropic drugs was associated with an improvement in NYHA score (standardised effect size -0.75, 95% CI: -1.42, -0.08). This was equivalent to an average improvement of approximately two-thirds of a point on the NYHA scale.
Authors' conclusions There is very little evidence that intravenous inotropic agents acting through the adrenergic pathways in patients with heart failure improve symptoms or patient outcomes. In addition, they may not be safe.
CRD commentary The aims of this review were described clearly. The review was clearly written and considerable details of the included trials were tabulated. However, there were some limitations. For example, the inclusion and exclusion criteria varied with some studies, including participants who were excluded from other studies. The search strategy was not described adequately and it is possible that some relevant trials may have been missed, particularly those published in languages other than English. No strategy for identifying unpublished trials was described. No details of the assessment of trial heterogeneity were given, although as heterogeneity was assumed, a priori, appropriate analyses were performed. Due acknowledgement was given to the limited data which gave rise to the wide confidence intervals, particularity for mortality and the NYHA score. The authors also correctly advise caution against the over-interpretation of results from the fixed-effect model which, in the absence of sufficient data, was given as a substitute for a random-effects model.
The authors also draw attention to the non significant trend in improved symptoms with dobutamine that may be attributable to inadequate blinding to therapy and haemodynamic data. However, since the main analysis was based on only four trials, the authors' conclusions may not be wholly justified, particularly with respect to the claim that these intravenous inotropic agents may not be safe. Furthermore, no data on adverse events were presented, despite this being a stated outcome. No procedure for assessing trial validity was reported, and it is not possible to replicate analyses due to the incomplete reporting of the number of events in each arm of the trials. In view of these comments, the authors' stated conclusions should be treated with caution.
Implications of the review for practice and research Practice: The authors state that guidelines should consider contraindicating conventional inotropic agents for worsening heart failure until more evidence is available.
Research: The authors state that further trials are required to investigate the safety and efficacy of inotropes in the context of contemporary management of severe heart failure and of acute cardiogenic shock. These studies should consider the longer-term consequences of treatment as well as the immediate outcome.
Bibliographic details Thackray S, Easthaugh J, Freemantle N, Cleland J G. The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure: a meta-regression analysis. European Journal of Heart Failure 2002; 4(4): 515-529 Other publications of related interest 1. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trial. JAMA 1995;273:408-12. 2. Fleiss J, Gross AJ. Meta-analysis in epidemiology, with special reference to studies of the association between exposure to environmental tobacco smoke and lung cancer. A critique. J Clin Epidemiol 1991;44:127-39. 3. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88. 4. Smith TC, Spiegelhalter DJ, Thomas A. Bayesian approaches to random-effects meta-analysis: a comparative study. Stat Med 1995;14:2685-99. 5. Carlin JB. Meta analysis for 2x2 tables: a Bayesian approach. Stat Med 1992;11:141-58. 6. Hardy RJ, Thompson,SG. A likelihood approach to meta-analysis with random effects. Stat Med 1996;15:619-29. 7. Spiegelhalter DJ, Thomas A. Best NG, Gilks WR. BUGS: Bayesian inference using Gibbs sampling. Version 0.50. Cambridge: MRC Biostatistics Unit; 1995. 8. Ioannidis JP, Cappelleri JC, Lau J, Skolnik PR, Melville B, Chalmers TC, et al. Early or deferred zidovudine therapy in HIV-infected patients without an AIDS defining illness. Ann Intern Med 1995;122:856-66. 9. Freemantle N, Mason JM, Eccles M. Deriving treatment recommendations from evidence within randomised trials: the role and limitation of meta-analysis. Int J Technol Assess Health Care 1999;15:304-15.
Indexing Status Subject indexing assigned by NLM MeSH Adrenergic beta-Agonists /administration & Cardiotonic Agents /administration & Heart Failure /drug therapy /mortality /physiopathology; Hemodynamics /drug effects /physiology; Humans; Infusions, Intravenous; Randomized Controlled Trials as Topic; Survival Rate; Treatment Outcome; dosage /adverse effects; dosage /adverse effects AccessionNumber 12002002136 Date bibliographic record published 31/08/2003 Date abstract record published 31/08/2003 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. |
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