BMJ  2004;328:189 (24 January), doi:10.1136/bmj.37938.645220.EE (published 16 January 2004)

Paper

Exercise training meta-analysis of trials in patients with chronic heart failure (ExTraMATCH)

¹ Department of Clinical Cardiology, Imperial College of Science, Technology, and Medicine, Royal Brompton Hospital, London SW3 6NP

Abstract

Objective To determine the effect of exercise training on survival in patients with heart failure due to left ventricular systolic dysfunction.

Design Collaborative meta-analysis.

Inclusion criteria Randomised parallel group controlled trials of exercise training for at least eight weeks with individual patient data on survival for at least three months.

Studies reviewed Nine datasets, totalling 801 patients: 395 received exercise training and 406 were controls.

Main outcome measure Death from all causes.

Results During a mean (SD) follow up of 705 (729) days there were 88 (22%) deaths in the exercise arm and 105 (26%) in the control arm. Exercise training significantly reduced mortality (hazard ratio 0.65, 95% confidence interval, 0.46 to 0.92; log rank ² = 5.9; P = 0.015). The secondary end point of death or admission to hospital was also reduced (0.72, 0.56 to 0.93; log rank ² = 6.4; P = 0.011). No statistically significant subgroup specific treatment effect was observed.

Conclusion Meta-analysis of randomised trials to date gives no evidence that properly supervised medical training programmes for patients with heart failure might be dangerous, and indeed there is clear evidence of an overall reduction in mortality. Further research should focus on optimising exercise programmes and identifying appropriate patient groups to target.

Introduction

Exercise training is known to reduce the debilitating symptoms of chronic heart failure, such as breathlessness and fatigue, through effects on the cardiovascular and musculoskeletal systems.^1-3 Despite this, it is not widely utilised, perhaps because data on its effect on survival are limited.⁴

Randomised controlled trials have focused largely on symptomatic benefits and on surrogate markers of prognosis, including neurohormonal balance, variability in heart rate, and peak oxygen consumption.¹ Individual trials have mostly been small. Meta-analyses of randomised trials can provide more reliable estimates of treatment effect than individual trials because they have greater statistical power. When based on data from individual patients they have several important advantages over those based solely on published data.⁵

We report a collaborative meta-analysis, based on individual patient data, of randomised controlled trials comparing exercise training with usual care in patients with chronic heart failure due to left ventricular systolic dysfunction. We aimed to obtain reliable and precise estimates of overall treatment benefit on death and on the secondary end point of death or admission to hospital.

Methods

A collaborative group was established, coordinated from the Heart Failure Unit of the Imperial College School of Medicine, London. A prospective protocol was written and agreed by the collaborative group before data collection, specifying the methods to be used, the main prespecified analyses, and a common dataset of collected variables.

We searched Medline for randomised controlled trials since 1990 of exercise training in patients with chronic congestive heart failure or left ventricular dysfunction. The characteristics of trials to be included were that they should be randomised parallel group controlled trials and should evaluate exercise training without any other simultaneous intervention that could confound the results, should study patients with stable heart failure (three months or more of stability) due to left systolic ventricular dysfunction (left ventricular ejection fraction less than 50%), should have an exercise programme lasting eight weeks or more, should utilise training involving at least both legs, and should have survival follow up of three months or more.

Initial screening identified 101 potential reports of which 41 were non-overlapping datasets. Nine met the eligibility criteria.

After formal agreement, all principal investigators were asked to provide datasets in the form of anonymised predefined individual patient data for each patient originally randomised. Only the first clinical event other than death was recorded. The number of events in this meta-analysis may differ slightly from those reported by the trials because follow up is now more complete.

We examined the potential for publication bias by constructing a funnel plot⁶ applying a regression method⁷ and the Kendall tau method.

The primary end point was time to death (from any cause). A secondary end point was death or time to admission to hospital (for any reason). Time to death was available for all studies, and time to death or admission to hospital was available for eight of the nine studies. The treatment arms were combined into one arm as were the placebo arms.

The effect of exercise was also assessed in prespecified subgroups—males versus females, New York Heart Association functional class I-II versus III-IV, ischaemic versus non-ischaemic causes, age, peak oxygen uptake (< 15 ml/kg/min v 15ml/kg/min), left ventricular ejection fraction (< 27% v 27%), and duration of training programme (< 28 weeks v at least 28 weeks). The continuous variables were each dichotomised at their corresponding median values over the whole dataset. For each subgroup we tested for interaction.

Results

Nine prospective studies met the criteria for the meta-analysis (see bmj.com).^{2 4 8-15} Tables 1 and 2 present the characteristics of the trials and patients. We found no evidence of publication bias.

View this table: [in this window] [in a new window]   Table 1 Characteristics of studies included in meta-analysis

 

View this table: [in this window] [in a new window]   Table 2 Characteristics of patients included in meta-analysis. Values are numbers (percentages) unless indicated otherwise

 

Overall, there were 88 deaths in the exercise arm (median time to event, 618 days) and 105 in the control arm (421 days). Mortality was significantly lower in the exercise group (P = 0.015). The hazard ratio for mortality was 0.65 (95% confidence interval 0.46 to 0.92) (figure). These results would imply a number needed to treat of 17 to prevent one death in two years.

View larger version (34K): [in this window] [in a new window]   Kaplan-Meier cumulative two year survival (top) and Kaplan-Meier cumulative two year survival or free from admission to hospital (bottom)

 

The secondary end point of death or admission to hospital occurred in 127 patients in the exercise arm and 173 in the control arm. The median time to admission to hospital was 426 days in the exercise arm and 371 days in the control arm (P = 0.011, figure). The hazard ratio for the combined end point was 0.72 (0.56 to 0.93).

In each subgroup (and for each end point) there was no significant interaction term between treatment allocation and subgroup (see bmj.com). No evidence was therefore found of a subgroup specific treatment effect.

Discussion

Exercise training significantly improves survival time in patients with chronic heart failure due to left ventricular systolic dysfunction. The mechanism on survival remains unknown. Observational studies in chronic heart failure are essentially unanimous in confirming a strong relation between exercise capacity and survival.¹⁶ Indeed, observational work in the general healthy population has shown that exercise capacity, even if assessed without metabolic measurements, is a more powerful prognostic indicator than traditional risk factors such as smoking, high blood pressure, blood cholesterol level, and diabetes.¹⁷

One explanation, applicable to patients with ischaemic causes, is that exercise training improves myocardial perfusion by alleviating endothelial dysfunction and therefore dilating coronary vessels and by stimulating new vessel formation by way of intermitent ischaemia.^{18 19} Ventricular remodelling has been shown to be attenuated by exercise training.¹¹

Even when the amount of time spent exercising as part of a programme is small, supervised and encouraged exercise is likely to lead to a more active lifestyle, so that the effective "dose" of exercise may be considerably greater than that directly prescribed. Arguably, this contrasts with pharmacotherapy.

Study limitations
One trial that met all the validity criteria was not included because its raw data could not be obtained.²⁰ This was a small trial (12 cases, 13 controls), and its results were of a net benefit of exercise training in exercise tolerance and quality of life. It is unlikely that the principal findings of our meta-analysis would have been altered if the raw data had been available.

Exercise training can necessarily only be trialled in open design studies, and it is important to consider the possibility that there may have been more vigorous prognostic pharmacotherapy in one arm than in the other. At baseline there was no significant difference in treatment pattern between groups. To assess the plausibility of changes in medical therapy as a cause for the reduction in mortality, we asked all the investigators about changes in drugs during the trial. Investigators in six of the nine trials, covering two thirds of the patients, were able to provide information. They stated that there was no change in angiotensin converting enzyme inhibitor, blocker, or antialdosterone therapies during the trial period. As is normal clinical practice, however, patients were allowed to vary their dosage of loop diuretic, but comprehensive data on this are not available.

What is already known on this topic Exercise training reduces the debilitating symptoms of chronic heart failure through effects on the cardiovascular and musculoskeletal systems Exercise training is not widely used because data on its effect on survival are not compelling What this study adds Mortality and admission to hospital are significantly reduced after exercise training in patients with chronic heart failure due to left ventricular systolic dysfunction This benefit was not restricted to any particular subgroup of patients

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This is the abridged version of an article that was posted on bmj.com on 16 January 2004 http://bmj.com/cgi/doi/10.1136/bmj.37938.645220.EE

Contributors: Members of the Exercise Training Meta Analysis of Trials in Chronic Heart Failure patients (ExTraMATCH) Collaborative are: (a) coordinating committee and writing committee, M F Piepoli, C Davos, D P Francis, and A J S Coats (Cardiac Medicine, Royal Brompton Hospital, Imperial College of Science Technology and Medicine, London); (b) principal investigators, R Belardinelli, A Purcaro (Cardiology Division, Lancisi Institute, Ancona, Italy); P Dubach, J Myers (Cardiology Department, Kantonsspital, Chur, Switzerland); P Giannuzzi, P L Temporelli (Fondazione Salvatore Maugeri, IRCCS, Istituto Scientifico di Veruno, Novara, Italy); R Hambrecht, A Linke (Herzzentrum, Universität Leipzig, Leipzig, Germany); K Kiilavuori, H Leinonen (Division of Cardiology, Central Hospital, Helsinki University, Finland); R S McKelvie, K K Teo (Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada); M Volterrani, A Giordano (Fondazione Salvatore Maugeri, IRCCS, Centro Medico di Gussago, Brescia, Italy); R P Wielenga, M R P Baselier (Amphia Hospital, Breda, Netherlands); R Willenheimer, E Rydberg (Department of Cardiology, University Hospital, Malmö, Sweden); and (c) other contributors, S Adamopoulos (Cardiology Department, Onassis Cardiac Surgery Centre, Athens, Greece); K Dickestein (Cardiology Division, Central Hospital in Rogaland, Stavanger, Norway); A Gordon (Department of Cardiology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden); J B Kostis (Medicine Department UMDNJ Robert Wood Institute, Johnson Medical School, New Brunswick, NJ, USA); P Sellier (Service de Readaptation Cardiaque, Hopital Broussais, Paris, France: and J Toman (First Medical Department, Masaryk University, Brno, Czech Republic). Also see bmj.com

Funding: This work was supported by a grant from the Royal Brompton and Harefield NHS Trust Clinical Research Committee (No 2000CS022B).

Conflict of interest: None declared.

Ethical approval: Not required.

References

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(Accepted 6 November 2003)

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Rapid Responses:

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We need efficacious “clinical” method in heart failure exercise training research

Sergio Stagnaro
bmj.com, 23 Jan 2004 [Full text]

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