Exercise training for chronic heart failure (ExTraMATCH II): Protocol for an individual participant data meta-analysis

Highlights

• We undertake an individual patient data meta-analysis of exercise training in heart failure.

• Randomised controlled trials were identified from the 2014 Cochrane review.

• This study seeks to produce definitive estimates of mortality, hospitalisation and quality of life impact.

• And to assess the influence of patient and intervention characteristics on outcomes.

Abstract

Background

Patients with chronic heart failure (HF) experience a marked reduction in their exercise capacity, health-related quality of life, and life expectancy. Despite substantive evidence supporting exercise training in HF, uncertainties remain in the interpretation and understanding of this evidence base. Clinicians and healthcare providers seek definitive estimates of impact on mortality, hospitalisation and health-related quality of life, and which HF patient subgroups are likely to most benefit. The original Exercise Training Meta-Analysis for Chronic Heart Failure (ExTraMATCH) individual participant data (IPD) meta-analysis conducted in 2004 will be updated by the current collaboration (ExTraMATCH II), to investigate the effects of exercise training in HF.

Methods

Randomised controlled trials have been identified from the updated 2014 Cochrane systematic review and the original ExTraMATCH IPD meta-analysis with exercise training of 3 weeks' duration or more compared with a non-exercise control and a minimum follow-up of 6 months. Particular outcomes of interest are mortality, hospitalisation and health-related quality of life plus key baseline patient demographic and clinical data. Original IPD will be requested from the authors of all eligible trials; we will check original data and compile a master dataset. IPD meta-analyses will be conducted using a one-step approach where the IPD from all studies are modelled simultaneously whilst accounting for the clustering of participants with studies.

Discussion

The information from ExTraMATCH II will help inform future national and international clinical and policy decision-making on the use of exercise-based interventions in HF and improve the quality, design and reporting of future trials in this field.

Introduction

Patients with chronic heart failure (HF) experience a marked reduction in exercise capacity, which has detrimental effects on their activities of daily living, health-related quality of life, hospital admission rate and survival [1].

Exercise training is known to reduce the debilitating symptoms of chronic HF, such as breathlessness and fatigue, through effects on the cardiovascular and musculoskeletal systems [2], [3]. Meta-analyses have shown that exercise interventions can improve short-term (up to 12 months' follow-up) exercise capacity of those with HF [4], [5]. Exercise training is therefore increasingly recognised as an important adjunct in the management of HF and is recommended by the American College of Cardiology Foundation/American Heart Association Task Force, the European Society of Cardiology, and other national guidelines [6], [7], [8], [9]. However, some key issues in the interpretation and understanding of the evidence base for exercise training in HF remain.

First is uncertainty of the impact of exercise training in HF on the outcomes of death and hospital admission. In 2004, the Exercise Training Meta-Analysis for Chronic Heart Failure (ExTraMATCH) Collaborative Group published an individual participant data (IPD) meta-analysis [10] that showed a reduction in both all-cause mortality (hazard ratio (HR): 0.65, 95% confidence interval (CI): 0.46 to 0.92) and death or admission to hospital (HR 0.72, 95% CI 0.56 to 0.93) in those who received exercise-based intervention compared with control, using data from nine randomised controlled trials (RCTs). However, a number of RCTs have since been published, including HF-ACTION, a large randomised trial of exercise training including 2331 HF patients across 82 centres in United States, Canada and France [11]. The recently updated Cochrane systematic review and meta-analysis now incorporates aggregate study level data from 33 RCTs in 4740 patients published up to January 2013 [12]. Whilst this 2014 Cochrane review confirms the benefit of exercise training in reduced hospital admissions (relative risk (RR): 0.75; 95% CI, 0.62 to 0.92), the authors reported no significant improvement in mortality in trials with up to 12 months' follow up (RR: 0.93; 95% CI, 0.69 to 1.27) and a trend towards improved pooled survival in six trials with longer term follow up (RR: 0.88; 95% CI, 0.75 to 1.02).

Second is uncertainty whether exercise training confers differential effects by HF patient subgroup; for example, do patients with less severe disease benefit more (or less) from exercise training than those with more severe disease? The original ExTraMATCH IPD meta-analysis reported no statistically significant subgroup (age, gender, HF aetiology, New York Heart Association (NYHA) class, ejection fraction, or exercise capacity) difference in exercise training effect on overall mortality [10]. The IPD analysis of the HF-ACTION trial also found no interactions between patient characteristics (age, gender, HF aetiology, NHYA class, ejection fraction, or depression score) and either the composite outcome of mortality and hospital admission or health-related quality of life [11]. Similarly, the 2014 Cochrane review meta-regression analysis found no association between average trial level patient characteristics (age, gender, ejection fraction) and mortality, hospitalisation or health-related quality of life [12]. However, even with the relatively large sample size of the HF-ACTION trial, the statistical power of these analyses to detect small subgroup effects is likely to be limited. Furthermore, the analysis in the Cochrane review risks study level confounding (ecological fallacy).

The third uncertainty is the amount of exercise training required to deliver optimal outcomes in HF patients. The trials included in the 2014 Cochrane review varied widely in their exercise prescription, overall exercise duration of exercise training ranging from 24 to 52 weeks with a study average of 2–7 sessions of exercise per week of 15–120 min per session and intensity of 40% maximal heart rate to 85% maximal oxygen uptake. Nevertheless, meta-regression showed that the average exercise dose per study (calculated as number of weeks × average number of sessions) / (week × average duration of session in hours) was not associated with mortality, hospitalisation or health-related quality of life. Similarly, the ExTraMATCH IPD meta-analysis review found no interaction between mortality outcome and study exercise duration (< 28 weeks versus ≥ 28 weeks). However, as with patient subgroups, these analyses are limited by statistical power and Cochrane analysis subject to ecological fallacy.

In the context of these uncertainties, IPD meta-analysis offers a number of important advantages [13], [14]. IPD allows the application of standardised and appropriate data analysis methods across studies and thereby improves statistical power and precision. In the case of exercise training trials, time-to-event analyses can be applied to mortality and hospitalisation outcomes, and analysis of covariance to exercise capacity and health-related quality of life data, thus allowing the consistent calculation of HRs and adjusted mean differences between exercise and control groups. Furthermore, IPD meta-analysis allows subgroup effects to be examined via interaction terms utilising within-trial data. These subgroup analyses can be consistently applied and tested across all exercise training trials for each pre-defined patient characteristic. In summary, IPD meta-analysis has greater statistical power, and is more likely to provide definitive estimation of overall and subgroup effects of an exercise-based intervention for HF than has been possible by previous aggregate data meta-analyses or analyses of single trials.

ExTraMATCH II is an international collaboration with the goal of undertaking IPD meta-analysis of RCTs that investigate impact of exercise training in HF based on a systematic review of contemporary RCT evidence. The information gained from the ExTraMATCH II project will help inform future national and international clinical and policy decision-making on the use of exercise-based interventions in HF.

The primary objectives of the ExTraMATCH II IPD meta-analysis are to:

• Provide definitive estimates of the impact of exercise-based interventions in HF versus control on all-cause mortality, hospitalisation and health-related quality of life.

• Analyse the influence of pre-randomisation patient characteristics on the impact of exercise-based interventions in HF, including age, gender, ejection fraction, heart failure aetiology, NYHA class and exercise capacity.

• Perform an exploratory analysis to assess whether the change in exercise capacity mediates the impact of the exercise-based interventions on all-cause mortality, hospitalisation and disease-specific health-related quality of life.

• Perform an exploratory analysis to assess the importance of both the amount of exercise prescribed and the setting in which exercise is undertaken (centre versus home) on the impact of exercise-based interventions in HF.

• Describe in detail the effect of exercise-based interventions versus control on hospitalisation outcomes including recurrent hospitalisation, total number of hospitalisations, and duration of stay.