Exercise training for chronic heart failure (ExTraMATCH II): Protocol for an individual participant data meta-analysis
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:
- 1.
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.
- 2.
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.
- 3.
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.
- 4.
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.
- 5.
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.
Section snippets
Search methods for identification of studies
Trials for inclusion in the ExTraMATCH II project were identified from the original ExTraMATCH study [10] and the recently updated 2014 Cochrane review [12]. The 2014 Cochrane review searched the following electronic databases up to January 2013: Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, EMBASE, MEDLINE, CINAHL, PsycINFO, and the NHS Centre for Reviews and Dissemination (CRD). Conference Proceedings were searched on the Web of Science. Trial registers (//Controlled-trials.com
Discussion
The ExTraMATCH II project will establish a collaborative group and conduct an IPD meta-analysis of randomised controlled trials of exercise-based interventions in HF. This project provides a unique opportunity to investigate a number of uncertainties in the literature regarding exercise training for those with HF. In particular, we will provide clinicians and healthcare policy makers with definitive estimates of the impact of exercise-based interventions in HF on all-cause mortality,
ExTraMATCH II Management Executive Group
All authors are members of the ExTraMatch II Management Executive Group.
ExTraMATCH II Collaborator Group (as of December 2013)
Emeline M. Van Craenenbroeck, Department of Cardiology, Antwerp University Hospital, Belgium,
Ugo Corrà, Division of Cardiology, Salvatore Maugeri Foundation, Veruno, Italy
Mark Haykowsky, Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Canada
Francesco Giallauria, Department of Clinical Medicine, Cardiovascular and Immunological Sciences, University of Naples Federico II, Naples, Italy.
Steven Keteyian, Division of Cardiovascular Medicine, Henry Ford Hospital, Detroit, USA
References (21)
- et al.
Physical training in patients with stable chronic heart failure: effects on cardiorespiratory fitness and ultrastructural abnormalities of leg muscles
J Am Coll Cardiol
(1995) - et al.
Exercise training for patients with heart failure: a systematic review of factors that improve mortality and morbidity
Am J Med
(2004) - et al.
2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines
J Am Coll Cardiol
(2013) - et al.
Exercise and sports science. Australia position statement on exercise training and chronic heart failure
J Sci Med Sport
(2010) Working Group on Cardiac Rehabilitation and Exercise Physiology and Working Group on Heart Failure of the European Society of Cardiology. Recommendations for exercise training in chronic heart failure patients
Eur Heart J
(2001)- et al.
Randomized, controlled trial of long term moderate exercise training in chronic heart failure: effects on functional capacity, quality of life, and clinical outcome
Circulation
(1999) - et al.
Exercise based rehabilitation for heart failure
Cochrane Database Syst Rev
(2004) - et al.
ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC
Eur Heart J
(2012) Clinical guideline for diagnosis and management of heart failure in primary and secondary care: management of chronic heart failure in adults in primary and secondary care
(August 2010)- et al.
Exercise training meta-analysis of trials in patients with chronic heart failure (ExTraMATCH). Exercise training meta-analysis of trials in patients with chronic heart failure (ExTraMATCH)
BMJ
(2004)
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2015, Heart Failure ClinicsCitation Excerpt :This lack of reimbursement was a reflection of the state of the science or lack of evidence related to exercise training in HF. Before the large multicenter HF-ACTION (Heart Failure–A Controlled Trial Investigating Outcomes of Exercise Training)1 trial, the benefits of exercise training for patients with HF and reduced ejection fraction (HFrEF) had only been documented in numerous small studies.2 As a result of the collective body of evidence and the established safety of exercise in patients with stable chronic HFrEF, the Centers for Medicare and Medicaid (CMS) extended coverage for patients with HFrEF in 2014.
- 1
This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.