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European Journal of Heart Failure 2006 8(8):841-850; doi:10.1016/j.ejheart.2006.02.013
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© 2006 European Society of Cardiology

Effects of exercise training on cardiac performance, exercise capacity and quality of life in patients with heart failure: A meta-analysis

Benno A.F. van Tola,*, Rosalie J. Huijsmansa, Dineke W. Kroona, Maaike Schothorsta and Gert Kwakkela,b

a Department of Physical Therapy, VU University Medical Center De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands
b Department of Rehabilitation Medicine, University Medical Centre Heidelberglaan 100, 3508 GA Utrecht and Institute for Fundamental and Clinical Human Movement Sciences, The Netherlands

* Corresponding author. Department of Physical Therapy, VU University Medical Centre, De Boelelaan 1118, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Tel.: +31 20 4440466; fax: +31 20 40469. E-mail address: baf.vantol{at}vumc.nl


   Abstract
Top
 Abstract
1. Background
 2. Methods
 3. Results
 4. Discussion
 Appendix A. Supplementary data
 References
 
Background: Despite major advances in pharmacological treatment of chronic heart failure (CHF), a number of patients still suffer from dyspnoea, fatigue, diminished exercise capacity and poor quality of life. It is in this context that exercise training is being intensively evaluated for any additional benefit in the treatment of CHF.

Aims: To determine the effect of exercise training in patients with CHF on cardiac performance, exercise capacity and health-related quality of life. A meta-analysis was performed to obtain this goal.

Methods and results: After including 35 randomised controlled trials, the methodological quality of each study was assessed, summary effect sizes (SESs) and the concomitant 95% confidence intervals (95% CI) were calculated for each outcome. Quantitative analysis showed statistically significant SESs, at rest, for diastolic blood pressure and end-diastolic volume. During maximal exercise, significant SESs were found for systolic blood pressure, heart rate, cardiac output, peak oxygen uptake, anaerobic threshold and 6-min walking test. The Minnesota Living with Heart Failure Questionnaire improved by an average of 9.7 points.

Conclusions: Exercise training has clinically important effects on exercise capacity and HRQL, and may have small positive effects on cardiac performance during exercise.

Key Words: Heart failure • Exercise • Physical fitness • Quality of life • Meta-analysis

Received October 30, 2005; Revised January 4, 2006; Accepted February 27, 2006


   1. Background
Top
 Abstract
 1. Background
2. Methods
 3. Results
 4. Discussion
 Appendix A. Supplementary data
 References
 
Over the past decade, chronic heart failure (CHF) has become more prevalent world wide [1]. This is mainly due to ageing of the population and the longer survival of people who have suffered myocardial infarction and heart failure. Also, the increasing prevalence of obesity and diabetes is likely to accelerate the incidence of CHF, resulting in high levels of health care utilization and thus increasing costs [2]. Due to the high cost of health care and the impact of CHF on the quality of life of patients, more attention to improving the overall management of patients with CHF is required.

In the last decade, a number of evidence based guidelines have been developed to help improve diagnosis and treatment for patients with chronic heart failure. These guidelines cover aetiology, prevention, diagnostic modalities and therapeutic interventions [3-7]. Despite major advances in pharmacological treatment of CHF, a large number of patients will still suffer from dyspnoea, fatigue, diminished exercise capacity and poor quality of life [5,8]. It is in this context that exercise training is now being intensively evaluated for any additional benefits in the treatment of CHF [9].

In 1998, The European Heart Failure Training Group concluded in a review article based on accumulated experience in 134 patients that appropriately selected chronic heart failure patients can be safely entered into exercise training programmes and that significant improvements in peak oxygen uptake and NYHA class can be anticipated. However, the need for larger randomised clinical trials was recognised [10].

In 2002, a systematic review about the effects of exercise training in patients with CHF was published by Lloyd-Williams et al., who concluded that ‘short-term physical exercise training in selected subgroups of patients with CHF, has physiological benefits and positive effects on quality of life’ [11]. Lloyd-Williams et al. based their conclusions on a systematic review of the literature, which included 22 randomised controlled trials (RCTs) and 9 non-RCTs. Unfortunately, a quantitative analysis of the included articles was not applied. In 2004, a meta-analysis by the ExTraMATCH Collaborative Group [12] concluded that there is no evidence that supervised medical training programmes for patients with CHF are dangerous and indeed there is clear evidence of an overall reduction in mortality. The authors did not perform a quantitative analysis on outcome of cardiac performance, exercise capacity or quality of life.

To date, there is a consensus about the positive effect of exercise training on peak oxygen consumption (peak VO2) and mortality in patients with CHF; however, the effects on other outcome measures remain controversial. Some authors suggest improvements in cardiac function [13-15], whereas others have not found any significant differences between exercise training and control [16,17]. In a recent randomised controlled trial, McKelvie et al. did not detect a difference in 6-min walking distance (6-MWD) for exercise training compared with usual care [18], whereas other studies have found a significant increase in 6-MWD ranging from 39 to 63 m [19,20]. Studies incorporating a health-related quality of life (HRQL) component showed wide variation in the measurement instruments used and the results obtained [21-23].

The purpose of the present study was to systematically investigate the effects of exercise training compared to usual care on cardiac performance, exercise capacity and HRQL in patients with CHF.


   2. Methods
Top
 Abstract
 1. Background
 2. Methods
3. Results
 4. Discussion
 Appendix A. Supplementary data
 References
 
2.1. Literature search
Studies on the effects of exercise training in patients with CHF published between January 1985 and October 2004 were independently identified by two researchers (RH and BvT), using the following electronic databases: MedLine, CINAHL, EMBASE, Cochrane Library Register of Controlled Trials, PEDro, SPORTDiscus, PiCarta and DocOnline. The search strategy, formulated in MedLine, was adapted for other electronic databases. The keywords and Medical Sub Headings (MeSH) were: (congestive) heart failure, cardiac failure, left ventricular failure, ischemic cardiomyopathy, exercise, training, rehabilitation, physiotherapy, physical therapy, oxygen uptake, anaerobic threshold, physical performance, exercise capacity, randomised, placebo, controlled trial and clinical trial. In addition, the researchers looked for cross-references in the studies found and in guidelines concerning exercise therapy and management of CHF. Articles written in languages other than English, Dutch, German or French were excluded.

2.2. Study selection
Two independent reviewers (RH, BvT) selected studies which were (1) RCTs (randomised cross-over trials were considered as RCTs) [24], (2) included patients with CHF in the control and in the intervention group (diagnosis based on clinical findings or a left ventricular ejection fraction <40%), (3) included at least one treatment group receiving exercise training and one control group which received standard medical treatment without additional exercise training, and (4) evaluated outcome measures in terms of cardiac performance, exercise capacity and/or HRQL. In addition, exercise training had to include at least one of the following training modalities: walking, cycling or resistive training of peripheral muscles. Studies, in which only respiratory muscles or one isolated muscle group was trained, were excluded.

Authors of studies were contacted if more information about the trial was required. When two or more articles included the same or some of the same patients, the article that described the largest population was used. When there was doubt about the same patient population being used, authors were contacted to provide additional information. When authors did not respond, a decision was made, based on similarities of patient and intervention characteristics, to prevent multiple publication bias (RH, BvT).

2.3. Overall study characteristics
Information about patient characteristics (age, weight, height, body mass index, NYHA class, left ventricular ejection fraction and aetiology of CHF), intervention (frequency, duration per session, length of program and hospital versus home-based programs) and measures of outcome (i.e., mean, standard error and difference between intervention and control group) were systematically extracted by two independent reviewers (RH, BvT).

2.4. Methodological quality
The methodological quality of each included study was assessed by applying ‘the Delphi score’ [25]. In order to use the Delphi score reliably, two practice sessions with studies other than those included were performed by two independent reviewers (MS, DK). Agreement between the reviewers was assessed by means of Cohen's {kappa} statistics [26]. The second practice session resulted in a Cohen's {kappa} of 0.81. Subsequently, all studies were evaluated separately by the same two reviewers in order to assess methodological quality. Disagreements regarding methodological quality were resolved by discussion between the reviewers. If an agreement could not be reached, a third reviewer (BvT) made the final decision. In our review, we did not use the methodological score as an additional criterion for inclusion of studies, since choosing a cut-off point for inclusion or exclusion continues to be arbitrary [27]. To assure a certain level of methodological quality, we included only RCTs and randomised cross-over studies.

2.5. Quantitative analysis
Outcomes of interest included cardiac performance, exercise capacity and HRQL. Effect sizes of each of the outcome measures were aggregated separately.

The effect sizes for each individual study were calculated by dividing the difference between changes in the treatment group and changes in the control group by the pooled standard deviation (S.D.) of the baseline outcome measure in the treatment group and control group (i.e., Hedges's g model). The calculated effect sizes were weighted for sample size and subsequently summarized to obtain a weighted summary effect size (SES) according to the fixed effect model [28,29].

Heterogeneity was assessed and quantified using methodology and criteria as described by Higgins et al. (calculating I2) [30]. When significant heterogeneity between individual effect sizes was found, a random effect model was applied [31] and a sensitivity analysis was applied in order to investigate the impact of (1) methodological quality and (2) type of intervention (i.e., frequency, duration and intensity) on calculated pooled effect size. Publication bias was assessed by visual examination of the funnel plots and by using Egger's asymmetry test [32]. Data are presented as mean (±S.D.) and tested two-tailed with a level of significance P<0.05.


   3. Results
Top
 Abstract
 1. Background
 2. Methods
 3. Results
4. Discussion
 Appendix A. Supplementary data
 References
 
3.1. Literature search and study selection
After screening titles and abstracts of all studies identified by the searching strategy, 131 potentially relevant articles were selected and retrieved for more detailed information. Further screening for eligibility was performed by two independent reviewers using the inclusion and exclusion criteria (Fig. 1). In the case of cross-over trials, only the data at baseline and results at point of cross-over after the first treatment phase were used for quantitative analysis [19,22,33]. In one study, the results of two groups receiving different exercise training modalities were compared with a common control group receiving no treatment [34]. These two intervention groups were considered as two separate studies. To establish characteristics of each included study as well as methodological quality, 35 articles were evaluated [15,17-23,33-59]. Articles with (some) of the same patient sample, were used for additional information about effect sizes of cardiac performance, exercise capacity or HRQL [13,14,60-80]. There was no evidence of publication bias when assessed by visual inspection of the funnel plots or by using Egger's asymmetry test. A complete list of the literature can be requested from the first author.


Figure 1
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  		Fig. 1 Selection process for studies included in meta-analysis.

 
3.2. Overall study characteristics
In the selected studies, a total of 1486 patients were included, 701 patients in the exercise training group (591 male, 110 female), 651 patients in the control group (551 male, 100 female) and 134 drop outs (Table 1, see electronic version). The overall main patient characteristics were as follows: age 60.6±7.5 years, height 1.72±0.03 m, weight 79.6±6.3 kg, body mass index 26.9±1.3, NYHA class 2.4±0.2 (class I/II/III/IV, respectively 2/61/35/2%) and LVEF 27.7±4.2%. The primary aetiology was ischaemia in 55.2±28.1% of patients. The average training period lasted 13.0±7.8 weeks with a mean duration of 50.0±22.0 min/session and an average frequency of 3.7±1.7 times/week. In 11 articles, the intensity of exercise training was given as a percentage of peak VO2 (range 50-80%), in six articles as a percentage of the maximum heart rate (range 60-80%) and in five articles as a percentage of the maximal heart rate reserve (range 60-80%). Exercise training usually consisted of aerobic activities, sometimes combined with callisthenics or ball games. Resistance training alone was performed in only three studies, 13 studies used interval training (Table 2). Sensitivity analysis did not show significant differences beyond the limits of 95% CI between calculated SESs for resistance training and other types of exercise training. None of the authors reported adverse effects during exercise training. Only five studies followed-up the patients after ending the intervention phase [18,23,41,69]. In four of these five trials, the follow-up period included a maintenance exercise training program. Maintenance programs showed preservation of specific training effects, whereas the follow-up without exercise training [41] showed a rapid decrease of outcome measures relative to baseline values.


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  		Table 2 Exercise training characteristics

 
3.3. Methodological analysis
In assessing the methodological quality of the studies with the Delphi list, agreement was reached for 297 of the 315 items. Disagreements regarding methodological quality were resolved by discussion between the two observers; however, the third observer (BvT) made the final decision on five occasions, where an agreement could not be reached.

Table 3 provides a summary of the Delphi scores of included studies. Overall, the Kappa statistic between the two independent reviewers was 0.91. The methodological quality score ranged from three to seven out of the nine points available. The main shortcomings were a lack of concealment of the randomisation procedure (criteria 1b), the absence of blinding procedures (criteria 4, 5, 6) and of intention-to-treat analysis (criteria 8). Sensitivity analysis did not show significant differences beyond the 95% CI interval of SESs between studies with a low or a high methodological quality.


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  		Table 3 Results of the methodological quality assessed with ‘the Delphi score’

 
3.4. Quantitative analysis
Table 4 presents the results of the meta-analyses concerning the outcome measures of (1) cardiac performance, (2) exercise capacity and (3) HRQL. For each outcome measure, the total number of studies, the model that was used to compute SESs, the change from baseline in natural units, the change from baseline as a percentage of baseline, the pooled effect size, the 95% CI and p-values are shown. Fig. 2 gives a graphical representation of the SESs of HRQL and measures of outcome during exercise.


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  		Table 4 Overview of the quantitative analysis

 


Figure 2
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  		Fig. 2 SESs of measures of outcome during exercise and quality of life that showed significant change. HR=heart rate, SBP=systolic blood pressure, CO=cardiac output, peak VO2=peak oxygen uptake, AT=anaerobic threshold, 6-MWD=6-min walking distance, MLWHFQ=Minnesota Living with Heart Failure Questionnaire.

 
3.5. Cardiac performance
At rest, SESs of diastolic blood pressure and end diastolic volume showed a statistically significant improvement. SESs of heart rate, systolic blood pressure, left ventricular ejection fraction and end systolic volume at rest did not show a significantly change after a period of training. During maximal exercise, the SESs of maximal heart rate, systolic blood pressure and cardiac output increased significantly after exercise training. Diastolic blood pressure did not change and there were insufficient data to obtain results of the left ventricular ejection fraction during exercise.

3.6. Exercise capacity
The SESs of peak VO2, ventilatory or lactic derived anaerobic threshold (AT), maximal power output (W) and 6-min walking distance (6-MWD) were all significantly improved. Outcome measures of peak VO2, anaerobic threshold, power output and maximal heart rate were all obtained during the same cardiopulmonary exercise testing.

3.7. Health-related quality of life and symptoms
HRQL as assessed with the Minnesota Living with Heart Failure Questionnaire (MLWHFQ) [81,82] decreased significantly. A few articles used measurements other than the MLWHFQ but because of the great diversity of dimensions, we did not think it was appropriate to pool these data. The same is true for measures of fatigue and dyspnoea, with the exception of NYHA classification. SES of the NYHA class showed a trend towards an improvement.


   4. Discussion
Top
 Abstract
 1. Background
 2. Methods
 3. Results
 4. Discussion
Appendix A. Supplementary data
 References
 
From the present meta-analysis, it is concluded that exercise training in stable patients with mild to moderate CHF, results in statistically significant improvements in maximum heart rate, maximum cardiac output, peak VO2, anaerobic threshold, 6-MWD and HRQL.

All patients included in the present meta-analysis had a diagnosis of CHF, which was based on clinical symptoms and a LVEF<40%. However, the average age (60 years) and the severity of CHF in this meta-analysis do not reflect previous epidemiological findings [83-85]. Because patients with CHF are generally older than those in our meta-analysis, it is possible that many will experience exercise limitation as a result of coexisting diseases such as neurological disorders, lung diseases, muscle skeletal abnormalities or orthopaedic problems. In addition, it is not clear whether training has the same effect in older patients. Unfortunately, in the present meta-analysis only two studies focussed on elderly patients with CHF. In one study [71], the training group and the control group were subdivided into patients below and above 65 years of age. Although it was concluded that physical training was equally effective in patients under and over 65 years, the average improvement in peak VO2 in the younger group was 1.2 ml kg–1 min–1, while in the older group the improvement was only 0.5 ml kg–1 min–1. Owen and Croucher [22] investigated the effect of a physical training program which lasted 12 weeks, in patients with CHF and a mean average age of 81 years. They showed a significant difference on the 6-MWD of 40.1 m in favour of exercise training. However, this difference was partially caused by a reduction of 18.4 m in the control group. In addition, no significant improvement in quality of life as measured by the MLWHFQ was found.

Pooling of outcomes of the included studies, revealed statistically significant SESs for resting diastolic blood pressure and resting end-diastolic volume, after training. However, these effects expressed in natural units were small and did not exceed 2.7%. In our meta-analysis cardiac output during maximum exercise showed a remarkable increase of 21.3% and there was a small increase in maximum heart rate of 2.5%. It should be noted that the increase in maximum cardiac output was based on only three studies, whereas the increase in HR was based on 17 studies. More importantly, none of the included studies reported unfavourable effects on cardiac performance.

The most profound effects of exercise training were found in measures of outcome that reflect exercise capacity. In agreement with the systematic reviews of Smart and Mason [86], Lloyd-Williams [11] and Rees et al. [87], we found a clinically important increase in peak VO2. Theoretically, the underlying mechanisms responsible for the increase in peak VO2 can be divided into mechanisms responsible for improvement in cardiac output and factors that improve oxygen extraction. According to the literature, mechanisms of oxygen extraction that might be positively affected by exercise training include increase in skeletal muscle blood flow [44,48,70,88], increase in mitochondria [66,89] and enhanced oxidative enzyme activity in skeletal muscles [19,55,66,90]. We hypothesized that small improvements in cardiac output and oxygen extraction are jointly responsible for the clinically significant increase in peak VO2, although it remains unclear to what extent each mechanism contributes.

Another frequently used test for exercise capacity is the 6-MWD. Advantages of the 6-MWD are close physiological resemblance to daily activity, low costs and simplicity in application. In our meta-analysis, the 6-MWD improved by 46.2 m in the exercise training group compared with control. In an observational study of patients with heart failure, the smallest difference in 6-MWD that was associated with a noticeable difference in the global rating of deterioration was 43 m [91]. This improvement in 6-MWD is therefore not only significant but can also be regarded as clinically relevant.

Besides the increases in peak VO2 and 6-MWD, the most impressive increase was found in anaerobic threshold. Although there are some problems associated with the detection of the ventilatory anaerobic threshold in patients with CHF [92], this finding suggests that sub-maximal exercise testing may be more sensitive for detecting changes than maximal exercise testing. In choosing a sub-maximal exercise test, the level of sub-maximal intensity is of crucial importance for detecting changes in sub-maximal exercise capacity after a period of training.

Numerous health related quality of life instruments are available to measure patients HRQL, disease specific questionnaires being more sensitive to detecting change than generic questionnaires [93]. In this meta-analysis, the MLWHFQ, which has been studied for its reliability and validity, was found to be the most frequently used measure of HRQL, [94-96]. The MLWHFQ showed a significant improvement, with a mean difference of 9.7 points, which is considered to be a clinically meaningful difference according to data from Pina et al. [97]. However, only one study [21] could demonstrate a significant positive correlation between gains in cardiorespiratory and HRQL measurements. These findings suggest that HRQL is only partly determined by physical fitness and that many other unknown factors affect the patient's perception of health.

This review shows that further research is required, especially in elderly patients and in those with more severe CHF. Such studies should adhere to methodological principles for concealment of treatment allocation, blinding of the outcome assessor and adequate description and analysis of the number of dropouts. In addition, there is an urgent need for general agreement about a core set of measurements to be used in CHF trials investigating the effectiveness of exercise training. Finally, in order to optimise the effectiveness of exercise training programs and to be able to predict which patients will benefit maximally from exercise training, a better understanding of the mechanisms responsible for the improvements related to exercise training is needed.


   Appendix A. Supplementary data
Top
 Abstract
 1. Background
 2. Methods
 3. Results
 4. Discussion
 Appendix A. Supplementary data
References
 
Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.ejheart.2006.02.013.


   References
Top
 Abstract
 1. Background
 2. Methods
 3. Results
 4. Discussion
 Appendix A. Supplementary data
 References
 

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