Exercise training meta-analysis of trials in patients with chronic heart failure (ExTraMATCH)
http://www.100md.com
《英国医生杂志》
for the ExTraMATCH Collaborative1
1 Department of Clinical Cardiology, Imperial College of Science, Technology, and Medicine, Royal Brompton Hospital, London SW3 6NP
Correspondence to: M F Piepoli m.piepoli@imperial.ac.uk
Abstract
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
Nine prospective studies met the criteria for the meta-analysis (fig 1). Of these, eight were conducted in Europe.9-16 The number of patients ranged from 27 to 181.2 13 The duration of the training programme ranged from eight weeks in a small trial (50 patients) to a year or more in the largest studies.2 4 9 10 14 Mean follow up was from 159 to 2284 days (table 1). One dataset had no date of admission to hospital and therefore could not be included in the Kaplan-Meier analysis for that variable.15 A total of 801 patients with evidence of left ventricular dysfunction and clinical heart failure were randomly assigned to an exercise training programme (n = 395) or to the control group (n = 406; table 2).
Fig 1 Selection process for studies included in meta-analysis
Table 1 Characteristics of studies included in meta-analysis
Table 2 Characteristics of patients included in meta-analysis. Values are numbers (percentages) unless indicated otherwise
Analysis of publication bias
We found no evidence of publication bias (fig 2). The intercept of the regression relation effect between effect size (standard error) and 1/standard error was not significantly different from zero, neither for death (intercept = 0.52, P = 0.58) nor for the combined end point of death or admission to hospital (intercept = -0.04, P = 0.97). The Kendall tau correlation coefficient between log of odds ratio and its standard error across the nine studies was 0.0 for mortality analysis, 0.25 for analysis of admission to hospital, and -0.06 for the combined end points of death or admission to hospital (P > 0.5 for all). The funnel plots for each end point showed no significant variation in the log odds ratio with precision of the estimate.
Fig 2 Funnel plot for detection of publication bias
Effect of training on outcomes
Primary end point of mortality
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 (log rank 2 = 5.9, P = 0.015). After verification of the Cox proportional hazards assumption (2 = 3.1, P > 0.05), the hazard ratio for mortality was computed to be 0.65 (95% confidence interval 0.46 to 0.92). The survival curves are shown in figure 3. These results would imply a number needed to treat of 17 to prevent one death in two years.
Fig 3 Kaplan-Meier cumulative two year survival (top) and Kaplan-Meier cumulative two year survival or free from admission to hospital (bottom)
Secondary end point of death or admission to hospital
The secondary end point of death or admission to hospital occurred in 127 patients in the exercise arm and 173 in the control arm. Data on time to death or admission to hospital was available for eight datasets. The median time to admission to hospital was 426 days in the exercise arm and 371 days in the control arm. Kaplan-Meier analysis of the secondary end point confirmed a significant benefit in the exercise arm (log rank 2 = 6.4, P = 0.011, fig 3). The Cox proportional hazards assumption was verified (2 = 1.5, P > 0.05), and the hazard ratio for the combined end point was 0.72 (0.56 to 0.93).
Outcomes stratified by baseline characteristics
Subgroup analyses for mortality and the combined end point of mortality or admission to hospital are shown in figures 4 and 5, respectively. In some instances one subgroup (for example, the one with ejection fraction < 27%) showed a statistically significant treatment effect whereas the contrary group (for example, the one with ejection fraction 27%) did not. In each subgroup (and for each end point) there was, however, no significant interaction term between treatment allocation and subgroup. No evidence was therefore found of a subgroup specific treatment effect.
Fig 4 Effect of exercise training on death
Fig 5 Effect of exercise training on death or admission to hospital
Discussion
European Heart Failure Training Group. Experience from controlled trials of physical training in chronic heart failure. Eur Heart J 1998;19: 466-75.
McKelvie RS, Teo KK, Roberts R, McCartney N, Humen D, Montague T, et al. Effects of exercise training in patients with heart failure: the Exercise Rehabilitation Trial (EXERT). Am Heart J 2002;144: 23-30.
Hambrecht R, Niebauer J, Fiehn E, Kalberer B, Offner B, Hauer K, 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;25: 1239-49.
Belardinelli R, Georgiou D, Cianci D, Purcaro A. 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;99: 1173-82.
Stewart LA, Parmar MKB. Meta-analysis of the literature of individual patient data: is there a difference? Lancet 1993;341: 418-22.
Begg CB. Publication bias. In: Cooper H, Hedges LV, eds. The handbook of research synthesis. New York: Russell Sage Foundation, 1994: 400-9.
Egger M, Davey-Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315: 629-34.
Grambsch P, Therneau T. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 1994;81: 515-26.
Dubach P, Myers J, Dziekan G, Goebbels U, Reinhart W, Muller P, et al. Effect of high intensity exercise training on central hemodynamic responses to exercise in men with reduced left ventricular function. J Am Coll Cardiol 1997;29: 1591-8.
Myers J, Wagner D, Schertler T, Beer M, Luchinger R, Klein M, et al. Effects of exercise training on left ventricular volumes and function in patients with nonischemic cardiomyopathy: application of magnetic resonance myocardial tagging. Am Heart J 2002;104: 719-25.
Giannuzzi P, Temporelli PL, Corra U, Gattone M, Giordano A, Tavazzi L. Attenuation of unfavorable remodeling by exercise training in postinfarction patients with left ventricular dysfunction: results of the Exercise in Left Ventricular Dysfunction (ELVD) trial. Circulation 1997;96: 1790-7.
Hambrecht R, Gielen S, Linke A, Fiehn E, Yu J, Walther C, et al. Effects of exercise training on left ventricular function and peripheral resistance in patients with chronic heart failure. A randomized trial. J Am Med Assoc 2000;283: 3095-101.
Kiilavuori K, Naveri H, Salmi T, Harkonen M. The effect of physical training on skeletal muscle in patients with chronic heart failure. Eur J Heart Fail 2000;2: 53-63.
Zanelli E, Volterrani M, Scalvini S, Musmeci G, Campana M, Zappa C, et al. Multidisciplinary non-pharmachological intervention prevents hospitalization, improves morbidity rates and functional status in patients with congestive heart failure. Eur Heart J 1997;18(abstract suppl): 647.
Wielenga RP, Huisveld IA, Bol E, Dunselman PH, Erdman RA, Baselier MR, et al. Safety and effects of physical training in chronic heart failure. Results of the chronic heart failure and graded exercise study (CHANGE) Eur Heart J 1999;20: 872-9.
Willenheimer R, Erhardt L, Cline C, Rydberg E, Israelsson B. Exercise training in heart failure improves quality of life and exercise capacity. Eur Heart J 1998; 774-81.
Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH Jr, Wilson JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 1991;83: 778-86.
Myers J, Prakash M, Froelicher V, Partington S, Atwood E. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med 2002;346: 793-801.
Laughlin MH, McAllister RM. Exercise training-induced coronary vascular adaptation. J Appl Physiol 1992;73: 2209-25.
White FC, Roth DM, McKirnan D, Carroll SM, Bloor CM. Exercise induced coronary collateral development: a comparison to other models of myocardial angiogenesis. In: Schaper W, Schaper J, eds. Collateral circulation. Norwell, MS: Kluwer Academic; 1993: 261-89.
Vanoli E, DeFerrari GM, Stramba-Badiale M, Hull SS Jr, Foreman RD, Schwartz PJ. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ Res 1991;68: 1471-81.
Quittan M, Sturm B, Wiesinger GF, Pacher R, Fialka-Moser V. Quality of life in patients with chronic heart failure: a randomised controlled trial of changes induced by a regular exercise program. Scand J Rehabil Med 1999;31: 223-8.
1 Department of Clinical Cardiology, Imperial College of Science, Technology, and Medicine, Royal Brompton Hospital, London SW3 6NP
Correspondence to: M F Piepoli m.piepoli@imperial.ac.uk
Abstract
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
Nine prospective studies met the criteria for the meta-analysis (fig 1). Of these, eight were conducted in Europe.9-16 The number of patients ranged from 27 to 181.2 13 The duration of the training programme ranged from eight weeks in a small trial (50 patients) to a year or more in the largest studies.2 4 9 10 14 Mean follow up was from 159 to 2284 days (table 1). One dataset had no date of admission to hospital and therefore could not be included in the Kaplan-Meier analysis for that variable.15 A total of 801 patients with evidence of left ventricular dysfunction and clinical heart failure were randomly assigned to an exercise training programme (n = 395) or to the control group (n = 406; table 2).
Fig 1 Selection process for studies included in meta-analysis
Table 1 Characteristics of studies included in meta-analysis
Table 2 Characteristics of patients included in meta-analysis. Values are numbers (percentages) unless indicated otherwise
Analysis of publication bias
We found no evidence of publication bias (fig 2). The intercept of the regression relation effect between effect size (standard error) and 1/standard error was not significantly different from zero, neither for death (intercept = 0.52, P = 0.58) nor for the combined end point of death or admission to hospital (intercept = -0.04, P = 0.97). The Kendall tau correlation coefficient between log of odds ratio and its standard error across the nine studies was 0.0 for mortality analysis, 0.25 for analysis of admission to hospital, and -0.06 for the combined end points of death or admission to hospital (P > 0.5 for all). The funnel plots for each end point showed no significant variation in the log odds ratio with precision of the estimate.
Fig 2 Funnel plot for detection of publication bias
Effect of training on outcomes
Primary end point of mortality
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 (log rank 2 = 5.9, P = 0.015). After verification of the Cox proportional hazards assumption (2 = 3.1, P > 0.05), the hazard ratio for mortality was computed to be 0.65 (95% confidence interval 0.46 to 0.92). The survival curves are shown in figure 3. These results would imply a number needed to treat of 17 to prevent one death in two years.
Fig 3 Kaplan-Meier cumulative two year survival (top) and Kaplan-Meier cumulative two year survival or free from admission to hospital (bottom)
Secondary end point of death or admission to hospital
The secondary end point of death or admission to hospital occurred in 127 patients in the exercise arm and 173 in the control arm. Data on time to death or admission to hospital was available for eight datasets. The median time to admission to hospital was 426 days in the exercise arm and 371 days in the control arm. Kaplan-Meier analysis of the secondary end point confirmed a significant benefit in the exercise arm (log rank 2 = 6.4, P = 0.011, fig 3). The Cox proportional hazards assumption was verified (2 = 1.5, P > 0.05), and the hazard ratio for the combined end point was 0.72 (0.56 to 0.93).
Outcomes stratified by baseline characteristics
Subgroup analyses for mortality and the combined end point of mortality or admission to hospital are shown in figures 4 and 5, respectively. In some instances one subgroup (for example, the one with ejection fraction < 27%) showed a statistically significant treatment effect whereas the contrary group (for example, the one with ejection fraction 27%) did not. In each subgroup (and for each end point) there was, however, no significant interaction term between treatment allocation and subgroup. No evidence was therefore found of a subgroup specific treatment effect.
Fig 4 Effect of exercise training on death
Fig 5 Effect of exercise training on death or admission to hospital
Discussion
European Heart Failure Training Group. Experience from controlled trials of physical training in chronic heart failure. Eur Heart J 1998;19: 466-75.
McKelvie RS, Teo KK, Roberts R, McCartney N, Humen D, Montague T, et al. Effects of exercise training in patients with heart failure: the Exercise Rehabilitation Trial (EXERT). Am Heart J 2002;144: 23-30.
Hambrecht R, Niebauer J, Fiehn E, Kalberer B, Offner B, Hauer K, 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;25: 1239-49.
Belardinelli R, Georgiou D, Cianci D, Purcaro A. 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;99: 1173-82.
Stewart LA, Parmar MKB. Meta-analysis of the literature of individual patient data: is there a difference? Lancet 1993;341: 418-22.
Begg CB. Publication bias. In: Cooper H, Hedges LV, eds. The handbook of research synthesis. New York: Russell Sage Foundation, 1994: 400-9.
Egger M, Davey-Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315: 629-34.
Grambsch P, Therneau T. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 1994;81: 515-26.
Dubach P, Myers J, Dziekan G, Goebbels U, Reinhart W, Muller P, et al. Effect of high intensity exercise training on central hemodynamic responses to exercise in men with reduced left ventricular function. J Am Coll Cardiol 1997;29: 1591-8.
Myers J, Wagner D, Schertler T, Beer M, Luchinger R, Klein M, et al. Effects of exercise training on left ventricular volumes and function in patients with nonischemic cardiomyopathy: application of magnetic resonance myocardial tagging. Am Heart J 2002;104: 719-25.
Giannuzzi P, Temporelli PL, Corra U, Gattone M, Giordano A, Tavazzi L. Attenuation of unfavorable remodeling by exercise training in postinfarction patients with left ventricular dysfunction: results of the Exercise in Left Ventricular Dysfunction (ELVD) trial. Circulation 1997;96: 1790-7.
Hambrecht R, Gielen S, Linke A, Fiehn E, Yu J, Walther C, et al. Effects of exercise training on left ventricular function and peripheral resistance in patients with chronic heart failure. A randomized trial. J Am Med Assoc 2000;283: 3095-101.
Kiilavuori K, Naveri H, Salmi T, Harkonen M. The effect of physical training on skeletal muscle in patients with chronic heart failure. Eur J Heart Fail 2000;2: 53-63.
Zanelli E, Volterrani M, Scalvini S, Musmeci G, Campana M, Zappa C, et al. Multidisciplinary non-pharmachological intervention prevents hospitalization, improves morbidity rates and functional status in patients with congestive heart failure. Eur Heart J 1997;18(abstract suppl): 647.
Wielenga RP, Huisveld IA, Bol E, Dunselman PH, Erdman RA, Baselier MR, et al. Safety and effects of physical training in chronic heart failure. Results of the chronic heart failure and graded exercise study (CHANGE) Eur Heart J 1999;20: 872-9.
Willenheimer R, Erhardt L, Cline C, Rydberg E, Israelsson B. Exercise training in heart failure improves quality of life and exercise capacity. Eur Heart J 1998; 774-81.
Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH Jr, Wilson JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 1991;83: 778-86.
Myers J, Prakash M, Froelicher V, Partington S, Atwood E. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med 2002;346: 793-801.
Laughlin MH, McAllister RM. Exercise training-induced coronary vascular adaptation. J Appl Physiol 1992;73: 2209-25.
White FC, Roth DM, McKirnan D, Carroll SM, Bloor CM. Exercise induced coronary collateral development: a comparison to other models of myocardial angiogenesis. In: Schaper W, Schaper J, eds. Collateral circulation. Norwell, MS: Kluwer Academic; 1993: 261-89.
Vanoli E, DeFerrari GM, Stramba-Badiale M, Hull SS Jr, Foreman RD, Schwartz PJ. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ Res 1991;68: 1471-81.
Quittan M, Sturm B, Wiesinger GF, Pacher R, Fialka-Moser V. Quality of life in patients with chronic heart failure: a randomised controlled trial of changes induced by a regular exercise program. Scand J Rehabil Med 1999;31: 223-8.