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Outcome of exercise training on the long-term burden of hospitalisation in patients with chronic heart failure. A restrospective study
International Journal of Cardiology 98 (2005) 487 – 491 www.elsevier.com/locate/ijcard
Outcome of exercise training on the long-term burden of hospitalisation in patients with chronic heart failure. A restrospective study I. Hagerman a,*, R. Tyni-Lenne´ b, A. Gordon a a
Department of Cardiology, Karolinska Institute, Huddinge University Hospital, M52, SE-141 86 Stockholm, Sweden b Department of Physical Therapy, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden Received 7 September 2003; accepted 12 October 2003 Available online 1 April 2004
Abstract Aims: Heart failure is a major cause of hospitalisation, particularly in patients more than 65 years of age in the western world. A common endpoint in studies designed to evaluate treatment effects in heart failure is mortality and morbidity, often reported as an event of hospitalisation. It has recently been reported that this endpoint is misleading with respect to the burden of the disease with regard to the patient, the health service and costs. Furthermore, it can be hypothesized that different treatment effects are better evaluated using more sensitive parameters than those traditionally used in clinical studies. Short-term beneficial effects of exercise training in heart failure patients have previously been showed. Therefore, the aim of this study was to evaluate the long-term effects of exercise training in heart failure patients with regard to different outcome parameters. Method and study group: Patients with chronic heart failure, stabilised on pharmacological treatment, who had participated in a physical training program for 8 weeks, were analysed retrospectively after 5 years. The study group was compared to a matched control group which received conventional treatment and was diagnosed during the same period but not participating in a training program. Results: Exercise training in heart failure patients resulted in significantly less hospitalisation events (2 F 3 vs. 3 F 3, p < 0.05) and hospitalisation days (10 F 17 vs. 20 F 27, p < 0.05) due to cardiac problems at 5 years after follow-up. Exercise training did not effect mortality. Conclusion: Long-term effects of exercise training on burden of disease in chronic heart failure patients is associated with significantly less events and days of hospitalisation due to worsening of cardiac disease. D 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Exercise training; Heart failure; Burden of disease; Hospitalisation; Mortality
1. Introduction With improved survival of patients with acute coronary syndromes and with the aging of the general population, heart failure is rapidly becoming one of the most common cardiovascular problems with considerable consequences for healthcare due to increasing costs for hospitalisation, diagnostics and treatment [1]. In some western countries, heart failure is the fourth leading cause of hospitalisation and the most frequent cause in the population over 65 years of age [2]. Both acute and chronic symptoms of heart failure result in increased hospitalisation time [3,4]. The patients with heart failure also have significantly reduced quality of life in all domains. Quality of life is suggested to be an important target for health care interventions in heart failure [5]. In addition, the physical health burden has found to be significantly * Corresponding author. Tel.: +46-8-58581746; fax: +46-8-58586710. E-mail address: [email protected] (I. Hagerman). 0167-5273/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2003.10.063
greater in those patients compared to others with serious common chronic disorders [5]. The Euro Heart Failure survey program concludes that heart failure patients are at high risk of early readmission and death and suggests that the prescription of recommended medications still is low [6]. Admission to hospital due to heart failure has also been associated with a significant increase in the risk of death [7]. Many studies evaluate effects of heart failure treatment with regard to the time of the first hospital event which will describe only a part of the burden of disease [8]. Recorded hospitalisation events due to only cardiac causes will further limit the analysis as will exclusion of total hospitalisation days. Despite advanced pharmacological therapy, patients with chronic heart failure are still characterised by exercise intolerance associated with prognostic unfavourable effects such as increased mortality and poor quality of life [9 –11]. We and others have previously showed the short-term beneficial effects of exercise training in both improved exercise capacity and health-related quality of life [6, 9 –11].
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I. Hagerman et al. / International Journal of Cardiology 98 (2005) 487–491
Therefore, the aim of this study was to retrospectively evaluate long-term effects on exercise training on burden of disease in a population of heart failure, with regard to mortality, hospitalisation events and hospitalisation days compared with a control group of heart failure patients who did not take part in an exercise training program.
2. Methods Forty-eight patients with moderate chronic heart failure of different ethiologies and in New York Heart Association II – III were, after stabilisation on pharmacological treatment, included in a physical training program. All patients had verified left ventricular systolic dysfunction determined by echocardiography and had been stable at least 1 month before entering the exercise program. Patients with claudication, diabetes mellitus, chronic obstructive pulmonary disease, neurological or any other disease than heart failure that might have limited physical performance were excluded from the study. The exercise program was performed for 8 weeks. All training was supervised and took place in Huddinge University Hospital. The training program consisted of dynamic endurance training with unilateral or bilateral quadricep Table 1 Patients baseline characteristics
Age Gender, female Aetiology: IDC IHD VHD HT NYHA class: II III LVEF (%) Heart rhythm: SR PAF CAF Medication: Digitalis Beta-blocker Diuretics Nitrates ACE-I AIIA Warfarin ASA Amiodarone
Training group (n = 48)
Nontraining group (n = 49)
p
61 F 9 20 (42%)
61 F 5 20 (41%)
27 20 1 0
14 28 5 2
ns ns < 0.05 < 0.01 ns < 0.01 ns
26 22 28 F 9
28 21 30 F 7
38 6 4
32 6 11
ns ns ns ns < 0.01 ns ns
17 19 44 6 39 1 12 16 1
14 30 45 14 29 1 17 20 1
ns < 0.05 ns ns < 0.05 ns ns ns ns
Idiopathic dilated cardiomyopathy (IDC), ischemic heart disease (IHD), valvular heart disease (VHD), hypertensive heart disease (HT), New York Heart Association (NYHA), left ventricular ejection fraction (LVEF), sinus rhythm (SR), paroxysmal atrial fibrillation (PAF), chronic atrial fibrillation (CAF), angiotensin converting enzyme inhibitor (ACE-I), angiotensin receptor II antagonist (AIIA), acetylsalicylic acid (ASA).
Table 2 Outcome of exercise training in hospitalisation events and days
Hospitalisation events Cardiac events Noncardiac events Hospitalisation days Cardiac hospitalisation days Noncardiac hospitalisation days Death
Training group
Nontraining group
p
2F3 2F3 1F1 14 F 19 10 F 17
4F3 3F3 1F2 26 F 30 20 F 27
< 0.05 < 0.05 ns < 0.05 < 0.05
5 F 11
7 F 12
16
16
ns ns
muscles according to special designed programs as described previously [9 –12]. Patients were included during the years 1993– 1997. Five years after completed physical training program, outcome in terms of morbidity and mortality was analysed retrospectively and compared to a matched control group which received conventional treatment but did not participate in a training program. Morbidity was characterised as hospitalisation event and total hospitalisation days at follow-up. The control group consisted of 49 patients which were identified retrospectively from records of heart failure patients diagnosed during the same time period and treated at the Department of Cardiology at Huddinge University Hospital. Patients in the control group were similarly excluded like the training group if they showed signs of claudication, diabetes mellitus, chronic obstructive pulmonary disease or neurological disease. Thus, the control group would have been eligible for exercise training. Patient baseline characteristics are described in Table 1. The study was approved by the local ethical committee at Karolinska Institute, Huddinge University Hospital.
3. Statistics Values are expressed as mean F S.D. Differences between groups were tested by two-tailed t-test for unpaired samples or Mann –Whitney U test for nonparametric variables. Analysis of nominal variables between groups was performed by using contingency tables (Chi-square). Covariation was tested by simple linear regression analysis. A p value < 0.05 was considered significant.
4. Results Patients who had participated in the physical training program had a significantly lower total hospitalisation event rate 5 years after training (2 F 3 vs. 4 F 3, p < 0.05, trained vs. untrained) and this difference was explained by less hospitalisation due to cardiac events (2 F 3 vs. 3 F 3, p < 0.05, trained vs. untrained) (Fig. 1). Furthermore, there were significantly fewer hospitalisation days due to cardiac
I. Hagerman et al. / International Journal of Cardiology 98 (2005) 487–491
Fig. 1. Outcome of exercise training in cardiac hospitalisation events and days. Solid bars = training group. Stretched bars = controls (nontrained).
problems in the trained group compared to the untrained group (10 F 17 vs. 20 F 27, p < 0.05) (Table 2). There was no difference between the two groups in number of deaths after 5 years of follow-up. Heart failure of idiopathic origin turned out to be more common in the training group as was valvular heart disease in the nontraining group. Treatment with beta-blocking agents was more common in the nontraining group, which may be explained by the somewhat higher prevalence of ischemic heart disease in this group. Accordingly, treatment with ACE inhibitor was more frequent in the training group of predominant idiopathic dilated cardiomyopathy. The effects of training or nontraining on hospitalisation days was further analysed according to possible contributing factors such as age, gender, medication, etiology, heart rhythm, ejection fraction and heart failure class according to the NYHA criteria. Patients with ischemic heart disease who had participated in the training group and patients in NYHA class II were associated with lower hospitalisation rate after 5 years of follow-up. Gender or treatment with ACE-inhibitor, beta-blocker or diuretics did not affect total hospitalisation days nor did left ventricular ejection fraction (r2 = 0.029, p = ns) (Table 3). Treatment with long-acting nitrates was associated with higher hospitalisation rate.
5. Discussion Recently, Metcalfe et al. [8] published an analysis and discussion of how outcome in clinical studies of heart failure are best described. According to their findings, there is a great variety in recorded data, such as different type of hospitalisations. Often, only the first event of hospitalisation is considered and the duration of the hospitalisation event is neglected etc. In some studies, only hospitalisation due to worsening of heart failure or cardiac disease is considered. These circumstances make it difficult to fully interpret and understand various effects of treatment regimes in heart failure. Hospitals tend to apply different strategies in the
489
care and management of heart failure patients. Several cardiac clinics have today outpatient clinics for heart failure patients, and interventions there may have effects on reduced hospitalisation. However, this improved management will further complicate interpretation of results in clinical trials because hospitalisation will be used in one center and the same intervention is taken care of by an outpatient clinic without hospitalisising the patient. At the time for the present study, our region did not have such an outpatient clinic and the management of the patients was similar in the two groups. When making the long-term follow-up of our exercised trained heart failure patients, we therefore wanted to analyse the results in the light of Metcalfe et al.’s findings. Therefore, we did not only count the number of hospitalisation events but valued the burden of disease with regard to the number of events, the duration of the events and the cause of the hospitalisation events. We hypothesised that exercise training in heart failure patients is beneficial also in the long term. Our group has previously described positive effects of different short-term exercise programs in heart failure both in improved functional capacity and in health-related quality of life [9]. The present study is a retrospective follow-up of patients that took part in an exercise program during a short period of 8 weeks maximum, and thereafter no formalised follow-up. The control group consisted of matched patients that were diagnosed during the same time period but not included in the exercise program. Data were collected by evaluating medical records of all patients 5 years after diagnosis. There was a slight difference between the patient groups with a higher prevalence of idiopathic dilated cardiomyopathy in the training group and a higher prevalence of ischemic heart failure in the nontraining group. As can be seen from the statistical analysis summarised in Table 3, the different origins of heart failure could not explain the differences in hospitalisation days. Heart failure of ischemic origin seemed to benefit most from exercise training. There was also a higher prevalence of the use of beta-blocking agents in the nontraining groups, which is in concordance with a higher prevalence of ischemic heart disease in this group. At the time for this study, the use of beta-blockers was more established in ischemic heart disTable 3 Factors contributing to differences in hospitalisation days
Training (yes/no) IHD (training/nontraining) NYHA II/III ACE-I (yes/no) Nitrates (yes/no) Beta-blocker (yes/no) Diuretics (yes/no) Gender, female (training/nontraining) Gender, male (training/nontraining)
Hospitalisation days
p
15 F 19/26 F 31 9 F 16/27 F 27 16 F 19/27 F 32 20 F 24/22 F 30 33 F 35/17 F 22 20 F 25/21 F 27 21 F 27/13 F 11 11 F 16/24 F 29
0.0318 0.012 0.0388 ns 0.0122 ns ns ns
18 F 21/28 F 32
ns
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I. Hagerman et al. / International Journal of Cardiology 98 (2005) 487–491
ease than in heart failure due to other causes. Despite that, and well aware of the positive effects of beta-blockers in heart failure [15 – 17], there was a significant difference in outcome with regard to hospitalisation events and hospitalisation days due to cardiac disease, in favour of the training group. There was no difference between the groups in terms of hospitalisation due to other causes than cardiac problems. This may be interpreted as a specific cardiac effect of exercise training. Heart failure is often described as a syndrome with high prevalence of comorbidity [18,19]. When analysing specific effects of exercise on cardiac performance, it seems logical to evaluate this in a highly selected group. The patients in this study were strictly selected with predominantly cardiac disease with only minor other health problems. The prevalence of ACE inhibitors was higher in the training group and the value of this treatment in heart failure is well established long since [20 – 22]. A further analysis of factors that could contribute to the difference in outcome between groups revealed that the positive long-term effects of exercise were most obvious in patients with heart failure due to ischemic heart disease. Several studies report beneficial effects of training after myocardial infarction [23] and our study can confirm this finding. Moreover, a higher functional NYHA class was associated with more positive outcome of exercise, which has also been described by others [23,24]. On the contrary, there was no association between left ventricular ejection fraction and effects of exercise training which is in line with previous knowledge that the most important prognostic factor is the functional status of the patient and not the systolic heart function per se [25 –27]. In the extended analysis (Table 3), treatment with beta-blockers or ACE inhibitors did not significantly contribute to the difference in hospitalisation days, nor did gender. However, we can not from this analysis exclude that a combined treatment of exercise and beta-blocking agents and/or ACE inhibitors could even more reduce hospitalisation days. Less frequent use of nitrates was associated with less hospitalisation days, which may reflect a difference in level of disease and symptoms among the heart failure patients due to ischemic heart disease. Not surprisingly, there was no difference in number of deaths between groups as the study groups were too small for such an analysis. The positive effects of exercise training on burden of disease with regard to both hospitalisation events and days due to cardiac problems were significant 5 years after a short, but professionally supervised training period. This is a promising finding which should be studied further. However, our previous studies have indicated that the patients after completed training program experience improved sense of safety and physical activity [9]. This may lead to a physically more active life in the long range. There was no other obvious difference between the two groups but physical training that can explain such a finding. We have not included specific data on exercise training in this paper
because this has been reported previously [9,12 –14]. The patients in those training programs used different quantities of muscle work, which resulted in incomparable indices of exercise performances such as peak VO2 and maximal workload. However, there was a consistent improvement in all training studies with an increase in exercise duration in the range of 20– 40%. We have not yet made any retrospective health quality survey or evaluation of degree of daily physical activity of the two patient groups. We can therefore only speculate in that there may be remaining influence in the degree of physical activity in patients that have been treated in specific exercise training groups several years ago and that this contributes to a lesser degree of need for hospitalisation due to cardiac disease. We have in this study practically demonstrated, in line with Metcalfe et al. [8] that outcome in heart failure should be evaluated as total number of hospitalisation events and total number of hospitalisation days. Limitation: This study design is a retrospective analysis, which of course is scientifically inferior to a prospective, randomized controlled trial. However, we tried to match the control group on the following characteristics: age, gender, aetiology, NYHA-class, ejection fraction and medication. The group also made the same exclusion criteria. Yet, there was a statistically significant difference between the groups according to aetiology. Subgroup analysis showed that this difference was significant for idiopathic dilated cardiomyopathy and heart failure due to valvular disease but not for ischemic heart disease, the group in which training seemed to reduce longterm hospitalisation rate. The aetiologies per se did not contribute to the difference in hospitalisation days. Preferably, a baseline exercise test should have been performed in both groups but was not possible in this retrospective design. In addition, activity index during the follow-up period would have been of great interest. We have focused in this analysis on the burden of hospitalisation in heart failure and then used one type of intervention in this sick patient population, namely exercise training. Our results underline the need to investigate the long-term effects of exercise training in heart failure but using controlled, prospective and randomised design.
References [1] Cowie MR, Mosterd A, Wood DA, et al. The epidemiology of heart failure. Eur Heart J 1997;18:208 – 15. [2] Haldeman GA, Croft JB, Giles WH, Rashidee A. Hospitalization of patients with heart failure: national hospital discharge survey, 1985 – 1995. Am Heart J 1999;137:352 – 60. [3] Krumholtz H, Chen Y, Wang Y. Predictors of readmission among elderly survivors of admission with heart failure. Am Heart J 2000; 139:72 – 7. [4] Yusuf S, Negassa A. Choice of clinical outcomes in randomised trials of heart failure therapies: disease-specific of overall outcomes? Am Heart J 2002;143:22 – 8. [5] Hobbs FDR, Kenkre JE, Roalfe AK, Davis RC, Hare R, Davies MK.
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Impact of heart failure and left ventricular systolic dysfunction on quality of life. Eur Heart J 2002;23:1867 – 76. Cleland JGF, Swedberg K, Follath F, et al. The EuroHeart Failure survey programme—a survey on the quality of care among patients with heart failure in Europe. Eur Heart J 2003;24:442 – 63. Dickstein K, Snapinn S. Prediction of mortality and morbidity following myocardial infarction. J Am Coll Cardiol 2002;39:194. Metcalfe C, Thompson SG, Cowie MR, Sharples LD. The use of hospital admission data as a measure of outcome in clinical studies of heart failure. Eur Heart J 2003;24:105 – 12. Tyni-Lenne´ R, Gordon A, Jensen-Urstad M, Europe E, Jansson E, Sylve´n C. Exercise-based rehabilitation improves skeletal muscle capacity, exercise intolerance and quality of life in women as well as in men with chronic heart failure. J Card Fail 1998;4:9 – 17. Adamopoulos S, Parissis JT, Kremastinos DT. New aspects for the role of physical training in the management of patients with chronic heart failure. Int J Cardiol 2003 (Jul.);90(1):1 – 14. McConnell TR, Mandak JS, Sykes JS, Fesniak H, Dasgupta H. Exercise training for heart failure patients improves respiratory muscle endurance, exercise tolerance, breathlessness, and quality of life. J Cardiopulm Rehabil 2003 (Jan. – Feb.);23(1):10 – 6. Belardinelli R, Georgiou D, Scocco V, Barstow T, Purcaro A. Low intensity exercise training in patients with chronic heart failure. J Am Coll Cardiol 1995;26:975 – 82. Tyni-Lenne´ R, Gordon A, Jensen-Urstad M, Dencker K, Jansson E, Sylve´n C. Aerobic training involving a minor muscle mass shows greater efficiency than training involving a major muscle mass in chronic heart failure patients. J Card Fail 1999;5:300 – 7. Gordon A, Tyni-Lenne´ R, Persson H, Kaijser L, Hultman E, Sylve´n C. Markedly improved skeletal muscle function with local muscle training in patients with chronic heart failure. Clin Cardiol 1996;19: 568 – 74. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334:1349 – 55. CIBIS-II Investigators and Committees JN. The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomised trial. Lancet 1999;353: 9 – 13.
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[17] MERIT Group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet 1999;353:2001 – 7. [18] Muntwyler J, Abetel G, Gruner C, Follath F. One year mortality among unselected outpatients with heart failure. Eur Heart J 2002; 23:1861 – 6. [19] Mosterd A, Cost B, Hoes AW, et al. The prognosis of heart failure on the general population: the Rotterdam study. Eur Heart J 2001;22: 1318 – 27. [20] SOLVD investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293 – 302. [21] The acute infarction Ramipril Efficacy (AIRE) Study Investigators. Effects of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821 – 8. [22] The CONCENSUS Trial Study Group. Effects of enalapril on mortality on mortality in severe congestive heart failure. Results of the cooperative north Scandinavian enalapril survival study (CONSENSUS). N Engl J Med 1987;316:1429 – 35. [23] Tavazzi L, et al. For the task force group of the working group on cardiac rehabilitation of the European society of cardiology. Definition of cardiac rehabilitation. Eur Heart J 1992;13(Suppl. C): 1 – 45. [24] Letac B, Cribier A, Desplanches JF. A study of left ventricular function in coronary patients before and after physical training. Circulation 1977;56:375 – 8. [25] Gordon A, Tyni-Lenne´ R, Jansson E, Jensen-Urstad M, Kaijser L. Beneficial effects of exercise training in heart failure patients with low cardiac output response to exercise—a comparison of two training models. J Int Med 1999;246:175 – 82. [26] Franciosa JA, Park M, Levine TB. Lack of correlation between exercise capacity and indexes of resting left ventricular performance in heart failure. Am J Cardiol 1981;7:33 – 9. [27] Miyashita T, Okano Y, Takai H, Satoh T, Kobayashi Y, Goto Y. Relation between exercise capacity and left ventricular systolic versus diastolic function during exercise in patients after myocardial infarction. Coron Artery Dis 2001 (May);12(3):217 – 25.
Outcome of exercise training on the long-term burden of hospitalisation in patients with chronic heart failure. A restrospective study I. Hagerman a,*, R. Tyni-Lenne´ b, A. Gordon a a
Department of Cardiology, Karolinska Institute, Huddinge University Hospital, M52, SE-141 86 Stockholm, Sweden b Department of Physical Therapy, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden Received 7 September 2003; accepted 12 October 2003 Available online 1 April 2004
Abstract Aims: Heart failure is a major cause of hospitalisation, particularly in patients more than 65 years of age in the western world. A common endpoint in studies designed to evaluate treatment effects in heart failure is mortality and morbidity, often reported as an event of hospitalisation. It has recently been reported that this endpoint is misleading with respect to the burden of the disease with regard to the patient, the health service and costs. Furthermore, it can be hypothesized that different treatment effects are better evaluated using more sensitive parameters than those traditionally used in clinical studies. Short-term beneficial effects of exercise training in heart failure patients have previously been showed. Therefore, the aim of this study was to evaluate the long-term effects of exercise training in heart failure patients with regard to different outcome parameters. Method and study group: Patients with chronic heart failure, stabilised on pharmacological treatment, who had participated in a physical training program for 8 weeks, were analysed retrospectively after 5 years. The study group was compared to a matched control group which received conventional treatment and was diagnosed during the same period but not participating in a training program. Results: Exercise training in heart failure patients resulted in significantly less hospitalisation events (2 F 3 vs. 3 F 3, p < 0.05) and hospitalisation days (10 F 17 vs. 20 F 27, p < 0.05) due to cardiac problems at 5 years after follow-up. Exercise training did not effect mortality. Conclusion: Long-term effects of exercise training on burden of disease in chronic heart failure patients is associated with significantly less events and days of hospitalisation due to worsening of cardiac disease. D 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Exercise training; Heart failure; Burden of disease; Hospitalisation; Mortality
1. Introduction With improved survival of patients with acute coronary syndromes and with the aging of the general population, heart failure is rapidly becoming one of the most common cardiovascular problems with considerable consequences for healthcare due to increasing costs for hospitalisation, diagnostics and treatment [1]. In some western countries, heart failure is the fourth leading cause of hospitalisation and the most frequent cause in the population over 65 years of age [2]. Both acute and chronic symptoms of heart failure result in increased hospitalisation time [3,4]. The patients with heart failure also have significantly reduced quality of life in all domains. Quality of life is suggested to be an important target for health care interventions in heart failure [5]. In addition, the physical health burden has found to be significantly * Corresponding author. Tel.: +46-8-58581746; fax: +46-8-58586710. E-mail address: [email protected] (I. Hagerman). 0167-5273/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2003.10.063
greater in those patients compared to others with serious common chronic disorders [5]. The Euro Heart Failure survey program concludes that heart failure patients are at high risk of early readmission and death and suggests that the prescription of recommended medications still is low [6]. Admission to hospital due to heart failure has also been associated with a significant increase in the risk of death [7]. Many studies evaluate effects of heart failure treatment with regard to the time of the first hospital event which will describe only a part of the burden of disease [8]. Recorded hospitalisation events due to only cardiac causes will further limit the analysis as will exclusion of total hospitalisation days. Despite advanced pharmacological therapy, patients with chronic heart failure are still characterised by exercise intolerance associated with prognostic unfavourable effects such as increased mortality and poor quality of life [9 –11]. We and others have previously showed the short-term beneficial effects of exercise training in both improved exercise capacity and health-related quality of life [6, 9 –11].
488
I. Hagerman et al. / International Journal of Cardiology 98 (2005) 487–491
Therefore, the aim of this study was to retrospectively evaluate long-term effects on exercise training on burden of disease in a population of heart failure, with regard to mortality, hospitalisation events and hospitalisation days compared with a control group of heart failure patients who did not take part in an exercise training program.
2. Methods Forty-eight patients with moderate chronic heart failure of different ethiologies and in New York Heart Association II – III were, after stabilisation on pharmacological treatment, included in a physical training program. All patients had verified left ventricular systolic dysfunction determined by echocardiography and had been stable at least 1 month before entering the exercise program. Patients with claudication, diabetes mellitus, chronic obstructive pulmonary disease, neurological or any other disease than heart failure that might have limited physical performance were excluded from the study. The exercise program was performed for 8 weeks. All training was supervised and took place in Huddinge University Hospital. The training program consisted of dynamic endurance training with unilateral or bilateral quadricep Table 1 Patients baseline characteristics
Age Gender, female Aetiology: IDC IHD VHD HT NYHA class: II III LVEF (%) Heart rhythm: SR PAF CAF Medication: Digitalis Beta-blocker Diuretics Nitrates ACE-I AIIA Warfarin ASA Amiodarone
Training group (n = 48)
Nontraining group (n = 49)
p
61 F 9 20 (42%)
61 F 5 20 (41%)
27 20 1 0
14 28 5 2
ns ns < 0.05 < 0.01 ns < 0.01 ns
26 22 28 F 9
28 21 30 F 7
38 6 4
32 6 11
ns ns ns ns < 0.01 ns ns
17 19 44 6 39 1 12 16 1
14 30 45 14 29 1 17 20 1
ns < 0.05 ns ns < 0.05 ns ns ns ns
Idiopathic dilated cardiomyopathy (IDC), ischemic heart disease (IHD), valvular heart disease (VHD), hypertensive heart disease (HT), New York Heart Association (NYHA), left ventricular ejection fraction (LVEF), sinus rhythm (SR), paroxysmal atrial fibrillation (PAF), chronic atrial fibrillation (CAF), angiotensin converting enzyme inhibitor (ACE-I), angiotensin receptor II antagonist (AIIA), acetylsalicylic acid (ASA).
Table 2 Outcome of exercise training in hospitalisation events and days
Hospitalisation events Cardiac events Noncardiac events Hospitalisation days Cardiac hospitalisation days Noncardiac hospitalisation days Death
Training group
Nontraining group
p
2F3 2F3 1F1 14 F 19 10 F 17
4F3 3F3 1F2 26 F 30 20 F 27
< 0.05 < 0.05 ns < 0.05 < 0.05
5 F 11
7 F 12
16
16
ns ns
muscles according to special designed programs as described previously [9 –12]. Patients were included during the years 1993– 1997. Five years after completed physical training program, outcome in terms of morbidity and mortality was analysed retrospectively and compared to a matched control group which received conventional treatment but did not participate in a training program. Morbidity was characterised as hospitalisation event and total hospitalisation days at follow-up. The control group consisted of 49 patients which were identified retrospectively from records of heart failure patients diagnosed during the same time period and treated at the Department of Cardiology at Huddinge University Hospital. Patients in the control group were similarly excluded like the training group if they showed signs of claudication, diabetes mellitus, chronic obstructive pulmonary disease or neurological disease. Thus, the control group would have been eligible for exercise training. Patient baseline characteristics are described in Table 1. The study was approved by the local ethical committee at Karolinska Institute, Huddinge University Hospital.
3. Statistics Values are expressed as mean F S.D. Differences between groups were tested by two-tailed t-test for unpaired samples or Mann –Whitney U test for nonparametric variables. Analysis of nominal variables between groups was performed by using contingency tables (Chi-square). Covariation was tested by simple linear regression analysis. A p value < 0.05 was considered significant.
4. Results Patients who had participated in the physical training program had a significantly lower total hospitalisation event rate 5 years after training (2 F 3 vs. 4 F 3, p < 0.05, trained vs. untrained) and this difference was explained by less hospitalisation due to cardiac events (2 F 3 vs. 3 F 3, p < 0.05, trained vs. untrained) (Fig. 1). Furthermore, there were significantly fewer hospitalisation days due to cardiac
I. Hagerman et al. / International Journal of Cardiology 98 (2005) 487–491
Fig. 1. Outcome of exercise training in cardiac hospitalisation events and days. Solid bars = training group. Stretched bars = controls (nontrained).
problems in the trained group compared to the untrained group (10 F 17 vs. 20 F 27, p < 0.05) (Table 2). There was no difference between the two groups in number of deaths after 5 years of follow-up. Heart failure of idiopathic origin turned out to be more common in the training group as was valvular heart disease in the nontraining group. Treatment with beta-blocking agents was more common in the nontraining group, which may be explained by the somewhat higher prevalence of ischemic heart disease in this group. Accordingly, treatment with ACE inhibitor was more frequent in the training group of predominant idiopathic dilated cardiomyopathy. The effects of training or nontraining on hospitalisation days was further analysed according to possible contributing factors such as age, gender, medication, etiology, heart rhythm, ejection fraction and heart failure class according to the NYHA criteria. Patients with ischemic heart disease who had participated in the training group and patients in NYHA class II were associated with lower hospitalisation rate after 5 years of follow-up. Gender or treatment with ACE-inhibitor, beta-blocker or diuretics did not affect total hospitalisation days nor did left ventricular ejection fraction (r2 = 0.029, p = ns) (Table 3). Treatment with long-acting nitrates was associated with higher hospitalisation rate.
5. Discussion Recently, Metcalfe et al. [8] published an analysis and discussion of how outcome in clinical studies of heart failure are best described. According to their findings, there is a great variety in recorded data, such as different type of hospitalisations. Often, only the first event of hospitalisation is considered and the duration of the hospitalisation event is neglected etc. In some studies, only hospitalisation due to worsening of heart failure or cardiac disease is considered. These circumstances make it difficult to fully interpret and understand various effects of treatment regimes in heart failure. Hospitals tend to apply different strategies in the
489
care and management of heart failure patients. Several cardiac clinics have today outpatient clinics for heart failure patients, and interventions there may have effects on reduced hospitalisation. However, this improved management will further complicate interpretation of results in clinical trials because hospitalisation will be used in one center and the same intervention is taken care of by an outpatient clinic without hospitalisising the patient. At the time for the present study, our region did not have such an outpatient clinic and the management of the patients was similar in the two groups. When making the long-term follow-up of our exercised trained heart failure patients, we therefore wanted to analyse the results in the light of Metcalfe et al.’s findings. Therefore, we did not only count the number of hospitalisation events but valued the burden of disease with regard to the number of events, the duration of the events and the cause of the hospitalisation events. We hypothesised that exercise training in heart failure patients is beneficial also in the long term. Our group has previously described positive effects of different short-term exercise programs in heart failure both in improved functional capacity and in health-related quality of life [9]. The present study is a retrospective follow-up of patients that took part in an exercise program during a short period of 8 weeks maximum, and thereafter no formalised follow-up. The control group consisted of matched patients that were diagnosed during the same time period but not included in the exercise program. Data were collected by evaluating medical records of all patients 5 years after diagnosis. There was a slight difference between the patient groups with a higher prevalence of idiopathic dilated cardiomyopathy in the training group and a higher prevalence of ischemic heart failure in the nontraining group. As can be seen from the statistical analysis summarised in Table 3, the different origins of heart failure could not explain the differences in hospitalisation days. Heart failure of ischemic origin seemed to benefit most from exercise training. There was also a higher prevalence of the use of beta-blocking agents in the nontraining groups, which is in concordance with a higher prevalence of ischemic heart disease in this group. At the time for this study, the use of beta-blockers was more established in ischemic heart disTable 3 Factors contributing to differences in hospitalisation days
Training (yes/no) IHD (training/nontraining) NYHA II/III ACE-I (yes/no) Nitrates (yes/no) Beta-blocker (yes/no) Diuretics (yes/no) Gender, female (training/nontraining) Gender, male (training/nontraining)
Hospitalisation days
p
15 F 19/26 F 31 9 F 16/27 F 27 16 F 19/27 F 32 20 F 24/22 F 30 33 F 35/17 F 22 20 F 25/21 F 27 21 F 27/13 F 11 11 F 16/24 F 29
0.0318 0.012 0.0388 ns 0.0122 ns ns ns
18 F 21/28 F 32
ns
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ease than in heart failure due to other causes. Despite that, and well aware of the positive effects of beta-blockers in heart failure [15 – 17], there was a significant difference in outcome with regard to hospitalisation events and hospitalisation days due to cardiac disease, in favour of the training group. There was no difference between the groups in terms of hospitalisation due to other causes than cardiac problems. This may be interpreted as a specific cardiac effect of exercise training. Heart failure is often described as a syndrome with high prevalence of comorbidity [18,19]. When analysing specific effects of exercise on cardiac performance, it seems logical to evaluate this in a highly selected group. The patients in this study were strictly selected with predominantly cardiac disease with only minor other health problems. The prevalence of ACE inhibitors was higher in the training group and the value of this treatment in heart failure is well established long since [20 – 22]. A further analysis of factors that could contribute to the difference in outcome between groups revealed that the positive long-term effects of exercise were most obvious in patients with heart failure due to ischemic heart disease. Several studies report beneficial effects of training after myocardial infarction [23] and our study can confirm this finding. Moreover, a higher functional NYHA class was associated with more positive outcome of exercise, which has also been described by others [23,24]. On the contrary, there was no association between left ventricular ejection fraction and effects of exercise training which is in line with previous knowledge that the most important prognostic factor is the functional status of the patient and not the systolic heart function per se [25 –27]. In the extended analysis (Table 3), treatment with beta-blockers or ACE inhibitors did not significantly contribute to the difference in hospitalisation days, nor did gender. However, we can not from this analysis exclude that a combined treatment of exercise and beta-blocking agents and/or ACE inhibitors could even more reduce hospitalisation days. Less frequent use of nitrates was associated with less hospitalisation days, which may reflect a difference in level of disease and symptoms among the heart failure patients due to ischemic heart disease. Not surprisingly, there was no difference in number of deaths between groups as the study groups were too small for such an analysis. The positive effects of exercise training on burden of disease with regard to both hospitalisation events and days due to cardiac problems were significant 5 years after a short, but professionally supervised training period. This is a promising finding which should be studied further. However, our previous studies have indicated that the patients after completed training program experience improved sense of safety and physical activity [9]. This may lead to a physically more active life in the long range. There was no other obvious difference between the two groups but physical training that can explain such a finding. We have not included specific data on exercise training in this paper
because this has been reported previously [9,12 –14]. The patients in those training programs used different quantities of muscle work, which resulted in incomparable indices of exercise performances such as peak VO2 and maximal workload. However, there was a consistent improvement in all training studies with an increase in exercise duration in the range of 20– 40%. We have not yet made any retrospective health quality survey or evaluation of degree of daily physical activity of the two patient groups. We can therefore only speculate in that there may be remaining influence in the degree of physical activity in patients that have been treated in specific exercise training groups several years ago and that this contributes to a lesser degree of need for hospitalisation due to cardiac disease. We have in this study practically demonstrated, in line with Metcalfe et al. [8] that outcome in heart failure should be evaluated as total number of hospitalisation events and total number of hospitalisation days. Limitation: This study design is a retrospective analysis, which of course is scientifically inferior to a prospective, randomized controlled trial. However, we tried to match the control group on the following characteristics: age, gender, aetiology, NYHA-class, ejection fraction and medication. The group also made the same exclusion criteria. Yet, there was a statistically significant difference between the groups according to aetiology. Subgroup analysis showed that this difference was significant for idiopathic dilated cardiomyopathy and heart failure due to valvular disease but not for ischemic heart disease, the group in which training seemed to reduce longterm hospitalisation rate. The aetiologies per se did not contribute to the difference in hospitalisation days. Preferably, a baseline exercise test should have been performed in both groups but was not possible in this retrospective design. In addition, activity index during the follow-up period would have been of great interest. We have focused in this analysis on the burden of hospitalisation in heart failure and then used one type of intervention in this sick patient population, namely exercise training. Our results underline the need to investigate the long-term effects of exercise training in heart failure but using controlled, prospective and randomised design.
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