Very short/short-term benefit of inpatient/outpatient cardiac rehabilitation programs after coronary artery bypass grafting surgery

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1 Received: 28 September 2016 Revised: 10 November 2016 Accepted: 13 November 2016 DOI /clc CLINICAL INVESTIGATIONS Very short/short-term benefit of inpatient/outpatient cardiac rehabilitation programs after coronary artery bypass grafting surgery Dejan Spiroski 1 Mojsije Andjić 1 Olivera Ilić Stojanović 2 Milica Lazović 2,3 Ana Djordjević Dikić 4,5 Miodrag Ostojić 4 Branko Beleslin 4,5 Snežana Kostić 2 Marija Zdravković 6 Dragan Lović 7 1 Department of Cardiovascular Rehabilitation, Institute for Rehabilitation, Belgrade, Serbia 2 Department of Physical Medicine and Rehabilitation, Institute of Rehabilitation, Belgrade, Serbia 3 Department of Physical Medicine, Belgrade University School of Medicine, Belgrade, Serbia 4 Department of Cardiology, Belgrade University School of Medicine, Belgrade, Serbia 5 Clinic for Cardiology Clinical Centre of Serbia, Belgrade, Serbia 6 Clinic for Cardiology, Hospital Medical Center Bežanijska Kosa, Belgrade, Serbia 7 Clinic for Internal Disease Inter Medica, Niš, Serbia Correspondence Dejan Spiroski, MD, Institute for Rehabilitation, Sokobanjska 17, Belgrade, Serbia spajk1907@gmail.com; dejan@spiroski.rs. Background: Exercise-based rehabilitation is an important part of treatment patients following coronary artery bypass graft (CABG) surgery. Hypothesis: To evaluate effect of very short/short-term exercise training on cardiopulmonary exercise testing (CPET) parameters. Methods: We studied 54 consecutive patients with myocardial infarction (MI) treated with CABG surgery referred for rehabilitation. The study population consisted of 50 men and 4 women (age years, left ventricular ejection fraction 55% 5.81%), who participated in a 3-week clinical and 6-month outpatient cardiac rehabilitation program. The Inpatient program consisted of cycling 7 times/week and daily walking for 45 minutes. The outpatient program consisted mainly of walking 5 times/week for 45 minutes and cycling 3 times/week. All patients performed symptom-limited CPET on a bicycle ergometer with a ramp protocol of 10 W/minute at the start, for 3 weeks, and for 6 months. Results: After 3 weeks of an exercise-based cardiac rehabilitation program, exercise tolerance improved as compared to baseline, as well as peak respiratory exchange ratio. Most importantly, peak VO 2 ( vs ml/kg/min, respectively, P < 0.05), peak VCO 2 ( vs , respectively, P < 0.05), peak ventilatory exchange ( vs L/min, respectively, P < 0.05), and peak breathing reserve (52.00% 13.73% vs 45.75% 14.84%, respectively, P < 0.05) were also improved. The same improvement trend continued after 6 months (respectively, P < and P < ). No major adverse cardiac events were noted during the rehabilitation program. Conclusions: Very short/short-term exercise training in patients with MI treated with CABG surgery is safe and improves functional capacity. KEYWORDS exercise training, coronary artery bypass grafting, cardiopulmonary exercise testing, cardiac rehabilitation 1 INTRODUCTION Comprehensive cardiac rehabilitation (CR) is effective in prolonging survival and reducing morbidity and disability after a coronary event. Therefore, it should be considered the standard of care after a myocardial infarction (MI) or coronary artery bypass graft (CABG) surgery. 1,2 Cardiovascular prevention and rehabilitation critically depend on physical activity and exercise training. 2,3 Exercise-based rehabilitation leads to reduction in all-cause mortality and the risk of reinfarction. CLINICAL CARDIOLOGY. 2017;40: wileyonlinelibrary.com/journal/clc 2017 Wiley Periodicals, Inc. 281

2 282 SPIROSKI ET AL. Also, it modulates other risk factors and improves exercise-based capacity. 4,5 Aerobic exercise consists of 3 major components that include intensity, duration, and frequency of exercise sessions. 4,6 The intensity of exercise training prescription is a key issue in a CR program. It has not been universally shown that exercise-based rehabilitation leads to improvement in exercise capacity and reduction in the incidence of cardiac events in patients following acute MI. 3,7 Cardiopulmonary exercise testing (CPET) using a ramp incremental protocol is the gold standard for exercise intensity assessment and prescription in patients with cardiovascular disease. It has been advocated that this test should be performed, where available, in patients before and after a CR program 8 10 to quantify exercise capacity, chronotropic and inotropic responses to exercise, as well as to detect presence and severity of arrhythmias and inducible myocardial ischemia. 11 Aerobic exercise training in cardiac patients is usually performed using the constant work-rate (CWR) exercise. The exercise intensity influences the metabolic and gas exchange responses to CWR. 7 Most studies have reported an increase in peak volume (V)O 2, in the range of 14% to 31%, after exercise training. 12 Thus, patients with comorbidities may potentially benefit the most from early CR, delivered in outpatient or inpatient settings depending on the functional and clinical risk status, assuring appropriate clinical management, proven risk reduction strategies, and programs aimed at promoting rapid functional recovery and therapeutic lifestyle changes. 13 The aim of our study was to evaluate the effect of very shortterm (3 weeks) and short-term (6 months) exercise training on CPET parameters in patients suffering MI treated with CABG surgery. 2 METHODS 2.1 Study population Our investigation included 54 consecutive patients admitted to the Institute for Rehabilitation Belgrade exercise-based rehabilitation program who met all of the following criteria: (1) previous acute MI treated with CABG surgery, (2) ability to perform a symptom-limited CPET, and (3) signed informed consent. Patients were excluded if they had previous MI or reintervention (other than for index event), unstable angina, significant provoked ischemia, complex ventricular arrhythmias, primary valvular disease, severe peripheral vascular disease, severe chronic obstructive pulmonary disease, neuromuscular disease, or orthopedic limitation. The study design was approved by the Belgrade University School of Medicine Ethics Committee, and written information and consent were obtained from all patients prior to any study procedure. 2.2 Cardiac rehabilitation program Patients participated in a comprehensive CR program that had 2 components: an inpatient and an outpatient program. The inpatient program was implemented 7 times a week for a period of 3 weeks. The program included exercise training, information sessions, dietary counseling, psychosocial support, and smoking cessation. There were 2 training sessions daily, each of 45 minutes duration. The first training session was performed in the morning, which included a warm-up and cool-down period and a 30-minute training phase (aerobic interval training consisting of 3 minutes of exercise and 3 minutes of rest on a cycle ergometer). The second session was performed in the afternoon, in which aerobic training included walking on a flat surface (continuous training) and walking up stairs (interval training). The training intensity was aimed to be between 60% and 80% of peak VO 2 as assessed by CPET. The outpatient program was implemented 5 times a week for a period of 6 months. The program incorporated the use of everything learned during the hospital stay, with implementation of brisk walking on a flat surface (continuous training, 45 minutes), cycling (3 times per week) that included a warm-up and cool-down period and a 45- minute training phase (aerobic continuous training consisting of 45 minutes cycling), and walking up stairs (interval training). The training intensity was aimed to be between 70% and 85% of peak heart rate (self-measurement) as assessed by CPET (after 3 weeks). 2.3 Cardiopulmonary exercise testing Symptom-limited CPET was performed on a bicycle ergometer (Ergometer DX1 and Ergometer AX1; Kettler, Ense-Parsit, Germany) with a ramp protocol of 10 W/m (workload was increased by 10 W/m). The aim was to achieve a maximal effort with a respiratory exchange ratio >1.05. Blood pressure was measured manually at rest and every 1 minute during the entire testing. The electrocardiogram and heart rate (HR) were monitored at rest and all the time throughout exercise. Breath-by-breath respiratory gas exchange parameters were measured by a computerized metabolic cart (Cardiovit AT 104 PC; Shiller, Baar, Switzerland). CPET was performed prior to the start of the program, immediately after the end of the 3-week exercise-based rehabilitation program and then after 6 months. The following CPET parameters were measured: (1) peak VO 2 expressed in milliliters/kilogram/minute and predicted percentage, (2) slope of minute ventilation vs carbon dioxide production (VE/VCO 2 ), (3) peak respiratory exchange ratio (RER), defined as the peak VCO 2 /peak VO 2 ratio, (4) peak VCO 2, (5) peak oxygen pulse, defined as peak VO 2 divided by peak HR and expressed in milliliters/beat (O 2 pulse), (6) ventilatory anaerobic threshold detection, using the V-slope method, (7) maximum ventilation (VE max), (8) peak end-tidal CO 2 partial pressure, (9) peak HR, (10) HR recovery, (11) test duration, (12) peak workload, (13) peak arterial systolic blood pressure, (14) peak diastolic blood pressure, and (15) breathing reserve (BR). 2.4 Echocardiography Complete echocardiographic evaluations were performed using dedicated echocardiographic equipment (Vivid 3; General Electric, Little Chalfont, United Kingdom). Left ventricular ejection fraction (EF) was calculated using the Simpson biplane method. Measurements were made just before the start of the rehabilitation program and then after 6 months.

3 SPIROSKI ET AL Laboratory Blood for biochemical analysis was drawn after a 12-hour fasting period. The following serum parameters were measured: total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, fasting glucose, urea, creatinine, sodium, potassium, red blood cells, and high-sensitivity C-reactive protein (hscrp). For estimated glomerular filtration rate (egfr) we used the Modification of Diet in Renal Disease Study equation. Measurements were made just before the start, after termination of the inpatient rehabilitation program, and after 6 months using a biochemical analyzer (Roche 902; Roche Diagnostics, Basel, Switzerland). 2.6 Statistical analysis The data were entered into an electronic database (Access; Microsoft Corp., Redmond, WA) and analyzed using SPSS 16.0 software (IBM, Armonk, NY). Continuous variables were expressed as mean and standard deviations. Categorical variables were expressed as percentages. The variables tested prior to the start of program, immediately after the end of 3-week exercise-based rehabilitation program, and after 6 months were analyzed and compared using analysis of variance. Dichotomous variables were analyzed using the χ 2 test and Fisher exact test, and continuous variables were analyzed using the t test. The level of statistical significance was set as a 2-tailed probability value of <0.05. An exercise-based rehabilitation program was started days after CABG surgery. 3.2 CPET parameters CPET parameters were examined at the start, 3 weeks, and 6 months after completion of both CR programs as listed in Table 2. After 3 weeks of an exercise-based CR program, exercise tolerance as compared to baseline (peak workload vs W, respectively, P < 0.05), as well as peak RER ( vs , respectively, P < 0.05) changed significantly. Peak VO 2 ( vs ml/kg/min, respectively, P < 0.05), peak VCO 2 ( vs , respectively, P < 0.05), peak VE ( vs L/ min, respectively, P < 0.05), and peak BR (52.00% 13.73% vs 45.75% 14.84%, respectively, P < 0.05) also changed significantly. The same trend continued when we looked at the difference between the initial value of CPET parameters after 6 months of the implementation of the CR program, with the only difference being statistically significant (respectively, P < and P < ) improvement in the monitored parameters. Significant difference was not achieved for peak VE and peak BR, comparing the measurements after 3 weeks and after 6 months, in relation to previously presented results, as shown in Table 2. Exercise electrocardiography indicated the presence of ischemia in 2 patients (3.7%) before and no patients (0%) after the CR program. There were no major adverse cardiac events during the rehabilitation program. 3 RESULTS 3.1 Demographic data and comorbidities Basic demographic data for the patients included in the study are shown in Table 1. The study population consisted of 50 men and 4 women, with a mean age of years. More than half of patients suffered acute MI with non ST-segment elevation. All patients had acute MI, severe 2- or 3-vessel coronary artery disease, and CABG surgery. Forty-three of the 54 patients (79.6%) actively smoked. Comorbidities are detailed in the Table 1. Patients received contemporary concomitant medical treatment; 54/54 (100%) patients were on antiplatelet therapy, 51/54 (94.4%) received β-blockers, 37/54 (68.6%) were on an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and 51/54 (94.5%) were on a statin. TABLE 1 Baseline demographic data and comorbidities Sex, male (%) 50/54 (92.6%) Age, y Diabetes, n (%) 16/54 (29.6%) Hypertension, n (%) 49/54 (90.7%) Hyperlipoproteinemia, n (%) 54/54 (100%) Obesity, n (%) 19/54 (35.2%) Smoking, n (%) 43/54 (79.6%) Family burden, n (%) 37/54 (68.6%) 3.3 Laboratory and clinical data We noticed a significant difference of all monitored lipid parameters, glucose, and hscrp values ( vs , respectively, P < 0.05) comparing a 3-week and 6-month measurement. Values of egfr in all patients was within the normal range. There were no significant differences in body mass index ( vs , not significant) and left ventricular EF (55% 5.81% vs 59.30% 4.26%, not significant), as shown in Table 3. 4 DISCUSSION Cardiac rehabilitation after CABG surgery is known to have several favorable effects. In these patients, training enhances exercise tolerance, activity of daily living, and quality of life. Additionally, shortness of breath during exercise is often noted to have diminished after physical training. 14,15 An essential finding of our study is that very short/short-term exercise training in patients with MI treated with CABG surgery is safe and improves functional capacity. Very short/short-term daily exercise training in these patients also improves peak workload and chronotropic parameters evaluated during CPET. This suggests that the effects of physical training depend on the total number of sessions regardless of the length of interval training.

4 284 SPIROSKI ET AL. TABLE 2 Cardiopulmonary exercise test parameters (at start, 3 weeks, and 6 months after exercise rehabilitation) Start 3 Weeks 6 Months Start/3 Weeks Start/6 Months 3 Weeks/6 Months Peak work load (W) <0.05 < <0.001 Test duration (min) <0.05 < <0.001 Peak SBP (mm Hg) < <0.05 Peak DBP (mm Hg) <0.05 <0.05 HR at rest (bpm) Peak HR (bpm) <0.05 < <0.05 HR recovery 1 minute (bpm) <0.001 <0.001 <0.05 RER at rest Peak RER <0.05 < VO 2 at rest (ml/kg/min) Peak VO 2 (ml/kg/min) <0.05 < <0.001 % Predicted peak VO <0.05 < < Peak VCO 2 (ml/kg/min) <0.05 < <0.001 Peak PET CO 2 (mm Hg) VE/VCO 2 slope Oxygen pulse (ml/beat) < Peak VE (L/min) <0.05 < Peak breathing reserve (%) <0.05 < Abbreviations: DBP, diastolic blood pressure; HR, heart rate; PET, peak end-tidal; RER, respiratory exchange ratio; SBP, systolic blood pressure; VCO 2, carbon dioxide output per unit of time; VE, ventilation; VO 2, oxygen uptake/consumption. Previous studies indicated that values of peak VO 2 on entry in a CR program are relatively low, particularly in women. It has been shown that peak VO 2 measured in 2896 patients prior to a CR program was higher in men than women ( ml/kg/min vs ml/kg/min, P < ). 16 In this study, the baseline VO 2 was significantly lower in the heart transplant recipients (HTR) group than in the CABG group, and both groups exhibited significantly lower VO 2 peak than the agematched healthy populations. After training, the HTR group increased 24.2% in VO 2 peak from to ml/kg/min. Meanwhile, the CABG group increased 19.3% in VO 2 peak from to ml/kg/min. Both groups displayed an increase of 3.6 ml/kg/min in VO 2 after 3 months of training, and the increase was similar to previous studies in HTR patients and patients after CABG surgery. 17 Data were reviewed on 1042 patients who represented 50.7% of all CABG patients referred to the cardiac care clinic for exercise training between March 1992 and March Patients in the supervised group demonstrated a 23.7% improvement, whereas those in the home-based group improved 17.2% in VO 2 peak after 6 months. 18 TABLE 3 Laboratory and clinical data (at start, 3 weeks, and 6 months after exercise rehabilitation) Laboratory Start 3 Weeks 6 Months Start/3 Weeks Start/6 Months 3 Weeks/6 Months Glucose (mmol/l) <0.05 <0.001 Total cholesterol (mmol/l) <0.05 LDL cholesterol (mmol/l) <0.05 HDL cholesterol (mmol/l) <0.05 Triglycerides (mmol/l) Creatinine (μmol/l) Urea (μmol/l) RBCs (10 12 /L) Na (mmol/l) K (mmol/l) hscrp (mg/l) <0.05 egfr (ml/min/1.73 m 2 ) Clinical data BMI (kg/m 2 ) LVEF (%) Abbreviations: BMI, body mass index; egfr, estimated glomerular filtration rate; HDL, high-density lipoprotein; hscrp, high-sensitivity C-reactive protein; K, potassium; LDL, low-density lipoprotein; LVEF, left ventricular ejection fraction; Na, sodium; RBCs, red blood cells.

5 SPIROSKI ET AL. 285 In a study of 57 patients, the minute ventilation carbon dioxide output (VE/VCO 2 ) slope decreased ( to , P < 0.05) in the exercise group, but failed to decrease in the sedentary group ( to ). Cardiac output during exercise at 20 W and at peak exercise, and peak oxygen pulse (VO 2 /HR) increased significantly only in the exercise group after training. 19 Previous studies have reported that in patients following acute MI, peak VO 2 and VO 2 at the anaerobic threshold increase between 7% and 54% after a period of a few weeks of exercise training. 4 Lack of improvement in exercise capacity after an exercise training program is a predictor of poor prognosis. The study that included 385 patients in a cardiac rehabilitation program showed that 81(21%) patients failed to improve peak VO 2 after termination of the program. 20 Similarly, patients with peak VO 2 bellow 10 ml/kg/min had a poor prognosis, and those above 18 ml/kg/min had a good prognosis. 21 Therefore, the increase in peak VO 2 after exercise training might contribute to better survival in patients following CABG surgery. Our data demonstrate an increase of 9% after 3 weeks and 24.1% after 6 months in peak VO 2 and 1.9% of VO 2 at the anaerobic threshold. It is worth emphasizing that VO 2 at the anaerobic threshold is independent of patient s motivation, and it is a good parameter to evaluate the training effect. 4 In a cohort of elderly adults (>65 years old) entering CR after CABG surgery, baseline VO 2 peak was increased 34% from ml/kg/min as a result of 3 weeks of inpatient CR. 22 In accordance with our findings are the results of a meta-analysis that reported an average increase in peak VO 2 of 2% to 22% following an exercise training program. 23 One study also used a 3-week exercise-training program, but with less frequent training sessions (3 days a week, total of 15 sessions). This study showed marked improvement in peak VO 2 (+14.25%) and peak workload (+30.8%), after completion of the program as compared to baseline. 24 Similarly, in a study that included 262 patients with coronary artery disease, the maximum exercise workload had improved significantly ( vs W, P < 0.001) after a 4-week, 3 times per week, ambulatory cardiac rehabilitation program. 25 An exercise training program can also improve HR recovery ( 10% to 12%), peak anaerobic threshold (+10% to 15%), as well as metabolic parameters including total cholesterol ( 5%), triglycerides ( 15%), HDL cholesterol (+5% to 10%), and LDL cholesterol ( 3%). 26 Our study showed that lipid and glucose profile deteriorated most likely due to noncompliance with prescribed guidelines in nutrition at home. Data on patients following MI treated with CABG surgery, as we also reported, showed improvement in heart rate recovery at 1 minute of rest following an exercise program, which indicates good training response and higher contribution to the autonomic nervous system. VE/VCO 2 slope is also an important parameter for prognosis, which is expected to decrease after exercise training. 27 Patients with a VE/VCO 2 slope exceeding 55 had a 2-year mortality of 65%. 21 Mainly due to low baseline values, our data failed to show improvement in VE/VCO2 slope after training. Our research has shown significant decline in the value of hscrp comparing the period of 3 weeks and 6 months, but not enough to classify our patients in the low-risk group, which corresponds with the results of other studies. 28 In our CABG registry cohort, we observed that CR participation was significantly associated with a 20% reduction in all-cause mortality after phase I CR and a 40% reduction after phase II CR. 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