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Rationale and design of a randomized trial on the effectiveness of aerobic interval training in patients with coronary artery disease: The SAINTEX-CAD study
International Journal of Cardiology 168 (2013) 3532–3536
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Rationale and design of a randomized trial on the effectiveness of aerobic interval training in patients with coronary artery disease: The SAINTEX-CAD study Viviane M. Conraads a, b,⁎, 1, Emeline M. Van Craenenbroeck a, b, Nele Pattyn c, d, Véronique A. Cornelissen c, d, Paul J. Beckers a, b, Ellen Coeckelberghs c, d, Catherine De Maeyer a, b, Johan Denollet a, e, Geert Frederix a, Kaatje Goetschalckx c, d, Vicky Y. Hoymans a, b, Nadine Possemiers a, Dirk Schepers c, d, Bharati Shivalkar a, b, Luc Vanhees c, d, 1 a
Department of Cardiology, Antwerp University Hospital, Edegem, Belgium University of Antwerp, Antwerp, Belgium c University Hospitals of Leuven, Leuven, Belgium d Department of Rehabilitation Sciences, Research Centre for Cardiovascular and Respiratory Rehabilitation, Katholieke Universiteit Leuven, Heverlee, Belgium e CoRPS–Centre of Research on Psychology in Somatic diseases, Tilburg University, Tilburg, The Netherlands b
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Article history: Received 30 January 2013 Received in revised form 20 April 2013 Accepted 3 May 2013 Available online 24 May 2013 Keywords: Exercise intensity Exercise training Coronary artery disease Secondary prevention Cardiac rehabilitation
a b s t r a c t Background: Exercise-based cardiac rehabilitation is considered an important adjunct treatment and secondary prevention measure in patients with coronary artery disease (CAD). However, the issues of training modality and exercise intensity for CAD patients remain controversial. Objective: Main aim of the present study is to test the hypothesis that aerobic interval training (AIT) yields a larger gain in peak aerobic capacity (peakVO2) compared to a similar training programme of moderate continuous training (MCT) in CAD patients. Study design: In this multicentre study stable CAD patients with left ventricular ejection fraction > 40% will be randomized after recent myocardial infarction or revascularization (PCI or CABG) to a supervised 12-week programme of three weekly sessions of either AIT (85–90% of peak oxygen uptake [peakVO2], 90–95% of peak heart rate) or MCT (60–70% of peakVO2, 65–75% of peak heart rate). The primary endpoint of the study is the change of peakVO2 after 12 weeks training. Secondary endpoints include safety, changes in peripheral endothelial vascular function, the evolution of traditional cardiovascular risk factors, quality of life and the number and function of circulating endothelial progenitor cells as well as endothelial microparticles. Possible differences in terms of long-term adherence to prescribed exercise regimens will be assessed by regular physical activity questionnaires, accelerometry and reassessment of peakVO2 12 months after randomization. A total number of 200 patients will be randomized in a 1:1 manner (significance level of 0.05 and statistical power of 0.90). Enrolment started December 2010; last enrolment is expected for February 2013. © 2013 Published by Elsevier Ireland Ltd.
1. Background In Europe, coronary artery disease (CAD) accounts for 1.8 million deaths each year [1]. Lifestyle interventions are an essential component and top priority of the contemporary management of CAD patients. Exercise-based cardiac rehabilitation involves a multidisciplinary disease management programme with physical exercise as one of the core components [2]. Exercise training in patients with cardiovascular (CV) disease reduces all-cause and cardiac mortality with 15 to 31% [3].
⁎ Corresponding author at: Department of Cardiology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium. Tel.: +32 3821 4672. E-mail address: [email protected] (V.M. Conraads). 1 VC principal Investigator site Antwerp University Hospital, LV principal Investigator site KULeuven. 0167-5273/$ – see front matter © 2013 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.ijcard.2013.05.007
Meta-analyses on exercise-based comprehensive rehabilitation for CAD [3] are criticized and considered obsolete in the context of modern management [4]. However, several recent publications provide evidence for a clear benefit of exercise-based cardiac rehabilitation in patients undergoing percutaneous coronary interventions (PCI) [5] or after an acute myocardial infarction (MI) [6], throughout different age categories and in large, more heterogeneous cohorts of patients with CAD [7,8]. Longevity is proportional to physical fitness, even after correction for multiple CV risk factors [9,10]. In male post-MI and coronary artery bypass (CABG) patients, Vanhees L et al. showed that peak oxygen uptake (peakVO2) was an independent predictor of outcome [11]. Kodama S et al. conducted a meta-analysis on the results of 33 studies and concluded that 3.5 ml/kg/min higher peakVO2 was associated with a 13% and 15% risk reduction of all-cause mortality and CAD events [12]. The independent CV mortality benefit of an exercise training-induced increase in peakVO2 has been confirmed in patients with CAD [13].
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Despite the class I, level A recommendation by the European Society of Cardiology [14], referral and participation rates to cardiac rehabilitation remain poor, with only 36.5% of European patients actually participating [15]. After a median follow-up of 1.24 years, 43% of cardiac rehabilitation attendees, interviewed for the EUROASPIRE III survey, reported to comply with the general guidelines on physical activity after a coronary event, compared to 29% of those who were not advised to participate [15]. These data illustrate that there is still ample room for more effective interventions that aim at sustained lifestyle adaptations. The issues of training modality and exercise intensity in CAD patients remain controversial [16]. The “traditional” approach is to prescribe moderate continuous exercise intensity at 60 to 80% of peakVO2, which results in a 10–20% increase on average. Whereas the implementation of high intensity interval exercise is common practice in sports medicine, only small, single centre trials have tested such an approach in distinct patient groups. In 32 patients with metabolic syndrome, aerobic interval training (AIT) improved peakVO2 with 35% compared to 16% following moderate continuous training (MCT) [17]. In another pilot study, involving 29 chronic heart failure patients, AIT elicited a highly significant improvement in peakVO2, peripheral endothelial function, as well as reverse left ventricular remodelling compared to MCT [18]. Since then, high intensity interval training in varying combinations of exercise intensity, set as high as 120% of estimated peakVO2 [19], has been compared to moderate intensity continuous training in small single-centre randomized studies [20–22] as comprehensively reviewed by Meyer P et al. [23]. A recent meta-analysis including the majority of these studies shows that AIT elicits larger benefits in peak VO2 and VE/VCO2 slope compared to MCT in patients with moderate to severe heart failure [24]. The results of sufficiently powered multi-centre studies to assess efficacy and safety, however, are awaited [25]. In a recent publication, usual care exercise for 60 min and AIT, as 4 times 4 min of treadmill walking at 90% of individual maximal heart rate, twice weekly, were compared in post-MI patients [26]. After 12 weeks, 30 patients in the AIT group demonstrated, on average, a 1.5 ml/kg/min larger peakVO2 compared to 59 patients in the usual care exercise group. After 30 months, the AIT group still performed better and adherence to twice weekly or more exercise activities was higher in the latter group (82% versus 58%, respectively). As pointed out in the systematic review from Cornish AK et al. [27], only two other small studies randomized patients with CAD to either AIT or MCT [28,29]. If AIT proves to be superior to MCT in the current study, refinement of interval protocols should be pursued in sufficiently powered trials that allow head-to-head comparison of various exercise intensities and interval durations. With regard to safety, a recent retrospective analysis from 4846 patients with CVD and more than 175 000 exercise training hours reported one fatal cardiac arrest per 129 456 exercise hours of MCT and two non-fatal cardiac arrests per 46 364 AIT sessions (1 per 23 182 exercise hours) [30]. Although this was a non-randomized study (patients performed both MCT and AIT), the data are reassuring.
threshold, oxygen uptake efficiency slope VE/VCO2 slope, circulatory power, VO2 T1/2 and heart rate recovery will be studied. The secondary objective is to determine whether AIT versus MCT has a differential effect in improving peripheral vascular function. To test this hypothesis, peripheral arterial tonometry (Endo-PAT2000®) as well as flow-mediated vasodilation (FMD) (high-resolution ultrasound) will be used. The third objective will evaluate the safety of AIT versus MCT and will also concentrate on the assessment of CV risk factors, including insulin sensitivity, abdominal obesity, blood pressure, body mass index (BMI), lipid levels, markers of oxidative stress, hs-CRP, adiponectin concentrations and intima-media thickness. The fourth objective will assess the evolution of physical activity behavior, quality of life, positive and negative affect, and personality that might determine whether beneficial effects of training, as well as adherence to training prescription are sustainable for longer periods of time. The fifth objective is to study the impact of AIT versus MCT on the number and function of circulating endothelial progenitor cells (EPC) and circulating angiogenic T-cells, which are considered endothelial repair mechanisms, and endothelial microparticles (EMP), reflecting endothelial damage. Changes in peakVO2 due to exercise training result from increased O2 delivery (due to increased stroke volume and exercise induced vasodilation) and enhanced O2 consumption (increased oxidative capacity of skeletal muscles). The rationale behind AIT is that it allows rest periods in between exercise bouts, which enables patients to complete short work periods at higher intensities. These high intensities challenge the pumping capacity of the heart to a much larger extent than regular MCT. It is conceivable that, besides the larger increase in stroke volume, AIT has a more profound effect on shear stress at the level of the endothelium. The promotion of transcription and stabilization of endothelial nitric oxide (NO) synthase mRNA and the enhancement of posttranslational phosphorylation, in addition to down-regulation of NADPH oxidase expression and up-regulation of anti-oxidant enzymes all lead to increased bioavailability of NO [31]. There is strong evidence that vascular adaptations following exercise training are key players in the observed effects of exercise on CV health [32]. In addition, in patients with CAD, endothelial dysfunction is an independent predictor of vascular events, and therefore an interesting target of exercise training [33]. Based on prior studies, we hypothesize that the magnitude of the increase in peakVO2 with AIT improves patients' perceived success and enhances the likelihood that regular physical activity will be continued. Therefore, re-assessment after 12 months is foreseen, as well as the distribution of physical activity questionnaires and accelerometers at regular time intervals. In addition, a more rapid gain of aerobic capacity may result in increased efficacy and, hence, a shorter rehabilitation period, allowing quicker integration into economic and social life. In order to capture such accelerated progress, CPET is also planned 6 weeks after starting the supervised training programme.
2. Rationale of the study
3. Study design
The main goal of the Study on Aerobic INTerval EXercise training in CAD (SAINTEX-CAD) study is to assess whether a 12-week programme of three weekly, supervised sessions of AIT yields a larger gain in peakVO2, compared to a similar training programme of MCT. Twohundred CAD patients, referred for cardiac rehabilitation, will be enrolled in a longitudinal, prospective randomized clinical study at the Antwerp University Hospital (centre 1) and University Hospital Leuven (centre 2). Patients will be randomized to AIT or MCT on a 1:1 base. The primary objective is to assess whether AIT versus MCT is superior in terms of increasing peakVO2, determined by cardio-pulmonary exercise testing with ventilatory gas analysis (CPET). Additionally, other exercise-test derived parameters such as VO2 at anaerobic
3.1. Patients The study will enroll 200 consecutive patients with CAD referred to the Cardiac Rehabilitation centres of the University Hospitals of Antwerp and Leuven, 100 patients at each site. All patients assessed for eligibility will be registered, with an age limit of 75 years. Inclusion and exclusion criteria are shown in Table 1. A recent meta-analysis concluded that an increase of 3.5 ml/kg/min in maximal aerobic capacity was associated with a 13% and 15% risk reduction of all-cause mortality and CAD/CV disease [12]. Preliminary calculations suggest that for an effect size of 0.5 (increase in peakVO2 of 3.5 ml/kg/min, standard deviation of 7 ml/kg/min) a total number of 172 patients randomized 1:1
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(n = 86 in each group) to the two intervention groups is needed to detect larger beneficial effects with AIT with a significance level of 0.05 and statistical power of 0.90. To correct for potential dropouts, 100 patients will be enrolled in each treatment arm. 3.2. Pre-inclusion screening Patients will be screened by medical history and physical examination. Eligible patients will undergo CPET and echocardiography; if no exclusion criteria are present, patients can be included in the study. 3.3. Randomization After informed consent, patients will be allocated either to an AIT or an MCT using an online protocol at the Coordinating Centre. Care was taken to assure that both participating centres will enroll 100 patients on a 1:1 base (AIT versus MCT). Laboratory personnel are blinded to treatment allocation. The study complies with the World Medical Association Declaration of Helsinki on ethics in medical research [34] and is approved by the local medical ethics committee. Written informed consent is to be obtained prior to enrolment. Clinical trial registration: NCT01226225.
Subjects will continuously wear a heart rate monitor to keep track of assigned exercise intensity. Heart rhythm will be followed continuously during training sessions with telemetry when considered indicated. Patients exercise on a bicycle; exercise load is adjusted, in order to comply with assigned heart rate throughout the 12-week training period. The Borg 6–20 scale is used to measure the rate of perceived exertion after each training session. • The AIT group warms-up for 10 min at moderate intensity (50–60% of peakVO2, 60–70% of peak heart rate, 11–13 Borg scale, no shortness of breath) and will cycle in 4-min intervals at high intensity with the aim to reach 85–90% of peakVO2, 90–95% of peak heart rate, 15–17 Borg scale, shortness of breath). Each interval is separated by 3-min active pauses, cycling at 50–70% of peak heart rate. The session ends with a 3 min cool-down. Total exercise time will be 38 min for the AIT group. • Patients in the MCT group will cycle continuously at moderate intensity (60–70% of peakVO2, 65–75% of peak heart rate) for 37 min. The session starts with 5 min warm-up (50–60% of peakVO2, 60–70% of peak heart rate) and ends with a 5 min cool-down. Total exercise time will be 47 min for the MCT group (isocaloric compared to AIT). • Exercise training will be terminated at any sign of a serious adverse effect, and all adverse effects will be reported in the CRF and carefully assessed. Patients are instructed to refrain from extra exercise beyond supervised training sessions. 4.3. Maintenance After the 12 weeks supervised programme, patients are encouraged to continue a similar training programme at home. Telephone calls every 4 weeks are organized in order to resolve questions, to detect adverse events and assess activity level by the IPAQ questionnaire. Home-based training will consist of walking or bicycling. Twelve months after inclusion, clinical and laboratory tests will be repeated. 4.4. Adherence
4. Methods
The requirements for adherence for final analysis will include:
4.1. Cardiopulmonary exercise testing Cardiopulmonary exercise testing will be performed at baseline, after 6 weeks (to adjust training intensity) and at the end of the programme using an individualized cycle ergometer ramp protocol (20 Watt +20 W/min or 10 Watt + 10 Watt/min). Twelve-lead ECG is recorded continuously and blood pressure is measured every minute and at peak exercise. Breath-by-breath gas exchange measurements allow on-line determination of ventilation (VE), oxygen uptake (VO2) and carbon dioxide production (VCO2) every 10 s. PeakVO2 is determined as the mean value of 3 measures of VO2 during the final 30 s of exercise. At the end of the test, patients recuperate during 3 min at a workload of 20 Watt; VO2 is measured until it reaches half of the peakVO2. In centre 1 (Antwerp University Hospital), Cardiovit CS 200 Ergospiro from Schiller AG Baar Switzerland will be used, whereas CPET in centre 2 (University Hospital of Leuven) will be performed on Oxycon ProTM JaegerTM from CareFusion 234 GmbH Hoechberg Germany. 4.2. Exercise training Supervised training takes place 3 times a week. Besides 36 exercise sessions, 6 additional multi-disciplinary education sessions are organized. Adherence to planned exercise sessions is recorded. At the end of the programme patients receive multi-disciplinary advice and guidance to allow and stimulate continuation of exercise training. Table 1 Inclusion and exclusion criteria. Inclusion criteria
Exclusion criteria
• CAD - prior angiographically documented stenotic lesion(s) of > 75%, or - documented MI (biochemical, ECG, echocardiographic documentation) • LVEF > 40% • enrolment between 4 weeks and 3 months following PCI, MI or CABG • optimal medical treatment • stable with regard to symptoms/ pharmacotherapy for at least 4 weeks
• acute and chronic significant illnesses that may interfere with actual training • severe ventricular arrhythmia, significant myocardial ischemia, hemodynamic deterioration or exercise-induced arrhythmia at baseline testing • other cardiac diseases (valve disease with significant hemodynamic consequences, hypertrophic cardiomyopathy etc.) • co-morbidities that limit exercise tolerance (hemoglobin b 10 g/dl, chronic obstructive pulmonary disease with FEV1 b 50%) • acute/chronic inflammatory diseases or malignancy, the use of anti-inflammatory drugs or immune suppression • co-morbidity that may significantly influence one-year prognosis • GFR b25 ml/min/1.73 m2 • participation in another clinical trial
LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention; MI = myocardial infarction; GFR = glomerular filtration rate.
• Minimum 32 exercise sessions in total and minimum 10 sessions during last 4 weeks • If >4 consecutive dropped sessions; permit prolonging of training intervention by 2 weeks • Minimum 2 consecutive sessions before final assessment 4.5. Baseline and follow-up investigations Patients will be evaluated at baseline, after 6 and 12 weeks training and 12 months after randomization (end of study). Fig. 1 provides a flowchart of the study protocol. Cardio-pulmonary exercise testing (vide supra) and comprehensive two-dimensional, Doppler and tissue Doppler echocardiography will be conducted according to standard procedures [35]. Peripheral arterial tonometry is used to calculate the reactive hyperemia index (Endo-PAT 2000 device, Itamar Medical) and simultaneously, FMD (high definition ultrasound) will be assessed, as described previously [36,37]. Endotheliumindependent vasodilation will be appreciated after oral administration of glyceryl trinitrate. Intima-media thickness will be measured with high-resolution ultrasound at the posterior wall of the right common carotid artery, using an automatic edge tracking method (Wall Tracker System, PIE-Medical, Maastricht, The Netherlands) in patients included in centre 1 only. Technicians are blinded to the study intervention. Quality of life will be measured by SF-36, Health-related quality of life and Global Mood Scale questionnaires, prior to and after the training period [38–40]. The level of physical activity will be assessed at 4 weekly intervals by the IPAQ questionnaire [41]. The 14-item Type D personality scale will be included in this study [42]. Blood pressure, BMI, waist-to-hip ratio will be repetitively measured (clinical examination) and blood samples will be obtained under fasting conditions to assess CV risk factors (creatinine, glucose, total cholesterol, triglycerides, LDL and HDL cholesterol, hs-CRP, adiponectin, insulin resistance), as well as EPC, angiogenic T-cells and EMP. Flow cytometric techniques and technical methodological descriptions have been published earlier [43,44]. Daily life physical activity will also be assessed through accelerometry (SenseWear® PRO, Bodymedia®, Pittsburgh, USA) at baseline, after 12 weeks of training and at 12 months after randomization. 4.6. Data handling OpenClinica, an open source clinical trial software for electronic data capture and clinical data management, was used to collect and store the data. The database was hosted and secured on the servers of the Antwerp University Hospital and was on-line accessible. Confidentiality of the data will be regulated by the central ethics committee of each participating centre. 4.7. Adverse events All serious adverse events (SAE) will be reported continuously to the project coordinating committee. SAE are defined as all-cause mortality, hospitalization for CV disease or atrial or ventricular arrhythmia. Training-related adverse events are expected to occur during the actual training period of 12 weeks.
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Fig. 1. Flowchart, illustrating randomization and investigations at different timepoints.
4.8. Statistics
5.3. Coordinating centre
All parameters will be analysed on intention-to-treat principle, according to initial randomization. However, a proportion of dropouts may be expected, and on-treatment analysis will give the physiological effect of training. Non-adherence has been defined in the protocol. All tests are two-sided and a p-value of b0.05 is considered statistically significant. Analyses will be performed using SPSS 20.0 (SPSS Inc., Chicago, IL, USA).
The coordinating centre is situated at the Antwerp University Hospital and is run by the project leader. Development and support of the electronic database takes place under supervision of the project leader, as well as maintenance of proper computer-based randomization, data monitoring and quality control.
5. Project organization 5.4. Endpoint committee 5.1. Study group The study group consists of all active investigators, including 2 project coordinators at each of the recruiting centres and heads of core labs (echocardiography and laboratory). 5.2. Steering committee The project is structured in “Workpackages”, run by Workpackage leaders, who have the role of the steering committee.
The endpoint committee reviews AEs and is blinded to randomization information. 5.5. Safety and Monitoring Committee The Safety and Monitoring Committee is independent and will be un-blinded to the randomization groups, monitoring SAEs during the exercise intervention, as well as monitoring the closure of the database at the appropriate time.
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Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Rationale and design of a randomized trial on the effectiveness of aerobic interval training in patients with coronary artery disease: The SAINTEX-CAD study Viviane M. Conraads a, b,⁎, 1, Emeline M. Van Craenenbroeck a, b, Nele Pattyn c, d, Véronique A. Cornelissen c, d, Paul J. Beckers a, b, Ellen Coeckelberghs c, d, Catherine De Maeyer a, b, Johan Denollet a, e, Geert Frederix a, Kaatje Goetschalckx c, d, Vicky Y. Hoymans a, b, Nadine Possemiers a, Dirk Schepers c, d, Bharati Shivalkar a, b, Luc Vanhees c, d, 1 a
Department of Cardiology, Antwerp University Hospital, Edegem, Belgium University of Antwerp, Antwerp, Belgium c University Hospitals of Leuven, Leuven, Belgium d Department of Rehabilitation Sciences, Research Centre for Cardiovascular and Respiratory Rehabilitation, Katholieke Universiteit Leuven, Heverlee, Belgium e CoRPS–Centre of Research on Psychology in Somatic diseases, Tilburg University, Tilburg, The Netherlands b
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Article history: Received 30 January 2013 Received in revised form 20 April 2013 Accepted 3 May 2013 Available online 24 May 2013 Keywords: Exercise intensity Exercise training Coronary artery disease Secondary prevention Cardiac rehabilitation
a b s t r a c t Background: Exercise-based cardiac rehabilitation is considered an important adjunct treatment and secondary prevention measure in patients with coronary artery disease (CAD). However, the issues of training modality and exercise intensity for CAD patients remain controversial. Objective: Main aim of the present study is to test the hypothesis that aerobic interval training (AIT) yields a larger gain in peak aerobic capacity (peakVO2) compared to a similar training programme of moderate continuous training (MCT) in CAD patients. Study design: In this multicentre study stable CAD patients with left ventricular ejection fraction > 40% will be randomized after recent myocardial infarction or revascularization (PCI or CABG) to a supervised 12-week programme of three weekly sessions of either AIT (85–90% of peak oxygen uptake [peakVO2], 90–95% of peak heart rate) or MCT (60–70% of peakVO2, 65–75% of peak heart rate). The primary endpoint of the study is the change of peakVO2 after 12 weeks training. Secondary endpoints include safety, changes in peripheral endothelial vascular function, the evolution of traditional cardiovascular risk factors, quality of life and the number and function of circulating endothelial progenitor cells as well as endothelial microparticles. Possible differences in terms of long-term adherence to prescribed exercise regimens will be assessed by regular physical activity questionnaires, accelerometry and reassessment of peakVO2 12 months after randomization. A total number of 200 patients will be randomized in a 1:1 manner (significance level of 0.05 and statistical power of 0.90). Enrolment started December 2010; last enrolment is expected for February 2013. © 2013 Published by Elsevier Ireland Ltd.
1. Background In Europe, coronary artery disease (CAD) accounts for 1.8 million deaths each year [1]. Lifestyle interventions are an essential component and top priority of the contemporary management of CAD patients. Exercise-based cardiac rehabilitation involves a multidisciplinary disease management programme with physical exercise as one of the core components [2]. Exercise training in patients with cardiovascular (CV) disease reduces all-cause and cardiac mortality with 15 to 31% [3].
⁎ Corresponding author at: Department of Cardiology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium. Tel.: +32 3821 4672. E-mail address: [email protected] (V.M. Conraads). 1 VC principal Investigator site Antwerp University Hospital, LV principal Investigator site KULeuven. 0167-5273/$ – see front matter © 2013 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.ijcard.2013.05.007
Meta-analyses on exercise-based comprehensive rehabilitation for CAD [3] are criticized and considered obsolete in the context of modern management [4]. However, several recent publications provide evidence for a clear benefit of exercise-based cardiac rehabilitation in patients undergoing percutaneous coronary interventions (PCI) [5] or after an acute myocardial infarction (MI) [6], throughout different age categories and in large, more heterogeneous cohorts of patients with CAD [7,8]. Longevity is proportional to physical fitness, even after correction for multiple CV risk factors [9,10]. In male post-MI and coronary artery bypass (CABG) patients, Vanhees L et al. showed that peak oxygen uptake (peakVO2) was an independent predictor of outcome [11]. Kodama S et al. conducted a meta-analysis on the results of 33 studies and concluded that 3.5 ml/kg/min higher peakVO2 was associated with a 13% and 15% risk reduction of all-cause mortality and CAD events [12]. The independent CV mortality benefit of an exercise training-induced increase in peakVO2 has been confirmed in patients with CAD [13].
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Despite the class I, level A recommendation by the European Society of Cardiology [14], referral and participation rates to cardiac rehabilitation remain poor, with only 36.5% of European patients actually participating [15]. After a median follow-up of 1.24 years, 43% of cardiac rehabilitation attendees, interviewed for the EUROASPIRE III survey, reported to comply with the general guidelines on physical activity after a coronary event, compared to 29% of those who were not advised to participate [15]. These data illustrate that there is still ample room for more effective interventions that aim at sustained lifestyle adaptations. The issues of training modality and exercise intensity in CAD patients remain controversial [16]. The “traditional” approach is to prescribe moderate continuous exercise intensity at 60 to 80% of peakVO2, which results in a 10–20% increase on average. Whereas the implementation of high intensity interval exercise is common practice in sports medicine, only small, single centre trials have tested such an approach in distinct patient groups. In 32 patients with metabolic syndrome, aerobic interval training (AIT) improved peakVO2 with 35% compared to 16% following moderate continuous training (MCT) [17]. In another pilot study, involving 29 chronic heart failure patients, AIT elicited a highly significant improvement in peakVO2, peripheral endothelial function, as well as reverse left ventricular remodelling compared to MCT [18]. Since then, high intensity interval training in varying combinations of exercise intensity, set as high as 120% of estimated peakVO2 [19], has been compared to moderate intensity continuous training in small single-centre randomized studies [20–22] as comprehensively reviewed by Meyer P et al. [23]. A recent meta-analysis including the majority of these studies shows that AIT elicits larger benefits in peak VO2 and VE/VCO2 slope compared to MCT in patients with moderate to severe heart failure [24]. The results of sufficiently powered multi-centre studies to assess efficacy and safety, however, are awaited [25]. In a recent publication, usual care exercise for 60 min and AIT, as 4 times 4 min of treadmill walking at 90% of individual maximal heart rate, twice weekly, were compared in post-MI patients [26]. After 12 weeks, 30 patients in the AIT group demonstrated, on average, a 1.5 ml/kg/min larger peakVO2 compared to 59 patients in the usual care exercise group. After 30 months, the AIT group still performed better and adherence to twice weekly or more exercise activities was higher in the latter group (82% versus 58%, respectively). As pointed out in the systematic review from Cornish AK et al. [27], only two other small studies randomized patients with CAD to either AIT or MCT [28,29]. If AIT proves to be superior to MCT in the current study, refinement of interval protocols should be pursued in sufficiently powered trials that allow head-to-head comparison of various exercise intensities and interval durations. With regard to safety, a recent retrospective analysis from 4846 patients with CVD and more than 175 000 exercise training hours reported one fatal cardiac arrest per 129 456 exercise hours of MCT and two non-fatal cardiac arrests per 46 364 AIT sessions (1 per 23 182 exercise hours) [30]. Although this was a non-randomized study (patients performed both MCT and AIT), the data are reassuring.
threshold, oxygen uptake efficiency slope VE/VCO2 slope, circulatory power, VO2 T1/2 and heart rate recovery will be studied. The secondary objective is to determine whether AIT versus MCT has a differential effect in improving peripheral vascular function. To test this hypothesis, peripheral arterial tonometry (Endo-PAT2000®) as well as flow-mediated vasodilation (FMD) (high-resolution ultrasound) will be used. The third objective will evaluate the safety of AIT versus MCT and will also concentrate on the assessment of CV risk factors, including insulin sensitivity, abdominal obesity, blood pressure, body mass index (BMI), lipid levels, markers of oxidative stress, hs-CRP, adiponectin concentrations and intima-media thickness. The fourth objective will assess the evolution of physical activity behavior, quality of life, positive and negative affect, and personality that might determine whether beneficial effects of training, as well as adherence to training prescription are sustainable for longer periods of time. The fifth objective is to study the impact of AIT versus MCT on the number and function of circulating endothelial progenitor cells (EPC) and circulating angiogenic T-cells, which are considered endothelial repair mechanisms, and endothelial microparticles (EMP), reflecting endothelial damage. Changes in peakVO2 due to exercise training result from increased O2 delivery (due to increased stroke volume and exercise induced vasodilation) and enhanced O2 consumption (increased oxidative capacity of skeletal muscles). The rationale behind AIT is that it allows rest periods in between exercise bouts, which enables patients to complete short work periods at higher intensities. These high intensities challenge the pumping capacity of the heart to a much larger extent than regular MCT. It is conceivable that, besides the larger increase in stroke volume, AIT has a more profound effect on shear stress at the level of the endothelium. The promotion of transcription and stabilization of endothelial nitric oxide (NO) synthase mRNA and the enhancement of posttranslational phosphorylation, in addition to down-regulation of NADPH oxidase expression and up-regulation of anti-oxidant enzymes all lead to increased bioavailability of NO [31]. There is strong evidence that vascular adaptations following exercise training are key players in the observed effects of exercise on CV health [32]. In addition, in patients with CAD, endothelial dysfunction is an independent predictor of vascular events, and therefore an interesting target of exercise training [33]. Based on prior studies, we hypothesize that the magnitude of the increase in peakVO2 with AIT improves patients' perceived success and enhances the likelihood that regular physical activity will be continued. Therefore, re-assessment after 12 months is foreseen, as well as the distribution of physical activity questionnaires and accelerometers at regular time intervals. In addition, a more rapid gain of aerobic capacity may result in increased efficacy and, hence, a shorter rehabilitation period, allowing quicker integration into economic and social life. In order to capture such accelerated progress, CPET is also planned 6 weeks after starting the supervised training programme.
2. Rationale of the study
3. Study design
The main goal of the Study on Aerobic INTerval EXercise training in CAD (SAINTEX-CAD) study is to assess whether a 12-week programme of three weekly, supervised sessions of AIT yields a larger gain in peakVO2, compared to a similar training programme of MCT. Twohundred CAD patients, referred for cardiac rehabilitation, will be enrolled in a longitudinal, prospective randomized clinical study at the Antwerp University Hospital (centre 1) and University Hospital Leuven (centre 2). Patients will be randomized to AIT or MCT on a 1:1 base. The primary objective is to assess whether AIT versus MCT is superior in terms of increasing peakVO2, determined by cardio-pulmonary exercise testing with ventilatory gas analysis (CPET). Additionally, other exercise-test derived parameters such as VO2 at anaerobic
3.1. Patients The study will enroll 200 consecutive patients with CAD referred to the Cardiac Rehabilitation centres of the University Hospitals of Antwerp and Leuven, 100 patients at each site. All patients assessed for eligibility will be registered, with an age limit of 75 years. Inclusion and exclusion criteria are shown in Table 1. A recent meta-analysis concluded that an increase of 3.5 ml/kg/min in maximal aerobic capacity was associated with a 13% and 15% risk reduction of all-cause mortality and CAD/CV disease [12]. Preliminary calculations suggest that for an effect size of 0.5 (increase in peakVO2 of 3.5 ml/kg/min, standard deviation of 7 ml/kg/min) a total number of 172 patients randomized 1:1
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(n = 86 in each group) to the two intervention groups is needed to detect larger beneficial effects with AIT with a significance level of 0.05 and statistical power of 0.90. To correct for potential dropouts, 100 patients will be enrolled in each treatment arm. 3.2. Pre-inclusion screening Patients will be screened by medical history and physical examination. Eligible patients will undergo CPET and echocardiography; if no exclusion criteria are present, patients can be included in the study. 3.3. Randomization After informed consent, patients will be allocated either to an AIT or an MCT using an online protocol at the Coordinating Centre. Care was taken to assure that both participating centres will enroll 100 patients on a 1:1 base (AIT versus MCT). Laboratory personnel are blinded to treatment allocation. The study complies with the World Medical Association Declaration of Helsinki on ethics in medical research [34] and is approved by the local medical ethics committee. Written informed consent is to be obtained prior to enrolment. Clinical trial registration: NCT01226225.
Subjects will continuously wear a heart rate monitor to keep track of assigned exercise intensity. Heart rhythm will be followed continuously during training sessions with telemetry when considered indicated. Patients exercise on a bicycle; exercise load is adjusted, in order to comply with assigned heart rate throughout the 12-week training period. The Borg 6–20 scale is used to measure the rate of perceived exertion after each training session. • The AIT group warms-up for 10 min at moderate intensity (50–60% of peakVO2, 60–70% of peak heart rate, 11–13 Borg scale, no shortness of breath) and will cycle in 4-min intervals at high intensity with the aim to reach 85–90% of peakVO2, 90–95% of peak heart rate, 15–17 Borg scale, shortness of breath). Each interval is separated by 3-min active pauses, cycling at 50–70% of peak heart rate. The session ends with a 3 min cool-down. Total exercise time will be 38 min for the AIT group. • Patients in the MCT group will cycle continuously at moderate intensity (60–70% of peakVO2, 65–75% of peak heart rate) for 37 min. The session starts with 5 min warm-up (50–60% of peakVO2, 60–70% of peak heart rate) and ends with a 5 min cool-down. Total exercise time will be 47 min for the MCT group (isocaloric compared to AIT). • Exercise training will be terminated at any sign of a serious adverse effect, and all adverse effects will be reported in the CRF and carefully assessed. Patients are instructed to refrain from extra exercise beyond supervised training sessions. 4.3. Maintenance After the 12 weeks supervised programme, patients are encouraged to continue a similar training programme at home. Telephone calls every 4 weeks are organized in order to resolve questions, to detect adverse events and assess activity level by the IPAQ questionnaire. Home-based training will consist of walking or bicycling. Twelve months after inclusion, clinical and laboratory tests will be repeated. 4.4. Adherence
4. Methods
The requirements for adherence for final analysis will include:
4.1. Cardiopulmonary exercise testing Cardiopulmonary exercise testing will be performed at baseline, after 6 weeks (to adjust training intensity) and at the end of the programme using an individualized cycle ergometer ramp protocol (20 Watt +20 W/min or 10 Watt + 10 Watt/min). Twelve-lead ECG is recorded continuously and blood pressure is measured every minute and at peak exercise. Breath-by-breath gas exchange measurements allow on-line determination of ventilation (VE), oxygen uptake (VO2) and carbon dioxide production (VCO2) every 10 s. PeakVO2 is determined as the mean value of 3 measures of VO2 during the final 30 s of exercise. At the end of the test, patients recuperate during 3 min at a workload of 20 Watt; VO2 is measured until it reaches half of the peakVO2. In centre 1 (Antwerp University Hospital), Cardiovit CS 200 Ergospiro from Schiller AG Baar Switzerland will be used, whereas CPET in centre 2 (University Hospital of Leuven) will be performed on Oxycon ProTM JaegerTM from CareFusion 234 GmbH Hoechberg Germany. 4.2. Exercise training Supervised training takes place 3 times a week. Besides 36 exercise sessions, 6 additional multi-disciplinary education sessions are organized. Adherence to planned exercise sessions is recorded. At the end of the programme patients receive multi-disciplinary advice and guidance to allow and stimulate continuation of exercise training. Table 1 Inclusion and exclusion criteria. Inclusion criteria
Exclusion criteria
• CAD - prior angiographically documented stenotic lesion(s) of > 75%, or - documented MI (biochemical, ECG, echocardiographic documentation) • LVEF > 40% • enrolment between 4 weeks and 3 months following PCI, MI or CABG • optimal medical treatment • stable with regard to symptoms/ pharmacotherapy for at least 4 weeks
• acute and chronic significant illnesses that may interfere with actual training • severe ventricular arrhythmia, significant myocardial ischemia, hemodynamic deterioration or exercise-induced arrhythmia at baseline testing • other cardiac diseases (valve disease with significant hemodynamic consequences, hypertrophic cardiomyopathy etc.) • co-morbidities that limit exercise tolerance (hemoglobin b 10 g/dl, chronic obstructive pulmonary disease with FEV1 b 50%) • acute/chronic inflammatory diseases or malignancy, the use of anti-inflammatory drugs or immune suppression • co-morbidity that may significantly influence one-year prognosis • GFR b25 ml/min/1.73 m2 • participation in another clinical trial
LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention; MI = myocardial infarction; GFR = glomerular filtration rate.
• Minimum 32 exercise sessions in total and minimum 10 sessions during last 4 weeks • If >4 consecutive dropped sessions; permit prolonging of training intervention by 2 weeks • Minimum 2 consecutive sessions before final assessment 4.5. Baseline and follow-up investigations Patients will be evaluated at baseline, after 6 and 12 weeks training and 12 months after randomization (end of study). Fig. 1 provides a flowchart of the study protocol. Cardio-pulmonary exercise testing (vide supra) and comprehensive two-dimensional, Doppler and tissue Doppler echocardiography will be conducted according to standard procedures [35]. Peripheral arterial tonometry is used to calculate the reactive hyperemia index (Endo-PAT 2000 device, Itamar Medical) and simultaneously, FMD (high definition ultrasound) will be assessed, as described previously [36,37]. Endotheliumindependent vasodilation will be appreciated after oral administration of glyceryl trinitrate. Intima-media thickness will be measured with high-resolution ultrasound at the posterior wall of the right common carotid artery, using an automatic edge tracking method (Wall Tracker System, PIE-Medical, Maastricht, The Netherlands) in patients included in centre 1 only. Technicians are blinded to the study intervention. Quality of life will be measured by SF-36, Health-related quality of life and Global Mood Scale questionnaires, prior to and after the training period [38–40]. The level of physical activity will be assessed at 4 weekly intervals by the IPAQ questionnaire [41]. The 14-item Type D personality scale will be included in this study [42]. Blood pressure, BMI, waist-to-hip ratio will be repetitively measured (clinical examination) and blood samples will be obtained under fasting conditions to assess CV risk factors (creatinine, glucose, total cholesterol, triglycerides, LDL and HDL cholesterol, hs-CRP, adiponectin, insulin resistance), as well as EPC, angiogenic T-cells and EMP. Flow cytometric techniques and technical methodological descriptions have been published earlier [43,44]. Daily life physical activity will also be assessed through accelerometry (SenseWear® PRO, Bodymedia®, Pittsburgh, USA) at baseline, after 12 weeks of training and at 12 months after randomization. 4.6. Data handling OpenClinica, an open source clinical trial software for electronic data capture and clinical data management, was used to collect and store the data. The database was hosted and secured on the servers of the Antwerp University Hospital and was on-line accessible. Confidentiality of the data will be regulated by the central ethics committee of each participating centre. 4.7. Adverse events All serious adverse events (SAE) will be reported continuously to the project coordinating committee. SAE are defined as all-cause mortality, hospitalization for CV disease or atrial or ventricular arrhythmia. Training-related adverse events are expected to occur during the actual training period of 12 weeks.
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Fig. 1. Flowchart, illustrating randomization and investigations at different timepoints.
4.8. Statistics
5.3. Coordinating centre
All parameters will be analysed on intention-to-treat principle, according to initial randomization. However, a proportion of dropouts may be expected, and on-treatment analysis will give the physiological effect of training. Non-adherence has been defined in the protocol. All tests are two-sided and a p-value of b0.05 is considered statistically significant. Analyses will be performed using SPSS 20.0 (SPSS Inc., Chicago, IL, USA).
The coordinating centre is situated at the Antwerp University Hospital and is run by the project leader. Development and support of the electronic database takes place under supervision of the project leader, as well as maintenance of proper computer-based randomization, data monitoring and quality control.
5. Project organization 5.4. Endpoint committee 5.1. Study group The study group consists of all active investigators, including 2 project coordinators at each of the recruiting centres and heads of core labs (echocardiography and laboratory). 5.2. Steering committee The project is structured in “Workpackages”, run by Workpackage leaders, who have the role of the steering committee.
The endpoint committee reviews AEs and is blinded to randomization information. 5.5. Safety and Monitoring Committee The Safety and Monitoring Committee is independent and will be un-blinded to the randomization groups, monitoring SAEs during the exercise intervention, as well as monitoring the closure of the database at the appropriate time.
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5.6. Timelines The first patient was included in December 2010. At the time of manuscript submission, 180 patients have been enrolled. Last enrolment is expected for February 2013. 6. Conclusion Continuous endurance training at moderate intensity is still widely adopted as the preferred training modality for CV and for CAD patients, in particular. Recent small single centre studies suggest that AIT at higher intensity may offer additional benefit in terms of maximal aerobic capacity. The SAINTEX-CAD study is a multicentre trial, designed to assess the effects of AIT versus MCT with a primary focus on aerobic capacity. Secondary objectives include safety, peripheral endothelial function, quality of life and physical activity adherence, CV risk factors and endothelial repair mechanisms. Funding This work is funded by the Agency of Innovation by Science and Technology (IWT-projectnummer: 090870). VMC and VAC are supported by FWO-Flanders as a Clinical Postdoctoral fellow and Postdoctoral fellow, respectively. References [1] Nichols M TN, Luengo-Fernandez R, Leal J, Scarborough P, Rayner M. European Cardiovascular Disease Statistics 2012. European Heart Network, Brussels, European Society of Cardiology, Sophia Antipolis 2012. [2] Piepoli MF, Corra U, Benzer W, et al. Secondary prevention through cardiac rehabilitation: from knowledge to implementation. A position paper from the Cardiac Rehabilitation Section of the European Association of Cardiovascular Prevention and Rehabilitation. Eur J Cardiovasc Prev Rehabil 2010;17:1–17. [3] Taylor RS, Brown A, Ebrahim S, et al. Exercise-based rehabilitation for patients with coronary heart disease: systematic review and meta-analysis of randomized controlled trials. Am J Med 2004;116:682–92. [4] West RR, Jones DA, Henderson AH. Rehabilitation after myocardial infarction trial (RAMIT): multi-centre randomised controlled trial of comprehensive cardiac rehabilitation in patients following acute myocardial infarction. Heart 2012;98:637–44. [5] Goel K, Lennon RJ, Tilbury RT, Squires RW, Thomas RJ. Impact of cardiac rehabilitation on mortality and cardiovascular events after percutaneous coronary intervention in the community. Circulation 2011;123:2344–52. [6] Marchionni N, Fattirolli F, Fumagalli S, et al. Improved exercise tolerance and quality of life with cardiac rehabilitation of older patients after myocardial infarction: results of a randomized, controlled trial. Circulation 2003;107:2201–6. [7] Suaya JA, Stason WB, Ades PA, Normand SL, Shepard DS. Cardiac rehabilitation and survival in older coronary patients. J Am Coll Cardiol 2009;54:25–33. [8] Martin BJ, Hauer T, Arena R, et al. Cardiac rehabilitation attendance and outcomes in coronary artery disease patients. Circulation 2012;126:677–87. [9] Keteyian SJ, Brawner CA, Savage PD, et al. Peak aerobic capacity predicts prognosis in patients with coronary heart disease. Am Heart J 2008;156:292–300. [10] Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med 2002;346: 793–801. [11] Vanhees L, Fagard R, Thijs L, Staessen J, Amery A. Prognostic significance of peak exercise capacity in patients with coronary artery disease. J Am Coll Cardiol 1994;23:358–63. [12] Kodama S, Saito K, Tanaka S, et al. Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis. JAMA 2009;301:2024–35. [13] Vanhees L, Fagard R, Thijs L, Amery A. Prognostic value of training-induced change in peak exercise capacity in patients with myocardial infarcts and patients with coronary bypass surgery. Am J Cardiol 1995;76:1014–9. [14] Perk J, De Backer G, Gohlke H, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2012;33:1635–701. [15] Kotseva K, Wood D, Backer GD, Bacquer DD. Use and effects of cardiac rehabilitation in patients with coronary heart disease: results from the EUROASPIRE III survey. Eur J Prev Cardiol 2013 Oct;20(5):817–26.
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