Technology Report Issue 34 March 2003

Transcription

1 Technology Report Issue 34 March 2003 Exercise-Based Cardiac Rehabilitation Programs for Coronary Artery Disease: A Systematic Clinical and Economic Review

2 Publications can be requested from: CCOHTA Carling Avenue Ottawa, Ontario, Canada K1S 5S8 Tel. (613) Fax. (613) or download from CCOHTA s web site: Cite as: Brown A, Taylor R, Noorani H, Stone J, Skidmore B. Exercise-based cardiac rehabilitation programs for coronary artery disease: a systematic clinical and economic review. Ottawa: Canadian Coordinating Office for Health Technology Assessment; Technology report no 34. Reproduction of this document for non-commercial purposes is permitted provided appropriate credit is given to CCOHTA. CCOHTA is a non-profit organization funded by the federal, provincial and territorial governments. Legal Deposit National Library of Canada ISBN: (print) ISBN: (electronic version) Publications Mail Agreement Number:

3 Canadian Coordinating Office for Health Technology Assessment Exercise-Based Cardiac Rehabilitation Programs for Coronary Artery Disease: A Systematic Clinical and Economic Review Allan Brown BSc MBA MA 1 Rod Taylor MSc PhD 2 Hussein Noorani MSc 1 James Stone MD PhD FRCPC FAACVPR FACC 3 Becky Skidmore BA MLS 1 March Canadian Coordinating Office for Health Technology Assessment, Ottawa, Ontario Department of Public Health & Epidemiology, University of Birmingham, UK University of Calgary, Calgary, Alberta 6

4 Reviewers These individuals kindly provided comments on this report. CCOHTA Scientific Advisory Panel Reviewers Philip Jacobs, BCom DPhil CMA Professor, Department of Public Health Sciences Faculty of Medicine and Oral Health Sciences University of Alberta Edmonton, Alberta Kenneth Marshall, BA MSC MD FRCPC FCFP Professor of Family Medicine (Retired) University of Western Ontario London, Ontario External Reviewers Neil Campbell, MA MD MB BChir Department of General Practice and Primary Care University of Aberdeen Aberdeen, United Kingdom Ilka Lowensteyn, PhD Medical Scientist The Montreal General Hospital Research Institute McGill University Montreal, Quebec Louise Morrin, BSc PT Senior Physiotherapist Prevention & Rehabilitation Centre University of Ottawa Heart Institute Ottawa, Ontario Neil B. Oldridge, PhD Center for Aging Research School of Allied Health Sciences Regenstrief Institute for Health Care Indianapolis, Indiana This report is a review of existing public literature, studies, materials and other information and documentation (collectively the source documentation ) which are available to CCOHTA. The accuracy of the contents of the source documentation on which this report is based is not warranted, assured or represented in any way by CCOHTA and CCOHTA does not assume responsibility for the quality, propriety, inaccuracies, or the reasonableness of any statements, information or conclusions contained in the source documentation. CCOHTA takes sole responsibility for the final form and content. The statements and conclusions in this report are those of CCOHTA and not of its Panel members or reviewers. Authorship All authors participated in planning the project, made comments on the sections drafted by the other authors and contributed to the responses to reviewer comments. Allan Brown was the overall project lead and as such was involved in all aspects of the project. In particular, he was lead author on the economics sections and wrote the executive summary. i

5 Rod Taylor was lead author on the clinical effectiveness sections for analysis and writing. Hussein Noorani was second reviewer for the clinical and economic reviews. He was also lead author for the introduction. James Stone acted as clinical content expert. He also was lead author on the health sector impact sections and wrote part of the introduction. Becky Skidmore was responsible for the design and execution of the literature search strategies, for writing the methods section and associated appendix on literature searching and for verifying and formatting bibliographic references. Acknowledgements The authors would like to thank Mrs. Anne Dickie (Administrative Assistant to Dr. James Stone at Foothills Hospital, Calgary Alberta), for invaluable assistance with this review, as well as Dr. Karen Rees and Mrs. Judy Joliffe, co-authors of the previous Cochrane review. Conflict of Interest No conflicts were disclosed by Allan Brown, Hussein Noorani and Becky Skidmore. Rod Taylor has written a number of papers on cardiac rehabilitation and was involved in the development and writing of the 2002 Scottish Intercollegiate Network Guidelines for Cardiac Rehabilitation. He is former Chair of the British Association of Cardiac Rehabilitation Scientific Programme Committee and sits on the steering group for two UK based cardiac rehabilitation trials. Jim Stone is the Chairman and Editor-in-Chief of the Canadian Association of Cardiac Rehabilitation (CACR) Guidelines for Cardiac Rehabilitation and Cardiovascular Disease Prevention. He is currently President of the CACR and is a member of the Steering Committee - Ontario Ministry of Health and Long-term Care Pilot Project in cardiac rehabilitation, managed by the Cardiac Care Network of Ontario. ii

6 REPORT IN BRIEF March 2003 Exercise-Based Cardiac Rehabilitation Programs for Coronary Artery Disease: A Systematic Clinical and Economic Review Technology Name Exercise-based cardiac rehabilitation programs for patients with coronary artery disease Disease/Condition Cardiovascular disease is the leading cause of death in Canada; over 50% of all cardiovascular deaths are due to coronary artery disease. Cardiovascular disease also accounts for billions of dollars spent in Canada s health care system annually and billions of dollars in lost productivity. Technology Description Cardiac rehabilitation (CR) programs are used to enhance recovery and to prevent future cardiac events in patients with coronary artery disease. CR programs are either based on exercise-only interventions, or can consist of a comprehensive care approach that includes psychological interventions and education in managing risk factors, in addition to training in physical exercise. The Issue CR programs vary widely; however, virtually all CR programs in Canada offer a component dedicated to physical exercise. Only about 10% of eligible patients actually enrol in CR programs. A previous systematic review of clinical evidence (by the Cochrane Collaboration) reporting on these programs covered the period up to Several new trials have occurred since then. In addition, previous systematic reviews did not include economic evidence. Assessment Objectives This report assesses the clinical- and costeffectiveness of CR programs and the potential policy and research implications for the health sector. Methodology Randomized controlled trials of CR programs with an exercise component were systematically reviewed in two groups: comprehensive care or exercise-only. The study population was men and women of all ages, with documented coronary artery disease, in hospital and community-based settings. The main outcome measures were total mortality and cardiac mortality. Forty-six clinical trials were analyzed in the clinical meta-analysis. Economic studies using the same population and interventions were also systematically reviewed; three full economic evaluations and three cost studies. Comprehensive searches of the literature and consultations with clinical experts were used to review the potential impact of CR programs on health policy. Conclusions CR programs that include exercise, both exercise-only and comprehensive care programs, have beneficial effects on cardiac mortality. However, with respect to total mortality, exercise-only programs show a statistically significant reduction, whereas the comprehensive care programs showed a trend in that direction. The literature reports that these programs are cost-effective and may reduce costs to the health care system, particularly when patients fully participate in maintaining the required level of exercise over the long term. This summary is based on a comprehensive health technology assessment report available from CCOHTA s web site ( Brown A, Taylor R, Noorani H, Stone J, Skidmore B. Exercise-based cardiac rehabilitation programs for coronary artery disease: a systematic clinical and economic review. Canadian Coordinating Office For Health Technology Assessment (CCOHTA) Carling Avenue, Ottawa, Ontario, Canada K1S 5S8 Tel: Fax: CCOHTA is an independent, non-profit health research agency funded by the federal, provincial and territorial governments. iii

7 EXECUTIVE SUMMARY The Issue Coronary artery disease (CAD) imposes a large burden on health and health care resources in industrialized countries. Cardiac rehabilitation (CR) with an exercise component is often offered to patients with CAD. Exercise-based CR can be delivered either as an exercise-only program (EX CR) or as part of a comprehensive CR program (CCR). CCR involves exercise in combination with other secondary measures such as CAD risk factor management, patient education and psychosocial interventions. Objectives The general objective was to systematically review the evidence for CR with an exercise component for secondary prevention of CAD in terms of its clinical effectiveness and its costeffectiveness. An additional objective was to discuss the impact of the evidence on the possible future direction and development of CR services for the secondary prevention of CAD for patients receiving care in the Canadian health care system. Methods The clinical effectiveness review was based on an update of the Cochrane systematic review of the effectiveness of CR with an exercise component, which covered literature to Dec 31, Where possible, the same methods as the Cochrane review were followed. Reviewed studies were randomized controlled trials (RCTs) of CR with an exercise component (either EX CR or CCR) versus usual care, with a follow-up period of six months or more post-randomization. The study population was men and women of all ages, in both hospital and community-based settings, who had documented CAD: i.e. had a myocardial infarction (MI), had undergone coronary artery bypass graft surgery, had undergone percutaneous transluminal coronary angioplasty or who had angina pectoris due to CAD defined by angiography. Trials of heart failure patients were excluded from the review. The quality of the trials was assessed using a modified Jadad scale. A quantitative meta-analysis was carried out using Stata v.6 software. Stratified and meta-regression analyses were undertaken to relate the magnitude of intervention effect to patient and intervention characteristics. For the review of economic evidence, the inclusion/exclusion criteria for the studies was the same as that for the clinical review, with one exception: both RCT and non-rct based studies were included. There was substantial heterogeneity amongst the included studies in terms of study design and patient characteristics. As a result, the study results could not be effectively pooled quantitatively. For the review of health sector impact, there was a comprehensive search of the literature, as well as consultation with clinical experts. Results The clinical literature search resulted in over 1,000 potentially relevant studies. Of these, 99 abstracts appeared to meet the review inclusion criteria and were retrieved for full text iv

8 assessment. From these 99 articles, 5 new EX CR trials and 5 new CCR trials were included in our review. The 10 new trials are more recent than those included in the Cochrane review, which included 36 trials. That brings the total number of trials analysed in our meta-analysis to 46. The clinical meta-analysis found that CCR showed a trend toward reduction in total mortality although this was not statistically significant (RR 0.87, 95% CI 0.74 to 1.02). However, cardiac mortality was reduced (RR 0.80, 95% CI 0.65 to 0.99). EX CR reduced total mortality (RR 0.76, 95% CI 0.59 to 0.98) and reduced cardiac mortality (RR 0.73, 95% CI 0.56 to 0.96). Health related quality of life (HRQoL) outcomes were not pooled, but there was evidence of a consistent improvement in HRQoL across the nine trials reporting this outcome, although few studies showed improvement above that measured in the usual care groups. Meta-regression analysis failed to demonstrate the presence of any significant sub-group effects. Sub-groups analysed included: EX CR or CCR, duration of program, intensity of program, follow-up period, all post MI or other than just MI patients, gender, age, trials pre- or post-1995 and quality of trials. In the review of economic evidence, 614 potentially relevant studies were found. Of these, 64 were retrieved for full text assessment, and 6 were ultimately included in the review. Three were full economic evaluations, and 3 were cost studies. Only 1 included study was RCT-based. It was an economic evaluation located in Canada, and concluded that an eight-week supervised exercise plus counselling program cost US$9,200 per QALY and US$21,800 per life-year gained during the year of follow-up. Another Canadian-based economic evaluation found that it costs less than US$15,000 per year of life saved for a supervised CR program for men. A US study found that it cost US$4,950 per year of life saved through CR. The cost studies, based in Sweden and the US, concluded that CR may be cost saving compared to standard care for patients with CAD, due to lower rehospitalization rates and lower mean patient costs. Conclusions The systematic review of clinical evidence supports the findings of the previous Cochrane review in that CR which includes exercise has beneficial effects on cardiac mortality and total mortality (although the trend for CCR on total mortality was not significant). It appears that CCR has a somewhat more positive effect overall on risk factors than EX CR. Few studies have examined the impact of CR on HRQoL, and in those that have there was a non-significant trend that CR which includes exercise enhances quality of life relative to usual care. Although recent trials have increasingly recruited patients who have had revascularization or angina, the representation of women and the elderly in the trials remains poor. The long-term (i.e. 10 years or more) mortality benefit of CR tends to diminish. This may be associated with a reduction in exercise behaviour. The results of the included economic studies were consistent in that the three full economic evaluations all suggested CR which includes exercise is cost-effective, and the three cost studies all suggested CR which includes exercise may reduce costs to health care systems due to reduced rehospitalization and drug utilization. Although the cost studies suggest that over time cost savings would result from switching to CR from standard care, in the short term there would likely be a significant budget impact. For example, at an average cost of C$1,000 per patient, making supervised cardiac rehabilitation standard practice for Canadian CAD patients could increase short run annual expenditures in Canada by C$225 million. v

9 CCOHTA s analysis of health sector impact found that Canadian CR programs which include exercise may be under-subscribed in the sense that only about 10% of eligible patients attend formal CR programs. As of the year 2002, about 25,000 patients were enrolled in formal CR programs. The need for CR services in Canada was estimated at 250,000 places for the year Uptake of CR in Canada requires improvement. vi

10 TABLE OF CONTENTS EXECUTIVE SUMMARY... iv ABBREVIATIONS...ix 1 INTRODUCTION General Background on Cardiac Rehabilitation Cardiac Rehabilitation Programs in Canada Current Levels of Resource Utilization for Cardiac Rehabilitation Programs in Canada The Availability and Distribution of Programs Across Canada OBJECTIVES CLINICAL EFFECTIVENESS REVIEW Methods Literature search strategy Eligibility Data extraction Quality assessment Data synthesis Results Selection of trials Study characteristics and quality Clinical events Modifiable primary CAD risk factors Health related quality of life Long-term follow-up Subgroup analyses REVIEW OF ECONOMIC EVIDENCE Methods Literature search strategy Eligibility criteria Data extraction Analysis Results Selection of studies Study selection and data extraction results...18 vii

11 5 DISCUSSION Clinical Effectiveness Review Economics Review POLICY AND RESEARCH IMPLICATIONS Comparing Users of CR Programs with those who could be Eligible Health Sector Impact Implications for Policy Makers Implications for Future Research CANADIAN CR RESEARCH A SELECTION OF PROJECTS CONCLUSIONS REFERENCES...35 Appendix 1: Literature Search Strategy...44 Appendix 2: Trials Currently Available Only in Abstract Form...50 Appendix 3: Clinical Review Inclusion/Exclusion Form...51 Appendix 4: Clinical Review Data Extraction and Quality Assessment Form...52 Appendix 5: Detailed QUOROM Flow Diagram of Selection of Additional Trials...57 Appendix 6: Summary of Studies that Compared Effects of EX CR with Usual Care...58 Appendix 7: Summary of Studies that Compared Effects of CCR with Usual Care...61 Appendix 8: Summary of Results of Health Related Quality of Life (HRQoL) Studies...65 Appendix 9: Trials Underway - Results Pending...67 Appendix 10: Economic Review Inclusion/Exclusion Form...69 Appendix 11: Data Extraction Form for Full Economic Studies...70 Appendix 12: Data Extraction Form for Cost Studies...71 viii

12 ABBREVIATIONS ACS ARIN C CABG CACR CAD CCN CCNO CCR CEA CHD CI CR CUA CVD EQ-5D EX CR HEED HRQoL HTA ICER IHD LYG MI NEHDP NHP NNT PTCA QALY QLMI QUOROM RCT RR SF-36 US Acute coronary syndrome Angioplasty risk intervention Canadian Coronary artery bypass graft Canadian Association of Cardiac Rehabilitation Coronary artery disease Cardiac Care Network Cardiac Care Network of Ontario Comprehensive cardiac rehabilitation Cost-effectiveness analysis Coronary heart disease Confidence interval Cardiac rehabilitation Cost-utility analysis Cardiovascular disease EuroQol 5D (a HRQoL measure developed in Europe) Exercise training interventions, i.e. exercise-only cardiac rehabilitation Health economic evaluations database Health related quality of life Health technology assessment Incremental cost-effectiveness ratio Ischemic heart disease Life-years gained Myocardial infarction National exercise and heart disease project Nottingham health profile Number needed to treat Percutaneous transluminal coronary angioplasty Quality adjusted life-years Quality of life post-myocardial infarction Quality of reporting of meta-analyses Randomized controlled trial Relative risk Short-form 36 (a HRQoL measure) United States ix

13 1 INTRODUCTION 1.1 General Background on Cardiac Rehabilitation Cardiovascular disease is the leading cause of death in Canada accounting for close to 80,000 Canadian deaths in ,2 Cardiovascular disease is also the leading cause of hospitalization for both men and women (excluding childbirth). Over 50% of all cardiovascular deaths are due to coronary artery disease (CAD). 2 CAD accounted for a total cost of C$ 7.8 billion in Canada in Cardiac rehabilitation (CR) programs have been promoted as a way to enhance recovery following acute cardiac events and encourage behaviour aimed at the secondary prevention of CAD. The Canadian Association of Cardiac Rehabilitation (CACR) has defined CR as the enhancement and maintenance of cardiovascular health through individualized programs designed to optimize physical, psychological, social, vocational and emotional status. This process includes the facilitation and delivery of secondary prevention through heart hazard (i.e. risk factor) identification and modification in an effort to prevent disease progression and the recurrence of cardiac events. 3 The term heart hazards, rather than the more generally recognized term risk factors, was used in this definition to reflect the direct causal relationship between diabetes, hypertension, dyslipidemias, tobacco abuse, physical inactivity and so on in the initiation and proliferation of vascular disease. 3,4 Hereafter, we will use risk factor in this context. CR is a complex intervention that often consists of three elements. First, CR can involve education and risk factor management. This can include providing the patient with information on the pathology of cardiac disease, the mechanism of drug action, resumption of physical and sexual activity, vocational advice, dietary advice, smoking cessation and other lifestyle changes. Second, there may be psychological interventions such as stress management through relaxation therapy and counselling techniques and the management of depression. Thirdly, rehabilitation includes exercise training. 5 The relative emphasis that different individual cardiac rehabilitation programs place on each of these three elements can vary widely and current guidelines advocate that programs should be individualized i.e. allocation and focus of interventions should be made on the basis of individual need. 5 Nevertheless, it is widely agreed that exercise training should form the basis of CR provision and it is therefore the focus of this systematic review. Reviews of the effectiveness of education-based and psychological-only interventions have been published elsewhere. 6,7 The subject for our review is exercise-based CR (i.e. CR programs with an exercise component). The actual components of CR programs vary across Canada depending on available local resources. Currently, CR programs usually combine exercise therapy with patient teaching and the encouragement and facilitation of behaviours aimed at the secondary prevention of CAD. The following list contains the usual elements of Canadian CR programs and is consistent with the current CACR guidelines. 3 1

14 1. Mechanism for outpatient referral 2. Intake assessment clinic 3. Clinical risk stratification a. Risk factor identification b. Exercise stress testing 4. Individualized exercise training programs a. Aerobic b. Resistance training c. Alternative techniques i. Yoga ii. Tai Chi 8 5. Patient education programs 6. Lifestyle modification and management programs a. Heart healthy lifestyles b. Vocational counselling 7. Behavioural counselling a. Identification and management of depression b. Stress identification and reduction 8. Patient follow-up a. Risk factor evaluation b. Repeat exercise testing 9. Outcomes assessment programs 10. Continuous quality improvement programs 11. Staff and professional development/education programs CR is not a new therapy. However, its uptake has not been consistent. 4 The reasons for this variation in utilization are varied and complex However, one of the strongest predictors of attendance in CR programs is referral and endorsement of the program by the patients physicians and caregivers. 11,13 Previous systematic reviews of the effectiveness of exercise-based rehabilitation for cardiac patients have distinguished between two types of exercise rehabilitation - exercise-only rehabilitation (EX CR) and exercise in conjunction with psychological (such as stress management) and educational (such as risk factor management) interventions, usually termed comprehensive cardiac rehabilitation (CCR). 3,4 A number of systematic reviews and metaanalyses of randomized controlled trials (RCTs) of exercise-based rehabilitation have shown reductions in mortality and improvements in both morbidity and CAD risk factor profile compared to usual medical care The most recent meta-analysis involved 8,440 CAD patients (with previous MI, revascularization or angina) in 36 trials. It was published in the Cochrane Library in 2001 and covered literature to Dec. 31, It found that exercise-only CR reduced all-cause mortality by 27% and cardiac death by 31%. 17 Similarly CCR reduced all-cause mortality, but to a lesser degree (13%), and reduced cardiac death by 26% compared to usual care. 17 A number of other systematic reviews of CR have also endorsed its benefits. 6,7 In addition, case-control studies have suggested a positive benefit of CR programs on cardiac risk factors. 18 2

15 A number of concerns, however, have been raised regarding the applicability of the metaanalyses and systematic reviews available to date. The trials included have been small and often of poor methodological quality. 7 Many of these trials were conducted before implementation of current medical therapies, including thrombolysis. There has been insufficient evidence to conclude if EX CR or CCR have equivalent effectiveness. Perhaps the main limitation has been the fact that the majority of trials have been conducted in low risk male post-mi patients, despite cardiovascular disease being the major cause of death and disability in women. 1 Finally, no systematic analysis of cost-effectiveness studies has been undertaken within these secondary reviews. This review will attempt to address many of these issues. In particular, our review covers an additional three years of trials since the Cochrane review. 1.2 Cardiac Rehabilitation Programs in Canada Like many countries, the availability and utilization of CR programs in Canada varies widely, not only province to province, but also from region to region. CR programs also differ in both the duration and type of patient care services they offer. Program length may vary from several weeks to a full year. Virtually all CR programs in Canada offer an exercise component and most offer additional programs such as patient education. Some programs offer fully integrated patient care services designed to improve therapeutic compliance and attainment of risk factor treatment targets. 4 The Canadian Guidelines on Cardiac Rehabilitation and Cardiovascular Disease Prevention 3 stress the need for individual patient assessments, careful risk stratification to determine each patient s clinical needs and the critical importance of targeted secondary prevention in reducing the recurrence of cardiac events. The term targeted secondary prevention refers to the use of, and adherence to, risk-factor treatment targets validated by RCTs. 4 In this manner, patients would have their blood pressure, serum lipids, blood sugar, physical activity levels etc. treated in an attempt to attain pre-specified levels that have been proven to reduce subsequent cardiac events. This emphasis on treating patients to achieve targeted parameters has important health care and economic implications. If patients in usual practice are expected to derive the same morbidity and mortality benefits from risk-factor modification as those benefits demonstrated in RCTs, then patients in usual practice must be treated to the same risk-factor target levels (for lipids, blood pressure etc.) as those attained in clinical trials. Unfortunately, there have been problems in achieving effectiveness levels, and the ability to achieve these levels of treatment in usual practice is the exception, rather than the rule. 19,20 3

16 1.3 Current Levels of Resource Utilization for Cardiac Rehabilitation Programs in Canada As of December 2002, it is estimated that there are over 25,000 patients in Canada enrolled in more than 120 formal CR programs (Marilyn Thomas, Canadian Association of Cardiac Rehabilitation, Winnipeg: personal communication, 2002 Dec). This represents approximately 10% of the overall cardiac population based on data from Health Canada. 21,22 The programs are situated all across Canada with the majority in Ontario and Quebec, as would be expected from population demographics. Most programs in Canada are currently running at or near capacity and they have waiting lists for program admission that vary from weeks to months. Although there is heterogeneity, the majority of programs still adhere to the standard 12-week format of CR This format includes supervised exercise 3 times per week for 12 weeks or a total of 36 exercise sessions. Patients may also receive education classes and/or supervision and management of risk factors. Recently, programs have begun to experiment with the length of their programs, the number of supervised exercise sessions and the exercise venue. 26,27 For example, the Ontario Ministry of Health and Long-term Care Pilot Project in CR, which is being managed by the Cardiac Care Network of Ontario (CCNO), is based on a six-month program in which patients receive supervised exercise twice per week (Terri Swabey, Cardiac Care Network of Ontario, Toronto: personal communication, 2002 Aug 20). 28 It is important to note that the overall CR program structure found in North America is heavily influenced by remuneration formulae present in the US. Many US third party payers will only reimburse programs for the standard 36-session supervised exercise model and only if the patients are on continuous cardiac telemetry during supervised exercise. US third party payers will often not specifically pay for education programs or additional medical/nursing input. This CR model has been extensively copied and directly impacts the provision of services within Canada. The strong international recognition and widespread utilization of the 36-exercise session, 12-week model has made it very difficult for programs in Canada to experiment with other potentially more cost-effective models of CR. 3, The Availability and Distribution of Programs Across Canada The CACR has CR programs registered in all 10 provinces. Larger urban centres frequently have more than one program. Many programs have waiting lists to admit patients. Programs usually function in outpatient clinics but these clinics are most frequently located within the physical plant of acute care institutions. The Ontario Pilot Project has used a hub and spoke model of regional coordinating centres and satellite service delivery centres (Terri Swabey: personal communication, 2002 Aug 20). 28 This model allows smaller CR programs to take advantage of the centralized expertise and resources present within larger CR programs while allowing for the delivery of CR services closer to the patient population. 4

17 2 OBJECTIVES The objectives of this assessment are: (1) to assess the evidence base for the clinical effectiveness of exercise-based cardiac rehabilitation for secondary prevention of CAD through a meta-analysis of RCT evidence; (2) to assess the evidence base for the cost-effectiveness of exercise-based cardiac rehabilitation for secondary prevention of CAD through a systematic review of economic evaluations; and (3) to discuss the impact of this evidence on the possible future direction and development of cardiac rehabilitation services for secondary prevention of CAD in the Canadian health care system. 5

18 3 CLINICAL EFFECTIVENESS REVIEW This section of the report updates the Cochrane systematic review of the effectiveness of exercise-based CR, which covered literature to the end of Methods Where possible, the methods used in this review followed those of the previous Cochrane review. In some cases, such as searching, we adapted and further developed these methods Literature search strategy Published literature was obtained by searching a number of databases (Appendix 1). On the DIALOG system, MEDLINE, EMBASE, HealthSTAR, Allied and Complementary Medicine, Manual, Alternative and Natural Therapy (MANTIS ), PASCAL, SciSearch and SPORTDiscus were searched, resulting in 940 unique records. Retrieval covered the publication years 1999 onward with no language restrictions. Database alerts/updates were established on Current Contents Search, EMBASE Alert, MEDLINE, PASCAL, and SciSearch ; the Current Contents Search and SciSearch updates were discontinued August Results from these alerts were considered for inclusion in the review until the end of February CINAHL and PubMed also yielded a large number of records, many of which were duplicates of the original DIALOG search. Searches were performed and updated throughout the duration of the project on the CD ROM version of The Cochrane Library. Grey literature was obtained through searching a number of specialized rehabilitation databases such as those of the National Rehabilitation Information Center and PEDro, as well as the Web sites of health technology assessment and related agencies and their associated databases. Clinical trial registries, including the National Research Register and the metaregister of Controlled Trials, were also searched for information on current or completed trials. The Google search engine was used to search for a variety of Internet materials. Further information was sought by hand searching the bibliographies of selected papers and through contacts with appropriate experts and agencies. Reference Manager (RM), a citation management software, was used to manage the references obtained from all DIALOG databases, CINAHL and PubMed. Relevant references identified in The Cochrane Library and from the various grey literature sources were also incorporated in the RM database. The database was customized to include study objectives and reviewer comments and new report formats were added to allow this information to be exchanged and consolidated electronically. 6

19 3.1.2 Eligibility Studies were included or excluded on the basis of the criteria as described below: a) Study design RCTs of CR with an exercise component (either EX CR or CCR programs) versus usual care with a follow-up period of six months or more post-randomization were sought. * Studies available in abstract form are tabulated in Appendix 2 but were not included in the meta-analysis. There was a lack of the level of detail on patient and intervention characteristics required for quantitative analysis. b) Population The study population was composed of men and women of all ages, in both hospital-based and community-based settings, who had experienced an MI, or undergone a coronary artery bypass graft (CABG) or percutaneous transluminal coronary angioplasty (PTCA), or who had angina pectoris or CAD defined by angiography. Studies predominantly involving participants with heart transplants, heart valve surgery, heart failure, pacemakers and congenital heart disease were excluded. c) Types of intervention CR was defined as an inpatient, outpatient, community or home-based exercise-based intervention that is applied to a cardiac patient. The intervention for the control or comparison group did not involve an exercise-based program. The control group patients received usual care such as drug therapy. d) Outcome measures The outcome measures sought were: i) All-cause mortality ii) Cardiac mortality iii) Non fatal MI iv) Revascularization: CABG, PTCA v) Modifiable primary risk factors: Smoking behaviour, blood pressure and blood lipid levels vi) Health related quality of life (HRQoL) ** * Observational studies have been excluded for the clinical review due to feasibility constraints. We recognize that relevant observational literature might better address drops-outs and other program failures. We note that our approach is consistent with the previous Cochrane review. ** Experience from the previous Cochrane review has shown that trials report a wide range of measures under the label of HRQoL. Our review therefore focuses on recognized/validated measures of HRQoL such as the Short-Form 36 (SF-36) (generic HRQoL) measure and the quality of life post-myocardial infarction (QLMI) (disease-specific HRQoL) measure. 7

20 3.1.3 Data extraction Two reviewers (RT and HN) independently selected trials to be included in this review. Disagreements about any study inclusions were resolved by consensus among the authors. Two reviewers (RT and HN) independently extracted the data once the trials were formally included in the review. The inclusion/exclusion and data extraction forms used are shown in Appendices 3 and Quality assessment The quality of trials was assessed independently by RT and HN in terms of the method of randomization, adequacy of allocation concealment, proportion of patients lost to follow-up and blinding of outcome assessment. The trials were scored using a modified Jadad scale the higher the Jadad score, the higher the quality (possible range 0 to 5). 30 Quality assessment was included as part of the data extraction process. (See Appendix 4) Data synthesis Dichotomous outcomes for each trial have been expressed as relative risks (RR) and 95% confidence intervals (CI). Continuous variables have been expressed as the mean change from baseline to follow-up and the standard deviation difference from baseline to follow-up for each comparison group. Where standard deviation differences have not been reported in the source papers, allowance has been made for within-patient correlation from baseline to follow-up measurements by using the correlation coefficient between the two (see Cochrane Heart Group web site for details and Follmann et al., 1992). 31 A weighted mean difference (WMD) and 95% CI have been calculated for each trial. Data from each trial were pooled as appropriate using a fixed effects model, except where substantial heterogeneity existed according to the χ 2 statistic. In that case a random effects model was used. Stratified and meta-regression analyses were undertaken to relate the magnitude of intervention effect to patient and intervention characteristics. All covariates were stated a priori and all analyses were performed using Stata v.6 software. 3.2 Results The review was divided into two comparisons: 1) Exercise training interventions (EX CR) vs. usual care (i.e. exercise-only vs. usual care). 2) Exercise training combined with psychosocial and/or educational interventions vs. usual care (i.e. comprehensive cardiac rehabilitation (CCR) vs. usual care). This division into EX CR and CCR was made not only because it reflected the methods used in the previous Cochrane review, but also because it represents a potentially important difference in terms of resource consumption. 8

21 3.2.1 Selection of trials Ninety nine primary studies were identified in this update to the evidence. Twelve articles, from ten RCTs, met the selection criteria: five EX CR trials and five CCR trials (Appendix 5, part d) Eighty seven studies did not meet the inclusion criteria for this study. The summary of document selection is displayed in Figure 1 below. Figure 1: Summary of the selection of trials for inclusion Potential articles identified from bibliographic searches n=1,107 Articles awaiting assessment from previous Cochrane review* n=26 Full text articles retrieved for further assessment n=99 Excluded: n=87 non-random allocation n=16 inappropriate patient group n=4 inappropriate control or intervention n=19 inappropriate outcomes n=18 abstract only n=2 both groups received exercise or inadequate follow-up n=28 New articles retained n=12 New articles included for review: Exercise-only n=7 (5 RCTs)** New articles included for review: Comprehensive n=5 (5 RCTs) *These are pre-1999 studies identified in the Cochrane review as reference to studies awaiting assessment. 17 **Seven new exercise-only CR articles were found, which reported on five new exercise-only CR trials. 9

22 A total of 36 RCTs were included in the original Cochrane review 14 EX CR trials and 22 CCR trials. 52,58-78 In addition we found longer follow-up reports of 4 trials originally included in the Cochrane review Two additional CCR trials by Schenck-Gustafsson et al. (2000) 85 and West et al. (2001) 86 were only available in an abstract form and were therefore excluded (See Appendix 2). A number of ongoing trials were identified, the details of which are listed in Appendix 9. Finally, one paper was identified that provided a detailed overview of the protocol of a randomized controlled CCR trial currently under way. 87 The lack of funnel plot asymmetry for total mortality (the most frequent outcome reported across the trials) suggested little evidence of publication bias (see Figure 2). This visual assessment was confirmed by the Egger test (p=0.319). 88 Figure 2: Funnel plot for all trials reporting total mortality 5 Variance 1/SElogOR Log Odds Ratio Study characteristics and quality Details of the study characteristics and quality of the 19 EX CR trials and 27 CCR trials are given in Appendices 6 and 7 respectively. The characteristics of the patients are summarized in Table 1. 10

23 Table 1: Summary of patient characteristics across trials Parameter EX CR trials N=19 trials n=2,984 patients CCR trials N=27 trials n=5,693 patients Mean sample size (range) 157 (37-651) 208 ( ) Mean age (range of means) 54 (50 to 70) yrs 56 (47 to 63) yrs Mean % females (range) 4.9 (0 to 20)% 12.0 (0 to 35) % Number of trials (%) Recruiting only post-mi patients Recruiting only CABG and PTCA patients Recruiting both 14 (74%) 3 (16%) 2 (10%) 16 (62%) 5 (19%) 5 (19%) Mean follow-up months (range) 24 (6-60) 26 (6-72) Median Jadad score (range) 2 (1-5) 2 (1-5) Where EX CR = exercise-only rehabilitation trials; CCR = comprehensive cardiac rehabilitation trials Most trials were of relatively low quality. Of the 46 trials, 17 (37%) provided details of randomization, 9 (20%) provided details of adequate concealment and 9 (20%) reported blinding of outcome assessment. Follow-up of 80% or more was achieved in 30 trials (65%). The overall median Jadad score was 2 [range of 1 (low quality) to 5 (high quality)]. The exercise component of the rehabilitation generally conformed to current guidelines for exercise prescription for individuals with coronary artery disease (CAD) 89 i.e. aerobic exercise at least three times per week, for at least 30 minutes at intensity 60 to 80% of VO 2 max. In CCR trials, a range of education and psychosocial interventions supplemented exercise. The usual arm of trials generally provided conventional or routine medical care. Typically, patients in both the usual care and rehabilitation arms of the trials received pharmacotherapy prescribed and monitored by their own physicians Clinical events The impact of EX CR and CCR on clinical events is summarized in Table 2 below. All-cause mortality Cardiac mortality Non-fatal MI CABG PTCA Table 2: Summary of pooled relative risks (RR) for clinical events EX CR trials CCR trials Outcome Measure Mean (95% CI) Mean (95% CI) 0.76 (0.59 to 0.98) N=12* 0.73 (0.56 to 0.96) N=10* 0.78 (0.59 to 1.03) N=13* 0.87 (0.58 to 1.29) N=11* 0.57 (0.28 to 1.16) N=4* (bolded items are statistically significant at P 0.05) EX CR = exercise-only rehabilitation trials; CCR = comprehensive rehabilitation trials RR < 1.0 favours rehabilitation; N number of trials contributing to pooling *For all outcomes, test of heterogeneity is non-significant and fixed effects meta-analysis model used 0.87 (0.74 to 1.02) N= (0.65 to 0.99) N= (0.85 to 1.35) N= (0.59 to 1.10) N= (0.59 to 1.19) N=8 11

24 EX CR trials significantly reduced both all-cause mortality and total cardiac mortality, compared to usual care. CCR trials reduced cardiac mortality but the reduction in all-cause mortality was statistically non-significant. Neither EX CR nor CCR intervention had a significant effect on the subsequent occurrence of non-fatal MI or the need for revascularization procedures (CABG and PTCA) Modifiable primary CAD risk factors The impact of EX CR and CCR on modifiable risk factors is summarized in the table below. Since some outcomes are reported in few trials, the precision of some of these results is likely to be low. Total cholesterol (mmol/l) HDL cholesterol (mmol/l) LDL cholesterol (mmol/l) Triglycerides (mmol/l) Risk Factor Systolic blood pressure (mmhg) Diastolic blood pressure (mmhg) Table 3: Pooled CHD risk factor results EX CR trials Mean difference (95% CI) CCR trials Mean difference (95% CI) (-0.34 to 0.00)*N= (-0.83 to 0.60)* N= ( to 0.09)* N= (-043 to 0.12)* N=3-0.18(-0.31 to 0.04)* N= (-6.6 to 2.1)* N=4 1.0 (-2.6 to 4.7)* N= (-0.01 to 0.16)* N= (-0.7 to 0.31)* N=2-0.29(-0.44 to 0.14)* N=8-3.5 (-6.1 to 0.9)* N= ( to 0.02)* N=4 Smoking Relative risk (95% CI) Relative risk (95% CI) 0.82 (0.62 to 1.18) N=5* 0.76 (0.58 to 1.00) N=8* (bolded items are statistically significant at P 0.05) EX = exercise-only rehabilitation trials; CCR = comprehensive rehabilitation trials Mean difference < 0 favours rehabilitation; N - number of trials contributing to pooling *Test of heterogeneity is significant and random effects meta-analysis model used There was evidence of a trend for improvement in a number of CAD risk factors with rehabilitation, including reductions in total cholesterol, low-density lipoprotein cholesterol, triglycerides, systolic blood pressure and smoking. However, these benefits only achieved statistical significance when pooled across the CCR trials. Both EX CR and CCR appeared to slightly increase HDL cholesterol in comparison to usual care. 12

25 3.2.5 Health related quality of life A total of nine trials (20%) assessed HRQoL using either validated measures or measures that covered the three fundamental HRQoL domains, i.e. physical, psychological and social well being (Appendix 8). 33,37,38,41,43,52,58,63,66,71 A range of both generic (SF-36, NHP, Karolinska, QWB, TTO) and disease-specific HRQoL measures were used (QLMI). Two trials used HRQoL measures the authors of this report were not familiar with. 33,37,38 Given variation in both HRQoL outcome measures and methods by which their results are reported, data pooling was considered inappropriate for this outcome. The HRQoL results of each of the studies are summarized in detail in Appendix 8. Although most studies reported an improvement in HRQoL domain scores with EX CR and CCR, there were few studies in which this improvement exceeded that observed in the usual care control groups Long-term follow-up We identified three trials that assessed the outcome of patients who had received CR after 10 or more years of follow-up. Bethell and colleagues (1999) reported 11-year follow-up. 82 Hamalainen et al. (1989; 1995) reported 10 and 15-year follow-up of the Kallio trial. 83,84 Finally, Dorn et al. (1999) reported 19-year follow-up of the National Exercise and Heart Disease Project (NEHDP) trial. 80 None of the individual studies observed a significant reduction in total mortality at long-term follow-up, although Hamalanen et al. did report a significant reduction in cardiac deaths and sudden deaths at 10 and 15 years. 83,84 Both Bethell and Dorn noted a fall in the level of exercise over time in the rehabilitation group. 80,82 Conceptually it is expected that for health benefits to be retained over time, patients need to continue to maintain their exercise behaviour, in a manner similar to the absolute requirement to take antihypertensive or lipid modifying medications, for them to actually have long term benefits Subgroup analyses Subgroup analyses were carried out using all trials (i.e. both EX CR and CCR combined) that assessed the outcome of total mortality, since total mortality was the clinical outcome reported in most trials. Details of important subgroups were available for most trials. The subgroups analyzed were: (1) EX CR versus CCR (2) Program duration less than 12 weeks versus program duration greater than or equal to 12 weeks (3) Dose less than 1,000 units versus dose greater than or equal to1,000 units (where dose is defined as total duration of rehabilitation in weeks, times the frequency of exercise sessions per week, times the duration of each session in minutes) (4) Follow-up of less than 30 weeks versus follow-up of greater than or equal to 30 weeks (5) Rehabilitation starts earlier than six months post-event versus rehabilitation starts later than or equal to six months post-event (6) All patients post-mi versus patients post-mi or other (7) Patients all male versus male and female patients (8) Patients less than 60 years of age versus patients greater than or equal to 60 years (9) Studies published after 1995 versus studies published in 1995 or earlier 13

26 (10) Studies assigned a Jadad quality assessment score less than three versus studies with a Jadad score greater than or equal to three Although stratified analyses indicated that the effect size appeared to vary with the total amount of intervention and with various patient characteristics, none of these within-stratum comparisons found statistically significant differences, in the sense that all of the 95% confidence intervals overlapped in the pair-wise comparisons (see Figure 3). These findings were confirmed by univariate and multivariate meta-regression analyses. Figure 3: Stratified (Sub-group) analysis for the outcome total mortality Exercise l Comprehensive Duration<12wks Duration>=12wks Dose<1000units Dose>=1000units Follow-up<30wks Follow-up>=30wks <6mths post event >=6mths post event All postmi MI & other grps all male male & female age<60yrs age>=60 yrs Post & pre Jadad<3 Jadad>= Relative Risk Dose = (total duration of rehab in weeks) x (frequency of exercise sessions per week) x (duration of each session in minutes) For example, 12 weeks program with 3 sessions/week of 30 minutes = 1,080 dose units. 14