Exercise-Based Cardiac Rehabilitation for Coronary Heart Disease

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 67, NO. 1, 2016

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2015.10.044

ORIGINAL INVESTIGATIONS

Exercise-Based Cardiac Rehabilitation for Coronary Heart Disease Cochrane Systematic Review and Meta-Analysis Lindsey Anderson, PHD,* Neil Oldridge, PHD,y David R. Thompson, PHD,z Ann-Dorthe Zwisler, MD,x Karen Rees, PHD,k Nicole Martin, MA,{ Rod S. Taylor, PHD*

ABSTRACT BACKGROUND Although recommended in guidelines for the management of coronary heart disease (CHD), concerns have been raised about the applicability of evidence from existing meta-analyses of exercise-based cardiac rehabilitation (CR). OBJECTIVES The goal of this study is to update the Cochrane systematic review and meta-analysis of exercise-based CR for CHD. METHODS The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, and Science Citation Index Expanded were searched to July 2014. Retrieved papers, systematic reviews, and trial registries were hand-searched. We included randomized controlled trials with at least 6 months of follow-up, comparing CR to no-exercise controls following myocardial infarction or revascularization, or with a diagnosis of angina pectoris or CHD defined by angiography. Two authors screened titles for inclusion, extracted data, and assessed risk of bias. Studies were pooled using random effects meta-analysis, and stratified analyses were undertaken to examine potential treatment effect modifiers. RESULTS A total of 63 studies with 14,486 participants with median follow-up of 12 months were included. Overall, CR led to a reduction in cardiovascular mortality (relative risk: 0.74; 95% confidence interval: 0.64 to 0.86) and the risk of hospital admissions (relative risk: 0.82; 95% confidence interval: 0.70 to 0.96). There was no significant effect on total mortality, myocardial infarction, or revascularization. The majority of studies (14 of 20) showed higher levels of healthrelated quality of life in 1 or more domains following exercise-based CR compared with control subjects. CONCLUSIONS This study confirms that exercise-based CR reduces cardiovascular mortality and provides important data showing reductions in hospital admissions and improvements in quality of life. These benefits appear to be consistent across patients and intervention types and were independent of study quality, setting, and publication date. (J Am Coll Cardiol 2016;67:1–12) © 2016 by the American College of Cardiology Foundation.

From the *Institute of Health Research, University of Exeter Medical School, Exeter, United Kingdom; yCollege of Health Sciences, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin; zCentre for the Heart and Mind, Australian Catholic University, Listen to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.

Melbourne, Australia; xNational Centre of Rehabilitation and Palliation, University Hospital Odense, and University of Southern Denmark, Odense, Denmark; kDivision of Health Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom; and the {Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom. Dr. Anderson is funded by the University of Exeter Medical School. Prof. Taylor is partly funded by the U.K. National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South West Peninsula at the Royal Devon and Exeter NHS Foundation Trust; and is currently the cochief investigator of a research program with the overarching aims of developing and evaluating a home-based cardiac rehabilitation intervention for people with heart failure and their careers (PGfAR RP-PG-0611-12004). Dr. Rees is supported by the NIHR Collaboration for Leadership in Applied Health Research and Care West Midlands at University Hospitals Birmingham NHS Foundation Trust. Dr. Zwisler is principal investigator of an included (DAHREHAB) and ongoing cardiac rehabilitation trials (CopenHeart trials). Prof. Taylor, Drs. Rees and

2

Anderson et al.

JACC VOL. 67, NO. 1, 2016 JANUARY 5/12, 2016:1–12

Exercise for Coronary Heart Disease: Systematic Review

ABBREVIATIONS AND ACRONYMS CABG = coronary artery bypass graft

CHD = coronary heart disease CI = confidence interval

explore whether effects vary with patient case mix, the

atic

nature of CR programs, and study characteristics.

coronary

heart

disease

(CHD), the effectiveness and accessibility of health services for people with CHD have never been more important. Cardiac rehabilgral to comprehensive care of CHD patients

CV = cardiovascular

and have been given a Class I recommenda-

HRQL = health-related quality of life

tion from the American Heart Association, the American College of Cardiology, and the

MI = myocardial infarction

European Society of Cardiology, with exer-

PCI = percutaneous coronary intervention

RCT = randomized controlled trial

(HRQL), and cost-effectiveness. We also sought to

ple living longer with symptom-

itation (CR) programs are recognized as inte-

CR = cardiac rehabilitation

RR = relative risk

W

ith increasing numbers of peo-

cise therapy consistently identified as a

METHODS We conducted and reported this systematic review in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement (13) and the Cochrane Handbook for Interventional Reviews (14). The protocol was published on the Cochrane Database of Systematic Reviews (2001) (15).

central element (1–4). Although exercise

DATA SEARCHES AND SOURCES. Search terms from

training remains a cornerstone intervention,

the 2011 Cochrane review (9) were updated and

international guidelines consistently recom-

CENTRAL (Cochrane Central Register of Controlled

mend the provision of comprehensive reha-

Trials), DARE (Database of Abstracts of Reviews of

bilitation that includes education and psychological

Effects),

input focusing on health and life-style behavior

MEDLINE and Medline in Process (Ovid), EMBASE

HTA

(Health

Technology

Assessment),

change, risk factor modification, and psychosocial

(Ovid), and CINAHL (Cumulative Index to Nursing and

well-being (1–3).

Allied Health Literature) Plus (EBSCO) were searched to July 2014. Conference proceedings were searched SEE PAGE 13

on the Web of Science Core Collection (Thomson

The first systematic reviews and meta-analyses of

Reuters) (1970 to June 2014), and bibliographies of

exercise-based CR by Oldridge et al. (5) and O’Connor

systematic reviews and trial registers (the World

et al. (6) were published more than 20 years ago,

Health Organization [WHO]’s International Clinical

showing a 20% to 25% reduction in all-cause and car-

Trials Registry Platform [ICTRP] and Clinicaltrials.gov)

diovascular (CV) mortality on the basis of data from 22

were hand-searched. No language or other limitations

randomized controlled trials (RCTs) in over 4,300 pa-

were imposed (see Online Appendix).

tients. Although there have been more recent updates

STUDY

to these meta-analyses (7–9), concerns have been

were sought that compared exercise-based CR with a

SELECTION. Randomized controlled trials

raised about the applicability of their results to policy

control and had a follow-up period of at least 6 months.

planning and the provision of CR services (10,11). It has

Exercise-based CR was defined as a supervised or un-

been argued that major advances in CHD medical

supervised inpatient, outpatient, community-based,

management may have led to a reduction in the in-

or home-based intervention that included some form

cremental effect on mortality of exercise-based CR

of exercise training, either alone or in addition to

compared with usual care alone. Other concerns have

psychosocial and/or educational interventions. The

included the inclusion of small, poor-quality RCTs,

comparator could include standard medical care and

which may have resulted in overestimation of the

psychosocial and/or educational interventions, but

benefits of CR, and the almost exclusive recruitment of

not any structured exercise training. We included pa-

low-risk, middle-aged, post-myocardial infarction

tients irrespective of sex or age who had an MI, had

(MI) men in early trials, thereby reducing the general-

undergone revascularization (coronary artery bypass

izability of their findings to the broader population of

grafting [CABG] or percutaneous coronary interven-

CHD patients (12). Our aim was to systematically up-

tion [PCI]), or who have angina pectoris or CHD defined

date existing meta-analyses to reassess the effects of

by angiography. Finally, studies needed to report 1 or

exercise-based CR in patients with CHD in terms of

more of the following outcomes: total or CV mortality;

mortality, morbidity, health-related quality of life

fatal or nonfatal MI; revascularizations (CABG or PCI);

Oldridge, and Prof. Thompson were authors of the original Cochrane review; and Prof. Taylor and Drs. Rees and Zwisler are authors on a number of other Cochrane cardiac rehabilitation reviews. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health in England. Ms. Martin has reported that she has no relationships relevant to the contents of this paper to disclose. Manuscript received July 14, 2015; revised manuscript received October 12, 2015, accepted October 14, 2015.

Anderson et al.

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Exercise for Coronary Heart Disease: Systematic Review

F I G U R E 1 Summary of Study Selection Process

RCTs included from 2011 Cochrane review N = 47 (N = 81 publications)

Titles identified from electronic bibliographies & screened for retrieval N = 11,028

Excluded N = 10,937

Potentially appropriate full-text publications retrieved for full evaluation N = 91 Excluded 2 ongoing studies 3 studies awaiting classification 65 excluded follow-up < 6 months N = 11; inappropriate comparator N=12; inappropriate outcomes N=16; inappropriate randomization N=15; inappropriate intervention N=7; inappropriate population N=2; population had previously received CR N=2

RCTs from updated search N = 16 (N = 21 publications)

Total RCTs included in review N = 63 (N = 102 Publications)

The 63 studies in this review included 47 studies (81 publications) from the 2011 version of the review, and a further 16 studies (21 publications) identified from the updated searches. RCT ¼ randomized controlled trial.

hospitalizations; HRQL, assessed using validated in-

software (16) was used to assess the overall quality of

struments; or costs and cost-effectiveness. Two re-

evidence for each outcome collected (17) (see the

viewers (L.A. and R.S.T.) independently assessed all

Online Appendix for full details).

identified titles/abstracts for possible inclusion, with

DATA

any disagreements resolved by discussion. Where

outcomes were expressed as relative risks (RRs) with

necessary, studies were translated into English.

95% confidence intervals (CIs). HRQL scores were

DATA

MANAGEMENT. One

expressed as mean differences. Heterogeneity among

reviewer (L.A.) extracted study and patient charac-

included studies was explored qualitatively and

teristics, intervention and comparator details, and

quantitatively (using the chi-square test of hetero-

outcome data from included studies using a stan-

geneity and I 2 statistic). Data from each study

dardized data collection form. A second author

were pooled using a conservative random effects

(R.S.T.) checked for accuracy, and disagreements

meta-analysis model.

EXTRACTION

AND

SYNTHESIS

AND

ANALYSIS. Dichotomous

were resolved by consensus. Duplicate publications

The meta-analysis of each outcome was stratified

of the same study were assessed for additional data

according to the duration of study follow-up (i.e., 6 to

and authors were contacted, where necessary, to

12 months [short-term]; 13 to 36 months [medium-

provide additional information.

term]; and >36 months [long-term]). Using the

ASSESSMENT OF RISK OF BIAS AND OVERALL

longest follow-up, we stratified meta-analyses to

QUALITY OF EVIDENCE. Risk of bias of included

explore heterogeneity and examine potential treat-

studies was assessed using the Cochrane Collabo-

ment effect modifiers. We tested 9 a priori hypotheses

ration’s core risk of bias items (14) and 3 further

that there may be differences in the effect of exercise-

items deemed relevant to this review. GRADEProfiler

based CR on outcomes at longest follow-up across the

3

4

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Exercise for Coronary Heart Disease: Systematic Review

T A B L E 1 Summary of Trial and Patient Characteristics (63 Included Studies)

Study characteristics

<1,000 U); 4) follow-up period; 5) year of publication; 6) sample size; 7) setting (home- or center-based CR); 8) risk of bias (low risk of bias in <5 of 8 domains);

Publication year

and 9) study location (continent).

1970–1979

2 (3)

1980–1989

12 (19)

The funnel plot and Egger test were used to

1990–1999

20 (32)

examine small-study bias (18). All statistical analyses

2000–2009

21 (33)

were performed using Review Manager 5.3 Software

8 (13)

(19) and STATA version 13.0 (StataCorp, College

2010 onwards Study location

Station, Texas) (20).

Europe

37 (59)

North America

12 (19)

RESULTS

Asia

6 (10)

Australasia

5 (8)

Other

2 (3)

SELECTION AND INCLUSION OF STUDIES. The 2011

Not reported

1 (2)

Cochrane review provided 47 RCTs (81 publications).

45 (71)

Our searches for this update yielded 11,028 titles, of

Single center Sample size Duration of follow-up, months

126 (28–2,304) 12 (6–120)

Population characteristics 18 (29)

Females only Both males and female

1 (2) 3 (5)

Fourteen studies were published before 1999, and

Diagnosis

49 have been published since 2000 (Table 1). The median follow-up was 12 months, with 50 studies

31 (49)

Revascularization only

2 (3)

Angina only

5 (8)

Mixed CHD population

and Online Table 1 for a list of included studies). STUDY, PATIENT, AND INTERVENTION CHARACTERISTICS.

56.0 (49.3–71.0)

Post-myocardial infarction only

Figure 1 for a summary of the study selection process

41 (65)

Not reported Age, yrs

Sixteen new RCTs (21 publications) were included, giving a total of 63 studies (102 publications; see

Sex Males only

which 91 full papers were considered for inclusion.

25 (40)

reporting at least 12 months of follow-up, and 18 reporting follow-up of 36 months or more. The majority of studies were conducted in Europe (37 studies) or North America (12 studies). Although we included

Intervention characteristics

14,486 patients, most studies were small in sample size

Intervention type Exercise-only programs

25* (38)

(median n ¼ 126; range 28 to 2,304), with 2 large

Comprehensive programs

39* (60)

multicenter trials (WHO and RAMIT [Rehabilitation

Duration of intervention, months

6 (1–48)

Dose of intervention

After Myocardial Infarction Trial]) (12,21) contributing a total of 4,177 patients (about 30% of all participants).

Duration

6 months (1–48)

Frequency

1–7 sessions/week

Length

20–90 min/session

Intensity

 50%–85% of maximal heart rate  50%–95% of maximal oxygen uptake (VO2 max)  Borg rating of 11–15

The median age of participants across studies was 56.0 years. Although 42 studies (66%) included women, they accounted for <15% of all patients recruited. Studies published since 2005 were less dominated by post-MI patients, included other CHD diagnoses (such as revascularization and angina), and

Setting Center-based only

33 (52)

were more likely to include older (average mean age

Combination of center- and home-based

13 (21)

61.7 years vs. 56.3 years) and female (20.0% vs. 12.5%)

Home-based only

15 (24)

Not reported

2 (3)

participants. Exercise-based CR programs were typically delivered in a supervised hospital/center-based setting,

Values are number of studies (%) or median (range). Median of study means: *1 study includes both exercise-only and comprehensive cardiac rehabilitation arms. CHD ¼ coronary heart disease.

either exclusively or in combination with some maintenance home exercise sessions. Fifteen studies were conducted in an exclusively home-based setting (22–36). Whereas the primary mode of exercise

following subgroups: 1) CHD case mix (MI-only trials

training across all studies was aerobic, the overall or

vs. other trials); 2) type of CR (exercise-only CR vs.

average duration, frequency, and intensity of ses-

comprehensive CR); 3) dose of exercise intervention

sions varied considerably across studies. A total of 24

(dose ¼ number of weeks of exercise training 

studies

average number of sessions/week  average duration

comprehensive CR, and 1 trial included both exercise-

of session in minutes) (dose $1,000 U vs. dose

only and comprehensive CR arms (37).

were

exercise-only

programs,

38

were

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Exercise for Coronary Heart Disease: Systematic Review

T A B L E 2 Summary of Meta-Analysis Effects of Exercise-Based CR on Clinical Event Outcomes

Number of Events/ Participants

Statistical Heterogeneity I2 Statistic Chi-Square Test (p Value)

Number of Participants (Number of Studies)

Intervention

Comparator

RR (95% CI)

12,455 (47)

838/6,424

865/6,031

0.96 (0.88–1.04)

Follow-up 6–12 months

8,800 (29)

226/4,573

238/4,227

0.88 (0.73–1.05)

0% (0.82)

Follow-up >12–36 months

6,823 (13)

338/3,495

417/3,328

0.89 (0.78–1.01)

0% (0.47)

3,828 (11)

476/1,902

493/1,926

0.91 (0.75–1.10)

35% (0.12)

7,469 (27)

292/3,850

375/3,619

0.74 (0.64–0.86)

0% (0.70) 0% (0.72)

Outcome

All-cause mortality (all studies)

Follow-up longer than 3 yrs CV mortality (all studies)

0% (0.58)

Follow-up 6–12 months

4,884 (15)

105/2,561

107/2,323

0.90 (0.69–1.17)

Follow-up >12–36 months

3,833 (7)

199/1,971

239/1,862

0.77 (0.63–0.93)

5% (0.38)

Follow-up longer than 3 yrs

1,392 (8)

56/690

100/702

0.58 (0.43–0.78)

0% (0.91)

9,717 (36)

356/4,951

387/4,766

0.90 (0.79–1.04)

0% (0.48)

Fatal and/or nonfatal MI (all studies) Follow-up 6–12 months

6,911 (20)

126/3,543

139/3,368

0.85 (0.67–1.08)

0% (0.58)

Follow-up >12–36 months

5,644 (11)

251/2,877

222/2,767

1.09 (0.91–1.29)

0% (0.72)

Follow-up longer than 3 yrs

1,560 (10)

65/776

5,891 (29)

208/3,021

CABG (all studies)

102/784

0.67 (0.50–0.90)

0% (0.67)

212/2,870

0.96 (0.80–1.16)

0% (0.86)

Follow-up 6–12 months

4,563 (21)

123/2,351

121/2,212

0.99 (0.77–1.26)

0% (0.83)

Follow-up >12–36 months

2,755 (98)

122/1,379

123/1,376

0.98 (0.78–1.25)

0% (0.93)

Follow-up longer than 3 yrs PCI (all studies)

675 (4)

19/333

29/342

0.66 (0.34–1.27)

18% (0.30)

4,012 (16)

171/2013

197/1999

0.85 (0.70–1.04)

0% (0.59)

Follow-up 6–12 months

3,564 (13)

90/1,778

99/1,786

0.92 (0.64–1.33)

16% (0.30)

Follow-up >12–36 months

1,983 (6)

114/996

116/987

0.96 (0.69–1.35)

26% (0.24)

Follow-up longer than 3 yrs

567 (3)

28/281

37/286

0.76 (0.48–1.20)

0% (0.81)

Hospital admissions (all studies)

3,030 (15)

407/1,556

453/1,474

0.82 (0.70–0.96)

34.5% (0.10) 37% (0.14)

Follow-up of 6–12 months

1,120 (9)

82/574

116/546

0.65 (0.46–0.92)

Follow-up >12–36 months

1,916 (6)

322/984

330/932

0.95 (0.84–1.07)

0/0

0/0

Follow-up longer than 3 yrs

0 (0)

Not estimable

GRADE Quality of the Evidence

þþþ moderate*

þþþ moderate*

þþ low*†

þþþ moderate*

þþþ moderate*

þþ low*†

0% (0.50) Not estimable

*Random sequence generation, allocation concealment, or blinding of outcome assessors were poorly described in >50% of included studies; bias likely. †Funnel plots and/or Egger test suggest evidence of asymmetry. GRADE Working Group grades of evidence: high ¼ further research is very unlikely to change our confidence in the estimate of effect; moderate ¼ further research is likely to have an important effect on our confidence in the estimate of effect and may change the estimate; low ¼ further research is very likely to have an important effect on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate. CABG ¼ coronary artery bypass graft; CI ¼ confidence interval; CR ¼ cardiac rehabilitation; CV ¼ cardiovascular; MI ¼ myocardial infarction; PCI ¼ percutaneous coronary intervention; RR ¼ relative risk.

RISK OF BIAS AND GRADE ASSESSMENT. The overall

seven studies (n ¼ 7,469) reported CV mortality

risk of bias across domains was judged to be low or

(Table 2, Central Illustration, Figure 3), and a statisti-

unclear (Online Table 2). Quality of reporting was

cally significant reduction in this outcome was seen

generally higher in more recent studies. Overall, the

with the no-exercise control subjects (RR: 0.74;

GRADE (Grading of Recommendations Assessment,

95% CI: 0.64 to 0.86). Twenty studies reported both

Development and Evaluation) quality of evidence for

mortality outcomes. Results for mortality outcomes

each outcome was assessed as low to moderate

in this subgroup were consistent with the overall

(Table 2).

meta-analysis results (all-cause mortality RR: 0.91,

OUTCOME RESULTS. As there was no difference in

95% CI: 0.82 to 1.01; CV mortality RR: 0.78,

the effect of exercise-based CR on clinical outcomes

95% CI: 0.67 to 0.90).

across length of follow-up (Table 2), the following

M o r b i d i t y . Thirty-six studies (n ¼ 9,717) reported

results focus on pooled findings across all trials at

the risk of fatal or nonfatal MI (Table 2, Online

their longest follow-up (median 12 months).

Figure 1), and no statistically significant difference

M o r t a l i t y . Forty-seven studies (n ¼ 12,455) reported

in the risk of total MI was found with exercise-based

total mortality (Table 2, Figure 2). There was no sta-

CR (RR: 0.90; 95% CI: 0.79 to 1.04). Twenty-nine

tistically significant reduction in total mortality with

(n ¼ 5,891), and 16 (n ¼ 4,012) studies reported the

exercise-based CR (RR: 0.96; 95% CI: 0.88 to 1.04)

risk of CABG and PCI, respectively (Table 2, Online

compared with no-exercise control subjects. Twenty-

Figures 2 and 3). There was no difference between

5

6

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Exercise for Coronary Heart Disease: Systematic Review

F I G U R E 2 Exercise-Based Rehabilitation Versus Usual Care: Total Mortality

Study ID

Relative risk random (95% CI)

Events, Treatment

Events, Control

Wilhelmsen 75 Kallio 79 Andersen 81 Sivarajan 82b Carson 82 Sivarajan 82a Bengtsson 83 WHO 83 Vermeulen 83 Roman 83 Stern 83 Erdman 86 Bethell 90 Fridlund 91 Leizorovicz (PRECOR) 91 Oldridge 91 Bertie 92 Schuler 92 Engblom 92 Heller 93 Fletcher 94 Holmback 94 Debusk 94 Haskell (SCRIP) 94 Carlsson 98 Bell 98 Stahle 99 Hofman-Bang 99 Dorn (NEHDP) 99 Toobert 00 Higgins 01 VHSG 03 Yu 04 Hambrecht 04 Montero 05 Briffa 05 Zwisler 08 Reid 11 West (RAMIT) 12 Mutwalli 12 Wang 12 Oerkild 12 Manchanda 00 Kovoor 06 Seki 08 Munk 09 Houle 12 Maddison 14 Overall (I-squared = 0.0%, p = 0.584)

0.79 (0.51, 1.24) 0.73 (0.51, 1.03) 1.22 (0.29, 5.12) 1.50 (0.16, 13.93) 0.58 (0.29, 1.13) 1.37 (0.15, 12.70) 1.85 (0.70, 4.87) 0.91 (0.75, 1.10) 0.43 (0.09, 2.13) 0.64 (0.37, 1.10) 0.23 (0.01, 5.52) 9.00 (0.50, 161.86) 1.37 (0.68, 2.76) 0.67 (0.31, 1.47) 0.11 (0.01, 2.05) 0.77 (0.18, 3.36) 0.13 (0.01, 2.52) 2.04 (0.19, 21.82) 0.85 (0.40, 1.77) 2.23 (0.56, 8.79) 0.86 (0.20, 3.62) 1.03 (0.07, 15.80) 1.20 (0.52, 2.72) 1.07 (0.22, 5.21) 0.99 (0.14, 6.91) 0.97 (0.44, 2.13) 1.58 (0.40, 6.28) 0.15 (0.02, 1.18) 1.09 (0.93, 1.28) 2.00 (0.09, 45.12) 2.73 (0.11, 65.43) 2.02 (0.19, 21.92) 0.55 (0.14, 2.12) 0.49 (0.05, 5.24) 0.44 (0.19, 1.01) 0.20 (0.01, 4.00) 1.16 (0.66, 2.03) 0.19 (0.01, 3.87) 1.02 (0.87, 1.18) 0.25 (0.01, 5.91) 0.33 (0.04, 3.14) 0.88 (0.28, 2.82) (Excluded) (Excluded) (Excluded) (Excluded) (Excluded) (Excluded) 0.96 (0.88, 1.04)

28/158 41/188 4/46 3/74 12/151 3/79 10/81 169/1208 2/47 16/93 0/42 4/40 16/113 9/87 0/60 3/99 0/57 2/56 12/119 6/213 3/41 1/34 12/293 3/145 2/113 19/251 5/56 1/46 162/315 1/17 1/54 2/98 4/132 1/51 7/90 0/57 24/227 0/115 245/903 0/28 1/80 4/19 0/21 0/72 0/18 0/20 0/32 0/85 838/6424

35/157 56/187 3/42 1/37 21/152 1/36 6/90 169/1096 5/51 27/100 1/29 0/40 12/116 14/91 4/61 4/102 3/53 1/57 13/109 3/237 4/47 1/35 10/292 3/155 2/112 8/102 3/53 6/41 150/319 0/11 0/49 1/99 4/72 2/50 16/90 2/56 20/219 2/108 243/910 1/21 3/80 5/21 0/21 0/70 0/16 0/20 0/33 0/86 865/6031

NOTE: Weights are from random effects analysis .1

1

Favors CR

10 Favors control

The boxes are proportional to the weight of each study in the analysis, and the lines represent their 95% confidence intervals (CIs). The open diamond represents the pooled relative risk, and its width represents its 95% CI. CR ¼ cardiac rehabilitation.

exercise CR and usual care for either CABG or PCI

trials in either mortality or morbidity outcomes (with

(CABG: RR: 0.96, 95% CI: 0.80 to 1.16; PCI: RR: 0.85,

exception of hospitalizations) (I 2 statistic: 35%).

95% CI: 0.70 to 1.04). Fifteen studies (n ¼ 3,030)

S t r a t i fi e d m e t a - a n a l y s e s . There was no evidence of

reported

Central

difference in CR versus control treatment effects ac-

Illustration, Figure 3). Risk of admissions was reduced

ross mortality and morbidity outcomes across any pa-

with exercise-based CR compared with usual care

tient, intervention, or study characteristics (Table 3).

(RR: 0.82, 95% CI: 0.70 to 0.96, random effects). There

H e a l t h - r e l a t e d q u a l i t y o f l i f e . Twenty studies

was no evidence of statistical heterogeneity across

(n ¼ 5,060) assessed HRQL using a range of validated

hospital

admissions

(Table

2,

Anderson et al.

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Exercise for Coronary Heart Disease: Systematic Review

CENTRAL I LLU ST RAT ION Exercise-Based Cardiac Rehabilitation for Coronary Heart Disease Versus Usual Care: CV Mortality and Hospitalization

Anderson, L. et al. J Am Coll Cardiol. 2016; 67(1):1–12.

Box sizes are proportional to the weight of each study in the analysis, and the lines represent their 95% confidence intervals (CIs). The open diamond represents the pooled RR, and its width represents its 95% CI. CV ¼ cardiovascular.

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Anderson et al.

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Exercise for Coronary Heart Disease: Systematic Review

T A B L E 3 Stratified Meta-Analysis by Patient, Intervention, and Study Characteristics at Longest Follow-Up

All studies

All-Cause Mortality

CV Mortality

MI

CABG

PCI

Hospitalization

0.96 (0.88–1.04)

0.74 (0.64–0.86)

0.90 (0.79–1.04)

0.96 (0.80–1.16)

0.85 (0.70–1.04)

0.82 (0.70–0.96)

Case mix 100% MI

0.89 (0.78–1.01)

0.75 (0.65–0.87)

0.89 (0.76–1.05)

0.67 (0.45–1.00)

0.87 (0.67–1.15)

0.71 (0.41–1.24)

<100% MI

1.06 (0.92–1.22)

0.63 (0.38–1.06)

0.73 (0.44–1.23)

1.06 (0.86–1.31)

0.82 (0.58–1.15)

0.82 (0.68–0.99)

<1,000

0.89 (0.26–3.15)

0.47 (0.19–1.15)

0.72 (0.30–1.70)

0.96 (0.35–2.66)

1.22 (0.34–4.34)

0.70 (0.48–1.00)

$1,000

1.01 (0.89–1.15)

0.75 (0.65–0.86)

0.74 (0.59–0.93)

0.99 (0.78–1.27)

0.80 (0.62–1.03)

0.85 (0.71–1.01)

Exercise only

0.94 (0.77–1.16)

0.65 (0.50–0.85)

0.76 (0.60–0.98)

0.98 (0.68–1.42)

0.87 (0.35–2.17)

0.61 (0.33–1.14)

Comprehensive CR

0.93 (0.841–1.03)

0.79 (0.66–0.94)

0.90 (0.72–1.14)

0.96 (0.77–1.19)

0.87 (0.71–1.07)

0.85 (0.72–1.00)

Dose of exercise*

Type of CR

Duration of follow-up #12 months

1.08 (0.51–2.33)

0.72 (0.62–0.84)

0.60 (0.39–0.91)

1.03 (0.74–1.44)

0.83 (0.54–1.27)

0.63 (0.46–0.88)

>12 months

0.96 (0.88–1.04)

1.00 (0.63–1.60)

0.92 (0.77–1.09)

0.93 (0.75–1.17)

0.84 (0.64–1.09)

0.92 (0.80–1.05)

Year of publication Pre-1995

0.85 (0.75–0.98)

0.78 (0.67–0.91)

0.96 (0.81–1.14)

0.87 (0.59–1.30)

0.80 (0.42–1.51)

0.85 (0.69–1.05)

Post-1995

1.03 (0.903–1.14)

0.56 (0.38–0.83)

0.76 (0.59–0.99)

0.99 (0.81–1.22)

0.86 (0.70–1.06)

0.78 (0.60–1.00) 0.89 (0.76–1.04)

Setting Center

0.91 (0.80–1.04)

0.75 (0.65–0.87)

0.96 (0.83–1.11)

0.97 (0.77–1.23)

0.90 (0.60–1.35)

Center þ home

0.78 (0.40–1.53)

0.67 (0.30–1.47)

0.40 (0.14–1.11)

0.79 (0.44–1.44)

0.65 (0.37–1.14)

0.83 (0.46–1.50)

Home

1.02 (0.68–1.54)

0.87 (0.34–2.20)

0.48 (0.28–0.83)

1.01 (0.59–1.7)

0.79 (0.53–0.18)

0.60 (0.33–1.05)

Risk of bias Low (bias in <5 of 8 domains)

1.01 (0.88–1.17)

0.91 (0.22–3.74)

0.96 (0.69–1.33)

0.92 (0.69–1.21)

0.91 (0.70–1.18)

0.85 (0.61–1.20)

High (bias in >5 of 8 domains)

0.90 (0.80–1.02)

0.74 (0.64–0.86)

0.83 (0.69–1.00)

1.00 (0.79–1.28)

0.79 (0.59–1.06)

0.79 (0.65–0.97)

Study location, continent Europe North America

0.90 (0.80–1.02)

0.73 (0.62–0.87)

0.93 (0.79–1.09)

0.94 (0.74–1.19)

0.85 (0.65–1.13)

0.72 (0.56–0.92)

1.10 (0.94–1.27)

0.89 (0.56–1.43)

0.62 (0.41–0.94)

1.05 (0.78–1.42)

0.78 (0.52–1.16)

0.95 (0.81–1.11)

Australasia

0.85 (0.35–2.07)

0.33 (0.01–7.88)

1.90 (0.33–10.72)

0.32 (0.07–1.55)

0.99 (0.32–3.02)

1.07 (0.74–1.54)

Other

0.62 (0.36–1.07)

0.58 (0.32–1.08)

0.25 (0.01–5.91)

NR

NR

0.27 (0.10–0.74)

#150

0.81 (0.51–1.29)

0.58 (0.33–1.00)

0.54 (0.35–0.83)

0.78 (0.53–1.16)

0.82 (0.47–1.42)

0.60 (0.46–0.78)

>150

0.95 (0.86–1.05)

0.76 (0.65–0.88)

0.93 (0.78–1.11)

1.02 (0.83–1.26)

0.87 (0.70–1.08)

0.93 (0.83–1.05)

Sample size

Values are relative risk (95% confidence interval). *Number of weeks of exercise training  average number of sessions/week  average duration of session in minutes. NR ¼ not measurable; other abbreviations as in Table 2.

generic or disease-specific outcome measures (Online

$42,535/quality-adjusted life-year (40) for CR to a

Table 3). Given the heterogeneity in both outcome

reduction of U.S. $650/quality-adjusted life-year (47)

measures and methods of reporting the findings, we

for CR compared with control subjects.

did not undertake meta-analysis. Fourteen of the 20

SMALL STUDY BIAS. There was no evidence of funnel

studies (65%) reported a higher level of HRQL in 1 or

plot asymmetry or significant Egger tests for mortal-

more subscales following exercise-based CR compared

ity or revascularization outcomes (Online Figures 4

with control subjects (23,27,29,31,33,35,36,38–44), and

to 7). However, Egger tests were significant for MI

in 5 studies (25%), there was a higher level of HRQL in

(p ¼ 0.009) and hospitalization (p ¼ 0.001), indicating

one-half or more of the subscales (23,33,35,36,38).

funnel plot asymmetry. This asymmetry appeared to

C o s t s a n d c o s t - e f f e c t i v e n e s s . Seven studies re-

be due to an absence of small- to medium-sized

ported data on costs (31,40,45–49) (Online Table 4).

studies with negative results for exercise-based CR

Three studies showed no difference in total health

(Online Figures 8 and 9).

care costs between CR and control groups (40,45,47), 1 reported lower health care costs for CR compared

DISCUSSION

with usual care (reduction of U.S. $2,378/patient) (48), another reported higher health care costs for CR

We conducted an updated systematic review and

(increase of U.S. $4,839/patient) (46), and 2 studies

meta-analysis of exercise-based CR in people with

did not report total health care costs (31,49).

existing CHD. Our study shows a reduction in pooled

Cost-effectiveness ranged from an additional U.S.

CV mortality (10.4% to 7.6%; number needed to treat:

Anderson et al.

JACC VOL. 67, NO. 1, 2016 JANUARY 5/12, 2016:1–12

Exercise for Coronary Heart Disease: Systematic Review

F I G U R E 3 Exercise-Based Rehabilitation Versus Usual Care: Cardiovascular Mortality and Hospitalization

Exercise-based rehabilitation versus usual care: cardiovascular mortality Study ID

Relative risk random (95% CI)

Events, Treatment

Events, Control

Wilhelmsen 75 Kallio 79 Shaw (NEDHP) 81

0.69 (0.43, 1.12) 0.63 (0.44, 0.92) 0.71 (0.37, 1.38) 0.20 (0.01, 3.97) 1.35 (0.15, 12.50) 3.61 (0.19, 67.81) 0.43 (0.09, 2.13) 0.58 (0.32, 1.08) 0.87 (0.70, 1.07)

23/158 35/188 14/323 0/25 3/71 3/65 2/47 13/93 144/1208

33/157 55/187 20/328 2/25 1/32 0/33 5/51 24/100 151/1096

Dugmore 99

0.71 (0.12, 4.20) 0.11 (0.01, 2.31) 1.11 (0.53, 2.33) 1.43 (0.14, 14.70) 5.09 (0.25, 103.66) 1.22 (0.51, 2.90) 0.40 (0.15, 1.10) 0.15 (0.02, 1.18) 0.67 (0.12, 3.85)

2/145 0/127 13/113 2/28 2/56 11/293 5/125 1/46 2/62

3/155 2/71 12/116 1/20 0/57 9/292 13/131 6/41 3/62

Toobert 00 La Rovere 02 Hambrecht 04 Briffa 05 Montero 05 Aronov 10 Belardinelli 01 Seki 08 Munk 09

2.00 (0.09, 45.12) 0.47 (0.19, 1.15) 0.20 (0.01, 3.99) 0.33 (0.01, 7.87) 0.50 (0.21, 1.18) 0.49 (0.13, 1.95) (Excluded) (Excluded) (Excluded)

1/17 6/49 0/51 0/57 7/90 3/197 0/59 0/20 0/20

0/11 12/46 2/50 1/56 14/90 6/195 0/59 0/19 0/20

Houle 12 Maddison 14 Overall (I-squared = 0.0%, p = 0.699)

(Excluded) (Excluded) 0.74 (0.64, 0.86)

0/32 0/85 292/3850

0/33 0/86 375/3619

Vecchio 81 Sivarajan 82a Sivarajan 82b Vermeulen 83 Roman 83 WHO 83 Haskell (SCRIP) 84 Miller 84 Bethell 90 Ornish 90 Schuler 92 Debusk 94 Specchia 96 Hofman-Bang 99

NOTE: Weights are from random effects analysis

.1

1

10

Favors CR

Favors control

Exercise-based rehabilitation versus usual care: hospitalization Study ID

Relative risk random (95% CI)

Events, Treatment

Events, Control

Shaw (NEDHP) 81

0.98 (0.79, 1.21)

109/323

113/328

Lewin 92

0.50 (0.25, 1.02)

9/58

18/58

Haskell 94

0.92 (0.71, 1.19)

62/145

72/155

Engblom 96

0.68 (0.45, 1.04)

26/102

34/91

Hofman-Bang 99

0.81 (0.51, 1.27)

19/46

21/41

Belardinelli 01

0.52 (0.28, 0.99)

11/59

21/59

VHSG 03

0.79 (0.38, 1.66)

11/98

14/99

Yu 04

1.16 (0.69, 1.95)

34/132

16/72

Hambrecht 04

0.14 (0.02, 1.10)

1/51

7/50

Briffa 05

0.98 (0.59, 1.65)

19/57

19/56

Giallauria 08

0.44 (0.13, 1.55)

3/30

7/31

Zwisler 08

0.98 (0.79, 1.21)

95/227

94/219

Reid 11

0.63 (0.18, 2.16)

4/115

6/108

Mutwalli 12

0.27 (0.10, 0.74)

4/28

11/21

Maddison 14

(Excluded)

0/85

0/86

Overall (I-squared = 34.5%, p = 0.099)

0.82 (0.70, 0.96)

407/1556

453/1474

NOTE: Weights are from random effects analysis .1 Favors CR

1

10 Favors control

Filled diamonds represent the relative risk for individual studies at the longest reported follow-up. The boxes are proportional to the weight of each study in the analysis, and the lines represent their 95% confidence interval (CIs). The open diamond represents the pooled relative risk, and its width represents its 95% CI.

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Exercise for Coronary Heart Disease: Systematic Review

37), and hospital admission (30.7% to 26.1%; number

the median outcome follow-up of 12 months is

needed to treat: 22) with exercise-based CR compared

limited when assessing the effect on mortality and

with no-exercise control subjects. There was no

morbidity outcome measures. However, our results

between-group difference in total mortality or the

were consistent when pooling was limited to RCTs

risk of fatal or nonfatal MI, CABG, or PCI. Outcome

with a follow up >12 months. Funnel plot asymmetry

effects were consistent across RCTs, irrespective

for the risk of MI and hospital admission is indicative

of patient case mix (i.e., % of MI patients), the

of possible publication bias. Included RCTs did not

nature of the CR program (i.e., exercise-only or

consistently report all outcomes relevant to this re-

comprehensive CR, dose of exercise training, or cen-

view, and events were often reported in study de-

ter- or home-based settings), and study characteris-

scriptions of dropout or withdrawal. Our results are,

tics (i.e., sample size, risk of bias, location, length

therefore, on the basis of small and different subsets

of follow-up, or year of publication). There was

of the overall RCT evidence base. However, we found

evidence of higher levels of HRQL following exercise-

our overall meta-analysis results to be consistent in

based CR compared with control subjects, and also

the subgroup of 20 studies reporting both overall and

that exercise-based CR can be a cost-effective use of

CV mortality outcomes. The minority of trials re-

health care resources.

ported non-CV causes of death. Only more recent

In contrast to previous meta-analyses, we did

studies have begun to consistently report data on

not observe a statistically significant reduction in

hospitalizations, but still often fail to differentiate

all-cause mortality with exercise-based CR. This may

between new and recurrent admissions, whereas

be explained by the inclusion of more recent studies

HRQL and cost data are still collected infrequently.

that include a more mixed population of CHD pa-

Finally, we sought to categorize the diagnoses of

tients, conducted in the era of optimal medical

study participants according to a more detailed

therapy for CHD. Our review included RCTs con-

framework on the basis of Braunwald’s classification

ducted over a period (1974 to 2014) during which

of

there have been a number of major advances in

exercise-based CR differs according to the pre-

medical CHD management, such as the increased

sentation, that is, acute coronary syndrome (MI,

use of statins. We found some support for this

non–ST-segment elevation MI, unstable angina pec-

hypothesis in our meta-regression analysis, which

toris) and stable angina pectoris or treatment mo-

shows a trend of a linear reduction (slope: 0.0063;

dality (PCI, CABG, or medication alone). The limited

95% CI: 0.00150 to 0.0141; p ¼ 0.08) in the all-

reporting by RCTs of inclusion and exclusion criteria

cause mortality effect (log RR) of CR over time

and participant characteristics prevented us from

(i.e., study publication date) (Online Figure 10).

applying

Despite the observed improvements in CV mortality,

believe this to be the most comprehensive review of

in a context of contemporary CHD medical treat-

evidence to date, summarizing the results of RCTs in

ments, the opportunity for additional gains in over-

>14,000 patients.

CHD

(50)

this

to

study

whether

categorization.

the

effect

Nevertheless,

of

we

all mortality with exercise-based CR may be small. Nonetheless, the observation that exercise-based CR

CONCLUSIONS

reduces the risk of CV mortality compared with noexercise control subjects, but does not reduce the

Among patients with established CHD, provision of

risk

that

exercise-based CR provides important health benefits

although CR does not improve coronary vascular

that include reductions in CV mortality and hospi-

function or integrity, it does confer improved sur-

talization (and associated health care costs) and im-

vival in patients post-MI.

provements in HRQL. On the basis of a meta-analysis

STUDY LIMITATIONS. The generally poor level of

of RCTs, these results support the Class I recom-

reporting in the included RCTs made it difficult to

mendation of current international clinical guidelines

assess their methodological quality and thereby

that CR should be offered to CHD patients. However,

judge their risk of bias. However, we did find some

future trials need to pay increased attention to

improvements in the quality of reporting in more

recruitment of patients who are more representative

recently published studies. Reassuringly, the find-

of the broader CHD population, including those at

ings of our meta-analysis were consistent when

higher risk, with major comorbidities, and also with

limited to studies with a lower risk of bias. Never-

stable angina. Future trials also need to improve their

theless, the general paucity of reporting led us to

quality of reporting, particularly in terms of risk of

downgrade the GRADE quality of evidence for

bias, details of the intervention and control, clinical

outcomes to low or moderate. We acknowledge that

events, HRQL, and health economic outcomes.

of

MI

or

revascularization,

suggests

Anderson et al.

JACC VOL. 67, NO. 1, 2016 JANUARY 5/12, 2016:1–12

ACKNOWLEDGMENTS The

Exercise for Coronary Heart Disease: Systematic Review

authors

thank

Zhivko

Zhelev, Shenqiu Zhang, and Oriana Ciani for their translation

services, and Harriot

Hunt

for

her

assistance with screening. The authors also thank all of the authors who provided additional information about their trials and the coauthors of the 2 previous versions of this review. Finally, the authors thank the Cochrane Heart Group for their support of the co-publication of this article with the full version of the review, which is published on the Cochrane Database of Systematic Reviews (51).

PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: Exercise-based CR reduces the risk of CV mortality and hospital admission and improves HRQL in patients with CHD, independent of patient characteristics, setting, or intervention. COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Exercise-based CR is a safe and effective adjunct to management of patients with CHD who are at low to moderate risk following MI or revascularization and those with stable angina.

REPRINT REQUESTS AND CORRESPONDENCE: Prof.

Rod S. Taylor, Institute of Health Services Research, University of Exeter Medical School, South Cloisters, St Luke’s Campus, Exeter EX1 2LU, United Kingdom.

TRANSLATIONAL OUTLOOK: Randomized trials should be undertaken to evaluate CR in a broad population of patients with CHD, including those with comorbidities who are at higher risk.

E-mail: [email protected].

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KEY WORDS coronary artery bypass graft, exercise therapy, exercise training, myocardial infarction, percutaneous coronary intervention, revascularization

A PPE NDI X For an expanded Methods section and supplemental figures and tables, please see the online version of this article.