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ORIGINAL INVESTIGATIONS

Exercise-Based Cardiac Rehabilitationfor 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,xKaren Rees, PHD,k Nicole Martin, MA,{ Rod S. Taylor, PHD*

ABSTRACT

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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 angiog-

raphy. 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 health-

related 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.

m the *Institute of Health Research, University of Exeter Medical School, Exeter, United Kingdom; yCollege of Health Sciences,

iversity of Wisconsin-Milwaukee, Milwaukee, Wisconsin; zCentre for the Heart and Mind, Australian Catholic University,

lbourne, Australia; xNational Centre of Rehabilitation and Palliation, University Hospital Odense, and University of Southern

nmark, Odense, Denmark; kDivision of Health Sciences, Warwick Medical School, University of Warwick, Coventry, United

gdom; and the {Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine,

ndon, United Kingdom. Dr. Anderson is funded by the University of Exeter Medical School. Prof. Taylor is partly funded by the

. National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South West

ninsula at the Royal Devon and Exeter NHS Foundation Trust; and is currently the cochief investigator of a research program

th the overarching aims of developing and evaluating a home-based cardiac rehabilitation intervention for people with heart

lure and their careers (PGfAR RP-PG-0611-12004). Dr. Rees is supported by the NIHR Collaboration for Leadership in Applied

alth Research and Care West Midlands at University Hospitals Birmingham NHS Foundation Trust. Dr. Zwisler is principal

estigator of an included (DAHREHAB) and ongoing cardiac rehabilitation trials (CopenHeart trials). Prof. Taylor, Drs. Rees and

ABBR EV I A T I ON S

AND ACRONYMS

CABG = coronary artery bypass

graft

CHD = coronary heart disease

CI = confidence interval

CR = cardiac rehabilitation

CV = cardiovascular

HRQL = health-related quality

of life

MI = myocardial infarction

PCI = percutaneous coronary

intervention

RCT = randomized controlled

trial

RR = relative risk

Oldridge, a

authors on

authors and

has no rela

Manuscript

Anderson et al. J A C C V O L . 6 7 , N O . 1 , 2 0 1 6

Exercise for Coronary Heart Disease: Systematic Review J A N U A R Y 5 / 1 2 , 2 0 1 6 : 1 – 1 2

2

W ith increasing numbers of peo-ple living longer with symptom-atic coronary heart disease

(CHD), the effectiveness and accessibility ofhealth services for people with CHD havenever been more important. Cardiac rehabil-itation (CR) programs are recognized as inte-gral to comprehensive care of CHD patientsand have been given a Class I recommenda-tion from the American Heart Association,the American College of Cardiology, and theEuropean Society of Cardiology, with exer-cise therapy consistently identified as acentral element (1–4). Although exercisetraining remains a cornerstone intervention,international guidelines consistently recom-mend the provision of comprehensive reha-

bilitation that includes education and psychologicalinput focusing on health and life-style behaviorchange, risk factor modification, and psychosocialwell-being (1–3).

SEE PAGE 13

The first systematic reviews and meta-analyses ofexercise-based CR by Oldridge et al. (5) and O’Connoret al. (6) were published more than 20 years ago,showing a 20% to 25% reduction in all-cause and car-diovascular (CV) mortality on the basis of data from 22randomized controlled trials (RCTs) in over 4,300 pa-tients. Although there have been more recent updatesto these meta-analyses (7–9), concerns have beenraised about the applicability of their results to policyplanning and the provision of CR services (10,11). It hasbeen argued that major advances in CHD medicalmanagement may have led to a reduction in the in-cremental effect on mortality of exercise-based CRcompared with usual care alone. Other concerns haveincluded the inclusion of small, poor-quality RCTs,which may have resulted in overestimation of thebenefits of CR, and the almost exclusive recruitment oflow-risk, middle-aged, post-myocardial infarction(MI) men in early trials, thereby reducing the general-izability of their findings to the broader population ofCHD patients (12). Our aim was to systematically up-date existing meta-analyses to reassess the effects ofexercise-based CR in patients with CHD in terms ofmortality, morbidity, health-related quality of life

nd Prof. Thompson were authors of the original Cochrane revie

a number of other Cochrane cardiac rehabilitation reviews. The

not necessarily those of the NHS, the NIHR, or the Department o

tionships relevant to the contents of this paper to disclose.

received July 14, 2015; revised manuscript received October 12,

(HRQL), and cost-effectiveness. We also sought toexplorewhether effects vary with patient casemix, thenature of CR programs, and study characteristics.

METHODS

We conducted and reported this systematic review inaccordance with the PRISMA (Preferred ReportingItems for Systematic Reviews and Meta-Analyses)statement (13) and the Cochrane Handbook forInterventional Reviews (14). The protocol was pub-lished on the Cochrane Database of SystematicReviews (2001) (15).

DATA SEARCHES AND SOURCES. Search terms fromthe 2011 Cochrane review (9) were updated andCENTRAL (Cochrane Central Register of ControlledTrials), DARE (Database of Abstracts of Reviews ofEffects), HTA (Health Technology Assessment),MEDLINE and Medline in Process (Ovid), EMBASE(Ovid), and CINAHL (Cumulative Index to Nursing andAllied Health Literature) Plus (EBSCO) were searchedto July 2014. Conference proceedings were searchedon the Web of Science Core Collection (ThomsonReuters) (1970 to June 2014), and bibliographies ofsystematic reviews and trial registers (the WorldHealth Organization [WHO]’s International ClinicalTrials Registry Platform [ICTRP] and Clinicaltrials.gov)were hand-searched. No language or other limitationswere imposed (see Online Appendix).

STUDY SELECTION. Randomized controlled trialswere sought that compared exercise-based CR with acontrol and had a follow-up period of at least 6months.Exercise-based CR was defined as a supervised or un-supervised inpatient, outpatient, community-based,or home-based intervention that included some formof exercise training, either alone or in addition topsychosocial and/or educational interventions. Thecomparator could include standard medical care andpsychosocial and/or educational interventions, butnot any structured exercise training. We included pa-tients irrespective of sex or age who had an MI, hadundergone revascularization (coronary artery bypassgrafting [CABG] or percutaneous coronary interven-tion [PCI]), or who have angina pectoris or CHD definedby angiography. Finally, studies needed to report 1 ormore of the following outcomes: total or CV mortality;fatal or nonfatal MI; revascularizations (CABG or PCI);

w; and Prof. Taylor and Drs. Rees and Zwisler are

views expressed in this publication are those of the

f Health in England. Ms. Martin has reported that she

2015, accepted October 14, 2015.

FIGURE 1 Summary of Study Selection Process

RCTs included from 2011 CochranereviewN = 47

(N = 81 publications)

Titles identified from electronic bibliographies &screened for retrieval

N = 11,028

ExcludedN = 10,937

Potentially appropriate full-text publicationsretrieved for full evaluation

N = 91

RCTs from updated searchN = 16

(N = 21 publications)

Excluded---

2 ongoing studies3 studies awaiting classification65 excludedfollow-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

Total RCTs included in reviewN = 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.

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hospitalizations; HRQL, assessed using validated in-struments; or costs and cost-effectiveness. Two re-viewers (L.A. and R.S.T.) independently assessed allidentified titles/abstracts for possible inclusion, withany disagreements resolved by discussion. Wherenecessary, studies were translated into English.

DATA EXTRACTION AND MANAGEMENT. Onereviewer (L.A.) extracted study and patient charac-teristics, intervention and comparator details, andoutcome data from included studies using a stan-dardized data collection form. A second author(R.S.T.) checked for accuracy, and disagreementswere resolved by consensus. Duplicate publicationsof the same study were assessed for additional dataand authors were contacted, where necessary, toprovide additional information.ASSESSMENT OF RISK OF BIAS AND OVERALL

QUALITY OF EVIDENCE. Risk of bias of includedstudies was assessed using the Cochrane Collabo-ration’s core risk of bias items (14) and 3 furtheritems deemed relevant to this review. GRADEProfiler

software (16) was used to assess the overall quality ofevidence for each outcome collected (17) (see theOnline Appendix for full details).

DATA SYNTHESIS AND ANALYSIS. Dichotomousoutcomes were expressed as relative risks (RRs) with95% confidence intervals (CIs). HRQL scores wereexpressed as mean differences. Heterogeneity amongincluded studies was explored qualitatively andquantitatively (using the chi-square test of hetero-geneity and I2 statistic). Data from each studywere pooled using a conservative random effectsmeta-analysis model.

The meta-analysis of each outcome was stratifiedaccording to the duration of study follow-up (i.e., 6 to12 months [short-term]; 13 to 36 months [medium-term]; and >36 months [long-term]). Using thelongest follow-up, we stratified meta-analyses toexplore heterogeneity and examine potential treat-ment effect modifiers. We tested 9 a priori hypothesesthat there may be differences in the effect of exercise-based CR on outcomes at longest follow-up across the

TABLE 1 Summary of Trial and Patient Characteristics (63 Included Studies)

Study characteristics

Publication year

1970–1979 2 (3)

1980–1989 12 (19)

1990–1999 20 (32)

2000–2009 21 (33)

2010 onwards 8 (13)

Study location

Europe 37 (59)

North America 12 (19)

Asia 6 (10)

Australasia 5 (8)

Other 2 (3)

Not reported 1 (2)

Single center 45 (71)

Sample size 126 (28–2,304)

Duration of follow-up, months 12 (6–120)

Population characteristics

Sex

Males only 18 (29)

Females only 1 (2)

Both males and female 41 (65)

Not reported 3 (5)

Age, yrs 56.0 (49.3–71.0)

Diagnosis

Post-myocardial infarction only 31 (49)

Revascularization only 2 (3)

Angina only 5 (8)

Mixed CHD population 25 (40)

Intervention characteristics

Intervention type

Exercise-only programs 25* (38)

Comprehensive programs 39* (60)

Duration of intervention, months 6 (1–48)

Dose of intervention

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

Setting

Center-based only 33 (52)

Combination of center- andhome-based

13 (21)

Home-based only 15 (24)

Not reported 2 (3)

Values are number of studies (%) or median (range). Median of study means: *1 study includesboth exercise-only and comprehensive cardiac rehabilitation arms.

CHD ¼ coronary heart disease.

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following subgroups: 1) CHD case mix (MI-only trialsvs. other trials); 2) type of CR (exercise-only CR vs.comprehensive CR); 3) dose of exercise intervention(dose ¼ number of weeks of exercise training �average number of sessions/week � average durationof session in minutes) (dose $1,000 U vs. dose

<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);and 9) study location (continent).

The funnel plot and Egger test were used toexamine small-study bias (18). All statistical analyseswere performed using Review Manager 5.3 Software(19) and STATA version 13.0 (StataCorp, CollegeStation, Texas) (20).

RESULTS

SELECTION AND INCLUSION OF STUDIES. The 2011Cochrane review provided 47 RCTs (81 publications).Our searches for this update yielded 11,028 titles, ofwhich 91 full papers were considered for inclusion.Sixteen new RCTs (21 publications) were included,giving a total of 63 studies (102 publications; seeFigure 1 for a summary of the study selection processand Online Table 1 for a list of included studies).STUDY, PATIENT, AND INTERVENTION CHARACTERISTICS.

Fourteen studies were published before 1999, and49 have been published since 2000 (Table 1). The me-dian follow-up was 12 months, with 50 studiesreporting at least 12 months of follow-up, and 18reporting follow-up of 36 months or more. The major-ity of studies were conducted in Europe (37 studies) orNorth America (12 studies). Although we included14,486 patients,most studieswere small in sample size(median n ¼ 126; range 28 to 2,304), with 2 largemulticenter trials (WHO and RAMIT [RehabilitationAfter Myocardial Infarction Trial]) (12,21) contributinga total of 4,177 patients (about 30% of all participants).

The median age of participants across studies was56.0 years. Although 42 studies (66%) includedwomen, they accounted for <15% of all patientsrecruited. Studies published since 2005 were lessdominated by post-MI patients, included other CHDdiagnoses (such as revascularization and angina), andwere more likely to include older (average mean age61.7 years vs. 56.3 years) and female (20.0% vs. 12.5%)participants.

Exercise-based CR programs were typically deliv-ered in a supervised hospital/center-based setting,either exclusively or in combination with somemaintenance home exercise sessions. Fifteen studieswere conducted in an exclusively home-based setting(22–36). Whereas the primary mode of exercisetraining across all studies was aerobic, the overall oraverage duration, frequency, and intensity of ses-sions varied considerably across studies. A total of 24studies were exercise-only programs, 38 werecomprehensive CR, and 1 trial included both exercise-only and comprehensive CR arms (37).

TABLE 2 Summary of Meta-Analysis Effects of Exercise-Based CR on Clinical Event Outcomes

OutcomeNumber of Participants(Number of Studies)

Number of Events/Participants

RR (95% CI)

Statistical Heterogeneity I2

Statistic Chi-Square Test(p Value)

GRADE Qualityof the EvidenceIntervention Comparator

All-cause mortality (all studies) 12,455 (47) 838/6,424 865/6,031 0.96 (0.88–1.04) 0% (0.58) þþþ�moderate*

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)

Follow-up longer than 3 yrs 3,828 (11) 476/1,902 493/1,926 0.91 (0.75–1.10) 35% (0.12)

CV mortality (all studies) 7,469 (27) 292/3,850 375/3,619 0.74 (0.64–0.86) 0% (0.70) þþþ�moderate*

Follow-up 6–12 months 4,884 (15) 105/2,561 107/2,323 0.90 (0.69–1.17) 0% (0.72)

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)

Fatal and/or nonfatal MI (all studies) 9,717 (36) 356/4,951 387/4,766 0.90 (0.79–1.04) 0% (0.48) þþ��low*†

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) 65/776 102/784 0.67 (0.50–0.90) 0% (0.67)

CABG (all studies) 5,891 (29) 208/3,021 212/2,870 0.96 (0.80–1.16) 0% (0.86) þþþ�moderate*

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 675 (4) 19/333 29/342 0.66 (0.34–1.27) 18% (0.30)

PCI (all studies) 4,012 (16) 171/2013 197/1999 0.85 (0.70–1.04) 0% (0.59) þþþ�moderate*

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) þþ��low*†

Follow-up of 6–12 months 1,120 (9) 82/574 116/546 0.65 (0.46–0.92) 37% (0.14)

Follow-up >12–36 months 1,916 (6) 322/984 330/932 0.95 (0.84–1.07) 0% (0.50)

Follow-up longer than 3 yrs 0 (0) 0/0 0/0 Not estimable 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 ofasymmetry. 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 importanteffect 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 tochange 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.

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RISK OF BIAS AND GRADE ASSESSMENT. The overallrisk of bias across domains was judged to be low orunclear (Online Table 2). Quality of reporting wasgenerally higher in more recent studies. Overall, theGRADE (Grading of Recommendations Assessment,Development and Evaluation) quality of evidence foreach outcome was assessed as low to moderate(Table 2).OUTCOME RESULTS. As there was no difference inthe effect of exercise-based CR on clinical outcomesacross length of follow-up (Table 2), the followingresults focus on pooled findings across all trials attheir longest follow-up (median 12 months).Morta l i ty . Forty-seven studies (n ¼ 12,455) reportedtotal mortality (Table 2, Figure 2). There was no sta-tistically significant reduction in total mortality withexercise-based CR (RR: 0.96; 95% CI: 0.88 to 1.04)compared with no-exercise control subjects. Twenty-

seven studies (n ¼ 7,469) reported CV mortality(Table 2, Central Illustration, Figure 3), and a statisti-cally significant reduction in this outcome was seenwith the no-exercise control subjects (RR: 0.74;95% CI: 0.64 to 0.86). Twenty studies reported bothmortality outcomes. Results for mortality outcomesin this subgroup were consistent with the overallmeta-analysis results (all-cause mortality RR: 0.91,95% CI: 0.82 to 1.01; CV mortality RR: 0.78,95% CI: 0.67 to 0.90).Morbid i ty . Thirty-six studies (n ¼ 9,717) reportedthe risk of fatal or nonfatal MI (Table 2, OnlineFigure 1), and no statistically significant differencein the risk of total MI was found with exercise-basedCR (RR: 0.90; 95% CI: 0.79 to 1.04). Twenty-nine(n ¼ 5,891), and 16 (n ¼ 4,012) studies reported therisk of CABG and PCI, respectively (Table 2, OnlineFigures 2 and 3). There was no difference between

FIGURE 2 Exercise-Based Rehabilitation Versus Usual Care: Total Mortality

StudyID

Relative riskrandom (95% CI)

Events,Treatment

Events,Control

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

28/15841/1884/463/7412/1513/7910/81169/12082/4716/930/424/4016/1139/870/603/990/572/5612/1196/2133/411/3412/2933/1452/11319/2515/561/46162/3151/171/542/984/1321/517/900/5724/2270/115245/9030/281/804/190/210/720/180/200/320/85838/6424

35/15756/1873/421/3721/1521/366/90169/10965/5127/1001/290/4012/11614/914/614/1023/531/5713/1093/2374/471/3510/2923/1552/1128/1023/536/41150/3190/110/491/994/722/5016/902/5620/2192/108243/9101/213/805/210/210/700/160/200/330/86865/6031

NOTE: Weights are from random effects analysis

.1 1 10Favors CR 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.

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exercise CR and usual care for either CABG or PCI(CABG: RR: 0.96, 95% CI: 0.80 to 1.16; PCI: RR: 0.85,95% CI: 0.70 to 1.04). Fifteen studies (n ¼ 3,030)reported hospital admissions (Table 2, CentralIllustration, Figure 3). Risk of admissions was reducedwith exercise-based CR compared with usual care(RR: 0.82, 95% CI: 0.70 to 0.96, random effects). Therewas no evidence of statistical heterogeneity across

trials in either mortality or morbidity outcomes (withexception of hospitalizations) (I2 statistic: 35%).Strat ified meta-analyses . There was no evidence ofdifference in CR versus control treatment effects ac-ross mortality and morbidity outcomes across any pa-tient, intervention, or study characteristics (Table 3).Health-re la ted qua l i ty of l i fe . Twenty studies(n ¼ 5,060) assessed HRQL using a range of validated

CENTRAL ILLUSTRATION 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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TABLE 3 Stratified Meta-Analysis by Patient, Intervention, and Study Characteristics at Longest Follow-Up

All-Cause Mortality CV Mortality MI CABG PCI Hospitalization

All studies 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)

Dose of exercise*

<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)

Type of CR

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)

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)

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) 0.89 (0.76–1.04)

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 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)

North America 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)

Sample size

#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)

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.

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generic or disease-specific outcome measures (OnlineTable 3). Given the heterogeneity in both outcomemeasures and methods of reporting the findings, wedid not undertake meta-analysis. Fourteen of the 20studies (65%) reported a higher level of HRQL in 1 ormore subscales following exercise-based CR comparedwith control subjects (23,27,29,31,33,35,36,38–44), andin 5 studies (25%), there was a higher level of HRQL inone-half or more of the subscales (23,33,35,36,38).Costs and cost-ef fect iveness . Seven studies re-ported data on costs (31,40,45–49) (Online Table 4).Three studies showed no difference in total healthcare costs between CR and control groups (40,45,47),1 reported lower health care costs for CR comparedwith usual care (reduction of U.S. $2,378/patient)(48), another reported higher health care costs for CR(increase of U.S. $4,839/patient) (46), and 2 studiesdid not report total health care costs (31,49).Cost-effectiveness ranged from an additional U.S.

$42,535/quality-adjusted life-year (40) for CR to areduction of U.S. $650/quality-adjusted life-year (47)for CR compared with control subjects.

SMALL STUDY BIAS. There was no evidence of funnelplot asymmetry or significant Egger tests for mortal-ity or revascularization outcomes (Online Figures 4to 7). However, Egger tests were significant for MI(p ¼ 0.009) and hospitalization (p ¼ 0.001), indicatingfunnel plot asymmetry. This asymmetry appeared tobe due to an absence of small- to medium-sizedstudies with negative results for exercise-based CR(Online Figures 8 and 9).

DISCUSSION

We conducted an updated systematic review andmeta-analysis of exercise-based CR in people withexisting CHD. Our study shows a reduction in pooledCV mortality (10.4% to 7.6%; number needed to treat:

FIGURE 3 Exercise-Based Rehabilitation Versus Usual Care: Cardiovascular Mortality and Hospitalization

Exercise-based rehabilitation versus usual care: cardiovascular mortality

Exercise-based rehabilitation versus usual care: hospitalization

Overall (I-squared = 0.0%, p = 0.699)

Haskell (SCRIP) 84

Belardinelli 01

Kallio 79

Hofman-Bang 99

Ornish 90

Seki 08

Vecchio 81

Toobert 00

Montero 05

Study

WHO 83

Debusk 94

Hambrecht 04

Roman 83

Dugmore 99

La Rovere 02

Sivarajan 82b

Schuler 92

Sivarajan 82a

Houle 12

Briffa 05

Miller 84

Munk 09

Bethell 90

Wilhelmsen 75

ID

Aronov 10

Shaw (NEDHP) 81

Maddison 14

Specchia 96

Vermeulen 83

0.74 (0.64, 0.86)

0.71 (0.12, 4.20)

(Excluded)

0.63 (0.44, 0.92)

0.15 (0.02, 1.18)

1.43 (0.14, 14.70)

(Excluded)

0.20 (0.01, 3.97)

2.00 (0.09, 45.12)

0.50 (0.21, 1.18)

Relative risk

0.87 (0.70, 1.07)

1.22 (0.51, 2.90)

0.20 (0.01, 3.99)

0.58 (0.32, 1.08)

0.67 (0.12, 3.85)

0.47 (0.19, 1.15)

3.61 (0.19, 67.81)

5.09 (0.25, 103.66)

1.35 (0.15, 12.50)

(Excluded)

0.33 (0.01, 7.87)

0.11 (0.01, 2.31)

(Excluded)

1.11 (0.53, 2.33)

0.69 (0.43, 1.12)

random (95% CI)

0.49 (0.13, 1.95)

0.71 (0.37, 1.38)

(Excluded)

0.40 (0.15, 1.10)

0.43 (0.09, 2.13)

292/3850

2/145

0/59

35/188

1/46

2/28

0/20

0/25

1/17

7/90

Events,

144/1208

11/293

0/51

13/93

2/62

6/49

3/65

2/56

3/71

0/32

0/57

0/127

0/20

13/113

23/158

Treatment

3/197

14/323

0/85

5/125

2/47

375/3619

3/155

0/59

55/187

6/41

1/20

0/19

2/25

0/11

14/90

Events,

151/1096

9/292

2/50

24/100

3/62

12/46

0/33

0/57

1/32

0/33

1/56

2/71

0/20

12/116

33/157

Control

6/195

20/328

0/86

13/131

5/51

Favors CR Favors control

1.1 1 10

NOTE: Weights are from random effects analysis

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

Maddison 14

Lewin 92

Haskell 94

VHSG 03

ID

Reid 11

Giallauria 08

Yu 04

Zwisler 08

Engblom 96

Shaw (NEDHP) 81

Briffa 05

Hofman-Bang 99

Mutwalli 12

Hambrecht 04

Belardinelli 01

Study

0.82 (0.70, 0.96)

(Excluded)

0.50 (0.25, 1.02)

0.92 (0.71, 1.19)

0.79 (0.38, 1.66)

random (95% CI)

0.63 (0.18, 2.16)

0.44 (0.13, 1.55)

1.16 (0.69, 1.95)

0.98 (0.79, 1.21)

0.68 (0.45, 1.04)

0.98 (0.79, 1.21)

0.98 (0.59, 1.65)

0.81 (0.51, 1.27)

0.27 (0.10, 0.74)

0.14 (0.02, 1.10)

0.52 (0.28, 0.99)

Relative risk

407/1556

0/85

9/58

62/145

11/98

Treatment

4/115

3/30

34/132

95/227

26/102

109/323

19/57

19/46

4/28

1/51

11/59

Events,

453/1474

0/86

18/58

72/155

14/99

Control

6/108

7/31

16/72

94/219

34/91

113/328

19/56

21/41

11/21

7/50

21/59

Events,

Favors CR Favors control

1.1 1 10

NOTE: Weights are from random effects analysis

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 J A N U A R Y 5 / 1 2 , 2 0 1 6 : 1 – 1 2

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37), and hospital admission (30.7% to 26.1%; numberneeded to treat: 22) with exercise-based CR comparedwith no-exercise control subjects. There was nobetween-group difference in total mortality or therisk of fatal or nonfatal MI, CABG, or PCI. Outcomeeffects were consistent across RCTs, irrespectiveof patient case mix (i.e., % of MI patients), thenature of the CR program (i.e., exercise-only orcomprehensive CR, dose of exercise training, or cen-ter- or home-based settings), and study characteris-tics (i.e., sample size, risk of bias, location, lengthof follow-up, or year of publication). There wasevidence of higher levels of HRQL following exercise-based CR compared with control subjects, and alsothat exercise-based CR can be a cost-effective use ofhealth care resources.

In contrast to previous meta-analyses, we didnot observe a statistically significant reduction inall-cause mortality with exercise-based CR. This maybe explained by the inclusion of more recent studiesthat include a more mixed population of CHD pa-tients, conducted in the era of optimal medicaltherapy for CHD. Our review included RCTs con-ducted over a period (1974 to 2014) during whichthere have been a number of major advances inmedical CHD management, such as the increaseduse of statins. We found some support for thishypothesis in our meta-regression analysis, whichshows a trend of a linear reduction (slope: 0.0063;95% CI: �0.00150 to 0.0141; p ¼ 0.08) in the all-cause mortality effect (log RR) of CR over time(i.e., study publication date) (Online Figure 10).Despite the observed improvements in CV mortality,in a context of contemporary CHD medical treat-ments, the opportunity for additional gains in over-all mortality with exercise-based CR may be small.Nonetheless, the observation that exercise-based CRreduces the risk of CV mortality compared with no-exercise control subjects, but does not reduce therisk of MI or revascularization, suggests thatalthough CR does not improve coronary vascularfunction or integrity, it does confer improved sur-vival in patients post-MI.STUDY LIMITATIONS. The generally poor level ofreporting in the included RCTs made it difficult toassess their methodological quality and therebyjudge their risk of bias. However, we did find someimprovements in the quality of reporting in morerecently published studies. Reassuringly, the find-ings of our meta-analysis were consistent whenlimited to studies with a lower risk of bias. Never-theless, the general paucity of reporting led us todowngrade the GRADE quality of evidence foroutcomes to low or moderate. We acknowledge that

the median outcome follow-up of 12 months islimited when assessing the effect on mortality andmorbidity outcome measures. However, our resultswere consistent when pooling was limited to RCTswith a follow up >12 months. Funnel plot asymmetryfor the risk of MI and hospital admission is indicativeof possible publication bias. Included RCTs did notconsistently report all outcomes relevant to this re-view, and events were often reported in study de-scriptions of dropout or withdrawal. Our results are,therefore, on the basis of small and different subsetsof the overall RCT evidence base. However, we foundour overall meta-analysis results to be consistent inthe subgroup of 20 studies reporting both overall andCV mortality outcomes. The minority of trials re-ported non-CV causes of death. Only more recentstudies have begun to consistently report data onhospitalizations, but still often fail to differentiatebetween new and recurrent admissions, whereasHRQL and cost data are still collected infrequently.Finally, we sought to categorize the diagnoses ofstudy participants according to a more detailedframework on the basis of Braunwald’s classificationof CHD (50) to study whether the effect ofexercise-based CR differs according to the pre-sentation, that is, acute coronary syndrome (MI,non–ST-segment elevation MI, unstable angina pec-toris) and stable angina pectoris or treatment mo-dality (PCI, CABG, or medication alone). The limitedreporting by RCTs of inclusion and exclusion criteriaand participant characteristics prevented us fromapplying this categorization. Nevertheless, webelieve this to be the most comprehensive review ofevidence to date, summarizing the results of RCTs in>14,000 patients.

CONCLUSIONS

Among patients with established CHD, provision ofexercise-based CR provides important health benefitsthat include reductions in CV mortality and hospi-talization (and associated health care costs) and im-provements in HRQL. On the basis of a meta-analysisof RCTs, these results support the Class I recom-mendation of current international clinical guidelinesthat CR should be offered to CHD patients. However,future trials need to pay increased attention torecruitment of patients who are more representativeof the broader CHD population, including those athigher risk, with major comorbidities, and also withstable angina. Future trials also need to improve theirquality of reporting, particularly in terms of risk ofbias, details of the intervention and control, clinicalevents, HRQL, and health economic outcomes.

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 moder-

ate risk following MI or revascularization and those with stable

angina.

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.

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ACKNOWLEDGMENTS The authors thank ZhivkoZhelev, Shenqiu Zhang, and Oriana Ciani for theirtranslation services, and Harriot Hunt for herassistance with screening. The authors also thankall of the authors who provided additional infor-mation about their trials and the coauthors ofthe 2 previous versions of this review. Finally,the authors thank the Cochrane Heart Group fortheir support of the co-publication of this articlewith the full version of the review, which is pub-lished on the Cochrane Database of SystematicReviews (51).

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.E-mail: r.taylor@exeter.ac.uk.

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

APPENDIX For an expanded Methods sectionand supplemental figures and tables, please seethe online version of this article.