Introduction
• How effective is cardiac rehabilitation?
• Are particular interventions in cardiac rehabil- itation more effective than others?
• Does cardiac rehabilitation offer benefits over and above other secondary prevention mea- sures, such as drug therapy?
• Are there groups of patients in which cardiac rehabilitation is more (or less) effective?
• Is home-based cardiac rehabilitation as effective a method of delivering cardiac rehabilitation as supervised center- or hospital-based programs?
• Does cardiac rehabilitation provide good value for money?
These are the principal questions raised by healthcare administrators, hospital managers, and regional and national healthcare policy makers involved in the commissioning of cardiac rehabil- itation (CR) services. This chapter examines the evidence for CR in order to address each of these questions. The question of value for money (or “cost-effectiveness”) will be dealt with in Chapter 60, Economic Evaluation of Cardiac Rehabilitation.
Before we examine the evidence for CR, we need to determine what constitutes “good” evidence and, specifically, consider the concept of the
“hierarchy of evidence.”
The Evidence Hierarchy – the Randomized Controlled Trial and the Systematic Review
It is well accepted that the gold standard study design for establishing the effect of a therapy (or collection of therapies as in the case of cardiac rehabilitation) is the randomized controlled trial (RCT).1 For example, let’s say we want to know the effectiveness of a 12-week outpatient cardiac rehabilitation program for patients with New York Heart Association (NYHA) class II and III heart failure (HF).
According to this design, patients would be randomly assigned (usually by means of a computer-generated random number sequence) to receive usual medical care (e.g. drug therapy, advice etc.) or outpatient CR plus usual medical care. Patients would undergo an assessment battery (e.g. exercise test, questionnaires of psychological well-being, number of hospitaliza- tions for HF in last 3 months) prior to random- ization and, then again, at various follow-up points thereafter. The strength of the RCT (assuming that the study size is large enough) is that the process of randomization ensures that the characteristics of the two groups (e.g.
age, sex, severity of disease) are identical.
Thus it can be assumed that any difference in the outcome at follow-up is due to CR rather
2
The Evidence Base for Cardiac Rehabilitation
Rod S. Taylor and Kate Jolly
9
than selection bias, that is, a difference in the patient characteristics of the two groups. Such is this bias, that it is well documented that non- randomized studies tend to overestimate the effect of therapies by some 20% to 30% compared to RCTs.2
Nevertheless, one RCT is rarely enough evi- dence on its own. A single study may well not be large enough to have the statistical power to detect the effect of the treatment being tested, particularly if that effect is fairly small – as most modern day therapies are. A single study may not be representative of the range of real world practice. For example, returning to the example RCT, it may be that your practice includes patients with NYHA class IV heart failure. It may be that your CR practice only includes exercise training while the RCT is based on exercise training plus stress manage- ment training and education. By looking for all RCTs that have investigated the question of the impact of CR on patients with HF, it is more likely that this overall body of evidence will reflect the range of real world practice than will one RCT alone.
The systematic review is a methodology that comprehensively gathers studies (RCTs or other design) together in as unbiased a manner as possible to address a particular healthcare question.3 Many systematic reviews include a “meta-analysis,” that is, a statistical technique that allows the results of several studies to be combined into a single numerical estimate. Meta-analyses provide greater statistical power than a single RCT alone. One of the best sources of good quality systematic reviews and meta-analyses over the last decade has become the Cochrane Library.4 The Cochrane Library is the output of the Cochrane Collabora- tion, an international movement with the bold mission of “Preparing, maintaining and dis- seminating systematic reviews of the effects of (whole of) health care.”
At the time of writing this chapter, three Cochrane systematic reviews were published that directly examine the effectiveness of CR.5–10 The remainder of this chapter dis- cusses the findings of these three systematic reviews in the context of the questions posed above.
How Effective Is CR?
Although the question “how effective is my therapy?” appears a simple one, for CR a careful framing of the question is required in order to provide a meaningful answer. In contrast to taking a drug, CR is a “complex intervention” – one
“made up of various interconnecting parts.”11CR is complex in a number ways. First, it is a multi- faceted intervention that can consist of exercise training, psychological therapy (e.g. stress man- agement), education, and other interventions (e.g.
occupational counseling) and is usually delivered by a multidisciplinary team. It can be delivered in a variety of different settings (hospital, commu- nity center, or patient’s own home) and at differ- ent points in the disease continuum (phase I to IV programs). Finally, CR is often targeted at/to a population of patients that include a variety of cardiac diagnoses, usually post acute myocardial infarction, post coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA) and, increasingly, heart failure.
Each of three Cochrane systematic reviews has been scoped to address specific aspects of the question of the effectiveness of cardiac rehabilitation.
1. Effectiveness of Exercise-Based Cardiac Rehabilitation for Coronary Heart Disease (CHD) – Taylor et al.
6This Cochrane review examines the question of the effectiveness of exercise-based CR (exercise training alone or exercise training combined with other therapies, such as education or psychologi- cal interventions) compared to usual care in patients with CHD (post myocardial infarction, angina pectoris, or following CABG and PTCA).
The latest version of this review was published in 2004 by Taylor and colleagues and updates the original Cochrane review on this subject per- formed in 2000 by Jolliffe et al. and previous sys- tematic reviews in 1988 by Oldridge et al. and 1989 by O’Connor et al. The 2004 review identified a total of 48 RCTs in 8940 CHD patients. A total of 19 RCTs assessed exercise training only, 30 RCTs combined exercise with other interventions
(“comprehensive CR”) and one RCT assessed both exercise only and comprehensive CR. The review reported three groups of outcomes – clinical end- points (mortality and morbidity), risk factor levels, and health-related quality of life. The meta- analysis of clinical endpoints is shown in Figure 2-1. Compared to usual care, exercise-based CR significantly reduced total mortality by 20% and cardiac mortality by 26%, although there was no significant reduction in nonfatal MI events or the need for recurrent CABG or PTCA. Exercise-based
cardiac rehabilitation was associated with improvements in a number of primary risk factors including lipid profile and smoking behavior (Table 2-1). A total of nine RCTs assessed patient health-related quality of life (HRQoL) using a validated outcome measure. Given the range of HRQoL instruments used, the authors were not able to pool results across studies. However, all RCTs reported an improve- ment in HRQoL (total or domain score) with exercise-based CR. Nevertheless, and perhaps
0.50 1.00 2.00
Need for PTCA [11]
Need for CABG [19]
Non fatal MI [19]
Cardiac mortality [16]
All cause mortality [33]
Favours rehabilitation Favours control
0.80 (0.68 to 0.94) Pooled Odds Ratio
0.74 (0.61 to 0.90) 0.79 (0.57 to 1.09) 0.87 (0.65 to 1.16) 0.81 (0.64 to 1.34)
FIGURE2-1. Summary of impact of exercise-based CR on clinical events in patients with CHD.6[ ], number of trials.
TABLE2-1. Summary of impact of exercise-based6and psychology-based CR7on primary risk factors
Exercise-based CR Psychology-based CR
Outcome Mean difference+
Total cholesterol (mmol/L) −0.34 (−0.56 to −0.11)* −0.27 (−0.55 to 0)*
HDL cholesterol (mmol/L) 0.03 (−0.06 to 0.11) 0.05 (−0.10 to 0.08) LDL cholesterol (mmol/L) −0.32 (−0.55 to −0.10)* −0.16 (−0.69 to 0.37)
Triglycerides (mmol/L) −0.28 (−0.49 to −0.06)* Not reported
Systolic blood pressure (mmHg) −0.5 (−6.5 to 5.5) 0.05 (0.01 to 0.08)*
Diastolic blood pressure (mmHg) −0.6 (4.5 to 2.8) −1.9 (−4.8 to −1.1)*
Relative risk++
Smoking 0.77 (0.62 to 0.94)* 0.81 (0.53 to 1.25)
*Statistically significant at P≤ 0.05.
+Mean difference <0: indicates reduced in the CR group than usual care.
++Relative risk <1.00 indicates lower probability of outcome in the CR group than usual care group.
surprisingly, only one RCT reported an improve- ment that exceeded that observed in the usual care controls.
2. Effectiveness of Psychology-Based CR – Rees et al.
7In the 2004 Cochrane review, Rees et al. examined the question of the effectiveness of psychology- based CR compared to usual care in patients with CHD.
This Cochrane review updates two previous systematic reviews by Linden et al. in 1996 and Dusseldorp et al. in 1999 that assessed this ques- tion. These latter two reviews have been criticized as being both non-systematic and including non- randomized evidence.7
Rees et al. identified a total of 36 RCTs across 12,841 CHD patients. The authors reported clini- cal endpoints, risk factor levels, psychological well-being and HRQoL. Meta-analysis showed a 28% reduction in the number of nonfatal MI events with psychological CR but no significant change in either all cause or cardiac mortality (Figure 2-2). Significant improvements in lipid profile and diastolic blood pressure
were observed with psychological CR (Table 2-1). The authors reported improvement in anxiety (−0.07 standard deviation units, 95% CI:
−0.15 to: 0.01) and depression (SMD: −0.032, 95% CI: −0.56 to −0.08) with CR. Two out of five RCTs reported improvements in HRQoL with CR.
3. Effectiveness of Exercise-Based CR for Heart Failure – Rees et al.,
8Smart et al.,
9and ExTraMATCH
10Three meta-analyses have recently been published that examine the effectiveness of exercise-based CR (aerobic training alone or combined aerobic and resistance training) compared to usual care in patients with heart failure – the Cochrane review by Rees et al. in 2003, a systematic review and meta-analysis by Smart and colleagues, and a meta-analysis performed by a collaboration of the trial authors (the ExTraMATCH group, 2004).
Because of their different timings (Rees et al. searched up to March 2001 while Smart et al. searched up to May 2003) and use of
0.50 1.00 1.5
Need for revascularation [15]
Non fatal MI [18]
Cardiac mortality [11]
All cause mortality [22]
Pooled Odds Ratio
0.93 (0.81 to 1.06)
0.86 (0.72 to 1.03) 0.78 (0.67 to 0.90)
0.87 (0.67 to 1.13)
Favours rehabilitation Favours control FIGURE2-2. Summary of psychology-based CR on clinical events in patients with CHD.7
systematic review methods (ExTraMATCH did not explicitly search for all published RCTs but used all those RCTs known to the authors) the comprehensiveness of these three studies varied (Table 2-2) as did, to some extent, their conclusions.
The main point of departure in the results of the three meta-analyses was total mor- tality. Compared to usual care, no significant difference in total mortality with CR was reported by either Rees et al. (pooled odds ratio 1.13, 95% CI: 0.58 to 2.22) or Smart et al. (pooled odds ratio 0.85, 95% CI: 0.51 to 1.41).
However, ExTraMATCH reported a statistically significant 35% reduction in total mortality with exercise training (pooled hazard ratio 0.65, 95% CI: 0.46 to 0.92). Why the difference in result? ExTraMATCH was a meta-analysis where the authors had access to individual patient outcome data from each RCT. This more positive result of ExTraMATCH was due to the inclusion of the recent 3-year follow-up of the Belardinelli et al. trial, a large and positive trial not included at the time of the Cochrane review by Rees et al. in 2003.
The greater number of events in the trials included in the ExTraMATCH review suggested that the authors might have had access to unpublished outcome results collected over a longer follow-up period. In view of the poten- tially non-systematic selection of evidence by the ExTraMATCH authors, the positive conclu- sion of exercise-based CR on total mortality should be interpreted cautiously.
Exercise-based CR appeared to have benefit for both exercise tolerance and HRQoL. Rees et al.
reported a significant increase in maximum oxygen consumption of 2.1 mL/kg/min (95% CI:
2.8 to 1.4). Seven out of the nine RCTs reported a significant improvement HRQoL following CR. In five of these trials the improvement exceeded that of the usual care group.
Are Particular Interventions Within Cardiac Rehabilitation More Effective Than Others?
Few RCTs have that been designed to directly assess the (“subgroup”) question of whether there are differences in the relative effectiveness of the different components of CR, for example exercise- training versus psychological interventions; dose
“x” of exercise training versus dose “y”; or com- prehensive rehabilitation versus exercise training only.
However, some (albeit indirect) evidence on this question is available from the Cochrane reviews. Meta-analyses potentially provide an opportunity to compare the results of one group of trials to another, so-called “meta-regression,”
and thereby allow these subgroup questions to be examined. Such subgroup analyses were reported by the meta-analyses of Taylor et al. (2004) and ExTraMATCH.
Taylor et al. found no significance in the impact of CR on total mortality when comparing trials TABLE2-2. Summary of scope of meta-analyses of exercise-based CR for heart failure
ExTraMATCH Smart et al. Rees et al. (2003;
(2004)10 (2004)9 Cochrane)8
Diagnosis Ejection fraction Ejection fraction Clinical diagnosis
<50% <40%
RCTs (n) 12 39 29
Aerobic alone 7 Not reported 23
Aerobic + resistance 2 6
Patients (n) 801 1394 1126
Outcomes Mortality Exercise tolerance Exercise tolerance
Hospitalization Mortality Mortality
Hospitalization Morbidity Hospitalization Quality of life
Dose: amount of exercise prescribed: 1,000 units is equivalent to 3 months of 3 sessions/week for 30 mins/session
Odds Ratio
0.5 1.0 1.5
Jadad score >3 [4]
Jadad score =<3 [28]
Publication after 1995 [6]
Publication up to 1995 [27]
Follow up >24 months [16]
Follow up ≤24 months [17]
Dose >1,000 [8]
Dose≤1,000 [5]
CCR [21]
EX CR [12]
All CHD diagnoses [9]
Post MI only [23]
All cause mortality
FIGURE2-3. Exercise-based CR for CHD: subgroup analyses I.7 of exercise-only CR to comprehensive CR or
when comparing trials of different exercise doses (based on overall duration, session fre- quency, and session duration) of exercise (Figure 2-3). Similarly, the ExTraMATCH group reported no difference in total mortality with CR comparing trials of less than 28 weeks
exercise training to trials of 28 weeks or more (Figure 2-4).
Therefore it appears that there is little evi- dence that one form or method of CR interven- tion is better than another. Nevertheless, given the indirect nature of these comparisons there is a need for caution in this conclusion12
Sex
Age
Cause
Left ventricular ejection traction
Peak oxygen consumption
Duration of training
Total 88/395 105/406
Functional class Male
>60 years
>27%
>15 ml/kg/min
>28 weeks 41/216 60/219
47/179 45/187
0.25 0.5 Exercise better
Exercise worse
1 2 4
<28 weeks
<15 ml/kg/min
<27%
NYHA I-II
Ischaemic Non-ischaemic NYHA III-IV
52/202
45/206
54/256 34/139
38/193
36/177 52/218
50/202 69/219
36/187
73/233 32/173 75/253 30/153 43/189
36/193
65/205 40/201
43/206 62/200
<60 years
79/349 95/354 0.60 (0.41 to 0.87) 7.30 0.01
0.27
0.74
0.84
0.10
0.30
0.43
0.53 1.17 (0.41 to 3.34) 0.09 0.77
0.64 (0.41 to 0.99) 3.97 0.05 0.65 (0.36 to 1.18) 2.02 0.16
0.69 (0.40 to 1.20) 1.75 0.19 0.63 (0.40 to 0.99) 4.03 0.05
0.54 (0.35 to 0.83) 7.78 0.01 0.93 (0.52 to 1.68) 0.06 0.81
0.83 (0.45 to 1.50) 0.40 0.53 0.59 (0.38 to 0.92) 5.54 0.02
0.74 (0.39 to 1.40) 0.86 0.35 0.63 (0.42 to 0.96) 4.59 0.03
0.64 (0.41 to 0.99) 4.08 0.04 0.66 (0.37 to 1.19) 1.88 0.17
0.65 (0.46 to 0.92) 5.92 0.015
9/46 10/52
Training No of events
No of events No at
risk
Hazard ratio (95% CI)
P value Effect Interaction χ2
No at risk Control
Death
Female
FIGURE2-4. Exercise-based CR for HF – subgroup analyses.10(Reproduced with permission of the BMJ.)
and further direct evidence on this issue is needed.
Does Cardiac Rehabilitation Offer Benefits over and above Other Secondary Prevention Measures, Such as Drug Therapy?
In the last 10 to 15 years, there has been a large increase in the use of drug therapies in secondary preventive management in patients with CHD, notably lipid-lowering agents, such as statins, and beta-blockers. Meta-analyses show that the im-
provement in survival with exercise-based CR appears to be similar to that of many accepted cardiac drug therapies (Table 2-3). However, the early systematic reviews of CR have been criticized because the usual care arm included RCTs that are not reflective of current practice. Indeed, it has been argued that the benefits of exercise and psychology-based interventions used in CR would be substantially reduced in the context of current therapy. In response, many rehabilitation special- ists argue it is artificial to attempt to partition sec- ondary prevention (including drug therapy) and CR. Nevertheless, what evidence do we have to support the benefits of CR over and above current cardiac drug therapy? To answer this question,
Taylor et al. (2004) compared the magnitude of all cause mortality reduction with exercise-based CR in more recent trials (1995 and later) to that found in older trials (before 1995) (Figure 2-3). It was assumed that the more recent trials would include standard care and current secondary preventative drugs. As Taylor et al. found no significant differ- ence between the two time periods (Figure 2-4), they concluded that the benefits of exercise-based CR “are not limited to particular CHD patient subgroups or particular models of exercise intervention.”6
Are There Groups of Patients in Which Cardiac Rehabilitation Is More
(or Less) Effective?
CR is increasingly being extended beyond the tra- ditional patient groups of CHD and post PTCA and CABG and, more recently, heart failure.
Patients with valvular disease, with an implanted intracardiac defibrillator or biventricular pace- maker, and unstable angina, including acute coronary syndrome, can now receive CR in some
Odds Ratio
0.8 1.0 1.2
age<60yrs [4]
age<=60yrs [29]
MI & other grps[9]
all MI [24]
male & female [18]
male only [14]
FIGURE2-5. Exercise-based CR for CHD – subgroup analyses II.7 TABLE2-3. Comparison of the mortality benefits of CR* versus cardiac therapies
Relative reduction Reduction in all
No. of trials in all cause cause mortality per
(no. of patients) mortality 1000 per year
Beta-blockers17 31 trials (24,974) 23% (15–31%) 12 (6–17)
ACE inhibitors18 22 trials (102,476) 17% (2–11%) 4 (1–6)
Statins19 3 trials (17,617) 23% (15–30%) 4 (2–6)
Antiplatelets20 11 trials (18,773) 24% (16–32%) 7 (1–3)
Cardiac 44 trials (8700) 16% (4–27%) 9 (15 to 116)
rehabilitation*
*Exercise-based CR.
Source: From Taylor et al.6
centers. It is beyond the scope of this section to discuss the evidence for the role of CR in these later patient groups. However, there remains the question of whether there are patients within the more traditional groups of CHD, post PCI and HF, in which CR is more (or less effective). Targeting of therapies to particular patient subgroups is often used to optimize the cost-effectiveness of a therapeutic regime.
The meta-analyses by Taylor et al. and ExTra- MATCH used meta-regression to examine the effect of a number of patient characteristics (e.g.
age, sex, diagnoses, NYHA classification) on the impact of exercise-based CR for CHD and HF, respectively. Both groups reported no significant difference in the benefit of CR across these patient subgroups (Figures 2-4 and 2-5). Thus there appears to be little evidence, at this time, to limit the use of CR in any particular CHD or HF subgroups.
Is Home-Based Cardiac Rehabilitation as Effective a Method of Delivering Cardiac Rehabilitation as Supervised Center- or Hospital-Based Programs?
Home-based CR provision has become more com- monplace in number of countries. For example, a number of healthcare providers in the UK have purchased the Heart Manual, a self-help resource designed for the home-based CR of CHD patients following a myocardial infarction. There are a number of reasons for the development of home-based programs: increasing pressure on hospital-based services; the difficulty in patient transportation; patients’ dislike of group-based CR sessions, and the belief that home-based reha- bilitation may facilitate a faster return to normal life and may better sustain an increase in activity.13 The question therefore arises as to whether home-based and hospital- (or center-) based pro- grams are equally effective.
This question was not addressed by the three Cochrane reviews. Indeed, most, if not all, of the RCT evidence in these reviews came from the tra- ditional hospital setting. However, Jolly and col- leagues in 2005 have undertaken a systematic review of home-based CR.
In this review, they identified 18 RCTs that compare home-based CR to usual care and 6 RCTs that compare home-based to center-based CR. The authors reported significant improvements in sys- tolic blood pressure (4 mmHg, 95% CI: 6.5, 1.5) and a reduced relative risk (RR) of being a smoker at follow-up (RR: 0.71, 95% CI: 0.51, 1.00) in home program participants. Nonsignificant improve- ments in exercise capacity, total cholesterol, and psychological well-being were all in favor of the home-based CR compared to usual care. There was insufficient evidence to comment on the impact on clinical events. When directly com- pared to center-based CR, the effects of home- based CR on exercise tolerance and risk factors appeared to be similar. However, only 750 patients have been included in these later trials to date.
Recent RCTs of home-versus-hospital-based cardiac rehabilitation confirm that outcomes and overall costs of the two approaches are similar.14,15
Conclusions
1. Three Cochrane systematic reviews/meta- analyses have assessed the effectiveness of cardiac rehabilitation.5–8
2. These reviews provide level I evidence16 that, when compared to usual care alone: (a) exercise-based cardiac rehabilitation reduces mortality and improves the risk factor profile of CHD patients; (b) psychology-based cardiac rehabilitation improves psychological well-being and risk factor profile of CHD patients; and (c) exercise-based cardiac rehabilitation improves exercise tolerance and HRQoL of heart failure patients. The impact of CR on total mortality at the time of writing remains uncertain. Further evidence is needed on the effects of cardiac rehabilitation on health-related quality of life in CHD patients and total mortality of heart failure patients.
3. There is currently little evidence to support the belief that particular cardiac rehabilitation interventions are more effective than others or that cardiac rehabilitation should be limited to any particular CHD or HF patient subgroups.
However, given the increasing resource and financial limitations of providing cardiac rehabil-
itation to all patients, there is a need for additional effectiveness and cost-effectiveness evidence on this issue.
4. Cardiac rehabilitation appears to have similar effects whether provided in a hospital- (or center-) based facility or at home. Therefore, where possible, patients should be offered hospital- or home-based CR. However, more evidence is needed, particularly as to the cost-effectiveness of CR provision in different settings.
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