Effectiveness of exercise after PCI in the secondary prevention of coronary heart disease: A systematic review

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European Journal of Integrative Medicine 3 (2011) e63–e69

Review Article

Effectiveness of exercise after PCI in the secondary prevention of coronary heart disease: A systematic review Ruo-Xi Yu 1 , Falk Müller-Riemenschneider ∗ Institute for Social Medicine, Epidemiology and Health Economics, Charité University Medical Centre Berlin, Luisenstraße 57, 10098 Berlin, Germany Received 7 December 2010; received in revised form 7 April 2011; accepted 8 April 2011

Abstract Introduction: Percutaneous coronary intervention (PCI) and exercise-based cardiac rehabilitation are cornerstones of treatment for coronary heart disease (CHD). Previous research indicates that exercise alone might be more effective than PCI. This systematic review aims to investigate the effectiveness of exercise training or PCI alone compared to the combination of both for the secondary prevention of CHD. Materials and methods: A structured database search identified eligible publications. Relevant studies, published between 1992 and 2009, that report mortality, cardiac events, restenosis or quality of life were included. Methodological quality was evaluated by two reviewers using standardised checklists. Results: Of 1282 studies identified, six met the inclusion criteria, five RCTs and one cohort study. Quality and outcome reporting of the studies was variable. Duration of follow-up ranged from three to fifteen months. No studies were found that compared the combination of PCI and exercise with just exercise. One study reported significantly lower mortality, four significantly lower incidence of coronary events in the intervention group undergoing PCI and exercise rehabilitation compared to the control group only undergoing PCI. Also, five studies found a significantly lower incidence of restenosis in the intervention group and one showed that quality of life was significantly higher in intervention patients. Conclusions: Our findings provide evidence for the positive effects of exercise in addition to PCI in secondary prevention of CHD. Despite the positive effects of exercise compared to PCI alone, no studies have investigated additional benefits of PCI in a combined approach compared to exercise alone. © 2011 Elsevier GmbH. All rights reserved. Keywords: Cardiac rehabilitation; Coronary heart disease; Percutaneous coronary intervention; Exercise training

Introduction Cardiovascular diseases are a much-discussed issue. Their high prevalence and the resulting morbidity and mortality cause many socio-economic and healthcare policy problems both in industrialized and developing countries. In 2005, they were responsible for 45% of all-cause mortality in western countries and 25% in developing countries [1]. Coronary heart disease (CHD) is by far the most common cause of death in industrialized countries [2]. In 2009, about 15% of deaths in Germany were caused by CHD and acute myocardial infarction (AMI) [3].

∗

Corresponding author. Tel.: +49 30 450529036; fax: +49 30 450529902. E-mail addresses: [email protected] (R.-X. Yu), [email protected] (F. Müller-Riemenschneider). 1 Fax: +49 30 450529902. 1876-3820/$ – see front matter © 2011 Elsevier GmbH. All rights reserved. doi:10.1016/j.eujim.2011.04.021

In 1998, the World Health Organisation (WHO) set out to reduce mortality caused by cardiovascular diseases in the age group beneath 65 by 40% until 2020 [4]. While the primary prevention of CHD is particularly important to achieve this goal, appropriate and effective secondary prevention strategies for patients with established CHD are also necessary. Percutaneous coronary intervention (PCI) is an increasingly popular procedure used for the treatment of CHD. In 1984, 56,797 cardiac catheter examinations were performed in Germany, of which 5% included stenting. In 2007, there were already 830,658 PCI procedures and the percentage of those performed with stent implantation increased to about 88% [5]. However, although positive effects of PCI in treatment of unstable CHD have been widely shown [6], a positive risk–benefit-ratio for PCI in the secondary prevention of stable CHD is not as clear. The procedure bears the risk of complications and not uncommonly needs reintervention due to restenosis.

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The positive effects of exercise in the primary and secondary prevention of CHD are well known. Numerous studies show the positive effects of physical exercise on the currently recognised causal risk factors of CHD such as hypercholesterolemia [7], arterial hypertension [8,9], diabetes mellitus [10], and other possible risk factors [11–13]. Randomised controlled trials (RCTs) have also shown that exercise is associated with a lower incidence of cardiac events [14,15]. A large meta-analysis of 8440 patients in 13 studies has shown a reduction in CHD mortality by 31% in patients who had exercise as part of their cardiac rehabilitation programmes compared to those who did not [16]. These results raise the question of how effective physical exercise and PCI are compared to each other in the secondary prevention of CHD. An RCT [17] comparing those two measures came to the conclusion that regular exercise results in a longer event-free survival at lower cost than PCI. Also, exercise was associated with a lower rate of rehospitalisation and revascularisation. There have been meta-analyses in review articles that show the positive effects of exercise as a part of a rehabilitation programme in CHD [18,19]. Those findings raise the question, whether exercise or PCI can individually prevail against the combination of both measures. This systematic review attempts to summarise the current evidence regarding this question. Our aim is to present results of studies that either compared PCI or exercise alone to a combination of PCI and an exercise.

- Comparison of PCI and exercise compared to PCI without exercise or to exercise without PCI - Outcomes: mortality, restenosis, cardiovascular events and quality of life (QoL) The exercise programme had to be clearly described. Studies that examined only surrogate parameters were excluded. We also included studies that did not have exercise as the only rehabilitation measure but as part of a multimodal programme. Studies were also included, if they did not only examine exercise as a rehabilitation programme after PCI, but also after other procedures, such as coronary artery bypass surgery or after AMI, as long as the population of those who underwent a PCI, was evaluated individually. Reasons for exclusion were documented. Data extraction and quality evaluation

Materials and methods

Data extraction was performed systematically using standardised checklists. Methodological quality of included studies was assessed independently by two reviewers based on the CONSORT 2010 Statement Checklist [20]. Statements about the main quality characteristic randomisation, blinding, documentation of drop-outs and baseline differences were documented (Table 2) and the studies were subsequently rated according to the Scottish Intercollegiate Guidelines Network [21], 1++ standing for high quality RCTs, 1+ for well conducted RCTs, 1− for RCTs with a high risk of bias and 2+ for well conducted cohort studies.

Search strategy

Results

A systematic search in the PubMed database was carried out in order to identify relevant studies. All entries before January 8, 2010 were considered. Standardised keywords under the “Medical Subject Headings” (MESH) system were used. In detail; the search strategy was as follows: (“Coronary Disease” [Mesh] OR “Angina Pectoris” OR “Coronary Disease”) AND (“Sports” [Mesh] OR “Exercise” [Mesh] OR “Physical Fitness” [Mesh] OR “Motor Activity” [Mesh] OR “Secondary Prevention” [Mesh] OR “Rehabilitation” [Mesh] OR Sport OR Exercise OR “Physical Fitness” OR “Motor Activity” OR “Physical Activity” OR Training) AND (“Angioplasty” [Mesh] OR “Stents” [Mesh] OR Angioplasty OR PCI OR PTCA OR Stent OR “Percutaneous Coronary Intervention”) In a first screening step, all references clearly not meeting the inclusion criteria were sorted out. The full texts of all potentially relevant references were analysed and checked for compliance with the inclusion criteria. The bibliographies of included articles were manually reviewed for relevant studies. In addition, references of two meta-analyses on secondary prevention of CHD were searched for further relevant publications [18,19]. The inclusion criteria were:

Search results

- Patients with established CHD - Prospective and retrospective studies - Publication in English or German

The search in PubMed yielded 1271 potentially relevant references. In addition, eleven articles were found by manual search of reference lists. 1235 references were excluded based on the review of titles and abstracts, which resulted in 47 publications for detailed review of full-text articles. Of those, six studies published between 1992 and 2009 were finally included in our systematic review (Fig. 1). Five studies were RCTs [22–26] and one was a retrospective cohort study [27]. Characteristics of included studies The main methodological characteristics of the included studies are summarised in Table 1. Inclusion criteria for patients in all studies were a scheduled or completed PCI. The PCI either included a mandatory [25] or facultative [27] stent implantation or was carried out only using balloon dilatation [26]. In two studies, the PCI was not described in detail [22,24]. Five out of six studies had exclusive exercise programmes as intervention, one had a multimodal rehabilitation programme with an exercise component [27]. The duration of the intervention ranged from three to eight months, follow-up period ranged from the end of the intervention to 12 months. In the retrospective cohort study [27], participants were evaluated 15 months after intervention onset.

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Fig. 1. Flow-chart of study selection; PCI, percutaneous coronary intervention; RCT, randomised controlled trial.

Table 1 Methodological characteristics of the studies. Author (year)

Description of the PCI

Study population (n; age; gender)

Duration of Intervention intervention/followup

Munk (2009), Norway

PCI w/ BMS or DES

I: n = 20; 61 yrs; f/m = 4/16, C: n = 20; 57 yrs; f/m = 3/17

6 mths/6 mths

Bäck (2008), Sweden

Elective PCI

I: n = 21; 62 yrs; f/m = 4/17, C: n = 16; 64 yrs; f/m = 1/15

8 mths/8 mths

Vasiliauskas (2007), Lithuania

PCI w/ balloon dilatation

I: n = 95; 58 yrs, C: n = 90; 60 yrs

6 mths/12 mths

Dendale (2005), Belgium

PCI w/ or w/o stent; stenting rate: I: 73%, C: 66%

I: n = 140; 62 yrs; f/m = 33/107, C: n = 83; 68 yrs; f/m = 29/52

3 mths/15 mths

Belardinelli (2001), Italy

PCI w/ or w/o stent

I: n = 59; 53 yrs; f/m = 10/49, C: n = 59; 59 yrs; f/m = 9/50

6 mths/12 mths

Kubo (1992), Japan

PCI

I: n = 18; 59 yrs; f/m = 4/14, C: n = 20; 58 yrs; f/m = 4/16

3 mths/3 mths

Ex: begin 11 ± 4 d after PCI; in group; 3x/w 1 h of interval training on treadmill or treadmill + strength training Ex: begin 2 mths after PCI; at home; 5x/w 30 min treadmill (or up to 2x/w running or swimming instead) + 3x/w strength training Ex: begin shortly after PCI; 1 mths stationary, 3 mths outpatient, 2 mths at home; 4 mths 20 to 40 min, 2 mths 30–60 min 7x/w treadmill Multimodal rehab prgm: begin 2 w after PCI; Ex: 3x/w 1 h treadmill, cycling, arm cycling; psychological and dietary counselling, advise to join smoking cessation prgm Ex: begin ca. 25 d after PCI; stationary, supervised; 3x/w 30 min treadmill, warm-up, cool-down (53 min total) Ex: begin after PCI, 6x/w 30–40 min treadmill or outdoor walk-run prgm

Control

No training, both I and C received drugs: ASA, clopidogrel, statin

Both I and C could join optional rehab prgm incl. lifestyle consulting, aerobic, strength training for 4–6 mths, 2x/w Drugs only

No organised rehab prgm

Basic daily mild physical activities and avoidance of any physical Ex recommended; both groups received drugs No Ex

PCI, percutaneous coronary intervention; yrs, years; f/m, relation of female to male participants; w/, with; BMS, Bare metal stent; DES, drug eluting stent; I, intervention group; C, control group; mth, month; Ex, exercise; d, day; w, week; h, hour; min, minutes; I: intervention groups; C, control group; ASA, acetylsalicylic acid; rehab, rehabilitation; prgm, programme; incl., including.

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Table 2 Quality characteristics. Author (year)

Study type

Level of evidence

Randomisation described

Blinding

Drop-outs documented

Baseline differences

Munk (2009) Bäck (2008) Vasiliauskas (2007) Dendale (2005) Belardinelli (2001) Kubo (1992)

RCT RCT RCT RCS RCT RCT

1+ 1+ 1− 2+ 1++ 1−

Yes Yes No – Yes No

No No No – Single-blinded No

Yes Yes Yes – Yes Yes

None Some None Some None None

RCT, randomised controlled trial; I, intervention group; C, control group; ex, exercise; prgm, programme; ns, not significant; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention; RCS, retroperspective cohort study.

The exercise programmes varied from study to study, as depicted in Table 1. However, they all had in common that aerobic exercise using a treadmill was one of the main components. The respective control groups mostly only received drug treatment, Belardinelli et al. [23] recommended control patients to avoid physical exercise in contrast to the study by Bäck et al. [22], where control patients could voluntarily participate in a rehabilitation programme with exercise. The age distribution was similar in the various studies and ranged from an average of 53 years to an average of 62 years. In all studies, significantly fewer women than men were enrolled. Quality characteristics One RCT [23] was rated 1++, two [22,25] 1+, two [24,26] 1−, the cohort study was rated 2+. Main reasons for limited quality were non-blinded assessment and lack of allocation concealment. Substantial differences at baseline were not found with few exceptions in the studies by Bäck et al. [22] and Dendale et al. [27]. Important quality characteristics are shown in Table 2. Effectiveness of exercise alone compared to PCI plus exercise Not a single study could be found that compared a patient group undergoing PCI and exercise to an exercise only control group. Therefore, no conclusions with regard to this research question can be drawn at present. Effectiveness of PCI alone compared to PCI plus exercise Except for one [22], all studies showed the superiority of PCI plus exercise compared to PCI alone regarding one or more of the relevant outcomes. Four of the studies [24–27] even showed significantly better results with respect to all the investigated outcomes that were relevant to this review. Only one study [27] explicitly examined the outcome mortality. In patients undergoing a three-month intervention, it was significantly lower in the intervention group (0.7%) than in the control group (6.0%) after 15 months. In another study [23], mortality was not among the investigated outcomes, but it was mentioned that it was 0% in both groups. In all other studies, the mortality rate was not reported.

The incidence of non-fatal coronary events was investigated in four [23,25–27] of the six studies. In all studies, it was significantly lower in the intervention group (see Table 3). A coronary event was defined differently in the studies and the various kinds of events were itemised in different ways so that a comparison of the events between studies was difficult. It must be noted that if angina pectoris was specified as a coronary event [25–27], its occurrence was significantly less frequent in the intervention group than in the control group. In two studies [25,27], the incidence of AMI was not significantly different between the groups; it was even lower in the control group in the study by Dendale et al. [27], but not significantly. In contrast, the study [23] with the highest methodological quality demonstrated a trend towards lower incidence in the intervention group (1.7–5.2%, p = 0.31). Further results on the individual events can be seen in Table 3. All six studies reported the incidence of restenosis. However, the determination of restenoses varied. In one study [22], no significant differences were found between the groups. While all remaining studies reported significant differences in restenosis rates, favouring intervention groups. Among these five studies, three [25–27] reported a lower incidence of restenosis and two studies [23,24] reported a lower residual diameter stenosis in the intervention groups. Only two studies reported QoL as an outcome. While Belardinelli et al. [23] reported the global QoL, Bäck et al. [22] investigated the health related QoL (HRQoL). The global QoL was measured with the help of two questionnaires, the Duke Activity Status Index (DASI) [28] and the Medical Outcomes Study short-form General Health Survey [29]. Within the patients of the intervention group, it was significantly higher six and twelve months from baseline than at the beginning of the intervention; it was also significantly higher in the intervention group compared to the control group at the last point of follow-up. The HRQoL was measured with the Short Form-36 questionnaire [30]. Bäck et al. [22] did not find significant differences between the groups six months from baseline except for the category physical role limitations, favouring intervention group patients. However, both intervention and control group had significantly higher HRQoL scores at follow-up compared to baseline. All results are summarised in Table 3.

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Table 3 Study results. Author (year)

Mortality

MACE; n (%)

QoL

Restenosis; n (%)

Munk (2009)

–

–

Sig lower in I; late luminal loss per patient: I: 0.10mm; C: 0.39 mm; late luminal loss per stent: I: 0.05 mm; C: 0.43 mm

Bäck (2008)

–

Sig lower in I; I: 8(40), C: 12(60) (hospitalisation due to AP attack I: 2, C: 4; coronary angiography I: 1, C: 4; revascularisation with PCI or CABG I: 4, C: 3; AMI I: 1, C: 1) –

Differences ns between the groups after 6 mths

Vasiliauskas (2007)

–

HRQoL assessed by SF-36: I and C sig higher scores after intervention exc physical role limitations within C; differences between the groups ns exc physical role limitations with higher scores in I –

Dendale (2005)

Sig lower in I: 1(1), C: 5(6)

Belardinelli (2001)

I: 0; C: 0

Kubo (1992)

–

Sig lower in I; I: 6(6), C: 18(20) (unstable AP with re-PCI I: 3, C: 17; CABG I: 3, C: 1) Sig lower in I; all MACE I: 34(17), C: 35(42) (revascularisation with PCI or CABG I: 24(17), C: 25(21); recurrent AP I: 10(7), C: 17(21); ns for AMI I: 4(3), C:2(2) Sig lower in I; I: 7(12), C: 19(32) (revascularisation I: 4, C: 11; AMI I: 1(2), C: 3(5); CABG I: 2(3), C: 5(9))

–

–

QoL assessed DASI and MOS questionnaires: sig higher scores after 6 and 12 mths in I compared to C and to baseline

–

Sig lower in I; in cases of unstable AP, restenoses were detected: I: 2(2); C: 14(16) Sig lower in I: 19(14), C: 19(23)

Differences in incidence ns; I: 15(29), C: 17(33), p = 0.81; residual diameter stenosis sig lower in I; I: 11 ± 13%, C: 9 ± 16% shortly after PCI, I: 41 ± 28%, C: 53.2 ± 27% after 6 mths Differences in incidence ns; I: 3(17), C: 8(41); residual diameter stenosis sig lower in I; I: 22 ± 9%, C: 25 ± 11% shortly after PCI, I: 40 ± 13%, C: 55 ± 20% after 3 mths

MACE, major adverse cardiac event; AP, angina pectoris; QoL, quality of life; sig, significant; I, intervention group; C, control group, PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; AMI, acute myocardial infarction; HRQoL, health related quality of life; SF-36, short form 36; exc, except; mth, month; ns, not sig; DASI, Duke activity status index; MOS, medical outcomes study.

Discussion In summary, despite PCI and exercise being cornerstones of the treatment of patients with established CHD, this systematic review found only few studies that specifically investigated the combined effectiveness of these strategies. More importantly, it needs to be pointed out that no studies were found that investigated whether a combination of PCI and exercise is superior to an exclusive exercise programme. Given the results of previous research, indicating a possible superiority of exercise to PCI and in view of the health economic consequences and possible adverse effects of PCI, this is an important question, which could have impact on future secondary prevention strategies. In contrast, our systematic review shows that there is considerable evidence for the effectiveness of the combination of PCI and exercise compared to PCI alone. The results are in particular convincing with respect to the incidence of cardiac events and restenosis. Thus, the review supports findings from previous reviews, which reported a positive effect of exercise-based rehabilitation for CHD [18,19]. Due to the low number of studies and the lack of studies investigating the comparative effectiveness of different exercisebased strategies, choice of the most appropriate strategy could not be determined within this systematic review. Warburton et al.

[31] found that high-intensity interval training in CHD patients results in a greater anaerobic tolerance than traditional continuous exercise without increasing the risk to the patient. Findings like those might be interesting for the future alignment of rehabilitation programmes. Although the results of our systematic review highlight the currently low number of appropriate studies investigating posed research questions, our findings also show that there seems to be an increasing interest in the effectiveness of various exercise strategies in the secondary prevention of CHD. While included studies were published between 1992 and 2009, more than half of the studies were published in 2007 or later. With respect to other potentially relevant lifestyle factors, the study by Munk et al. [25] showed that five of six smokers in the intervention group gave up smoking after the intervention of six months, but only one of six patients in the control group. The Body Mass Index (BMI) decreased significantly in many intervention group patients in the studies, whereas in the control groups it did not significantly decrease or even increased. The effects on smoking behaviour and BMI lead to the assumption that participation in an exercise programme is generally associated with better health awareness and healthy lifestyle, so that a healthier lifestyle through exercise could be an additional positive side effect of exercise.

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During the literature research, we also found many studies that examined the effect of exercise on several other than the investigated outcomes. Also, in included studies, other outcomes were examined. Positive effects of physical exercise in rehabilitation after PCI were reported, e.g. on cardiac function, blood pressure and heart rate, serum parameters such as blood cholesterol, C-reactive protein, interleukin-6, tumour necrosis factor-␣ or blood glucose [32–34]. Many of the parameters are associated with coronary heart disease or are accepted long-term risk factors for cardiac events. In particular, the positive effects on these parameters might have great influence on the patients’ cardiac health also long time after follow-up. Therefore, this review may even underestimate the positive effect of exercise. As in any systematic review, certain limitations should be noted. Most importantly, the studies were very heterogeneous. Not only did the exercise programmes vary, but there was also a multimodal programme, which limited comparability. Also, the PCIs varied, some were performed only with balloon dilatation, some with stent implantation, partly using bare-metal stents, partly drug-eluting stents. In some studies, the type of PCI was not even specified. However, in the study by Dendale et al. [27], PCI was performed either with or without stent implantation with no significant differences in the occurrence of cardiac events, so that both patient groups where pooled for evaluation. The studies varied also widely in their duration and investigated outcomes, so that there were only few results available on the outcomes relevant for the present systematic review. The outcomes were also itemised in different ways. Since only two studies investigated the QoL using two different questionnaires, the validity of the findings should not be overestimated. The age of participants only ranged from an average of 53 years to an average of 68, also women were clearly underrepresented. Moreover, it should be noted that there was a high compliance in all groups among the intervention studies, which is rarely accomplished under real life conditions. Studies have shown that in reality less than 50% of patients are willing to participate in rehabilitation programmes, even if they are free of charge [35]. In summary, there is considerable evidence for the effectiveness of the combination of PCI and physical exercise compared to PCI without exercise in the secondary prevention of CHD. However, although further studies are warranted to investigate e.g. the effectiveness of this approach in certain underrepresented subgroups and the comparative effectiveness of different exercise strategies, findings highlight that exercise should be an integral part of secondary prevention strategies. No studies are at present available, which investigate the effectiveness of exercise compared to PCI plus exercise. This should be addressed in future research. Financial support None. Conflict of interest None declared.

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