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Taylor RS, Walker S, Ciani O, et al. Exercise-based cardiac rehabilitation for chronic heart failure: the EXTRAMATCH II individual participant data meta-analysis. Southampton (UK): NIHR Journals Library; 2019 May. (Health Technology Assessment, No. 23.25.)

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Exercise-based cardiac rehabilitation for chronic heart failure: the EXTRAMATCH II individual participant data meta-analysis.

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Chapter 5Impact of exercise-based cardiac rehabilitation on mortality and hospitalisation

One trial that provided IPD was not included in the mortality and hospitalisation analyses, as no data were provided to allow calculation of survival time or time to hospitalisation.59 This resulted in the inclusion of 18 trials,19,50,51,53–58,60–67,73 comprising 3912 patients (1948 ExCR patients and 1964 control patients), with a median follow-up of 19 months for mortality outcomes and 11 months for hospitalisation outcomes. Figure 2 summarises the study selection process for the mortality and hospitalisation analyses.

FIGURE 2. The PRISMA flow diagram summarising the selection of studies for mortality and hospitalisation analyses.

FIGURE 2

The PRISMA flow diagram summarising the selection of studies for mortality and hospitalisation analyses.

Characteristics of included patients and trials

Patient baseline characteristics were well balanced between ExCR patients and control patients (Table 4). The majority of patients were male (75%), with a mean age of 61 years (SD 13 years). The mean baseline left ventricular ejection fraction was 27% (SD 8.1%), no included studies recruited patients with HFpEF (i.e. an ejection fraction of > 45%), and most patients were in NYHA functional class II (59%) or III (37%). Studies were published between 1999 and 2012 across a number of countries (see Table 2). Sample size ranged from 50 to 2130 patients. All trials evaluated an aerobic exercise intervention; six also included resistance training.52,57,58,61,64,65 Exercise training was most commonly delivered in either an exclusively centre-based setting or a centre-based setting in combination with some home exercise sessions (Table 5). Three trials were conducted in an exclusively home-based setting.52,54,58 The dose of exercise training ranged widely across studies, with an average session duration of 15–120 minutes (including warm-up and cool-down), two to seven sessions per week, of exercise intensity equivalent of 50–85% VO2peak and delivery duration of 12–90 weeks.

TABLE 4

TABLE 4

Baseline characteristics of patients in the mortality and hospitalisation analyses

TABLE 5

TABLE 5

Characteristics of included trials in the mortality and hospitalisation analyses

Assessment of study quality and risk of bias

There was no evidence of significant small-study bias for the four outcomes (Figure 3). The overall quality of included trials was judged to be moderate to good, with a median TESTEX31 score of 11 (range 9–14) out of a maximum score of 15 (Table 6). The criteria of allocation concealment and physical activity monitoring in the control groups were met in only three studies;19,58,66 the other TESTEX criteria were met in ≥ 50% of the trials.

FIGURE 3. Funnel plots for mortality and hospitalisation analyses.

FIGURE 3

Funnel plots for mortality and hospitalisation analyses. (a) All-cause mortality, Egger’s test –0.26, p = 0.458; (b) HF-specific mortality, Egger’s test –1.60, p = 0.147; (c) all-cause hospitalisation, (more...)

TABLE 6

TABLE 6

Assessment of quality using TESTEX scale of included studies in mortality and hospitalisation analysis

Findings

Primary analysis

Compared with control, all time-to-event mean treatment effects from the two-stage random-effects IPD meta-analysis were in favour of ExCR, but had wide CIs and were not statistically significant [all-cause mortality: HR 0.83 (95% CI 0.67 to 1.04; p = 0.107, 17 studies,19,50–55,57,58,60–67 3782 patients, τ2 = 0.04, I2 = 26%); HF-specific mortality: HR 0.84 (95% CI 0.48 to 1.46; p = 0.527, 9 studies,51–54,58,60,64,65,67 915 patients, τ2 = 0.00, I2 = 0%); all-cause hospitalisation: HR 0.90 (95% CI 0.76 to 1.06; p = 0.210, 11 studies,19,51,54,55,57,58,60,61,64–66 3190 patients, τ2 = 0.01, I2 = 12.4%); and HF-specific hospitalisation: HR 0.98 (95% CI 0.72 to 1.35; p = 0.902, 13 studies,19,50,51,52,56–58,60,61,64–67 3494 patients, τ2 = 0.10, I2 = 45%)] (Figure 4 and Tables 7–10).

FIGURE 4. Effect of ExCR on mortality and hospitalisation across patient subgroups: two-stage IPD meta-analysis.

FIGURE 4

Effect of ExCR on mortality and hospitalisation across patient subgroups: two-stage IPD meta-analysis. (a) All-cause mortality; (b) HF-specific mortality; (c) all-cause hospitalisation; and (d) HF-specific hospitalisation. DANREHAB, DANish Cardiac ReHABilitation (more...)

TABLE 7

TABLE 7

All-cause mortality: overall treatment effect and subgroup (interaction) effects

TABLE 10

TABLE 10

Heart failure-specific hospitalisation: overall treatment effect and subgroup (interactions) effects in studies included in IPD meta-analysis

TABLE 8

TABLE 8

Heart failure-specific mortality: overall treatment effect and subgroup (interaction) effects

TABLE 9

TABLE 9

All-cause hospitalisation: overall treatment effect and subgroup (interaction) effects

Interaction analyses for the two-stage model revealed no consistent interaction between the effect of ExCR and any of the predefined subgroups (age, sex, ejection fraction, NYHA class, HF aetiology, ethnicity or baseline exercise capacity) for all-cause mortality, HF-related mortality, all-cause hospitalisation or HF-related hospitalisation (see Tables 7–10). In order to make further comparisons of mortality and hospitalisation rates within each subgroup, the HR and associated 95% CI from individual subgroup one-stage IPD meta-analyses are shown in Figure 5. The p-values from the interaction test in the two-stage IPD meta-analyses are presented alongside these estimates.

FIGURE 5. Effect of ExCR on mortality and hospitalisation across patient subgroups: individual subgroup one-stage IPD meta-analyses.

FIGURE 5

Effect of ExCR on mortality and hospitalisation across patient subgroups: individual subgroup one-stage IPD meta-analyses. (a) All-cause mortality; (b) HF-related mortality; (c) all-cause hospitalisation; and (d) HF-related hospitalisation. a, Although (more...)

Secondary analyses

These primary analysis results were broadly consistent across secondary analyses.

Sensitivity analyses

In sensitivity analyses, four weak interaction effects (p < 0.05) were seen:

  1. Age compared with all-cause mortality (p = 0.034) in the two-stage 2-year truncation model (i.e. larger reduction in all-cause mortality with ExCR in older patients).
  2. Age compared with HF-related mortality (p = 0.017) in the two-stage 2-year truncation model (i.e. larger reduction in HF-related mortality with ExCR in older patients).
  3. Ischaemic status compared with HF-related mortality (p = 0.047) in the one-stage model (i.e. larger reduction in HF-related mortality with ExCR in ischaemic patients).
  4. Standardised baseline exercise capacity compared with all-cause hospitalisation (p = 0.027) in the two-stage 1-year truncation model (i.e. larger reduction in all-cause hospitalisation with ExCR in patients with lower than average baseline exercise capacity) (see Tables 7–10).

Inferences did not change following the addition of trial-level data from trials that met the study inclusion criteria but did not contribute IPD (data are not shown here, but are available from the authors of this report).

Copyright © Queen’s Printer and Controller of HMSO 2019. This work was produced by Taylor et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.
Bookshelf ID: NBK541559
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