Inclusion of trials in the ExTraMATCH II surrogate analyses

All 19 trials from the ExTraMATCH II study were eligible for inclusion in the surrogate analyses, if they provided the required data (as detailed in Chapter 3). Only 10 trials^{19,51,58,61–67} provided data for the surrogate analyses. Figure 12 summarises the availability of studies and patient data for exercise capacity and the patient-relevant outcomes of mortality, hospitalisation and HRQoL.

FIGURE 12

The PRISMA flow diagram summarising the selection of studies for the ExTraMATCH II surrogate analyses. Δ6MWT, change in 6-minute walk test; ΔVO₂peak, change in VO₂peak.

Characteristics of included patients and trials

Patient baseline characteristics were well balanced across the ExCR and control groups (Table 19). Patients had a mean age of 62 years and the majority were male (73%). The mean baseline left ventricular ejection fraction was 26% and most patients were in NYHA functional class II (63%) or III (34%). Studies were published between 2000 and 2012 from a range of geographical locations (Table 20). Sample size was typically small and ranged from 50 to 2130 patients. All trials included ExCR based on an aerobic exercise intervention. The dose of ExCR ranged widely across studies, with an average session duration of 15–60 minutes, of two to seven sessions per week, exercise intensity equivalent of 40–70% VO₂peak and delivery duration of 4–120 weeks. The change in exercise capacity and final patient-relevant outcomes for each included study are shown in Table 21.

TABLE 19

Baseline characteristics of patients in surrogate analyses

TABLE 20

Characteristics of included studies and interventions in surrogate analyses

TABLE 21

Change in exercise capacity and final patient-relevant outcomes for each included study

Assessment of study quality and risk of bias

The overall quality of included trials was judged to be moderate to good, with a median TESTEX³¹ score of 11 (range 10–14) out of a maximum score of 15 (Table 22).

TABLE 22

Assessment of quality of included studies in surrogate analyses using TESTEX scale

Findings

Mediation analysis

The four criteria that must be satisfied to establish that change in exercise capacity is a mediator of mortality, hospitalisation and change in HRQoL are listed in Table 23. First, mean improvements were seen in all exercise capacity metrics of ExCR compared with control, although none reached statistical significance at p < 0.05. Second, greater differences in exercise capacity significantly reduced the risk of mortality and hospitalisation and were associated with a larger gain in HRQoL. Third, although ExCR decreased both the risk of mortality and hospitalisation, and was also associated with a larger gain in HRQoL, there was no statistically significant difference compared with the control. Finally, the effect of ExCR compared with control on final patient-relevant outcomes was attenuated by adding Δ6MWT and ΔVO₂peak (directly and indirectly measured) to the model. No attenuation was seen with the addition of ΔVO₂peak when measured directly.

TABLE 23

Criteria to establish change in exercise capacity as a mediator in the relationship between treatment effect and patient-relevant final outcomes

Meta-analytic regression: R² and surrogate threshold effect

Regression coefficients of determination (R²) and correlation coefficients (p-value) between the change in exercise capacity and hospitalisation were poor (R²_trial < 50% and p < 0.50). Moderate to good levels of correlation (R²_trial > 50% and p > 0.50) between exercise capacity VO₂peak and 6MWT with mortality and HRQoL were seen (Table 24). The STE for MLHFQ score ranged from an increase of 1.6 to 4.6 ml/kg/minute for VO₂peak. The STE was not estimable for the 6MWT. Negative correlation coefficients indicate that larger ExCR effects on exercise capacity are associated with larger ExCR effects on mortality and HRQoL. Figures 13–15 illustrate the results of the meta-regression and STE analyses.

TABLE 24

Surrogacy metrics for change in exercise capacity and final outcomes

FIGURE 13

Regression analyses: relationship at the 6-month follow-up between ΔVO₂peak direct and (a) log(HR) of all-cause mortality; (b) ΔHRQoL all outcomes; (c) log(HR) of all-cause hospitalisation; and (d) ΔMLHFQ score. Circles represent (more...)

FIGURE 15

Regression analyses: relationship between ΔVO₂peak direct and indirect and (a) log(HR) of all-cause mortality; (b) ΔHRQoL all outcomes; (c) log(HR) of all-cause hospitalisation; and (d) ΔMLHFQ score. Circles represent trial-level (more...)

FIGURE 14

Regression analyses: relationship at the 6-month follow-up between Δ6MWT and (a) log(HR) of all-cause mortality; (b) ΔHRQoL all outcomes; (c) log(HR) of all-cause hospitalisation; and (d) ΔMLHFQ score. Circles represent trial-level (more...)

Small-study bias

There was no evidence of significant small-study bias, as shown by the funnel plots (Figure 16) or Egger’s test p-values, for any of the exercise capacity outcomes (ΔVO₂peak direct, p = 0.699; Δ6MWT, p = 0.93; ΔVO₂peak direct and indirect, p = 0.553), or for the four patient-relevant final outcomes (ΔMLHFQ score, p = 0.607; ΔHRQoL outcomes, p = 0.659; mortality, p = 0.745; hospitalisation, p = 0.733).

FIGURE 16

Funnel plots for the surrogate analyses. (a) VO₂peak; (b) 6MWT; (c) converted exercise capacity score; (d) HRQoL; (e) MLHFQ score; (f) mortality; and (g) hospitalisation.