Assessment of measurement properties of peak VO(2) in children with pulmonary arterial hypertension

Abstract

Background: The 6-minute walk test evaluates the effect of pharmacologic intervention in adults with pulmonary arterial hypertension (PAH) but, for reasons of compliance or reliability, may not be appropriate for children at all ages. Thus, peak oxygen consumption (VO2, maximal exercise test) was used instead in a pediatric PAH trial (STARTS-1) to evaluate pharmacologic intervention with sildenafil. This was the first large placebo-controlled trial to use the peak VO2 endpoint in this population. Our working hypothesis was that, as with other populations, percentage changes in peak VO2 in pediatric patients with PAH are reliable and are associated with changes in other clinical endpoints.

Methods: Using data from the subpopulation of 106 patients who were developmentally and physically able to perform exercise testing, all of whom were World Health Organization Functional Class (WHO FC) I, II, or III, reliability was assessed using the intraclass correlation coefficient and Bland-Altman plot on screening and baseline data. Relationships between percentage change in peak VO2 from baseline to end of treatment and other endpoints were evaluated using correlation coefficients and regression analyses.

Results: The intraclass correlation was 0.79 between screening and baseline peak VO2, an agreement that was supported by the Bland-Altman plot. Percentage change in peak VO2 correlated well (r ≥0.40) and showed responsiveness to a physician global assessment of change and with change in WHO FC (for baseline classes I and III). Percentage change in peak VO2 did not correlate with change in the Family Cohesion of the Child Health Questionnaire (r = 0.04) or with a subject global assessment of change (r = 0.12). The latter may have been influenced by child and parental-proxy response and instrument administration.

Conclusion: In pediatric PAH patients who are developmentally and physically able to perform exercise testing, peak VO2 measurements exhibited good reliability and improvements that were associated with improvements in certain other clinical endpoints, such as the WHO FC and a physician global assessment.

Trial registration: ClinicalTrials.gov identifier NCT00159913.

Figures

Figure 1

Bland-Altman plot assessing the agreement between screening and baseline mean peak VO2. Note: mean (standard deviation) difference = 0.23 (2.81). VO2 = oxygen consumptio7n.

Figure 2

Relationship of percentage change in peak VO2with the physician global assessment of change. Percentage change in peak VO2 was for baseline to end of treatment values. Physician global assessment of change was responded to at the end of treatment. Note: the linear slope estimate, indicated by the straight line, was 8.0. A sensitivity analysis, which was performed excluding outliers, achieved similar results. VO2 = oxygen consumption.

Figure 3

Relationship of percentage change in peak VO2with the subject global assessment of change. Percentage change in peak VO2 was for baseline to end of treatment values. Subject global assessment of change was responded to at the end of treatment. Note: the linear slope estimate, indicated by the straight line, was 2.2. A sensitivity analysis, which was performed excluding outliers, achieved similar results. VO2 = oxygen consumption.

Figure 4

Relationship of percentage change in peak VO2with change in WHO FC. Percentage change in peak VO2 and change in WHO FC was for baseline to end of treatment values. Patients with WHO FC I (A), WHO FC II (B), and WHO FC III (C) at baseline. Note: no improvement was possible for patients with WHO FC I at baseline and improvement of only 1 FC was possible for patients with WHO FC II at baseline. VO2 = oxygen consumption; WHO FC = World Health Organization Functional Class.