Background
Pulmonary arterial hypertension (PAH) is a relatively rare condition associated with high mortality [
1]. It is characterized by increased pulmonary vascular resistance and pulmonary arterial pressure leading to right ventricular failure and ultimately death [
2]. It may be inherited (heritable PAH [HPAH], classified as familial or sporadic), develop spontaneously (idiopathic PAH [IPAH]), or occur in association with congenital heart defects, connective tissue disease, or other causes (associated PAH [APAH]) [
3]. Oral sildenafil citrate (REVATIO®, Pfizer Inc, New York, NY) has been found to be efficacious and generally well tolerated in the treatment of chronic PAH in adults, both as disease-specific monotherapy and as add-on to intravenous therapy with epoprostenol [
4,
5]. However, safe and effective therapy to increase the functional capacity, quality of life, and survival of pediatric patients with PAH is also needed.
A widely used, noninvasive technique to assess PAH severity and response to treatment is the 6-minute walk test, which is based on improvements in submaximal exercise capacity [
6,
7]. However, when the first large, multicenter, randomized, double-blind, placebo-controlled clinical trial to investigate the effectiveness of sildenafil treatment for PAH in children who require treatment despite conventional therapy was being designed (ClinicalTrials.gov: NCT00159913) [
8], many specialists believed that compliance with the directions for the 6-minute walk test could be difficult for children. Children may become uninterested or demotivated by factors unrelated to PAH, which could impact reliability of the test. Additionally, they may walk at a variable pace, resulting in unreliable or unstable measurements. Thus, for the design of the clinical trial, it was decided to use formal cardiopulmonary exercise testing that could be more readily standardized.
The ability to perform aerobic work is defined by peak oxygen consumption (VO
2) at maximal effort [
9]. Peak VO
2 is a parameter of noninvasive cardiopulmonary exercise testing that is affected by age, sex, conditioning status, disease, or medications. Its prognostic value in terms of survival has been demonstrated in adult patients with IPAH [
10]. Thus, percentage change from baseline to end of treatment in peak VO
2 was selected as the primary efficacy endpoint in the controlled clinical trial of sildenafil treatment for PAH in children, making it the first trial of its kind with the potential to evaluate the correlation between changes in peak VO
2 and other clinical endpoints [
8].
The aim of this paper is to investigate the measurement properties of peak VO2 in terms of its associations with other clinical endpoints and its reliability. It was hypothesized that, as observed with other populations, percentage changes in peak VO2 in pediatric patients with PAH are reliable and are associated with changes in certain clinical endpoints.
Discussion
In general, the results indicate that the peak VO2 has favorable measurement properties in pediatric patients with PAH who are developmentally and physically able to perform exercise testing. The magnitude of the correlation of mean percentage change in peak VO2 with the PGA was dependent on active or placebo treatment. This is to be expected because the placebo group is likely to have a more restricted range of values (which represent measurement variability and random fluctuations over time). In contrast, the active treatment group is likely to have a wider range of values (from the additional variability of individual treatment responses).
In a 16-week trial, it is not surprising that only 4 patients (all WHO FC I at baseline) reported deterioration in WHO FC. The importance of this endpoint is in the observance of improvement in WHO FC. However, for the large proportion of patients who were WHO FC I or II at baseline, there was no or limited room for improvement (unlike in WHO FC III patients). Eight of the 56 patients (14%) who were WHO FC II at baseline improved, but 14 of 21 patients (67%) who were WHO FC III at baseline improved. For these patients with WHO FC III at baseline, there was a strong positive association with percentage change in peak VO2.
It was unexpected that the percentage change in peak VO2 would share a low correlation with the SGA, and it may reflect influence by factors associated with child and parental-proxy responses and with instrument administration. A placebo response may have been observed with the SGA, in which patients (regardless of treatment group) are shifted toward a “mild improvement” response whether or not peak VO2 improves. In contrast, “markedly improved” on the SGA is unlikely to be caused by a placebo response and most such patients had clear improvement in peak VO2. This disparity can impair the correlation. The low correlation between the percentage change in peak VO2 and the SGA becomes less surprising given that a post-hoc correlation between PGA and SGA was not very high (0.39). The PGA correlated well with the change in WHO FC in the subgroup with baseline FC III but the SGA did not. The SGA is a mixture of parent and patient (child) responses, the meaning of which may be confounded, especially when the patient is young.
Endnotes
aRoyal Children's Hospital Ethics in Human Research Committee, Royal Children's Hospital, Parkville, VIC AUSTRALIA; Comitê de Ética em Pesquisa do Instituto Dante Pazzanese de Cardiologia, São Paulo, BRAZIL; The Hospital for Sick Children Research Ethics Board, Toronto, ON, CANADA; Health Research Ethics Board, Biomedical Research, University of Alberta Walter Mackenzie Health Science Centre, Edmonton, AB, CANADA; Children's and Women's Health Centre of BC Research Review Committee, Vancouver, BC, CANADA; Clinical Research Ethics Board, Vancouver, BC, CANADA; Comité Ético Científico Pediátrico, Santiago, CHILE; Comité de Evaluación Etico Científico, Hospital Dr. Sótero del Río Servicio de Salud Metropolitano Sur Oriente, Santiago, CHILE; Comite de Etica en Investigacion - Hospital Santa Clara – Empresa Social del Estado, Bogota, Cundinamarca, COLOMBIA; Comite de Etica en Investigacion Clinica - Fundacion Cardio Infantil, Instituto de Cardiologia, Departmento de Investigaciones, Bogota, Cundinamarca, COLOMBIA; Comite de Etica de la Clinica Cardiovascular, Medellin, Antioquia, COLOMBIA; Consejo Nacional de Investigacion en Salud, CONIS, Ministerio de Salud, San Jose, COSTA RICA; UCIMED Comite Etico Cientifico de la Universidad de Ciencias Medicas, San Jose, COSTA RICA; Latin Ethics, Guatemala, GUATEMALA; Medical Research Council Ethics Committee for Clinical Pharmacology, Budapest, HUNGARY; Institutional Ethics Committee, CARE Foundation - CARE Hospital, Hyderabad, Andhra Pradesh, INDIA; Research and Ethics Committee, Amrita Institute of Medical Sciences & Research Centre, Kochi, Kerala, INDIA; Comitato Etico dell'azienda ospedaliera di Bologna – Policlinico S.Orsola-Malpighi, Bologna, ITALY; Toho University Omori Medical Center Institutional Review Board, Ohta-ku, Tokyo, JAPAN; Joint Penang Independent Ethics Committee, Clinical Research Center, Gleneagles Medical Center, Penang, MALAYSIA; Comité de Bioética, Instituto Nacional de Cardiologia "Dr. Ignacio Chavez", Mexico, DF, MEXICO; Komisja Bioetyczna przy Instytucie, Pomnik Centrum Zdrowia Dziecka, Warszawa, POLAND; Komisja Bioetyczna Slaskiego, Uniwersytetu Medycznego w Katowicach, Katowice, POLAND; Komisja Bioetyczna Uniwersytetu Jagiellonskiego, Krakow, POLAND; Ethics Committee at the Federal Service on Surveillance in Healthcare and Social Development, Moscow, RUSSIAN FEDERATION; The Ethics Committee under Federal Agency of Quality Control Medicines, Moscow, RUSSIAN FEDERATION; Regionala etikprovningsnamnden i Lund, Lund, SWEDEN; Joint Institutional Review Board, Taipei, TAIWAN; National Taiwan University Hospital Ethics Committee, Taipei, TAIWAN; Western Institutional Review Board, Olympia, WA, UNITED STATES; Children's Hospital of Wisconsin, Milwaukee, WI, UNITED STATES; Children's Research Institute, Human Subjects Research Committee/CHRF Administration, Columbus, OH, UNITED STATES; Stanford University Medical Center Institutional Review Board, Stanford, CA, UNITED STATES; Colorado Multiple Institutional Review Board, Aurora, CO, UNITED STATES; Children's Hospital Boston, Committee on Clinical Investigators, Boston, MA, UNITED STATES; Washington University Medical Center Institutional Review Board, Human Studies Committee, St. Louis, MO, UNITED STATES; University of Michigan Institutional Review Board – Medicine, University of Michigan Hospitals and Health Systems, Ann Arbor, MI, UNITED STATES; Children's Hospital Medical Center Institutional Review Board, Seattle, WA, UNITED STATES; Medical University of South Carolina, Office of Research Integrity, Charleston, SC, UNITED STATES; Vanderbilt University Institutional Review Board, Nashville, TN, UNITED STATES.
Competing interests
Joseph C. Cappelleri, Lie-Ju Hwang, Jack Mardekian and Marko A. Mychaskiw are employees of Pfizer Inc (USA), the manufacturer of sildenafil citrate.
Authors’ contributions
All authors participated in varying ways to the conception, design, analysis, or interpretation of results; and to the drafting of the manuscript or to its revision for important intellectual content. In addition, all authors read and approved the final manuscript.