HONOLULU – The use of oral sildenafil helped improve oxygen delivery and exercise capacity in children with pulmonary arterial hypertension, results from a randomized, multicenter trial showed.

The study, which employed cardiopulmonary exercise testing – including assessment of ventilation to carbon dioxide (VE/VCO₂) slope – "confirmed our suspicion that ventilatory efficiency, as measured by VE/VCO₂, appears to be a sensitive measurement to assess exercise ability in pediatric pulmonary arterial hypertension as long as the children are old enough and developmentally able to exercise reliably," lead investigator Dr. Robyn J. Barst said in an interview in advance of the annual meeting of the American College of Chest Physicians, where the study was presented. Using such measures may allow future trials to determine drug effectiveness and safety with fewer study participants, thus shortening time to approval for new drugs, she said.

The STARTS-1 study included 234 treatment-naive children with pulmonary arterial hypertension (PAH), who were aged 1-17 years and weighed 8 kg or more. Participants were randomized to receive placebo or low, medium, or high doses of oral sildenafil three times a day at 1 of 32 centers in 16 countries, including the United States. Doses were based on weight groups – 8-20 kg, 20-45 kg, and more than 45 kg – with the doses ranging from 10 to 80 mg t.i.d. Sildenafil is approved in the European Union for the treatment of PAH in children at a dose of 10 mg t.i.d. for children who weigh less than 20 kg and a dose of 20 mg t.i.d. for children who weigh more than 20 kg, but is not currently approved in the United States for this population.

The researchers measured peak oxygen consumption (VO₂) and VE/VCO₂ levels at the beginning of the study and again at 16 weeks in 106 children who could reliably exercise on a bicycle. The primary outcome was percent change in peak VO₂. Cardiopulmonary exercise testing, rather than the more frequently used 6-minute walk test, was used to assess exercise capacity, because cardiopulmonary exercise testing is "considered a more sensitive exercise test than the 6-minute walk test; many patients have a fairly good 6-minute walk test despite significant pulmonary arterial hypertension," explained Dr. Barst, professor emeritus of pediatrics at Columbia University, New York.

Although the primary end point of percent change in peak VO₂ comparing the combined three sildenafil dose groups with placebo did not meet predefined criteria (P = .056), children in the medium- and high-dose sildenafil groups did have significantly greater improvements in peak VO₂ and VE/VCO₂ slope, compared with those on placebo, whether the pulmonary arterial hypertension was idiopathic/heritable or associated with congenital heart disease. Upper respiratory tract infections, pyrexia, and vomiting occurred more often with sildenafil than placebo. The majority of adverse events were mild or moderate.

The study demonstrated that cardiopulmonary exercise testing "is a relatively simple exercise test that can be carried out safely in an exercise lab experienced in caring for children and adults with PAH," Dr. Barst said. "Further, measurement of ventilatory efficiency does not require the patient to exercise to maximal exertion. And there now is a more simplified gas analysis system available than what was used in this study to assess these same parameters. It is a miniaturized, simplified, and portable system that has been designed for submaximal exercise testing. Utilizing the [Shape-HF Cardiopulmonary Testing System, Shape Medical Systems] should be useful to clinicians for long-term follow-up assessments to determine if their patients are responding adequately to their current treatments."

Dr. Barst acknowledged certain limitations of the study, including the fact that not all children were old enough or able to perform cardiopulmonary exercise testing. "However, all enrolled patients did have safety assessments, functional capacity evaluations, and pulmonary hemodynamic parameters obtained by invasive right heart catheterization at both baseline and at the end of the 16-week study, to obtain objective parameters of disease severity known to be prognostic for long-term outcomes," she said.

An additional limitation of most controlled studies performed in PAH, she added, is the relatively short study duration – 16 weeks in this case. "When the data from STARTS-1 [were] combined with interim data – more than 2 years – from the ongoing extension STARTS-2 study, in which all patients received active drug, the overall profile [favored] the medium dose," she said. "Further investigation is warranted to determine optimal dosing based on age and body weight."

Pfizer funded the study. Dr. Barst served as a consultant for the company during the July 2010 Food and Drug Administration advisory committee meeting on sildenafil treatment for pediatric pulmonary arterial hypertension. Dr. Barst also has received honoraria from Actelion, Eli Lilly, Gilead, GlaxoSmithKline, Ikaria, Merck, and Novartis for consulting work.

Sildenafil Found Beneficial in Pediatric PAH