STARTS-2: Long-Term Survival With Oral Sildenafil Monotherapy in Treatment-Naïve Pediatric Pulmonary Arterial Hypertension

Study Questions:

What is the long-term survival of patients treated with sildenafil as monotherapy for pediatric pulmonary arterial hypertension (PAH)?


The STARTS-2 (Sildenafil in Treatment-Naïve Children, Aged 1-17 Years With Pulmonary Arterial Hypertension) trial is an extension study of the STARTS-1 trial, published in 2012. In STARTS-1, 234 children were randomly assigned to low-, medium-, or high-dose sildenafil or placebo three times daily. PAH was idiopathic or heritable in 33% of patients and associated with a congenital heart defect in 67%. Patients requiring additional PAH-specific therapy discontinued study treatment.


As of August 2011, all children had received ≥3 years of treatment from the onset of the STARTS-1 study. A total of 37 deaths were reported, of which 26 occurred on treatment, and one occurred within the first year of treatment. The majority (28/37) of patients who died had idiopathic/heritable PAH, and a larger proportion (38% vs. 15% overall) were functional class II/IV disease at baseline. Kaplan-Meier estimated 3-year survival rates from initiation of sildenafil for patients on low-, medium-, and high-dose sildenafil were 94%, 93%, and 88%, respectively. Hazard ratios for mortality were 3.95 (95% confidence interval, 1.46-10.65) for high- versus low- and 1.92 (95% confidence interval, 0.65-5.65) for medium- versus low-dose sildenafil. Multiple additional analyses suggested uncertainty regarding the relationship of dose to mortality.


The authors concluded that while children randomized to higher as compared with lower sildenafil doses had an unexplained increased mortality, all dose groups displayed favorable survival, as compared with historical data for children with pulmonary hypertension.


The use of sildenafil in pediatric patients with PAH has been controversial since the STARTS-1 trial suggested higher mortality in patients treated with higher- as compared with lower-dose sildenafil. The primary prespecified endpoint for the STARTS-1 trial was placebo-corrected change in peak oxygen consumption, an outcome which was not met. Secondary outcomes, including functional class and hemodynamics, improved in patients in the medium- and combined medium-/high-dose groups, but not in the low- or high-dose groups. As a result of concerns for lack of efficacy of lower doses, and increased mortality with higher doses, the US Food and Drug Administration recommended against the use of sildenafil in pediatric pulmonary hypertension. Subsequently, significant concerns regarding the methodology and implications of the STARTS-1 trial have been raised. Two of the primary concerns regarding the trial are the lack of a clear mechanism of increased mortality for patients on higher doses of sildenafil, as well as significant confounding of the survival analysis. This extension study again showed increased mortality in children randomized to higher doses of sildenafil, but also provided additional reasons to doubt the validity of the dose/mortality relationship described in the original study. The risk of treatment-related mortality is likely lower than the perceived risk, which prompted the recommendation against the use of sildenafil in pediatric pulmonary hypertension. Practitioners considering sildenafil in pediatric pulmonary hypertension should acquaint themselves with the nuances of these trials and perform individual risk/benefit assessments for patients in this highly heterogeneous population.

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