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

Background —The double-blind, placebo-controlled STARTS-1 study assessed sildenafil in pediatric patients with pulmonary arterial hypertension (PAH); improved hemodynamics and exercise capacity occurred in medium- and high-dose groups. STARTS-2 was the extension study. Methods and Results —In STARTS-1, 234 children ≥8 kg were randomly assigned to low-, medium-, or high-dose sildenafil or placebo orally thrice daily; within-group dose depended on weight. In STARTS-2, sildenafil-treated patients continued STARTS-1 dosing; placebo-treated patients were randomized to 1 of the 3 sildenafil dose groups. Patients requiring additional PAH-specific therapy discontinued study treatment; survival follow-up was attempted. As of August 2011, all children received ≥3 years of treatment (unless discontinued) from STARTS-1 baseline; 37 deaths were reported (26 on study treatment), 1 of which occurred within the first year of treatment. Most patients who died (28/37) had idiopathic/heritable PAH (76% vs 33% overall) and baseline functional class III/IV disease (38% vs 15% overall); patients who died had worse baseline hemodynamics. Kaplan-Meier estimated 3-year survival from start of sildenafil was 94%, 93%, and 88% for patients randomized to low-, medium-, and high-dose sildenafil, respectively; 87%, 89% and 80% were known to be alive at 3 years. Hazard ratios for mortality were 3.95 (95% CI, 1.46-10.65) for high vs low and 1.92 (95% CI, 0.65-5.65) for medium vs low dose; however, multiple analyses raised uncertainty about the survival/dose relationship. Conclusions —Though children randomized to higher compared with lower sildenafil doses had an unexplained increased mortality, all sildenafil dose groups displayed favorable survival for children with PAH. Clinical Trial Registration Information —http://clinicaltrials.gov. Identifier: [NCT00159874][1] (extension study of [NCT00149913][2]). [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00159874&atom=%2Fcirculationaha%2Fearly%2F2014%2F03%2F17%2FCIRCULATIONAHA.113.005698.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00149913&atom=%2Fcirculationaha%2Fearly%2F2014%2F03%2F17%2FCIRCULATIONAHA.113.005698.atom