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.
- Received August 16, 2013.
- Revision received February 6, 2014.
- Accepted February 18, 2014.