This study evaluated long-term survival of pediatric patients with pulmonary arterial hypertension treated with oral sildenafil monotherapy. It found that over 3 years, 71% of patients remained on therapy. However, the highest sildenafil dose was associated with increased mortality, especially in patients over 20kg or with more severe disease. Overall survival was still favorable compared to other pediatric PAH treatments. The reasons for higher death rates in the high dose group remain unclear.

1. STARTS-2: Long-Term Survival With Oral
Sildenafil Monotherapy in Treatment-
Naive Pediatric Pulmonary Arterial
Hypertension
Circulation. March 17, 2014

2. Background
• STARTS-1:
-Double-blind, placebo-controlled
-Sildenafil in pediatric(1-17 years) patients with
pulmonary arterial hypertension
• STARTS-2 was the extension study.
• PAH, defined as mean pulmonary artery pressure
(mPAP) 25 mm Hg at rest, pulmonary capillary
wedge pressure <15 mm Hg, and pulmonary vascular
resistance index (PVRI) >3 Wood units m2, was
confirmed by right heart catheterization at baseline.

3. STARTS-1
• The primary comparison was percent change from
baseline in peak oxygen consumption for the 3
sildenafil doses combined versus placebo
• Actual 3-times-a-day doses within a group were
dependent on weight (low: 10 mg; medium: 10, 20, or
40 mg; high: 20, 40, or 80 mg).(For 16 weeks)

4. • PV(O(2)), functional class(who), and hemodynamics
improved with medium and high doses versus
placebo;
• low-dose sildenafil was ineffective

6. STARTS-2
Study Design
• Placebo-treated STARTS-1 patients were randomized
(stratified by weight) to 1 of the 3 sildenafil dose
groups at the beginning of STARTS-2. Patients in the
>20 to 45 kg and >45 kg weight group strata were
randomized in a 1:1:1 ratio; patients 8 to 20 kg were
randomized to medium- or high-dose sildenafil in a
1:2 ratio
• Patients who received sildenafil in STARTS-1
continued the same dose

7. • Throughout STARTS-2, both upward (for disease
progression or lack of improvement) and downward
(for intolerability) dose titrations of sildenafil were
permitted, per investigator judgment
• A maximum of 2 uptitrations and 1 downtitration
were allowed during the study
• STARTS-1 took place at 32 centers in 16 countries

9. Statistical Analysis
• Kaplan-Meier estimates of survival were assessed (1)
from baseline of the STARTS-1 study and (2) from
the start of sildenafil treatment to account for the 16-
week delay in receipt of sildenafil for patients
randomized to placebo in STARTS-1.
• Cox proportional hazards models, stratified by
baseline weight (≤20 versus >20 kg), were used to
make comparisons between treatment groups

10. Results
• Of the 234 patients who were randomized and treated
in STARTS-1, 6 patients discontinued STARTS-1,
and an additional 8 did not enter STARTS-2
• From STARTS-1 baseline, 206 (88%), 184 (79%),
and 166 patients (71%) received therapy for >1, >2,
and >3 years, respectively

13. Kaplan-Meier estimated survival from start of sildenafil treatment in Sildenafil in Treatment-
Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension (STARTS-1) and
STARTS-2 overall

14. Kaplan-Meier estimated survival from start of sildenafil treatment in patients weighing
≤20 kg

15. Kaplan-Meier estimated survival from start of sildenafil treatment in patients weighing
>20 kg

16. DISCUSSION
• In pediatric patients with PAH, treatment with high-dose
sildenafil was associated with an increased risk
of mortality compared with lower doses of sildenafil.
A higher risk of death specifically was observed in
patients with greater disease severity at baseline, in
patients >20 kg, and in patients with IPAH/HPAH.

17. • This study was unique for being a large, randomized,
dose- ranging study of a single monotherapy in
treatment-naive patients. Overall, survival in all dose
groups was favorable compared with other reports in
children using PAH-specific drugs that were only
approved for adult PAH

18. PITFALLS
• This study is inconsistent with results obtained using
sildenafil monotherapy in adults with PAH (SUPER-1
study and SUPER-2 extension)
• Pediatric PAH patients who received placebo in the
16-week STARTS-1 study and subsequently received
sildenafil had better long-term survival than children
who began sildenafil in STARTS-1
• An explanation of the higher incidence of deaths
observed after 2 years of STARTS-1 and -2 treatment
in patients randomized to higher sildenafil doses
remains elusive.

19. CONCLSIONS
• Although children randomized to the high-dose
sildenafil group had an unexplained increased
mortality compared with the lower-dose sildenafil
groups, all dose groups displayed favorable survival
for children with PAH