journal club presentation

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