STARTS-2: Long-Term Survival With Oral

Sildenafil Monotherapy in Treatment-

Naive Pediatric Pulmonary Arterial

Hypertension

Circulation. March 17, 2014

Background

• STARTS-1:

-Double-blind, placebo-controlled

-Sildenafil in pediatric(1-17 years) patients withpulmonary arterial hypertension

• STARTS-2 was the extension study.

• PAH, defined as mean pulmonary artery pressure(mPAP) 25 mm Hg at rest, pulmonary capillarywedge pressure <15 mm Hg, and pulmonary vascularresistance index (PVRI) >3 Wood units m2, wasconfirmed by right heart catheterization at baseline.

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)

• PV(O(2)), functional class(who), and hemodynamics

improved with medium and high doses versus

placebo;

• low-dose sildenafil was ineffective

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

• 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

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

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

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

Kaplan-Meier estimated survival from start of sildenafil treatment in patients weighing

≤20 kg

Kaplan-Meier estimated survival from start of sildenafil treatment in patients weighing

>20 kg

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.

• 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

PITFALLS

• This study is inconsistent with results obtained usingsildenafil monotherapy in adults with PAH (SUPER-1study and SUPER-2 extension)

• Pediatric PAH patients who received placebo in the16-week STARTS-1 study and subsequently receivedsildenafil had better long-term survival than childrenwho began sildenafil in STARTS-1

• An explanation of the higher incidence of deathsobserved after 2 years of STARTS-1 and -2 treatmentin patients randomized to higher sildenafil dosesremains elusive.

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