Children with pulmonary arterial hypertension and prostanoid therapy: Long-term hemodynamics

Abstract

BACKGROUND Pediatric patients with severe pulmonary arterial hypertension (PAH) are treated with intravenous epoprostenol or intravenous or subcutaneous treprostinil. Little is known about longitudinal hemodynamics and outcomes of epoprostenol, treprostinil, and transitions from epoprostenol to treprostinil. METHODS This was retrospective study of 77 pediatric patients (47 idiopathic PAH, 24 congenital heart disease-PAH) receiving epoprostenol or treprostinil from 1992 to 2010 at 2 centers. Outcomes were defined as living vs dead/transplant. RESULTS Mean age at baseline was 7.7 ± 5.2 years, with follow-up of 4.3 ± 3.4 years. Thirty-seven patients were treated with epoprostenol, 20 with treprostinil, and 20 were transitioned from epoprostenol to treprostinil. Mean pulmonary-to-systemic vascular resistance ratio (Rp/Rs) for epoprostenol was 1.0 ± 0.4, 0.8 ± 0.4, 0.8 ± 0.4, 1.0 ± 0.4, and 1.2 ± 0.4, respectively, at baseline, 1, 2, 3, and 4 years. For treprostinil, Rp/Rs was 0.9 ± 0.3, 0.7 ± 0.3, 0.5 ± 0.2, (p < 0.01 vs baseline), and 1.1 ± 0.2, respectively, at baseline, 1, 2, and 3 to 4 years, respectively. There were similar changes in mean pulmonary artery pressure and pulmonary vascular resistance index. The Rp/Rs 1 year after epoprostenol to treprostinil transition increased from 0.6 to 0.8 (n = 7). Changes not statistically significant unless noted. Eight patients died or received a transplant within 2 years of baseline; compared with the rest of the cohort, mean baseline Rp/Rs, right atrial pressure, and pulmonary vascular resistance index were significantly worse in this group. Thirty-nine patients remain on prostanoids, 17 are off, 16 died, and 5 received heart-lung transplant. Kaplan-Meier 5-year transplant-free survival was 70% (95% confidence interval, 56%-80%). CONCLUSION There was improvement in Rp/Rs on both therapies at 1 to 2 years that was not sustained. The 5-year transplant-free survival was better than in similar adult studies.

The challenges in paediatric pulmonary arterial hypertension

“…For non-vasoreactive patients or those failing to respond to CCB therapy, the approach to treatment is currently based on risk of death (table 1), with lower risk patients typically commencing oral monotherapy. Data regarding the efficacy and safety of PAH-targeted monotherapy in children are limited to endothelin receptor agonists [32,33], intravenous or subcutaneous prostanoids [34], and the phosphodiesterase type-5 (PDE5) inhibitors sildenafil [35,36] and tadalafil [37]. Sildenafil is currently the only approved treatment in Europe for PAH in children, based on data from the 16-week STARTS-1 (Sildenafil in Treatment-Naïve Children, Aged 1-17 Years, with Pulmonary Arterial Hypertension) trial, reporting improvements in peak oxygen consumption (primary end-point) at higher sildenafil doses [36].…”

“…In cases of paediatric patients at higher risk of deterioration, switching to i.v. prostacyclin should be considered [34,40]. For patients in WHO functional class IV, patients should be started on i.v.…”

Subcutaneous Treprostinil for Pulmonary Hypertension in Chronic Lung Disease of Infancy

“…5,8 Transition from IV epoprostenol to SCTre has been reported without clinical deterioration in adults and children. 9,10 Adverse effects of the SC infusion include site pain in 89% to 92% of adults, and site reactions in 81% to 100%. 5,8 In adults, 23% discontinued SCTre owing to adverse effects, mainly site pain.…”

Treatment of pulmonary arterial hypertension in children

“…Initiation of subcutaneous treprostinil or intravenous epoprostenol, iloprost, or treprostinil should be considered in children with progressive, severe PAH and high predicted risk of PAH worsening, or an inadequate response or clinical deterioration when receiving combination therapy. 19,75,76 Continuously applied intravenous epoprostenol is still considered the most effective drug to treat severe IPAH or familial PAH in children. 67,69 Treatment goals 'Goal-oriented therapy' requires a treatment strategy that uses known prognostic indicators as treatment targets, and a systematic approach to evaluate the adequacy of clinical results.…”