First-in-child use of the oral selective prostacyclin IP receptor agonist selexipag in pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a complex disease with a poor prognosis. Selexipag is a selective prostacyclin receptor agonist with vasodilatory, anti-proliferative, anti-inflammatory, and pro-angiogenic properties. However, no clinical data on its therapeutic use in children with PAH are currently available. Here, we report the case of a 12-year-old girl who presented in World Health Organization (WHO) functional class III and right ventricular (RV) failure with recurrent syncope, dizziness, and progressive fatigue for two years. Cardiac catheterization revealed severe precapillary PAH: mean right atrial pressure (RAP) = 10-13 mmHg, right ventricular end-diastolic pressure (RVEDP) = 13 mmHg, left ventricular end-diastolic pressure (LVEDP) = 7 mmHg, mean pulmonary arterial pressure (PAP) = 81 mmHg, and mean aorta ascendens pressure = 89 mmHg. The pulmonary vascular resistance index (PVRi) was 25.2 WU × m². An oral combination therapy was started with a phosphodiesterase type 5 inhibitor (sildenafil 3 × 20 mg) and an endothelin-1 receptor antagonist (bosentan 2 × 62.5 mg). No significant clinical/hemodynamic improvement was seen after nine months of dual therapy, so that the patient was transferred to our institution. We agreed upon the off-label add-on use of oral selexipag. Within ten days, we up-titrated selexipag to a final (max. adult) dose of 1600 mcg twice daily. After six months, the patient had: (1) decrease in PVR index, pulmonary artery acceleration time, RAP, RVEDP, right atrial/RV size; (2) re-gain of vasoreactivity; and (3) improvement of cardiac index, 6-minute walking distance, functional class, body weight, and CAMPHOR score. Our encouraging results suggest the consideration of off-label use of oral selexipag in children with severe PAH, preferably in a protocol-driven prospective study.

Keywords: IP receptor; children; prostacyclin; pulmonary hypertension; right heart failure.

Fig. 1.

Hemodynamic and clinical improvement in a 12-year-old girl with severe PAH during the first six months after reaching the target dose of oral selexipag, as add-on to background therapy (sildenafil, bosentan). Decrease in PAP and transpulmonary pressure gradient (TPG), measured by cardiac catheterization six months after start of add-on oral selexipag treatment (a). Decrease in RVEDP and mean RAP and slight increase of CI, measured by cardiac catheterization six months after start of selexipag treatment (b). Decrease of PVR index as measured by cardiac catheterization six months after start of selexipag treatment (c). Improvement of right ventricular dilation (RV/LV end-systolic ratio) and left ventricular compression (LV end-systolic eccentricity index) as demonstrated on transthoracic echocardiography three and six months after start of selexipag treatment (d). Increase in PAAT measured by PW-Doppler in the parasternal short axis view, three and six months after start of selexipag treatment (e). Reduction in RA size measured by echocardiography from the four-chamber view, three and six months after start of selexipag treatment (f). Improvement of the 6-minute walking distance three and six months after start of selexipag treatment (g). Reduction of symptoms, physical impairment, and quality of life impairment, as reported by self-assessment using the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) questionnaire before and six months after start of oral selexipag therapy. (h) CAMPHOR, Cambridge Pulmonary Hypertension Outcome Review Questionnaire; CATH, cardiac catheterization; CI, cardiac index; dPAP, diastolic pulmonary arterial pressure, dTPG, diastolic transpulmonary pressure gradient; Ecc. Index, eccentricity index; ECHO, echocardiography; LV, left ventricle; mPAP, mean pulmonary arterial pressure; mRAP, mean right atrial pressure; PA, pulmonary artery; PAAT, pulmonary artery acceleration time; PVR, pulmonary vascular resistance; QoL, quality of life; RA, right atrium; RV, right ventricle; RVEDP, right ventricular end-diastolic pressure; sPAP, systolic pulmonary arterial pressure; WU, Wood units.