Upfront triple combination therapy in pulmonary arterial hypertension : a pilot study European respiratory journal 2014;43:

Introduction  Pulmonary arterial hypertension(PAH) is a progressive and devastating disease  The complex pathogenesis of PAH involves dysfunction of three key pathways : endothelin, prostacyclin, nitric oxide pathway  This dysfunction results → increased cellular proliferation, remodelling of the pulmonary vasculature and vasoconstriction → increased PVR & Rt heart failure & death

Introduction  PAH severity classified according to New York Heart Association(NYHA) functional class (FC)  Current guidelines recommend prostacyclins(eg. Epoprostenol) first-line therapy in NYHA FC III/IV  In this pilot study, the efficacy and safety of a triple combination therapy regimen(epoprostenol, bosentan, sildenafil) in patients with severe PAH(NYHA III/IV) was investigated.

Material and Method  Retrospective analysis  Data from newly diagnosed NYHA FC III/IV PAH and with severe haemodynamic impairment patients (n=19) initiated on upfront triple combination therapy (intravenous epoprostenol, bosentan and sildenafil)  Severe haemodynamic impairment was defined as cardiac index 20 mmHg and/or PVR ≥1000 dyn/s/cm 5

Material and Method  Treatment regimen  Epoprostenol(prostacyclin) infused continuously using a portable infusion pump 1 ng/kg/min → 10 ng/kg/min(On day 5) → 16 ng/kg/min  Bosentan(endothelin receptor antagonist) started concomitantly with epoprostenol 62.5 mg bid → 125mg tid(After 4 weeks)  Sildenafil(PDE 5 inhibitor) started on study day 5 20 mg tid  ≥1000 dyn/s/cm 5

Results

 All patients initiated with upfront triple combination therapy were still alive after a mean f/u of 41.2±13.4months  Overall survival estimates were 100%, 100%, and 100% at at 1, 2 and 3 years  Expected survival calculated from the French equation was 75% (95% CI 68–82%), 60% (95% CI 50–70%) and 49% (95% CI 38–60%) at 1, 2 and 3 years, respectively.

Conclusion  This pilot study provides preliminary evidence of the long-term benefits of upfront triple combination therapy in patients with severe PAH  Limitation  small number of patients, who were highly selected in terms of disease severity and aetiology  not a randomised controlled trial → Large, randomised controlled trials are required