Pulmonary arterial hypertension (PAH) is fatal if untreated. Intravenous epoprostenol improves exercise capacity and haemodynamics in PAH, and increases survival in idiopathic PAH (IPAH). To evaluate the effects of subcutaneous (SC) treprostinil, a longeracting prostacyclin analogue, followed by the addition of other PAH therapies if needed, 860 PAH patients treated with SC treprostinil for up to 4 yrs were followed.Survival is reported as Kaplan-Meier estimates. For 332 IPAH patients with baseline haemodynamics, observed survival is also compared with predicted survival using the National Institute of Health formula.Out of the 860 patients, 199 (23%) discontinued due to adverse events, 136 (16%) died, 117 (14%) discontinued due to deterioration, 29 (3%) withdrew consent and 11 (1%) underwent transplantation. In total, 97 patients (11%) switched from SC treprostinil to an alternative prostacyclin analogue; bosentan was added in 105 patients (12%) and sildenafil in 25 (3%).In conclusion, survival was 87-68% over 1-4 yrs for all 860 patients and 88-70% over 1-4 yrs with subcutaneous treprostinil monotherapy. For the idiopathic pulmonary arterial hypertension subset with baseline haemodynamics (n5332), survival was 91-72% over 1-4 yrs. In contrast, predicted survival was 69-38% over 1-4 yrs. The safety profile for long-term subcutaneous treprostinil was consistent with previous short-term trials with no unexpected adverse events.
Treprostinil sodium is a chemically stable analogue of prostacyclin administered as a chronic, continuous subcutaneous infusion for the treatment of pulmonary arterial hypertension (PAH). There has been significant clinical interest in determining the feasibility of delivering treprostinil by intravenous infusion. Therefore, a bioequivalence and comparative pharmacokinetics study of the two routes of administration was conducted in normal volunteers. A randomized, two-period, crossover study design was employed. Each subject was dosed at 10 ng/kg/min for 72 hours by each route, with the infusions separated by a 4-day wash-out period. In the 51 subjects who received at least 24 hours of treprostinil administered subcutaneously and intravenously, the steady-state ratios of the geometric means (i.v./s.c.) and 90% confidence intervals for AUCss and Cmaxss were 92.9% (89.8-96.1%) and 106% (99.4-113%), respectively. Secondary pharmacokinetic assessments confirmed the comparability of the two routes of administration at steady state, and also demonstrated that the elimination half-life of treprostinil was 4.4 and 4.6 hours following intravenous and subcutaneous administration, respectively. Based on these findings it was concluded that intravenously and subcutaneously administered treprostinil are bioequivalent at steady state.
Despite previous investigations suggesting efficacy, these results indicate that beraprost is not an effective treatment to improve symptoms of intermittent claudication in patients with PAD. The potential benefit of beraprost on critical cardiovascular events would require confirmation in a larger prospective investigation.
Intravenous epoprostenol improves exercise capacity and survival in patients with pulmonary arterial hypertension (PAH); however, chemical instability and a short half-life have caused limitations in its use. The chemically stable prostacyclin analogue treprostinil has a longer half-life, and improves hemodynamics and signs/symptoms of PAH. This study investigated the feasibility of transitioning patients with PAH from intravenous epoprostenol to intravenous treprostinil using a rapid switch protocol. Twelve PAH patients were enrolled in a 12 week prospective open label study. Patients were switched from intravenous epoprostenol to intravenous treprostinil (1:1 ng/kg/min) by a direct switch of the medication reservoir from epoprostenol to treprostinil. The dose of treprostinil was adjusted throughout the study to achieve a 2-fold increase of treprostinil compared with the baseline epoprostenol dose. Rapid transition to treprostinil was achieved without serious adverse events and, baseline clinical status was maintained over 12 weeks. The mean baseline epoprostenol dose was 28 +/- 14 ng/kg/min. At week 12, the mean treprostinil dose was 62 +/- 30 ng/kg/min. All patients reported less prostacyclin-related side effects with treprostinil and remained on treprostinil after study completion. Selected patients with PAH can be safely transitioned from intravenous epoprostenol to intravenous treprostinil using a rapid switch protocol.
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