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The Patient with Non-Group 2 Pulmonary Hypertension
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Sophia Anastasia Mouratoglou, George Giannakoulas
Treprostinil is a synthetic prostanoid that can be administered IV, subcutaneously (sc), or inhaled. It is stable at room temperature and has a half-life of four hours, characteristics that allow for continuous sc infusion. Treprostinil is also produced in formulations that allow oral use. The treatment with subcutaneous treprostinil is initiated at a dose of 1–2 ng/kg/min, up-titrated by 2 ng/kg/min, with the optimal dose determined by patient tolerability and the development of side effects, such as headache, jaw pain, myalgia, and flushing. Neuropathic pain at the site of sc infusion is the most severe side effect, affecting adherence. SC treprostinil improves exercise capacity and hemodynamics in patients with PAH,67 and also has favorable effects in patients with PAH related to congenital heart disease68 and chronic thromboembolic PH.69 Intravenous treprostinil had favorable results on functional capacity in a randomized, double-blind, placebo-control, clinical trial prematurely discontinued due to ethical issues.70 Inhaled treprostinil also generated promising results on 6-minute walk distance, quality of life, and NT-proBNP level when used as an add-on therapy on patients already on background advanced treatment with bosentan or sildenafil,71 although oral treprostinil has yielded mixed results in clinical trials, ranging from no improvement on functional capacity to reduction of the risk of clinical worsening when administered soon after the initiation of background advanced PH therapy.72–75
Therapeutics in pulmonary hypertension
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Maria F. Acosta, Don Hayes, Jeffrey R. Fineman, Jason X.-J. Yuan, Stephen M. Black, Heidi M. Mansour
TYVASO® (treprostinil) inhalation solution is another inhaled prostacyclin analog used to treat PH (Group 1). TYVASO can improve the ability to exercise in people who also take bosentan or sildenafil (54). The dosage form is a sterile solution for oral inhalation as a 2.9 mL ampule containing 1.74 mg treprostinil (0.6 mg per mL) (54). Dosing frequency is 4 times daily (2–3 minutes each). A single breath of TYVASO delivers about 6 µg of iloprost. Treprostinil is also delivered by nebulization using an Optineb ultrasonic device. The inhaled excipients are sodium chloride, sodium citrate, sodium hydroxide, hydrochloric acid, and water for injection (pH 6.0–7.2). It is important to mention that treprostinil is a photosensitive drug; therefore, it should be protected from light (55).
Pulmonary hypertension: Hemodynamic assessment and response to vasodilators
Published in Debabrata Mukherjee, Eric R. Bates, Marco Roffi, Richard A. Lange, David J. Moliterno, Nadia M. Whitehead, Cardiovascular Catheterization and Intervention, 2017
Myung H. Park, Vallerie V. Mclaughlin
Treprostinil. Treprostinil is a PGI2 analogue with a half-life of 4 hours. It was studied as a continuous subcutaneous infusion in a 12-week, placebo-controlled, randomized trial of 470 patients with FC II, III, or IV PAH.119 There was a modest but statistically significant median increase of 16 m in 6MWD; the improvement was dose related, and patients in the highest dose quartile reported close to 40 m improvement. However, the major hindrance of using subcutaneous treprostinil is pain and erythema at the infusion site, which was reported by 85% of the patients and limited the dose increases. It is now recognized that site pain is not dose related, and that some patients feel better after proper dose escalation, which helps them to improve their PAH symptoms.
An update on current and emerging drug treatments for idiopathic pulmonary fibrosis
Published in Expert Opinion on Pharmacotherapy, 2023
Athina Trachalaki, Nadiya Sultana, Athol Umfrey Wells
Treprostinil is a prostacyclin receptor agonist with high affinity for prostaglandin E receptor 2 (EP2) and the prostaglandin D receptor 1 (DP1) [143]. Treprostinil acts in the pulmonary and arterial vasculature causing vasodilation and inhibition of platelet aggregation [144]. Inhaled treprostinil has gained FDA approval for the management of PH-ILDs. In the INCREASE study, treprostinil was more effective than placebo in reducing the decline in six-minute walk distance (difference 31.12 meters, 95% confidence interval [CI], 16.85–45.39) [38]. In post hoc analysis, treprostinil-treated patients had less decline in FVC percent predicted compared to placebo (treatment effect 1.8%, 95% CI 0.2% − 3.4%; P = 0.03) by week 16, with an absolute gain in FVC of 44.4 ml [38]. The largest treatment effect was noted in IPF patients.
Prostacyclin analogues decrease platelet aggregation but have no effect on thrombin generation, fibrin clot structure, and fibrinolysis in pulmonary arterial hypertension: PAPAYA coagulation
Published in Platelets, 2022
Aleksander Siniarski, Aleksandra Gąsecka, Miłosz Starczyński, Marta Banaszkiewicz, Szymon Darocha, Adam Torbicki, Marcin Kurzyna, Krzysztof J. Filipiak, Jadwiga Nessler, Grzegorz Gajos
Epoprostenol was infused intravenously through a surgically placed central venous catheter with a portable pump. Doses ranged from 26.5 ng/kg/min to 117.1 ng/kg/min (median: 40.9 ng/kg/min). Treprostinil was administered subcutaneously as a continuous infusion through a pump. Doses ranged from 21.2 ng/kg/min to 127 ng/kg/min (median: 59.0 ng/kg/min). Iloprost was administered in an inhaled form through a nebulizer (Breelib). The number of inhalations was 8 per day which is equivalent to 20 micrograms of drug per administration [36]. Since combined therapy including ERA, PDE5i and PGI2 analogues is recommended in WHO functional class II–IV PAH [14], both groups of patients also received oral PDE-5i and/or ERA. All patients with a positive response to the acute vasoreactivity test were administered CCB at high doses. In addition to specific pharmacotherapy for PAH, patients received individualized treatment at the discretion of the treating physician, including diuretics for symptoms of right ventricular failure and fluid retention and chronic oxygen supplementation for hypoxemia [14]. All patients continued their standard treatment according to comorbidities, such as β-blockers, statins, and oral anticoagulants.
Selexipag for the treatment of pulmonary arterial hypertension
Published in Expert Review of Respiratory Medicine, 2021
Léon Genecand, Julie Wacker, Maurice Beghetti, Frédéric Lador
Oral treprostinil was associated with an increase in 6MWD but had no effect on the time to clinical worsening (TTCW) when administered to PAH patients without background therapy in one RCT (FREEDOM-M) [15]. Two RCT (FREEDOM-C and FREEDOM-C2) tested oral treprostinil on patients with background therapy with an ERA or a PDE5-I and failed to show improvement in 6MWD or other endpoints [16,17]. Oral treprostinil was administered at a dose of 1 mg bid in FREEDOM-C and FREEDOM-M. This dosage had major side effects leading to important drop out in the treatment group (14.4% for FREEDOM-C and 9.9% for FREEDOM M). This led to a change of protocol in FREEDOM-M with modified intention to treat analysis for patients starting at a dose of 0.25 mg bid and a new study (FREEDOM-C2) that started at a dose of 0.25 mg bid [15,17]. Even though this modification of dose reduced the dropout, the study failed to show an improvement of the primary outcome (6MWD). The last RCT (FREEDOM-EV) tested oral treprostinil in addition to a background monotherapy (ERA or PDE-5I or GCs) [18]. Oral treprostinil was started at a dose of 0.125 mg tid and uptitrated to a maximum dose of 12 mg tid. It showed a reduction in the TTCW (hazard ratio 0.75). However the adverse effects led to discontinuation of treatment in 18.8% of patients in the treprostinil arm against 4.1% of patients in the placebo arm. In summary, oral treprostinil showed inconsistent clinical effect and an unfavorable side effect profile. Oral Treprostinil has only been used in North America and has never been authorized in Europe.