Case report: Stepwise transition from subcutaneous treprostinil to epoprostenol in high-risk pulmonary arterial hypertension

Background Idiopathic pulmonary arterial hypertension is associated with high morbidity and mortality. In recent years, the use of targeted therapies has led to an improvement in prognosis. Prostacyclin analogues treprostinil and epoprostenol require continuous subcutaneous or intravenous infusion and are generally administered in a stepwise approach. However, there are no clear recommendations for transition in high-risk patients requiring high doses of prostacyclin analogues. Case summary In this report, we describe the case of a 20-year-old woman under combined treatment with sildenafil, macitentan, and treprostinil who required transition from subcutaneous treprostinil therapy to intravenous epoprostenol due to erratic drug absorption and functional class progression. The transition was performed over 48 h in a stepwise approach reducing treprostinil dose 4 ng/kg/min every 3 h while increasing epoprostenol infusion 2 ng/kg/min until achieving a maintenance dose of 32 ng/kg/min. There were no side effects requiring changes in the infusion rate. Discussion Patients with advanced pulmonary arterial hypertension may necessitate switching from subcutaneous treprostinil to epoprostenol. Although many protocols have been used to date, there are no guidelines to direct this process safely. This 48-h scheme based on the pharmacokinetic properties of each drug was successful and well-tolerated.

Inhaled prostacyclin analogues in COVID-19 associated acute respiratory distress syndrome: scientific rationale

Background COVID-19 associated acute respiratory distress syndrome (CARDS) is a severe form of SARS CoV-2 infection and affects about 15–30% of hospitalized patients with a high mortality rate. Growing research and data suggest several available drugs with appropriate pharmacological effects to treat COVID-19. Main body Prostacyclin analogues are regiments for pulmonary artery hypertension. Prostacyclin analogues are expected to be beneficial in treating CARDS based on at least four rationales: (1) inhaled prostacyclin analogues improve oxygenation, V/Q mismatch, and act as an ARDS therapy alternative; (2) it alleviates direct SARS-CoV-2-related coagulopathy; (3) increases nitric oxide production; and (4) possible anti-inflammatory effect. Prostacyclin analogues are available in oral, intravenous, and inhaled forms. The inhaled form has the advantage over other forms, such as parenteral administration risks. Previously, a meta-analysis demonstrated the beneficial effects of inhaled prostaglandins for ARDS treatment, such as improved PaO2/FiO2 and PaO2 along with reduced pulmonary artery pressure. Currently, two ongoing randomized controlled trials are evaluating inhaled epoprostenol (VPCOVID [NCT04452669]) and iloprost (ILOCOVID [NCT04445246]) for severe COVID-19 patients. Conclusions Inhaled prostacyclin could be considered in patients with refractory, life-threatening hypoxia despite standard management.

Prostacyclin Analogues Inhibit Platelet Reactivity, Extracellular Vesicle Release and Thrombus Formation in Patients with Pulmonary Arterial Hypertension

(1) Background: Prostacyclin analogues (epoprostenol, treprostinil, and iloprost) induce vasodilation in pulmonary arterial hypertension (PAH) but also inhibit platelet function. (2) Objectives: We assessed platelet function in PAH patients treated with prostacyclin analogues and not receiving prostacyclin analogues. (3) Methods: Venous blood was collected from 42 patients treated with prostacyclin analogues (49.5 ± 15.9 years, 81% female) and 38 patients not receiving prostacyclin analogues (55.5 ± 15.6 years, 74% female). Platelet reactivity was analyzed by impedance aggregometry using arachidonic acid (AA; 0.5 mM), adenosine diphosphate (ADP; 6.5 µM), and thrombin receptor-activating peptide (TRAP; 32 µM) as agonists. In a subset of patients, concentrations of extracellular vesicles (EVs) from all platelets (CD61+), activated platelets (CD61+/CD62P+), leukocytes (CD45+), and endothelial cells (CD146+) were analyzed by flow cytometry. Platelet-rich thrombus formation was measured using a whole blood perfusion system. (4) Results: Compared to controls, PAH patients treated with prostacyclin analogues had lower platelet reactivity in response to AA and ADP (p = 0.01 for both), lower concentrations of platelet and leukocyte EVs (p ≤ 0.04), delayed thrombus formation (p ≤ 0.003), and decreased thrombus size (p = 0.008). Epoprostenol did not affect platelet reactivity but decreased the concentrations of platelet and leukocyte EVs (p ≤ 0.04). Treprostinil decreased platelet reactivity in response to AA and ADP (p ≤ 0.02) but had no effect on the concentrations of EVs. All prostacyclin analogues delayed thrombus formation and decreased thrombus size (p ≤ 0.04). (5) Conclusions: PAH patients treated with prostacyclin analogues had impaired platelet reactivity, EV release, and thrombus formation, compared to patients not receiving prostacyclin analogues.

Short term effect of Selexipag in comparison to parenteral prostacyclin analogues in pulmonary arterial hypertension patients started on double-combination therapy with ERA and PDE-5 inhibitors

Background The event-driven, phase 3, randomized, double-blind, placebo-controlled GRIPHON trial demonstrated that Selexipag reduces the risk of a composite end point of death or morbidity events in patients with pulmonary arterial hypertension (PAH). Despite the advantage of a per os formulation, its efficacy in comparison to parenteral prostacyclin analogues in patients already on oral double-combination therapy with endothelin receptor antagonist (ERA) and phosphodiesterase-5 inhibitor (PDE5-I) is not known. Purpose The aim of this study was to compare the effects of Selexipag (S) vs subcutaneous Treprostinil (T) vs intravenous Epoprostenol (E) in PAH patients initially started with double-combination therapy with ERA and PDE5-I. Methods We enrolled patients on double combination therapy with ERA + PDE5-I starting S, T or E. Drugs were gradually uptitrated to the maximum tolerated/approved dose. All patients were systematically assessed with WHO-functional class (FC), six minute walk test (6MWT) and right heart catheterization before treatment and 3 months after reaching a stable dose of the drug. Baseline characteristics and changes in 6MWT and haemodynamic parameters were analyzed using Wilcoxon signed-rank test and compared between the 3 drugs with Kruskal-Wallis test. Results One hundred and seventy-one patients with PAH were enrolled. Results are shown in the Table. Patients with a complete re-evaluation were 61% of S, 85% of T, 79% with E. Conclusions S was prescribed to the oldest and least severe PAH patients. E was prescribed to the youngest and most severe PAH patients and led to the strongest improvement of exercise capacity and haemodynamic profile. T has intermediate characteristics. Table 1 Funding Acknowledgement Type of funding source: None

Balloon atrial septostomy and transition of subcutaneous to intravenous prostacyclin infusion for rescuing advanced right heart failure in idiopathic pulmonary arterial hypertension: a case report

Background Intravenous (IV) prostacyclin analogues infusion and balloon atrial septostomy (BAS) are two important treatment options for managing advanced right heart failure in patients with idiopathic pulmonary arterial hypertension (IPAH). References and protocols are rare for dose titrations and transitions between subcutaneous and IV prostacyclin in functional Class IV IPAH patients. Balloon atrial septostomy is rarely done in very few expert centres. Case summary A young female with IPAH who had received maximal medication including subcutaneous prostacyclin analogues injection was admitted due to advanced right heart failure. She received ascites drainage twice. Later, we directly switched the administration route of prostacyclin from subcutaneous to IV at a ratio of 1:1 instantly. Such rapid conversion led her into a state of profound hypotension and drowsy consciousness, which was resolved after escalating IV inotropics and reducing prostacyclin dosage. Five days later, she received BAS under the guidance of intracardiac echocardiography. Her urine output increased and dyspnoea improved gradually. Six months later, clinical worsening happened again with increase of ascites and dyspnoea. She underwent 2nd and 3rd session of graded BAS with relief of symptoms again. She received permanent transition to IV prostacyclin analogues infusions via a peripherally inserted central catheter after three sessions of BAS. Discussion Balloon atrial septostomy is effective in stabilizing the critical right heart failure in IPAH patients but should be intended as a bridge to lung transplant procedure. Transition from subcutaneous to IV prostacyclin is helpful but needs to be titrated in proper aliquots and time intervals to avoid abrupt haemodynamic changes.