Epoprostenol is the intravenous formulation of prostacyclin I2 (PGI₂), a synthetic, stabilized compound initially approved by the FDA in 1995 for idiopathic PAH. As such, the most robust longitudinal and mortality data are available for this compound. Following a number of encouraging, smaller clinical trials of prostacyclin therapy in PAH [44–47], a pivotal, 12-week, prospective, placebo-controlled randomized trial evaluating hemodynamics, functional capacity, quality of life, and survival in 81 patients with New York Heart Association functional class (FC) III or IV idiopathic PAH (IPAH) (previously known as primary pulmonary hypertension) was performed. Patients receiving epoprostenol demonstrated significant improvements in pulmonary vascular resistance, pulmonary artery pressure, and cardiac index with marginal effects on mean systemic arterial pressure. Additionally, 6-min walk distance (6MWD) and quality of life scores improved in the epoprostenol-treated participants compared to the placebo group, with the placebo patients experiencing a worsening of quality of life and 6MWD. There were no deaths in the epoprostenol group compared to eight deaths in the placebo arm [47]. Subsequent to this trial in IPAH, similar hemodynamic and functional improvements were observed in scleroderma-related PAH treated with IV epoprostenol over a 12-week period but with similar survival rates in the IV epoprostenol group compared to the conventional therapy group [48].

Since the completion of the key epoprostenol PAH clinical trials, three additional, observational studies have compared survival in those treated with epoprostenol to historical controls from the original US National Institutes of Health registry of PAH [49, 50]. In the first study, Shapiro and colleagues prospectively followed 69 patients with FC III and IV idiopathic PAH at a single center and observed an improved survival at 1, 2, and 3 years respectively as compared to historical controls [51]. Those subjects followed for more than 1 year had additional improvements in non-invasively assessed pulmonary vascular resistance (PVR) indices, suggesting a long-term hemodynamic benefit of the therapy [51]. Similarly, a survival benefit from epoprostenol was observed by McLaughlin and colleagues in 162 patients PAH with functional class III or IV treated at a single center. With a median follow up of 31 months, a substantial survival benefit was observed in those on epoprostenol therapy at 1 year, 2 years, 3 years, and 5 years, respectively. Long-term improvements in symptoms and invasively measured hemodynamic parameters were demonstrated as well [52]. Around the same time, Sitbon and colleagues reported similar findings of improved symptoms, hemodynamics and survival at 1, 2, 3, and 5 years, respectively, in a French PAH cohort [53].

The chemical and pharmacokinetic properties of IV epoprostenol necessitate the intricate delivery system for the drug. Epoprostenol is prepared in sterile, freeze-dried powder which requires cool storage recommended at 15 to 20 °C. The half-life of the drug is 6 min as the drug is rapidly degraded in the blood and ultimately renally excreted. Therefore, the drug must be delivered via continuous infusion with a central catheter via a positive pressure pump (Fig. 16.2); abrupt discontinuation of therapy may lead to cardiovascular collapse and death [54]. In the hospital setting in the treatment naïve patient, epoprostenol is typically initiated via a peripherally inserted central catheter or central line. As the transition to outpatient care occurs, the placement a durable, tunneled central venous catheter is strongly advised. Additionally, the intravenous pump is converted to a battery operated portable pump (Fig. 16.2). Veletri™, a generic formulation of epoprostenol (Flolan™), is stable at room temperature and gained FDA approval in 2012. This l-arginine formulation purportedly provides a more thermally stable preparation with an administration time of up to 7 days after mixing the drug without a compromise in potency [55, 56].

The continuous nature of the drug infusion via central venous access, the associated equipment, and the required meticulous care can be a substantial barrier for some patients. Extensive education is required with documented competency in pump management (including alarms), sterile technique, medication preparation and storage, and awareness of pump or catheter related complications (including sepsis and thrombosis) [57]. As such, the administration and longitudinal follow up care for patients on parenteral therapy including epoprostenol should be coordinated by an experienced integrated health center expert in the management of PAH.

Given the variability and relatively short follow-up duration in clinical trials, dosing recommendations for the long-term use of epoprostenol therapy comes from empiric clinical experience. Traditionally, epoprostenol has been initiated at a dose of 2 ng/kg/min and titrated daily to a dose that results in the initial optimization of PAH symptoms and hemodynamics while limiting side effects. In the pivotal trial by Barst and colleagues, a mean dose of 9 ng/kg/min was achieved at 8 weeks [47]. In the later studies by McLaughlin et al. and Sitbon et al., mean doses of approximately 22–27 ng/kg/min and 14 ng/kg/min respectively at 12 weeks were achieved [52, 53, 58]. Recently, McLaughlin and Palevsky provided a contemporary dosing recommendation for the initiation and dose escalation for intravenous epoprostenol therapy targeting an eventual average dose of 35–50 ng/kg/min at 1 year [57].

The off-target effect profiles are similar for all forms of prostacyclin therapies with a few exceptions. With the slow initiation of therapy, systemic vasodilation due to epoprostenol may induce a modest decrease in systemic blood pressure in addition to common side effects including flushing, headache, diarrhea, and a specific jaw discomfort that occurs with the initial mastication during a meal [52, 53]. In overdose states, patients may report extreme side effects with a predominance of diarrhea and flushing and invasive hemodynamic monitoring may even demonstrate a high cardiac output state [58]. However, many of these side effects will abate as a steady state dose is achieved and the drug is used chronically. In addition, there are potential adverse events associated with the intravenous delivery system. As with any catheter-based system, the patient and physician must remain vigilant in the monitoring of thrombotic complications and perhaps more commonly, local or systemic infections [57].

Treprostinil was the second prostacyclin therapy approved by the FDA in 2002, initially via the subcutaneous route. The subcutaneous delivery of treprostinil provided an alternative, parenteral route of prostanoid delivery given some of the limitations related to intravenous therapy. The main clinical data examining the safety and efficacy of subcutaneous treprostinil comes from a single placebo-controlled trial and a subsequent observational study. Simonneau and colleagues conducted a 12 week, multinational, double-blinded trial in four-hundred and seventy patients with PAH. The primary endpoint of 6MWD improved significantly in those treated with SC treprostinil and secondary outcomes of dyspnea scores and hemodynamic parameters also improved [59]. This study was followed by an observational study of eight-hundred sixty patients by Barst and colleagues, providing longer term follow-up data on safety and survival. Participants were followed for up to 4 years with Kaplan-Meier derived survival estimates compared to the NIH predicted mortality and suggested possible improved survival on therapy [60]. Following the approval of SC epoprostenol, the safety and efficacy of IV treprostinil was demonstrated in a prospective, open-label, 12-week trial of 16 patients with mixed etiologies of PAH (8 with idiopathic) in whom improvements in 6MWD, dyspnea scores, and hemodynamics were observed [61].

The longer half-life, thermal stability at room temperature, and avoidance of a central catheter delivery system were all leveraged when developing the subcutaneous formulation. Treprostinil is a thermally stable tricyclic benzene analog of prostacyclin with peak plasma concentrations of the drug occurring within 2 to 3 h of subcutaneous delivery [62, 63]. Treprostinil also has a longer half-life of approximately 4.5 h as compared to epoprostenol. The longer half-life may mitigate the risk of cardiovascular collapse that may be seen with the acute discontinuation of epoprostenol [64, 65]. Similar to the intravenous formulations of prostacyclin therapies, the subcutaneous delivery is via a positive pressure infusion pump but with a self-inserted catheter. The initiation of subcutaneous treprostinil can be performed in the inpatient or outpatient setting with close monitoring. The initial FDA approved dose is recommended at 1.25 ng/kg/min, however there is clinical data suggesting the safety of a 2.5 ng/kg/min initial dose with rapid escalation upon demonstrating improved clinical and hemodynamic endpoints compared to a slower escalation strategy beginning at a dose of 2 ng/kg/min. When studied, those participants in the rapid titration group had a higher average dose of approximately 20 ng/kg/min at 12 weeks [59]. Particular attention to early pump and site complications should be noted by the patient and alert the care team as soon as possible [54]. Contrary to other subcutaneously-based therapies, a specific infusion pump site is not required for appropriate absorption: the abdomen is the preferred site although the buttock, flank, thigh, and upper arm are potential alternative sites. Although rotation of the administration site is recommended to occur at three day intervals, patients will often administer the drug at the same site for up to 30 days and typically rotate the site every 2–4 weeks without obvious detrimental effects. Additionally, the transition from SC to IV treprostinil (and vice versa) can be generally done safely without deterioration in clinical status as long as it is performed in an appropriate clinical setting and under expert supervision [66, 67].

As with IV epoprostenol, IV treprostinil is typically initiated in the hospital setting at an initial dose of 2 ng/kg/min with incremental increases of 2 ng/kg/min titrated to hemodynamic and clinical endpoints and limited by tolerability. The ultimate, average dose of treprostinil achieved will typically be about two to three-times the dose of epoprostenol [61, 63]. The side effects of IV and SC treprostinil are similar to that of epoprostenol including flushing, headache, diarrhea, and jaw discomfort [54, 59, 60]. With SC treprostinil, perhaps the most limiting side effect is severe site pain, which may occur in up to 85 % of patients. Rarely, abscess formation may occur at the infusion site requiring local drainage and systemic antibiotics. With IV treprostinil, patients may be at higher risk of bacteremia, particularly gram negative rod sepsis as compared to IV epoprostenol. The concern of gram-negative systemic infections were noted in an examination of the REVEAL registry (Registry to Evaluate Early and Long Term PAH Disease Management) that demonstrated a rate of 0.36 vs. 0.12 per 1000 treatment days compared to epoprostenol therapy. A subsequent multivariate analysis of the data adjusting for potential confounders reported an approximately 3- and 6-fold increase in the risk of bloodstream infections and gram-negative infections respectively with IV treprostinil when compared to epoprostenol [68]. Interestingly, a subsequent study demonstrated that the increased risk of gram negative bacteremia may be attenuated when epoprostenol diluent is used with IV treprostinil administration, perhaps best explained by differences in the pH between the respective diluents [69].

Iloprost (Ventavis™) was the first inhaled prostacyclin to gain approval in 2004 following a 12 week, randomized, double blind, placebo-controlled trial of 203 patients with predominantly PAH but also chronic thromboembolic pulmonary hypertension (CTEPH). Patients were randomized to either 2.5 μg or 5.0 μg of iloprost versus placebo with the combined primary endpoint of improvement in at least one functional class and a 10 % improvement in 6MWD without clinical deterioration or death. By study’s end, those randomized to iloprost achieved a significant improvement in the primary endpoint (17 % with iloprost versus 5 % with placebo). Improvements in secondary endpoints of dyspnea score, quality of life, and hemodynamics also favored iloprost (though it should be noted that hemodynamics were measured shortly after drug administration) [72].

A different inhaled prostanoid, inhaled treprostinil, was evaluated in two small studies of PAH and chronic thromboembolic pulmonary hypertension (CTEPH) and demonstrated encouraging clinical and hemodynamic improvements [73, 74]. These findings led the way for the Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension 1 (TRIUMPH-1) clinical trial of 235 patients with FC III PAH on background therapy with either bosentan or sildenafil randomized to inhaled treprostinil or placebo over a 12 week period. By study’s end, a significant median improvement in peak 6MWD was seen in the inhaled treprostinil cohort although no significant improvements in secondary endpoints of time to clinical worsening or functional class were observed [75]. In a subsequent observational extension study, 118 patients who remained on inhaled treprostinil demonstrated a persistent improvement in 6MWD at 2 years. Inhaled treprostinil received FDA approval in 2009 [76].