Selection of Infusion Prostacyclin Therapy in Pulmonary Arterial Hypertension: Not Just a Last Resort

Transcription

1 Selection of Infusion Prostacyclin Therapy in Pulmonary Arterial Hypertension: Not Just a Last Resort Robert Schilz, DO, PhD, FCCP Medical Director, Lung Transplantation and Pulmonary Vascular Disease Associate Professor of Medicine Case Western Reserve University School of Medicine Cleveland, OH Myung Park, MD Chief, Division of Heart Failure and Transplant Department of Cardiology Methodist DeBakey Heart & Vascular Center Houston Methodist Hospital Houston, TX Pulmonary arterial hypertension (PAH) is a progressive, fatal vasculopathy that clinically manifests as increased pulmonary vascular resistance and elevation of pulmonary arterial pressures, ultimately leading to right heart failure and death. Median untreated survival period is 2.8 years, with a survival rate of 34% at 5 years before the availability of epoprostenol. 1 Parenteral prostacyclin therapy is arguably the most effective and longest Food and Drug Administration-approved class of drugs for PAH and has been included in guidelines for treatment of PAH for almost 20 years. Intravenous epoprostenol as Flolan remains the only drug that has demonstrated a survival advantage (Figure 1). 2 Despite this demonstration of survival advantage and early evidence in its ability to improve a majority (70%) of patients to a point where they no longer required active listing for lung transplantation, 3 epoprostenol or other infusion agents have consistently been shown to be withheld or underutilized in patients with advanced PAH. 4,5 This apparent paradox as well as significant successful prostacyclin therapy in a variety of PAH patients 6-8 forms the basis of our discussion on the role of infusion prostacyclins in modern management of PAH. EVOLUTION OF GUIDELINES REGARDING THE USE OF PARENTERAL PROSTACYCLINS 1998 Executive Summary From the World Symposium on Primary Pulmonary Hypertension 9 Probably the first mention of prostacyclins in widely published consensus discussions regarding pulmonary arterial hypertension (PAH) treatment in the modern era was contained within the executive summary from the World Symposium on Primary Pulmonary Hypertension in Although the classification guidelines introduced there were relatively robust and have only been refined without major conceptual change, the discussions about treatment and the use of prostacyclins in particular were quite limited. The discussion acknowledged the existing data on effectiveness of epoprostenol in New York Heart Association Functional Classification (NYHC) III and IV patients and the promise of continued therapy, but raised concerns about optimal dosing regimens and long-term effects. Since no other choices for approved therapy existed at that time, decision making was limited to parenteral prostacyclin therapy (PPT) in patients who failed or were not candidates for calcium channel blockers almost all patients! 2004 CHEST GUIDELINES 10 A substantial expansion of both treatment options and guideline recommendations were embodied in the joint guidelines issued by the American College of Chest Physicians and the American College of Cardiology in 2004, 10 which arguably ushered in the modern era of PAH guidelines. This group of statements represented a significant expansion of early consensus conference summaries and incorporated discussions of existing data and experience to set forth a framework for a comprehensive approach to the diagnosis and care of patients with pulmonary hypertension. This algorithm was developed at the third World Symposium on Pulmonary Hypertension (Venice, Italy, 2003) and included modifications to include levels of recommendation for various treatment decisions. Those guidelines brought forward levels of evidence for 5 available drugs in the United States (calcium channel blockers, epoprostenol, subcutaneous treprostinil, inhaled iloprost, and bosentan) and bera- Key Words endothelin receptor antagonist, guidelines, infusion prostacyclins, parenteral prostacyclin therapy Correspondence: robert.schilz@uhhospitals.org Disclosures: Dr Schilz serves as a consultant/advisory board/steering committee member for Actelion Pharmaceuticals US, Inc.; Bayer HealthCare; Genentech, Inc.; Arena Pharmaceuticals, Inc.; and United Therapeutics Corporation. He serves as a speaker s bureau member for Actelion Pharmaceuticals US, Inc.; Bayer HealthCare; Genentech, Inc.; and Gilead Sciences, Inc. He has received institutional grant/ research support from Athersys, Inc.; Community Health & Emergency Services Inc.; United Therapeutics Corporation; Arena Pharmaceuticals, Inc.; and Eiger BioPharmaceuticals, Inc. Dr Park serves as a consultant/advisory board member for Actelion, Bayer HealthCare, United Therapeutics Corporation, and Gilead Sciences, Inc. Figure 1: Survival among the 41 patients treated with epoprostenol and the 40 patients receiving conventional therapy. From Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334(5): Copyright 1996 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. 14 Advances in Pulmonary Hypertension Volume 16, Number 1; 2017

2 prost. The recommendations advocated initial therapy for epoprostenol (Grade of Recommendation, A) for NYHC III and IV patients and consideration of PPT for patients displaying failure to improve or deteriorating, generally suggesting a patient worsening from functional class (FC) III-IV. Subcutaneous (SC) treprostinil was approved by the Food and Drug Administration (FDA) in May 2002 for NYHC II-IV patients and appeared for the first time in guidelines in The recommendations were for consideration as initial therapy in NYHC III and IV patients (Grade of Recommendation, B). The treatment algorithm figure in this guideline contained a branch decision point labeled No improvement or deterioration, which suggested moving from initial therapies in FC III patients to additional therapies of which 3 of 4 were PPT. No further discussion elaborating upon this concept occurred within the guidelines. Of note, no recommendations regarding treatment of FC II patients were included in these guidelines despite the fact that subcutaneous treprostinil was approved for FC II-IV patients at the time CHEST GUIDELINE UPDATE 11 The 2004 Chest Guidelines were updated in 2007, with a focus on medical therapy. This incremental update provided new recommendations on treatment of FC II patients recommending sildenafil (A recommendation) and intravenous (IV) or SC treprostinil (C recommendation). In general, this guideline broadened the consideration for PPT to FC II patients and incorporated evidence from (then) newly approved IV treprostinil EUROPEAN SOCIETY OF CARDIOLOGY AND EUROPEAN RESPIRATORY SOCIETY GUIDELINES 12 In addition to incorporating additional approved therapies within the recommendations, the 2009 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines presented the important concept of long-term prognosis and risk of deterioration into decision-making. This idea was originally introduced by McLaughlin and McGoon in 2006, 13 recognizing the important prognostic factors they suggested be used in both the initial selection of therapies and subsequent determination of escalation of therapies in patients failing to meet initial therapeutic goals. Terminology of stable and satisfactory, stable and not satisfactory, and unstable and deteriorating, depending on whether patient characteristics fulfilled most, some, or few of the low-risk or better prognosis factors was suggested to gauge attainment of goals of therapy and guide escalation of therapy (Table 1). The following recommendations were made regarding PPT based on World Health Organization (WHO) functional class. WHO FC II patients: Nonresponders to acute vasoreactivity testing who are in WHO-FC II should be treated with an endothelin receptor antagonist (ERA) or a phosphodiesterase type-5 inhibitor. WHO FC III patients: Nonresponders to acute vasoreactivity testing, or responders who remain in (or progress to) WHO-FC III should be considered candidates for treatment with either an ERA or a phosphodiesterase type-5 inhibitor, or a prostanoid. WHO FC IV: Continuous IV epoprostenol is recommended as first-line therapy for WHO-FC IV PAH patients because of the survival benefit in this subset. SC and IV treprostinil have been also approved for the treatment of WHO-FC IV patients in the USA. Table 1. Definition of Inadequate Response to PAH Treatments This guideline represented the beginning of an alteration in primary recommendations for FC II patients favoring initial oral and combination therapies over monotherapy with PPT. It is important to note that this did not occur because of head-to-head comparisons of those therapies demonstrating superior efficacy, but rather due to accumulating trial evidence of nonparenteral agents in FC II patients. FC III patient treatment suggestions continued to include prostanoids along with a growing list of newly approved agents without clear guidance between them. It was acknowledged, however, that, Some experts still use first-line IV epoprostenol in WHO- FC III patients because of its survival benefits. Oral therapies were relegated to a second-line choice in FC IV patients in these guidelines, and although additional treatment was advocated for patients not achieving goals, PPT was not distinguished among the proliferating oral agents as initial add-on choices unless patients deteriorated to FC IV CHEST GUIDELINES 14 American College of Chest Physicians (ACCP) Guidelines continued to extend and specify concepts of therapy goals, the importance of escalation of therapy, and greater clarity of recommendations for PPT by functional class. In that consensus statement, the following recommendations were made. FC II patients: parenteral or inhaled prostanoids not be chosen as initial therapy for treatment-naive PAH patients with WHO-FC II symptoms or as second-line agents for PAH patients with Inadequate clinical response for patients who were initially in WHO-FC II or III: 1. Resulting clinical status defined as stable and not satisfactory 2. Resulting clinical status defined as unstable and deteriorating Inadequate clinical response for patients who were initially in WHO-FC IV: 1. No rapid improvement to WHO-FC III or better 2. Resulting clinical status defined as stable and not satisfactory Adapted from Galiè, N, Hoeper MM, Humbert M, et al; ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30(20): Advances in Pulmonary Hypertension Volume 16, Number 1;

3 WHO-FC II symptoms who have not met their treatment goals. This statement implies, but does not overtly state, that PPT may be appropriate for patients who have not met their treatment goals in the setting of dual therapies. FC III patients: For treatment-naive PAH patients with WHO-FC III symptoms who have evidence of rapid progression of their disease, or other markers of a poor clinical prognosis, we advise consideration of initial treatment with a parenteral prostanoid. For PAH patients in WHO-FC III who have evidence of progression of their disease, and/or markers of poor clinical prognosis despite treatment with 1 or 2 classes of oral agents, we advise consideration of the addition of a parenteral or inhaled prostanoid. FC IV patients: For treatment-naive PAH patients in WHO-FC IV, we advise initiation of monotherapy with a parenteral prostanoid agent. Overall, PPT continued to be advocated as initial therapy for FC IV and for FC III patients with a poor clinical prognosis. Previous FC II recommendations for initial monotherapy with PPT were altered, favoring institution of oral therapy with advancement to dual oral or the addition of inhaled agents for initially failing to meet goals of therapy and remaining FC II. Consideration of advancement to PPT for FC II patients failing to achieve goals on these initial therapies was mentioned ESC/ERS GUIDELINES 15 The most recent PAH diagnosis and treatment guidelines as of this publication are the ESC/ERS guidelines published in These guidelines represent the integration of all previously identified important steps in the evaluation of patient severity, risk for deterioration, and levels of clinical evidence for efficacy. The guidelines also carefully evaluate starting with monotherapy, followed by sequential addition Figure 2: 2015 ESC/ERS PH evidence-based treatment algorithm. Galiè, N, Humbert M, Vachiery JL, et al ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1): Reproduced by permission of Oxford University Press/European Society of Cardiology. of therapy to patients failing to achieve treatment goals. These recommendations are summarized below (Figure 2). Low- or intermediate-risk FC II-III patients: Nonresponders to acute vasoreactivity testing who are at low or intermediate risk can be treated with either initial monotherapy or initial oral combination therapy. High-risk FC III and IV patients: In nonvasoreactive and treatment-naïve patients at high risk, initial combination therapy including IV prostacyclin analog should be considered. Patients failing to meet goals of therapy defined in these guidelines as attainment of a low-risk profile are suggested for continuing escalation of therapy, choices guided by risk profile. Regardless of their position in the therapeutic continuum, high-risk patients would be considered for PPT. These recommendations mirror the 2014 Chest Guidelines, 14 which immediately preceded them with regard to PPT. Importantly, this reiterates the role of PPT in high-risk patients, FC IV patients, and patients failing to meet goals of therapy. The evolution of guidelines has included substantial changes in the 16 Advances in Pulmonary Hypertension Volume 16, Number 1; 2017

4 recommendations for PPT, accommodating increasing numbers of additional therapeutic agents and existing data from clinical trials. PPT started as the sole therapy for PAH more than 20 years ago, albeit with limited experience in almost all patients, including those other than NYHC III-IV. As additional therapies became available with data almost exclusively from monotherapy, guidelines integrated recommendations based on placebo-controlled trials without head-to-head trials that would identify superiority or rank of therapy in most patients. This effectively decreased the proportion of patients who may have potentially been initiated on PPT with multiple options listed from The most recent set of guidelines 14,15 in many ways have returned to a broader advocacy of PPT use in all high-risk patients (FC III or IV) and in patients failing treatment goals even though they may be class II. This return to increasing PPT recommendation occurred as additional experience accumulated with recognition of at least 4 important trends that emerged in the treatment of PAH in the current era. 1. Patients with poor functional status, walk distance, and right ventricular function that fail to improve or approximate normal under initial regimens have substantial risk of deterioration and death. 2. Incremental addition of oral or inhaled therapies to such patients that are typically offered resulted in modest improvements at best, which often failed to achieve aggressive goals of therapy. 3. PPT continued to offer substantial clinical improvements even in such patient populations. 4. Patients offered PPT late in their treatment course appear to have inferior outcomes compared to patients that were treated more aggressively earlier in the course. The following section explores some of the data leading to these pivotal concepts shaping recommendations for PPT. KEY CONSIDERATIONS IN SELECTING PATIENTS FOR PARENTERAL PROSTACYCLIN THERAPY As noted in the Editor s Memo and the Roundtable Discussion in this issue of Advances, current guidelines offer broad suggestions for treatment, which must be individualized for each patient, and most importantly, take into account patient goals, preferences, and abilities. Continuing the theme of this issue, we suggest that at least 3 additional key areas should be considered in making decisions regarding the use of PPT, namely efficacy of parenteral therapy, limitations with nonparenteral therapies, and potential consequence of underutilization of parenteral therapy. EFFICACY OF PPT Epoprostenol therapy has been shown to improve hemodynamics, exercise capacity, and survival in patients with idiopathic PAH (IPAH). 2,16-18 Epoprostenol remains the only agent to date demonstrating a survival advantage in a randomized, controlled trial. Eight of 40 patients randomized to conventional therapy died during the 12-week trial vs 0 of 41 in the epoprostenol arm. 2 This was accompanied by improvements in functional status in 40% of patients and exercise tolerance. Long-term reports of unblinded epoprostenol use similarly suggest substantial improvements in survival when compared to historical controls 18 or predicted survival based on the National Institutes of Health Registry equation. 17 Survival in these series was as follows: 1-year, 85%-87.5%; 3-year, 62.8%-63%; and 5-year, 55%. Epoprostenol therapy improved exercise hemodynamics and historical survival in patients with PAH associated with scleroderma, a group with traditionally less response to PAH medications. The initial trial 8 and long-term, open-label extension showed a placebo-corrected increase in 6-minute walk distance (6MWD) of 94 meters (+46 meters, -48 meters in treated and control groups, respectively). Mean pulmonary pressures decreased by 5 mm Hg, with 1- and 2-year survival of 71% and 55%, respectively. As noted previously, lung transplant listing was substantially deferred in 60% to 70% of patients by the use of PPT. 3 In one of the initial series utilizing IV treprostinil, Tapson et al 19 reported de novo PPT in 16 FC III or IV PAH patients. After 12 weeks of therapy, 6MWD improved by a mean of 82 meters, from 319 to 400 meters (P<0.001). There were also improvements in hemodynamics including mean pulmonary artery pressure (mpap), cardiac index, and pulmonary vascular resistance (PVR) index. Although not directly comparable or done in a controlled fashion, an 82-meter increase far exceeds typical improvements seen in non-ppt trials, which have been reported as 3-15 meters Long-term experience with SC treprostinil has also shown a similar magnitude of increase in 6MWD and survival 24 as other PPT options. Lang et al reported a mean increase of 100 meters, with 1- and 4-year survival of 91% and 72%, respectively, for IPAH patients. Most recently, a triple therapy regimen containing epoprostenol also has demonstrated (in an uncontrolled fashion) impressive improvements in exercise tolerance and survival. Six-minute walk distance increased by a mean of 236 meters (227 to >463 meters) in 4 months, which slightly increased by a mean follow-up of months. Survival in this cohort was 100% at 1, 2, and 3 years. 25 Predicted survivals in this group were 75%, 60%, and 49%, respectively. Taken together, these reports chronicle an experience of PPT associated with significantly improved survivals and exercise capacity increases, and speaks to the efficacy of this group of medications when administered by the parenteral route. POTENTIAL LIMITATIONS OF NONPARENTERAL THERAPIES In contrast, there is significant evidence that oral or inhaled agents frequently fail to achieve goals of therapy in patients with PAH. Modern goals of therapy, as have been discussed elsewhere in this issue, involve attaining a low-risk profile that is associated with FC I-II along with achieving clinically Advances in Pulmonary Hypertension Volume 16, Number 1;

5 meaningful walk distances, most recently suggested to be >440 meters. If one reviews the pivotal clinical studies for monotherapies and applies these criteria, no oral or inhaled regimens using mean increases fulfill the walk distance goals (recognizing that there are likely small groups of hyper-responders in these studies). Improvement in functional class fares somewhat better, with improvements ranging from 4% to 42%. Hemodynamic improvements (when available) also failed to attain a low-risk profile, with typical short-term improvements of mpap of approximately 3-5 mm Hg. Randomized, controlled trials of combination therapy do appear to provide dramatically better outcomes using the above criteria. Even combinations containing 1B recommendations such as ambrisentan + tadalafil 34 fail to achieve a satisfactory clinical response more often than not. That study defined a satisfactory clinical response as achieving FC I-II and improvement of walk distance by >10%, which was reached in only 39% of patients receiving initial upfront combination oral therapy. INCIDENCE AND CONSEQUENCES OF UNDERUTILIZATION OF PPT Clinical trials and guidelines uniformly support the use of PPT in severe pulmonary hypertension. Analysis of usage from large, retrospective databases, however, shows substantial deviation from these recommendations in practice among patients dying from PAH. Analysis of the REVEAL registry demonstrate that among the 56% (272/487) of patients who died from PAH, 43% (391/908) never received PPT. Furthermore, 61% to 67% of patients who showed clinical worsening to FC IV failed to receive PPT within 90 days. 4 While causality cannot be inferred from these retrospective studies, it would seem that these adverse events could have been substantially reduced and/or delayed with PPT given the clinical trial experience in patients with progressing PAH as noted above. Additional indirect evidence of the potentially detrimental effect of delaying parenteral therapy comes from the analysis of the PROSPECT registry study, showing significantly worse survival among patients transitioned from inhaled treprostinil to IV epoprostenol compared to de novo patients. 35 Patients on inhaled prostacyclins had a slightly longer mean disease duration (5.7 vs 4.0 years), slightly shorter mean 6MWD (274 meters vs 311 meters), and a poorer outcome at 1 year (63% vs 83% survival) compared to prostacyclin-naive patients. The patients are not therapy naive. The proportion of class III/IV patients was similar. The conclusion was that this population represented a high-risk population requiring close observation and therapy escalation to PPT before deterioration. One plausible explanation is that the increased adverse outcomes and apparent decreased efficacy of PPT in this population was a consequence of delay in starting treatment with PPT. Further evidence of delay in PPT leading to adverse outcomes comes from a summary of management outcomes from a PAH referral center focusing on patients requiring urgent PPT presumably due to delayed referral to a PAH center. 36 In that study, nonsurvivors were more frequently referred on oral therapy (83% vs 36%; P<0.01) and had a higher rate of urgent prostanoid treatment (69% vs 17%; P<0.0001). The authors explained their data regarding the adverse outcomes of referred patients as follows: A comparison of the clinical and hemodynamic status at diagnosis shows the 2 populations receiving oral therapy had a similar profile, but the referred oral patients received a prostanoid in a sicker status because they remained on oral therapy for a longer period than would have been allowed at our centre. While no direct, prospective, head-tohead trial of PPT compared to oral or inhaled regimens have been performed, the existing evidence and experience suggest the following: Non-PPT regimens frequently fail to achieve treatment goals. PPT tends to provide substantial benefit to patients failing such regimens. PPT-containing regimens are uniformly recommended for very ill patients with high levels of experimental confidence (2004 and subsequent guidelines for class IV epoprostenol). Delay of PPT regimens are likely detrimental to patient outcomes. Taken together, this summons a powerful argument for timely utilization of these agents in many patients. Paradoxically, history suggests that they are not used in a timely manner in spite of guidelines and efficacy. CONCLUSION Current guidelines suggest that PPT may be a consideration for WHO-FC II-IV patients, emphasizing the importance of risk stratification and identifying those with potential for progression toward aggressive goals of therapy as important determinants in treatment selection and decision-making. Recent evidence supports the efficacy of up-front combination therapy in the treatment of PAH including initial data on regimens containing PPT. 25 Although the ongoing debate about intensity of therapies and one approach to PAH is far from settled, it is clear that broader groups of patients with PAH should be considered for PPT therapy with increasing urgency in patients who are at high risk and/or initially fail to respond toward aggressive treatment goals as currently suggested in guidelines. Practicing parenteral prostacyclin avoidance in most cases seems ill advised, as delaying this important therapy or failing to consider this very effective group of treatments appears to be detrimental as discussed above. For these reasons, experience and evidence suggests that PPT should not be reserved as a last resort, but should be carefully considered and not delayed in the treatment of a significant number of patients with PAH. References 1. D Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115(5): Barst RJ, Rubin LJ, Long WA, et al; Primary Pulmonary Hypertension Study Group. A comparison of continuous intravenous epoprostenol 18 Advances in Pulmonary Hypertension Volume 16, Number 1; 2017

6 (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334(5): Conte JV, Gaine SP, Orens JB, Harris T, Rubin LJ. The influence of continuous intravenous prostacyclin therapy for primary pulmonary hypertension on the timing and outcome of transplantation. J Heart Lung Transplant. 1998;17(7): Farber HW, Miller DP, Meltzer LA, McGoon MD. Treatment of patients with pulmonary arterial hypertension at the time of death or deterioration to functional class IV: insights from the REVEAL Registry. J Heart Lung Transplant. 2013;32(11): Tankersley MA, D Albini LD, Ozanich AN, Whitman AJ. A 36-month survival analysis of patients beginning oral PAH monotherapy: an indication for escalation of therapy? Poster 1062 presented at: Pulmonary Hypertension Association International Conference; June 20-22, 2008; Houston, Texas. 6. Robbins IM, Gaine SP, Schilz R, Tapson VF, Rubin LJ, Loyd JE. Epoprostenol for treatment of pulmonary hypertension in patients with systemic lupus erythematosus. Chest. 2000;117(1): Krowka MJ, Frantz RP, McGoon MD, Severson C, Plevak DJ, Wiesner RH. Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): A study of 15 patients with moderate to severe portopulmonary hypertension. Hepatology. 1999;30(3): Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med. 2000;132(6): Rich S, ed. Executive Summary from the World Symposium on Primary Pulmonary Hypertension, 1998; September 6-10, 1998; cosponsored by the World Health Organization. Evian, France. 10. Badesch DB, Abman SH, Ahearn GS, et al; American College of Chest Physicians. Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126(1 Suppl):35S-62S. 11. Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest. 2007;131(6): Galiè, N, Hoeper MM, Humbert M, et al; ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30(20): McLaughlin VV, McGoon MD Pulmonary arterial hypertension. Circulation. 2006;114(13): Taichman DB, Ornelas J, Chung L, et al. Pharmacologic therapy for pulmonary arterial hypertension in adults: CHEST guideline and expert panel report. Chest. 2014;146(2): Galiè, N, Humbert M, Vachiery JL, et al ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1): Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med. 1990;112(7): McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002;106(12): Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40(4): Tapson VF, Gomberg-Maitland M, McLaughlin VV, et al. Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, open-label, 12-week trial. Chest. 2006;129(3): Tapson VF, Jing ZC, Xu KF, et al; FREE- DOM-C2 Study Team. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trial. Chest. 2013;144(3): Pulido T, Adzerikho I, Channick RN, et al; SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9): McLaughlin V, Channick RN, Ghofrani HA, et al. Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension. Eur Respir J. 2015;46(2): McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010;55(18): Lang I, Gomez-Sanchez M, Kneussl M, et al. Efficacy of long-term subcutaneous treprostinil sodium therapy in pulmonary hypertension. Chest. 2006;129(6): Sitbon O, Jaïs X, Savale L, et al. Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study. Eur Respir J. 2014;43(6): Rubin LJ, Badesch DB, Barst, RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346(12): Barst RJ, Langleben D, Frost A, et al; STRIDE-1 Study Group. Sitaxentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004;169(4): Galié N, Olschewski H, Oudiz RJ, et al; Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (ARIES) Group. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and Circulation. 2008;117(23): Galiè N, Ghofrani HA, Torbicki A, et al; Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353(20): Galiè N, Brundage BH, Ghofrani HA, et al; Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119(22): Olschewski H, Simonneau G, Galiè N, et al; Aerosolized Iloprost Randomized Study Group. Inhaled iloprost in severe pulmonary hypertension. N Engl J Med. 2002:347(5): Jing ZC, Parikh K, Pulido T, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation. 2013;127(5): Sitbon O, Channick R, Chin K, et al; GRI- PHON Investigators. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2015;373(26): Galiè N, Barbera JA, Frost A, et al; AMBI- TION Investigators. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med. 2015;373(9): Farber HW, Frantz RP, Schilz RJ, et al. The PROSPECT Registry of Pulmonary Arterial Hypertension (PAH): Description of Patients Who Transitioned From Inhaled Prostacyclin to Intravenous Epoprostenol. J Heart Lung Transplant. 2014;33(4 Supplement):S Badagliacca R, Pezzuto B, Poscia R, et al. Prognostic factors in severe pulmonary hypertension patients who need parenteral prostanoid therapy: the impact of late referral. J Heart Lung Transplant. 2012;31(4): Advances in Pulmonary Hypertension Volume 16, Number 1;