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Abstract
In the past 18 months, the U.S. Food and Drug Administration approved macitentan, riociguat, and treprostinil as oral agents for the treatment of pulmonary arterial hypertension (PAH); riociguat also became the first agent approved for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). These new agents are welcome additional therapeutic options for PAH and CTEPH. However, their use can be complicated by potential drug interactions, adverse effects, dosing complexity, and cost. Macitentan, the newest endothelin receptor antagonist, showed significant benefits in a long-term event-driven trial of morbidity and mortality. Dosed once daily and with minimal liver toxicity, it has potential drug interactions with potent CYP 3A4 inhibitors and inducers, and can decrease hemoglobin levels. Riociguat is approved for PAH and clinically inoperable CTEPH to improve exercise capacity and functional status. Riociguat requires dose titration beginning with 1 mg up to 2.5 mg three times a day, as tolerated, and should be used with caution in patients with underlying risk factors for systemic hypotension. Oral treprostinil, approved to improve exercise capacity in PAH, is associated with gastrointestinal side effects and headaches that are often dose limiting. Doses can begin with 0.125 mg or 0.25 mg twice a day with gradual increases on up to a weekly basis, as tolerated. Thrice daily dosing and administration with a meal can improve tolerance. These newer agents represent advances, but their specific roles in relation to pre-existing therapies are undergoing further evaluation. Therefore, close collaboration with clinicians at centers with therapeutic expertise is highly recommended to optimize patient outcomes.
Pulmonary hypertension (PH) is characterized by elevated pulmonary arterial pressure, often leading to right heart failure and premature death. PH has varied etiologies, and since 1998, has been categorized into five major groups based on clinical characteristics and genetic and pathophysiologic mechanisms. Recently, at the Fifth World Symposium on Pulmonary Hypertension (WSPH) held in Nice, France, a consensus recommendation was made to maintain the current classification system, albeit with some modifications to groups 1 and 5 (1).
The pathogenesis of group 1 pulmonary arterial hypertension (PAH) is thought to be due, in part, to altered vasomotor tone of the pulmonary arterial circulation related to dysregulation of the endothelin, nitric oxide (NO), and prostacyclin pathways (2). Abnormalities in the vasomotor and cell proliferation regulatory function of these and other pathways also contribute to structural remodeling of pulmonary arteries (2, 3). Combined, these phenomena lead to pulmonary arterial remodeling and increased pulmonary vascular resistance.
Currently available pharmacologic therapeutic approaches consist of drugs that antagonize the endothelin receptors (bosentan and ambrisentan), enhance the NO/cyclic guanosine monophosphate (cGMP) pathway (the phosphodiesterase [PDE] type 5 inhibitors sildenafil and tadalafil), or supplement the prostacyclin pathway (epoprostinol, treprostinil, and iloprost) (4). Each of the newly approved agents targets one of these known pathways in the pathogenesis of PAH: riociguat the NO/cGMP pathway; macitentan the endothelin pathway; and oral treprostinil the prostacyclin pathway. Each of these agents has features that broaden the physician’s pharmacologic armamentarium for the treatment of PH. However, they also have attributes that must be carefully considered to optimize the effectiveness and safety of these compounds.
The choice of agent is determined by such factors as disease severity, underlying comorbid conditions, the drug’s adverse event profile and drug–drug interaction potential, ease of use, practitioner and patient preferences, and cost. Subtle differences between drugs or responses of patients to drugs within the same therapeutic class can affect choice and usage.
Macitentan is the most recently approved drug (October 2013) in the endothelin receptor antagonist (ERA) class, which also includes bosentan and ambrisentan.
Macitentan is a dual ERA that has sustained receptor binding and enhanced tissue penetration (5). Long-term therapy with macitentan was evaluated in a multicenter, event-driven morbidity and mortality Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) (6). Patients were randomized to placebo, 3 mg macitentan, or 10 mg macitentan. The primary endpoint was time to first event, defined as clinical worsening of PAH, death from any cause, prostanoid initiation, or lung transplantation.
Macitentan delayed time to clinical worsening of PAH. The hazard ratios for the 3 and 10 mg doses of macitentan compared with placebo were 0.70 (97.5% confidence interval [CI] = 0.52–0.96; P = 0.01) and 0.55 (97.5% CI = 0.39–0.76; P < 0.0001), respectively. Over the average 2-year follow-up period of the study, this corresponded to a 43% reduction in events with the 10 mg dose compared with placebo. The difference in event rate between the 10 mg macitentan and placebo groups was driven mainly by the worsening of PAH component of the composite endpoint. There were also minor improvements in 6-minute-walk distance (6MWD) and functional class at 6 months. Headache, nasopharyngitis, and anemia were adverse events more frequently observed in the macitentan groups than in placebo.
The long-term design of the event-driven trial is an improvement over previous trial designs. The other approved ERAs have also shown delays in the rate of clinical worsening as secondary endpoints, but in trials lasting only 12–16 weeks. However, because the other ERAs were not tested using the event-driven design and there is no head-to-head comparison data with other ERAs, it is unknown how other drugs in the same class would compare with macitentan under the same testing conditions. One needs to exercise caution regarding potential overinterpretation of macitentan’s effect on PAH mortality. Although the trial showed a highly significant effect on the combined morbidity and mortality endpoint, there was no significant effect on either all-cause mortality or PAH-specific mortality per se.
When choosing an ERA to treat PAH, the potential for drug–drug interactions is an important consideration. With macitentan, unlike bosentan, there are no clinically significant drug interactions with sildenafil or cyclosporine-A. However, increased macitentan levels were observed in pharmacokinetic studies using strong CYP 3A4 inhibitors, such as ketoconazole, and thus are likely to occur with other potent inhibitors of this enzyme. The need for concomitant use of other drugs that are potent CYP 3A4 inhibitors, such as some human immunodeficiency virus therapies, would be an important consideration when selecting PAH drugs.
Based on the information from the trial and our own practice experiences, macitentan would be an option in patients in whom treatment with an ERA is desired. Advantages over bosentan include not only fewer drug–drug interactions, but also the once a day as opposed to twice a day dosing, and a low potential for liver toxicity obviating mandatory monthly liver function testing, which is required with bosentan. However, these advantages are also shared by ambrisentan, and we perceive no clearly demonstrable differences in clinical outcomes between these two agents, despite the longer duration of the macitentan trial. If macitentan is chosen, complete blood count monitoring is important, because decreased hemoglobin levels below 8 g/dl occurred in some patients in the clinical trial. In addition, if a patient is doing well on another ERA, it would be appropriate to continue that therapy because there is no assurance that a replacement ERA would perform as well. In addition, the pharmacokinetic data, especially drug–drug interactions, and cost (including reduction in need for hospitalization, as was reported with macitentan) are important considerations when choosing between ERAs.
Macitentan is prescribed as one 10-mg pill daily. Fetal abnormalities are associated with ERAs and, consequently, it is important to exclude the possibility of pregnancy in women of childbearing age before starting therapy. Women of childbearing age must use two effective methods of birth control or have had tubal ligation, an intrauterine device, or a hysterectomy. Although liver function abnormalities were not encountered more frequently with macitentan than placebo in the randomized controlled trial, liver function tests should be obtained at baseline. Repeated liver function tests are not mandatory, but checking them periodically along with complete blood counts during the first 6 months of therapy would be prudent, and then as clinically indicated. Fluid retention is another side effect of ERAs. Prescribers should warn patients to monitor their weights daily, and provide a plan to adjust diuretics or to contact their caregivers if they experience rapid weight gain exceeding a few pounds or encounter increased swelling.
Riociguat is a soluble guanylate cyclase stimulator that not only acts synergistically with endogenous NO, but also directly stimulates soluble guanylate cyclase to produce cGMP independently of NO availability (7). Riociguat was approved for two indications: (1) chronic thromboembolic PH (CTEPH) in patients who are not surgical candidates or have persistent or recurrent PH after surgical pulmonary thromboendarterectomy (PTE) WSPH group 4 PH; and (2) WSPH group 1 PAH to improve exercise capacity and functional class.
In a 16-week randomized controlled trial in patients with CTEPH (8), riociguat increased 6MWD by 39 m from baseline as opposed to a 6-m decrease in the placebo group (least-squares = 46 m mean difference; 95% CI = 25–67; P < 0.001). Pulmonary vascular resistance, N-terminal pro–brain natriuretic peptide levels and World Health Organization functional class also improved significantly, but not slowing of clinical worsening.
It is important to remember that the trial was conducted in patients who were surgically inoperable for CTEPH or had persistent or recurrent PH after PTE, as PTE can be curative and is the preferred therapy in properly selected patients (9, 10). Thus, the need for a thorough examination at a center experienced in the evaluation and treatment of CTEPH must be emphasized. In addition, although several small studies have examined the use of intravenous prostacyclin and bosentan in the preoperative period as a bridge to PTE (11, 12), this application of medical therapy remains controversial, because hemodynamic parameters may improve preoperatively, but it is not clear that these lead to improved surgical outcomes (11, 12). A larger retrospective analysis of patients referred for surgery at a CTEPH center found no differences in surgical outcomes between patients who had been given preoperative PH therapy and those who had not (13).
Although riociguat should be considered the medical therapy of first choice (and is currently the only approved drug) for patients with inoperable CTEPH and those with persisting postoperative PH, it should not be used for CTEPH in lieu of a careful evaluation for potentially curative surgery. In addition, riociguat has not been studied adequately for use as a bridge to potentially curative surgery, and should not be routinely advocated for this application pending further evidence from clinical trials.
Riociguat was evaluated for WSPH group 1 PAH in a 12-week, double-blind, randomized, placebo-controlled study (Pulmonary Arterial Hypertension Soluble Guanylate Cyclase Stimulator Trial 1 [PATENT 1]) (14). Riociguat significantly improved exercise capacity and other secondary endpoints. Treatment with the maximum riociguat dose of 2.5 mg three times daily increased the 6MWD by a mean of 30 m compared with a 6-m decrease in the placebo group (95% CI = 20–52; P < 0.001). Improvements were also observed in hemodynamics, N-terminal pro–brain natriuretic peptide, Borg dyspnea scores, and World Health Organization functional class, and there was a slowing in the time to clinical worsening. Treatment-related adverse events were headache, gastrointestinal symptoms, including dyspepsia, nausea, vomiting, and diarrhea, and hypotension.
Riociguat is available in a range of dosing strengths (0.5, 1.0, 1.5, 2.0, and 2.5 mg). The usual starting dose is 1 mg three times a day and requires dosing up-titrations of 0.5 mg at no less than 2-week intervals, to a maximum dose of 2.5 mg three times a day, while carefully assessing the effect on systemic blood pressure. Because of the potential for significant systemic hypotension, riociguat should be used cautiously in patients with underlying conditions that may predispose them to hypotension. If hypotension should develop, riociguat should be withheld or the dose lowered, depending on the severity. In addition, if a patient is already taking a strong CYP or breast cancer resistance protein and P-glycoprotein inhibitor, consider using a lower starting dose of 0.5 mg three times a day. Riociguat is contraindicated with the use of other agents that increase intracellular cGMP, including nitrates, the nonspecific PDE inhibitors, and specific PDE-5 inhibitors, such as sildenafil, tadalafil, and vardenafil.
Riociguat should not be considered a first-line agent for the treatment of group 1 PAH, because of its similar efficacy profile, greater risk for systemic hypotension, more complex initiation, and greater cost relative to PDE5 inhibitors. However, in patients intolerant of or allergic to PDE5 inhibitors or those manifesting an inadequate response to initial oral therapy after 2 to 3 months, switching to riociguat from a PDE5 inhibitor or adding riociguat to an ERA would be an option, although there is a need for more study on these applications. If a switch from a PDE 5 inhibitor to riociguat is indicated, a 24-hour washout period for sildenafil and 48 hours for tadalafil before starting riociguat is recommended.
Like the ERAs, riociguat also has the potential for fetal abnormalities, and should not be used in pregnant women. Those who are of childbearing age must adhere to strict contraceptive practices, and monthly monitoring for pregnancy is required while taking riociguat.
The first commercially available oral prostacyclin, oral treprostinil, was approved by the U.S. Food and Drug Administration in December 2013. Oral treprostinil was studied in a 12-week, randomized, placebo-controlled trial in patients with PAH not receiving ERAs, PDE5 inhibitors, or prostacyclins (A 12-Week, International, Multicenter, Double-Blind, Randomized, Placebo-Controlled Comparison of the Efficacy and Safety of Oral UT-15C Sustained Release Tablets in Subjects With Pulmonary Arterial Hypertension [FREEDOM M] [for monotherapy]) (15). There was a 23-m median increase in the 6MWD compared with placebo (95% CI = 4–41 m; P = 0.0125), but no significant differences in the secondary endpoints. Common treatment-related adverse events seen typically with prostacyclins included headache, nausea, diarrhea, and jaw pain. Treatment with oral treprostinil as an adjunct to treatment with an ERA or PDE-5 inhibitor or both was studied in two 16-week trials (FREEDOM C1 and C2 [for combination]) (16, 17), and there were no significant improvements in 6MWD.
Oral treprostinil is approved to treat WSPH group 1 PAH to improve exercise capacity. Dosing should be determined based on the individual’s clinical response. Doses are gradually increased over many months at weekly or biweekly intervals as patients develop tolerance to the side effects. Doses usually begin at 0.125 or 0.25 mg twice a day or three times a day. Subsequent increases are usually in the 0.125–0.25 mg range per dose, and are often limited by gastrointestinal intolerance or headache. Three times daily dosing has recently been introduced to reduce fluctuations in blood levels compared with twice-daily dosing and, anecdotally, this can ameliorate side effects. The mean dose in the 12-week monotherapy trial was 3.4 mg twice a day. Dosages of at least 4–6 mg twice a day (or 3–4 mg three times a day) appear to be needed to achieve a good therapeutic response (15). Interruptions in therapy and abrupt discontinuations should be avoided, as PAH symptoms may rebound.
The efficacy of prostacyclins is dose dependent and, of the oral PAH therapies now available, treprostinil has the most complex and challenging dosing scheme. Dosing with prostacyclins by any route requires close attention to dose titration while monitoring for tolerability and side effects to achieve the desired clinical response. When dosing by the oral route, food can help mitigate some of the gastrointestinal side effects and improve tolerability; however, some of the authors have found that high caloric meals are often needed. If careful attention is not paid to the management of the side effects, one may end up not achieving an optimal therapeutic dose. Because of the complexities of administration, oral treprostinil is best managed in the hands of clinicians who are expert in the use of parenteral prostacyclins at an experienced PAH treatment center.
The role of oral treprostinil in the PAH therapeutic armamentarium remains to be established. Because of complexity of administration, frequent side effects, and high cost, use as a first-line agent is not recommended. Rather, despite the negative findings of the FREEDOM C trials, its best application may be as an add-on agent to one or two other agents when the clinical response is inadequate, but patients had not deteriorated enough to warrant initiation of, were not deemed candidates for, or had refused an infusion with prostacyclin.
The potential for using oral treprostinil to replace or augment parenteral formulations (intravenous, subcutaneous, and inhaled) is intriguing, and is of interest to many patients already on infusion therapy, especially those on subcutaneous therapy experiencing substantial site pain. However, there are only preliminary clinical studies (18), and very little clinical experience to guide these transitions or additions. There is concern that underdosing with the oral agent after a transition could predispose to clinical deterioration. In addition, the conversion ratio commonly cited (1 mg po tid = 5 ng/kg/min infusion) would mean that the pill burden for patients transitioned from usual doses of intravenous/subcutaneous (40 to >100 ng/kg/min) to oral therapy could be very large and extremely costly. Thus, the authors recommend caution until more data and experience have accrued.
Oral treprostinil is available in multiple dosage strengths (0.125, 0.25, 1, 2.5 mg) to allow for fine tuning of dose titration. The maximum dose is determined by tolerability. Due to the increased systemic exposure of oral treprostinil in patients with severe hepatic impairment, its use is contraindicated in this patient group. Oral treprostinil is considered pregnancy category C, and use is discouraged during pregnancy, although, unlike the other newer agents, it is not contraindicated.
PAH remains a severe, life-limiting condition, despite the introduction of multiple PAH-specific therapies. Data from the Registry to Evaluate Early And Long-term PAH Disease Management (REVEAL) suggest that the current pharmacologic agents have had an impact on long-term survival (19); however, morbidity is significant, and mortality remains high. It is clear that the recently approved drugs for the treatment (but not cure) of PAH have given the medical community more therapeutic options and flexibility with respect to individual patient needs and preferences. However, with this flexibility comes greater complexity, due to increased potential for drug interactions, dosing challenges, titration, tolerability, and cost considerations.
Over time, clinical studies should help clarify the role of the new agents relative to the previously available therapies and better define pharmacokinetics, efficacy, and toxicity. In addition, in the near future, we may see other agents approved. The Prostacyclin (PGI2) Receptor agonist in pulmonary arterial hypertension (GRIPHON) study (20) of selexipag, a prostacyclin receptor agonist, recently released preliminary results of a completed phase III study. Selexipag decreased the risk of a morbidity/mortality event versus placebo by 39% (P < 0.0001). What role this agent will play in relation to oral treprostinil remains to be seen, pending the release of the complete data in article form and the determination by the U.S. Food and Drug Administration.
Combination drug therapy has become increasingly prevalent in PAH therapy, with approximately 50% of patients in the REVEAL registry receiving at least two PAH-specific therapies. The recently completed randomized, double-blind, multicenter study of first-line combination therapy with AMBrIsentan and Tadalafil in patients with pulmonary arterial hypertensION (AMBITION) Study (21) poses additional considerations in the future management of PAH. Results from this trial of the efficacy and safety of the up-front combination of ambrisentan 10 mg and tadalafil 40 mg versus the pooled monotherapy ambrisentan and tadalafil arms showed a 50% reduction in clinical failure for the combination therapy group. This study is unique, because previous studies had combined therapies in add-on fashion. These findings are likely to encourage greater use of combination therapy, especially upon initiation, but whether these findings will be reproducible with other combinations of PAH therapies is yet to be determined.
General recommendations of the roundtable for each recently introduced agent are listed in Table 1. Given the complexity involved in the diagnosis and treatment of PAH, it is highly recommended that an experienced multidisciplinary team be involved in the care of patients with PAH, including clinicians expert in the differential diagnosis and management of PAH, as well as a team consisting of nurses, respiratory therapists, pharmacists, social workers, and others who can provide support services and, in collaboration with community pulmonologists, cardiologists, and rheumatologists, can optimize patient care and provide access to clinical trials. The recently established Pulmonary Hypertension Association program for accrediting PH Centers of Excellence will aid in identifying such centers.
| Macitentan is an option when an ERA is desired for first-line or add-on therapy of PAH. It has clear advantages over bosentan, including once-daily dosing, no need for monthly LFT monitoring, and fewer drug–drug interactions, but shares these with ambrisentan. |
| Riociguat should be considered first-line therapy for CTEPH, but not for PAH unless patients have known sensitivity or intolerance of PDE5 inhibitors. For PAH, switching to riociguat is an option for patients not responding adequately to initial PDE5 inhibitor therapy. |
| Oral treprostinil should not be considered a first-line therapy. It is an option for patients receiving one or two background oral PAH therapies for whom prostacyclin therapy is desired, but infusion therapy is deemed unnecessary or undesirable. |
| 1 . | Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013;62:D34–D41. |
| 2 . | Seeger W, Pullamsetti SS. Mechanics and mechanisms of pulmonary hypertension—conference summary and translational perspectives. Pulm Circ 2013;3:128–136. |
| 3 . | Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F. Mechanisms of disease: pulmonary arterial hypertension. Nat Rev Cardiol 2011;8:443–455. |
| 4 . | McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, et al.; American College of Cardiology Foundation Task Force on Expert Consensus Documents; American Heart Association; American College of Chest Physicians; American Thoracic Society, Inc; Pulmonary Hypertension Association. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 2009;53:1573–1619. |
| 5 . | Gatfield J, Mueller Grandjean C, Sasse T, Clozel M, Nayler O. Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells. PLoS ONE 2012;7:e47662. |
| 6 . | Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani HA, Jansa P, Jing ZC, Le Brun FO, Mehta S, et al.; SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013;369:809–818. |
| 7 . | Schermuly RT, Janssen W, Weissmann N, Stasch JP, Grimminger F, Ghofrani HA. Riociguat for the treatment of pulmonary hypertension. Expert Opin Investig Drugs 2011;20:567–576. |
| 8 . | Ghofrani HA, D’Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, et al.; CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013;369:319–329. |
| 9 . | Fedullo P, Kerr KM, Kim NH, Auger WR. Chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2011;183:1605–1613. |
| 10 . | Madani MM, Auger WR, Pretorius V, Sakakibara N, Kerr KM, Kim NH, Fedullo PF, Jamieson SW. Pulmonary endarterectomy: recent changes in a single institution’s experience of more than 2,700 patients. Ann Thorac Surg 2012;94:97–103, discussion 103. |
| 11 . | Nagaya N, Sasaki N, Ando M, Ogino H, Sakamaki F, Kyotani S, Nakanishi N. Prostacylin therapy before pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension. Chest 2003;123:338–343. |
| 12 . | Reesink HJ, Surie S, Kloek JJ, Tan HL, Tepaske R, Fedullo PF, Bresser P. Bosentan as a bridge to pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. J Thorac Cardiovasc Surg 2010;139:85–91. |
| 13 . | Jensen KW, Kerr KM, Fedullo PF, Kim NH, Test VJ, Ben-Yehuda O, Auger WR. Pulmonary hypertensive medical therapy in chronic thromboembolic pulmonary hypertension before pulmonary thromboendarterectomy. Circulation 2009;120:1248–1254. |
| 14 . | Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A, et al.; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013;369:330–340. |
| 15 . | Jing ZC, Parikh K, Pulido T, Jerjes-Sanchez C, White RJ, Allen R, Torbicki A, Xu KF, Yehle D, Laliberte K, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation 2013;127:624–633. |
| 16 . | Tapson VF, Jing ZC, Xu KF, Pan L, Feldman J, Kiely DG, Kotlyar E, McSwain CS, Laliberte K, Arneson C, et al.; FREEDOM-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;144:952–958. |
| 17 . | Tapson VF, Torres F, Kermeen F, Keogh AM, Allen RP, Frantz RP, Badesch DB, Frost AE, Shapiro SM, Laliberte K, et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study): a randomized controlled trial. Chest 2012;142:1383–1390. |
| 18 . | White RJ, Chakinala M, Rischard F, Howell M, Laliberte K, Feldman J. Safety and tolerability of transitioning from parenteral treprostinil to oral treprostinil in patients with pulmonary arterial hypertension [abstract]. Am J Respir Crit Care Med 2014;189:A2460. |
| 19 . | Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest 2012;142:448–456. |
| 20 . | Selexipag (ACT-293987) in pulmonary arterial hypertension, GRIPHON trial. clinicaltrials.gov identifier: NCT01106014 [updated 2014 Sep 25; accessed 2015 Feb 20]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT01106014?term=NCT01106014&rank=1 |
| 21 . | A study of first-line ambrisentan and tadalafil combination therapy in subjects with pulmonary arterial hypertension (PAH). clinicaltrials.gov identifier: NCT01178073 [updated 2015 Jan 2; accessed 2015 Feb 20]. Available from: https://www.clinicaltrials.gov/ct2/results?term=NCT01178073&Search=Search |
The meeting was supported by Actelion Pharmaceuticals, Inc. and an educational grant from Bayer HealthCare Pharmaceuticals.
The views and opinions expressed in this report do not necessarily represent those of the American Thoracic Society.
The American Thoracic Society (ATS) convened a panel of pulmonary arterial hypertension (PAH) experts to discuss the recently approved agents based on published data and experiences from the clinical trials and clinical practice. The Roundtable Discussion on Recently Approved PAH Treatments was held on May 15, 2014 in San Diego, California. The ATS nominated the chair (N.S.H.), who selected the other panelists based on their recognition as PAH experts, participation in the clinical trials, and geographic diversity. One panelist (T.A.D.) was chosen based on prior experience in pharmaceutical industry clinical trials, including those dealing with pulmonary hypertension (not associated with the sponsors of the newly approved agents) to assist in the development and the facilitation of the discussion topics.
Author Contributions: all panelists, with the exception of T.A.D., were participants in one or more of the clinical trials and all had experience in the use of these agents in the research setting and in their clinical practices. Each of the panelists had detailed knowledge of the pivotal clinical trial publications and received a discussion guide developed by N.S.H. and T.A.D. to assist in the organization of the questions and issues to be addressed. The sponsoring companies did not have any role in the selection of the panelists, the development of the discussion guide or the drafting or review of the manuscript.
Author disclosures are available with the text of this article at www.atsjournals.org.
