An Exploration of the Newly Approved PAH Agents and the Future of PAH

In 2013, three new agents were approved by the U.S. Food and Drug Association (FDA) for the treatment of pulmonary arterial hypertension (PAH): the non-selective endothelin receptor antagonist (ERA) macitentan, an oral formulation of the prostacyclin treprostinil, and the first in a new class of agents, the soluble guanylate cyclase (sGC) stimulator riociguat. The approval of these agents for use in clinical practice has increased the number of treatment options for PAH patients while adding a new dimension of complexity to clinical decisions involving comparative effectiveness of these drugs as monotherapy a well as in combination with other available treatments. To discuss these updates further, CardioSource interviewed three pulmonary hypertension specialists, John J. Ryan MD, University of Utah, Salt Lake City, Bradley A. Maron MD, Brigham and Women's Hospital, Boston and Jonathan D. Rich, Northwestern Memorial Hospital, Chicago.

Can you talk us through the data that got each of these agents approved?

JJR: The macitentan data were published in NEJM in the Fall of 2013 as part of the SERAPHIN study. This is the largest iPAH randomized controlled trial (RCT) to date with 742 patients enrolled. Patients were randomized to placebo, 3mg or 10mg of macitentan. The study is unique to pulmonary hypertension trials insofar as the primary end point was not six minute walk distance, but rather a composite end point of time to first event related to PAH or death. In this setting there was an absolute risk reduction in the combined endpoint of 15% with 10mg of macitentan once daily compared to the placebo group (31% vs. 46%). There was also a modest ~22 m improvement in six minute walk distance, a secondary endpoint, in the 10mg macitentan group as compared to placebo. The 3mg dose of macitentan had an absolute risk reduction of 8% for the primary end point (38% vs. 46%) and a modest improvement in six minute walk distance of ~17 m. The 10mg dose was approved by the FDA. While the drug appeared to be relatively safe, there was an increased risk of headache as well as increased anemia with macitentan, both of which are worth discussing with patients ahead of therapy and will require close post-marketing surveillance.

BAM: In pulmonary blood vessels, diminished soluble guanylyl cyclase (sGC) activity due to decreased levels of bioavailable nitric oxide is a bona fide mechanism involved in the pathobiology of PAH. The effect of riociguat on outcome in PAH patients was therefore evaluated recently in the PATENT-1 trial1 owing, in part, to the unique ability of this drug to stimulate sGC through a nitric oxide-independent mechanism. In a phase 3 trial, 380 symptomatic patients receiving treatment with endothelin receptor antagonists or nonintravenous prostanoids were randomized in 30 countries to receive placebo (N=126) or riociguat at a maximum dose of 2.5 mg three times daily (N=254) for 12 weeks. The primary end point was change in six-minute walk distance from baseline at 12 weeks, and the secondary end-points included changes in pulmonary vascular resistance (PVR) and biochemical/clinical indices of heart failure severity. Compared to placebo, riociguat was associated with an increase from baseline in 6-minute walk distance (-6 vs. +36 m, p<0.001), improvements to PVR (-9 ± 317 vs. -233 ± 260 dyn•sec•cm-5, p<0.001), NT-pro-brain natriuretic peptide levels (+232 ± 1011 vs. -198 ± 1721 pg/ml, p<0.001), World Health Organization Functional Class, and dyspnea burden. Generally, riociguat was well tolerated in this study, although systemic hypotension was noted in 10% of study participants, which may reflect some off-target effects of this therapy on the systemic vasculature.

JDR: Oral Treprostinil is the most recently approved drug for the treatment of PAH. In contrast to macitentan and riociguat, its path to FDA approval was a bit more circuitous. The first study to evaluate oral treprostinil was the FREEDOM study which was a 16-week, multicenter, double-blind, placebo-controlled study in 350 patients with PAH randomized to placebo or oral treprostinil. All patients in the study were already on background therapy with an ERA, PDE-5 inhibitor, or both. While there was an 11m placebo-corrected median increase in six minute walk in the treprostinil cohort, this did not reach statistical significance (p=0.07). Complicating the analyses was the fact that nearly a quarter of the patients randomized to treprostinil discontinued the study drug prematurely. Subsequently, two additional studies of oral treprostinil were performed. The FREEDOM-C2 study was also a multicenter, double-blind, placebo-controlled study in 310 patients with PAH all of whom were already on background therapy with either a phosphodiesterase 5 inhibitor (PDE5i) or ERA. Patients were randomized to either oral treprostinil or placebo for 16-weeks. Once again, the study failed to meet its primary efficacy endpoint of 6 minute walk distance (p=0.89) and side effects of headache (71%), diarrhea (55%), and nausea (46%) were common in those treated with treprostinil. Finally, another multicenter, randomized, placebo controlled trial of 349 PAH patients who were NOT receiving any background PAH therapy was performed over a 12 week duration (treprostinil monotherapy, n=233; placebo, n=116). Unlike the FREEDOM studies, this time the primary endpoint of 6 minute walk distance favored treprostinil with a 23m increase compared to placebo (p=0.125).

How does the introduction of these data change your practice, if at all?

JJR: Heretofore, in patients who were Functional Class 2 and maybe 3, most providers were starting with either PDE5i or an ERA and would add on another oral agent if patients were to worsen. Ultimately, Functional Class 4 patients were started on prostacylins (preferably subcutaneous or intravenous but sometimes inhaled). The availability of sGC stimulators (riociguat) will change that practice somewhat. It is unclear if riociguat will become an oral agent that we start patients on upfront, or if it will be reserved as additive therapy on top of the more familiar ERAs. sGC stimulators are contraindicated in patients on PDE5i. However, if patients are already on two oral agents such as an ERA and PDE5i and are failing clinically, my opinion is that these patients are just too sick to be given a trial of yet another oral agent, and we would opt for a prostacyclin (SC or IV) as the next step due to the demonstrated survival benefit of infused prostacyclins. Furthermore, in this setting of the worsening PAH patient to a Functional Class IV, I do not expect us to be using the newly approved oral prostacyclin as an add-on agent.

BAM: Based on data reported in the PATENT-1 trial, it is clear that riociguat treatment results in modest improvements to exercise tolerance, biochemical evidence of heart failure, and Functional Class in PAH patients. However, akin to other PAH trials, matching patients in clinical practice to the PATENT-1 study population may be a difficult task. For example, a majority of riociguat-treated patients in this study reported WHO Functional Class III symptoms, and the number of patients on a stable dose of endothelin-receptor antagonist and/or prostanoid therapy was nearly equal to patients on no PAH-specific therapy. Yet, with the multitude of approved drugs available today, untreated PAH patients with advanced symptomatology are uncommon. Because a positive correlation between PAH severity and therapy response has been reported for other PAH drugs, the clinical benefits observed by riociguat in PATENT-1 may have been, in part, a consequence of patient under-treatment at baseline. Additionally, the dosing strategy for riociguat in PATENT-1 was somewhat complex, and may have required up to four dose adjustments each occurring at two-week intervals. In light of the systemic hypotension rates reported for riociguat-treated patients, this raises concerns that achieving the maximal effective dose of riociguat in clinical practice may be practically difficult. These issues notwithstanding, one compelling scenario for riociguat use may be as a first-line therapy in newly symptomatic PAH patients, a point of view based on meaningful improvements to PVR and cardiac output observed with riociguat in the PATENT-1 trial, which in my practice and as supported in the literature, appears to be a key determinate of long-term prognosis.

JDR: What excites me most about the addition of these PAH drugs to the existing PAH armamentarium is not so much the particular drugs themselves but the possibility to begin to tailor our treatments in a more individualized way. What has been clear to me is that certain patients respond favorably to a PDE5i but less so to an ERA and the converse may be true as well. And on the basis of its mechanism of action, those who do not respond to a PDE5i, may actually respond to an sGC stimulator such as riociguat. But with the excessive cost of many of these drugs and the variable response observed from patient to patient, it is imperative that we begin to more critically evaluate patient responses in objective ways and to have a very low threshold to stop drugs that simply are not working instead of layering on drug after drug. We also need continued scientific investigation and improved clinical tools to better understand which of the many, often redundant pathways are most responsible for an individual patient's PAH pathobiology. In my practice, I will likely continue to prescribe early-stage Functional Class patients initially with an oral agent. If the patient has a favorable response to that particular drug but remains symptomatic, I would consider adding an additional drug possessing a unique mechanism of action. But as stated above, I would rather substitute for a new drug rather than add an additional agent to one that does not appear to be working. Finally, I always have a low threshold to escalate to IV or SC prostanoid therapy when I suspect that the RV is beginning to fail, irrespective of Functional Class.

What's next in PAH therapy?

BAM: In the current era that favors identifying the genetic and molecular substrate of PAH, a host of new and exciting research has been reported in the literature that expands the breadth of factors linked to PAH pathobiology. In some ways, this has fractionated PAH in a way similarly to how cardiologists regard left ventricular hypertrophy, in which understanding the root cause (e.g., systemic hypertension vs. aortic valve disease) is required to select appropriate treatment. Further characterizing the underpinnings of PAH, however, also plays into a key challenge in assessing PAH treatments clinically: should drug entry criteria match more specifically the root cause of patients' specific form of PAH? Conducting clinical trials in PAH is already difficult enough given the low prevalence of this disease and high financial expenditures required to perform multi-centered randomized clinical trials. However, over the long term, improved clarity regarding PAH patients' central disease mechanism may allow physicians to match drug treatments with the most appropriate patients ... I believe this fits within the larger mission ongoing in cardiovascular medicine today: developing personalized therapies.

JJR: We need better ways of predicting and preventing right ventricular failure (RVF) from PAH. Currently, for patients admitted with RVF from PAH, the in-hospital mortality is approximately 15% and the mortality reaches almost 50% if patients require inotropic support in the ICU. Therefore, we need to do a better job of early identification of patients at high risk for RVF, and determining optimum management strategies to prevent this. Leveraging contemporary imaging technologies to better understand and predict pulmonary vascular-right ventricular function is essential to identifying patients at risk for pulmonary vascular disease, as well as characterizing optimal timing of therapy initiation. This may come in the form of standardized protocols for RV imaging such as cardiac MRI, cardiac PET scans or serum biomarkers or more sophisticated invasive assessments in the cardiac catheterization laboratory. Ultimately we likely need to be more aggressive in offering advanced prostacyclin therapy to appropriately sick patients before they reach an irrevocable clinical state.

JDR: Dr. Ryan hit the nail on the head as far as the right ventricle is concerned. In my opinion, we need to begin to redouble our efforts into developing strategies to optimize right ventricular performance, which is the most powerful predictor of outcomes in PAH. With the exception of the 10-15% of patients who respond favorably to vasoreactivity testing at the time of diagnosis, the vast majority of patients with PAH possess a pulmonary vasculature with a relatively fixed pulmonary vascular resistance. In fact, if one were to combine all of the clinical trials of the existing PAH drugs, the average change in mean PA pressure is a trivial 3mm Hg. Those drugs that more potently improve cardiac output (i.e., intravenous prostacyclins and perhaps newer agents such as the sGC stimulators) are more likely, in my opinion, to improve long-term outcomes. However, until pharmaceuticals are developed that actually attack the proliferative disease process itself (a disease that has in some ways been aptly compared to a vascular malignancy), we need to be thinking a bit more outside the box, focusing on device therapies that are able to support the failing right ventricle. Patients can walk around for years with systemic PA pressures; but when the right ventricle fails, the game is over.


  1. Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013;369:330-40.

Clinical Topics: Congenital Heart Disease and Pediatric Cardiology, Dyslipidemia, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Valvular Heart Disease, Congenital Heart Disease, CHD & Pediatrics and Imaging, CHD & Pediatrics and Prevention, CHD & Pediatrics and Quality Improvement, Lipid Metabolism, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Computed Tomography, Nuclear Imaging, Hypertension

Keywords: Anemia, Aortic Valve, Biological Markers, Cardiac Catheterization, Cardiac Output, Cost of Illness, Diarrhea, Double-Blind Method, Dyspnea, Endothelin Receptor Antagonists, Endothelins, Epoprostenol, Exercise Tolerance, Guanylate Cyclase, Heart Defects, Congenital, Heart Failure, Heart Valve Diseases, Heart Ventricles, Hospital Mortality, Hypertension, Hypotension, Natriuretic Peptide, Brain, Phosphodiesterase 5 Inhibitors, Positron-Emission Tomography, Receptors, Endothelin, Vascular Diseases, Vascular Resistance, Ventricular Function, Right

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