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Pulmonary Arterial Hypertension: Applying Emerging Trial Data to Clinical Practice

New treatment options in the management of pulmonary arterial hypertension are on the horizon. We review the status and data of several new, novel agents.


Recent decades have witnessed a dramatic shift in the outcomes and survival of patients with pulmonary arterial hypertension (PAH). Whereas the National Heart, Blood, and Lung Institute's landmark registry conducted in the 1980s estimated a 1-year mortality rate of 32% and median survival from diagnosis of 2.8 years, contemporary registries report 1-year mortality rates of 15%, and 3-, 5-, and 7-year survival rates of 68%, 57%, and 49%, respectively.1, 2 The improvement in survival is attributable to the advent of PAH-specific therapies including endothelin receptor agonists (ERAs), phosphodiesterase type (PDE)-5 inhibitors, and prostacyclin analogs that act on PAH's underlying pathophysiologic pathways (Figure 1). Nevertheless, PAH remains an incurable and progressively debilitating syndrome associated with high morbidity and mortality.2, 3 Current treatment options are frequently limited by toxicity, inconsistent efficacy, and cumbersome delivery methods (eg, continuous intravenous [IV] and subcutaneous infusions). Emerging oral therapies may provide new options for the long-term management of this chronic disease. These include riociguat, mecitentan, and selexipag. Each targets different PAH disease pathways and all are in late stages of clinical development.


Nitric oxide (NO) deficiency is a well-established pathophysiologic feature of PAH. NO is a potent endothelium-derived vasodilator that acts on vascular smooth muscle cells inducing vasodilation and inhibiting smooth muscle cell proliferation.4, 5 The vasodilatory effect of NO is mediated via activation of soluble guanylate cyclase and increased production of cyclic guanosine monophosphate (cGMP). Cyclic GMP induces vasodilation, but is quickly degraded by PDEs, resulting in a limited, transient effect. Inhibition of PDE-5 with sildenafil or tadalafil prevents the breakdown of cGMP, thereby maintaining cGMP-mediated vasodilation.4-6 Although effective in many patients, PDE-5 inhibitors require the presence of NO to function, and may have limited activity when NO levels are low.6, 7

Another approach to increasing NO-mediated vasodilation in patients with PAH is to directly stimulate soluble guanylate cyclase and increase sensitivity to low NO levels.5, 8 Riociguat is the first agent in a novel class of drugs known as soluble guanylate cyclase (sGC) stimulators. Riociguat directly stimulates soluble guanylate cyclase independently of NO availability, and increases sensitivity to low levels of endogenous nitric oxide.5, 7

In the phase III PATENT-1 trial, riociguat was compared with placebo in 445 treatment-naïve patients with PAH and PAH patients previously treated with ERAs or inhaled or subcutaneous prostanoids.8, 9 The primary endpoint was the placebo-corrected change from baseline in 6-minute walk distance (6MWD) after 12 weeks of treatment. Preliminary analysis, presented in late 2012, showed riociguat produced a statistically significant 35.8 m increase in 6MWD as compared to placebo (p<0.0001). The effect was consistent among treatment-naïve patients and those who received previous treatment. The secondary endpoints of pulmonary vascular resistance (PVR), N-terminal brain natriuretic peptide (NT-proBNP), functional class, and other measures were also reported to improve with riociguat, and riociguat was considered well tolerated. Headache, dyspepsia, and peripheral edema were the most frequently reported adverse events.8, 9 Additional safety and efficacy data are expected from the open-label PATENT-2 extension trial.

Riociguat was also evaluated in a phase III trial of patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH).10 In the 263-patient, placebo-controlled CHEST-1 study, riociguat produced a statistically significant improvement of 46 m in 6MWD, the trial's primary endpoint.10, 11 Secondary endpoints, including PVR, NT-proBNP levels, and functional class also favored riociguat. An interim analysis of the trial's open-label extension supported the initial findings.11 In April 2013, the US Food and Drug Administration (FDA) granted riociguat priority review.12


Endothelin-1 is a potent, direct vasoconstrictor. It is also a proinflammatory molecule associated with fibrosis, co-mitogen activity, and proliferation of vascular smooth muscle cells.4 The effects of endothelin-1 are mediated via the ETA receptor, which induces continuous vasoconstriction and smooth-muscle cell proliferation, and the ETB receptor, which is responsible for mediating pulmonary endothelin clearance, and stimulating endothelial-based NO and prostacyclin production.4 These effects are reported to occur deep within the tissue. Oral ERAs—bosentan and ambrisentan—given as monotherapy or in combination with other classes of agents, inhibit ET-receptor activity and are an established therapeutic option for the management of PAH.

Macitentan is an investigational oral, dual ERA (meaning it antagonizes both endothelin receptors), reported to have improved tissue penetration, receptor binding, and efficacy as compared to currently available ERAs.5 Macitentan was compared with placebo in the phase III, double-blind SERAPHIN trial, which randomized 742 patients with PAH to 3 or 10 mg of macitentan or placebo.13 The study's primary endpoint was the time from treatment initiation to the occurrence of a first morbidity or mortality event, a composite endpoint that included death, atrial septostomy, lung transplantation, initiation of IV or subcutaneous prostanoids, or worsening of PAH.

The risk of a morbidity or mortality event was significantly reduced by 30% and 45% with the 3- and 10-mg doses of macitentan, respectively, as compared to placebo (p=0.0108 and p<0.0001, respectively).13 Among patients receiving some form of background therapy, the risk of a morbidity or mortality event was reduced by 17% and 38% for the low and high doses, respectively. The risk was reduced by 47% and 55% for the 3 and 10 mg doses among patients who were not taking background therapy.13 The prespecified secondary endpoint of death due to PAH or hospitalization for PAH was reduced by 33% (p=0.0146) and 50% (p<0.0001) with low- and high-dose macitentan, as well. A non-statistically significant trend towards a reduction in all-cause mortality was also observed with macitentan.13 Macitentan was well tolerated in the trial. Headache, nasopharyngitis, and anemia were more common with macitentan than placebo, but changes in liver function—a common complication of ERA therapy—were the same among the 3 treatment arms. In the placebo arm, 4.5% of patients experienced elevations of liver alanine or aspartate aminotransferases greater than 3 times the upper limit of normal. In the macitentan 3 and 10 mg arms, the rates were 3.6% and 3.4%, respectively.14

In late 2012, a New Drug Application for macitentan was submitted to the US FDA and European Medicines Agency for the treatment of patients with PAH.14


Prostacyclin (prostaglandin I2 [PI2]) is a vasodilator and mediator of cellular proliferation, platelet activity, and hypertrophy. Prostacyclin deficiency is a key component of the pathophysiology of PAH, and its absence contributes to the vasoconstriction, cellular proliferation, thrombosis, and hypertrophy common to PAH.4 Intravenous prostacyclin (epoprostenol) has been a cornerstone of PAH therapy since the 1980s and is associated with improved survival.15 However, because of a short half-life, it must be administered as a continuous IV infusion via an indwelling central venous catheter, making it a burdensome therapy. Other inhaled and subcutaneous prostacyclin analog formulations have been developed and are associated with various improvements in clinical and hemodynamic measures, but not survival, and all have limitations, including their delivery systems.15 Orally available prostacyclin analogs have been the subject of much research, but none have proved clinically effective. An oral formulation of treprostinil was the focus of the FREEDOM trials, a series of phase III trials comparing the agent with placebo.5 In the monotherapy study, but not the combination therapy studies, treprostinil improved 6MWD but not functional class or time to clinical worsening. Clinical development of another agent, beraprost, was suspended after it, too, failed to produce clinical benefits.5

Selexipag is a prostacyclin IP receptor agonist. It is not prostacyclin or a prostacyclin analog. It is orally available and undergoes rapid hydrolysis to the active metabolite, ACT-333679, which is more selective for the IP receptor than prostacyclin analogs, possibly making the agent more tolerable, while restoring prostacyclin levels.5, 15

In a phase II proof-of-concept trial, 17 weeks of treatment with selexipag was associated with a statistically significant 30.3% reduction in the mean PVR vs placebo (p=0.0045), and a trend towards improved 6MWD (24.7 m increase from baseline).15, 16 It was also safe and well tolerated. Selexipag is currently being investigated in the 1150-patient phase III GRIPHON trial. This multicenter, randomized, double-blind trial is designed to show a reduction in morbidity and mortality events. As of May 2013, more than 1000 patients were enrolled. Results are expected by mid-2014.17


Despite recent improvements in survival among patients with PAH, treatment remains challenging and outcomes suboptimal. Emerging treatment options such as riociguat, macitentan, and selexipag target different PAH pathophysiologic pathways. Riociguat and macitentan are under regulatory review and selexipag is in the late stages of clinical development. These agents, with their novel mechanisms of action, given as monotherapy or, possibly, in combination with new or existing therapies, may provide clinicians with new management options and help to further improve patient outcomes.



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;115:343-349.

2 Benza RL, Miller DP, Barst RJ, et al. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest. 2012;142:448-456.

3 Archer SL, Weir EK, Wilkins MR. Basic science pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation. 2010;121:2045-2066.

4 Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425-1436.

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5 Sitbon O, Morrell NW. Pathways in pulmonary arterial hypertension: the future is here. Eur Respir Rev. 2012;21:321-327.

6 McLaughlin VV, Archer SL, Badesch DB, et al. 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 Assocation: Developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation. 2009;119:225-2294

7 Kim NH. Riociguat: an upcoming therapy in chronic thromboembolic pulmonary hypertension? Eur Respir Rev. 2010;19:68-71

8 Ghofrani H, Nazzareno G, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study (PATENT-1). Chest. 2012;142(4_MeetingAbstracts):1027A.

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9 Bayer Healthcare. Bayer's investigational riociguat meets primary endpoint in phase III study of patients with chronic thromboembolic pulmonary hypertension (CTEPH). Accessed May 1, 2013.

10 Ghofrani H, Grimminger F, Hoeper M, et al. Riociguat for the treatment of inoperable chronic thromboembolic pulmonary hypertension: a randomized, double-blind, placebo controlled study (CHEST-1). Chest. 2012;142(4_MeetingAbstracts):1023A.

11 Bayer Healthcare. Bayer's investigational riociguat meets primary endpoint in phase III study of patients with chronic thromboembolic pulmonary hypertension (CTEPH). Accessed May 1, 2013.

12 Chauduri S. Bayer: NDA for riociguat gets priority review. Wall Street Journal. Accessed May 1, 2013.

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13 Rubin L, Pulido T, Channick R, et al. Effect of macitentan on morbidity and mortality in pulmonary arterial hypertension (PAH): results from the SERAPHIN trial. Chest. 2012;142(4_MeetingAbstracts):1026A.

14 Actelion. Phase III PAH outcome study with macitentan (Opsumit) presented at CHEST-significant reduction in the risk of morbidity and mortality. Accessed May 1, 2013.

15 McLaughlin VV. Looking to the future: a new decade of pulmonary arterial hypertension therapy. Eur Respir Rev. 2011;20:262-269.

16 Simoneau G, Torbicki A, Hoeper MM, et al. Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J. 2012;40:874-880.

17 Acetlion. Selexipag. Accessed May 1, 2013.

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Figure 1

Figure 1 — Key pathways involved in the pathogenesis of pulmonary arterial hypertension:
a) endothelin (ET) pathway;   b) nitric oxide pathway; and   c) prostacyclin (PGI2) pathway
ERA: ET receptor antagonist;   ETA/ETB: ET receptor subtypes A and B;   SMCs: smooth muscle cells;   cGMP: cyclic guanosine monophosphate (GMP);   PDE-5: phosphodiesterase type-5;   PDE-5i: PDE-5 inhibitor;   cAMP: cyclic adenosine monophosphate.

Source: Sitbon O, Morrell NW. Pathways in pulmonary arterial hypertension: the future is here. Eur Respir Rev. 2012;21:321-327.
Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425-1436. Reproduced with permissions from the publishers.

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