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Breath of Fresh Air for PAH and CTEPH: Pharmacotherapy Update

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Jim Coons, PharmD, BCPS (AQ Cardiology)
University of Pittsburgh/UPMC
Pittsburgh, PA, USA

Pharmacotherapeutic advances in the treatment of pulmonary arterial hypertension (PAH) have coincided with reductions in overall morbidity and mortality for this progressive, fatal disease [1,2]. Despite these improvements, PAH, in the modern management era, is still associated with a significant clinical burden for patients in the form of advanced symptoms, poor quality of life, and suboptimal outcomes [3]. The mainstays of treatment encompass prostacyclins, endothelin receptor antagonists (ERA) and phosphodiesterase-type 5 (PDE-5) inhibitors. The year 2013, however, was particularly notable in the PAH field as three new medications gained regulatory approval: riociguat (Adempas®), macitentan (Opsumit®), and oral treprostinil (Orenitram®) [4-6]. Riociguat also became the first approved medication to treat select patients with chronic thromboembolic PH (CTEPH). In parallel, new international evidence-based treatment guidelines for PH were published and integrate new data with riociguat and macitentan [7]. Consequently, the focus of this article will be on these therapies. A focused review of oral treprostinil was previously published in the March 2014 issue of the Links by Dr. Veronica Franco.

Riociguat is the first approved medication in a novel therapeutic class known as soluble guanylate cyclase (sGC) stimulators. sGC is the molecular target for nitric oxide (NO) and is responsible for the enzymatic production of cyclic guanosine monophosphate (cGMP). Riociguat acts by sensitizing sGC in the presence of NO, but is also effective when NO is depleted. Ultimately, the principal therapeutic effect is vasodilation but there are also antithrombotic, antiproliferative, and anti-fibrotic effects that are mediated [8].

Riociguat was evaluated in two landmark, international, placebo-controlled trials of different patient populations. The PATENT-1 trial enrolled 443 patients with World Health Organization (WHO) Group I PAH (61% idiopathic, 25% associated with connective tissue disease [CTD]) and primarily WHO functional class (FC) II and III symptoms [9]. 44% of patients were on background treatment with an ERA, whereas only 6% of patients were on a prostanoid (mostly inhaled iloprost). The primary efficacy analysis revealed a 36 meter increase in the 6MWD at 12 weeks with riociguat (target dose of 2.5 mg PO tid) vs. placebo (p<0.001) from a baseline of 363 meters. Other secondary endpoints demonstrated improvements in hemodynamics (HD), WHO FC, and time to clinical worsening [9]. The CHEST-1 trial enrolled 261 patients with inoperable CTEPH [72%] or persistent or recurrent PH after pulmonary endarterectomy (PEA) [28%]. The majority of patients were in WHO FC III (64%). Overall, riociguat was associated with a 46 m increase in 6MWD at 16 weeks with riociguat (target dose of 2.5 mg PO tid) vs. placebo (p<0.001) from a baseline of 348 meters. Significant improvements were also found in HD and WHO FC [10].

Current treatment guidelines for PAH recommend riociguat as a potential alternative to a PDE-5 inhibitor for patients with primarily WHO FC II or III symptoms [7]. For inoperable CTEPH and residual disease despite PEA, riociguat would be recommended as a first-line therapy based upon the positive findings from the CHEST-1 trial [11].

Macitentan is the most recently approved ERA which exhibits dual inhibition of endothelin-A and -B receptors. It is a synthetic derivative of bosentan characterized by increased tissue penetration and sustained receptor binding [12,13]. Like other ERA's, macitentan exerts vasodilatory, antiproliferative, and anti-fibrotic effects [7,12].

Macitentan was evaluated in the landmark, international, SERAPHIN trial which was an outcomes-driven study of 742 patients with Group I PAH (55% idiopathic, 30% associated with CTD) and primarily FC II and III symptoms [14]. Approximately 60% of patients were on background PDE-5 inhibitor therapy, but only 5% were receiving an inhaled or oral prostacyclin. Patients were randomized to 3 or 10 mg macitentan once daily or placebo and followed for approximately 100 weeks. The primary composite endpoint was the time to first event related to PAH (worsening of PAH [defined as decrease in 6MWD by ≥ 15% from baseline, worsening of symptoms, and need for additional treatment], initiation of treatment with IV or SC prostanoids, lung transplantation, or atrial septostomy) or all-cause death. The composite endpoint was significantly lowered with macitentan (3 mg; p = 0.01) and (10 mg; p < 0.001) vs. placebo. The benefit of macitentan was driven mainly by a reduction in worsening of PAH and fewer PAH-related hospitalizations [14].

The current PAH guidelines recommend macitentan for patients with primarily WHO FC II or III symptoms [7]. Macitentan may be preferable to bosentan based on the lower risk of transaminitis (incidence > 3 times upper limit of normal with macitentan not different vs. placebo) and lack of requirement for monthly liver function monitoring.


Adverse Events


Risk Management Program

Drug Interactions


Headache, dizziness, dyspepsia, reflux, nausea, vomiting, diarrhea, anemia, hypotension,† teratogenicity

-Baseline & monthly pregnancy tests


-Strong CYP 3A4 inhibitors and p-glycoprotein inhibitors
-PDE-5 inhibitors


Nasopharyngitis, headache, anemia,‡ teratogenicity

-Baseline liver function tests
-Baseline & monthly pregnancy tests


-Strong CYP 3A4 inhibitors (i.e., ritonavir)
-Strong CYP 3A4 inducers (rifampin)

† Patients at risk for hypotension or receiving interacting medications (see table) should start at 0.5 mg PO tid. Dosing titrations should not occur more often than every 2 weeks and BP should be monitored during these intervals [4].
‡ Hemoglobin drop to ? 8 g/dL was 4.3% in the 10 mg group [14]

In summary, ongoing medical advances in PAH and CTEPH have been commensurate with the availability of new medications, formulations, and identification of novel therapeutic targets. Each of these therapies offers patients and clinicians the potential for improved outcomes in managing these complex diseases. ■

Disclosure Statement: The author has no conflicts of interest to disclose.


  1. Galie N, Manes A, Negro L, et al. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009;30:394-403.
  2. Bai Y, Sun L, Hu S, eta l. Combination therapy in pulmonary arterial hypertension: a meta-analysis. Cardiology 2011;120:157-65.
  3. McGoon MD, Benza RL, Escribano-Subias P, et al. Pulmonary arterial hypertension. J Am Coll Cardiol 2013;62:D51-9.
  4. Adempas package insert. Whippany, NJ: Bayer Healthcare Pharmaceuticals, Inc; 2014 May.
  5. Opsumit package insert. San Francisco, CA: Actelion Pharmaceuticals, Inc; 2013 Oct.
  6. Orenitram package insert. Research Triangle, NC: United Therapeutics Corp; 2013 Dec.
  7. Galie N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol 2013;62:D60-72.
  8. Schermuly RT, Janssen W, Weissmann N, et al. Riociguat for the treatment of pulmonary hypertension. Expert Opin Investig Drugs 2011;20:567-76.
  9. GhofraniH, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013;369:330-40.
  10. Ghofrani H, D'Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013;369:319-29.
  11. Kim NH, Delcroix M, Jenkins DP, et al. Chronic thromboembolic pulmonary hypertension. J Am Coll Cardiol 2013;62:D92-9.
  12. Iglarz M, Binkert C, Morrison K, et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther 2008;327:736-45.
  13. Gatfield J, Mueller Grandjean C, Sasse T, et al. Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells. PloS One 2012;7:e47662.
  14. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013;369:809-18.

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