Did you know...? Therapy of Pulmonary Hypertension – What’s New

PVRI Member Authors: Natascha Sommer

Therapeutic options for pulmonary hypertension (PH) have increased over the past years and include pharmacological approaches as well as surgical procedures. Pharmacological therapies approved for pulmonary arterial hypertension (PAH, group 2 according Nice classification, Table 1) include drugs addressing the signaling pathways of nitric oxide (NO), prostacyclin and endothelin (Figure 1), well known to be phosphodiesterase-5- (PDE5) inhibitors (sildenafil, tadalafil), prostacyclins/prostacyclin analoga (iloprost, epoprostenol, treprostinil) or endothelin receptor antagonists (ERAs: bosentan, ambrisentan). In the last years the spectrum of drugs was extended by a stimulator of the soluble guanylate cyclase (sGC) “riociguat” (Adempas, FDA approval: 2013), the prostacyclin receptor agonist “selexipag” (FDA approval: 2015) and the ERA “macicentan” (Opsumit, FDA approval: 2013). Most importantly, for the first time pharmacological therapy for another form of PH besides PAH became available, as riociguat was approved for the treatment of chronic thromboembolic PH (CTEPH). For continuous intravenous treatment with treprostinil the application of an implantable pump has been developed. This article provides an overview about currently approved new therapies for PH.

New pharmacological therapies in PH

Macitentan for treatment of PAH

Macitentan (Opsumit, 10mg, once per day, oral) was approved by FDA in 2013 and acts as dual ERA with better tissue penetration and less interaction with other drugs [3]. In contrast to other ERAs liver toxicity seems to be negligible, as the respective clinical trial showed liver toxicity on the level of placebo. The placebo controlled study “SERAPHIN” (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome) enrolled 742 patients with a mean follow up of 3.5 years. For the first time a composite endpoint of morbidity and mortality (e.g. lung transplantation, initiation of treatment with i.v. or subcutaneous prostanoids or worsening of PAH) was chosen for an approval-relevant clinical phase III trial. The trial showed that application of 3 or 10 mg Macitentan reduced the relative risk to reach the combined primary endpoint by 30 or 45%, respectively, compared to the placebo group. The combined endpoint was mainly reduced by decreasing PAH related hospitalizations and worsening of PAH, but not mortality. Moreover, Macitentan was the first ERA, which showed positive effects in combination with PDE5 inhibitors. Main side effect at a dose of 10 mg was a decreased a hemoglobin value [10]. In contrast to bosentan, Macitentan neither interacts with Warfarin [11]nor with oral contraceptives [7].

Riociguat for treatment of PAH

Riociguat (Adempas, standard dose 2.5 mg, three times per day, oral) was approved for the therapy of PAH in 2013 and acts as sGC stimulator. Thus, Riociguat addresses similar to sildenafil the NO-cyclic guanosine monophosphate (cGMP) signaling pathway. In contrast to sildenafil, which increases the concentration of cGMP by inhibition of its degradation, Riociguat enhances the sensitivity of the sGC for NO and stimulates production of cGMP independently of NO [14]. In the study conducted for approval of Riociguat for PAH (“PATENT-1” Pulmonary Arterial Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1) Riociguat improved the primary endpoint of 6-minute-walk-distance as well as secondary endpoints such as exercise capacity, pulmonary vascular resistance and time to clinical worsening. Adverse effects included particularly systemic arterial hypotony [5]. Therefore, in clinical practice Riociguat is up-titrated during a time period of approximately 6 weeks according to a titration scheme supervised by monitoring of blood pressure (starting dose 1 mg, three times per day) until reaching the standard dose, if tolerated. Combination of Riociguat and sildenafil is contraindicated due to arterial hypotony  [2].

Riociguat for treatment of CTEPH

CTEPH is the only form of PH for which a potential curative approach is available, which is the removal of thromboembolic material by the surgical procedure of pulmonary endarterectomy (PEA). PEA is performed during circulatory arrest in deep hypothermia [9]. Furthermore, life-long sufficient anticoagulation is considered standard basic therapy.

Since approval of Riociguat in April 2014, the first pharmacological therapy for CTEPH was approved. However, Riociguat is only approved for technical inoperable CTEPH, or if the benefit-risk ratio limits PEA, as well as in persistent or recurrent PH after PEA. First line therapy for CTEPH is still PEA. Thus every patient should be evaluated for PEA after diagnosis of CTEPH, before considering pharmacological therapy. Moreover, pharmacological therapy with Riociguat for the purpose of bridging the time until PEA in conditions of severe CTEPH has not yet been evaluated in clinical studies. In the randomized controlled CHEST trial (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial)application of Riociguat resulted in improved exercise capacity determined by the six minute walk distance, and decreased pulmonary vascular resistance [4]. However, time-to-clinical worsening (defined as combined end point of e.g. mortality, transplantation) was unchanged. In a prior study in CTEPH, Bosentan improved hemodynamics, but not exercise capacity, allowing this drug to only be used as off-label medication [8].

Selexipag for treatment of PAH

Selexipag is an oral, selective prostacyclin receptor agonist with long half-life (6,2-13,5 h) and was approved by FDA  at the end of 2015. In the clinical phase III trial GRIPHON PGI2 (Receptor agonist In Pulmonaryarterial Hypertension)Selexipag -as mono- or combination-therapy with ERAs and/or PDE5-inhibitors- reduced the mixed endpoint of morbidity and mortality [12].

New application forms in PAH

Treprostinil: implantable pump

Intravenous application of prostacyclins can be cumbersome due to the persistent indwelling i.v. line which predisposes for infections and dislocations. A more preferable way of application was achieved by development of a fully implantable pump system with a titanium reservoirwhich can be re-filled from outside every 2-4 weeks percutaneously by an injection through a membrane with a special needle by trained personnel. The pump is implanted in the subcutaneous tissue of the abdominal wall and delivers the treprostinil in the superior vena cava via a tunneled catheter. The pump is driven by a purely mechanical system and does not need any battery. The pump speed is constant, so that the delivered dose is adjusted by varying the concentration of treprostinil filled into the reservoir. The pump can be implanted during local anesthesia and is thus suitable for PAH patients presenting with severe disease [1].


In the past year several promising drugs for treatment of PAH have been evaluated in clinical trials. Unfortunately some of them did not fulfill the requirements for approval (e.g. the serotonin receptor agonist, inhaled vasoactive peptide). Particularly the tyrosine kinase inhibitor Imatinib showed significant improvements in the primary endpoint, but development was stopped due to serious side effects [6].

In a current study efficacy and safety of inhaled NO for treatment of PAH is tested (NCT01457781). Soon results of a trial with dichloroacetate which reverses metabolic alterations of PAH will be published (NCT01083524). Another study with Tacrolimus was recently finished. Case reports show beneficial effects, but final results have to be waited for [13]


Table 1: Clinical Classification of PH and therapy


BMPR: bone morphogenic protein receptor, ALK: activin-like kinase, CI: cardiac Index


Figure 1: Signaling pathways and pharmacological therapy (red: recently approved therapeutics)

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Abbreviations: IP receptor: Prostacyclin receptor, ETA/B: Endothelin A/B, GMP: guanosine monophosphate, cGMP: cyclic guanosine monophosphate, sGC: soluble guanylate cyclase, PDE5: phosphodiesterase 5, cAMP: cyclic adenosine monophosphate, ERA: endothelin receptor antagonist.


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PVRI Chronicle Vol 3: Issue 2 cover image

August 2016

PVRI Chronicle Vol 3: Issue 2

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