*3.3.4.1.3 Riociguat*

It is a direct activator of guanylate-cyclase, which synthesizes NO. In the 12-week PATENT-1 study, Riociguat was well tolerated and improved several clinically relevant end-points in patients with PAH who had never received a treatment or had been pretreated with endothelin-receptor antagonists or prostanoids. The PATENT-2 trial assessed the long-term safety and efficacy of Riociguat, which resulted to be safe in the long-term treatment of these patients [41].

### *3.3.4.2 Drugs targeting the ET1 pathway: endothelin receptor antagonist (ERA)*

## *3.3.4.2.1 Bosentan*

It is a dual acting ERA, binding to both the ETA and ETB receptors. Two subtypes of ET1 receptor exist: endothelin receptor subtype A (ETA) is mainly found in smooth muscle and also on fibroblasts, while ET 1 receptor subtype B (ETB) is expressed on smooth muscle and endothelial cells. Endothelial ETB activation mediates clearance of ET1 and vasodilatation by NO and prostacyclin release. Bosentan has been studied in several clinical PAH trials, such as BREATHE-1, TRUST, and EARLY [42], with generally positive results. One of the main problems with Bosentan is hepatotoxicity, which initially presents as a raised levels of alanine aminotransferase and aspartate aminotransferase.

#### *3.3.4.2.2 Ambrisentan*

It is an ERA that only blocks receptor ETA. It has been shown to increase exercise capacity and hemodynamics with an acceptable side-effect profile. It has also proven to be safely used in combination with other PAH-specific medications, especially with 5-PDEi. In the recent randomized trial ambition, it was proven that upfront dual therapy of ambrisentan and tadalafil considerably decreases the risk of clinical failure compared with monotherapy [43].

## *3.3.4.2.3 Macitentan*

It is a dual ERA developed by adjusting the basic structure of bosentan, in order to increase the efficacity and safety, and it is approved for the treatment of PAH.

In contrast with bosentan, macitentan also has a longer binding with the ET1 receptor and a better tissue penetration [44]. One of the most important trials on Macitentan was the SERAPHIN trial, a multicenter, double-blind, randomized, placebo-controlled, and event-driven phase 3 trial. This trial demonstrated a significant reduction in morbidity and mortality in patients with PAH [45]. Common adverse effect is anemia.

## *3.3.4.3 Drugs targeting the prostacyclin pathway: prostacyclin analogues and prostacyclin receptor agonist*

#### *3.3.4.3.1 Epoprostenol*

It is a synthetic prostacyclin, approved by FDA in December 1995 for the treatment of PAH. The pharmacological effects of epoprostenol are due to pulmonary and systemic arterial vasodilation. The effects on platelet aggregation are directly opposite to TXA2. Epoprostenol has been demonstrated to be one of the safest treatment protocols for PH. It is also one of the best treatments to reduce the mortality rate in patients with idiopathic PAH [46]. Due to its short half-life (3–5 min), epoprostenol must be administered intravenously via continuous infusion pomp and a permanent tunneled catheter and, in order to maintain its safety-efficacy profile dose-dependent adjustments are necessary. Major adverse events are headaches, nausea/vomiting, flushing, myalgias, jaw pain, diarrhea, and upper respiratory tract infections.

#### *3.3.4.3.2 Treprostinil*

Treprostinil is an analog of Epoprostenol and can be administered by subcutaneous injection, intravenous infusion, or inhalation.

The several methods of administration, an extended half-life, and its stability at room temperature give treprostinil a pro over Epoprostenol, Iloprost, and Selexipag, the three other FDA-approved drugs targeting the prostacyclin pathway. Moreover, in clinical trials, treprostinil enhanced exercise capacity measured with 6MWT, quality of life, WHO functional class, and the clinical status of patients [47].

Usual adverse effects are dizziness, nausea, pain in the jaw and extremities, diarrhea, flushing, and headache.

#### *3.3.4.3.3 Iloprost*

It is a stable prostacyclin analog, available as an inhalant and intravenous preparation for PAH. The principal limitation of this inhaled formulation is the need for daily recurring iloprost inhalations, ranging from 6 to 9, and this can decrease patients' compliance with pharmacological treatment.

#### *3.3.4.3.4 Selexipag*

It is an oral, non-prostacyclin, and IP receptor agonist, approved by FDA in December 2015. Its molecule is very stable and has a long half-life: its effects are vasodilation of the pulmonary circulation, inhibition of platelet aggregation, and antiinflammatory effects. In the GRIPHON study, a phase 3 multicenter, randomized, double-blind, and placebo-controlled trial. 1156 patients with PAH were randomly assigned to receive either placebo or Selexipag. It resulted that among patients with PAH, the risk of the primary composite end point of death or complication related to PAH was significantly lower with Selexipag than with placebo. Instead, there was no significant difference in mortality between the two study groups [48]. Therefore, selexipag is indicated for use in patients with World Health Organization functional class (FC) II or III diseases. Common adverse effects are headache, diarrhea, and nausea.

#### *Pulmonary Hypertension DOI: http://dx.doi.org/10.5772/intechopen.107281*

Treatment is started with an oral combination therapy of two different types of drugs; then, patients are evaluated after 3–6 months. If patients are at high risk, triple therapy can be considered, adding parenteral prostanoids.

#### **3.4 Chronic thromboembolic pulmonary hypertension**

Chronic thromboembolic PH (CTEPH) is a specific subtype of PH, included within Group 4. It is characterized by partial obstruction or total occlusion of subsegmental, segmental, or larger pulmonary arteries by post-embolic fibrotic material. CTEPH incidence is uncertain due to difficulties in diagnosing this disease and lack of specific symptoms: incidence is estimated to be 4 cases per million [49]. Incidence after acute pulmonary embolism is estimated to vary between 0.4% and 9.1% [50]. The pathophysiology is peculiar: CTEPH is the result of partial and incomplete resolution of embolic clots after acute pulmonary embolism, because of impaired fibrinolysis.

The residual intraluminal thrombi phenomena of inflammation, fibrosis, and organization lead to development of typical CTEPH lesions characterized by yellow clots highly adherent to the pulmonary vascular wall, containing collagen, elastin, and inflammatory cells (in contrast to fresh and red clots of acute pulmonary embolism, mainly consisting of erythrocytes and platelets in a fibrin mesh). In addition, vascular remodeling characterized by intimal fibrosis and fibromuscular proliferation, similar to idiopathic PAH, has been described in small vessels distal to unoccluded arteries. The pathogenesis of this micro vasculopathy is not clear: it has been proposed that pulmonary blood flow redistribution from occluded vessels to non-obstructed areas leads in the long term to local high-flow pressure and shear stress promoting endothelial dysfunction [51].

Vascular remodeling resulting from incomplete clot resolution and microvasculopathy leads to increased pulmonary vascular resistance and right ventricular failure. Patients affected by CTEPH can display many and non-specific symptoms, such as shortness of breath on exertion in the early stages and at rest in advanced stages, chest pain, and increased fatigue.

Early diagnosis remains a challenge and it affects prognosis and survival rate.

The gold standard for diagnosis is RHC, which displays mPAP >20 mmHg, but it has to be associated with ventilation/perfusion (V/Q) scintigraphy that shows at least one large perfusion defect in one segment or two subsegments. CT scan has also shown an excellent diagnostic efficacy, and it is usually included in the diagnostic pathway of CTEPH. A correct and early diagnosis is of fundamental importance, as CTEPH is the only PH subtype suitable for a surgical treatment and potentially curable.

Treatment of choice is pulmonary endarterectomy (PEA): within the use of circulatory arrest and hypothermia, it implicates the removal of organized tissue from pulmonary vessels. The milestone of the surgical treatment is to define the operability of patient: this is based on age, comorbidities (diabetes mellitus, lung diseases, hypertension, asthma, and coronary heart disease) and anatomical reasons (inaccessible or distal thrombi). Although, the progress in diagnostic pathways and the accumulation of surgical experience have contributed to the latest surgical development, redefining the distal limits of PEA. Therefore, in expert centers, surgery can be performed successfully in patients with thromboembolism of the distal vessels. Balloon pulmonary angioplasty (BPA) is an emerging interventional treatment and has been included in the treatment algorithm of CTEPH: it is reserved for patients that cannot undergo surgical treatment with PEA due to distal thrombi or continuous

symptoms after surgery. It involves the insertion of a balloon catheter into pulmonary vessels to dilate pulmonary stenosis in order to improve hemodynamics parameters, clinical symptoms, exercise capacity, and RH compliance, with a low rate of complications [52]. Complications can occur during the procedure (vascular injury, wire perforation, vascular dissection, balloon over dilatation, and others) or after the procedure, and include lung injury, contrast-induced kidney injury, and peripheral access site problems.

Likely between 20% and 40% of patients cannot undergo either of these treatments or show residual PH after interventional therapy and are amenable to medical therapy. This includes diuretics, oxygen therapy, and lifelong anticoagulation. Anticoagulation therapy can be done with either warfarin or direct oral anticoagulants: the choice is up to the doctor, who evaluates bleeding risk, renal impairment, and decides which therapy suits better for the patient.

Riociguat has been approved for the treatment of CTEPH, it determines vasodilatation and has anti-fibrotic, anti-proliferative, and anti-inflammatory activity.

Other specific drugs are currently tested with positive results in these patients, such as Macitentan and Treprostinil [53].

## **4. A look to the future**

PH is a complex and multifactorial disease, triggered and sustained by many pathological alterations. The three main modified pathways in PAH (NO, ET1, and PGI2) have been uncovered and targeted with appropriate pharmacological therapy, leading to an improvement in symptoms, quality of life, and survival of these patients.

In the next few years, scientists will focus their attention on researching new molecular targets that can have a role in the pathogenesis of the disease. For example, there is a trial ongoing on Rho-associated protein kinase (ROCK), which is involved in many cellular functions, such as smooth muscle cell contraction, cell migration, and others. It also has been demonstrated to play a role in the pathogenesis of PH. So, scientists are developing ROCK's inhibitors [54]. Another target is apelin, an endogenous vasodilator, which levels are decreased in PAH. Therefore, apelin infusion is being considered and trials are still ongoing [55].

Other drugs target inflammation and immunity: Ubenimex has been tested in a clinical trial but reported no improvement of symptoms and exercise capacity, tested with 6MWT [56].

Additionally, cytokines like IL-6 are overexpressed in PH, so drugs that function as inhibitors of this cytokine can play a role in future pharmacological treatment and are still going through appropriate development and testing [57].

Also, therapy targeting BMPR2 pathway has been considered: it has been shown that there is a decreased expression of this gene in heritable PAH and 20% of idiopathic PAH [58].

Moreover, there is evidence that PAH patients usually have low levels of iron. Actual guidelines suggest that iron supplementations should be considered. Kramer et al., assessed with a long-term study the use of ferric carboximaltose in PAH patients with iron deficiency: iron supplementation has demonstrated an improvement in clinical status, exercise capacity, and a decrease in hospitalization rate [59]. This resulted in an increase in 6MWT distance and a better WHO-FC and, consequently, a decreased risk calculated by ESC/ESR risk score.

*Pulmonary Hypertension DOI: http://dx.doi.org/10.5772/intechopen.107281*
