Pulmonary arterial hypertension in systemic sclerosis: Diagnosis and treatment according to the European Society of Cardiology and European Respiratory Society 2015 guidelines

Abstract

Scleroderma (systemic sclerosis) is an autoimmune connective tissue disease which presents endothelial dysfunction and fibroblast dysregulation, resulting in vascular and fibrotic disorders. Pulmonary hypertension is frequent in patients with systemic sclerosis: the natural evolution of the disease can induce the development of different forms of pulmonary hypertension, representing one of the main causes of death. Among the different forms of pulmonary hypertension in systemic sclerosis, pulmonary arterial hypertension is the most frequent one (rate of occurrence is estimated between 7% and 12%). This pulmonary vascular complication should be treated with a combination of drugs that is able to counteract endothelial dysfunction, antagonizing the endothelin-1 system and replacing prostaglandin I₂ and nitric oxide activity. A correct diagnosis is mandatory, because it is possible only for pulmonary arterial hypertension to use specific drugs that are able to control the symptomatic condition and the evolution of the disease. According to the most recent guidelines, for the patients with systemic sclerosis, also without pulmonary hypertension symptoms, echocardiography screening for the detection of pulmonary hypertension is recommended. Pulmonary arterial hypertension screening programs in systemic sclerosis patients is able to identify milder forms of the disease, allowing earlier management and better long-term outcome.

Introduction

When we talk about pulmonary hypertension (PH), it is very important to think that it is not a specific disease, but it is a hemodynamic condition characterized by a mean pulmonary arterial pressure (PAP), at right heart catheterization (RHC) ⩾ 25 mmHg. ¹

This clarification is very important because different pathological conditions exist which induce a PH status. Since 1998, there is a clinical classification of PH, which identifies six categories of PH that share pathological and hemodynamic characteristics, as well as similar management. ² The six pulmonary hypertension categories are: “pulmonary arterial hypertension” (PAH), identified as group 1, pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis, identified as group 1-bis’, “pulmonary hypertension due to left heart disease” which represents the group 2, “pulmonary hypertension due to chronic lung disease and/or hypoxia” known as group 3, “chronic thromboembolic pulmonary hypertension” identified as CTEPH and classified in group 4, and the last, “pulmonary hypertension due to unclear multifactorial mechanisms” which represents the group 5. ³

Scleroderma (systemic sclerosis (SSc)) is an autoimmune connective tissue disease (CTD) which presents endothelial dysfunction and fibroblast dysregulation, resulting in vascular and fibrotic disorders. Clinically, scleroderma has been classified into two categories: diffuse cutaneous scleroderma (dSSc) and limited cutaneous scleroderma (lSSc), based on the skin fibrotic extension, using the elbows and knees as “limits” to distinguish between them. ⁴ The natural evolution of the disease can induce the development of different forms of PH characterized by different pathological mechanisms. A recent cross-sectional study, conducted in Europe, North America, and Asia with 466 adult SSc patients involved, showed that 31% of patients were affected by PH: in particular, 19% belonged to group 1 because of PAH, 6% belonged to group 2 because of a left heart disorder, and 6% belonged to group 3 because of a pulmonary disease. No patients were found belonging to groups 4 and 5.^5,6

Group 1, PAH, is defined by specific hemodynamic feature: a mean PAP (mPAP) at RHC ⩾ 25 mmHg, pulmonary capillary wedge pressure ⩽ 15 mmHg, and pulmonary vascular resistance (PVR) > 3 Wood units (WU). It is very important to highlight that values between 21 and 24 mmHg are not considered normal, even if this cohort of patients has not been widely studied. One exception represented by SSc patients is a special population, where the “borderline” values of pulmonary pressure are associated with high probability to develop PAH. ⁷

The mechanisms which lead to the increase in PAP are represented by vasoconstriction process, vascular remodeling, and in situ thrombosis—pathological conditions that drive the increase in PVR. ⁸ At the base of these phenomena, there are, probably, numerous events and different factors which act on top of a genetic predisposition background. One of the most important mediators in the vascular remodeling is endothelin-1 (ET-1). ET-1, produced by endothelial cells, induces vasoconstriction in contrast to nitric oxide (NO) and prostaglandin I₂ (PGI₂), in order to maintain the vascular tone. In SSc and PAH patients, it is possible to observe an abnormal increase in ET-1 and a decrease in PGI₂ and NO. In physiological condition, ET-1 binds two receptors called ET_A, prevalently expressed on the muscle cells of the blood vessels, and ET_B, mainly present in the endothelial cells. ET-1 binds ET_A and induces vasoconstriction; at the same time, it binds ET_B inducing vasodilation. In PAH and SSc patients, a different expression of the ET-1 receptors has been observed: ET_A receptors are expressed as usual, while ET_B receptors are up-regulated on muscle cells and down-regulated on endothelial cells. It is not well established if this condition is genetically pre-defined or if it is due to a receptor’s clearance impairment. In any case, the result is a vascular remodeling. ET-1, binding ET_B receptors expressed in muscles cells, causes an uncontrolled cell proliferation resulting in vessel obliteration. Consequentially, the PVR increases, the pulmonary pressure increases, resulting in “pulmonary arterial hypertension” (group 1). ⁹

The prevalence of PAH in SSc patients is estimated between 7% and 12%;^10,11 the outcome remains poor and, probably, it is the worst comparing to the other PAH subgroups belonging to group 1. At 1 year, the mortality rate in patients affected by idiopathic pulmonary arterial hypertension (IPAH) is 15%; ¹² in SSc patients with PAH, it is exactly twice, that is, 30%. ¹³ Fortunately, it seems that an early diagnosis of PAH and a consequent early pharmacological approach could improve the long-term outcome. ¹⁴

The onset of PAH in SSc patients is on average 6.3 ± 6.6 years after diagnosis and, in the older patients, it is possible to record an earlier onset of PAH from the time of diagnosis, compared to younger patients who develop this complication later in the history of disease (on average 58 ± 12.5 years). lSSc seems to be a predisposing factor to PAH onset. ¹⁵

About PH due to left heart disorder (group 2), the pathophysiological conditions which impact the left heart functionality are variable, but the common process able to increase pulmonary pressure is a passive backward transmission from left heart (pulmonary veins) to right heart (pulmonary arteries). ¹⁶ The onset could be the left ventricular dysfunctions (systolic and/or diastolic), vascular disease, or congenital cardiomyopathies. From a hemodynamic point of view, in these situations, PVR and trans-pulmonary pressure gradient remain normal. ¹⁷ Cardiac involvement is very common in SSc and the most frequent cause is the myocardial fibrosis, as it was possible to show in 50%–80% of cases, after necropsies studies. Recently, magnetic resonance imaging (MRI) showed that the majority of patients have at least one cardiac abnormality. One-third of patients have diastolic dysfunction, and around 21% have myocardial delayed contrast enhancement suggestive of myocardial fibrosis. Myocardial fibrosis can induce left ventricular dysfunction and could explain the development of post-capillary PH. ¹⁸ About PH inducted by lung diseases (group 3), the pathological process which leads to the increase in pressure is really a physiological vasoconstriction which manifests itself when the partial pressure of oxygen gets down to a specific threshold. This condition induces PH, which worsens the prognosis of the patients with pulmonary fibrosis, inducing a progressive right heart failure. ¹⁹ Fortunately, the majority of the patients with lung involvement develop a mild or moderate PH, and only a few patients evolve to a severe PH. ²⁰ In SSc, the prevalence of PH due to lung fibrosis is approximately 30% and it involves prevalently patients with diffuse disease. ²¹ The treatment of this form of PH is focused on the pharmacological and non-pharmacological approaches aimed to control hypoxia and lung functionality. ²² PVOD has been recognized in consanguineous families, suggesting recessive transmission; ⁷ however, vasculopaty in scleroderma patients may involve post-capillary pulmonary venules, resulting in PVOD. ²³ This pathological condition is a rare cause of PH in SSc but, because of the similar clinical characteristics and signs of right failure, PVOD is difficult to distinguish from PAH. However, it is mandatory to distinguish because veno-occlusive disease has a worse prognosis and the administration of PAH-specific therapy can precipitate severe acute pulmonary edema. ²⁴

Diagnosis of PAH

A correct diagnosis is mandatory because it is possible only for PAH to use specific drugs that control the symptomatic condition and the evolution of the disease.

Unfortunately, a specific marker does not exist to identify PAH, so the goal of diagnostic process is to exclude the most common group of PH. The diagnostic algorithm has been thought to identify or exclude left heart disease, lung disease, CTEPH, or rare condition collected in group 5.

Transthoracic echocardiography is the first step of instrumental analysis process, which is very useful for screening, but not for definitive diagnosis. This tool allows to estimate the pulmonary pressure, starting from the velocity of tricuspid regurgitation, by the simplified Bernoulli’s equation (tricuspid regurgitation pressure = 4 × (tricuspid regurgitation velocity)). ² In order to estimate the systolic pulmonary pressure (PAPs), we have to consider the right atrial pressure (RAP; pulmonary arterial systolic pressure = tricuspid regurgitation pressure + estimated RAP). By using echocardiography, the procedure that evaluates RAP is based on the evaluation of diameter, and the respiratory variation of the inferior vena cava with a fixed value of 5 or 10 mmHg is assumed.

In the past, the presence of tricuspid regurgitation less than 2.8 m/s was considered as a normal value, excluding PH. A recent study showed that echocardiography has some limitations with high risk of false negatives. ⁵ PH could also be present in the absence of tricuspid regurgitation: so, for values ⩽2.8 m/s (in the presence of a clinical suspect of PH), we cannot exclude PH although we have to consider this case as a low-probability condition of PH. When regurgitation velocity is between 2.9 and 3.4 m/s, there is an intermediate probability of PH. If the value is >3.4 m/s, there is a high probability of PH. When the probability is low or intermediate, cardiologists have to look for the presence of other echo PH signs as reported in Table 1. ⁷

Table 1.

Echocardiographic pulmonary hypertension signs.

Ventricles	Pulmonary artery	Inferior vena cava and right atrium
Right ventricle/left ventricle basal diameter ratio >1.0	Right ventricular outflow Doppler acceleration time <105 ms and/or mid-systolic notching	Inferior cava diameter >21 mm with decreased inspiratory collapse (<50% with a sniff or <20% with quiet inspiration)
Flattening of the interventricular septum (left ventricular eccentricity index >1.1 in systole and/or diastole)	Early diastolic pulmonary regurgitation velocity >2.2 m/s	Right atrial area (end-systole) >18 cm2; PA diameter >25 mm
	PA diameter >25 mm

The second step defines the clinical group. If transthoracic echocardiography is suggestive of PH, by the same tool and usual electrocardiogram, it is possible to evaluate the left heart involvement in order to confirm or to exclude PH group 2. Pulmonary function tests identify the presence of airway or parenchymal lung disease (group 3). Usually, PAH patients have a decrement in diffusing capacity of the lungs for carbon monoxide (DLCO, 40%–80% predicted) and mild-to-moderate reduction in lung volumes with normal left heart function. Scleroderma patients are regularly subjected to pulmonary functional test in order to evaluate the interstitial lung disease (ILD) evolution. A significant decline in forced vital capacity (FVC) and DLCO defines ILD worsening. ²⁵ Moreover, DLCO is probably one of the most important parameters that we have to evaluate in scleroderma patients because it can represent a marker of ILD worsening as well as a marker of PAH. When DLCO and FVC are proportionally reduced, there is, naturally, an evolution of interstitial disease, but if DLCO is reduced and FVC is conserved, probably there is a pulmonary vascular disease and, very probably in SSc patients, PAH. ⁶ Annual lung function test with DLCO is recommended in scleroderma patients. ⁷

High-resolution computed tomography (HRCT) provides detailed views of the lung parenchyma and facilitates the diagnosis of ILD and emphysema. ¹⁹ Moreover, HRCT may also be very helpful where there is a clinical suspicion of PVOD. Characteristic changes of interstitial edema with diffuse central ground-glass opacification and thickening of interlobular septa support the diagnosis of PVOD; additional findings may include lymphadenopathy, pleural shadows, and effusions. ⁷

The exclusion of left heart disease and lung involvement leads to a potential suspect of thromboembolism. Ventilation/perfusion lung scan will allow to identify or exclude a CTEPH. This tool seems to be better than chest tomography, because it has a higher sensitivity and specificity about pulmonary chronic obstruction. ²⁶ It is important to underline that CTEPH is not common in SSc patients. If ventilation/perfusion lung scan results negative, the last possibility is a diagnosis of PAH. The last procedure is the RHC, a fundamental procedure to confirm the diagnosis of PAH, to evaluate the severity of the hemodynamic impairment and to undertake vosoreactivity testing of the pulmonary circulation in patients affected by IPAH, heritable PAH, and PAH due to drugs. This kind of test identifies patients treatable with high doses of calcium channel blockers. Scleroderma patients are not tested for vosoreactivity because they usually do not respond to the test, and the procedural risk is too high compared to the less probability to identify a responder patient. ⁷

Early diagnosis and early treatment may improve long-term outcome in patients with PAH associated with SSc. ²¹ According to the most recent guidelines, for the patients with SSc, also without PH symptoms, echocardiography screening for the detection of PH is recommended.^27,28 PAH screening programs in SSc patients identify milder forms of the disease, allowing earlier management and better results. ²⁹ A recent retrospective observational study showed that, SSc patients with early diagnosis of PAH obtained by screening before the symptom onset have a better prognosis compared to patients identified after symptom onset. Eight years after the diagnosis, patients screened and immediately treated according to the guidelines are alive in the 64% of the population compared to 17% of survivor in the group with diagnosis after symptom onset. ¹⁴

SSc is a systemic disease, which involves heart, lungs, and vessels: so, it is possible to have different forms of PH in the same patient.^4,7 Despite the prevalence of this “mixed” condition is unknown, it is very important to make an appropriate diagnosis in order to use the best pharmacological approach. The key of the problem is to understand whether the PAP values are proportionate or disproportionate compared to the underlying disease. In the proceedings of the 5th World Symposium on PH, the concept of “out of proportion” is better identified than in the past European Society of Cardiology (ESC) and European Respiratory Society (ERS) PH guidelines. ²

The hemodynamic definition of PH, secondary to left heart disease, combines an mPAP ⩾ 25 mmHg, a pulmonary artery wedge pressure (PAWP) > 15 mmHg, and a normal or reduced cardiac output (CO). In order to understand whether the PH is completely post-capillary or there is a pre-capillary component, it is possible to use the “Diastolic Pressure Gradient” (DPG) defined as “diastolic PAP—mean PAWP.” Thanks to this data; it is possible to define post-capillary hypertension when there is PAWP > 15 mmHg, DPG < 7 mmHg, and PVR < 3 WU; combined pre/post-capillary hypertension when PAWP > 15 mmHg, DPG > 7 mmHg, and PVR > 3 WU. ¹⁷ SSc patients occasionally develop pulmonary fibrosis and PH, but they can also develop PAH. The main issue is still to understand whether PH originates from lung disease (group 3) or from vascular remodeling (group 1). In order to overcome the term “out of proportion,” the NICE Proceedings 2013 indicates that, if there is a conserved pulmonary exchange (characterized by a forced expiratory volume in 1 s (FEV1) ⩾60% of predicted and FVC ⩾70% of predicted in the absence or in the presence of mild parenchymal abnormalities) and if the mPAP is ⩾35 mmHg at rest, the most probable diagnosis will be PAH (group 1) with concomitant mild or moderate lung disease. In patients with both lung disease and PAH, the use of PAH-approved drug may be considered through monitoring of gas exchange and inclusion in prospective registries. ²

Risk assessment

Once the patient affected by PAH is identified, a regular assessment in expert centers is strongly recommended. The assessment is a complex procedure because a single variable does not exist which produces the reliable prognostic information. At each visit, we have to verify whether there is clinical evidence of deterioration compared to the last visit. If there is a clinical evolution, first of all, it is fundamental to understand whether this condition is caused by PH or by other comorbidities. It is important to evaluate the right ventricular (RV) function and staging the patient according to the risk level. This kind of evaluation needs a multidimensional approach as recommended by guidelines that suggest a table containing a list of the most important parameters which correlate with the patients’ prognosis at 1 year.

This kind of approach is not so simple to apply, and it has been created in order to evaluate the risk at the diagnosis. However, a recent and wide retrospective study analyzed 1017 patents enrolled in the French registry, with a median follow-up of 34 months, trying to evaluate whether this method could be used also in order to evaluate the risk at the follow-up. The authors evaluated the presence of four low-risk criteria, which were defined as follows: World Health Organization (WHO)/New York Heart Association (NYHA) functional class I or II, 6-min walk distance (6MWD) >440 m, RAP <8 mmHg, and cardiac index ⩾2.5 L·min⁻¹·m⁻². ⁷ The results have been very interesting because the analysis highlighted that patients with only one or two low-risk criteria at follow-up had a worse long-term prognosis than those who attained three or four low-risk criteria. So, patients who achieve or maintain all low-risk criteria have a better long-term prognosis at re-evaluation.

This simplified version of the 2015 ESC/ERS risk assessment could become a valid method to assess prognosis also at follow-up. ³⁰

PAH treatment

The treatment of patients with PAH associated with CTD is more complex compared to patients affected by IPAH. As reported before, scleroderma patients, usually, have a negative response to the vosoreactivity test, and the consequence is that the response to calcium channel blocker is reported in less than 1% of cases. So, patients with SSc have less therapeutic possibilities and it is true also for the treatment with anticoagulant. Unfortunately, for scleroderma patients, the long-term risk–benefit ratio of oral anticoagulation is less favorable than in IPAH because of the increased risk of bleeding, so oral anticoagulation may be considered for each patient if risk–benefit ratio is favorable and in the presence of the thrombophilic predisposition. ⁷ Most of the data about PAH, SSc, and anticoagulation are related to the use of warfarin; however, in the COMPERA study, 6% of the patients were treated with the new class of anticoagulant and the results, despite the small sample, seem to be positive for the new oral anticoagulant compared to warfarin, showing the same efficacy and less number of bleeding. ³¹

The other treatment of patients with CTD and PAH should follow the same treatment algorithm as in IPAH. The initial approach includes the following general measures: physical activity and supervised rehabilitation, avoid pregnancy, infection prevention, psychosocial support, and supportive therapy, in particular, oxygen and diuretics. Although O₂ administration has been demonstrated to reduce the PVR in patients with PAH, there are no randomized data to suggest that long-term O₂ therapy is beneficial; anyway, when arterial blood O₂ pressure is consistently <8 kPa (60 mmHg; alternatively, 91% of arterial O₂ saturation), patients are advised to take O₂ to achieve an arterial blood O₂ pressure >8 kPa.

About diuretics, decompensated right heart failure leads to fluid retention, raised central venous pressure, hepatic congestion, ascites, and peripheral edema. Although there are no randomized controlled trials (RCTs) on the use of diuretics in PAH, clinical experience shows clear symptomatic benefit in fluid overloaded patients treated with this therapy. ⁷

As underlined before, patients with PAH and SSc do not respond to calcium channel blocker therapy, so it is important to begin the treatment with specific vasodilators as soon as possible.

PAH pharmacological approach starts from pathophysiological knowledge: therefore, the aim of the treatments is to correct endothelial dysfunction, antagonizing the ET-1 action and replacing PGI₂ and NO activity.

Inhibition of the cyclic guanosine monophosphate (cGMP) degrading enzyme phosphodiesterase-5 (PDE-5) results in vasodilation through the NO–cGMP pathway. ³² The inhibitor of PDE-5 sildenafil and tadalafil causes significant pulmonary vasodilation. The approved dose of oral sildenafil is 20mg three times a day³³ or 10mg three times a day in intravenous bolus. ³⁴ Tadalafil, a selective PDE-5i approved for PAH patients, is dispensed at the dose of 40mg once a day. Soluble guanlylate-cyclase stimulators enhance the NO-cGMP pathway, stimulating cGMP production.^35–37

Prostacyclin (also called PGI₂) is a physiological powerful vasodilator produced by endothelial cells; this prostaglandin can also inhibit platelet aggregation and cell proliferation. ³⁸ In patients with PAH, a dysregulation of the PGI₂ metabolic pathways has been showed, as assessed by reduction in prostacyclin synthase expression in the pulmonary arteries. ³⁹

Epoprostenol is a synthetic prostacyclin characterized by a short half life (3–5 min) and poor stability at room temperature. It requires cooling, continuous administration by means of an infusion pump, and a permanent tunneled catheter.^40–42 A thermo-stable formulation of epoprostenol is actually approved and it does not require refrigeration in order to maintain stability. ⁴³

Treprostinil is a tricyclic benzidine analog of epoprostenol, stable at room temperature, and these characteristics allow administration of the compound by the intravenous as well as the subcutaneous route.

Inhaled iloprost is a stable analog of PGI₂, approved for PAH treatment. It is administered by inhalation, thus avoiding most of the systemic side-effects associated with intravenous or subcutaneous prostanoid infusion. ¹⁰

The most recent drug that acts on the prostacyclin pathway is selexipag, an oral selective IP prostacyclin receptor agonist. About the chemical structure, it is not a prostacyclin but a synthetic drug able to bind specifically only IP receptors. ⁴⁴

Activation of the endothelin system has been demonstrated in plasma and lung tissue of PAH patients, and these data support the important role of ET-1 in the pathogenesis of PAH.^9,45,46

Ambrisentan is an endothelin receptor antagonist, non-sulfonamide, and propanoic acid class, which is selective for the ET_A receptor, ⁴⁷ and it is approved for PAH patients. Bosentan has been the first oral drug for the PAH treatment, and it is a dual-receptor antagonist. WHO-FC classes II and III are approved for PAH patients. In the last years, in the pharmacological armamentarium, it is possible to find another dual endothelin receptor antagonist called macitentan. It has been developed by modifying the structure of bosentan in order to increase efficacy and safety. Macitentan is characterized by sustained receptor binding, enhanced tissue penetration, and once-a-day administration. ⁴⁷

Which is the best pharmacological approach for the patients affected by scleroderma and PAH? The goal of the treatment of PAH in SSc patients is to achieve the lower risk status; the most recent guidelines suggest a different pharmacological approach for different basic risk level. Patients at low or intermediate risk (functional classes II–III) must be treated with oral monotherapy or oral combination therapy. In patients at high risk, also if they are naïve, a combination therapy including intra venous prostacyclin analogs should be considered. ⁷

Guidelines suggest to achieve the low-risk status because it means to change the prognosis of the patients. When we talk about risk, we consider the probability for the patient to die in the next 12 months, so it could be useful to consider drugs that are able to change morbidity and mortality.^48–49

There are no studies with morbidity/mortality endpoint for sildenafil and tadalafil in monotherapy. Bosentan plus sildenafil, as shown in COMPASS-2 study, was not able to delay the time to the first morbidity/mortality event. ⁵⁰ Ambrisentan alone was not able to control the morbidity/mortality events, but the drug, in combination with tadalafil, seems to reduce the relative risk of morbidity/mortality by 50%. ⁵¹

Macitentan was able to reduce the morbidity/mortality relative risk by 55% versus placebo and 38% in combination with sildenafil versus sildenafil alone, in prevalent patients and sequential combination therapy. ⁵² In incident patients, macitentan alone and in combination with sildenafil reduce the relative risk by 57%. ⁵³

Selexipag in monotherapy, in combination with PDE-5 inhibitor and in combination with PDE-5 inhibitor plus endothelin receptor antagonist, reduces the morbidity/mortality relative risk by 40%. ⁴⁴ The epoprostenol treatment, in scleroderma PAH patients, showed an increase in the survival rate. ⁵⁴

In each study, double combination therapy with endothelin receptor antagonist (ERA) plus PDE-5 inhibitor is better than single therapy, and the addition of selexipag to background double combination therapy provides an increase in the benefit in terms of morbidity and mortality. ⁵⁵

Conclusion

The natural evolution of SSc induces the development of different forms of PH. A correct diagnosis is mandatory because it is possible only for PAH to use specific drugs, which control the symptomatic condition and the evolution of the disease.

Once the patient affected by PAH is identified, a regular assessment in expert centers is strongly recommended; the guidelines suggest a table containing a list of the most important parameters which correlate with the patients’ prognosis at 1 year. Recently, a wide retrospective study analyzed 1017 patents enrolled in the French registry, and it showed that a simplified version of the 2015 ESC/ERS risk assessment can be a valid and easier method to assess prognosis.

About the treatment, guidelines suggest to achieve the lowest risk status, with the aim of positively influencing the prognosis of the patients. When we talk about risk, we consider the probability for the patient to die in the next 12 months. Therefore, it could be useful to consider drugs that are able to achieve the morbidity/mortality endpoint. We want to emphasize this concept: double combination therapy is better than single therapy, and triple therapy is better than double therapy.

Presently, a phase-3 study called “TRITON Study” is ongoing. The aim of the study is to compare the efficacy and safety of two different therapeutic strategies: initial triple oral treatment regimen (macitentan, tadalafil, and selexipag) versus an initial dual oral treatment regimen (macitentan, tadalafil, and placebo) in newly diagnosed, treatment-naïve PAH patients. ⁵⁶

Probably, starting immediately with three drugs could correct all the metabolic pathways involved in PAH pathogenesis and could mean slowdown the evolution of the disease and increase survival.