Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are life-threatening diseases. Patients benefit from early therapy. Unfortunately, diagnosis is often made late in the disease, partly due to non-specific symptomatology.
- PH is classified in five groups. PAH (group 1) and CTEPH (group 4) patients should be managed in PH expert centers.
- PAH patients benefit from specific treatments directly targeting the pulmonary endothelium. Initial bitherapies are increasingly used in clinical practice. For patients with an insufficient clinical response, therapy should be progressively increased up to a maximal treatment including a parenteral prostacyclin.
- CTEPH patients should undergo PEA whenever possible. For inoperable patients, alternatives include BPA and medical treatment. Lifelong anticoagulation is recommended for these patients.
Pulmonary hypertension: generalities
Pulmonary vasculature is a low-pressure system with a normal mean pulmonary artery pressure (mPAP) ranging from 15 mmHg to 20 mmHg. Pulmonary hypertension (PH) is defined as mPAP ≥ 25 mmHg assessed at rest during right heart catheterisation (RHC).1 PH is subdivided into pre- and post-capillary according to the pulmonary artery wedge pressure (PAWP), which reflects the left atrial pressure. PH is pre-capillary when PAWP is ≤ 15 mmHg and post-capillary if PAWP is > 15 mmHg.1 PH is combined (post- and pre-capillary components) when PAWP is > 15 mmHg with abnormally elevated pulmonary vascular resistance (PVR) and/or diastolic pressure gradient (diastolic PAP– PAWP), respectively > 3 wood units and ≥ 7 mmHg.2 PH is subdivided into five groups sharing similar pathological findings, hemodynamic characteristics and management.3 Group 1 contains PAH, pulmonary veino-occlusive disease and/or pulmonary capillary haemangiomatosis and persistent pulmonary hypertension of the newborn. Group 2 includes all PH due to left heart diseases.2 Pulmonary disease and/or hypoxia causing PH define group 3.4 Group 4 corresponds to CTEPH and other pulmonary artery obstructions leading to PH.5 Finally, PH with unclear multifactorial mechanisms composes group 5. Groups 1, 3 and 4 cause pre-capillary PH.1 Group 2 leads to post-capillary PH, which can become combined with chronicity.2 PH is a rare condition with a prevalence of 97 cases per million.1 Groups 2 and 3 are more frequent than groups 1 and 4.1 PH leads to progressive right ventricular failure and eventually death. Signs and symptoms are typically insidious, starting with dyspnea during exercise and progressing towards severe limitations and signs of right ventricular dysfunction. In this context, PH is often suspected belatedly during transthoracic echocardiography (TTE) screening for unexplained dyspnea. TTE is the best screening tool for PH especially by its evaluation of tricuspid regurgitation. After TTE, the diagnostic workup should be continued according to figure 1.
When a disease from groups 2 or 3 is suspected, RHC should not be systematically performed to confirm PH, as it would not modify the treatment. For these two groups, management targets the underlying pathology. On the other hand, RHC is mandatory to confirm PH in groups 1 and 4 because they benefit from specific treatments, which we will now summarize.
PAH is a vasculopathy of the small pulmonary arteries, showing proliferation of endothelial and smooth muscle cells with medial hypertrophy.6 Three main pathophysiological pathways involved in this process are identified:7
1. Overexpression of endothelin, a powerful vasoconstrictor;
2. Reduced activity of nitric oxide (NO), a vasodilator;
3. Diminished prostacyclins, known for vasodilating, platelet inhibiting and antiproliferative properties.
The first step to orienting treatment is given by the vasoreactive challenge where NO is administered during RHC. A positive test is defined as a reduction of mPAP of ≥ 10 mmHg to an absolute mPAP ≤ 40 mmHg, with an increased or unchanged cardiac output.1 Patients with a positive test benefit from high dose calcium channel blockers (CCB).1 For all others, CCB are inefficient and specific therapies targeting the three main pathophysiological pathways are used. NO is increased with phosphodiesterase type 5 inhibitors (PDE5i) (e. g. sildenafil, tadalafil) or soluble guanylate cyclase (sGC) stimulator (i. e. riociguat). The prostacyclin pathway is targeted with synthetic prostacyclins (i. e. epoprostenol), their analogues (i. e. iloprost, tresprostinil) or a prostacylin receptor agonist (i. e. selexipag). Endothelin receptor antagonists (ERA) (i. e. bosentan, ambrisentan, macitentan) are the third option. PDE5i, sGC stimulator and ERA are available in oral form. Treatments targeting the prostacyclin pathway are administered in parenteral form (except the oral selexipag). Complexity of specific PAH treatments mainly resides in choosing the correct introduction pattern, either as initial monotherapy or combination therapy. Treatments seek to achieve a low mortality risk (< 5 %) as defined by the ESC/ERS Guidelines.1 This risk is evaluated according to symptoms, signs, World Health Organization functional classes (WHO-FC) ranging from I to IV, exercise capacity exams, NT pro-BNP, imaging (e. g. TTE) and RHC. Low-risk patients may have two initial oral therapy options: monotherapy or bitherapy. Monotherapy’s strongest evidence is in favor of ambrisentan8, bosentan9, 10, sildenafil11, tadalafil12, and riociguat13. Macitentan14 and oral selexipag15 are also recommended with a slightly lower level of evidence.1 Recent studies now encourage initial bitherapies when the benefit/ risk ratio is favorable16, 17, the most commonly used combination being an ERA with a PDE5i. Other oral combinations targeting the prostacyclin pathway are now made possible by the emergence of selexipag, the first oral agonist of prostacyclin receptor.17, 18 Indeed, parenteral prostacyclins are usually reserved for intermediate and high-risk patients because of their cumbersome management. Patients with initial intermediate risk usually benefit from oral bitherapy.19 Recent studies have even suggested the use of an initial tritherapy including an oral prostacyclin.18 Highrisk patients suffer from a very serious disease, with similar survival rates to advanced malignancies.20, 21 They may benefit from an upfront tritherapy including i. v. epoprostenol.22 This zealous therapy significantly improves patients’ symptoms as well as exercise capacity and hemodynamics, thus reducing the need for lung transplantation.22 After treatment initiation, patients should be evaluated every 3 to 6 months. Parenteral prostacyclins are recommended in case of insufficient therapy response or initial high-risk profile.23–27 I. v. epoprostenol shows the strongest evidence, with now numerous studies proving its benefits and making it a key treatment.28 If low-risk profile is not reached, therapy should be optimized with additional molecules up to a maximal treatment (i. e. tritherapy including an i. v. or s. c. prostacyclin, an ERA and a PDE5i or sGC stimulator). Data from a national registry revealed that only 43 % of PAH patients received maximal treatment with an i. v./s. c. prostacyclin at the time of death, showing room for further improvement.29 Lung/heart-lung transplantation should be considered early on as a last resort if medical therapy fails. Figure 2 summarizes the treatment’s introduction according to the WHO-FC and risk profiles.
About 60 % of newly diagnosed PAH patients fall in WHO-FC III and would benefit from an initial bi- or tritherapy.30 Even though initial tritherapy seems promising, cost-efficiency and additional adverse effects should be thought through. In addition to previously discussed specific treatments, other issues should be managed (Tab. 1). Furthermore, general measures should not be overlooked, such as physical activity and supervised rehabilitation, evaluation of adherence to treatments, psychological support and genetic counseling for hereditary PAH.
CTEPH is defined as pre-capillary PH with mismatched perfusion defects on V/Q scan and specific diagnostic signs seen during imaging (e. g. CT pulmonary angiography) after at least 3 months of effective anticoagulation.1 The cumulative incidence of CTEPH is 0.1–9.1 % within the first 2 years after a symptomatic pulmonary embolism (PE) event.31 Routine screening for CTEPH after PE is not supported by current evidence but symptoms such as dyspnea or signs of right ventricular dysfunction developing after acute PE should raise immediate attention.1 In this context, a TTE must be done. CTEPH can also occur without previous symptomatic PE event. For these reasons, CTEPH is a challenging diagnosis and the median time between symptoms’ onset and diagnosis in expert centres is 14 months.32 Once the diagnosis is made, therapeutic measures must be taken.
Pulmonary endarterectomy (PEA)
Pulmonary endarterectomy, the current gold standard for operable patients, is a procedure that can eventually be curative with most patients experiencing a significant relief of symptoms.5 This surgery removes the intimal and medial layers from the pulmonary arteries and is performed under cardiopulmonary bypass and deep hypothermia cardiac arrest. The mean inhospitality mortality rate of this procedure in Europe is of 4.7 %.33 However, it depends greatly on the patient’s pre-operative condition including hemodynamic severity and the center’s experience.33 The WHO-FC and localisation of thrombi are the main determinants for assessment of operability status.5
Balloon pulmonary angioplasty (BPA)
BPA is a recently developed option where the pulmonary arteries are reached during RHC. An angioplasty is then selectively performed where thrombi are present. No stents are needed because the risk of restenosis is described as neglectable, probably because of the low-pressure system. Reperfusion pulmonary edema (RPE) and vessel rupture are the most serious complications of BPA.5 BPA is performed in multiple sessions with small balloons to avoid RPE. One recent publication showed the absence of RPE when BPA was performed according to strict standards (n = 145 patients).34 BPA showed good clinical and hemodynamic results and is an alternative for non-operable patients either because they are considered highrisk for surgery or because the lesions are too distal in the pulmonary arteries (i. e. after segmental pulmonary arteries).34 Riociguat is the first drug that showed significant evidence in CTEPH. It can be administered to patients not eligible for PEA or those with persistent/recurrent PH after PEA.35 In a recent study, Macitentan significantly decreased PVR and increased exercise capacity (6MWD) in inoperable patients and could be recommended in the future.36 In addition to the previously discussed therapies, all CTEPH patients have an indication for long-term anticoagulation. No data concerning the new oral anticoagulants for this indication have been published. Antivitamin K anticoagulants are the actual recommendation.
Swiss CTEPH Board
In Switzerland, a national CTEPH board has been recently launched by the Swiss Society for Pulmonary Hypertension (SSPH). It is driven by the Zurich (USZ) and Geneva (HUG) expert centers. CTEPH patients from all over the country can be discussed in a multidisciplinary panel including experts of PEA and BPA. This unique proposal allows the best possible diagnostic and therapeutic strategy for each patient. Patients’ cases can be submitted simply using the email address: firstname.lastname@example.org.