The treatment of pulmonary arterial hypertension (PAH) has evolved rapidly over the past decade, and treatment guidelines have evolved based on evidence-based medicine. This article discusses the latest treatment advances for PAH, which includes general and supportive therapy, treatment of related diseases, targeted drug therapy, and surgical treatment.
I. General and supportive treatment
1. General treatment: Even after the release of targeted drugs for PAH, general treatment is still very important to maintain patients’ quality of life and reduce rehospitalization rates, including infection prevention, supervised light physical activity, contraception and psychological support.
Prevention of infection includes routine annual vaccination with live streptococcal and influenza vaccines. Streptococcus pneumoniae and influenza are the leading causes of pneumonia in patients with PAH, which causes 7% of deaths, and routine vaccination reduces the incidence of infection in PAH.
Light physical activity under supervision is recommended. If supervision is not possible, patients should be educated on how to exercise. Daily exercise training can improve mobility and quality of life. However, strenuous exercise should be avoided to prevent exacerbation of the disease, and supervised rehabilitation is recommended for patients with WHO pulmonary hypertension class III or IV.
Women with PAH need strict contraception. Studies have shown that women with PAH have a 30-50% mortality rate during pregnancy. Stillbirth, preterm delivery and intrauterine growth retardation are common in patients with PAH. Therefore, planned contraception is recommended. Contraceptive measures include oral contraceptives or the Manned IUD. Progesterone-based oral contraceptives alone are preferred because they also avoid the potential risks associated with estrogen. Therapeutic termination of pregnancy during the first 3 months of pregnancy should be done with caution.
Psychological problems such as depression and anxiety are common for patients and families with PAH. Referral to a psychologist should be prompt for some patients. Social gatherings can be helpful in addressing the psychological problems of patients.
2. Supportive treatment: including oral anticoagulants, oxygen therapy, diuretics and digoxin.
The use of oral anticoagulants is based on previous pathological studies, and autopsy results show a higher incidence of thrombotic vasculopathy in patients with idiopathic pulmonary arterial hypertension. Abnormal coagulation and fibrinolytic pathways have been reported in patients with PAH, and the risk of thromboembolism is increased by low daily activity and right ventricular insufficiency. Current guidelines recommend anticoagulation for patients with idiopathic pulmonary hypertension, hereditary pulmonary hypertension, and appetite suppressant-related pulmonary hypertension.
Patients with congenital heart disease and connective tissue disease-associated pulmonary hypertension have a higher risk of hemoptysis and gastrointestinal bleeding, and anticoagulation strategies need to be individualized. The optimal international standardized index (INR) depends on each center (usually 1.5-3.0), and the recommended target for our center is consistent with North America, namely INR l.5-2.5.
Oxygen inhalation is beneficial for patients who are hypoxic at rest and during exercise. Hypoxia is a powerful inducer of vasoconstriction and hyperoxia reduces pulmonary vascular resistance in patients with PAH. However, there are no randomized controlled clinical studies to confirm the efficacy of long-term oxygenation. Existing guidelines, based on experience with chronic obstructive pulmonary disease (COPD), recommend that patients with an arterial partial pressure of oxygen (Pao2) <60 mmHg (l mmHg=0.133 kPa) should receive oxygen for >15 h/d. Outpatient oxygenation is recommended for patients with severe hypoxia after exercise whose symptoms improve with oxygenation.
Diuretics are effective in reducing edema and symptoms of right heart failure. Reduction of edema can improve hepatic, intestinal and peripheral edema. The intestinal oedema can lead to a significant increase in the number of patients with PAH. s control because it can lead to miosis and malabsorption. Although there are no randomized controlled clinical studies of diuretics in patients with PAH, experience tells us that diuretic therapy improves symptoms and quality of life. The choice of diuretic type and dose depends on the clinician.
Intravenous loop diuretics can rapidly reduce preload in PAH patients with ascites and intestinal edema, but patients’ electrolytes need to be monitored to avoid hypokalemia and prerenal azotemia. Digoxin may rapidly improve right ventricular contractility and increase cardiac output in patients with PAH in the short term, but long-term efficacy has not been demonstrated. Digoxin may improve patients’ symptoms and reduce readmission rates.
PAH is divided into different subgroups according to the associated diseases. Specialists should be involved in the treatment of different underlying diseases. Intervention and surgery may be effective in some patients with congenital heart disease-associated PAH. In patients with PAH in combination with SLE, lupus activity should be controlled first. Detailed consultation with specialists in congenital heart disease, thoracic surgery, rheumatology, infection, hematology, and genetics is necessary depending on the patient’s specific situation.
III. Targeted therapy
Calcium channel blockers: The majority of PAH targeted therapeutic agents currently in clinical use have emerged in the last 20 years, mainly targeting PAH pathogenesis to exert multiple pulmonary vasodilatory effects. Calcium channel blockers are the longest clinically used targeted therapeutic agents, however, they are only effective in a very small number of patients with idiopathic pulmonary hypertension with positive acute pulmonary vasodilation tests.
Nifedipine, diltiazem? Calcium channel blockers affect the heart rate and the preference is for diltiazem in patients with a rapid heart rate. The dose of calcium channel blockers can cause adverse effects such as dizziness, hypotension and peripheral edema, so a slow increase to the maximum tolerated dose is recommended.
Patients who are effectively treated with calcium channel blockers have a good prognosis. Patients with negative acute pulmonary vasodilatation tests or without such tests should not be treated with calcium channel blockers. In patients with pulmonary hypertension associated with connective tissue disease, calcium channel blockers are not effective even if the acute pulmonary vasodilatation test is positive.
Prostacyclin analogs: Prostacyclin is a naturally occurring vasodilator produced by vascular endothelial cells and has anti-proliferative, cytoprotective and anti-platelet aggregation activities.
Prostacyclin was the first targeted drug approved for the treatment of PAH, with a short half-life (3-5 min). A randomized controlled clinical study has demonstrated that epoprostenol improves symptoms, cardiac function and survival in patients with idiopathic pulmonary arterial hypertension.
Eprostenol is effective in both scleroderma-associated pulmonary hypertension and inoperable chronic thromboembolic pulmonary hypertension (CTEPH). For treatment, epoprostenol can only be pumped continuously through a permanent tunneled catheter, so catheter-related complications (infusion pump failure, catheter blockage, and infection) are the most important factors affecting the widespread use of epoprostenol. Common adverse effects of epoprostenol include flushing, diarrhea, headache, and nausea and vomiting.
Treprostinil is a prostacyclin analogue that is far more stable than epoprostenol and can be used to treat patients by the subcutaneous or intravenous continuous pump route. Subcutaneous pumping can be achieved through a tiny pump similar to an insulin pump, which is not only small and easy to handle, but also minimizes patient discomfort. The most common adverse reaction is pain at the injection site, and other common adverse reactions include flushing, vomiting, and abscesses. The effectiveness of travoprost has been confirmed by large randomized controlled trials, improving patients’ activity tolerance, hemodynamic parameters and clinical symptoms.
Iloprost is a more stable synthetic prostacyclin analog and is available in a variety of dosage forms (e.g., oral, inhaled, and intravenous).The AIR study confirmed the efficacy of inhaled iloprost (2.5-5 μg/ dose, 6-9 doses/d, mean 30 μg/d). The efficacy of low-dose intravenous iloprost is similar to that of epoprostenol, and no studies of oral iloprost for PAH have been reported. Inhaled iloprost is gentler and better tolerated than epoprostenol, but patient compliance is a key factor in treatment due to the need for frequent inhalation and the resulting dry mouth.
Endothelin receptor antagonists: Endothelin is a small molecule secreted mainly by the endothelium, and its receptors are mainly expressed in endothelial cells and vascular smooth muscle cells. Endothelin is associated with cell proliferation and pulmonary vasoconstriction. It has been reported that patients with PAH have significantly increased serum endothelin concentrations and overexpressed vascular smooth muscle endothelin receptors, thus endothelin receptor antagonists (ERAs) may be targeted therapeutic agents for PAH.
Currently, bosentan, aniracetam and macitentan have been approved by the FDA for PAH treatment. Bosentan, a dual antagonist of endothelin A and B receptors, is the first oral PAH-targeted therapy and the first approved endothelin receptor antagonist. Bosentan has been shown to be effective in the treatment of patients with moderate to severe pulmonary hypertension in several large randomized controlled clinical studies (BREATH-1. BREATH-2 and EARLY studies), and its efficacy in Eisenmenger syndrome was confirmed in the BREATH-5 study. Elevated liver enzymes occur in approximately 10% of patients with PAH on bosentan, but are reversible with dose reduction or discontinuation of the drug. Relatively common adverse reactions include nasal congestion, edema, headache, and gastrointestinal reactions.
Anrisentan is the second approved endothelin receptor antagonist on the market and is a selective endothelin A receptor antagonist. Two randomized controlled clinical studies (ARIES-1 and ARIES-2) completed in Europe and the United States showed that both anrisentan 5 and 10 mg once daily improved exercise tolerance in patients with PAH. Open-label studies showed good long-term (2 years) efficacy and safety of aniracetam, and elevated liver enzymes were uncommon, but peripheral edema was more common than with bosentan.
Macitentan is a new oral endothelin receptor antagonist that was just approved by the FDA in 2013 and significantly reduced disability and mortality in patients with PAH (SERAPHIN study). A study of macitentan for the treatment of Eisenmenger syndrome (MAESTERO study) is ongoing.
4.5 Phosphodiesterase (PDE-5) inhibitors and soluble guanylate cyclase agonists (sGC): Sildenafil and tadalafil are currently marketed as PDE-5 inhibitors. cGMP is catabolized by PDE-5, thereby inhibiting vasodilation via NO/cGMP channels. Thus, inhibition of cGMP degradation activates the NO system and induces pulmonary vasodilation. Sildenafil was the first PDE-5 inhibitor shown to improve exercise tolerance, hemodynamic parameters and symptoms in patients with PAH (SUPER study). The approved dose of sildenafil is 20 mg 3 times daily, with a maximum tolerated dose of 80 mg 3 times daily in clinical practice.
Tadalafil, another PDE-5 inhibitor, at 40 mg once daily, is effective in improving clinical symptoms, exercise tolerance, hemodynamic parameters and prolonging the time to clinical deterioration (PHIRST study). The combination of PDE-5 inhibitors with nitrates may induce hypotension and should be avoided.
Riosquat is a novel NO/cGMP channel-related drug that acts directly on the sGC. studies have reported NO depletion in patients with advanced PAH, and NO deficiency may explain PDE-5 inhibitor resistance in some patients with PAH. riociquat significantly improves exercise tolerance, hemodynamic parameters, cardiac function, and prolongs the time to clinical deterioration (e.g., the time to clinical deterioration). riociquat significantly improved exercise tolerance, hemodynamic parameters, cardiac function, prolonged time to clinical deterioration (PATENT study), and was also effective in the treatment of CTEPH (CHEST study). The indications for FDA approval of riociquat include PAH and CTEPH.
The BREATH-2 study found that the combination of epoprostenol and bosentan was more effective than epoprostenol alone in improving patient hemodynamics. The AMBITION study, a clinical study comparing the combination of eprosentane-tadalafil with either eprosentan or tadalafil alone, is ongoing and is the largest combination study to date. Current clinical guidelines recommend considering the combination only when the starting treatment strategy is not effective.
Fourth, balloon atrial septal fistula and pulmonary transplantation atrial septal fistula as bridging therapy for patients awaiting lung transplantation reduces right ventricular afterload, increases cardiac output, and thus reduces right ventricular tone. However, medically induced right-to-left shunts can lead to hypoxia, so the size of the fistula should depend on the patient’s cardiac output and hypoxia.
Lung transplantation is the last and most radical treatment for refractory PAH, but the long-term disability and mortality rates remain high (5-year survival rate of approximately 50%), and the high cost of care and lack of donors are significant problems.
In conclusion, the treatment of PAH has progressed rapidly in the last decade, and patient survival has improved significantly. The treatment of PAH should be based on conventional supportive care with close follow-up and timely adjustment of treatment regimen or consideration of lung transplantation in case of poor outcome.