Pulmonary hypertension (PH) is a complex disorder that was first described in a case report as “pulmonary vascular sclerosis” in 1891 by German internist Dr Ernst von Romberg.1 Without treatment, it is a progressive, fatal disease that is characterized by elevated pulmonary arterial pressure and secondary right ventricular failure. According to the most recent evidence from a national French registry, the prevalence of pulmonary arterial hypertension (PAH) is about 15 cases per 1 million adult inhabitants with an incidence of 2.4 cases per 1 million adult inhabitants.2 According to a registry that evaluates early and long-term PAH disease management, the prevalence of PAH in the United States is 12.4 cases per million and the incidence is 2.3 cases per million.3 Unfortunately, not all cases of PAH are reported to the registries, so both the prevalence and incidence data are considered low estimates.The clinical course of this disease varies greatly from one individual to another and also varies on the basis of the number and severity of complications. Pulmonary arterial hypertension is incurable, and without appropriate treatment, many patients die within 3 years of onset. Fortunately, several classes of medications can improve symptoms, and some may reduce mortality for patients with PAH. Health care providers must be familiar with this disease and the medications used to treat it. The purpose of this article is to provide an overview of PAH, with a specific focus on the medications used to treat this disease.Pulmonary arterial hypertension is characterized by progressive proliferation, remodeling, and obstruction of the small pulmonary arteries. The general mechanism of PAH results from the restriction of blood flow through the pulmonary arterial circulation, which leads to increases in peripheral vascular resistance and, ultimately, right-sided heart failure. Current medical therapies target the imbalance between vasoconstrictor and vasodilator mediators.The revised World Health Organization (WHO) classification for PH divides this disease into 5 groups based on the cause of the PH (Table 1). Patients in the first group are considered to have PAH, and patients in the remaining 4 groups are classified as having PH. In addition, patients also are assigned WHO functional classes I to IV, which measure the limitations placed on them due to the progression of their disease. Class I involves no increased dyspnea, fatigue, chest pain, or presyncope with normal activities. In class II, patients are comfortable at rest, but normal physical activity causes increased dyspnea, fatigue, chest pain, or presyncope. Patients in class III are comfortable at rest, but any level of additional exertion causes increased dyspnea, fatigue, chest pain, or presyncope. In class IV, patients have signs of right ventricular failure and are unable to perform any physical activity without symptoms of dyspnea, fatigue, chest pain, or presyncope.5 The functional classes are a strong predictor of mortality and help guide PH therapy.All patients suspected of having PAH after noninvasive testing, such as Doppler echocardiogram or exercise echocardiogram, should undergo a right-sided heart catheterization.6 A mean pulmonary artery pressure at rest is considered to be normal at 20 mm Hg or less. Mean pulmonary artery pressures of 21 to 24 mm Hg are considered to be borderline normal. A patient with a mean pulmonary artery pressure that is 25 mm Hg or greater is considered to have PH.Overall, the prognosis for most patients with PAH is poor, with a 15% one-year mortality rate, even for patients being treated with appropriate medications and other therapies.6 Symptomatic parameters used to determine severity of disease and general prognosis are summarized in Table 2.Treatment strategies for patients with PH can vary depending on the underlying cause of the disease. Treatment goals include improving symptoms of dyspnea, increasing distance on the 6-minute walk test, lowering pulmonary arterial pressure, and normalizing cardiac output. In addition, reversing or preventing progression of the disease and improving survival are important treatment goals for patients with PAH. The treatment modalities used for WHO groups 2 to 5, with PH, target the causative disease states. These targets include left-sided heart disease for group 2, lung diseases and/or hypoxemia for group 3, thrombotic/embolic causes for group 4, and treatment of miscellaneous causes of PH, such as sarcoidosis, histiocytosis X, and lymphangiomatosis, for group 5. Patients in group 1 generally have idiopathic PAH and usually require advanced treatments, as no effective primary therapies are available. Patients in all groups of PH with WHO functional class II, III, or IV and persistent symptoms despite appropriate primary therapy require advanced therapies.Pharmacological therapy for PAH is targeted toward reduction of pulmonary vascular resistance, with goals of treatment aimed at vasodilation and suppression of cellular proliferation within the pulmonary arterial wall. Advanced therapies (Figure) can improve patients’ quality of life and prolong survival. Frontline therapies used to treat PAH include 4 main classes: calcium channel blockers, endothelin receptor antagonists, phosphodiesterase-5 (PDE-5) inhibitors, and prostacyclin analogues.Treatment with calcium channel blockers, such as amlodipine, diltiazem, nifedipine, or verapamil, is considered for patients who have a positive response to vasoreactive testing with adenosine, epoprostenol, or nitric oxide. They work by relaxing artery wall muscles, dilating the pulmonary arterial system, and reducing pressure. However, only a small subset of patients (8.7%) meet these criteria and benefit from therapy with calcium channel blockers, and only 5.8% have sustained hemodynamic improvement.9 Patients who respond to calcium channel blocker therapy often have an excellent 5-year survival rate.10 For these patients, therapy is titrated up and monitored frequently for residual vasoreactivity during right-sided heart catheterization. Because of the potential negative inotropic effects of these agents, they should not be initiated before vasoreactive testing.Endothelial cells regulate local vascular tone and integrity through the coordinated release of vasoactive molecules (endothelins).7,8 Currently, only 2 endothelin receptor antagonists, bosentan and ambrisentan, have been approved by the Food and Drug Administration for the treatment of PH. Both are highly teratogenic, so women of childbearing age should use 2 forms of birth control and take monthly pregnancy tests, while being treated with these medications. Other common adverse effects include hepatotoxicity, peripheral edema, decreased hemoglobin, and decreased sperm counts.11,12Bosentan (Tracleer)11 is indicated for the treatment of PAH to improve exercise ability and to decrease clinical worsening. Bosentan is administered orally twice a day, and has a half-life of 5 hours. It is metabolized via the liver, so patients are at increased risk for hepatotoxicity and significant drug interactions. Patients are required to have liver enzyme tests prior to initiation and then monthly while taking this medication (Table 3).11 Because of the risks of hepatotoxicity and birth defects, the FDA required the manufacturer to create a Risk Evaluation and Mitigation Strategies (REMS) program for bosentan (Table 4).Ambrisentan (Letairis)12 is newer to the market than bosentan and is indicated for the treatment of PAH to improve exercise ability and delay clinical worsening. Ambrisentan is administered once daily, and has a half-life of 15 hours. Similar to bosentan, it carries a risk of hepatotoxicity but does not require monthly liver enzyme testing (Table 3).12 For women, because of the embryo-fetal toxicity, ambrisentan is available with use of a Letairis REMS program (Table 4). Overall, both bosentan and ambrisentan are effective and well tolerated.Phosphodiesterase-5, an enzyme responsible for degradation of mediators that are necessary for vasodilation, is heavily expressed in the pulmonary vasculature. Blockade of PDE-5 permits proper vasodilation of the pulmonary vasculature, thereby lowering pulmonary artery pressure. Two PDE-5 inhibitors, sildenafil and tadalafil, have been approved by the Food and Drug Administration for the treatment of PAH.13,14Sildenafil (Revatio) is indicated for the treatment of PAH to improve exercise ability in classes II and III.13 It is administered orally 3 times daily, and has a half-life of 3 to 5 hours. Because this drug is metabolized hepatically, health care providers should be cautious about drug interactions. When sildenafil is used with other vasodilating agents, severe hypotension can occur. In patients taking sildenafil, for whom nitrate administration is deemed medically necessary, at least 24 hours should elapse after the last dose of sildenafil before nitrate administration is considered.13Tadalafil (Adcirca) is indicated for the treatment of PAH to improve exercise capacity in classes II and III.14 It is administered once daily, and has a half-life of 17.5 hours. Tadalafil is well tolerated. The most common adverse effects are headaches, myalgias, and flushing. Organic nitrates should be avoided in patients taking tadalafil. In patients taking tadalafil, for whom nitrate administration is deemed medically necessary, at least 48 hours should elapse after the last dose of tadalafil before nitrate administration is considered.14Prostacyclin is produced in endothelial cells. It acts as a potent vasodilator and inhibits platelet aggregation. In the vascular smooth muscle, it causes dilation and prohibits cell proliferation. Three prostacyclin analogues are used in the treatment of PAH: epoprostenol, treprostinil, and iloprost. In general, these agents are used in combination with other PAH therapies for the treatment of more severe cases of PAH.Epoprostenol is indicated for the treatment of PAH to improve exercise capacity in patients with class III and IV symptoms and causes. Epoprostenol has a very short half-life, less than 3 minutes; therefore, it must be administered via continuous infusion. Some forms of epoprostenol, such as Flolan, are unstable at room temperature and must be kept cold (36° F to 46° F) during infusion. Veletri, a newer formulation, is stable at room temperature.15,16 Patient education is a crucial component to therapy, and home health services are often necessary for long-term use. Abrupt discontinuation of epoprostenol should be avoided, as it can lead to life-threatening deterioration of PAH.15,16Treprostinil (Remodulin) is indicated for the treatment of PAH to improve exercise capacity in classes II to IV.17,18 It has a longer half-life than epoprostenol, 2 to 4 hours, and is available as an intravenous, subcutaneous, or inhaled formulation. The intravenous and subcutaneous forms of treprostinil are stable at room temperature and are delivered continuously.17 The subcutaneous administration is associated with less risk of infection because treprostinil is not administered through a central catheter, but administration via this route is very painful and may affect patient compliance. Other adverse effects include jaw pain, diarrhea, and edema.17 Treprostinil inhalation (Tyvaso) is indicated to improve exercise ability in patients with PAH. Tyvaso is given in 4 treatment sessions, approximately 4 hours apart, while the patient is awake. Initial dosing is 3 inhalations per treatment session and is increased to a target dose of 9 inhalations per treatment session as tolerated. The most common adverse reactions are cough, headache, nausea, dizziness, flushing, throat irritation, pharyngolaryngeal pain, and diarrhea.18Iloprost (Ventavis) is indicated for the treatment of PAH to improve exercise tolerance, reduce symptoms, and prevent deterioration in classes III and IV. It has a half-life of 20 to 30 minutes and is administered via inhalation 6 to 9 times daily while the patient is awake. Although this inhaled medication carries less risk of infection and avoids painful injections, patients have difficulty with compliance. Adherence becomes a challenge because of the “9 times a day” dosing.19Combination therapy is the use of 1 or more PAH treatments to produce a more proficient or additive effect. With the complex nature of PAH, it is only logical that patients would benefit from the use of combination therapy. Despite the short- and long-term benefits of approved therapies, many patients die or remain severely symptomatic from PAH on monotherapy. These limitations have formed the basis for combination therapy. The benefit of combining therapies is the ability to target the different pathological pathways in PAH and improve efficacy of treatment.27 Patients commonly are initiated on monotherapy, with additional agents added as symptoms progress.Three new agents for the treatment of PAH have become available in the last year. The first, riociguat (Adempas), is a stimulator of soluble guanylate cyclase, an enzyme in the cardiopulmonary system and receptor for nitric oxide. When bound to nitric oxide, it works by stimulating the signaling molecule cyclic guanosine monophosphate, which plays an important role in regulating processes that influence vascular tone, proliferation, fibrosis, and inflammation. Riociguat is the first drug in this class with an approved indication for treatment of PH and is indicated to improve exercise capacity and activity level in patients with persistent recurrent or chronic thromboembolic PH after surgical treatment or if surgery is not an option.20 The recommended starting dosage of riociguat is 1 mg orally taken 3 times daily, but therapy may be initiated at 0.5 mg 3 times daily if the patient is unlikely to tolerate the drug’s hypotensive effects. Doses may be increased in 0.5-mg increments up to a maximum of 2.5 mg taken 3 times daily, if tolerated. At least 2 weeks should lapse between dose increases. Dosage levels greater than 2.5 mg 3 times daily may be considered, if tolerated, for patients who smoke. A lower dose may be required if a patient quits smoking. In clinical trials, the most common adverse events reported were headache, dizziness, gastrointestinal symptoms, and anemia.20 An REMS program has been developed for all women who take the drug (Table 4).The second therapy is macitentan (Opsumit), a dual endothelin receptor antagonist. It is indicated to delay progression of PAH. Studies establishing effectiveness included predominantly patients with functional classes II and III.21 The recommended dosage is 10 mg once daily. Because macitentan is a category X drug, it also carries an REMS program for women and a black box warning for clinicians to exclude the possibility of pregnancy in female patients before therapy begins, monthly during treatment, and 1 month after treatment stops. Instruction also is given for clinicians to obtain liver-enzyme tests and hemoglobin levels for patients before initiating therapy and thereafter “as clinically indicated.” In clinical trials, the most common adverse events reported were nasopharyngitis, pharyngitis, headache, anemia, bronchitis, urinary tract infection, and influenza.21The third therapy is an oral form of treprostinil (Orenitram). As the first orally approved prostacyclin analogue, Orenitram is approved for the treatment of PAH to improve exercise capacity. Available in 4 strengths, 0.125 mg, 0.25 mg, 1 mg, and 2.5 mg, Orenitram is initially dosed at 0.25 mg twice daily with food and is increased as tolerated in increments of 0.25 mg to 0.5 mg every 3–4 days until optimal response is achieved. The total daily also can be given up to three times daily if response is not achieved with twice daily dosing. Doses are increased on the basis of tolerability to achieve optimal response. Maximum dose is determined by patient tolerability. In clinical trials, the most common adverse effects included headache, nausea, and diarrhea. The use of Orenitram is contraindicated in patients with severe hepatic impairment and should be avoided in patients who consume alcohol, because it can increase the rate at which the drug is released from the tablet.22Adjunctive therapies are frequently prescribed for patients with PAH to reduce symptoms and treat comorbidities associated with the disease. Besides studies on the use of anticoagulation, the literature surrounding adjunctive therapy is underwhelming, with few clinical trials to support practices. The evidence is based mainly on prospective observation studies and case reports. Common adjunctive therapies include anticoagulation, diuretics, and inotropes.7,8,28Patients with PAH are at increased risk for thrombosis. The American College of Chest Physicians recommends anticoagulation in patients with more advanced disease, such as those being treated with continuous intravenous therapy, in the absence of contraindications, to prevent pulmonary embolus or stroke.7,8 Improvement in survival rate has been observed when warfarin at an international normalized ratio goal of 1.5 to 2.5 was used.28Diuretic therapy often is prescribed in patients with right-sided heart failure who experience volume overload, providing symptomatic relief from edema and shortness of breath. Most commonly loop diuretics (furosemide and bumetanide) are prescribed. Patients being treated with diuretic therapy should be monitored for fluid and electrolyte imbalances.7,8In addition to volume overload, patients with PAH have decreased myocardial contractility and may be treated with digoxin. Digoxin may offer some benefit in preserving right ventricle contractility, reducing circulating catecholamines, and increasing resting cardiac output. The decision to initiate digoxin therapy is based on clinical judgment, as long-term data on effects of treatment are lacking.7,8Although PAH has no cure, current available treatments have led to considerable improvements in symptoms and outcomes for these patients. Early diagnosis is important in improving outcomes in this patient population. Understanding the mechanism of disease, coordinating care, initiating appropriate therapy, and improving the patient’s quality of life remain the top priorities in the treatment of PAH.
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Feb 29, 2024
Philippe Rola + 4