Pulmonary Arterial Hypertension 

Updated: Apr 25, 2018
Author: Kristin E Schwab, MD; Chief Editor: Zab Mosenifar, MD, FACP, FCCP 

Overview

Background

Pulmonary hypertension, defined as a mean pulmonary arterial pressure greater than 25 mm Hg at rest or greater than 30 mm Hg during exercise, is often characterized by a progressive and sustained increase in pulmonary vascular resistance that eventually may lead to right ventricular failure. It can be a life-threatening condition if untreated. Therapy for pulmonary hypertension is targeted at the underlying cause and its effects on the cardiovascular system, with success rates varying according to the etiology. Novel therapeutic agents, such as prostacyclin and others undergoing clinical trials, have led to the possibility of specific therapies for these once untreatable disorders.

The World Health Organization (WHO) has divided pulmonary hypertension into five groups on the basis of similarities in pathophysiology, clinical presentation, and therapeutic options.[1] These groups include the following:

  • Group 1 - Pulmonary arterial hypertension (PAH)
  • Group 2 - Pulmonary hypertension due to left-sided heart disease
  • Group 3 - Pulmonary hypertension due to lung diseases and/or hypoxia
  • Group 4 - Chronic thromboembolic pulmonary hypertension (CTEPH)
  • Group 5 - Pulmonary hypertension with unclear or multifactorial etiologies, including hematologic disorders (eg, myeloproliferative disorders), systemic disorders (eg, sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis), metabolic disorders (eg, glycogen storage disease, Gaucher disease, thyroid disorders), and miscellaneous conditions (eg, tumor obstruction, mediastinal fibrosis, chronic renal failure on dialysis)

Recognition of fetal causes and developmental abnormalities has also led to a pediatric-specific classification.[2]

This review focuses on group 1 pulmonary hypertension, which is also referred to as pulmonary arterial hypertension.

Note the gross pathology images of PAH below.

Gross pathology on patient who died of severe pulm Gross pathology on patient who died of severe pulmonary arterial hypertension secondary to persistent patent ductus arteriosus.
Close-up view of gross pathology on patient who di Close-up view of gross pathology on patient who died of severe arterial pulmonary hypertension secondary to persistent patent ductus arteriosus.

For patient education resources, see the Lung and Airway Center.

Pathophysiology

Increased pulmonary vascular resistance is the main pathogenic mechanism in pulmonary arterial hypertension (PAH). This is typically due to vasoconstriction, remodeling, and thrombosis of the small pulmonary arteries and arterioles.[3]  

On pathology, patients with PAH are found to have hyperplasia and hypertrophy of the intima, media, and adventitia of the pulmonary arterial vasculature. On the molecular level, this is related to endothelial dysfunction, which leads to disorganized endothelial cell proliferation, decreased production of vasodilators such as prostacyclin and nitric oxide, and overexpression of vasoconstrictors like endothelin. These pathophysiologic mechanisms are particularly important as they guide the therapeutic targets of pharmacotherapies for advanced PAH disease.

Etiology

Pulmonary arterial hypertension (PAH) can be further divided into the following subgroups:

  • Subgroup 1 - Idiopathic PAH (IPAH)
  • Subgroup 2 - Heritable PAH, including those with BMPR2 and ALK2 gene mutations
  • Subgroup 3 - Drug- and toxin-induced PAH (Aminorex, fenfluramine derivatives, and toxic rapeseed oil have been identified as definite risk factors for PAH. [1] Other drugs implicated as possible risk factors for PAH include amphetamine and amphetamine derivatives, cocaine, L-tryptophan, phenylpropanolamine, St. John’s wort, leflunomide, phentermine, mazindol, dasatinib, and interferon.)
  • Subgroup 4 - Conditions with known localization of lesions in the small pulmonary arterioles, which include (1) collagen-vascular disease (scleroderma/ CREST syndrome), (2) congenital left-to-right shunts, (3) portopulmonary hypertension, (4) HIV-associated pulmonary hypertension, and (5) schistosomiasis

Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis have been designated as 1’ to reflect the fact that although related, they are clinicopathologically and therapeutically distinct entities from PAH (ref 62)

Of note, while persistent pulmonary hypertension of the newborn was previously classified under group 1 PAH, the 2013 classification schema removed this from group 1 to better reflect the differences between this and other PAH subgroups. The updated schema also moved chronic hemolytic anemia from group 1 to group 5 pulmonary hypertension.[4]

Epidemiology

The overall prevalence of pulmonary arterial hypertension (PAH) is difficult to determine given the disease’s heterogeneity and likely underdiagnosis.

Worldwide, schistosomiasis is likely the most prevalent cause of PAH,[5] with studies suggesting that over 7% of patients with hepatosplenic schistosomiasis have pulmonary hypertension.[6, 7] However, data registries in countries most burdened by schistosomiasis-related PAH are limited.[5]

Data registries in areas without endemic schistosomiasis such as the United States and Europe report a PAH prevalence ranging from 6.6-26 cases per million adults.[8] The majority of these cases are idiopathic. While approximately 10% are classified as heritable, it is likely that this number will increase with time as genetic testing becomes more widespread.

Studies have also estimated the prevalence of specific subgroups of PAH. An observational study of 277 patients with HIV infection found that 0.46% of patients had pulmonary hypertension.[9] In comparison with prior studies,[10] no change in prevalence rate was seen with modern highly active antiretroviral treatment (HAART). In scleroderma patients, the incidence has been estimated to be 6-60% of all patients, with the variance based on the extent of disease.[11]

Women are more likely to have PAH, with registries reporting a 65-80% female predominance of the disease.[8] Interestingly, while prior studies suggested a mean age of diagnosis in the thirties, current registries suggest a mean age of diagnosis in the fifties.[8] Although PAH can affect all races, data from the US REVEAL registry suggest a white predominance (73% white vs 12% African American, 9% Latino, and 3% Asian).[12]  

Prognosis

The prognosis of patients with pulmonary arterial hypertension (PAH) is variable and depends on the etiology, severity, and treatment.

US registry data suggest a 5-year survival rate of 57% without treatment (from the time of diagnostic right-sided heart catheterization).[13] Risk score calculators for patients with newly diagnosed PAH are available and validated.[13, 14] In general, male sex, age older than 50 years, worse WHO functional status, and right ventricular dysfunction confer a worse prognosis. For example, patients with right-sided heart failure survive approximately 1 year without treatment.

Important to note is that longitudinal trends suggest that survival in patients with PAH has improved. Since the introduction of advanced pharmacotherapies, scleroderma-associated PAH, for example, has seen an improved prognosis.[15] Overall, although, etiology remains important for prognostication, patients with PAH secondary to connective-tissue disease, portal hypertension, and familial causes tend to have worse survival than patients with other etiologies of PAH.

 

Presentation

History

The clinical manifestations of pulmonary arterial hypertension (PAH) are frequently masked by the underlying disease entities. Obtaining a careful history may help differentiate PAH from groups 2-5 pulmonary hypertension. Important clues to a specific cause include the following:

  • History of heart murmur
  • Deep venous thrombosis (DVT) or pulmonary embolism (PE)
  • Arthritis or arthralgias
  • Rash
  • Heavy alcohol consumption
  • Hepatitis
  • Heavy snoring
  • Daytime hypersomnolence
  • Morning headaches
  • Morbid obesity
  • Family history of pulmonary hypertension
  • Drug use, in particularly diet drugs and illicit drugs
  • Medications

Patients with PAH may also have nonspecific symptoms secondary to pulmonary hypertension. These may include the following:

  • Dyspnea upon exertion
  • Fatigue
  • Lethargy
  • Syncope with exertion
  • Chest pain
  • Anorexia
  • Right upper quadrant pain

Less common symptoms include the following:

  • Cough
  • Hemoptysis
  • Hoarseness (due to compression of the recurrent laryngeal nerve by the distended pulmonary artery)

Physical Examination

The intensity of the pulmonic component of the second heart sound (P2) may be increased and the P2 may demonstrate fixed or paradoxic splitting. A systolic ejection murmur may be heard over the left sternal border. The murmur may be augmented by inspiration. A right ventricular heave may be palpated.

A prominent A wave may be observed in the jugular venous pulse. A right-sided fourth heart sound (S4) with a left parasternal heave may be auscultated.

Right ventricular failure leads to systemic venous hypertension and cor pulmonale. The signs of right ventricular failure include a high-pitched systolic murmur of tricuspid regurgitation, hepatomegaly, a pulsatile liver, ascites, and peripheral edema. In this scenario, a right ventricular third heart (S3) sound is also heard.

Signs of underlying cardiac, pulmonary, hepatic, or collagen-vascular disease are often present.

Patients with pulmonary arterial hypertension (PAH) often develop cor pulmonale, which further worsens hypoxemia and perpetuates pulmonary hypertension.

Complications

The most common—and feared—complication from pulmonary hypertension is right-sided heart failure. Progression to right-sided heart failure is part of the natural history of pulmonary arterial hypertension (PAH), and it is often present to some degree at the time of diagnosis. Registry and institutional data further implicate this as the most common cause of death in PAH patients, with data suggesting that 44-73% of PAH patients who die do so because of right-sided heart failure or sudden cardiac death.[16, 17]

In addition to right-sided heart failure, other causes of death include complications that arise because of dilatation of the pulmonary artery. These include pulmonary artery dissection and rupture, massive hemoptysis, and left main compression syndrome, where the left main coronary artery is compressed by the pulmonary artery trunk.[18] Hemoptysis is often secondary to a bronchial arterial source, as hypoxic vasoconstriction in the pulmonary arteries leads to collateralization and proliferation of the bronchial arteries. Supraventricular and, less commonly ventricular, arrhythmias may also occur, presumably triggered by right-sided heart disease.

 

DDx

 

Workup

Approach Considerations

Findings from the history, physical examination, chest radiography, and electrocardiography (ECG) may suggest the presence of pulmonary hypertension and right ventricular dysfunction. Two-dimensional transthoracic echocardiography (TTE) with Doppler analysis should be used as an initial screening measure to estimate the pulmonary artery pressure and assess ventricular function.

Right-sided cardiac catheterization is recommended as the confirmatory test for pulmonary hypertension. This can also be useful for assessment of the reversibility of pulmonary arterial hypertension (PAH) with vasodilatory therapy.

Further studies should then be performed to assess for the etiology of the pulmonary hypertension, as the etiology determines treatment options and prognosis. PAH is a diagnosis of exclusion, and so it is imperative that the practitioner first assess for WHO groups 2-5 pulmonary hypertension. Given this, European guidelines recommend first evaluating for significant group 2 or 3 disease by ordering a TTE, pulmonary function tests with arterial blood gas assessment, and chest imaging.[19]

If this workup is unrevealing, patients should then undergo ventilation-perfusion lung scanning to assess for group 4 disease. If defects are present, pulmonary angiography or spiral CT should be performed. This is crucial in all patients suspected of having PAH, as chronic thromboembolic pulmonary hypertension (CTEPH) is often curable by surgical endarterectomy.

Patients should also be screened clinically for possible nocturnal desaturation and obstructive sleep apnea.

Finally, laboratory studies should be performed in the appropriate clinical scenarios to evaluate for causes of WHO group 1 disease, or PAH. 

Laboratory Studies

A complete blood (CBC) count, biochemistry panel, prothrombin time (PT), and activated partial thromboplastin time (aPTT) should be obtained at baseline. Arterial blood gas determinations should be performed to assess for hypoxemia.

Collagen-vascular disease screening can be performed by measuring antinuclear antibody (ANA) levels, as well as checking for rheumatoid factor (RF) and antineutrophil cytoplasmic antibody (ANCA). When there is clinical suspicion for scleroderma, anti-Scl-70, anticentromere, and anti-U1-RNP antibodies can also be checked.

Liver function tests, as well as markers of synthetic function (ie, albumin, international normalized ratio [INR]), and platelet levels may indicate liver disease and/or portal hypertension.

Brain natriuretic peptide (BNP of NT-proBNP) should be performed on appropriate patients.

HIV testing, hepatitis serology tests, and urine toxicology screening should also be considered.

In patients at risk for heritable pulmonary arterial hypertension (PAH), screening for gene mutations such as BMPR2 also may be considered.

Iron studies may also be indicated in at risk patients with PAH, as a study by Soon et al found a high prevalence of iron deficiency in patients with PAH.[20] It was found to be significantly more common in patients with idiopathic PAH (IPAH) than in those with CTEPH.

Chest Radiography and Computed Tomography

The classic finding on a chest radiograph from a patient with pulmonary arterial hypertension (PAH) is enlargement of central pulmonary arteries, attenuation of peripheral vessels, and oligemic lung fields (see the first and second images below). Findings of right ventricular (diminished retrosternal airspace) and right atrial dilatation (prominent right-sided heart border) are possible. Abnormalities may be followed up with a CT scan of the chest (see the third image below).

Chest radiograph of patient with nonidiopathic pul Chest radiograph of patient with nonidiopathic pulmonary hypertension shows enlarged pulmonary arteries. This patient had atrial septal defect.
A 34-year-old woman with history of scleroderma (C A 34-year-old woman with history of scleroderma (CREST variety—ie, calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia) developed dyspnea that worsened upon exertion. The patient was found to have severe pulmonary arterial hypertension.
A 34-year-old woman with history of scleroderma (C A 34-year-old woman with history of scleroderma (CREST variety—ie, calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia) developed dyspnea that worsened upon exertion. The patient was found to have severe pulmonary arterial hypertension.
A 34-year-old woman with history of scleroderma (C A 34-year-old woman with history of scleroderma (CREST variety—ie, calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia) developed dyspnea that worsened on exertion. A CT pulmonary angiogram showed a massively enlarged pulmonary artery.

Cardiac Studies

Electrocardiography

On ECG, signs of right ventricular hypertrophy or strain may be observed. These include right-sided axis deviation, an R-to-S wave ratio greater than 1 in lead V1, increased P-wave amplitude, and an incomplete or complete right bundle-branch block pattern.

Echocardiography

Two-dimensional echocardiography

Echocardiography is generally used to screen patients for pulmonary hypertension. It is also used to rule out left ventricular and valvular dysfunction.

On two-dimensional echocardiography, signs of chronic right ventricular pressure overload are present, including increased thickness of the right ventricle and paradoxical bulging of the septum into the left ventricle during systole. In later stages, right ventricular dilatation occurs, leading to right ventricular hypokinesis. Right atrial dilatation, septal flattening, tricuspid regurgitation, pulmonic insufficiency, and midsystolic closure of the pulmonic valve may develop.

Doppler echocardiography

Doppler echocardiography is the most reliable noninvasive method of estimating pulmonary arterial pressure.

Tricuspid regurgitation is usually present in patients with pulmonary arterial hypertension (PAH), which facilitates measurement of pulmonary arterial pressure with the modified Bernoulli equation. The efficacy of Doppler echocardiography depends on the ability to locate the tricuspid regurgitant jet. Furthermore, acoustic windows may be limited in patients who have other diseases (eg, chronic obstructive pulmonary disease [COPD]) or in those who are obese.

Tricuspid regurgitation is generally detected in more than 90% of patients with severe pulmonary hypertension, and a correlation of greater than 95% is observed when the pressure is measured by means of catheterization. Doppler echocardiography is a useful noninvasive test for long-term follow-up.

Visual inspection of the shape of the right ventricular Doppler flow velocity envelope provides insight into the hemodynamic basis of PAH.[21] Midsystolic notch was associated with the most severe pulmonary vascular disease and right-sided heart dysfunction.

Ventilation-Perfusion Lung Scanning

Ventilation-perfusion scanning should be performed to exclude CTEPH. A high- or low-probability scan result is most useful, whereas intermediate-probability results should lead to the performance of pulmonary angiography.

Diffuse mottled perfusion can be observed in patients with pulmonary arterial hypertension (PAH), as opposed to the segmental or subsegmental mismatched defects observed in patients with CTEPH (see the image below).

Ventilation-perfusion scan of bilateral mismatched Ventilation-perfusion scan of bilateral mismatched segmental and subsegmental defects, suggesting chronic thromboembolic hypertension.

Pulmonary Function Testing

Pulmonary function tests (ie, spirometry and diffusing capacity for carbon monoxide) should be performed in patients with pulmonary hypertension to exclude an underlying pulmonary disorder. Diffusing capacity is universally reduced in patients with pulmonary hypertension.

These tests may show an obstructive pattern suggestive of COPD or a restrictive pattern suggestive of an interstitial lung disease. Furthermore, the severity of the lung disorder may be established by pulmonary function test findings because these tests provide both qualitative and quantitative data.

Polysomnography

In patients with symptoms of suspected obstructive sleep apnea, polysomnography should be performed. Polysomnography may offer both diagnostic and therapeutic options for sleep-disordered breathing.

Right-Sided Cardiac Catheterization

Right-sided heart catheterization is the procedure of choice in the diagnosis, quantification, and characterization of pulmonary hypertension. Left-sided heart dysfunction and intracardiac shunts can be excluded, and the cardiac output can be measured.

The indications for right-sided cardiac catheterization are as follows:

  • Making a definitive diagnosis of pulmonary hypertension
  • Measuring pulmonary pressures accurately (ie, when there is difficulty in measuring pulmonary pressures with Doppler echocardiography)
  • Conducting a vasoreactivity test for assessment of the acute response to vasodilators.

Vasoreactivity testing is indicated in patients with hereditary, idiopathic, and anorexigen-induced PAH.[22] Acute vasoreactivity is determined by administering a short-acting vasodilator such as prostacyclin, inhaled nitric oxide, or adenosine. A positive vasoreactivity test requires that multiple conditions are met, such that (1) a decrease in mean pulmonary artery pressure of at least 10 mm Hg, (2) to a value less than 40 mm Hg, and (3) without a concurrent decrease in carbon monoxide or blood pressure

An acute response often predicts a beneficial effect from oral agents, such as calcium channel blockers.[23]

Histologic Findings

The histopathologic lesions in patients with pulmonary arterial hypertension (PAH) are the result of long-standing pulmonary hypertension rather than a consequence of different causes.

The plexiform lesion is observed in patients with all types of PAH. These lesions consist of medial hypertrophy, eccentric or concentric laminar intimal proliferation and fibrosis, fibrinoid degeneration, and thrombotic lesions. Fresh or organized and recanalized thrombi may also be present. Diverse types of intimal and muscular lesions of the small muscular arteries may cause the clinical syndrome of PAH, and a plexiform lesion reflecting the abrupt onset of PAH is likely, rather than the lesion being a distinctive cause.

Staging

On the basis of information adapted from the executive summary of the world symposium on Primary Pulmonary Hypertension in Evian, France, in 1998, pulmonary hypertension may be divided into the following functional classes:

  • Class I: These are patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near-syncope in patients.
  • Class II: These are patients with pulmonary hypertension resulting in slight limitation of physical activity. The patients are comfortable at rest, but ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near-syncope.
  • Class III: These are patients with pulmonary hypertension resulting in marked limitation of physical activity. Patients are comfortable at rest, but even less-than-ordinary activity causes undue dyspnea or fatigue, chest pain, or near-syncope.
  • Class IV: These are patients with pulmonary hypertension who are unable to perform any physical activity without symptoms. These patients manifest signs of right-sided heart failure, dyspnea or fatigue may even be present at rest, and discomfort is increased by any physical activity.
 

Treatment

Approach Considerations

Management of pulmonary arterial hypertension (PAH) is multifaceted and consists of supportive therapy as well as advanced vasodilatory therapy. Effective therapy should be instituted in the early stages, before irreversible changes in pulmonary vasculature occur.

Supportive therapy includes oxygen therapy, diuretics, digoxin, exercise, and anticoagulation. Decisions regarding starting each of these therapies should be made on a patient-by-patient basis in the appropriate clinical scenario. These therapies are not specific to PAH and are frequently used in all WHO groups of pulmonary hypertension.

In contrast, advanced vasodilatory therapies are largely confined to cases of PAH. Guidelines recommend against using these advanced therapies in cases of pulmonary hypertension from left-sided heart disease or pulmonary disease, and initiation of these should be in specialized centers and by providers well experienced in treating PAH.[24] Since the WHO group 1 classification, multiple advanced vasoactive therapies have become available to treat the prostacyclin, endothelin, and nitric oxide/cyclic guanosine monophosphate (cGMP) pathways. Research is ongoing with new medications continually in the pipeline, with the hope that these new therapies may halt or reverse disease progression.[25]

The CHEST guideline, based on reviews of English-language literature published between 1990 and 2013 using the MedLine and the Cochrane databases, concluded that current pharmacotherapy for PAH should be based on high-level recommendations, but further study is needed to address gaps in such evidence-based information.[26]

Oxygen Supplementation

Oxygen has proved beneficial for reducing patient mortality in selected patients with pulmonary hypertension. Two large trials demonstrated a definite mortality benefit for patients with WHO group 3 pulmonary hypertension secondary to chronic obstructive pulmonary disease (COPD). Although long-term study results are not available for other WHO groups, it appears that oxygen administration likely benefits these other groups as well. Accordingly, long-term oxygen therapy should be prescribed for patients whose arterial oxygen tension (PaO2) is lower than 55 mm Hg at rest from any cause, those who have desaturation during exercise, and those who perform better on oxygen therapy.

Medicare indications for continuous long-term oxygen therapy include the following:

  • PaO 2 of 55 mm Hg or less, or oxygen saturation (SaO 2) of 88% or less
  • PaO 2 of 56-59 mm Hg or SaO 2 of 89%, in the presence of evidence of cor pulmonale, right-sided heart failure, or erythrocytosis (hematocrit >55%).

Preventive Care

To decrease the risk of developing pneumonia (which has been found to be the cause of death in 7% of patients with pulmonary arterial hypertension [PAH]), patients should receive vaccinations against influenza and pneumococcal pneumonia.[19]

Given the high mortality rate associated with pregnancy in patients with PAH, females of childbearing age should be offered birth control and counseled extensively about pregnancy.

Pharmacologic Therapy

Diuretics

Although no randomized controlled trials have evaluated diuretics for pulmonary arterial hypertension (PAH), practitioners frequently use these based on their clear value for fluid removal in patients with evidence of right-sided heart volume overload. Loop diuretics such as furosemide and bumetanide are first line, with aldosterone antagonists sometimes considered as adjunctive agents.

Diuretics are indicated in patients with PAH who have signs of right-sided heart volume overload, as evidenced by lower extremity edema, ascites, hepatic congestion, or elevated jugular venous pressure. As patients with right-sided heart failure are preload dependent, however, caution must be used. Hypovolemia should be avoided, as this can lead to a drop in cardiac output and hemodynamic compromise.

Digoxin

Digoxin is primarily used in PAH patients who have atrial tachyarrhythmias. Although its inotropic properties have been shown to be useful in acutely improving cardiac output in certain PAH patients, its long-term effects are unknown.[19] For this reason, its main indication remains slowing the ventricular rate in patients prone to arrhythmias.

Anticoagulants

Anticoagulation (specifically, with warfarin) may be helpful because evidence suggests that patients with idiopathic PAH (IPAH) develop thrombotic arteriopathy (with abnormalities of blood coagulation factors, antithrombotic factors, and the fibrinolytic system).[27] This contributes to a prothrombotic state. In a review of seven observational studies evaluating anticoagulation in IPAH, five demonstrated a mortality benefit.[28] Evidence also suggests a benefit for anticoagulation in patients with hereditary PAH, anorexigen-induced PAH, and pulmonary venoocclusive disease (PVOD). However, evidence in other forms of PAH is lacking, and decisions regarding anticoagulation in these cases should be made on a patient-by-patient basis after weighing the risks and benefits of anticoagulant therapy. Given limited experience with the novel oral anticoagulants such as dabigatran, rivaroxaban, and apixaban in PAH, warfarin remains the anticoagulant of choice.[19]

Specific drug therapy

Advanced therapies should be considered after right-sided heart catheterization for PAH patients in functional class II, III, or IV. Patients with IPAH, heritable PAH, or anorexigen-induced PAH should undergo a vasoreactivity test as these patients may be candidates for calcium channel blockers (per below). Of note, even in this subset of patients, only a small minority of patients are vasoreactive and thus candidates for calcium channel blocker therapy.

Therefore, for the majority of PAH patients, treatment requires initiation of one or more of the advanced vasodilatory therapies. At present, three main classes of therapy exist, with each targeting a separate pathophysiologic arm, as follows:

  • Endothelin receptor antagonists (ambrisentan, bosentan, and macitentan): Activation of the endothelin system causes increased levels of the vasoconstrictor endothelin-1 in PAH patients. These agents act to antagonize this pathway.
  • Phosphodiesterase-5 (PDE-5) inhibitors (sildenafil, tadalafil, vardenafil) and guanylate cyclase stimulators (riociguat): Cyclic guanosine monophosphate (cGMP) results in vasodilation through the nitric oxide/cGMP pathway, and PDE-5 is responsible for degrading cGMP. PDE-5 inhibitors thus prevent this degradation
  • Prostacyclin analogues (beraprost, epoprostenol, iloprost, treprostinil) and prostacyclin receptor agonists (selexipag): Prostacyclin is a potent vasodilator, and dysregulation of prostacyclin synthesis metabolism has been identified in PAH patients.

For patients with WHO functional class II or III disease, experts often begin with a combination of two oral agents targeting separate pathways. The combination of ambrisentan and tadalafil is the most frequently used combination and was approved as first-line treatment by the US Food and Drug Administration (FDA) in October 2015 based on the AMBITION trial.[29] The trial involved 605 patients with WHO functional class II or III PAH. Patients were randomly assigned to receive once-daily ambrisentan plus tadalafil or to either drug alone. Doses were titrated from 5-10 mg/day for ambrisentan and from 20-40 mg/day for tadalafil. Treatment with the combination was associated with an approximately 50% reduction in risk for clinical failure compared with either drug alone (P = .0002), with improved exercise ability as well as decreased disease progression and hospitalization.[29]

Other trials have looked at other combinations as well. In a controlled study of 25 patients with IPAH and scleroderma-associated PAH in whom monotherapy with bosentan had failed and sildenafil was added, a significant improvement in WHO functional status and exercise capacity was observed in patients with IPAH but not in the patients with scleroderma-associated PAH.[30] In another controlled trial, sildenafil 80 mg was added to an intravenous epoprostenol regimen, and the combination proved to be more effective than placebo for improving exercise capacity and pulmonary arterial pressure.[31] It also demonstrated a significant reduction in the number of patients showing clinical worsening and an improvement of survival among the patients with the most severe disease.

Patients with WHO functional class IV disease are typically started on parenteral prostanoid therapy.

For patients who progress or are poorly responsive to initial therapy, practitioners typically add agents from a different class. Agents within the same class (including PDE-5 inhibitors and guanylate cyclase stimulators) should not be used together.

For more details on the specifics of agents within these classes, see the Medication.

Balloon Atrial Septostomy

Balloon atrial septostomy involves creation of an atrial right-to-left shunt by graded balloon dilation of the atrial septum. The technique has been performed via a femoral catheter, with a Brockenbrough septal needle and Mansfield balloons to dilate the septostomy.

This has been used with success in carefully selected patients who are symptomatic despite maximal medical therapy. The benefit (improved exercise function) occurs at the cost of a fall in arterial SaO2. Important to note is that this should only be regarded as a palliative or bridging procedure (prior to transplantation) and is not part of the recommended pulmonary arterial hypertension (PAH) treatment guidelines at this time.

Lung Transplantation

Although lung transplantation is reserved for patients with severe pulmonary arterial hypertension (PAH), a number of patients have undergone successful transplantation at several centers. These patients had PAH due to collagen-vascular disease, drug-induced PAH, or pulmonary veno-occlusive disease (PVOD). The stability of the underlying causative disorder and the ability of the patient to tolerate an extensive operation are prerequisites. Heart-lung transplantation has been performed in patients with PAH due to congenital cardiac disease or severe left ventricular dysfunction.[32]

Although lung transplantation has historically been the treatment of choice for severe PAH, at present it is typically needed only for patients who are still in New York Heart Association (NYHA) functional class IV after 3 months of therapy with epoprostenol. The long-term outcomes of lung transplantation remain disappointing, with 50% survival at 5 years.

Consultations

Patients with pulmonary arterial hypertension (PAH) should be seen at a center that specializes in pulmonary hypertension treatment. This is particularly important prior to the initiation of advanced vasodilatory therapies. Referral to a lung transplantation center is recommended for patients who require maximal medical therapy (ie, triple vasodilator therapy).[22]

Diet

While no specific guidelines exist, patients with pulmonary arterial hypertension (PAH) should generally follow a low-sodium diet to minimize excessive fluid retention.

Activity

Guidelines recommend that patients with pulmonary arterial hypertension (PAH) remain active, although they should avoid excessive activity that precipitates symptoms. Supervised exercise rehabilitation should also be recommended to deconditioned patients, as this has been shown to increase functional capacity and quality of life.[33]

Prevention

The majority of cases of pulmonary arterial hypertension (PAH) are not preventable. Patients should avoid using anorexigen drugs as well as illicit stimulant drugs such as amphetamine-derivatives and cocaine. To minimize potential contributions from WHO group 3 disease, patients should not smoke. Those with obstructive sleep apnea or other lung disease should be optimally treated for these diseases to avoid further insults from hypoxemia/chronic pulmonary disease.

Long-Term Monitoring

Once a diagnosis of pulmonary arterial hypertension (PAH) has been made, patients should be evaluated at regular intervals by a PAH specialist. Medical assessment including 6-minute walk distance (6MWD) testing should be performed at least twice a year to assess for a decline in functional status.[22] Transthoracic echocardiography is often performed on at least an annual basis as well, with right-sided heart catheterization undertaken for patients who have a change in clinical status.

 

Guidelines

 

Medication

Medication Summary

Although treatment of pulmonary arterial hypertension (PAH) consists primarily of that necessary for the underlying disease, several medications are used in different clinical settings, as is oxygen supplementation. Currently, definite proof of effectiveness is lacking for several of these treatments.

Calcium channel blockers

Calcium channel blockers (CCBs) have been evaluated primarily in patients with idiopathic pulmonary arterial hypertension (IPAH).[34, 35] In a controlled study of 70 patients treated with these agents, approximately 50% maintained actual long-term New York Heart Association (NYHA) functional class improvement at 1 year, without the need for another treatment.[35] The most commonly observed adverse effects of these agents are systemic hypotension and lower-extremity edema. In one study, 10-14% of patients with IPAH were seen to develop Raynaud syndrome. CCBs act by inhibiting calcium ions from entering slow channels or select voltage-sensitive areas of vascular smooth muscle. CCBs may include nifedipine, diltiazem, and amlodipine.

Vasodilators

Prostacyclin analogues and agonists

Prostacyclin is a strong vasodilator of all vascular beds and a potent endogenous inhibitor of platelet aggregation. Platelet effects result from activation of intracellular adenylate cyclase and from increased cyclic adenosine monophosphate (cAMP) concentrations within platelets. Prostacyclin may decrease thrombogenesis and platelet clumping in the lungs by inhibiting platelet aggregation. These agents may include epoprostenol, treprostinil, iloprost, and selexipag.

Epoprostenol is a synthetic prostacyclin that is available only as an intravenous infusion. It induces relaxation of vascular smooth muscle and inhibits its growth and platelet aggregation through the increase in intracellular cyclic adenosine monophosphate (cAMP).[36, 37, 38] A prospective, randomized, open-label trial was conducted on 81 patients with PAH. After 12 weeks, epoprostenol therapy led to functional improvement, as shown by an improved 6-minute walk test and a decrease of 8% in mean pulmonary arterial pressure.[36] Intravenous epoprostenol improved exercise tolerance, hemodynamics, and long-term survival in another cohort of 178 patients with PAH, as compared with historical controls.[38] Another trial, in which a cohort of 162 patients was studied after 1 year of receiving epoprostenol therapy, confirmed that patients’ clinical function improved significantly, even though improvements in hemodynamic measures were modest. Improvement with epoprostenol has also been reported in patients who had PAH associated with congenital left-to-right cardiac shunts, portal hypertension, and HIV infection.[39] Of note, epoprostenol is also the only treatment that has shown a mortality reduction, although this was in a single randomized controlled trial.[36] Epoprostenol is administered only by continuous intravenous infusion via a portable infusion pump connected to a permanent catheter. Compared with other prostacyclin-based therapies, epoprostenol has a very short half-life (3-5 min) and is not stable at room temperature for more than 8 hours. Sudden drug interruption can thus be life-threatening. The dosage is determined during a dose-effect study performed in a catheterization laboratory or ICU. The selected dosage produces maximum vasodilation with minimum systemic hypotension. Common adverse effects of epoprostenol include jaw pain, headache, diarrhea, flushing, leg pain, and nausea, although these are generally mild and dose-related. Other complications include catheter-related sepsis, pump failure, or dislocation of the central venous catheter.

Treprostinil is a stable prostacyclin analogue that can be administered parenterally (Remodulin), as a continuous subcutaneous infusion delivered by a minipump (Remodulin), as an inhaled therapy (Tyvaso), or as an oral tablet (Orenitram). Treprostinil elicits direct vasodilation of pulmonary and systemic arterial vessels and inhibits platelet aggregation. Vasodilation reduces right and left ventricular afterload and increases cardiac output and stroke volume. A multicentric randomized trial evaluating treprostinil versus placebo over 12 weeks in 470 patients documented that patients with PAH had increases in 6-minute walk distances (6MWDs), dyspnea, and hemodynamic measurements.[40] A subsequent multicenter retrospective study of 122 patients with PAH or chronic thromboembolic pulmonary hypertension (CTEPH) treated over a 3-year period demonstrated significant improvement in long-term survival rates.[41] A randomized controlled trial by McLaughlin et al demonstrated the addition of inhaled treprostinil improved exercise capacity and quality of life among 212 patients with PAH, who remained symptomatic despite therapy with bosentan or sildenafil.[42] In December 2013, the FDA approved treprostinil extended-release tablets (Orenitram) for pulmonary arterial hypertension. The primary efficacy study, FREEDOM-M, demonstrated patients taking titrated treprostinil orally twice daily improved median 6MWD by +23 meters (P = .013) compared with placebo.[43] Two other phase 3 studies (FREEDOM-C and FREEDOM-C2) did not demonstrate a benefit in exercise with median 6MWD at week 16 (11 meters [P = .072] and 10 meters [P = .089], respectively).[44, 45] Adverse effects depend on the mode of administration (ie, infusion site pain is the most common adverse effect with the subcutaneous form), but are otherwise similar to epoprostenol. Compared with epoprostenol, treprostinil has gained more widespread use, largely because of its longer half-life and thus better safety profile.

Iloprost is a chemically synthetic analogue of prostacyclin that dilates systemic and pulmonary arterial vascular beds. It can be delivered through an inhaler by producing aerosol particles that deposit in the alveoli. It is indicated for patients with NYHA class III or IV symptoms to improve exercise tolerance and symptoms and to delay deterioration. A 12-week trial involving 203 patients showed an increase in patient scores on a 6-minute walk test and an improvement in NYHA functional class, as well as improved hemodynamics.[46] The long-term efficacy of inhaled iloprost remains disappointing because the only trials performed exhibited a high dropout rate and no improvement in survival compared with conventional therapy.[46, 47] Adverse effects include cough, hypotension, and syncope associated with vasodilation. Its disadvantage is its short duration of action. Therefore, it must be inhaled as many as six times a day.

Selexipag is the first prostacyclin agonist approved in the United States. It is available in tablet form. It selectively activates the prostacyclin receptor (ie, IP-receptor), one of five types of prostanoid receptors. Unlike prostacyclin analogs, selexipag is selective for the IP receptor over other prostanoid receptors (ie, EP1-4, DP, FP, TP). Activating the IP receptor induces vasodilation and inhibits proliferation of vascular smooth muscle cells. It was approved in December 2015 for adults with PAH to delay disease progression and reduce the risk of hospitalization. Approval of selexipag was based on the phase 3 GRIPHON study (n=1156). Results showed that selexipag decreased the risk of morbidity/mortality by 39% compared with placebo (P <.0001). Efficacy observed was consistent across the key subgroups (eg, age, sex, WHO functional class, PAH etiology, and background PAH therapy).[48, 49, 50] Adverse effects are similar to the other prostacyclins and include headache, diarrhea, nausea, flushing, muscle aches, and jaw pain. Although these are mostly mild, they are reported in the majority of patients.

Endothelin-receptor antagonists

Endothelin-1 exerts a direct vasoconstrictor effect, leads to the proliferation of vascular smooth muscle cells, and is a proinflammatory mediator. Its effects are mediated through the EtA and EtB endothelin receptors: the former mediate sustained vasoconstriction and proliferation of vascular smooth muscle cells, and the latter result in clearance of endothelin and induce production of nitric oxide and prostacyclin by endothelial cells. Endothelin-receptor antagonists competitively bind to the endothelin-1 receptors EtA and EtB, causing reductions in pulmonary arterial pressure, pulmonary vascular resistance, and mean right atrial pressure. Agents may include bosentan, ambrisentan, and macitentan.

Bosentan is an orally active dual (EtA/EtB) endothelin-receptor antagonist used to treat PAH.[51, 52, 53, 54] It inhibits vessel constriction and elevation of blood pressure by competitively binding to EtA and EtB receptors in endothelium and vascular smooth muscle. This leads to a significant increase in cardiac index associated with significant reductions in pulmonary arterial pressure, pulmonary vascular resistance, and mean right atrial pressure. The efficacy of oral bosentan in patients with PAH has been evaluated in multiple randomized controlled trials, including the BREATHE trials. It has been found to increase 6MWD as well as cardiac index, right ventricular systolic function, and left ventricular function. Reduced clinical worsening (defined as death, lung transplantation, or hospitalization for PAH) has also been reported. Because of its teratogenic potential, bosentan can be prescribed only through the Tracleer Access Program (phone: 1-866-228-3546).Ten percent of patients may have liver function test (LFT) abnormalities with use of the drug, thus monthly LFT monitoring is recommended.[19]

Ambrisentan is a selective type A endothelin-1 antagonist[55] indicated for the treatment of PAH (1) to improve exercise ability and delay clinical worsening and (2) in combination with tadalafil to improve exercise ability, as well as reduce the risks of disease progression and hospitalization for worsening PAH. It inhibits vessel constriction and elevation of blood pressure by competitively binding to EtA and EtB receptors in endothelium and vascular smooth muscle. This leads to a significant increase in cardiac index associated with significant reductions in pulmonary arterial pressure, pulmonary vascular resistance, and mean right atrial pressure. While the incidence of LFT abnormalities is less with ambrisentan compared with bosentan, ambrisentan is available only through the Letairis Education and Access Program (LEAP). Prescribers and pharmacies must register with LEAP in order to prescribe and dispense. For more information, see http://www.letairis.com or call (866) 664-LEAP (5327).

Macitentan is a dual endothelin receptor antagonist that prevents binding of ET1 to both EtA and EtB receptors. It is indicated to delay disease progression of PAH (WHO group I) and was approved by the FDA in October 2013. In the SERAPHIN trial (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome), macitentan was shown to lower the risk of clinical events in patients with PAH. According to the study, macitentan given at 10 mg/day led to a 45% reduction (P<.001) in a clinical primary endpoint that included death, initiation of intravenous or subcutaneous prostanoids, or worsening of PAH. The benefit was driven primarily by reductions in PAH worsening. A dosage of 3 mg/day was also shown to improve clinical outcome (P =.01) but to a lesser degree.[56, 57, 58] Anemia was observed in 4% of trial participants; LFT abnormalities were not noted.

Phosphodiesterase-5 enzyme inhibitors

The antiproliferative effects of the phosphodiesterase type 5 (PDE5) pathway, which regulates cyclic guanosine monophosphate (cGMP) hydrolysis, is significant in the long-term treatment of PAH. Agents may include sildenafil, tadalafil, and vardenafil.

Sildenafil promotes selective smooth-muscle relaxation in lung vasculature, possibly by inhibiting PDE5. This results in a subsequent reduction of blood pressure in pulmonary arteries and an increase in cardiac output. It is dosed as a three-times-a-day medication. Its main adverse effects include headache, flushing, and epistaxis, which are likely related to its vasodilatory properties. Sildenafil has been studied as a single agent in PAH in multiple trials.[59, 60, 61, 62] In one randomized controlled trial evaluating 278 patients treated with sildenafil for 12 weeks, patients demonstrated improved 6-minute exercise capacity, reduced mean pulmonary arterial pressure, and a decrease in WHO functional class for a 12-month period.[59] An uncontrolled study of 104 CTEPH patients treated with sildenafil for 12 months documented significant improvements in WHO functional class and pulmonary vascular resistance.[61] It has also been studied as an additive agent with epoprostenol, and again showed improved 6MWD in this trial.[31]

Tadalafil is a PDE5 inhibitor indicated for improving exercise capacity in patients with PAH.[63] It increases cGMP, the final mediator in the nitric oxide pathway. It is indicated as a single agent for improving exercise capacity in patients with PAH, as well as in combination with ambrisentan based on the AMBITION trial (per above). It is dosed as a once-daily medication and has a similar adverse effect profile as sildenafil.

Vardenafil is a PDE5 inhibitor. This medication has been demonstrated to increase 6MWD.[64] It is dosed as once or twice daily.

Soluble guanylate cyclase stimulators

Soluble guanylate cyclase (sGC) is an enzyme in the cardiopulmonary system and the receptor for nitric oxide. PAH is associated with endothelial dysfunction, impaired synthesis of nitric oxide, and insufficient stimulation of the nitric oxide-sGC-cGMP pathway.

Riociguat is the first sGC stimulator approved in the United States. It elicits a dual mode of action. It sensitizes sGC to endogenous nitric oxide by stabilizing the nitric oxide-sGC binding, and it directly stimulates sGC via a different binding site, independently of nitric oxide. It is indicated for CTEPH and PAH. Approval was based on data from the two randomized, double-blind, placebo-controlled, global phase III studies, CHEST-1 and PATENT-1. In each study, riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with PAH.[65, 66]

Cardiac glycosides

Cardiac glycosides are used for prevention and treatment of supraventricular arrhythmias associated with PAH and for patients who have concomitant left-sided heart failure. Digoxin is not useful in the treatment of right-sided ventricular failure.

Digoxin is a cardiac glycoside with direct inotropic effects and indirect effects on the cardiovascular system. It acts directly on cardiac muscle, increasing myocardial systolic contractions. Its indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure.

Loop diuretics

Diuretics should be used in patients who develop right-sided heart failure and those who have systemic congestion manifested by hepatomegaly, ascites, and marked lower extremity edema. Severe right-sided heart failure may also compromise the function of the left ventricle, leading to pulmonary congestion. Therefore, judicious use of diuretics helps reduce systemic congestion and edema. However, excessive hypovolemia may lower cardiac output further and interfere with tissue oxygenation. Agents may include furosemide and bumetanide.

Furosemide increases excretion of water by interfering with the chloride-binding cotransport system, thereby, in turn, inhibiting sodium and chloride reabsorption in the ascending loop of Henle and the distal renal tubule. The dosage must be individualized to the patient. Depending on the response, administer furosemide in increments of 20-40 mg, no sooner than 6-8 hours after the previous dose, until the desired diuresis occurs.

Bumetanide increases excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in the ascending loop of Henle. These effects increase urinary excretion of sodium, chloride, and water, resulting in profound diuresis. Renal vasodilation occurs following administration, renal vascular resistance decreases, and renal blood flow is enhanced. The dose should be individualized to the patient. One milligram of bumetanide is equivalent to approximately 40 mg of furosemide.

Anticoagulants

Long-term anticoagulation with warfarin should be considered in selected patients with PAH. These include patients with pulmonary venoocclusive disease as well as those with low bleeding risk in who the benefit outweighs the risk (eg, those with cor pulmonale or immobility secondary to severe dyspnea).

Warfarin interferes with hepatic synthesis of vitamin K–dependent coagulation factors. It is used for prophylaxis and treatment of deep venous thrombosis, pulmonary embolism, and thromboembolic disorders. It is also used to decrease the risk of embolic stroke in patients with atrial fibrillation. The practitioner typically tailors the dose to maintain an international normalized ratio in the range of 2-3. Recurrence of deep venous thrombosis and pulmonary embolism increases dramatically when the international normalized ratio drops below 2 and decreases when it is kept between 2 and 3. Serious bleeding risk (including hemorrhagic stroke) is approximately constant when the international normalized ratio is between 2.5 and 4.5, but rises dramatically when it exceeds 5.

Calcium Channel Blockers

Class Summary

Calcium channel blockers act by inhibiting calcium ions from entering slow channels or select voltage-sensitive areas of vascular smooth muscle.

Nifedipine (Adalat, Procardia, Nifedical)

Nifedipine is a dihydropyridine calcium channel blocker. It is a vasodilator that dilates both systematic and pulmonary vascular beds. Higher doses of nifedipine are required for optimal vasodilation of pulmonary arteries.

Diltiazem (Cardizem, Dilacor, Cartia XT, Tiazac)

Diltiazem is a nondihydropyridine calcium channel blocker. During depolarization, diltiazem inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes. Serum calcium levels remain unchanged. The resultant decrease in intracellular calcium inhibits the contractile processes of myocardial smooth muscle cells, resulting in dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue. It decreases conduction velocity in atrioventricular node and increases refractory period via blockade of calcium influx.

Amlodipine (Norvasc)

Amlodipine is a dihydropyridine calcium channel blocker that has antianginal and antihypertensive effects. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

Vasodilators

Class Summary

Prostacyclin is a strong vasodilator of all vascular beds and a potent endogenous inhibitor of platelet aggregation. Platelet effects result from activation of intracellular adenylate cyclase and from increased cyclic adenosine monophosphate (cAMP) concentrations within platelets. Prostacyclin may decrease thrombogenesis and platelet clumping in the lungs by inhibiting platelet aggregation.

Epoprostenol (Flolan, Veletri)

Epoprostenol has potent vasodilatory properties, an immediate onset of action, and a half-life of approximately 5 min. In addition to its vasodilator properties, this agent also contributes to inhibition of platelet aggregation and plays a role in inhibition of smooth muscle proliferation. The latter effect may have implications for beneficial remodeling of pulmonary vascular bed.

Treprostinil (Remodulin, Tyvaso, Orenitram)

The prostanoid treprostinil is used to treat PAH. It is structurally similar to epoprostenol but stable at room temperature and has a longer half-life; therefore, it can be given as an intravenous or subcutaneous continuous infusion via a smaller pump. This agent elicits direct vasodilation of pulmonary and systemic arterial vessels and inhibits platelet aggregation. Vasodilation reduces right and left ventricular afterload and increases cardiac output and stroke volume.

Iloprost (Ventavis)

Iloprost is a synthetic analogue of prostacyclin that dilates systemic and pulmonary arterial vascular beds. It is indicated for WHO class I PAH in patients with NYHA class III or IV symptoms to improve exercise tolerance and symptoms and to delay deterioration.

PAH, Prostacyclin Agonists

Class Summary

Selexipag is the first prostacyclin agonist approved in the United States.

Selexipag (Uptravi)

Selexipag selectively activates the prostacyclin receptor (ie, IP-receptor), one of five types of prostanoid receptors. Unlike prostacyclin analogs, selexipag is selective for the IP receptor over other prostanoid receptors (ie, EP1-4, DP, FP, TP). Activating the IP receptor induces vasodilation and inhibits proliferation of vascular smooth muscle cells.

Endothelin-Receptor Antagonists

Class Summary

Endothelin-receptor antagonists competitively bind to the endothelin-1 receptors EtA and EtB, causing reductions in pulmonary arterial pressure, pulmonary vascular resistance, and mean right atrial pressure.

Bosentan (Tracleer)

Bosentan is indicated for the treatment of PAH in patients with WHO class III or IV symptoms to improve exercise ability and decrease the rate of clinical decline. It inhibits vessel constriction and elevation of blood pressure by competitively binding to EtA and EtB receptors in endothelium and vascular smooth muscle. This leads to a significant increase in cardiac index associated with significant reductions in pulmonary arterial pressure, pulmonary vascular resistance, and mean right atrial pressure. Because of its teratogenic potential, bosentan can be prescribed only through the Tracleer Access Program (phone: 1-866-228-3546).

Ambrisentan (Letairis)

Ambrisentan inhibits vessel constriction and elevation of blood pressure by competitively binding to EtA and EtB receptors in endothelium and vascular smooth muscle. This leads to a significant increase in cardiac index associated with significant reductions in pulmonary arterial pressure, pulmonary vascular resistance, and mean right atrial pressure. Ambrisentan is indicated for the treatment of WHO group 1 PAH in patients to improve exercise ability and delay clinical worsening. It is also indicated in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability. Because of the risks of hepatic injury and potential teratogenesis, ambrisentan is available only through the Letairis Education and Access Program (LEAP). Prescribers and pharmacies must register with LEAP in order to prescribe and dispense. For more information, see http://www.letairis.com or call (866) 664-LEAP (5327).

Macitentan (Opsumit)

Macitentan is a dual endothelin receptor antagonist that prevents binding of ET1 to both EtA and EtB receptors. It is indicated to delay disease progression of PAH (WHO group I).

Phosphodiesterase-5 Enzyme Inhibitors

Class Summary

The antiproliferative effects of the phosphodiesterase type 5 (PDE5) pathway, which regulates cyclic guanosine monophosphate (cGMP) hydrolysis, may be significant in the long-term treatment of PAH with PDE5 inhibitors such as sildenafil.

Sildenafil (Revatio)

Sildenafil promotes selective smooth-muscle relaxation in lung vasculature, possibly by inhibiting PDE5. This results in a subsequent reduction of blood pressure in pulmonary arteries and an increase in cardiac output.

Tadalafil (Adcirca)

Tadalafil is a PDE5 inhibitor indicated for improving exercise capacity in patients with WHO group 1 PAH. It increases cGMP, the final mediator in the nitric oxide pathway.

Vardenafil (Levitra, Staxyn ODT)

Vardenafil is a PDE5 inhibitor. This medication has been demonstrated to increase 6-minute walk distance. It is dosed as once or twice daily.

Soluble Guanylate Cyclase (sGC) Stimulators

Class Summary

Soluble guanylate cyclase (sGC) is an enzyme in the cardiopulmonary system and the receptor for nitric oxide. PAH is associated with endothelial dysfunction, impaired synthesis of nitric oxide, and insufficient stimulation of the nitric oxide-sGC-cGMP pathway.

Riociguat (Adempas)

Riociguat elicits a dual mode of action. It sensitizes sGC to endogenous nitric oxide by stabilizing the nitric oxide-sGC binding, and it directly stimulates sGC via a different binding site, independently of nitric oxide. It is indicated for chronic thromboembolic pulmonary hypertension and PAH.

Cardiac Glycosides

Class Summary

Cardiac glycosides are used for prevention and treatment of supraventricular arrhythmias associated with nonidiopathic pulmonary hypertension and for patients who have concomitant left-sided heart failure. Digoxin is not useful in the treatment of right-sided ventricular failure.

Digoxin (Lanoxin)

Digoxin is a cardiac glycoside with direct inotropic effects and indirect effects on the cardiovascular system. It acts directly on cardiac muscle, increasing myocardial systolic contractions. Its indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure.

Diuretics, Loop

Class Summary

Diuretics should be used in patients who develop right-sided heart failure and those who have systemic congestion manifested by hepatomegaly, ascites, and marked lower extremity edema. Severe right-sided heart failure may also compromise function of left ventricle leading to pulmonary congestion. Therefore, judicious use of diuretics helps reduce systemic congestion and edema. However, excessive hypovolemia may lower cardiac output further and interfere with tissue oxygenation.

Furosemide (Lasix)

Furosemide increases excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and the distal renal tubule.

Bumetanide

Bumetanide increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in ascending loop of Henle. These effects increase urinary excretion of sodium, chloride, and water, resulting in profound diuresis.

Anticoagulants

Class Summary

Long-term anticoagulation with warfarin should be considered in selected patients with PAH. These include patients with chronic pulmonary embolism, pulmonary veno-occlusive disease, and atrial fibrillation induced by left- or right-sided heart failure who are at high risk for developing venous thromboembolism (eg, those with cor pulmonale or immobility secondary to severe dyspnea).

Warfarin (Coumadin, Jantoven)

Warfarin interferes with hepatic synthesis of vitamin K–dependent coagulation factors. It is used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders.

 

Questions & Answers

Overview

What is pulmonary hypertension?

What are the WHO clinical classifications of pulmonary hypertension?

What is the pathophysiology of pulmonary arterial hypertension (PAH)?

What are the subtypes of pulmonary arterial hypertension (PAH)?

What is the prevalence of pulmonary arterial hypertension (PAH)?

What is the prognosis of pulmonary arterial hypertension (PAH)?

Presentation

What should be the focus of history in the evaluation of pulmonary arterial hypertension (PAH)?

What are the nonspecific symptoms of pulmonary arterial hypertension (PAH)?

What are the less common symptoms of pulmonary arterial hypertension (PAH)?

Which physical findings suggest pulmonary arterial hypertension (PAH)?

What are the complications of pulmonary arterial hypertension (PAH)?

DDX

What are the differential diagnoses for Pulmonary Arterial Hypertension?

Workup

Which studies are performed in the workup of pulmonary arterial hypertension (PAH)?

What is the role of lab studies in the workup of pulmonary arterial hypertension (PAH)?

What is the role of imaging studies in the workup of pulmonary arterial hypertension (PAH)?

Which findings on an ECG suggest pulmonary arterial hypertension (PAH)?

Which findings on a two-dimensional echocardiography suggest pulmonary arterial hypertension (PAH)?

Which findings on a Doppler echocardiography suggest pulmonary arterial hypertension (PAH)?

What is the role of ventilation-perfusion scanning for the workup of pulmonary arterial hypertension (PAH)?

What is the role of pulmonary function testing in the workup of pulmonary arterial hypertension (PAH)?

What is the role of polysomnography in the workup of pulmonary arterial hypertension (PAH)?

What is the role of right-sided heart catheterization in the diagnosis of pulmonary arterial hypertension (PAH)?

What is the role of vasoreactivity testing in the workup of pulmonary arterial hypertension (PAH)?

Which histologic findings are characteristic of pulmonary arterial hypertension (PAH)?

What are the functional stages of pulmonary hypertension?

Treatment

What is included in supportive therapy for pulmonary arterial hypertension (PAH)?

What is the role of advanced vasodilatory therapies in the treatment of pulmonary arterial hypertension (PAH)?

What is the role of oxygen supplementation in the management of pulmonary arterial hypertension (PAH)?

What is the role of vaccines in the management of pulmonary arterial hypertension (PAH)?

Why should women with pulmonary arterial hypertension (PAH) be offered birth control?

What is the role of diuretics in the management of pulmonary arterial hypertension (PAH)?

What is the role of digoxin in the management of pulmonary arterial hypertension (PAH)?

What is the role of anticoagulants in the management of pulmonary arterial hypertension (PAH)?

When is calcium channel blocker therapy indicated to treat pulmonary arterial hypertension (PAH)?

What are the types of advanced vasodilatory therapies used in the treatment of pulmonary arterial hypertension (PAH)?

What are the treatment options for functional class II or III pulmonary arterial hypertension (PAH)?

What are the treatment options for functional class IV pulmonary arterial hypertension (PAH)?

What is the role of a balloon atrial septostomy in the treatment of pulmonary arterial hypertension (PAH)?

What is the role of lung transplantation in treatment of pulmonary arterial hypertension (PAH)?

Where should patients with pulmonary arterial hypertension (PAH) be treated?

Which dietary modifications are used in the management of pulmonary arterial hypertension (PAH)?

Which activity modifications are used in the treatment of pulmonary arterial hypertension (PAH)?

How is pulmonary arterial hypertension (PAH) prevented?

What is included in the long-term monitoring of patients with pulmonary arterial hypertension (PAH)?

Guidelines

Which organizations have issued treatment guidelines for pulmonary arterial hypertension (PAH)?

Medications

What is the role of medications in the treatment of pulmonary arterial hypertension (PAH)?

What is the efficacy of calcium channel blockers (CCBs) for the treatment of pulmonary arterial hypertension (PAH)?

What is the role of prostacyclin analogues and agonists in the treatment of pulmonary arterial hypertension (PAH)?

What is the efficacy of epoprostenol for the treatment of pulmonary arterial hypertension (PAH)?

What is the efficacy of treprostinil for the treatment of pulmonary arterial hypertension (PAH)?

What is the efficacy of iloprost for the treatment of pulmonary arterial hypertension (PAH)?

What is the efficacy of selexipag for the treatment of pulmonary arterial hypertension (PAH)?

What is the efficacy of endothelin-1 for the treatment of pulmonary arterial hypertension (PAH)?

What is the efficacy of bosentan for the treatment of pulmonary arterial hypertension (PAH)?

What is the efficacy of ambrisentan for the treatment of pulmonary arterial hypertension (PAH)?

What is the efficacy of macitentan for the treatment of pulmonary arterial hypertension (PAH)?

What is the efficacy of sildenafil for the treatment of pulmonary arterial hypertension (PAH)?

What is the role of tadalafil for the treatment of pulmonary arterial hypertension (PAH)?

What is the role of vardenafil for the treatment of pulmonary arterial hypertension (PAH)?

What is the role of soluble guanylate cyclase (sGC) for the treatment of pulmonary arterial hypertension (PAH)?

What is the efficacy of riociguat for the treatment of pulmonary arterial hypertension (PAH)?

What is the role of cardiac glycosides for the treatment of pulmonary arterial hypertension (PAH)?

What is the role of digoxin for the treatment of pulmonary arterial hypertension (PAH)?

What is the role of diuretics for the treatment of pulmonary arterial hypertension (PAH)?

What is the role of furosemide for the treatment of pulmonary arterial hypertension (PAH)?

What is the role of bumetanide for the treatment of pulmonary arterial hypertension (PAH)?

When is long-term anticoagulation with warfarin indicated in the treatment of pulmonary arterial hypertension (PAH)?

Which medications in the drug class Anticoagulants are used in the treatment of Pulmonary Arterial Hypertension?

Which medications in the drug class Diuretics, Loop are used in the treatment of Pulmonary Arterial Hypertension?

Which medications in the drug class Cardiac Glycosides are used in the treatment of Pulmonary Arterial Hypertension?

Which medications in the drug class Soluble Guanylate Cyclase (sGC) Stimulators are used in the treatment of Pulmonary Arterial Hypertension?

Which medications in the drug class Phosphodiesterase-5 Enzyme Inhibitors are used in the treatment of Pulmonary Arterial Hypertension?

Which medications in the drug class Endothelin-Receptor Antagonists are used in the treatment of Pulmonary Arterial Hypertension?

Which medications in the drug class PAH, Prostacyclin Agonists are used in the treatment of Pulmonary Arterial Hypertension?

Which medications in the drug class Vasodilators are used in the treatment of Pulmonary Arterial Hypertension?

Which medications in the drug class Calcium Channel Blockers are used in the treatment of Pulmonary Arterial Hypertension?