Idiopathic Pulmonary Arterial Hypertension 

Updated: Jun 21, 2018
Author: Ronald J Oudiz, MD, FACP, FACC, FCCP; Chief Editor: Zab Mosenifar, MD, FACP, FCCP 

Overview

Practice Essentials

Idiopathic pulmonary arterial hypertension (IPAH) is a rare disease characterized by elevated pulmonary artery pressure with no apparent cause. IPAH is also termed precapillary pulmonary hypertension and was previously termed primary pulmonary hypertension. Untreated IPAH leads to right-sided heart failure and death.

In approximately a third of patients with pulmonary arterial hypertension (PAH), echocardiography demonstrates right-to-left shunting across a patent foramen ovale (see the image below).

Two-dimensional short-axis echocardiogram image. N Two-dimensional short-axis echocardiogram image. Note the flattened interventricular septum due to right ventricular overload.

Signs and symptoms

Symptoms of IPAH are nonspecific and commonly include the following:

  • Dyspnea

  • Weakness

  • Recurrent syncope

Cardiovascular examination in patients with PAH often reveals the following findings:

  • The pulmonic component of the second heart sound is usually increased, which may demonstrate fixed or paradoxic splitting in the presence of severe right ventricular dysfunction; occasionally, the second heart sound may be palpable

  • A pulmonic regurgitation (Graham Steell murmur) may be apparent

  • A murmur of tricuspid regurgitation can be present, and a right ventricular lift (heave) may be noted

  • Jugular venous pulsations may be elevated in the presence of volume overload, right ventricular failure, or both; large V waves are often present because of the commonly present severe tricuspid regurgitation, and large a waves thought to be secondary to poor right ventricular compliance may also be present

  • Right-sided S3 gallop

Other findings may include the following:

  • Hepatomegaly with palpable pulsations of the liver

  • Abnormal abdominal-jugular reflex

  • Ascites - Not uncommon in untreated patients and in patients with worsening decompensated right heart failure

  • Pitting edema - In the extremities

  • Presacral edema - In patients who are bedridden

See Clinical Presentation for more detail.

Diagnosis

Cardiac catheterization

Cardiac catheterization is the criterion standard test to definitively confirm any form of PAH. It is essential in the workup of all patients suspected of IPAH. Excluding left-sided heart disease, including diastolic dysfunction, is especially important in these patients because of major treatment implications. Catheterization is also performed to determine pulmonary vasoreactivity, which can be prognostic and figures in the initiation and titration of high-dose calcium channel blocker (CCB) therapy.

Laboratory studies

  • Antinuclear antibody

  • Thyroid function

  • B-type natriuretic peptide

Imaging studies

  • Radiography

  • Echocardiography

  • Computed tomography (CT), magnetic resonance imaging (MRI), and lung scanning

  • Pulmonary angiography

Electrocardiography

Electrocardiographic results are often abnormal in patients with PAH, revealing right atrial enlargement, right axis deviation, right ventricular hypertrophy, and characteristic ST depression and T-wave inversions in the anterior leads. Sometimes, an incomplete RBBB may be seen (usually in patients with atrial septal defects). However, some patients with IPAH have few or no abnormal electrocardiographic findings.

Histology

Several histologic subtypes are associated with pulmonary arteriopathy in IPAH, one of which involves in situ thrombosis.

Exercise testing

In patients with IPAH, values for peak exercise oxygen consumption, oxygen pulse, and ventilator equivalents (ratio of expired volume to carbon dioxide output [ie, wasted ventilation fraction] at the anaerobic threshold) during exercise are abnormal to varying degrees.

Commonly, a 6-minute walk test is performed in the office as a crude measurement of exercise capacity.

See Workup for more detail.

Management

Calcium channel blocker therapy

Long-term treatment improves the quality of life and survival rate in patients who are proven responders to calcium channel blockers (CCBs). In general, CCBs are used at high doses in patients with IPAH.

PAH-specific therapy

For patients with IPAH in whom CCBs are contraindicated (most IPAH patients), or in whom CCBs are ineffective or poorly tolerated, guidelines from the American College of Chest Physicians (ACCP) recommend using the patient’s New York Heart Association (NYHA) functional class to guide the choice of PAH-specific therapy.[1, 2]

More comprehensive guidelines encompass several clinical parameters that are used to determine risk of adverse outcomes. These include functional class, exercise capacity, symptom progression rate, the presence or absence of heart failure on examination, certain biomarkers, and findings on echocardiography.[3]

Transplantation and septostomy

  • Lung transplantation - A single- or double-lung transplant is indicated for patients who do not respond to medical therapy

  • Septostomy - Atrial septostomy is a palliative procedure that may afford some benefit to patients whose condition is deteriorating

See Treatment and Medication for more detail.

Background

Idiopathic pulmonary arterial hypertension (IPAH) is a rare disease characterized by elevated pulmonary artery pressure with no apparent cause. IPAH is also termed precapillary pulmonary hypertension and was previously termed primary pulmonary hypertension. The term IPAH is now the preferred term for pulmonary arterial hypertension of unknown etiology; thus, IPAH represents pulmonary vascular disease with a spectrum of clinical presentations.

A complete classification of all pulmonary hypertension (PH) types has been updated[4] :

1. Pulmonary arterial hypertension (PAH)

1.1 Idiopathic PAH

1.2 Heritable PAH

1.2.1 BMPR2

1.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK3

1.2.3 Unknown

1.3 Drug- and toxin-induced

1.4 Associated with:

1.4.1 Connective tissue disease

1.4.2 HIV infection

1.4.3 Portal hypertension

1.4.4 Congenital heart disease

1.4.5 Schistosomiasis

1'. Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis

1". Persistent pulmonary hypertension of the newborn (PPHN)

2. Pulmonary hypertension due to left heart disease

2.1 Left ventricular systolic dysfunction

2.2 Left ventricular diastolic dysfunction

2.3 Valvular disease

2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies

3. Pulmonary hypertension due to lung diseases and/or hypoxia

3.1 Chronic obstructive pulmonary disease

3.2 Interstitial lung disease

3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern

3.4 Sleep-disordered breathing

3.5 Alveolar hypoventilation disorders

3.6 Chronic exposure to high altitude

3.7 Developmental lung diseases

4. Chronic thromboembolic pulmonary hypertension (CTEPH)

5. Pulmonary hypertension with unclear multifactorial mechanisms

5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy

5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis

5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders

5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH

Within this classification, IPAH represents a subset of pulmonary vascular disease called pulmonary arterial hypertension (Group I PH, or PAH), which includes conditions known to be associated with pulmonary hypertension that share similar pathophysiology to IPAH. Conditions in which PAH and these associated conditions co-exist are called associated PAH (APAH).

Dresdale and colleagues first reported a hemodynamic account of IPAH in 1951.[5] However, the pathophysiology of IPAH remains poorly understood. At least 15-20% of patients previously thought to have IPAH actually have a familial (heritable) form of PAH involving at least one genetic defect, which has only recently been characterized (see Pathophysiology).

By definition, pulmonary hypertension refers to the condition in which resting mean pulmonary arterial pressure (mPAP) is greater than 25 mmHg. Further, in order to hemodynamically distinguish PAH (IPAH and APAH) from other forms of PH, the pulmonary capillary wedge (PCW) pressure must be less than 15 mmHg, and the pulmonary vascular resistance (PVR) must be more than 3 Wood Units. Thus, cardiac catheterization is the criterion standard test to definitively confirm any form of PAH, including IPAH. However, a thorough workup includes a range of additional testing to exclude all reasonable causes of secondary pulmonary hypertension (see Workup).

Until recently, calcium channel blockers (CCBs) had been the most widely used class of drugs for IPAH. Patients with IPAH in whom CCBs are contraindicated, ineffective, or poorly tolerated may respond to long-term PAH-specific therapy (see Treatment and Management).

Treating IPAH requires significant knowledge of and exposure to the available therapies for IPAH and their potential complications. Because IPAH is relatively rare, management is best left to expert personnel at centers with regular exposure to these patients (see Treatment and Management).

Also see Pediatric Idiopathic Pulmonary Artery Hypertension.

Pathophysiology

The pathophysiology of IPAH is poorly understood. An insult (eg, hormonal, mechanical, other) to the endothelium may occur, possibly in the setting of increased susceptibility to pulmonary vascular injury (ie, multiple hit theory), resulting in a cascade of events characterized by vascular scarring, endothelial dysfunction, and intimal and medial (smooth muscle) proliferation.

At least 15-20% of patients previously thought to have IPAH actually have a familial form of PAH involving at least one genetic defect. The most common genetic defect in these cases involves the BMPR-II gene. However, only about a third of affected patients with a family history of PAH have an identifiable BMPR-II mutation. This suggests that additional genetic abnormalities and/or additional external factors may exist that predispose individuals to developing PAH.

In 2013, 6 mutations that appear to be associated with PAH and that may be treatable with PAH drugs were discovered in a gene, KCNK3, that had not previously been linked to the disease. Each of the 6 mutations was linked to a loss of function of potassium ion channels.[6, 7] In vitro examination of the investigational agent ONO-RS-082 (2-[p-amylcinnamoyl]amino-4-chlorobenzoic acid), a phospholipase A2 inhibitor, found that for 2 of the 3 mutations tested, the drug restored function to nonworking potassium ion channels.

The current Nice Classification system of PH now lists the following genetic defects that are known to be associated with PAH[8] :

  • BMPR2

  • ALK1

  • ENG

  • SMAD9

  • CAV1

  • KCNK3

Early in IPAH (and probably in APAH), as the pulmonary artery pressure increases because of increasing right ventricle work, thrombotic pulmonary arteriopathy occurs. Thrombotic pulmonary arteriopathy is characterized by in situ thrombosis of small muscular arteries. In later stages, as the pulmonary pressure continues to rise, plexogenic pulmonary arteriopathy develops. This is characterized by a remodeling of the pulmonary vasculature with intimal fibrosis and replacement of normal endothelial structure.

For more information, see the Medscape Reference article Persistent Newborn Pulmonary Hypertension.

Associated conditions

Pulmonary vascular disease can be associated with portal hypertension (sometimes called portopulmonary hypertension), suggesting that patients with shunting of splanchnic blood, with or without liver disease, have a higher risk of developing PAH.

Additionally, exposure of the pulmonary circulation to substances from the splanchnic circulation that are normally detoxified via the liver may contribute to the development of pulmonary hypertension. More research is necessary to better understand this relationship.

Patients with connective-tissue diseases, namely the CREST (calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia) variant of scleroderma, systemic lupus erythematosus, and mixed connective-tissue disease, are also predisposed to developing IPAH-like disease. This is now termed associated PAH, or APAH.

The pathophysiologic nature of this predisposition is unclear. In the past, most experts used the term "secondary" pulmonary arterial hypertension for these diseases, indicating that, similar to IPAH, the process involves the precapillary circulation but is somehow caused by or at least associated with the underlying (predisposing) disease.

A study by Soon et al determined that unexplained iron deficiency is more prevalent in patients with idiopathic pulmonary artery hypertension than in those with chronic thromboembolic pulmonary hypertension (CTEPH).[9] Interleukin-6 (IL-6) may play a role in this difference in prevalence.

Etiology

The strict definition of IPAH is pulmonary hypertension with no known cause. However, associations have been recognized (eg, connective-tissue diseases, liver cirrhosis, exposure to anorexigens and likely other alpha-adrenergic stimulants [eg, cocaine, amphetamines],[10] HIV infection). How these associated conditions predispose to or cause PAH remains unknown.

Epidemiology

IPAH is responsible for approximately 125-150 deaths per year in the United States and has an incidence rate of approximately 2-6 cases per million population per year. The incidence and prevalence of APAH are considerably higher than those of IPAH. The worldwide incidence of IPAH approximates that observed in the United States, but variations in prevalence exist worldwide. A registry of patients with IPAH in France found a prevalence of IPAH of about 6 cases per million population.[11] IPAH occurs at a female-to-male ratio ranging from 2-9:1, depending on the treatment center sampled. In the United States, the average female-to-male ratio reported in clinical trials and registries is close to 4:1. The reasons for this female predilection remain unknown.Typically, younger women of childbearing age develop IPAH. However, IPAH can also affect individuals in their fifth and sixth decades of life or older.[12]

Prognosis

IPAH has no cure. Untreated IPAH leads to right-sided heart failure and death. Prior to the 1990s, therapeutic options were limited. The emergence of prostacyclin analogues, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and other novel drug therapies has greatly improved the outlook for patients with IPAH and IPAH-like diseases.

For untreated IPAH, the estimated 3-year survival rate is approximately 41%. In one study of long-term continuous intravenous prostacyclin therapy, 3-year survival increased to approximately 63%.[13] With newer therapies, perhaps in combination, these figures are expected to improve further.

Data on long-term survival in patients treated with other pulmonary vascular therapies are emerging. Patients whose disease progresses and is unresponsive to medical treatments either undergo transplantation or die of progressive right-sided heart failure.

Using the largest registry of patients with PAH to date, the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry), Benza et al analyzed factors determining survival in 2716 patients.[14] Using this data, they derived a multivariable, weighted risk formula incorporating 19 independent factors identified as having an impact on PAH patient survival, thus allowing clinicians to incorporate factors encountered in real-world management of PAH in their overall risk/severity assessment.

In another analysis of data from the REVEAL Registry, Frost et al found that PAH patients with mean pulmonary capillary wedge pressure (PCWP) of 16-18 mmHg at diagnostic right heart catheterization were heavier, older, and were more likely to have comorbidities associated with left ventricular diastolic dysfunction at diagnosis than patients with PCWP ≤15 mmHg. Five-year survival was poor in both PCWP subgroups.[15]

Patient Education

Patient education about this rare fatal disease is paramount. If applicable, instruct patients on how to administer their daily parenteral medication. For patient education information, see the Lung and Airway Center and Heart and Blood Vessels Center.

 

Presentation

History

The average time from symptom onset to diagnosis has been reported to be approximately 2 years. Despite recent attempts at increasing the awareness of pulmonary arterial hypertension (PAH), especially associated PAH (APAH), this delay in diagnosis has not changed appreciably in recent years.

Early symptoms are nonspecific. Often, neither the patient nor the physician recognizes the presence of the disease, which leads to delays in diagnosis. Complicating matters, idiopathic PAH (IPAH) requires an extensive workup in an attempt to elucidate an identifiable cause of the elevated pulmonary artery pressure.

The most common symptoms and their frequency, reported in a national prospective study, are as follows:

  • Dyspnea (60% of patients)

  • Weakness (19%)

  • Recurrent syncope (13%)

Additional symptoms include fatigue, lethargy, anorexia, chest pain, and right upper quadrant pain. Cough, hemoptysis, and hoarseness are less common symptoms.

Women are more likely to be symptomatic than men.

Physical Examination

Physical findings in persons with PAH can be quite variable.

Cardiovascular examination often reveals the following findings:

  • The pulmonic component of the second heart sound is usually increased, which may demonstrate fixed or paradoxic splitting in the presence of severe right ventricular dysfunction; occasionally, the second heart sound may be palpable.

  • Pulmonic regurgitation (Graham Steell murmur) may be apparent.

  • A murmur of tricuspid regurgitation can be present, and a right ventricular lift (heave) may be noted.

  • Jugular venous pulsations may be elevated in the presence of volume overload, right ventricular failure, or both; large V waves are often present because of the commonly present severe tricuspid regurgitation, and large a waves thought to be secondary to poor right ventricular compliance may also be present.[16]

  • Right-sided S3 gallop

Other findings may include hepatomegaly with palpable pulsations of the liver and an abnormal abdominal-jugular reflex. In untreated patients and patients with worsening decompensated right heart failure, ascites is not uncommonly present.

Lung examination findings are usually normal.

Extremity examination may reveal pitting edema of varying degrees. Patients who are bedridden may have presacral edema.

Complications

Complications of IPAH include the following:

  • Advanced right-sided heart failure with hepatic congestion

  • Pedal edema

  • Pleural effusions

  • Ascites

  • Worsening dyspnea upon exertion

 

DDx

Diagnostic Considerations

Pulmonary vascular disease can be associated with portal hypertension and connective-tissue diseases. Other associations with pulmonary arterial hypertension (PAH) include exposure to anorexigens and likely other alpha-adrenergic stimulants (eg, cocaine, amphetamines) and HIV seropositivity. Other problems to be considered include cor pulmonale, pulmonary embolism, and cardiogenic pulmonary edema.

Go to Cor Pulmonale for more complete information on this topic.

Differential Diagnoses

 

Workup

Approach Considerations

Diagnostic algorithms can help in completing a thorough workup. In 2004, the American College of Chest Physicians (ACCP) published a consensus statement with diagnostic and treatment recommendations.[17, 18] In 2009, the American Heart Association (AHA) and the American College of Cardiology (ACC) published a joint guideline that provides extensive coverage of PAH diagnosis and management.[3]

Imaging Studies

Radiography

Chest radiography may be the first diagnostic step in the evaluation of a patient with dyspnea; however, for many patients with PAH, the findings do not help reveal the underlying etiology. Chest radiography is useful for excluding interstitial and alveolar processes that may cause hypoxia-mediated pulmonary vasoconstriction.

Findings sometimes seen in IPAH include enlargement of the central pulmonary arteries with peripheral arterial pruning, oligemia of the lung fields, right ventricular enlargement with diminished retrosternal airspace, and right atrial enlargement manifesting with a prominent right heart border.

Echocardiography

Echocardiography is often the first clue that PH exists, and it is often recommended as a screen for APAH for high risk populations (such as connective tissue disease patients). Echocardiography is extremely useful for assessing right and left ventricular function, estimating pulmonary systolic arterial pressure, and excluding congenital anomalies and valvular disease. This is particularly important in the initial workup of patients with PH because the findings can help steer the clinician towards the likely type of PH (ie, Group 1, Group 2, etc).

Findings on echo in IPAH patients include flattening of the intraventricular septum (D-shaped left ventricle) during systole and diastole, right ventricular enlargement and hypertrophy, and reduced right ventricular function. Tricuspid regurgitation (TR) is usually present, and TR waveform is used to estimate right ventricular systolic pressure. Pulmonic insufficiency may be present. On M-Mode echocardiography, early mid-systolic notching of the pulmonic valve is associated with poorer right ventricular function and worse hemodynamics in PAH patients, including IPAH. Finally, the presence of a pericardial effusion denotes a poor prognosis in PAH patients, including IPAH.

In approximately a third of patients with PAH, echocardiography demonstrates right-to-left shunting across a patent foramen ovale. (See the image below.)

Two-dimensional short-axis echocardiogram image. N Two-dimensional short-axis echocardiogram image. Note the flattened interventricular septum due to right ventricular overload.

Computed tomography and lung scanning

High-resolution chest CT scanning and ventilation-perfusion (V/Q) lung scanning are frequently obtained to help exclude interstitial lung disease and thromboembolic disease. The V/Q scan is the preferred method for excluding chronic thromboembolic disease because it is more sensitive for chronic pulmonary embolism than CT scanning.

Pulmonary angiography

This test is occasionally required to help definitively exclude thromboembolic disease. While considered a high-risk procedure in patients with elevated pulmonary arterial pressures and/or right ventricular failure, a carefully performed study is generally safe.

For more information, see the Medscape Reference topic Imaging of Pulmonary Hypertension.

Cardiac Catheterization

Right heart catheterization is the criterion standard test to definitively confirm any form of PAH, including IPAH. However, it must be understood that a thorough workup for suspected IPAH includes a range of tests to exclude all reasonable causes of PH. Excluding left-sided heart disease (including diastolic dysfunction) with catheterization is especially important in these patients because of major treatment implications (see Catheter Placement for Long-term Therapy). Catheterization is also performed to determine pulmonary vasoreactivity, which may have implications in the initiation and titration of high-dose calcium channel blocker (CCB) therapy. The initiation of intravenous therapy with prostacyclin analogues requires placement of a central venous catheter and detailed instruction on the long-term use of PAH-specific therapy.

Serologic Analyses

Excluding autoimmune disorders is an important part of the workup in a patient with suspected pulmonary hypertension. Reportedly, up to 40% of patients with IPAH have a positive finding on an antinuclear antibody (ANA) assay but no other clinical manifestations of autoimmune disease.

Most connective-tissue diseases associated with pulmonary artery hypertension are diagnosed on the basis of clinical findings (ie, physical examination), with serology results used as adjunctive confirmation of the disease. These serologies may include rheumatoid factor (RF), anti-neutrophil cytoplasmic antibody (ANCA), and anti-topoisomerase antibody (SCL70), (Also see Scleroderma.)

Thyrotropin

Screen for thyroid abnormalities during the initial workup for IPAH because these abnormalities are common in patients with IPAH. Thyroid abnormalities may be the cause of or contribute to symptoms similar to IPAH. In addition, hyperthyroidism itself may lead to an elevation in pulmonary artery pressure.

B-Type Natriuretic Peptide

Levels of B-type natriuretic peptide (BNP) and N-terminal BNP have been shown to be elevated in patients with IPAH, and levels appear to be prognostic.[19] Data are conflicting as to whether changes in BNP over time are also predictive.

Electrocardiography

ECG results are often abnormal in patients with PAH, revealing right atrial enlargement, right axis deviation, right ventricular hypertrophy, and characteristic ST depression and T-wave inversions in the anterior leads. Sometimes, an incomplete RBBB may be seen (usually in patients with atrial septal defects). However, some patients with IPAH have few or no abnormal ECG findings. Thus, normal ECG results do not exclude a diagnosis of PAH.

Exercise Testing

Six-minute walk testing is commonly used as a surrogate test for aerobic capacity and IPAH severity. It is simple and relatively easy to perform; however, it lacks specificity in that it cannot be used to discern between several causes of an impaired ability to walk.[20]

Assessment of aerobic capacity and ventilatory efficiency can help identify a pulmonary vascular limit to exercise and can be used to differentiate intrinsic pulmonary vascular disease from cardiac deconditioning and restrictive or obstructive lung disease or left-sided cardiac dysfunction.

In patients with IPAH, values for peak exercise oxygen consumption, oxygen pulse, and ventilator equivalents (ratio of expired volume to carbon dioxide output [ie, wasted ventilation fraction] at the anaerobic threshold) during exercise are abnormal to varying degrees.

Histologic Findings

Several histologic subtypes are associated with pulmonary arteriopathy in IPAH, one of which involves in situ thrombosis. Thrombotic pulmonary arteriopathy may be observed, with or without plexiform lesions. It is characterized by in situ thrombosis of small muscular arteries of the pulmonary vasculature. Thrombotic pulmonary arteriopathy is often present at earlier stages of IPAH (ie, before the development of plexogenic pulmonary arteriopathy) or as an irreversible lesion in later stages. Platelet activation and increased levels of circulating procoagulant factors are observed.

Other Studies

Assessment of mechanical lung function can also help differentiate intrinsic pulmonary vascular disease from restrictive or obstructive lung disease. The diffusing capacity of the lung for carbon dioxide (DLCO) is known to decrease in proportion to the degree of IPAH severity.

Sleep apnea must be excluded as a contributor or cause of pulmonary hypertension if the patient's history suggests this diagnosis.

HIV-positive patients have a higher rate of IPAH than the general population; therefore, include an HIV test as part of the routine evaluation.

Staging System

Traditionally, New York Heart Association/World Health Organization functional classification is used to grade IPAH disease severity. This grading system has obvious limitations because it is subjective.

Other means to characterize disease severity include hemodynamic findings after right-sided heart catheterization, exercise capacity (eg, peak exercise oxygen consumption, 6-min walk distance), and clinical severity of heart failure signs found during the physical examination.

More recent studies show that the echocardiographically determined parameters such as eccentricity index, a marker of interventricular septum flattening, and indices of right ventricular function such as tricuspid annular plane systolic excursion (TAPSE) are prognostic. Positive findings for serum troponin and the presence of a pericardial effusion are also of prognostic utility, indicating a worse prognosis.[21]

 

Treatment

Approach Considerations

Treating IPAH requires significant education regarding, and exposure to, the available therapies for IPAH and their potential complications. Because IPAH is relatively rare, management is best left to expert personnel at centers with regular exposure to these patients. Failure to heed this advice can result in medicolegal pitfalls should patient outcome be less than optimal.

A national program designed to develop accredited PH Care Centers (PHCC) has begun, with the goal of raising the overall quality of care and outcomes in patients with PH.[22]

Note that there are no therapies approved for use as primary prevention of IPAH. All approved treatments are for use in patients that have already developed clinical manifestations of IPAH.

Calcium Channel Blocker Therapy

Until about 15 years ago, calcium channel blockers (CCBs) had been the most widely used class of drugs for IPAH. These drugs are thought to act on the vascular smooth muscle to dilate the pulmonary resistance vessels and lower the pulmonary artery pressure. Several studies report clinical and hemodynamic benefits from the use of long-term calcium channel blockade.

Only patients with an acute vasodilator response to an intravenous or inhaled pulmonary vasodilator challenge (eg, with inhaled nitric oxide at 10 to 20 parts per million, intravenous epoprostenol (2 to 12 ng/kg/min), intravenous adenosine (50 to 350 mg/min), or inhaled iloprost [5 mg]) derive any long-term benefit from CCBs. Such patients constitute less than 5% of patients with IPAH and probably less than 3% of patients with other forms of PAH. By consensus definition, a positive acute vasodilator response is defined by a decrease in mPAP 10 mm Hg or more to reach a mPAP less than 40 mm Hg. It should be noted that less than 50% of responders derive a long-term favorable response to CCBs, and thus close clinical monitoring of patients on CCBs for IPAH is required.

Long-term treatment improves the quality of life and survival rate in patients who are proven responders to such therapy. In general, CCBs are used at high doses in patients with IPAH.

The use of CCBs should be limited to patients without overt evidence of right-sided heart failure. In patients with IPAH (or any other form of PAH), a cardiac index of less than 2 L/min/m2 or a right atrial pressure above 15 mm Hg is a contraindication to CCB therapy, as these agents may worsen right ventricular failure in such cases.

Stable patients who demonstrate vasoreactivity and are candidates for high-dose CCB therapy should undergo a CCB challenge to determine their vasodilator response.

Perform this challenge in a critical care unit with a balloon flotation catheter in the pulmonary artery. Administer oral nifedipine every hour (diltiazem can be used if resting tachycardia is present) until a 20% decrease in pulmonary artery pressure and pulmonary vascular resistance is observed or systemic hypotension or other adverse effects preclude further drug administration.

Calculate the daily dosage requirement at half the total initial effective dose and administer this every 6-8 hours. Typical doses of nifedipine and diltiazem can reach 240 mg/d and 900 mg/d, respectively. Use caution when withdrawing CCBs because rebound pulmonary hypertension upon cessation of PAH therapy has been reported.

PAH-Specific Therapy

Approved medications for PAH (including IPAH) currently available in the United States are as follows:

  • Epoprostenol (Flolan or generic) - Intravenous, parenteral prostacyclin analogue, sometimes referred to as a "prostanoid"[23, 24]

  • Treprostinil (Remodulin) - Intravenous or subcutaneous, parenteral prostacyclin analogue, sometimes referred to as a prostanoid[25, 26]

  • Treprostinil inhaled (Tyvaso) - Nebulized inhalation; prostacyclin analogue

  • Treprostinil extended-release tablet (Orenitram) - Twice-daily oral prostacyclin analogue

  • Iloprost (Ventavis) - Nebulized inhalation; prostacyclin analogue, sometimes referred to as a prostanoid[27]

  • Selexipag (Uptravi) - Oral prostacyclin agonist that is selective for the IP receptor over other prostanoid receptors[28]

  • Bosentan (Tracleer) - Oral; endothelin receptor antagonist (ERA)[29, 30]

  • Ambrisentan (Letairis) - Oral ERA[31, 32]

  • Sildenafil (Revatio) - Oral phosphodiesterase type 5 (PDE-5) inhibitor[33]

  • Tadalafil (Adcirca) - Oral PDE-5 inhibitor[34]

  • Riociguat (Adempas) - Oral soluble guanylate cyclase (sGC) stimulator[35, 36, 37, 38] (currently approved only for adults)

  • Macitentan (Opsumit) – Oral ERA[39, 40] (also currently approved for adults[41, 42] )

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. Administration of macitentan at 10 mg/day led to a 45% reduction in a clinical primary endpoint that included death, initiation of intravenous or subcutaneous prostanoids, or worsening of PAH. Benefit was driven primarily by reductions in PAH worsening. A dosage of 3 mg/day also improved clinical outcome but to a lesser degree.[39, 40, 42, 41]

Combination therapy of ambrisentan (an ERA) with tadalafil (a PDE-5 inhibitor) was approved as first-line treatment by the FDA in October 2015. The combination decreased disease progression and hospitalization, and more effectively improved exercise ability. Approval of the first-line ambrisentan/tadalafil combination for PAH is based on results of the ambrisentan and tadalafil in patients with pulmonary arterial hypertension (AMBITION) trial involving 605 patients with World Health Organization 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 ~50% reduction in risk for clinical failure compared with either drug alone (P = 0.0002).[43]

For patients with IPAH in whom CCBs are contraindicated, ineffective, or poorly tolerated, ACCP guidelines recommend using the patient’s World Health Organization’s modified New York Heart Association (NYHA) functional class (WHO FC) to guide the choice of PAH-specific therapy.[1, 2] PAH-specific therapies by functional class from the ACCP are as follows:[44]

  • WHO FC II – Monotherapy may be initiated with a currently approved endothelin receptor antagonist (ETA), phosphodiesterase-5 (PDE5) inhibitor, or the soluble guanylate cyclase stimulator riociguat.

  • WHO FC III (treatment-naïve) - Monotherapy be initiated with a currently approved ERA, a PDE5 inhibitor, or the soluble guanylate cyclase stimulator riociguat.

  • WHO FC III (treatment-naïve with rapid progression or other markers of poor prognosis) - Parenteral prostanoid.

  • WHO FC III (non-treatment-naïve with rapid progression or other markers of poor prognosis) - Parenteral or inhaled prostanoid.

  • WHO FC IV (treatment-naïve) - Parenteral prostanoid. If unable to manage parenteral prostanoid therapy, use inhaled prostanoid in combination with an ERA.

A newer concept of goal-oriented therapy has been developed after observations that patients with an inadequate clinical response to an initial therapy have a much worse prognosis. Thus:

  • For WHO FC III or IV PAH patients with unacceptable clinical status despite established PAH-specific monotherapy, a 2nd class of PAH therapy to improve exercise capacity is recommended in addition to referral to a center with expertise in the evaluation and treatment of complex patients with PAH.

Finally, for patients who do not fall into the above categories, reference to the ACCP Guideline for specific evidence-based scenarios and simultaneous referral to an expert PAH center is suggested. Failure of medical therapy dictates prompt consideration for lung transplantation.

It is important to perform vasoactivity testing in patients with IPAH before prescribing PAH-specific therapy. Intravenous epoprostenol or adenosine or inhaled nitric oxide are used most commonly for acute vasodilator testing. Oxygen, nitroprusside, and hydralazine should not be used as pulmonary vasodilator testing agents.

Note that while the above agents are often referred to as pulmonary vasodilator medications, their actions are likely pleiotropic, affecting endothelial function and intimal and smooth muscle proliferation. Their ability to dilate pulmonary arteries and thereby lower pulmonary arterial pressure is modest in most cases.

Patients who do not have an acute vasodilator response to a vasodilator challenge have a worse prognosis on long-term oral PAH-specific therapy compared with those who have an initial response. However, the absence of an acute response to intravenous or inhaled vasodilators does not preclude the use of intravenous prostanoid therapy. In fact, continuous intravenous prostanoid therapy is strongly suggested for these patients because CCBs are contraindicated.

Patients receiving epoprostenol or intravenous treprostinil therapy must have a central venous catheter placed surgically and receive their initial dose in an inpatient setting. This allows for monitoring of acute adverse effects and provides the opportunity for the patient and support personnel to master the drug preparation and administration technique before discharge.

Continuous intravenous prostanoid therapy is delivered via an ambulatory infusion pump.

Despite concerns regarding ocular toxicity with chronic PDE-5 inhibition, no detrimental effects were observed during a pivotal phase III randomized clinical trial of sildenafil versus placebo for patients with pulmonary arterial hypertension.[45]

A 52-week extension study demonstrated the long-term safety and efficacy of tadalafil in patients with pulmonary arterial hypertension.[46]

Ancillary Treatment

Patients with IPAH may benefit from therapy with anticoagulants, digoxin, diuretics, or supplemental oxygen.

Anticoagulation

Several studies, using both univariate and multivariate analyses, have shown that survival in IPAH, regardless of histopathologic subtype, is increased when patients are treated with anticoagulant therapy. However, these studies were retrospectively performed. No randomized, controlled clinical trials of anticoagulation in IPAH exist; thus, the data are mostly consensus-driven rather than based on prospective evidence-based medicine.

Warfarin should be used, provided the patient has no contraindications to anticoagulation. Maintain an international normalized ratio (INR) of 1.5 to 2.

Digoxin

Digoxin therapy can be used to improve right ventricular function in patients with right ventricular failure. However, no randomized controlled clinical study has been performed to validate this strategy for patients with IPAH or any other form of PAH.

Diuretics

Use diuretics to manage peripheral edema. The use of loop diuretics (eg, furosemide, bumetanide) requires potassium supplementation and close monitoring of serum potassium. Potassium-sparing diuretics may have a role in ameliorating the sometimes-intractable hypokalemia observed with daily diuretic use.

Oxygen therapy

Give supplemental oxygen in patients with resting or exercise-induced hypoxemia. Use caution if patients have a left-to-right shunt via a patent foramen ovale, because supplemental oxygen in these instances may provide little or no benefit.

Consider supplemental oxygen for PAH patients who are planning air travel, as mild hypobaric hypoxia can start at altitudes between 1500 and 2000 m, and commercial airliners are pressurized to the equivalent of an altitude between 1600 and 2500 m.[47] A prospective observational study of 34 air travelers with pulmonary hypertension found that 1 in 4 travelers experienced hypoxemia, which was associated with lower cabin pressure, ambulation during flight, and longer flight durations. Results suggest travelers with PH, who will be traveling on long flights or those with a history of oxygen use, should be considered for supplemental in-flight oxygen.[48]

Diet

No specific diet is recommended; however, a low-sodium and low-fluid diet is recommended in patients with significant volume overload due to right ventricular failure.

Patients taking warfarin must limit their intake of vitamin K–containing foods, such as green leafy and coliform vegetables.

L -arginine supplementation (a precursor to nitric oxide) has not been proven to improve outcome in IPAH or any other form of PAH.

Activity

Limited data are available on cardiopulmonary rehabilitation. The generally accepted recommendation is that patients with pulmonary hypertension and heart failure should perform mild symptom-limited aerobic activity and avoid complete bed rest. Isometric exercises (weight lifting) are contraindicated.

A European study involving an intensive inpatient and outpatient exercise training and conditioning program demonstrated the safety and efficacy of exercise as a treatment modality for patients with PAH.[49] While longer-term outcomes are needed, the PAH community considers exercise in moderation a safe and potentially effective adjunctive nonpharmacologic therapy.

Transplantation and Septostomy

A single- or double-lung transplant is indicated for patients who do not respond to medical therapy. Simultaneous cardiac transplantation may not be necessary even with severe right ventricular dysfunction; however, this depends on the transplant institution. Interestingly, IPAH is not thought to recur after transplant.

Go to Pediatric Lung Transplantation for more complete information on this topic.

Atrial septostomy is a palliative procedure that may afford some benefit to patients whose condition is deteriorating. This procedure works by allowing interatrial right-to-left shunting to occur, thus delivering more overall oxygen content to the respiring tissues, albeit with a lower overall saturation.

Long-Term Monitoring

Currently, no precise dosage adjustment algorithm is available for patients with IPAH who are on PAH-specific therapy. Monitor the patient with frequent physical examinations and focus the history on heart failure symptoms and adverse effects of medications.

Echocardiography has been used in several studies to serially monitor changes in the right ventricular–right atrial pressure gradient and the right and left ventricular chamber sizes. Findings from other noninvasive modalities (eg, electron-beam CT measurements of cardiac chamber sizes) correlate with hemodynamic improvements in pulmonary physiology.

More recently, cardiopulmonary exercise testing, serial invasive hemodynamic testing, and 6-minute walk testing have been used to monitor the disease status of patients with IPAH.

Future Therapies

Clinical trials are under way to determine the safety and efficacy of several new therapies for IPAH. These include oral and inhaled prostanoids, phosphodiesterase inhibitors, tyrosine kinase inhibitors, and other novel agents.[50] Efforts are currently focused on prostacyclin analogues, newer endothelin antagonists, and PDE-5 inhibitors.

 

Guidelines

Guidelines Summary

The following clinical guidelines on treatment of PAH have been published:

  • Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines and the 2007 addendum[1, 2]

  • Guidelines on diagnosis and treatment of pulmonary arterial hypertension: The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology[29]

  • ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension[3]

 

Medication

Medication Summary

Current pulmonary vascular therapies appear to exert their actions on the pulmonary circulation by mechanisms that remain poorly defined. Clearly, the magnitude of the pulmonary vasodilator actions of prostanoids, PDE-5 inhibitors, and endothelin antagonists do not account for the degree of clinical benefit observed with these drugs. Rather, additional effects on the "endothelial health" of the pulmonary circulation and on the inhibition of pathologic intimal fibrosis and smooth muscle proliferation are likely to be the predominant mechanisms involved in the treatment responses.

Calcium Channel Blockers

Class Summary

Calcium channel blockers are believed to act on the vascular smooth muscle, dilating the pulmonary resistance vessels and lowering the pulmonary artery pressure. Several studies report clinical and hemodynamic benefits from the use of long-term calcium channel blockade. Long-term treatment improves the quality of life and survival rate in patients who have a proven response to such therapy. In general, CCBs are used at high doses in patients with IPAH.

The use of CCBs should be limited to patients without overt evidence of right-sided heart failure. In patients with IPAH (or any other form of PAH), a cardiac index of less than 2 L/min/m2 or a right atrial pressure above 15 mm Hg is a contraindication to CCB therapy, as these agents may worsen right ventricular failure in such cases.

Nifedipine (Adalat CC, Nifedical XL, Procardia)

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, Cardizem LA, 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 AV node and increases refractory period via blockade of calcium influx.

Parenteral Prostanoids

Class Summary

Parenteral prostanoids are used for patients whose IPAH fails to respond to calcium channel blockers or who cannot tolerate these agents and who have New York Heart Association (NYHA) type III or IV right-sided heart failure.

Epoprostenol (Flolan, Veletri)

An analogue of aerosolized prostacyclin (PGI2) that was approved by the FDA in 1995 for use in patients with IPAH, and later for use in APAH, 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. Epoprostenol is FDA-approved for treatment of IPAH.

Treprostinil (Remodulin)

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.

Treprostinil recently received FDA approval for IV use as a bioequivalent of subcutaneous treprostinil, using the same delivery pump used for epoprostenol. Dosing is similar to subcutaneous delivery.

Adenosine (Adenocard)

Adenosine is an antiarrhythmic agent that is used for the treatment of paroxysmal supraventricular tachycardia. It slows conduction time through the AV node, which can interrupt the re-entry pathways through the AV nodes, in turn restoring normal sinus rhythm.

Oral Phosphodiesterase (Type 5) Enzyme Inhibitors

Class Summary

Inhibition of the antiproliferative effects of the PDE-5 pathway, which regulates cyclic guanosine monophosphate hydrolysis, may be significant in the long-term treatment of pulmonary hypertension.

Despite concerns regarding ocular toxicity with chronic PDE-5 inhibition, no detrimental effects were observed during a pivotal phase III randomized clinical trial of sildenafil versus placebo for patients with pulmonary arterial hypertension.

A 52-week extension study demonstrated the long-term safety and efficacy of tadalafil in patients with pulmonary arterial hypertension.

Sildenafil (Revatio)

Sildenafil promotes selective smooth muscle relaxation in lung vasculature, possibly by inhibiting PDE-5. This results in subsequent reduction of blood pressure in pulmonary arteries and an increase in cardiac output.

Tadalafil (Adcirca)

Tadalafil is a PDE-5 inhibitor indicated for improving and increasing exercise capacity in patients with World Health Organization (WHO) class I PAH. This agent increases cyclic guanosine monophosphate (cGMP), which is the final mediator in the nitric oxide pathway.

Inhaled Prostanoids

Class Summary

Inhaled prostacyclin (PGI2) synthetic analogues are an alternative to parenteral administration. They are used in an attempt to limit systemic adverse effects.

Iloprost (Ventavis)

A synthetic analogue of PGI2 that dilates systemic and pulmonary arterial vascular beds, iloprost 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.

Treprostinil, inhaled (Tyvaso)

The prostanoid, treprostinil is indicated for PAH in patients with NYHA class III symptoms. It 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.

Oral Prostacyclin Analogues

Class Summary

Oral prostacyclin (PGI2) synthetic analogues are an alternative to parenteral administration.

Treprostinil tablet (Orenitram)

Treprostinil extended-release tablets are the first oral prostacyclin analogue approved by the FDA for PAH. It acts by causing vasodilation toboth pulmonary and systemic arterial vascular beds. It also decreases ventricular afterload and inhibits platelet aggregation.

Prostacyclin Receptor Agonists

Class Summary

Approval of the first prostacyclin agonist, selexipag, was based on the phase 3 GRIPHON study (n=1,156). 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).

Selexipag (Uptravi)

Selectively activates the prostacyclin receptor (ie, IP-receptor), one of 5 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 is indicated for adults with PAH, WHO Group I to delay disease progression and reduce the risk of hospitalization.

Endothelin Receptor Antagonists

Class Summary

Endothelin receptor antagonists (ERAs) are therapeutic alternatives to parenteral prostacyclin agents. Given orally, they competitively bind to endothelin 1 (ET-1) receptors endothelin-A and endothelin-B, causing a reduction in pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and mean right atrial pressure (RAP). This agent is indicated for treatment of PAH in patients with WHO class III or IV symptoms to improve exercise ability and decrease the rate of clinical deterioration.

Bosentan (Tracleer)

The first oral IPAH therapy to be approved in United States, bosentan is a mixed endothelin-A and endothelin-B receptor antagonist indicated for PAH, including IPAH. In clinical trials, bosentan improved exercise capacity, decreased the rate of clinical deterioration, improved functional class, and improved hemodynamics.

Bosentan improves pulmonary arterial hemodynamics by competitively binding to ET-1 receptors endothelin-A and endothelin-B in pulmonary vascular endothelium and pulmonary vascular smooth muscle. This leads to a significant increase in the cardiac index associated with a significant reduction in PAP, PVR, and mean RAP. These changes result in an improvement in exercise capacity (as measured by the 6-min walk test) and improved PAH symptoms.

Because this drug has teratogenic potential and because of the need for careful scrutiny in choosing appropriate candidates for ERA therapy, bosentan can be prescribed only through the Tracleer Access Program. Call 1-866-228-3546.

Ambrisentan (Letairis)

Ambrisentan is an endothelin receptor antagonist indicated for WHO group 1 PAH to 1) improve exercise ability and delay clinical worsening; and 2) in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability. It inhibits vessel constriction and elevation of blood pressure by competitively binding to endothelin-1 receptors ETA and ETB in endothelium and vascular smooth muscle. This leads to a significant increase in cardiac index associated with significant reduction in PAP, PVR, and mean RAP. Because of the risks of hepatic injury and teratogenic potential, this agent 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[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 pulmonary arterial hypertension (WHO Group I).

Soluble Guanylate Cyclase (sGC) Stimulators

Class Summary

Soluble guanylate cyclase (sGC) is an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). Pulmonary arterial hypertension (PAH) is associated with endothelial dysfunction, impaired synthesis of NO, and insufficient stimulation of the NO-sGC-cGMP pathway.

Riociguat is the first sGC stimulator approved in the United States. Approval was based on data from the 2 randomized, double-blind, placebo-controlled, global phase III studies CHEST-1 and PATENT-1, as well as long-term data from these studies. In each study, riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension.

Riociguat (Adempas)

Riociguat elicits a dual mode of action. It sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding, and it directly stimulates sGC via a different binding site, independently of NO. It is indicated for chronic thromboembolic pulmonary hypertension and PAH.

Diuretics

Class Summary

Diuretics are used in pulmonary hypertension to manage peripheral edema. The use of loop diuretics (eg, furosemide, bumetanide) requires potassium supplementation and close monitoring of serum potassium.

Furosemide (Lasix)

Furosemide is a loop diuretic that increases excretion of water by interfering with chloride-binding cotransport system, which in turn inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. It increases renal blood flow without increasing the filtration rate. It increases potassium, sodium, calcium, and magnesium excretion.

Diuretics have major clinical uses in managing disorders involving abnormal fluid retention (edema) or in treating hypertension, in which their diuretic action causes decreased blood volume.

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. Renal vasodilation occurs following administration, renal vascular resistance decreases, and renal blood flow is enhanced.

Spironolactone

Spironolactone is a potassium-sparing diuretic. Potassium-sparing diuretics may have a role in ameliorating the sometimes-intractable hypokalemia observed with daily diuretic use.

Anticoagulants

Class Summary

Several studies, using both univariate and multivariate analyses, have shown that survival in IPAH, regardless of histopathologic subtype, is increased when patients are treated with anticoagulant therapy. However, these studies were retrospectively performed. No randomized, controlled clinical trials of anticoagulation in IPAH exist; thus, the data are mostly consensus-driven rather than based on prospective evidence-based medicine.

Warfarin should be used, provided the patient has no contraindications to anticoagulation. Maintain an international normalized ratio (INR) of 1.5 to 2.

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.

The efficacy of novel oral anticoagulants (NOACs) has not been evaluated in PAH.

Cardiac Glycosides

Class Summary

Digoxin therapy can be used to improve right ventricular function in patients with right ventricular failure. However, no randomized controlled clinical study has been performed to validate this strategy for patients with IPAH or any other form of PAH.

Digoxin (Lanoxin)

Digoxin enhances myocardial contractility by inhibition of Na+/K+ ATPase, a cell membrane enzyme that extrudes Na+ and brings K+ into the myocyte. It has direct inotropic effects in addition to indirect effects on the cardiovascular system. It increases myocardial systolic contractions and exerts vagomimetic action on sinus and AV nodes (slowing heart rate and conduction). Also, it decreases the degree of activation of sympathetic nervous system and renin-angiotensin system, which is referred to as the deactivating effect.

 

Questions & Answers

Overview

What is idiopathic pulmonary arterial hypertension (IPAH)?

What are the symptoms of idiopathic pulmonary arterial hypertension (IPAH)?

What are the cardiovascular findings in idiopathic pulmonary arterial hypertension (IPAH)?

What are the physical exam findings in idiopathic pulmonary arterial hypertension (IPAH)?

What is the role of cardiac catheterization in idiopathic pulmonary arterial hypertension (IPAH)?

Which lab studies are indicated in the workup of idiopathic pulmonary arterial hypertension (IPAH)?

Which imaging studies are indicated in the diagnosis of idiopathic pulmonary arterial hypertension (IPAH)?

What ECG findings are associated with idiopathic pulmonary arterial hypertension (IPAH)?

What is the role of exercise testing in the workup of idiopathic pulmonary arterial hypertension (IPAH)?

What is the role of calcium channel blocker therapy in the treatment of idiopathic pulmonary arterial hypertension (IPAH)?

What is the approach to treatment of idiopathic pulmonary arterial hypertension (IPAH) in patients who cannot take calcium channel blockers (CCBs)?

What is the role of transplantation and septostomy in the treatment of idiopathic pulmonary arterial hypertension (IPAH)?

What is idiopathic pulmonary arterial hypertension (IPAH) (precapillary pulmonary hypertension)?

How is pulmonary hypertension classified?

How is idiopathic pulmonary arterial hypertension (IPAH) classified?

How is idiopathic pulmonary arterial hypertension (IPAH) defined?

Which medications are most effective for the treatment of idiopathic pulmonary arterial hypertension (IPAH)?

What is the pathophysiology of idiopathic pulmonary arterial hypertension (IPAH)?

Which genetic mutations are associated with idiopathic pulmonary arterial hypertension (IPAH)?

Which genetic defects are associated with idiopathic pulmonary arterial hypertension (IPAH) according to the Nice Classification system related to?

How is thrombotic pulmonary arteriopathy characterized in idiopathic pulmonary arterial hypertension (IPAH)?

Which medical conditions are the associated with idiopathic pulmonary arterial hypertension (IPAH)?

What causes idiopathic pulmonary arterial hypertension (IPAH)?

How common is idiopathic pulmonary arterial hypertension (IPAH)?

What is the prognosis of idiopathic pulmonary arterial hypertension (IPAH)?

How is the REVEAL Registry used in the prognosis of idiopathic pulmonary arterial hypertension (IPAH)?

What patient education is indicated for patients with idiopathic pulmonary arterial hypertension (IPAH)?

Presentation

What are the early symptoms of idiopathic pulmonary arterial hypertension (IPAH)?

What are the most common symptoms of idiopathic pulmonary arterial hypertension (IPAH)?

What are common findings of cardiovascular exam in patients with idiopathic pulmonary arterial hypertension (IPAH)?

What physical findings are associated with idiopathic pulmonary arterial hypertension (IPAH)?

What are the complications of idiopathic pulmonary arterial hypertension (IPAH)?

DDX

What are the diagnostic considerations of idiopathic pulmonary arterial hypertension (IPAH)?

What are the differential diagnoses for Idiopathic Pulmonary Arterial Hypertension?

Workup

What are the approach considerations in the workup of idiopathic pulmonary arterial hypertension (IPAH)?

How is echocardiography used in the workup of idiopathic pulmonary arterial hypertension (IPAH)?

What is the role of radiography in the workup of idiopathic pulmonary arterial hypertension (IPAH)?

How are CT and V/Q lung scanning used in the workup of idiopathic pulmonary arterial hypertension (IPAH)?

How is pulmonary angiography used in the workup of idiopathic pulmonary arterial hypertension (IPAH)?

What is the role of cardiac catheterization in the workup of idiopathic pulmonary arterial hypertension (IPAH)?

What is the role of serologic analyses for idiopathic pulmonary arterial hypertension (IPAH)?

What is the role of thyroid studies in the workup of idiopathic pulmonary arterial hypertension (IPAH)?

What is the role B-type natriuretic peptide studies in the workup of idiopathic pulmonary arterial hypertension (IPAH)?

What is the role of ECG in the workup of idiopathic pulmonary arterial hypertension (IPAH)?

What is the role of exercise testing in the assessment of idiopathic pulmonary arterial hypertension (IPAH)?

What are the histologic findings of idiopathic pulmonary arterial hypertension (IPAH)?

Which studies are indicated in the workup of idiopathic pulmonary arterial hypertension (IPAH) with comorbidities?

How is idiopathic pulmonary arterial hypertension (IPAH) staged?

Treatment

What are the treatment approach considerations of idiopathic pulmonary arterial hypertension (IPAH)?

What is the role of calcium channel blockers (CCBs) in the treatment of idiopathic pulmonary arterial hypertension (IPAH)?

When is calcium channel blocker therapy indicated for the treatment of idiopathic pulmonary arterial hypertension (IPAH)?

How is a calcium channel blocker challenge used in the treatment of idiopathic pulmonary arterial hypertension (IPAH)?

Which medications are used in the treatment of idiopathic pulmonary arterial hypertension (IPAH)?

What were the results of the SERAPHIN trial on the treatment of idiopathic pulmonary arterial hypertension (IPAH)?

Which PAH-specific therapies are indicated for patients with idiopathic pulmonary arterial hypertension (IPAH) in whom calcium channel blockers (CCBs) are contraindicated?

What is the role of goal-oriented therapy for idiopathic pulmonary arterial hypertension (IPAH)?

Why is vasoactivity testing important for patients with idiopathic pulmonary arterial hypertension (IPAH)?

What is the prognostic value of a vasodilator challenge for idiopathic pulmonary arterial hypertension (IPAH)?

What is the risk of ocular toxicity in the treatment of idiopathic pulmonary arterial hypertension (IPAH)?

Which ancillary treatments are used in patients with idiopathic pulmonary arterial hypertension (IPAH)?

What is the role of anticoagulant therapy in the treatment of idiopathic pulmonary arterial hypertension (IPAH)?

What is the role of digoxin in the treatment of idiopathic pulmonary arterial hypertension (IPAH)?

What is the role of diuretics in the treatment of idiopathic pulmonary arterial hypertension (IPAH)?

What is the role of oxygen therapy in the treatment of idiopathic pulmonary arterial hypertension (IPAH)?

What dietary recommendations are indicated for patients with idiopathic pulmonary arterial hypertension (IPAH)?

What physical activity is indicated for patients with idiopathic pulmonary arterial hypertension (IPAH)?

What is the role of transplantation and septostomy for the treatment of idiopathic pulmonary arterial hypertension (IPAH)?

What is the role of long-term monitoring in patients with idiopathic pulmonary arterial hypertension (IPAH)?

What novel therapies for idiopathic pulmonary arterial hypertension (IPAH) are being investigated?

Guidelines

What are the treatment guidelines for idiopathic pulmonary arterial hypertension (IPAH)?

Medications

What is the importance of medication for idiopathic pulmonary arterial hypertension (IPAH)?

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

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

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

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

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

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

Which medications in the drug class Oral Prostacyclin Analogues are used in the treatment of Idiopathic Pulmonary Arterial Hypertension?

Which medications in the drug class Inhaled Prostanoids are used in the treatment of Idiopathic Pulmonary Arterial Hypertension?

Which medications in the drug class Oral Phosphodiesterase (Type 5) Enzyme Inhibitors are used in the treatment of Idiopathic Pulmonary Arterial Hypertension?

Which medications in the drug class Parenteral Prostanoids are used in the treatment of Idiopathic Pulmonary Arterial Hypertension?

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