Pulmonary Arterial Hypertension: An Update on Diagnosis and Treatment

Am Fam Physician. 2010 Aug 15;82(4):370-377.

  Patient information: See related handout on pulmonary hypertension.

Pulmonary arterial hypertension is defined as a mean pulmonary arterial pressure greater than 25 mm Hg at rest or 30 mm Hg during physical activity. Pulmonary arterial hypertension is classified into subgroups, including idiopathic, heritable, and pulmonary arterial hypertension associated with other conditions. A detailed history, thorough physical examination, and most importantly, a high index of suspicion are essential to diagnosis. Evaluation includes echocardiography and exclusion of other causes of symptoms. Targeted laboratory testing can help identify the subgroup of pulmonary arterial hypertension. Right heart catheterization is required to confirm the diagnosis. Standard treatment options include oral anticoagulation, diuretics, oxygen supplementation, and for a small percentage of patients, calcium channel blockers. Newer treatments include prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. Combination therapy has been shown to improve pulmonary arterial pressure, but more research is needed. Interventional procedures for patients with pulmonary arterial hypertension include balloon atrial septostomy and lung transplantation.

Pulmonary arterial hypertension (PAH) is a rare, underdiagnosed condition defined as elevation of mean pulmonary arterial pressure. In patients with PAH, the average pulmonary arterial pressure is greater than 25 mm Hg at rest (compared with 15 mm Hg in patients without PAH) or 30 mm Hg during physical activity, as measured by right heart catheterization. The prevalence of PAH varies among specific populations, but one study estimated that it affects 15 in 1 million adults.1 Idiopathic PAH occurs mainly in persons in their 20s and 30s, with an overall female-to-male ratio of 1.7:1, which is higher in black persons (4.3:1).2  Risk factors for PAH include a family history of PAH, congenital heart disease, connective tissue disease, portal hypertension, sickle cell disease, thyroid disease, human immunodeficiency virus (HIV), and use of certain drugs and toxins. Table 1 lists the clinical classification of PAH, which was updated in 2008.3

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References

Echocardiography is an effective evaluation technique for PAH, and the results of pulmonary arterial systolic pressure measurements correlate with right heart catheterization.

C

911

Coumadin (Warfarin) treatment is beneficial for patients with PAH.

B

19, 20

Sildenafil (Revatio) improves cardiopulmonary hemodynamics and exercise capacity in patients with PAH.

B

36, 37


PAH = pulmonary arterial hypertension.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidencerating system, go to http://www.aafp.org/afpsort.xml

SORT: KEY RECOMMENDATIONS FOR PRACTICE

View Table

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References

Echocardiography is an effective evaluation technique for PAH, and the results of pulmonary arterial systolic pressure measurements correlate with right heart catheterization.

C

911

Coumadin (Warfarin) treatment is beneficial for patients with PAH.

B

19, 20

Sildenafil (Revatio) improves cardiopulmonary hemodynamics and exercise capacity in patients with PAH.

B

36, 37


PAH = pulmonary arterial hypertension.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidencerating system, go to http://www.aafp.org/afpsort.xml

Table 1.

Clinical Classification of PAH

Idiopathic

Heritable

BMPR2 gene

ALK1 gene, endoglin (with or without hereditary hemorrhagic telangiectasia)

Unknown

Drug- and toxin-induced

Definite causal relationship

  Aminorex*

  Dexfenfluramine*

  Fenfluramine*

  Toxic rapeseed oil

Likely causal relationship

  Amphetamines

  L-tryptophan

  Methamphetamines

Possible causal relationship

  Chemotherapeutic agents

  Cocaine

  Phenylpropanolamine*

  Selective serotonin reuptake inhibitors

  St. John's wort

Unlikely causal relationship

  Cigarette smoking

  Estrogen

  Oral contraceptives

Conditions associated with PAH

Chronic hemolytic anemia

Congenital heart disease

Connective tissue disease

Human immunodeficiency virus infection

Portal hypertension

Schistosomiasis

Persistent pulmonary hypertension of the newborn


PAH = pulmonary arterial hypertension.

*—Not available in the United States.

Information from reference 3.

Table 1.   Clinical Classification of PAH

View Table

Table 1.

Clinical Classification of PAH

Idiopathic

Heritable

BMPR2 gene

ALK1 gene, endoglin (with or without hereditary hemorrhagic telangiectasia)

Unknown

Drug- and toxin-induced

Definite causal relationship

  Aminorex*

  Dexfenfluramine*

  Fenfluramine*

  Toxic rapeseed oil

Likely causal relationship

  Amphetamines

  L-tryptophan

  Methamphetamines

Possible causal relationship

  Chemotherapeutic agents

  Cocaine

  Phenylpropanolamine*

  Selective serotonin reuptake inhibitors

  St. John's wort

Unlikely causal relationship

  Cigarette smoking

  Estrogen

  Oral contraceptives

Conditions associated with PAH

Chronic hemolytic anemia

Congenital heart disease

Connective tissue disease

Human immunodeficiency virus infection

Portal hypertension

Schistosomiasis

Persistent pulmonary hypertension of the newborn


PAH = pulmonary arterial hypertension.

*—Not available in the United States.

Information from reference 3.

Clinical Features

The early phases of PAH may be asymptomatic. Patients usually present with dyspnea exacerbated by exertion, fatigue, chest pain, and palpitations. The diagnosis of PAH is often delayed because many other conditions can cause similar symptoms. The differential diagnosis includes congestive heart failure, coronary artery disease, pulmonary embolism, and chronic obstructive pulmonary disease. Advanced PAH may present as clinically evident right-sided heart failure, dizziness, syncope, edema, or cyanosis.

If PAH is incidentally discovered, the physician should attempt to find or exclude possible modifiable causes. Confirmation by right heart catheterization should be considered before beginning an extensive search for an underlying cause, starting therapy, or providing prognostic advice.4

Diagnosis

A detailed history, thorough physical examination, and most importantly, a high index of suspicion are essential to diagnosing PAH.5 A French study reported an average delay of 27 months from the onset of symptoms to diagnosis.1  PAH should be considered in any patient with dyspnea who shows no or minimal signs of specific heart or lung disease. Suspicion should be especially high in patients who also have conditions associated with PAH, such as sickle cell anemia, HIV, and systemic sclerosis. The American College of Cardiology Foundation and the American Heart Association offer screening guidelines for patients with known risk factors for PAH (Table 2).6

Table 2.

Risk Factors for PAH and Screening Recommendations

Risk factors Further assessment Rationale

BMPR2 gene mutation

Echocardiography yearly

Early detection of PAH; 20 percent chance of developing PAH

RHC if echocardiography demonstrates evidence of PAH*

Congenital heart disease with shunt

Echocardiography and RHC at time of diagnosis

High probability of PAH developing in unrepaired shunt (Eisenmenger syndrome)

Consider repair of defect if significant left-to-right shunt present

First-degree relative with BMPR2 gene mutation or within pedigree of two or more patients with a diagnosis of PAH

Genetic counseling and recommendation for BMPR2 genotyping; proceed as above if positive

Autosomal dominant transmission

HIV infection

Echocardiography if symptoms or signs suggestive of PAH

0.5 percent prevalence of PAH

RHC if echocardiography demonstrates evidence of PAH*

Portal hypertension

Echocardiography if OLT considered

4 percent prevalence of PAH in candidates for OLT; PAH is predictive of poor OLT outcome

RHC if echocardiography demonstrates evidence of PAH*

Previous use of appetite suppressant (fenfluramine†)

Echocardiography only if patient is symptomatic

Incidence of PAH is approximately0.005 percent if agent is used longer than three months

Recent acute pulmonary embolism

Ventilation-perfusion scintigraphy three months after event if symptomatic; pulmonary angiography if positive

3 percent risk of chronic thromboembolic PH; negative ventilation-perfusion scan excludes chronic thromboembolism

Sickle cell disease

Echocardiography yearly

Increased mortality if PH is present; early detection of PH; 30 percent develop PH; about 10 percent develop PAH

RHC if echocardiography demonstrates evidence of PAH*

Systemic sclerosis

Echocardiography yearly

About 8 percent (by RHC) to 27 percent(by echocardiography) prevalence of PAH in systemic sclerosis

RHC if echocardiography demonstrates evidence of PAH*


HIV = human immunodeficiency virus; OLT = orthotopic liver transplantation; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension; RHC = right heart catheterization.

*—Elevated right ventricular systolic pressure or right heart chamber enlargement.

†—Not available in the United States.

Source: McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association [published correction appears in Circulation. 2009;120(2):e13]. Circulation. 2009;119(16):2263.

Table 2.   Risk Factors for PAH and Screening Recommendations

View Table

Table 2.

Risk Factors for PAH and Screening Recommendations

Risk factors Further assessment Rationale

BMPR2 gene mutation

Echocardiography yearly

Early detection of PAH; 20 percent chance of developing PAH

RHC if echocardiography demonstrates evidence of PAH*

Congenital heart disease with shunt

Echocardiography and RHC at time of diagnosis

High probability of PAH developing in unrepaired shunt (Eisenmenger syndrome)

Consider repair of defect if significant left-to-right shunt present

First-degree relative with BMPR2 gene mutation or within pedigree of two or more patients with a diagnosis of PAH

Genetic counseling and recommendation for BMPR2 genotyping; proceed as above if positive

Autosomal dominant transmission

HIV infection

Echocardiography if symptoms or signs suggestive of PAH

0.5 percent prevalence of PAH

RHC if echocardiography demonstrates evidence of PAH*

Portal hypertension

Echocardiography if OLT considered

4 percent prevalence of PAH in candidates for OLT; PAH is predictive of poor OLT outcome

RHC if echocardiography demonstrates evidence of PAH*

Previous use of appetite suppressant (fenfluramine†)

Echocardiography only if patient is symptomatic

Incidence of PAH is approximately0.005 percent if agent is used longer than three months

Recent acute pulmonary embolism

Ventilation-perfusion scintigraphy three months after event if symptomatic; pulmonary angiography if positive

3 percent risk of chronic thromboembolic PH; negative ventilation-perfusion scan excludes chronic thromboembolism

Sickle cell disease

Echocardiography yearly

Increased mortality if PH is present; early detection of PH; 30 percent develop PH; about 10 percent develop PAH

RHC if echocardiography demonstrates evidence of PAH*

Systemic sclerosis

Echocardiography yearly

About 8 percent (by RHC) to 27 percent(by echocardiography) prevalence of PAH in systemic sclerosis

RHC if echocardiography demonstrates evidence of PAH*


HIV = human immunodeficiency virus; OLT = orthotopic liver transplantation; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension; RHC = right heart catheterization.

*—Elevated right ventricular systolic pressure or right heart chamber enlargement.

†—Not available in the United States.

Source: McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association [published correction appears in Circulation. 2009;120(2):e13]. Circulation. 2009;119(16):2263.

Physical examination of a patient with PAH may reveal a right parasternal lift, accentuated pulmonary second heart sound, pansystolic murmur (tricuspid regurgitation), third heart sound, and a diastolic murmur (pulmonary valve insufficiency). Edema may present as jugular vein distension, hepatomegaly, peripheral edema, or ascites.6

DIAGNOSTIC TESTING

Diagnostic testing options for PAH are listed in Table 3.6 Electrocardiography (ECG) may show right ventricular hypertrophy and right axis deviation, but ECG has inadequate sensitivity and specificity to reliably detect PAH.7 One study showed that a combination of P- and T-wave indicators may provide an effective means of assessing treatment response in patients with PAH.8

Table 3.

Diagnostic Testing Options for PAH

Blood tests

Anticentromere antibody levels (if clinically indicated)

Antinuclear antibody levels (if clinically indicated)

Anti-Scl-70 antibody levels (if clinically indicated)

Arterial blood gas measurement

Complete blood count

Complete chemistry panel

Human immunodeficiency virus test

Ribonucleoprotein antibody levels (if clinically indicated)

Sickle cell screening (if clinically indicated)

Thyroid-stimulating hormone levels

Other noninvasive tests

Cardiac magnetic resonance imaging (if clinically indicated)

Chest radiography

Computed tomography of chest (if clinically indicated)

Echocardiography (bubble study optional)

Electrocardiography

Liver ultrasonography

Pulmonary function test

Procedures

Right heart catheterization with vasoreactivity testing

Six-minute walk test (to assess severity of PAH)


PAH = pulmonary arterial hypertension.

Information from reference 6.

Table 3.   Diagnostic Testing Options for PAH

View Table

Table 3.

Diagnostic Testing Options for PAH

Blood tests

Anticentromere antibody levels (if clinically indicated)

Antinuclear antibody levels (if clinically indicated)

Anti-Scl-70 antibody levels (if clinically indicated)

Arterial blood gas measurement

Complete blood count

Complete chemistry panel

Human immunodeficiency virus test

Ribonucleoprotein antibody levels (if clinically indicated)

Sickle cell screening (if clinically indicated)

Thyroid-stimulating hormone levels

Other noninvasive tests

Cardiac magnetic resonance imaging (if clinically indicated)

Chest radiography

Computed tomography of chest (if clinically indicated)

Echocardiography (bubble study optional)

Electrocardiography

Liver ultrasonography

Pulmonary function test

Procedures

Right heart catheterization with vasoreactivity testing

Six-minute walk test (to assess severity of PAH)


PAH = pulmonary arterial hypertension.

Information from reference 6.

Chest radiography is abnormal in 90 percent of patients at diagnosis and usually shows right ventricular enlargement, a prominent central pulmonary artery, or peripheral hypovascularity7 (Figure 1). A normal chest radiograph does not rule out the diagnosis.7

Figure 1.

Chest radiography shows bilateral hilar enlargement, which is a typical finding in patients with pulmonary arterial hypertension, as well as cardiomegaly.

View Large


Figure 1.

Chest radiography shows bilateral hilar enlargement, which is a typical finding in patients with pulmonary arterial hypertension, as well as cardiomegaly.


Figure 1.

Chest radiography shows bilateral hilar enlargement, which is a typical finding in patients with pulmonary arterial hypertension, as well as cardiomegaly.

Studies have shown a correlation in pulmonary arterial systolic pressure measurement between transthoracic echocardiography and right heart catheterization.911 Echocardiography has been used to identify PAH in patients with associated conditions.1214 Measuring parameters such as septal systolic strain and strain rate may allow for earlier detection of PAH.15 Increased tricuspid regurgitation, and right ventricular and atrial enlargement are echocardiographic signs of PAH.7

PAH must be distinguished from other causes of pulmonary hypertension. Pulmonary function tests and arterial blood gas measurements help identify underlying lung disease. Patients may have mild to moderate reduction of lung volumes on these tests, but the partial arterial oxygen tension (PaO2) is normal or only slightly decreased and the partial arterial carbon dioxide tension (PaCO2) is usually decreased from hyperventilation.7 High-resolution computed tomography can assist in the evaluation of thromboembolic disease, emphysema, or interstitial lung disease. Although cardiac magnetic resonance imaging (MRI) is not currently used as a routine assessment tool, continued improvement in MRI acquisition and spatial resolution may lead to improved understanding of PAH pathophysiology, and aid in diagnosis and prognosis. Cardiac MRI may replace more invasive diagnostic tests.16

Evidence of associated conditions may identify the type of PAH. Routine chemistry panels, complete blood count, and thyroid function tests should be obtained. Antinuclear antibody (ANA), anti-Scl-70, anticentromere, and ribonucleoprotein antibody levels are recommended to evaluate for connective tissue disease.7 About one third of patients with idiopathic PAH have low ANA titers (less than 1:80). If the ANA levels are elevated or if clinical features suggestive of connective tissue disease are present, rheumatologic consultation is recommended.7 All patients should be tested for HIV.7 Liver ultrasonography is a reliable test to exclude cirrhosis or portal hypertension.7

CONFIRMATORY AND PROGNOSTIC TESTING

Right heart catheterization is required to confirm the diagnosis of PAH and to evaluate the severity of hemo-dynamic dysfunction. This should be performed at an institution with considerable experience with PAH, specifically with vasoreactivity testing because of potential procedural complications.6 Vasoreactivity testing is also needed to identify patients who may benefit from treatment with calcium channel blockers.17 Patients with a mean pulmonary arterial pressure decrease of more than 10 mm Hg to below 40 mm Hg and with an unchanged or increased cardiac output when challenged are considered vasoreactive.6 Lung biopsy is not recommended because it has considerable risks and a very low likelihood of altering the diagnosis or treatment.6

The best test to classify the severity of PAH and estimate prognosis is the six-minute walk test. This simple test measures the distance walked in six minutes. It is predictive of survival in idiopathic PAH.18 Research is ongoing to better assess prognosis for patients with all subtypes of PAH.6

Treatment

Because of the complexity of treatment, patients should be followed regularly at an institution that specializes in PAH.6 Family physicians should be aware of PAH treatments and their potential adverse effects. Figure 2 presents an algorithm for the treatment of PAH.6

Treatment of PAH

Figure 2.

Algorithm for the treatment of PAH. (ERAs = endothelin receptor antagonists; IV = intravenous; PAH = pulmonary arterial hypertension; PDE5 = phosphodiesterase type 5.)

Source: McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association [published correction appears in Circulation . 2009;120(2):e13]. Circulation. 2009;119(16):2276.

View Large

Treatment of PAH


Figure 2.

Algorithm for the treatment of PAH. (ERAs = endothelin receptor antagonists; IV = intravenous; PAH = pulmonary arterial hypertension; PDE5 = phosphodiesterase type 5.)

Source: McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association [published correction appears in Circulation . 2009;120(2):e13]. Circulation. 2009;119(16):2276.

Treatment of PAH


Figure 2.

Algorithm for the treatment of PAH. (ERAs = endothelin receptor antagonists; IV = intravenous; PAH = pulmonary arterial hypertension; PDE5 = phosphodiesterase type 5.)

Source: McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association [published correction appears in Circulation . 2009;120(2):e13]. Circulation. 2009;119(16):2276.

STANDARD TREATMENTS

A number of established treatment options for PAH continue to be useful. Two retrospective analyses have reported favorable results with the oral anticoagulant warfarin (Coumadin).19,20 Although there is no expert consensus, an International Normalized Ratio of 1.5 to 2.5 is recommended.6 Patients with right-sided heart failure may benefit symptomatically from diuretics, although no randomized controlled trials have been performed to demonstrate improvement in symptoms or outcomes with diuretic use.6

Most patients with PAH have only mild arterial hypoxia at rest. Although symptomatic improvement has been reported with oxygen supplementation, this has not been confirmed in controlled studies.6 An oxygen saturation greater than 90 percent at all times is recommended.6 Inotropic agents, such as digoxin, have been considered for treatment, but no data are available on the effects of long-term treatment.6

Less than 10 percent of patients with idiopathic PAH have a clinically significant reduction of pulmonary arterial pressure with calcium channel blocker therapy.17

NEWER TREATMENTS

More recent medications for PAH include prostacyclin analogues, endothelin receptor antagonists (ERAs), and phosphodiesterase type 5 inhibitors (Table 4 6,2138). Prostacyclin is a potent vasodilator that maintains low vascular tone, has antiproliferative properties, and prevents platelet aggregation. The prostacyclin analogues currently approved in the United States are epoprostenol (Flolan), iloprost (Ventavis), and treprostinil (Remodulin).

Table 4.

New Medications for PAH

Class Medication Dosing Adverse effects Comments Cost per unit* Cost per day

Prostacyclin analogues

Epoprostenol (Flolan)

Commonly started in hospital at 2 ng per kg per minute by continuous intravenous infusion; typical dosing is around 15 ng per kg per minute; titration based on symptoms and adverse effects

Flushing, headache, skeletal pain, diarrhea Local infections (related to central venous catheter system) Abrupt interruption of treatment can lead to worsening of PAH

First medication shown to improve survival in idiopathic PAH21 Improves symptoms, exercise capacity, and hemodynamic measures22,23 Recommended for unstable patients in functional classes III and IV 6

$52 for 1.5-mg intravenous dose

$52, based on 15 ng per kg per minute for patient weighing 70 kg (154 lb)

Iloprost (Ventavis)

Inhaled: 2.5 to 5.0 mcg taken six to nine times per day, but not more than once every two hours, via adaptive aerosol device Intravenous infusion: maintenance dosage of 2 to 4 ng per kg per minute Oral: 50 to 300 mcg twice per day

Cough (from inhaled formulation), flushing, headaches, insomnia, vomiting

Inhaled formulation shows small but statistically significant improvement of symptoms in patients with severe PAH24 Approved for patients in functional classes III and IV

$39 for 2-mL inhalation (10 mcg per mL)

$39, based on 2.5 mcg via inhaled formulation eight times per day

Treprostinil (Remodulin)

Maintenance dosage typically around 15 ng per kg per minute via continuous subcutaneous or intravenous infusion

Similar to epoprostenol, including facial flushing, headache, jaw pain, nausea, diarrhea Infusion site pain occurs in 85 percent of patients; can lead to discontinuation of treatment in 8 percent of patients when administered via continuous transcutaneous system26 Increased risk of gram-negative bacteremia27

Improves exercise capacity; hemodynamics and survival similar to epoprostenol25 Approved for patients in functional classes II and III; intravenous use approved in patients who cannot tolerate subcutaneous infusion6

$1,345 for 20-mL multidose vial (1 mg per mL)

$100, based on 15 ng per kg per minute for patient weighing 70 kg

Endothelin receptor antagonists

Ambrisentan (Letairis)

5 to 10 mg orally once per day

Generally well tolerated Adverse effects generally unrelated to dose28 Peripheral edema mostly in patients older than 65 years28 Hepatic transaminase elevations occur at lower rate than with bosentan28

Prescribed only through the Letairis Education and Access Program Specific to endothelin A receptor Approved in the United States in 2007 for patients in functional classes II and III29,30 FDA requires liver function testing once per month and hematocrit testing every three months Contraindicated in pregnancy

$192 for 10-mg tablet

$192 for 10 mg per day

Bosentan (Tracleer)

125 mg orally twice per day

Dose-dependent reversible elevations of hepatic transaminase levels in 10 percent of patients Anemia and edema can occur

Nonspecific endothelin receptor antagonist Improves hemodynamics, exercise capacity, and echocardiographic results; delays time to clinical worsening31-33 Approved for patients with symptomatic heart failure; benefits shown in patients in functional class II34 FDA requires liver function testing once per month and hematocrit testing every three months

$96 for 125-mg tablet

$192

Sitaxsentan†

Dosages of 100 to 300 mg orally once per day are being studied

Appears similar to other medications in the class

Specific to endothelin A receptor Benefit and safety demonstrated,35 although currently not approved by the FDA

NA

NA

Phosphodiesterase type 5 inhibitors

Sildenafil (Revatio)

20 mg orally three times per day (FDA-approved for PAH treatment)

Headache, dyspepsia, flushing

Improves cardiopulmonary hemodynamics and exercise capacity36,37

$17 for 20-mg tablet

$51

Tadalafil (Adcirca)

2.5 to 40 mg orally once per day (40 mg was needed for statistically significant effects38)

Headache, flushing, myalgias38

Slowed incidence of clinical worsening and improved six-minute walk test38 Approved in the United States in 2009 for patients in functional classes II and III

$19 for 20-mg tablet

$38 for 40 mg per day


FDA = U.S. Food and Drug Administration; NA = not applicable; PAH = pulmonary arterial hypertension.

*— Average wholesale cost based on Red Book. New York, NY: Thomson Reuters; 2009.

†—Currently not approved by the FDA (update 12/15/10: sitaxsentan was withdrawn from the market December 2010).

Information from references 6, and 21 through 38.

Table 4.   New Medications for PAH

View Table

Table 4.

New Medications for PAH

Class Medication Dosing Adverse effects Comments Cost per unit* Cost per day

Prostacyclin analogues

Epoprostenol (Flolan)

Commonly started in hospital at 2 ng per kg per minute by continuous intravenous infusion; typical dosing is around 15 ng per kg per minute; titration based on symptoms and adverse effects

Flushing, headache, skeletal pain, diarrhea Local infections (related to central venous catheter system) Abrupt interruption of treatment can lead to worsening of PAH

First medication shown to improve survival in idiopathic PAH21 Improves symptoms, exercise capacity, and hemodynamic measures22,23 Recommended for unstable patients in functional classes III and IV 6

$52 for 1.5-mg intravenous dose

$52, based on 15 ng per kg per minute for patient weighing 70 kg (154 lb)

Iloprost (Ventavis)

Inhaled: 2.5 to 5.0 mcg taken six to nine times per day, but not more than once every two hours, via adaptive aerosol device Intravenous infusion: maintenance dosage of 2 to 4 ng per kg per minute Oral: 50 to 300 mcg twice per day

Cough (from inhaled formulation), flushing, headaches, insomnia, vomiting

Inhaled formulation shows small but statistically significant improvement of symptoms in patients with severe PAH24 Approved for patients in functional classes III and IV

$39 for 2-mL inhalation (10 mcg per mL)

$39, based on 2.5 mcg via inhaled formulation eight times per day

Treprostinil (Remodulin)

Maintenance dosage typically around 15 ng per kg per minute via continuous subcutaneous or intravenous infusion

Similar to epoprostenol, including facial flushing, headache, jaw pain, nausea, diarrhea Infusion site pain occurs in 85 percent of patients; can lead to discontinuation of treatment in 8 percent of patients when administered via continuous transcutaneous system26 Increased risk of gram-negative bacteremia27

Improves exercise capacity; hemodynamics and survival similar to epoprostenol25 Approved for patients in functional classes II and III; intravenous use approved in patients who cannot tolerate subcutaneous infusion6

$1,345 for 20-mL multidose vial (1 mg per mL)

$100, based on 15 ng per kg per minute for patient weighing 70 kg

Endothelin receptor antagonists

Ambrisentan (Letairis)

5 to 10 mg orally once per day

Generally well tolerated Adverse effects generally unrelated to dose28 Peripheral edema mostly in patients older than 65 years28 Hepatic transaminase elevations occur at lower rate than with bosentan28

Prescribed only through the Letairis Education and Access Program Specific to endothelin A receptor Approved in the United States in 2007 for patients in functional classes II and III29,30 FDA requires liver function testing once per month and hematocrit testing every three months Contraindicated in pregnancy

$192 for 10-mg tablet

$192 for 10 mg per day

Bosentan (Tracleer)

125 mg orally twice per day

Dose-dependent reversible elevations of hepatic transaminase levels in 10 percent of patients Anemia and edema can occur

Nonspecific endothelin receptor antagonist Improves hemodynamics, exercise capacity, and echocardiographic results; delays time to clinical worsening31-33 Approved for patients with symptomatic heart failure; benefits shown in patients in functional class II34 FDA requires liver function testing once per month and hematocrit testing every three months

$96 for 125-mg tablet

$192

Sitaxsentan†

Dosages of 100 to 300 mg orally once per day are being studied

Appears similar to other medications in the class

Specific to endothelin A receptor Benefit and safety demonstrated,35 although currently not approved by the FDA

NA

NA

Phosphodiesterase type 5 inhibitors

Sildenafil (Revatio)

20 mg orally three times per day (FDA-approved for PAH treatment)

Headache, dyspepsia, flushing

Improves cardiopulmonary hemodynamics and exercise capacity36,37

$17 for 20-mg tablet

$51

Tadalafil (Adcirca)

2.5 to 40 mg orally once per day (40 mg was needed for statistically significant effects38)

Headache, flushing, myalgias38

Slowed incidence of clinical worsening and improved six-minute walk test38 Approved in the United States in 2009 for patients in functional classes II and III

$19 for 20-mg tablet

$38 for 40 mg per day


FDA = U.S. Food and Drug Administration; NA = not applicable; PAH = pulmonary arterial hypertension.

*— Average wholesale cost based on Red Book. New York, NY: Thomson Reuters; 2009.

†—Currently not approved by the FDA (update 12/15/10: sitaxsentan was withdrawn from the market December 2010).

Information from references 6, and 21 through 38.

Endothelin is a potent vasoconstrictor and stimulator of vascular smooth muscle cell proliferation and is believed to be important in the pathophysiology of PAH.39 In the United States, currently available ERAs include ambrisentan (Letairis) and bosentan (Tracleer). A third ERA, sitaxsentan, is undergoing investigation pending approval from the U.S. Food and Drug Administration (update 12/15/10: sitaxsentan was withdrawn from the market December 2010).

Phosphodiesterase type 5 inhibitors increase the intracellular concentration of cyclic guanosine mono-phosphate, increase nitric oxide (which induces relaxation of blood vessels), and create antiproliferative effects on vascular smooth muscle cells. Sildenafil (Revatio) and tadalafil (Adcirca) are two phosphodi-esterase type 5 inhibitors currently approved for PAH treatment.

Because multiple pathophysiological mechanisms may be involved in PAH, combination therapy may be considered. The addition of sildenafil to epoprostenol monotherapy has been shown to safely improve pulmonary arterial pressure.40 More research is needed in this area. More research is also needed to determine whether patients with different types of PAH should have different treatment strategies.

INTERVENTIONAL PROCEDURES

Severe PAH may benefit from an interatrial defect by allowing right-to-left shunting and increasing systemic output. Balloon atrial septostomy has been evaluated only in small studies and the benefit is uncertain. Mortality rates for this procedure range from 5 to 15 percent.7  At this time, balloon atrial septostomy is recommended only for patients in advanced functional classes III and IV (Table 541) to relieve symptoms before lung transplantation or as a sole treatment modality when no other options are available.6

Table 5.

Functional Assessment Classification of Patients with Pulmonary Hypertension

Class Description

I

Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea, fatigue, chest pain, or near syncope.

II

Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest, but ordinary physical activity causes undue dyspnea, fatigue, chest pain, or near syncope.

III

Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest, but less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or near syncope.

IV

Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. They manifest signs of right- sided heart failure. Dyspnea and/or fatigue may be present at rest. Discomfort is increased by any physical activity.


Adapted with permission from Rich S, ed. Executive summary from the World Symposium on Primary Pulmonary Hypertension 1998. Evian, France, September 6–10, 1998; cosponsored by the World Health Organization.

Table 5.   Functional Assessment Classification of Patients with Pulmonary Hypertension

View Table

Table 5.

Functional Assessment Classification of Patients with Pulmonary Hypertension

Class Description

I

Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea, fatigue, chest pain, or near syncope.

II

Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest, but ordinary physical activity causes undue dyspnea, fatigue, chest pain, or near syncope.

III

Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest, but less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or near syncope.

IV

Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. They manifest signs of right- sided heart failure. Dyspnea and/or fatigue may be present at rest. Discomfort is increased by any physical activity.


Adapted with permission from Rich S, ed. Executive summary from the World Symposium on Primary Pulmonary Hypertension 1998. Evian, France, September 6–10, 1998; cosponsored by the World Health Organization.

Lung transplantation has been evaluated only in prospective uncontrolled series because formal randomized controlled trials are considered unethical in the absence of alternative treatment options. The three- and five-year survival rates after transplantation are 55 and 45 percent, respectively.6 Lung and heart-lung transplantation are indicated in patients in advanced functional classes III and IV who are refractory to available medical treatments.6 Compared with other lung transplant recipients, patients with PAH have a poorer postoperative course and a higher mortality rate.42 The unpredictability of the waiting list period and the donor organ shortage complicate the decision-making process.

Prognosis, Preventive Care, and Pregnancy

There is no cure for PAH, and the overall prognosis is poor. The course of PAH is progressive and irreversible, with an approximate mortality rate of 15 percent within one year, despite modern therapy.43 Lifestyle changes and appropriate therapy can relieve symptoms and potentially slow disease progression.

Patients with PAH should receive the pneumococcal vaccine and annual influenza immunization. Smoking cessation is recommended. A healthy lifestyle, including physical activity as tolerated and a nutritious diet, is also advised.

The mortality rate for pregnant women with PAH approaches 30 percent.4446 Contraception is strongly recommended in women of childbearing age with PAH,44,45 particularly mechanical contraception (intrauterine device) or surgical sterilization.47

The Authors

RICHARD STRINGHAM, MD, FAAFP, is an assistant professor of clinical family medicine in the Department of Family Medicine and associate director of medical student education at the University of Illinois at Chicago College of Medicine.

NIPA R. SHAH, MD, is an associate professor of clinical family medicine in the Department of Family Medicine and director of medical student education at the University of Illinois at Chicago College of Medicine.

Address correspondence to Richard Stringham, MD, FAAFP, University of Illinois at Chicago College of Medicine, 1919 W. Taylor St., Chicago, IL 60612 (e-mail: rstring@uic.edu). Reprints are not available from the authors.

The authors thank Bharati Prasad, MD, for her assistance in the preparation of the manuscript. Dr. Prasad practices pulmonary, critical care, and sleep medicine at the University of Illinois at Chicago College of Medicine.

Author disclosure: Nothing to disclose.

REFERENCES

1. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173(9):1023–1030.

2. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987;107(2):216–223.

3. Simonneau G, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(1 suppl):S43–S54.

4. Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12 suppl S):40S–47S.

5. Nauser TD, Stites SW. Diagnosis and treatment of pulmonary hypertension. Am Fam Physician. 2001;63(9):1789–1798.

6. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association [published correction appears in Circulation. 2009;120(2):e13]. Circulation. 2009;119(16):2250–2294.

7. Galiè N, Torbicki A, Barst R, et al. 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. Eur Heart J. 2004;25(24):2243–2278.

8. Henkens IR, Gan CT, van Wolferen SA, et al. ECG monitoring of treatment response in pulmonary arterial hypertension patients. Chest. 2008;134(6):1250–1257.

9. Denton CP, Cailes JB, Phillips GD, Wells AU, Black CM, Bois RM. Comparison of Doppler echocardiography and right heart catheterization to assess pulmonary hypertension in systemic sclerosis. Br J Rheumatol. 1997;36(2):239–243.

10. Ben-Dor I, Kramer MR, Raccah A, et al. Echocardiography versus right-sided heart catheterization among lung transplantation candidates. Ann Thorac Surg. 2006;81(3):1056–1060.

11. Mogollón Jiménez MV, Escoresca Ortega AM, Cabeza Letrán ML, et al. Correlation of echocardiographic and hemodynamic parameters in pulmonary hypertension assessment prior to heart transplantation. Transplant Proc. 2008;40(9):3023–3024.

12. Sitbon O, Lascoux-Combe C, Delfraissy JF, et al. Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med. 2008;177(1):108–113.

13. Caldas MC, Meira ZA, Barbosa MM. Evaluation of 107 patients with sickle cell anemia through tissue Doppler and myocardial performance index. J Am Soc Echocardiogr. 2008;21(10):1163–1167.

14. Hachulla E, Gressin V, Guillevin L, et al. Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum. 2005;52(12):3792–3800.

15. Kittipovanonth M, Bellavia D, Chandrasekaran K, Villarraga HR, Abraham TP, Pellikka PA. Doppler myocardial imaging for early detection of right ventricular dysfunction in patients with pulmonary hypertension. J Am Soc Echocardiogr. 2008;21(9):1035–1041.

16. Benza R, Biederman R, Murali S, Gupta H. Role of cardiac magnetic resonance imaging in the management of patients with pulmonary arterial hypertension. J Am Coll Cardiol. 2008;52(21):1683–1692.

17. Sitbon O, Humbert M, Jaïs X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111(23):3105–3111.

18. Miyamoto S, Nagaya N, Satoh T, et al. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2000;161(2 pt 1):487–492.

19. Frank H, Mlczoch J, Huber K, Schuster E, Gurtner HP, Kneussl M. The effect of anticoagulant therapy in primary and anorectic drug-induced pulmonary hypertension. Chest. 1997;112(3):714–721.

20. Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med. 1992;327(2):76–81.

21. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40(4):780–788.

22. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002;106(12):1477–1482.

23. Paramothayan NS, Lasserson TJ, Wells AU, Walters EH. Prostacyclin for pulmonary hypertension in adults. Cochrane Database Syst Rev. 2005;(2):CD002994.

24. Olschewski H, Simonneau G, Galiè N, et al.; Aerosolized Iloprost Randomized Study Group. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002;347(5):322–329.

25. Skoro-Sajer N, Lang I, Naeije R. Treprostinil for pulmonary hypertension. Vasc Health Risk Manag. 2008;4(3):507–513.

26. Simonneau G, et al.; Treprostinil Study Group. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo- controlled trial. Am J Respir Crit Care Med. 2002;165(6):800–804.

27. Centers for Disease Control and Prevention (CDC). Bloodstream infections among patients treated with intravenous epoprostenol or intravenous treprostinil for pulmonary arterial hypertension—seven sites, United States, 2003–2006. MMWR Morb Mortal Wkly Rep. 2007;56(8):170–172.

28. Kingman M, Ruggiero R, Torres F. Ambrisentan, an endothelin receptor type A-selective endothelin receptor antagonist, for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother. 2009;10(11):1847–1858.

29. Hrometz SL, Shields KM. Role of ambrisentan in the management of pulmonary hypertension [published correction appears in Ann Pharmacother. 2009;43(4):794]. Ann Pharmacother. 2008;42(11):1653–1659.

30. Galiè N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. 2008;117(23):3010–3019.

31. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension [published correction appears in N Engl J Med. 2002;346(16):158]. N Engl J Med. 2002;346(12):896–903.

32. Sitbon O, Gressin V, Speich R, et al. Bosentan for the treatment of human immunodeficiency virus-associated pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004;170(11):1212–1217.

33. McLaughlin VV, Sitbon O, Badesch DB, et al. Survival with first-line bosentan in patients with primary pulmonary hypertension [published correction appears in Eur Respir J. 2005;25(5):942]. Eur Respir J. 2005;25(2):244–249.

34. Galiè N, Rubin LJ, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008;371(9630):2093–2100.

35. Benza RL, Barst RJ, Galie N, et al. Sitaxsentan for the treatment of pulmonary arterial hypertension: a 1-year, prospective, open-label observation of outcome and survival [published correction appears in Chest. 2009;135(4):1114]. Chest. 2008;134(4):775–782.

36. Pepke-Zaba J, Gilbert C, Collings L, Brown MC. Sildenafil improves health-related quality of life in patients with pulmonary arterial hypertension. Chest. 2008;133(1):183–189.

37. Shafiq N, Reddy S, Pandhi P, Manoj R, Talwar KK, Malhotra S. Sildenafil for pulmonary hypertension: need for evidence generation. Int J Clin Pharmacol Ther. 2008;46(12):644–651.

38. Galiè N, Brundage BH, Ghofrani HA, et al.; Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119(22):2894–2903.

39. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004;351(16):1655–1665.

40. Simonneau G, Rubin LJ, Galiè N, et al.; PACES Study Group. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial [published corrections appear in Ann Intern Med. 2009;150(1):63, and Ann Intern Med. 2009;151(6):435]. Ann Intern Med. 2008;149(8):521–530.

41. Rich S, ed. Executive summary from the World Symposium on Primary Pulmonary Hypertension 1998. Evian, France, September 6–10,1998; cosponsored by the World Health Organization.

42. Ceriana P, Kiersy C, Veronesi R, Braschi A, D'Armini A, Viganò M. Influence of underlying lung disease on early postoperative course after single lung transplantation. Cardiovasc Surg (Torino). 2002;43(5):715–722.

43. Thenappan T, Shah SJ, Rich S, Gomberg-Maitland M. A USA-based registry for pulmonary arterial hypertension: 1982–2006. Eur Respir J. 2007;30(6):1103–1110.

44. Bonnin M, Mercier FJ, Sitbon O, et al. Severe pulmonary hypertension during pregnancy: mode of delivery and anesthetic management of 15 consecutive cases. Anesthesiology. 2005;102(6):1133–1137.

45. Sitbon O, Humbert M, Simonneau G. Primary pulmonary hypertension: current therapy. Prog Cardiovasc Dis. 2002;45(2):115–128.

46. Weiss BM, Zemp L, Seifert B, Hess OM. Outcome of pulmonary vascular disease in pregnancy: a systematic overview from 1978 through 1996. J Am Coll Cardiol. 1998;31(7):1650–1657.

47. Boutet K, Montani D, Jaïs X, et al. Therapeutic advances in pulmonary arterial hypertension. Ther Adv Respir Dis. 2008;2(4):249–265.


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