Review
`
`Evaluation and Management of the Patient with Pulmonary
`Arterial Hypertension
`
`Lewis J. Rubin, MD, and David B. Badesch, MD
`
`Increased pressure in the pulmonary circulation, or pulmonary
`hypertension, is a common disorder that may complicate various
`cardiopulmonary conditions, including severe obstructive airways
`disease and left ventricular dysfunction. An increase in pulmonary
`arterial pressure that is not due to coexistent cardiopulmonary
`disease, known as pulmonary arterial hypertension, may occur in
`the absence of a demonstrable cause (idiopathic or familial); as a
`complication of systemic conditions, such as connective tissue
`disease, HIV infection, or chronic liver disease; or as a result of the
`use of fenfluramine anorexigens, amphetamines, or cocaine. The
`
`development of disease-specific therapies for pulmonary arterial
`hypertension over the past decade underscores the importance of
`diagnosing pulmonary hypertension early in the course of the
`condition and implementing a treatment strategy that is based on
`the condition’s cause and severity. In this review, the authors
`present approaches to the diagnosis and management of pulmo-
`nary arterial hypertension, using a hypothetical case to highlight
`the key management points.
`
`Ann Intern Med. 2005;143:282-292.
`For author affiliations, see end of text.
`
`www.annals.org
`
`Until recently, management of pulmonary arterial hy-
`
`pertension (PAH) was generally ineffective in alleviat-
`ing symptoms or improving survival. However, the past
`decade has witnessed remarkable advances in our under-
`standing of the pathogenesis of PAH, advances that have
`led to the development of disease-specific treatments. De-
`spite these achievements, PAH remains a challenging con-
`dition to diagnose and manage. This article reviews recent
`developments in the diagnosis and management of PAH in
`the context of a typical case, illustrating the importance of
`collaboration between the internist and the specialist in
`patient care.
`
`A 33-year-old woman presented to her primary care phy-
`sician with a 6-month history of gradually progressive exer-
`tional dyspnea. She had lightheadedness and near-syncope while
`climbing steps. She was mildly obese but had otherwise previously
`been in good health. Her vital signs were normal, her lungs were
`clear, and cardiac examination showed a slightly prominent sec-
`ond heart sound and a systolic murmur over the left-heart border.
`An initial diagnosis of exercise-induced asthma was made, and
`use of an inhaled bronchodilator was prescribed.
`The patient’s symptoms did not diminish. A chest radio-
`graph showed mild cardiomegaly and a slightly prominent
`main pulmonary artery. Pulmonary function tests showed only
`a mild reduction in the diffusing capacity for carbon monox-
`ide, and an electrocardiogram showed right-axis deviation and
`possible right ventricular hypertrophy. On the basis of these
`results, echocardiography was done, and the echocardiogram
`showed right ventricular hypertrophy, right atrial enlargement,
`flattening of the interventricular septum, and moderate tricus-
`pid regurgitation with an estimated pulmonary artery systolic
`pressure of 60 mm Hg. Serologic test results did not suggest
`connective tissue disease. A ventilation–perfusion lung scan
`was normal. Overnight oximetry showed mild nocturnal oxy-
`gen desaturation, and a formal sleep study excluded sleep ap-
`nea syndrome. The patient was referred to a regional center
`with a provisional diagnosis of pulmonary hypertension.
`
`282 © 2005 American College of Physicians
`
`WHAT IS PULMONARY HYPERTENSION, AND WHEN IS
`IT CONSIDERED TO BE PRESENT?
`Pulmonary hypertension is an elevation in pulmonary
`vascular pressure that can be caused by an isolated increase
`in pulmonary arterial pressure or by increases in both pul-
`monary arterial and pulmonary venous pressures. The term
`pulmonary arterial hypertension refers to conditions that
`share common isolated elevations in pulmonary arterial
`pressure (Table 1), hemodynamically defined as a resting
`mean pulmonary arterial pressure greater than 25 mm Hg
`with a normal pulmonary capillary or left atrial pressure
`(⬍15 mm Hg) (1, 2). Pulmonary arterial hypertension that
`occurs without a demonstrable cause, formerly known as
`primary pulmonary hypertension, may occur sporadically (id-
`iopathic PAH) or as an inherited condition (familial PAH).
`Mutations in the bone morphogenetic protein receptor II
`gene occur in approximately 50% of families with a history
`of familial PAH and in nearly 25% of patients believed to
`have sporadic idiopathic PAH (3, 4). Genetic testing and
`counseling have been recommended for relatives of pa-
`tients with familial PAH (4). Pulmonary arterial hyperten-
`sion occurs in association with connective tissue diseases,
`particularly scleroderma (5–9); HIV infection (10 –12);
`sickle-cell disease (13); and chronic liver disease (14, 15).
`Pulmonary hypertension is suggested when an echocardio-
`gram-derived estimate of pulmonary arterial systolic pres-
`sure exceeds 40 mm Hg at rest.
`
`See also:
`
`Web-Only
`CME quiz
`Conversion of figure and tables into slides
`
`Liquidia's Exhibit 1052
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`

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`Evaluation and Management of the Patient with Pulmonary Arterial Hypertension
`
`Review
`
`WHEN SHOULD PAH BE SUSPECTED?
`Although PAH may be asymptomatic, exertional dysp-
`nea is the most frequently encountered symptom (16). Ac-
`cordingly, PAH should be suspected in patients with un-
`explained dyspnea. Angina or syncope is less common and
`portends a poor prognosis. Peripheral edema or ascites in-
`dicates right ventricular failure. The symptoms of PAH are
`nonspecific and are similar to those in more common dis-
`eases, such as obstructive lung disease and left-sided heart
`disease.
`A family history of pulmonary hypertension may lead
`to early recognition of clinical disease in other persons
`(17). A history of use of fenfluramine appetite suppressants
`(18, 19) and current or previous use of amphetamines or
`cocaine should be explored, because these factors have been
`implicated in the development of PAH in some users. A
`history of acute pulmonary embolism requires a careful
`search for chronic thromboembolic pulmonary hyperten-
`sion, although this condition may occur in the absence of
`symptomatic venous thromboembolic disease (20).
`
`WHEN PAH IS SUSPECTED, HOW DO YOU CONFIRM
`THE DIAGNOSIS AND ESTABLISH A CAUSE?
`The diagnostic strategy systematically uses testing to
`determine whether the patient’s symptoms are due to PAH
`and, if so, the underlying cause (Figure). Screening with
`less invasive, less complex, and lower-risk tests is followed
`by specific and direct confirmatory tests.
`The electrocardiogram may provide evidence of hemo-
`dynamically significant pulmonary hypertension, such as
`right ventricular hypertrophy, right-axis deviation, or right
`atrial enlargement. Radiographic signs of pulmonary hy-
`pertension include enlarged main and hilar pulmonary ar-
`terial shadows (⬎17 mm) with attenuation of peripheral
`pulmonary vascular markings (pruning). Right ventricular
`enlargement is evidenced by anterior displacement of the
`right ventricle into the retrosternal space on the lateral
`view. The chest radiograph is also useful in showing co-
`morbid or causal conditions, such as pulmonary venous
`congestion, chronic obstructive pulmonary disease, or in-
`terstitial lung disease.
`Doppler echocardiography is often the first test with
`results that suggest a diagnosis of pulmonary hypertension
`(21). Echocardiography also provides information about
`the cause and consequences of pulmonary hypertension.
`Studies in patients with PAH (22–25) have reported good
`correlations between Doppler-derived estimates of pulmo-
`nary arterial systolic pressure and direct measurements ob-
`tained by right-heart catheterization. Echocardiography
`also provides direct evidence about left ventricular systolic
`and diastolic function, as well as valvular function and
`morphologic characteristics that can give clues to causes of
`pulmonary hypertension due to elevated pulmonary ve-
`nous pressures. Left atrial enlargement, even in the absence
`of definite left ventricular dysfunction, should raise the
`
`www.annals.org
`
`Table 1. Nomenclature and Classification of Pulmonary
`Hypertension*
`
`Pulmonary arterial hypertension
`Sporadic
`Familial
`Related to:
`Collagen vascular disease
`Congenital systemic-to-pulmonary shunts (large, small, repaired, or
`nonrepaired)
`Portal hypertension
`HIV infection
`Drugs and toxins
`Other (glycogen storage disease, Gaucher disease, hereditary
`hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative
`disorders, splenectomy)
`Associated with significant venous or capillary involvement
`Pulmonary veno-occlusive disease
`Pulmonary capillary hemangiomatosis
`
`Pulmonary venous hypertension
`Left-sided atrial or ventricular heart disease
`Left-sided valvular heart disease
`
`Pulmonary hypertension associated with hypoxemia
`Chronic obstructive pulmonary disease
`Interstitial lung disease
`Sleep-disordered breathing
`Alveolar hypoventilation disorders
`Long-term exposure to high altitude
`
`Pulmonary hypertension due to chronic thrombotic or embolic disease
`Thromboembolic obstruction of proximal pulmonary arteries
`Thromboembolic obstruction of distal pulmonary arteries
`Pulmonary embolism (tumor, parasites, foreign material)
`
`Miscellaneous
`Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary
`vessels (adenopathy, tumor, fibrosing mediastinitis)
`
`* Adapted with permission from reference 1. This classification schema was based
`on one proposed at the 3rd World Conference on Pulmonary Hypertension,
`Venice, Italy, 2003.
`
`possibility of elevated left-sided filling pressures that may
`contribute to pulmonary hypertension.
`The evaluation of PAH includes assessment for an un-
`derlying autoimmune– collagen vascular disorder, includ-
`ing physical examination and serologic testing for anti-
`nuclear antibodies. However, as many as 40% of patients
`with idiopathic PAH have serologic abnormalities (16),
`usually an antinuclear antibody in a low titer and nonspe-
`cific pattern. Additional serologic studies may be appropri-
`ate if initial testing suggests an underlying autoimmune
`disorder.
`Pulmonary function testing is necessary in the initial
`evaluation of patients with suspected pulmonary hyperten-
`sion, primarily to exclude or characterize the contribution
`of underlying airways or parenchymal lung disease. In gen-
`eral, the degree of pulmonary hypertension in patients with
`chronic obstructive lung disease is less severe than that in
`patients with PAH, and the presence and severity of pul-
`monary hypertension correlate with the degree of airflow
`obstruction and hypoxemia. Approximately 20% of pa-
`tients with idiopathic PAH have a mild restrictive defect
`(16). In chronic thromboembolic pulmonary hypertension,
`
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`Review Evaluation and Management of the Patient with Pulmonary Arterial Hypertension
`
`Figure. Guideline for approaching the differential diagnosis of pulmonary hypertension (PH).
`
`Is There a Reason To Suspect PAH?
`Clinical history (symptoms, risk factors, family history),
`Do examination, radiography, ECG
`
`No
`
`No further
`evaluation for
`PAH
`
`Yes
`
`Is PAH
`Likely?
`Do echocardiography
`
`Rationale
`
`Yes
`
`Is PH due to
`Left-Heart Disease?
`Do echocardiography
`
`No
`
`Is PAH due to
`CHD?
`Do echocardiography
`with contrast
`
`No
`
`Is PAH due to
`CTD, HIV?
`Do serologic tests
`
`No
`
`Is Chronic PE
`Suspected?
`Do VQ scan
`
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`No
`
`VQ normal
`
`TRV to measure RVSP; RVE; RAE; RV dysfunction
`
`Diagnosis of LV systolic, diastolic dysfunction and valvular disease:
`Appropriate treatment and further evaluation if necessary, including
`right- and left-heart catheterization
`
`Diagnosis of abnormal morphologic characteristics, shunt:
`Surgery. Medical treatment of PAH or evaluation for further definition or other contribution,
`including right- and left-heart catheterization
`
`Diagnosis of scleroderma, SLE, other CTD, HIV infection:
`Medical treatment of PAH and further evaluation for other contributing causes,
`including right- and left-heart catheterization
`
`Is Chronic PE Confirmed
`and Operable?
`Do pulmonary angiography
`
`Yes
`
`No
`
`Anatomic definition (CT and MRI may provide
`additional useful but not definitive information):
`Do thromboendarterectomy if appropriate or
`medical treatment; clotting evaluation
`
`Is PAH due to Lung Disease
`or Hypoxemia?
`Do PFTs, arterial saturation
`
`Yes
`
`Diagnosis of parenchymal lung disease, hypoxemia, or sleep disorder:
`Medical treatment, oxygen, positive-pressure breathing as appropriate, and further
`evaluation for other contributing causes, including right-heart catheterization if necessary
`
`No
`
`What Limitations Are
`Caused by PAH?
`Functional class;
`6-minute walk test
`
`Document exercise capacity regardless of cause of PH:
`Establish baseline and prognosis and document progression/response to treatment with
`serial reassessments
`
`What Are the Precise
`Pulmonary
`Hemodynamic Characteristics?
`Right-heart catheterization
`
`Document PA and RA pressures, PCWP (LV or LA pressure if PCWP unobtainable or
`uncertain), transpulmonary gradient, CO, PVR, SvO2, response to vasodilators:
`Confirm PAH, or IPAH if no other cause identified; discuss genetic testing and counseling
`of IPAH family members; refer to section on Therapy
`
`CHD ⫽ congenital heart disease; CO ⫽ cardiac output; CT ⫽ contrast-enhanced computed tomography of the chest; CTD ⫽ connective tissue disease;
`ECG ⫽ electrocardiogram; Echo ⫽ Doppler transthoracic echocardiogram; IPAH ⫽ idiopathic pulmonary arterial hypertension; LA ⫽ left atrial; LV ⫽ left
`ventricular; MRI ⫽ magnetic resonance imaging; PA ⫽ pulmonary arterial; PAH ⫽ pulmonary arterial hypertension; PCWP ⫽ pulmonary capillary wedge
`pressure; PE ⫽ pulmonary embolism; PFTs ⫽ pulmonary function tests; PVR ⫽ pulmonary vascular resistance; RA ⫽ right atrial; RAE ⫽ right atrial
`enlargement; RV ⫽ right ventricular; RVE ⫽ right ventricular enlargement; RVSP ⫽ right ventricular systolic pressure; SLE ⫽ systemic lupus erythematosus;
`⫽ mixed venous oxygen saturation; TRV ⫽ tricuspid regurgitant velocity; VQ ⫽ ventilation–perfusion. (Adapted with permission from reference 1.)
`SvO2
`
`284 16 August 2005 Annals of Internal Medicine Volume 143 • Number 4
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`Evaluation and Management of the Patient with Pulmonary Arterial Hypertension
`
`Review
`
`a mild to moderate restrictive defect is thought to be due to
`parenchymal scarring from previous infarctions (26). In
`both conditions, the diffusing capacity for carbon monox-
`ide is often mildly to moderately reduced (16, 26). Mild to
`moderate arterial hypoxemia is due to ventilation–perfu-
`sion mismatch and reduced mixed venous oxygen satura-
`tion resulting from low cardiac output. Severe hypoxemia
`is due to right-to-left
`intracardiac or
`intrapulmonary
`shunting. Twenty percent of patients with systemic sclero-
`sis have an isolated reduction in diffusing capacity (27); a
`diffusing capacity less than 45% to 55% of predicted or
`one that is decreasing may signal the development of pul-
`monary hypertension (28).
`Overnight oximetry may show frequent desaturations
`and may be the first clue to sleep apnea sufficient to con-
`tribute to pulmonary hypertension. Nocturnal hypoxemia
`occurs in more than 75% of patients with idiopathic PAH
`without sleep apnea (29). Because hypoxemia is a potent
`pulmonary vasoconstrictor, all patients with unexplained
`pulmonary hypertension require assessment of oxygen sat-
`uration during both sleep and exercise (30).
`Chronic thromboembolic pulmonary hypertension is
`potentially curable and should be sought in all patients
`with pulmonary hypertension. Ventilation–perfusion lung
`scanning is the preferred test to evaluate for this condition
`(4). Chronic thromboembolic pulmonary hypertension
`manifests as at least 1 segmental-sized or larger perfusion
`defect, which is typically mismatched and larger than ven-
`tilation abnormalities (20, 31, 32). Patchy, nonsegmental
`defects are less specific but may be associated with chronic
`thromboembolic pulmonary hypertension. Perfusion scans
`tend to underestimate the extent of large-vessel obstruction
`in this condition (32). Although a normal perfusion scan
`essentially excludes surgically accessible chronic thrombo-
`embolic disease, scans suggestive of thromboembolic dis-
`ease may also be seen in patients with pulmonary arterial
`sarcoma, large-vessel pulmonary arteritis, extrinsic vascular
`compression, or pulmonary veno-occlusive disease (33).
`Pulmonary angiography is the definitive test for diagnosing
`chronic thromboembolic pulmonary hypertension and de-
`termining operability, and it should be done in experi-
`enced centers when chronic thromboembolic pulmonary
`hypertension remains possible.
`Computed tomographic scanning may suggest a cause
`of PAH, such as severe airway or parenchymal lung dis-
`eases. A spectrum of abnormalities on computed tomo-
`graphic scans has been described in chronic thromboem-
`bolic pulmonary hypertension, including right ventricular
`enlargement, dilated central pulmonary arteries, chronic
`thromboembolic material within the central pulmonary ar-
`teries, increased bronchial artery collateral flow, variability
`in the size and distribution of pulmonary arteries, paren-
`chymal abnormalities consistent with previous infarctions,
`and mosaic attenuation of the pulmonary parenchyma
`(34). A ground-glass, mosaic-attenuation pattern predom-
`
`www.annals.org
`
`inantly in the lower lobes is also suggestive of pulmonary
`veno-occlusive disease (35).
`Cardiac catheterization is ultimately required to con-
`firm the presence of pulmonary hypertension, definitively
`establish its cause, assess severity, and guide therapy. Open
`or thoracoscopic lung biopsy entails substantial risk for
`hemorrhage, hypoxemia, and death in patients with PAH.
`Because it has a low likelihood of altering the clinical di-
`agnosis, routine biopsy is discouraged. Under certain cir-
`cumstances, histopathologic diagnosis may be needed
`when vasculitis, granulomatous or interstitial lung disease,
`pulmonary veno-occlusive disease, or bronchiolitis are sug-
`gested clinically (36).
`
`Initial evaluation at the referral center included a 6-min
`walk test of 305 m. Right-heart catheterization showed a pul-
`monary arterial pressure of 65/30 mm Hg (mean, 42 mm
`Hg), right atrial pressure of 12 mm Hg, pulmonary capillary
`wedge pressure of 6 mm Hg, and cardiac output of 3.2 L/min.
`Little change was seen in hemodynamic measurements with
`the inhalation of nitric oxide. The patient was thought to have
`idiopathic PAH, falling into New York Heart Association
`(NYHA) functional class III on the basis of her symptoms.
`Treatment options were discussed with the patient and her
`family. Medical therapy, diet, exercise, travel, altitude expo-
`sure, and pregnancy were all discussed.
`There are few data on which to base recommendations
`about physical activity or cardiopulmonary rehabilitation
`in patients with PAH. Potentially hazardous exposure ac-
`tivities are listed in Table 2. We encourage cautious, grad-
`uated physical activity. Heavy physical activity can precip-
`itate exertional
`syncope. Hot baths or
`showers are
`discouraged because the resultant peripheral vasodilatation
`can produce systemic hypotension and syncope. Excessive
`sodium intake can contribute to fluid retention.
`We discourage exposure to high altitudes (more than
`approximately 1800 m above sea level), as this may pro-
`duce hypoxic pulmonary vasoconstriction and further
`compromise oxygen transport. Supplemental oxygen
`should be used to maintain oxygen saturations greater than
`91%. Air travel can be problematic for patients with PAH,
`as commercial aircraft are typically pressurized to the
`equivalent of approximately 2400 m above sea level. While
`on commercial aircraft, patients who have borderline oxy-
`gen saturations at sea level may require 3 to 4 L/min of
`supplemental oxygen, and those already using supplemen-
`tal oxygen at sea level should increase their oxygen flow
`rate. Because of the potentially devastating effects of respi-
`ratory infections,
`immunization against
`influenza and
`pneumococcal pneumonia is recommended.
`The hemodynamic changes occurring during preg-
`nancy impose substantial stress in women with PAH, lead-
`ing to a 30% to 50% mortality rate (37, 38). Although
`successful use of long-term intravenous epoprostenol and
`inhaled nitric oxide to treat pregnant patients with idio-
`
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`Review Evaluation and Management of the Patient with Pulmonary Arterial Hypertension
`
`Table 2. Potentially Hazardous Activities for Patients with Pulmonary Arterial Hypertension
`
`Activity
`
`Exposure to high altitude
`
`Air travel
`
`Heavy exertion
`
`Potential Adverse Effects
`
`Hypoxemia, pulmonary vasoconstriction,
`worsening pulmonary hypertension,
`right-heart failure
`Hypoxemia, pulmonary vasoconstriction,
`worsening pulmonary hypertension
`Near-syncope, syncope
`
`Bending over and rising quickly
`
`Near-syncope, syncope
`
`Use of decongestant medications
`
`Vasoconstriction, worsening pulmonary
`hypertension
`
`Use of appetite suppressants or diet pills
`
`Worsening pulmonary hypertension
`
`High sodium intake
`Cigarette smoking
`
`Fluid retention, right-heart failure
`Worsening of intrinsic lung disease; nicotine
`is a vasoconstrictor and may contribute
`to worsening pulmonary hypertension
`
`Recommendations
`Avoid altitudes ⬎ 1800 m above sea level; use
`supplemental oxygen as needed to keep
`oxygen saturation ⱖ 91% at all times
`Use supplemental oxygen as needed to keep
`oxygen saturation ⱖ 91% at all times
`Engage in low-level activity or cautious,
`graduated exercise, such as walking
`Rise slowly from bending, sitting, or lying
`positions
`Avoid using decongestants; consider nonsedating
`antihistamines or local treatments, such as
`nasal steroids
`Have dietary and nutritional consultation;
`engage in cautious low-level exercise
`Follow 2-g sodium diet
`Stop smoking (preferably without use of nicotine
`replacement therapy)
`
`pathic PAH has been reported (39 – 42), most experts rec-
`ommend early termination of the pregnancy (43).
`Estrogen-containing contraceptives may increase risk
`for venous thromboembolism and are not recommended
`for women of childbearing potential with PAH. Also, the
`endothelin-receptor antagonist bosentan may decrease the
`efficacy of hormonal contraception, and dual mechanical
`barrier contraceptive techniques are recommended in
`women of childbearing age using this medication.
`Physicians should discuss with their patients the use of
`any concomitant medications or herbal preparations. The
`use of vasoconstricting sinus or cold medications (such as
`pseudoephedrine) or the use of serotonergic medications
`for migraine headaches may be problematic. Concomitant
`use of glyburide or cyclosporine with bosentan is contrain-
`dicated, and use of azole-type antifungal agents is discour-
`aged because of potential drug interactions that may in-
`crease risk for hepatotoxicity. Patients using warfarin
`should be cautioned about the many drug interactions pos-
`sible with this medication. Bosentan may slightly decrease
`international normalized ratios in patients using warfarin.
`Invasive procedures and surgery can be associated with
`increased operative and perioperative risks. Patients with
`severe PAH are especially prone to vasovagal events leading
`to syncope, cardiopulmonary arrest, and death. Cardiac
`output is particularly dependent on heart rate in this set-
`ting, and the bradycardia and systemic vasodilatation ac-
`companying a vasovagal event can result in hypotension.
`Heart rate should be monitored during invasive proce-
`dures, and an anticholinergic agent should be readily avail-
`able. Oversedation can lead to ventilatory insufficiency and
`precipitate clinical deterioration. Caution should be used
`with laparoscopic procedures in which carbon dioxide is
`used for abdominal insufflation, as absorption can produce
`hypercarbia, which is a pulmonary vasoconstrictor. Anes-
`thesia and intubation can be particularly problematic be-
`cause they can induce vasovagal events, hypoxemia, hyper-
`
`286 16 August 2005 Annals of Internal Medicine Volume 143 • Number 4
`
`carbia, and shifts in intrathoracic pressure and associated
`changes in cardiac filling pressures.
`
`WHAT ARE THE TREATMENTS FOR PAH, AND HOW
`DOES ONE CHOOSE AND MONITOR THERAPY?
`Medical therapy for PAH has recently been addressed
`in detail in 2 major consensus documents (43, 44) that use
`similar evidence-based therapeutic algorithms.
`General Measures
`Two small retrospective studies (45, 46) reported im-
`proved survival with oral anticoagulation in patients with
`idiopathic PAH. On the basis of these reports and the
`knowledge that microscopic in situ thrombosis can occur,
`anticoagulation with warfarin is recommended. Although
`little evidence is available to guide such therapy, current
`consensus suggests a target international normalized ratio
`of approximately 1.5 to 2.5 (43, 44). Anticoagulation is
`controversial for patients who have PAH due to other
`causes, such as scleroderma or congenital heart disease, be-
`cause of a lack of evidence supporting efficacy, an increased
`risk for gastrointestinal bleeding in patients with sclero-
`derma, and an increased risk for hemoptysis in patients
`with congenital heart disease. The relative risks and bene-
`fits of anticoagulant therapy should be considered on a
`case-by-case basis. Patients with documented right-to-left
`intracardiac shunting due to an atrial septal defect or
`patent foramen ovale and a history of transient ischemic
`attack or embolic stroke should receive anticoagulation.
`Patients treated with long-term intravenous epoprostenol
`generally receive anticoagulation in the absence of contra-
`indications, partly because of the additional risk for cathe-
`ter-associated thrombosis.
`Diuretics are indicated for right ventricular volume
`overload. However, rapid and excessive diuresis may pre-
`cipitate systemic hypotension and renal insufficiency. Spi-
`ronolactone, an aldosterone antagonist that is of benefit in
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`Evaluation and Management of the Patient with Pulmonary Arterial Hypertension
`
`Review
`
`patients with left-heart failure, is also used by some experts
`to treat right-heart failure. Serum electrolytes and renal
`function should be monitored closely.
`Hypoxemia is a pulmonary vasoconstrictor, and sup-
`plemental oxygen should be used to maintain an oxygen
`saturation greater than 90%. Supplemental oxygen use is
`more controversial in patients with Eisenmenger complex
`but may decrease the need for phlebotomy and reduce the
`occurrence of neurologic complications (47).
`Although not extensively studied in PAH, digitalis is
`sometimes used for refractory right ventricular failure (48).
`In addition, atrial flutter or other atrial dysrhythmias often
`complicate late-stage right-heart dysfunction, and digoxin
`may be useful for rate control.
`
`Vasodilator Testing and Calcium-Channel Blockers
`Patients with idiopathic PAH who respond to vasodi-
`lators in the short term have improved survival with long-
`term use of calcium-channel blockers (46, 49). Various
`short-acting agents, including intravenous epoprostenol or
`adenosine and inhaled nitric oxide, have been used to test
`short-term response to vasodilators (50, 51). The recently
`formulated consensus definition of a positive short-term
`response to vasodilators in PAH is a decrease of at least 10
`mm Hg in mean pulmonary arterial pressure to 40 mm Hg
`or less, with increased or unchanged cardiac output (43,
`44). Most experts feel that true vasoreactivity is uncom-
`mon, occurring in approximately 10% of patients with
`idiopathic PAH and rarely in other forms of PAH. Vaso-
`reactivity testing should be done in experienced centers.
`Only patients who have a substantial response to a
`short-acting vasodilator should be considered candidates
`for treatment with oral calcium-channel blockers; treat-
`ment should be monitored closely because maintenance of
`response is not universal. Agents with negative inotropic
`effects, such as verapamil, should be avoided.
`
`Prostanoids
`Prostacyclin is a metabolite of arachidonic acid pro-
`duced in vascular endothelium. It is a potent vasodilator,
`affecting both the pulmonary and systemic circulations,
`and has antiplatelet aggregator effects. A relative deficiency
`of endogenous prostacyclin may contribute to the patho-
`genesis of PAH (52, 53).
`In idiopathic PAH, continuous intravenous infusion
`of epoprostenol improved exercise capacity, as assessed by
`the 6-min walk test; cardiopulmonary hemodynamic vari-
`ables; and survival compared with conventional therapy
`(such as oral vasodilators and anticoagulation) (54). A sim-
`ilar study (55) showed that epoprostenol improved exercise
`capacity and hemodynamic variables in patients with PAH
`due to the scleroderma spectrum of disease. The beneficial
`effects of epoprostenol therapy are sustained for years in
`many patients with idiopathic PAH (56 –59), and epopro-
`stenol therapy remains the treatment of choice for the most
`severely ill patients.
`Epoprostenol therapy is complicated by the need for
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`www.annals.org
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`continuous intravenous infusion. Because epoprostenol has
`a short half-life and has irritant effects on peripheral veins,
`and because of the risk for rebound worsening with inter-
`ruption of the infusion, the drug should be administered
`through an indwelling central venous catheter. Common
`side effects include headache, flushing, jaw pain, diarrhea,
`nausea, a blotchy erythematous rash, and musculoskeletal
`pain. Acute overdose can lead to systemic hypotension, and
`long-term overdosage can produce a hyperdynamic circu-
`latory state with high-output cardiac failure (60). Serious
`complications include catheter-related sepsis and thrombo-
`sis. Although epoprostenol is approved by the U.S. Food
`and Drug Administration for patients in functional NYHA
`class III and IV with idiopathic PAH or PAH due to
`scleroderma,
`it is generally reserved for those with ad-
`vanced disease refractory to oral therapies. Because of its
`complexity, epoprostenol therapy should be given in cen-
`ters experienced with its administration.
`Beraprost is an orally active prostacyclin analogue
`(61). In a 12-week trial done in patients with PAH in
`NYHA functional class II and III, beraprost increased the
`6-min walking distance without substantially affecting car-
`diopulmonary hemodynamic variables or survival (62).
`However, a longer-term trial (63) found that improvement
`was not present after 9 to 12 months. Beraprost is ap-
`proved for treatment of PAH in Japan.
`Treprostinil is a stable prostacyclin analogue with a
`half-life of 3 hours, and it can be administered subcutane-
`ously or intravenously. In a multicenter study of subcuta-
`neously infused treprostinil in patients with PAH (64),
`6-min walking distance and hemodynamic variables im-
`proved modestly with treprostinil compared with placebo.
`Common side effects include pain at the infusion site,
`headache, diarrhea, nausea, rash, and jaw pain. Treprostinil
`is approved by the U.S. Food and Drug Administration for
`subcutaneous or intravenous treatment of patients with
`PAH in NYHA functional class II, III, and IV and is gen-
`erally used when oral therapy has failed to produce benefit.
`To receive treprostinil therapy, patients should be referred
`to experienced centers.
`Iloprost is a stable prostacyclin analogue with a serum
`half-life of 20 to 25 minutes. Although it may be possible
`to administer iloprost intravenously, the drug has gained
`attention recently for delivery by inhalation. In idiopathic
`PAH, short-term inhalation of iloprost resulted in greater
`pulmonary vasodilatation than did nitric oxide (65). For
`long-term use, the relatively short duration of action of
`inhaled iloprost necessitates 6 to 9 inhalations per day (66,
`67). In a 3-month multicenter trial, iloprost administered
`in a dosage of 2.5 or 5 ␮g 6 or 9 times daily improved the
`6-min walking distance and NYHA functional class (68).
`Hemodynamic variables measured after iloprost inhalation
`were also improved at 3 months. Cough, flushing, and
`headache occurred more frequently in the iloprost group
`than in the group receiving placebo. Inhaled iloprost may
`be useful as an adjunct to oral therapy. It is approved in
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`16 August 2005 Annals of Internal Medicine Volume 143 • Number 4 287
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`Liquidia's Exhibit 1052
`Page 6
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`

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`Review Evaluation and Management of the Patient with Pulmonary Arterial Hypertension
`
`Europe for patients with idiopathic PAH in NYHA func-
`tional class III and was recently approved by the U.S. Food
`and Drug Administration for patients with PAH