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).
View Image | Two-dimensional short-axis echocardiogram image. Note the flattened interventricular septum due to right ventricular overload. |
Symptoms of IPAH are nonspecific and commonly include the following:
Cardiovascular examination in patients with PAH often reveals the following findings:
Other findings may include the following:
See Clinical Presentation for more detail.
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
Imaging studies
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.
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
See Treatment and Medication for more detail.
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.
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] :
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.
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.
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.
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]
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 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.
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:
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 findings in persons with PAH can be quite variable.
Cardiovascular examination often reveals the following findings:
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 of IPAH include the following:
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]
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 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.)
View Image | Two-dimensional short-axis echocardiogram image. Note the flattened interventricular septum due to right ventricular overload. |
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.
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.
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.
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.)
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.
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.
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.
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.
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.
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.
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]
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.
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.
Approved medications for PAH (including IPAH) currently available in the United States are as follows:
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]
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:
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]
Patients with IPAH may benefit from therapy with anticoagulants, digoxin, diuretics, or supplemental oxygen.
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 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.
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.
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]
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.
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.
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.
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.
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.
The following clinical guidelines on treatment of PAH have been published:
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.
Clinical Context: 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.
Clinical Context: 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.
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.
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: 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.
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.
Clinical Context: 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.
Clinical Context: 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.
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.
Clinical Context: 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.
Clinical Context: 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.
Inhaled prostacyclin (PGI2) synthetic analogues are an alternative to parenteral administration. They are used in an attempt to limit systemic adverse effects.
Clinical Context: 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.
Oral prostacyclin (PGI2) synthetic analogues are an alternative to parenteral administration.
Clinical Context: 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.
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).
Clinical Context: 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.
Clinical Context: 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).
Clinical Context: 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).
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.
Clinical Context: 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.
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.
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: Spironolactone is a potassium-sparing diuretic. Potassium-sparing diuretics may have a role in ameliorating the sometimes-intractable hypokalemia observed with daily diuretic use.
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.
Clinical Context: 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.
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.
Clinical Context: 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.
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.