Pulmonary Hypertension
Pulmonary Hypertension
Introduction
Pulmonary hypertension (PH) is a disorder of the pulmonary circulation in which elevated pressure in the pulmonary vascular circuit can, when severe, lead to right heart failure and eventually cause death. The last 20 years have seen significant advances in our understanding of PH and the development of novel therapies for treatment. Pulmonary arterial hypertension (PAH), a subtype of PH, will be the focus of this article with special attention to its diagnosis and management. A successful and comprehensive approach to the diagnosis and treatment of this complex and rapidly progressive disease requires collaboration between the patient, the resources at the pulmonary hypertension center, and the community resources.[1]
Classification and Staging
For many years, PH was classified as either "primary" or "secondary." In 2003 the Third World Symposium updated the classification system, notably dropping the term "primary" altogether (Table 1).[2] They also stressed that the staging of patients with PH should be based on the functional capacity of the patient rather than on hemodynamic parameters. The World Health Organization classification system, a modified form of the New York Heart Association functional classification system, was recommended by the Symposium as the preferred staging system (Table 2).[3]
Table 1. Revised Clinical Classification of Pulmonary Hypertension (Venice 2003)
|Pulmonary arterial hypertension (PAH) |
|1.1. Idiopathic (IPAH) |
|1.2. Familial (FPAH) |
|1.3. Associated with (APAH): |
|1.3.1. Collagen vascular disease |
|1.3.2. Congenital systemic-to-pulmonary shunts |
|1.3.3. Portal hypertension |
|1.3.4. HIV infection |
|1.3.5. Drugs and toxins |
|1.3.6. Other (thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, |
|myeloproliferative disorders, splenectomy) |
|1.4 Associated with significant venous or capillary involvement |
|1.4.1 Pulmonary veno-occlusive disease (PVOD) |
|1.4.2 Pulmonary capillary hemangiomatosis (PCH) |
|Pulmonary hypertension with left heart disease |
|2.1. Left-sided atrial or ventricular heart disease |
|2.2. Left-sided valvular heart disease |
|Pulmonary hypertension associated with lung disease and/or hypoxemia |
|3.1. Chronic obstructive pulmonary disease |
|3.2. Interstitial lung disease |
|3.3. Sleep-disordered breathing |
|3.4. Alveolar hypoventilation disorders |
|3.5. Chronic exposure to high altitude |
|3.6. Developmental abnormalities |
|Pulmonary hypertension due to chronic thrombotic and/or embolic disease |
|4.1. Thromboembolic obstruction of proximal pulmonary arteries |
|4.2. Thromboembolic obstruction of distal pulmonary arteries |
|4.3. Non-thrombotic pulmonary embolism (tumor, parasites, foreign material) |
|Miscellaneous |
|Sarcoidosis, histiocytosis-X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis) |
Reprinted from: Simmoneau G, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43:10S.[2] Copyright 2004, reprinted with permission from American College of Cardiology Foundation.
Table 2. World Health Organization Classification of Functional Status of Patients with Pulmonary Hypertension
|Class I: Patients with PH without limitation of usual activity |
|Class II: Patients with PH with slight limitation of usual physical activity |
|Class III: Patients with PH with marked limitation of usual physical activity |
|Class IV: Patients with PH with inability to perform any physical activity without symptoms and who may have signs of right ventricular |
|failure |
Adapted from Rubin LJ. Diagnosis and management of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:7S-10S.[3]
Screening
Current recommendations suggest that screening should be performed only on persons at increased risk for developing PAH.[1,4,5] Those with first-degree relatives with idiopathic pulmonary arterial hypertension (IPAH), those with a known genetic mutation that has been associated with the development of familial pulmonary arterial hypertension (FPAH), those with the scleroderma spectrum of diseases, patients with portal hypertension undergoing evaluation for liver transplantation, and patients with congenital heart disease and systemic-to-pulmonary shunts should undergo screening for occult PH. The American College of Chest Physicians (ACCP) recently recommended that genetic testing and counseling should be offered to relatives of patients with FPAH and that patients with IPAH should be made aware of the availability of this testing for their relatives.[5]
Screening is generally done with Doppler echocardiography, but the evidence supporting the use of this test as a screening tool is limited.[5] Exercise echocardiography was studied in 2 families with FPAH in an attempt to detect asymptomatic gene carriers, and the sensitivity of this test was 87.5% with a specificity of 100%.[6] Because the anaerobic threshold and the oxygen consumption at peak exercise are known to be abnormal in patients with PAH, it has been suggested that cardiopulmonary exercise testing (CPET) be used as a screening tool; however, issues regarding the availability, reliability, and safety of this test in patients with PAH have limited its use as a screening tool.[7,8]
Prenatal testing is also available for screening in cases where FPAH has been identified in family members; however, because of the low occurrence of the disease, even when the test is positive, only 10% to 20% will go on to develop PAH. For this reason, the role of prenatal screening has been questioned, particularly if it is being performed for the purpose of pregnancy termination.[5]
Diagnosis
The diagnosis of PAH is usually made during the process of evaluating symptoms such as dyspnea, exercise intolerance, chest pain, or syncope. Electrocardiographic changes, elevated brain natriuretic peptide (BNP) levels, and echocardiographic changes may suggest the diagnosis; however, current recommendations state that a right-heart catheterization (RHC) is "strongly advised" to formally make the diagnosis of PH (Table 3).[5] It is the author's belief that all patients who are suspected to have PH should have RHC prior to initiation of therapy. A mean pulmonary artery pressure > 25 mmHg at rest or > 30 mmHg with exercise along with a pulmonary artery occlusion pressure of < 15 mmHg are required to establish the diagnosis of PAH.[5]
Table 3. Evaluation of a Patient With Suspected Pulmonary Hypertension
|Essential Evaluation |Contingent Evaluation |
|History and physical examination |Transesophageal echo |
|Chest x-ray |Echo with bubble study |
|Electrocardiogram |CT chest ± high resolution |
|Pulmonary function testing |Pulmonary angiogram |
|Ventilation-perfusion scan |Arterial blood gas |
|Transthoracic echo |Cardiac MRI |
|Blood tests: HIV, TFTs, LFTs, ANA |Blood tests: Uric acid, BNP |
|Six-minute walk test |Polysomnography |
|Overnight oximetry |Cardiopulmonary exercise |
|Right heart catheterization |Open lung biopsy |
Initial Evaluation
The initial evaluation of patients with PH should consist of testing to confirm the diagnosis, a search for causative disorders and complications from the disease, and a determination of the severity of the disease.[1,9] Left-heart disease, valvular heart disease, and parenchymal lung disease deserve special attention during this initial period of evaluation as they are common causes of pulmonary arterial pressure elevation and right ventricular failure; however, their prognosis, treatment, and outcome are far different from those seen with PAH. Recent ACCP evidence-based guidelines provide an excellent overview of the diagnostic strategy to be employed in patients with suspected PAH (see Figure 1).
[pic]
Figure 1. Diagnostic strategy.
Published with permission from McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:14S-34S.[5]
A detailed history should be taken from the patient in an attempt to define the severity, duration, and degree of acceleration in symptom severity. The patient should also be questioned about drugs of abuse, herbal medicines and supplements, and prescription drugs including appetite suppressants and anorexigens. Patients with PH usually present with nonspecific symptoms including dyspnea (60%), chest pain (40%), and fatigue.[10] Symptoms are typically related to inability to increase cardiac output sufficiently in response to exertion and suboptimal oxygen transport. History and physical examination should focus on signs and symptoms compatible with an underlying disease including collagen vascular diseases, liver disease, sleep apnea, thromboembolic disease, and abnormalities in thyroid function.[11]
The cardiac examination may reveal signs such as an increased pulmonic component of the second heart sound, an early systolic ejection click, a right ventricular fourth heart sound, a right ventricular heave, elevation of the jugular venous pulsations, or a murmur of either pulmonic or tricuspid insufficiency; however, none of these findings is specific to PAH.[5,11,12] In addition to undergoing a careful cardiac examination, the patient should be questioned about congenital heart disease and previous catheter ablation therapy for atrial fibrillation, a procedure that has been associated with pulmonary vein stenosis and PH.[13]
The electrocardiogram (ECG) may be suggestive of right ventricular hypertrophy or right atrial enlargement and may demonstrate a right axis deviation. The sensitivity and specificity of the ECG for detecting PH are sufficiently poor to preclude its use as a screening tool; however, patients with newly diagnosed PH should have at least 1 ECG to establish a baseline for future comparison.[5] Right ventricular or pulmonary artery enlargement may be demonstrated on chest x-ray (Figure 2). Chest x-ray typically shows central enlargement of the pulmonary arteries with peripheral "pruning." Lupi and colleagues[14] have described an index of PH based on the ratio of the summed horizontal measurements of the pulmonary arteries from midline to their first divisions, divided by the transverse diameter. Chest radiography can be extremely helpful in identification of coexisting conditions such as COPD, kyphoscoliosis, and interstitial lung disease that may be responsible for the PH. In most cases, a CT scan of the chest (Figure 3) with high-resolution cuts should be performed to evaluate for the presence of parenchymal lung disease and mediastinal disorders that could cause obstruction of the pulmonary vessels.
[pic]
Figure 2. Chest radiograph of a patient with PAH showing central enlargement of pulmonary arteries bilaterally with peripheral "pruning."
[pic]
Figure 3. CT scan of the chest in a patient with PAH showing enlarged main and right and left pulmonary arteries with clear lung fields.
A ventilation-perfusion (V/Q) scan should be performed to evaluate for chronic thromboembolic disease. Prior studies have shown that V/Q scans have a high sensitivity and specificity for distinguishing between IPAH and chronic thromboembolic PH.[15-17] Patients with a normal V/Q scan likely need no further evaluation for thromboembolic disease, but the poor correlation between the findings on V/Q scanning and the severity of vascular obstruction demands that those patients with a positive scan be sent for pulmonary angiography to accurately define the degree of vascular obstruction and to identify patients who would benefit from surgical thromboendarterectomy.[5,7]
In addition to basic testing such as a complete blood count, an arterial blood gas, and a complete metabolic panel, the initial laboratory evaluation for patients with PH should include thyroid function tests, liver function tests (LFT), antiphospholipid antibodies, testing for collagen vascular diseases, and testing to detect the human immunodeficiency virus (HIV).[1] A baseline BNP value should be obtained because, as will be discussed later, a change in this value over time carries prognostic significance.[11]
All patients with PH should undergo baseline pulmonary function testing including spirometry, determination of lung volumes, and evaluation of the diffusion limitation for carbon monoxide (DLCO). Pulmonary function testing may reveal evidence of significant obstructive or restrictive ventilatory defects that may be relevant to the etiology of PH.[12] While the DLCO has not been shown to correlate with the severity of PH, it has been shown that a reduction in the DLCO out of proportion to the decline in forced vital capacity is one of the earliest signs of PAH in patients with scleroderma.[18] A DLCO < 55% may identify a group of patients with scleroderma at high risk of developing PAH.
Quantification of exercise tolerance is often performed by measuring the distance that a patient can walk in 6 minutes (6MWD). The 6MWD is a useful tool for following patients over time and, for this reason, serial determinations of the 6MWD distance should be made.[19] The 6MWD has been used to evaluate patients and has been utilized as a primary end point in recent clinical trials since earlier trials showed that 6MWD was predictive of survival in patients with IPAH.[20,21] Arterial oxygen desaturation > 10% during 6MWD has been shown to predict a 2.9 times increased risk of mortality over a median follow-up of 26 months.[22]
Screening for unsuspected nocturnal hypoxemia and sleep apnea should also be performed in those patients newly diagnosed with PH. No further testing is warranted if overnight oximetry on room air shows no desaturation. Abnormal oximetry necessitates a full polysomnogram to formally diagnose and determine the severity of sleep apnea, as nocturnal hypoxia may be an aggravating or even a causative factor for PH.[19] In a recent prospective study of 43 patients with PAH without significant lung disease, Minai and colleagues (Minai OA, Pandya C, Avecillas J, et al. Significance and risk factors for nocturnal hypoxemia in pulmonary arterial hypertension. Submitted for publication)reported that 30 (70%) had evidence of nocturnal hypoxemia (defined as >10% of sleep time < 90% oxygen saturation). Nocturnal desaturators had a higher hemoglobin level than non-desaturators (14.5 vs 12.9; P = .002). They found that although 12/14 (86%) of those that desaturated during 6MW were nocturnal desaturators, only 43% of nocturnal desaturators required oxygen supplementation during 6MW. Nocturnal desaturators were more likely to be older (P = .030), have higher BNP (P = .004), and have lower cardiac index (P = .030). Among echocardiographic parameters, nocturnal desaturators were more likely to have RV dilation and a pericardial effusion compared with non-desaturators. Pulmonary function was normal in both groups; however, all patients with DLCO < 50% of predicted and MVO2 < 55% were desaturators.
Mechanisms of exercise limitation in PH include arterial hypoxemia, poor cardiac output and stroke volume in response to increased demand, lactic acidosis at low work rates, and V/Q mismatching. Cardiopulmonary exercise testing provides more physiologic information than the standard 6MWD; however, because it is technically more difficult, is time-consuming, is not available at all centers, and may be less sensitive at detecting responses to treatment, it is not routinely used.[7,8] Patients with PAH typically show reduced peak VO2, reduced peak work rate, reduced anaerobic threshold, reduced peak oxygen pulse, increased VE and VCO2 slope indicating inefficient ventilation, and reduced ratio of VO2 increase to work rate increase.[23]
The final essential, noninvasive test in the evaluation of PH is Doppler echocardiography. Echocardiography can help to exclude the presence of left-heart disease by evaluating left ventricular function and detecting diastolic dysfunction and valvular heart disease. The degree of right atrial and ventricular enlargement, right ventricular hypertrophy, pulmonary artery dilatation, presence or absence of pericardial effusion, and estimates of right ventricular function may all be determined by echocardiography. Doppler assessments can be used to estimate the right ventricular systolic pressure (RVSP) and to evaluate for the presence of intracardiac shunts and other forms of congenital heart disease. RVSP can be derived by adding the RAP to the RV/RAP gradient measured during systole, approximated by the modified Bernoulli equation as 4v2, where v is the tricuspid regurgitant jet velocity in meters/sec (RVSP = 4v2+RAP).
Numerous studies have examined the correlation between RVSP as estimated by Doppler echocardiography and RVSP as directly measured during RHC, and most of these studies reported a relatively tight correlation (the r value ranged from 0.57-0.95).[24-28] In a study by Hinderliter and colleagues,[29] systolic pulmonary pressure was underestimated by at least 20 mmHg in 31% of patients.Other studies have demonstrated that the concordance between Doppler echocardiography and direct measurement via RHC worsens as the pressure rises, with poorest correlation when the systolic pulmonary pressure is over 100 mmHg.[30] Doppler echo may also overestimate systolic PAP in a population comprising people with normal pressure.[31,32]
RHC is initially performed for the purpose of diagnosing PH; other important information can also be obtained from this test. The right atrial pressure, the mixed venous oxygen saturation, the cardiac output and index, and the pulmonary vascular resistance all may be either measured or calculated during RHC. If a congenital heart defect or a left-to-right shunt is suspected, one may measure the oxygen saturation at several points throughout the course of the systemic venous system, right heart, and pulmonary arterial system looking for a step-up in saturation that would suggest the presence of a left-to-right shunt. Pressure measurements obtained during RHC have been used to derive a prediction equation[33] that has been used to assess "predicted survival" and long-term effects of new treatments on survival. The equation to predict survival based on the National Institutes of Health (NIH) registry data is:
P(t) = [H(t)]A(x,y,z); H(t) = [0.88 - 0.14t + 0.01t2]; A(x,y,z) = e(0.007325x + 0.0526y - .3275z)
where P(t) = a patient's chances of survival at 't' years; t = 1, 2, or 3 years; x = mean pulmonary artery pressure; y = mean right atrial pressure; and z = cardiac index.[33]
If RHC confirms the diagnosis of PH, a vasodilator should be given to determine the degree of pulmonary arterial vasoreactivity, a factor that carries therapeutic and prognostic significance, as will be discussed later. No consensus exists regarding which agent should be used to perform this test; however, intravenous epoprostenol, intravenous adenosine, or inhaled nitric oxide is often chosen because all of these are potent yet short-acting vasodilators. If the administration of a vasodilator causes the mean pulmonary arterial pressure to decrease ≥ 10 mmHg and reach ≤ 40 mmHg, with an unchanged or increased cardiac output, the patient is said to be vasoresponsive.[34] The main reason for vasodilator testing is to identify patients who are likely to have a good long-term response to treatment with calcium channel blockers (CCBs) alone. Patients with IPAH are more likely to have a positive vasodilator response that those with PAH associated with collagen vascular diseases. Overall, only a minority of patients (approximately 10% to 15%)[35,36] are likely to have a positive vasodilator response.
The most recent recommendations from the ACCP did not advocate the routine use of magnetic resonance imaging (MRI) or open lung biopsy in the evaluation of patients with newly diagnosed PH. Cardiac MRI may provide additional pressure estimates and estimates of right ventricular mass and volume; however, at present the incremental value of this tool over standard testing measures is not sufficiently high to recommend its use in all patients. Likewise, because of the risks associated with the procedure, the ACCP recommends lung biopsy "only if a specific question could be answered by tissue examination" in patients with PH and its "routine use to diagnose PH or determine its cause is discouraged."[5] Such indications could include the detection of pulmonary veno-occlusive disease, bronchiolitis, active vasculitis, or pulmonary capillary hemangiomatosis.
Treatment
The treatment options for patients with PAH have expanded greatly in the recent past with novel therapies now available and others on the way.[19] Patients should be referred to a specialty center[1] that has experience in treating patients with PAH, and it is essential that there is a mutual understanding between the specialists at the referral center and the patient's regular physicians regarding the overall direction and goals of care. Recent evidence-based recommendations made by the ACCP indicate that treatment options considered for specific patients should be based on their baseline New York Heart Association (NYHA) functional class (Figure 4).[34]
[pic]
Figure 4. Treatment algorithm for PAH based on NYHA functional class at presentation.
Adapted from: Badesch DB, et al. Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:45S.[34]
General Management-Related Issues
Hypobaric hypoxia may induce pulmonary vasoconstriction, and even patients with PAH who did not require supplemental oxygen during the 6MW may require oxygen supplementation during flight. (Minai OA, McCarthy K, Arroliga AC. Altitude simulation in pulmonary arterial hypertension: applications and implications. Submitted for publication.) All patients planning to travel by commercial airliners should either undergo a standardized altitude simulation test or use supplemental oxygen. Cautious use of diuretics and a sodium-restricted diet are indicated for patients with evidence of right ventricular failure. Digitalis has not been studied extensively in patients with PAH, but it is often used in patients who have atrial dysrhythmias or refractory right ventricular failure.[34] Experts recommend using the least invasive surgical approach and avoiding the use of general anesthesia when possible until larger studies clearly define the risk that surgery imposes on patients with PAH.[7,37] It is the author's belief that, when possible, vasoactive therapy should be initiated in an attempt to decrease pulmonary arterial pressure and improve right ventricular function prior to surgical intervention. Aggressive steps should be taken to avoid pregnancy in patients with PAH, as the 30% to 50% rise in cardiac output that is normally seen in pregnancy may cause the already taxed right ventricle to decompensate.[38]
Oxygen Therapy
It has been proposed that most patients with PAH (not due to congenital heart disease) have only mild hypoxemia at rest, most likely due to low MVO2 and only minimal ventilation perfusion mismatching.[7] No consistent data are available regarding the effects of long-term oxygen therapy. Supplemental oxygen should be given to keep the oxygen saturation ≥ 90% at all times in patients with PAH given the adverse consequences of chronic hypoxia (submitted for publication). As a result, both daytime and nocturnal hypoxemia should be screened for with a 6MW and nocturnal oximetry in all newly diagnosed patients with PAH. Even in patients for whom use of oxygen may be more controversial, such as patients with congenital heart disease who have large right-to-left shunts, use of supplemental oxygen has the potential to reduce the need for phlebotomy and neurologic sequelae.
Anticoagulation
Whether it is a cause or an effect of the increased pulmonary pressures, intravascular thrombosis is observed in patients with PAH. Anticoagulation with warfarin has been shown to reduce mortality in patients with IPAH. Studies by Rich and colleagues and Fuster and associates demonstrated improved survival among patients with IPAH who took warfarin compared with those patients who did not.[39,40] There is some concern that patients with PH in association with congenital heart disease may be at increased risk for hemoptysis. Even though warfarin has not been specifically studied in randomized, prospective trials, ACCP consensus guidelines recommend anticoagulating all patients with PAH with the target level of anticoagulation being an international normalized ratio (INR) of approximately 2.0 unless there is a clear contraindication.[34]
Calcium-Channel Blockers
The development of more effective therapies has led to a dramatic reduction in the role of CCBs in the therapy of patients with PAH. The main role of vasodilator testing during RHC is to identify patients more likely to respond to CCB.[9] In a 1992 study, Rich and colleagues[39] demonstrated that treatment with CCBs in persons who had displayed a positive vasoreactivity challenge during RHC resulted in a long-term reduction in the pulmonary artery pressure, pulmonary vascular resistance, and right ventricular hypertrophy and a significant survival benefit at 1, 3, and 5 years compared with nonresponders. There have been no prospective, randomized, controlled trials of oral CCBs in PAH. In view of the proven efficacy of newer therapies, it is now recommended that CCBs not be used in patients without demonstrated vasoreactivity and that they never be used to empirically treat PAH. According to present recommendations, a trial of CCBs is still acceptable for patients with PAH who demonstrate vasoreactivity (as defined during the Venice Symposium) and have a preserved functional status and cardiac index.[34] The percentage of patients with PAH who respond to acute vasodilator testing has varied between reports,[39,41-43] but a more recent report suggests that such patients may comprise approximately 10% to 15% of IPAH patients.[35] It is also recognized that approximately 50% of patients initiated on CCBs alone will experience deterioration over time, necessitating the addition of newer forms of therapy.[35] As such, patients demonstrating vasoreactivity initiated on CCBs alone should be followed very closely for signs of deterioration or progressive disease.[44] Nifedipine, diltiazem, or amlodipine can be used, depending on baseline heart rate. CCBs with a significant negative inotropic effect, such as verapamil, should be avoided.
Prostanoids
Prostacyclin is a potent vasodilator with antiplatelet effects, and therapy with prostacyclin analogs (prostanoids) has become a cornerstone in the treatment of patients with PAH (Figure 5).[45] To date, 4 different prostanoids have been studied (see Table 4), each with unique delivery systems, side effects, and evidence of efficacy.
Table 4. Randomized Trials Demonstrating the Effectiveness of Therapies for PAH
|Drug |Trial |First Author, Journal, Year |Patients |Duration (wks) |
|Epoprostenol |Pilot |Rubin, Ann Intern Med, 1990 |23 |8 |
|Epoprostenol |Pivotal |Barst, NEJM, 1998 |81 |12 |
|Epoprostenol |CTD |Badesch, Ann Intern Med, 2000 |111 |12 |
|Treprostinil |Pivotal |Simmoneau, AJRCCM, 2002 |469 |12 |
|Iloprost |AIR |Olschewsi, NEJM, 2002 |203 |12 |
|Beraprost |ALPHABET |Galie, JACC, 2002 |130 |12 |
|Bosentan |Pilot |Channick, Lancet, 2001 |33 |12 |
|Bosentan |BREATHE-1 |Rubin, NEJM, 2002 |213 |16 |
|Sitaxsentan |STRIDE-1 |Barst, AJRCCM, 2004 |172 |12 |
|Sitaxsentan |STRIDE-2 |Unpublished |240 |12 |
|Sildenafil |SUPER-1 |Unpublished |278 |12 |
|Drug |Etiology of PH |NYHA Functional |6MWD (m)# |Hemodynamic Improvement |Clinical Parameters|
| |(%)8 |Class (%)* | | | |
|Epoprostenol |IPAH (100) |II (9) |45 |Yes |Improved |
| | |III (65) | | | |
| | |IV (26) | | | |
|Epoprostenol |IPAH (100) |III (75) |47 |Yes |Improved |
| | |IV (25) | | | |
|Epoprostenol |CTD (100) |II (5) |94 |Yes |No Change |
| | |III (78) | | | |
| | |IV (17) | | | |
|Treprostinil |IPAH (58) |II (11) |1688 |Yes |Improved |
| |CHD (24) |III (82) | | | |
| |CTD (19) |IV (7) | | | |
|Iloprost |IPAH (54) |III (59) |36 |Yes† |Improved |
| |CTD (17) |IV (41) | | | |
|Beraprost |IPAH (48) |II (49) |25 |No |No Change |
| |CHD (21) |III (51) | | | |
| |Po-PH (16) | | | | |
| |CTD (7) | | | | |
| |HIV (7) | | | | |
|Bosentan |IPAH (85) |III (100) |76 |Yes |Improved |
| |CTD (15) | | | | |
|Bosentan |IPAH (70) |III (91) |44 |Yes^ |Improved |
| |CTD (30) |IV (9) | | | |
|Sitaxsentan |IPAH (53) |II (33) |34 |Yes |Improved |
| |CTD (24) |III (66) | | | |
| |CHD (24) |IV (1) | | | |
|Sitaxsentan |IPAH (59) |II (38) |31 |N/A |Yes |
| |CTD (30) |III (59) | | | |
| |CHD (11) |IV (4) | | | |
|Sildenafil |IPAH (63) |I (1) |36 (20 TID)|Yes^^ |Yes |
| |CTD (30) |II (39) |46 (40 TID)| | |
| |CHD (7) |III (58) |50 (80 TID)| | |
| | |IV (3) | | | |
CHD = congenital heart disease-associated PAH; CTD= connective tissue disease associated PAH; CTEPH: chronic thromboembolic PH; IPAH = idiopathic pulmonary arterial hypertension; N/A = not available; NS = not statistically significant
*Sum may be greater than 100% since 0.5 was rounded up to a whole number
#Net improvement in 6MWD compared with placebo
†Post-inhalation
^Hemodynamics only assessed by echocardiography post-therapy
^^All 3 doses
[pic]
Figure 5. Rationale for vasoactive therapy: critical pathways in PAH.
With permission from: Galie N, et al. Emerging medical therapies for pulmonary arterial hypertension. Prog Cardiovasc Dis. 2002;45:213-224.[45] © 2002 Elsevier Inc.
Epoprostenol was the first studied prostanoid, and its introduction some 10 years ago revolutionized the treatment of patients with PAH. Epoprostenol is unstable at room temperature and must be kept cold prior to and during infusion. Because of its short half-life in the bloodstream (only about 3-5 minutes), epoprostenol requires continuous intravenous administration; usually via a tunneled catheter into a central vein. The initial dosing for epoprostenol generally ranges from 2-10 ng/kg/min, with side effects or systemic hypotension limiting the use of higher doses. Tachyphylaxis is common, and doses often require elevation over time. The exact dosing protocol varies between centers,[9] but it is generally accepted that most patients will have a positive response at a dose between 20 and 45 ng/kg/min.
Epoprostenol is stored as a dry powder, reconstituted with a sterile diluent, and then continuously infused via an ambulatory infusion pump worn by the patient. Common side effects include flushing, diarrhea, headache, arthralgias, tachycardia, and jaw pain. High doses may produce hypotension and heart failure, and, because of epoprostenol's potent vasodilatory properties, patients with coronary artery disease may develop a coronary "steal" phenomenon and experience cardiac ischemia with the administration of epoprostenol. Sudden reductions in dose or abrupt cessation of the drug may result in severe rebound pulmonary hypertension or even sudden death. Patients are at increased risk of line infections and thrombosis because the drug must be infused through a central venous catheter.[46,47]
Two large studies of epoprostenol therapy have been conducted in patients with IPAH (Table 4).[21,48] The landmark study demonstrating the effectiveness of epoprostenol was published in 1996 by Barst and colleagues.[21] In this study of functional class III and IV patients with IPAH, 41 patients were treated with epoprostenol plus standard therapy (anticoagulation and diuretics) while 40 patients were treated with standard therapy alone. The epoprostenol group showed a reduction in pulmonary artery pressure (8% drop in the epoprostenol group vs a 3% rise in the standard group) and pulmonary vascular resistance (21% drop in the epoprostenol group vs a 9% increase in the standard group) while also showing significant improvement in 6MWD distance, echocardiographic parameters, and quality of life. Eight patients died in this study, all in the standard therapy group.
Epoprostenol was also studied by Badesch and colleagues[49] in the treatment of patients with PAH associated with the scleroderma spectrum of disease (Table 4). Again, epoprostenol plus standard therapy was compared with standard therapy alone, and the epoprostenol group demonstrated a 46-meter improvement in 6MWD whereas the standard group had a 48-meter decline. Significant changes were also seen in the mean pulmonary artery pressure, pulmonary vascular resistance, and functional class. No difference in mortality was noted in this study. Epoprostenol therapy has also shown positive results in nonrandomized studies in patients with PAH in association with congenital heart defects,[50] systemic lupus erythematosus,[51] PAH associated with HIV infection[52] or Gaucher's disease,[53] porto-pulmonary hypertension,[54] and pediatric IPAH.[55]
These studies demonstrated the effectiveness of epoprostenol in small numbers of patients over short periods of time; however, subsequent studies have established that the drug is effective over long periods of time in large numbers of patients. McLaughlin and colleagues[46] reported that a group of 162 epoprostenol-treated patients followed for a mean of 36.3 months had significant improvements in 1-, 2-, and 3-year survival compared with expected survival (Figure 6) based on the NIH Registry prediction equation. Likewise, Sitbon and colleagues[47] reported that 178 functional class III or IV patients treated with epoprostenol had significantly better survival at 1, 2, 3, and 5 years compared with historical controls. This study also showed that improvements in functional class and hemodynamics at 3 months could predict long-term survival in these patients.[47]
[pic]
Figure 6. Survival in 162 patients with PAH treated with epoprostenol. The observed survival rates (diamonds) at 1, 2, and 3 years were 87.8%, 76.3%, and 62.8%, respectively, and were much better than the expected survival rates (squares) of 58.9%, 46.3%, and 35.4%, respectively, based on the NIH registry prediction equation.
With permission from: McLaughlin VV, et al. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002;106:1477.[46]
There have been occasional reports of patients weaned off epoprostenol or treprostinil with the addition of bosentan.[56-58] Such cases of successful withdrawal are very few and there are no clear criteria, at present, regarding who can be safely transitioned off intravenous or subcutaneous prostanoid therapy. It is the opinion of the author that such withdrawal is risky and should only be attempted at PH centers by physicians who are experienced at treating PH, and then only in carefully selected patients with close follow-up.
Treprostinil is a prostacyclin analog that is stable at room temperature and has a half-life of 3 hours. Because of its longer half-life, treprostinil can be delivered subcutaneously rather than through a central venous line, thus minimizing the line infection and thrombosis seen with epoprostenol use. Unlike epoprostenol, treprostinil is stable at room temperature and can be dispensed as a premixed solution and directly inserted into the pump without the need to mix the solution or the use of ice packs.[9] As with epoprostenol, the usual starting dose for treprostinil is low (1-2 ng/kg/min), and this dose is often limited by symptoms or by systemic hypotension. The side-effect profile for treprostinil is similar to that for epoprostenol except that therapy with subcutaneous treprostinil is also associated with significant pain at the infusion site in many patients. Topical analgesics, anti-inflammatory drugs, tricyclic antidepressants, and rotation of the infusion sites are often used to alleviate the symptoms; however, in some patients pain at the infusion site is such that therapy with treprostinil has to be discontinued.
Intravenous (IV) treprostinil has been demonstrated to achieve a similar hemodynamic response to that of epoprostenol, and the IV form has been demonstrated to achieve hemodynamic responses similar to those seen with the subcutaneously delivered form.[59] Efficacy of subcutaneous treprostinil was established in a placebo-controlled, randomized, controlled, 12-week study (Table 4) involving 470 patients with IPAH or PAH associated with connective tissue disease or congenital systemic to pulmonary shunts. Treatment with treprostinil improved 6MWD distance (16-meter improvement for the treprostinil group and no change for the control group; P = .006), symptoms, and hemodynamics. Treatment effect was related to dose achieved (patients who received > 13.8 ng/kg/min improved their 6MWD by 36 m), however, only one quarter of patients achieved this dose due to infusion site pain. There was no difference in mortality between the two groups.[60]
The magnitude of improvement with treprostinil was not as great as that seen in the epoprostenol trials; however, most experts believe that the reason the treatment effect was not as robust had more to do with patient selection and trial design rather than true differences in efficacy between the drugs. It is also noteworthy that 85% of patients in the study had pain at the infusion site, 83% had erythema or induration at the infusion site, and 8% withdrew from the trial due to pain at the infusion site, underscoring the magnitude of the site pain problem.[61]
Treprostinil was recently approved by the FDA for IV administration in patients with PAH. The potential advantages of IV treprostinil over epoprostenol include stability at room temperature (thus avoiding ice packs), the fact that it comes in a prefilled and premixed syringe so patients only need to place the syringe in the pump and do not have to mix it daily in a sterile fashion, and the fact that the cassette can be changed every 3 days. The longer half-life also provides added peace of mind to both patients and physicians in case of pump or catheter malfunction.
Although not currently approved in the United States, beraprost, the first available oral prostanoid, is rapidly absorbed with peak concentrations achieved after 30 minutes and a half-life of 35-40 minutes. Beraprost has been used in Japan since the mid-1990s; however, the evidence supporting its use consisted of uncontrolled and retrospective studies until 2002. At this time, Galie and colleagues[62] published the results of a study involving 130 subjects with PAH and class II or III symptoms who were treated with beraprost 4 times daily (Table 4). In this 12-week study, there was an increase in 6MWD between 25 and 45 meters in treated patients, but there was no difference in hemodynamics or mortality. A second trial among 116 patients with PAH and class II or III symptoms showed that while treated patients had improved 6MWD distances at 3 and 6 months, this effect was not sustained at 9 or 12 months and, again, there was no effect on hemodynamics or mortality.[63]
Iloprost is a prostanoid that may be delivered intravenously, orally, or via aerosolization. It has a serum half-life of 20-25 minutes and, when delivered via aerosolization, is given 6 to 9 times a day. Aerosolized treatment with iloprost, which is the route approved in the United States, can be complicated by cough; otherwise, the side effects from iloprost are similar to those seen with the other prostanoids.
In 2002, a 3-month, prospective, randomized, double-blind, placebo-controlled trial involving 203 subjects with PAH and a functional class of III and IV (Table 4) demonstrated that patients treated with iloprost were more likely to improve their 6MWD (median 36-meter improvement in the iloprost group; P = .004), functional class (P < .05), quality of life (P < .05), and post-inhalation hemodynamics than those patients who did not receive iloprost.[64] Iloprost was administered at a dose of 2.5 mcg or 5.0 mcg 6 to 9 times a day. The primary composite end point consisting of a 10% improvement in 6MWD, NYHA functional class improvement, and lack of clinical deterioration was seen in 17% of iloprost patients and only 5% of placebo treated patients (P = .007). Additionally, 14% of control patients in this study withdrew due to progressive symptoms or death, compared with only 4% in the iloprost group. Even though cough and other side effects occurred more often in the iloprost group than in the placebo group, the side effects were generally mild. Given the cumbersome nature of epoprostenol delivery, the infusion site pain associated with treprostinil, and the disappointing results seen with beraprost, iloprost seems to be an attractive alternative for patients requiring prostanoid therapy.
Endothelin Antagonists
Endothelin-1 has been shown to be a potent vasoconstrictor and a mediator of the pulmonary vascular remodeling seen in PAH.[65-67] Two receptors for endothelin-1 have been identified, ETA and ETB. ETA mediates vasoconstriction and remodeling and ETB is involved in the clearance of endothelin-1 and perhaps also in vasodilatation and nitric oxide release. Many endothelin receptor antagonists, including sitaxsentan and ambrisentan, are being studied in PH; however, only bosentan is currently available for use in the United States.
Bosentan blocks both the ETA and ETB receptors and was the first available endothelin antagonist. Bosentan is dispensed as a tablet that is generally taken twice daily.[19] Multiple studies demonstrated that bosentan prevents or reverses the development of PH in various animal models of PH.[68-70]
The first randomized, placebo-controlled, double-blind trial documenting the effect of bosentan was published in 2001 by Channick and colleagues (Table 4).[61] Thirty-two NYHA Class III patients with IPAH or PAH due to scleroderma were randomized to receive either bosentan or placebo for 12 weeks. The group of patients receiving bosentan saw significant improvements in 6MWD (70-meter improvement for the bosentan group vs a 12-meter reduction in the control group; P < .05), cardiac output (0.5-L/min increase in the bosentan group vs a 0.5-L/min reduction in the control group; P < .001), pulmonary vascular resistance (223 dyne-sec/cm5 reduction in the bosentan group vs a 191 dyne*cm*sec-5 elevation in the control group, P < .001), and functional class. Liver function test abnormalities were rare in this study and, among those patients who experienced elevation, all levels returned to normal with discontinuation of the drug or reduction in dose. Bosentan is contraindicated in pregnancy. Bosentan is primarily eliminated via the P450 enzyme pathway, as such use of glyburide and cyclosporin A is contraindicated in patients taking bosentan.
A second, larger randomized, double-blind, placebo-controlled study was performed over 16 weeks on 213 NYHA Class III or IV patients with either IPAH or PAH associated with connective tissue disease (Table 4).[71] Unlike the previous trial where the maximum dose of bosentan was 125 mg twice daily, patients in the Bosentan Randomized Trial of Endothelin Receptor Antagonist Therapy of Pulmonary Hypertension (BREATHE-1) study were randomized to receive placebo, bosentan 125 mg twice daily, or bosentan 250 mg twice daily. Again, treatment with bosentan was shown to improve 6MWD (36-meter improvement in the bosentan group vs an 8-meter fall in the control group; P = .002) (Figure 7), and the time to clinical worsening (P = .0015 with log-rank test) (Figure 8). A comparable overall treatment effect was seen in patients with IPAH where bosentan improved the 6MWD from baseline (+46 meters in the treatment group vs -5 in the placebo group) and PAH associated with scleroderma where bosentan use prevented deterioration of 6MWD (+3 meters in treatment group vs -40 meters in the placebo group). In addition, 42% of those receiving bosentan had an improvement in their functional class at Week 16, while only 30% of those receiving placebo had an improvement in functional class (mean treatment effect was 12% in favor of bosentan, 95% confidence interval -3% to 25%). Of note, the group receiving 250 mg twice daily had a higher incidence of abnormalities in LFT and no statistically significant benefit over the 125-mg dose. A subgroup of 85 patients enrolled to be part of an echocardiographic study showed that bosentan improved right ventricular function and early diastolic filling of the left ventricle.[72] Bosentan was evaluated in a 16-week study of patients with PAH related to HIV disease. The study showed an improvement in 6MWD (+91 ± 60 m; P < .001), NYHA functional class, and hemodynamics (CI: +0.9 ± 0.7 L/min/m2; P < .001).[73]
[pic]
Figure 7. Six-minute walk distance improvement seen in 213 patients with PAH, demonstrating a significant effect of bosentan.
With permission from: Rubin LJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896.[71] Copyright © 2002 Massachusetts Medical Society. All Rights Reserved.
[pic]
Figure 8. Delay in clinical worsening in 213 patients with PAH treated with bosentan, demonstrating a significant effect.
* With permission from: Rubin LJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896.[71] Copyright © 2002 Massachusetts Medical Society. All Rights Reserved.
Bosentan is associated with abnormal hepatic function, and it should not be prescribed to patients with moderate to severe hepatic impairment. The mechanism for hepatic impairment is a dose-dependent inhibition of bile salt excretion that can be toxic to hepatocytes.[74] The FDA requires that LFTs be checked monthly in patients taking bosentan, and if the transaminases rise to more than 3 times the upper limit of normal, the dose should be decreased and the transaminases should be monitored very closely. Transaminase elevation above 5 times the upper limit of normal should prompt temporary cessation of the drug until LFTs return to normal followed by a rechallenge. Elevation of LFTs more than 8 times the upper limit of normal should prompt permanent discontinuation of the drug. To date there have been no reports of acute liver failure or chronic liver injury with the use of bosentan. Bosentan is listed as a pregnancy risk factor "X," meaning that pregnancy must be excluded prior to beginning therapy with bosentan and females of childbearing age on bosentan should be counseled regarding contraception. Bosentan may interfere with the action of hormonal contraceptives, so many experts recommend 2 forms of contraception in those on bosentan. Bosentan may cause testicular atrophy and male infertility, so a discussion regarding reproductive options should be had with young, male patients before the drug is begun. Bosentan has been associated with worsening of peripheral edema and mild anemia, and many adverse drug interactions have been reported, including (but not limited to) cyclosporine, glyburide, fluconazole, and hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors.[34]
McLaughlin and colleagues[75] recently reported on the long-term survival of 139 functional class III and IV patients treated with bosentan as first-line therapy over 36 months. At the end of 1 year, 96% of patients initially treated with bosentan monotherapy were still alive, and at the end of 2 years 89% were alive, compared with the 69% and 57% expected survival based on the NIH Registry prediction equation.[33] Of patients started on bosentan, 85% were still on monotherapy at 12 months and 70% were still on monotherapy at 2 years in this study. Factors associated with a worse outcome included NYHA Class IV symptoms and 6MWD less than 358 meters at baseline.
A comparison of the outcome of these patients to that of a group of 346 functional class III patients who had previously been treated with epoprostenol over a 36-month period[76] demonstrated that first-line treatment with bosentan did not negatively impact survival compared with epoprostenol. In fact, analysis by a Cox regression model suggested that the group of patients treated with epoprostenol had a greater mortality risk than the patients treated with bosentan as a first-line agent (hazard ratio 2.327; P = .0059).[76]
Selective ETA Antagonists
Selective ETA antagonists are under study with the rationale that selective blockade of the ETA receptor will allow the continued favorable activity of the ETB receptor.[9] The two agents that have received the greatest attention are sitaxsentan and ambrisentan. Sitaxsentan is approximately 6000-fold more selective for the ETA than the ETB receptors compared with bosentan. Sitaxsentan has many adverse drug interactions (including warfarin) and carries concern regarding liver toxicity, testicular atrophy, male infertility, peripheral edema, and teratogenesis. Sitaxsentan is not currently available for use in the United States outside the setting of a clinical trial.
In 2004, Barst and colleagues[77] published the results of the Sitaxsentan to Relieve Impaired Exercise (STRIDE-1) study, a prospective, randomized, double-blind, placebo-controlled trial involving 178 NYHA Class II, III, and IV patients with PAH who were randomized to placebo or 1 of 2 doses of sitaxsentan: 100 mg or 300 mg daily (Table 4). The groups receiving the 100-mg dose improved 6MWD by 35 meters (P < .01) and the group receiving 300-mg dose improved their 6MWD by 33 meters (P < .01). Both groups showed statistically significant improvements in hemodynamics and functional class as compared with placebo. The incidence of liver function abnormalities was 10% with the 300-mg dose but only 3% with the 100-mg dose. A follow-up study of 11 patients from this group demonstrated that at 1 year, only 1 patient required escalation of therapy to epoprostenol and no patients on therapy had evidence of hepatotoxicity. Further, the remaining treated patients demonstrated a 50-meter improvement in 6MWD (P = .04), a 0.9-L/min improvement in cardiac output (P = .009), a 157-dyne*cm*sec-5 improvement in pulmonary vascular resistance (P = .04), and an improvement in functional class (all 10 patients were now class II) at 1 year.[78] Hepatotoxicity has been a concern in patients on sitaxsentan. In the pilot study, a case of fatal hepatitis occurred when using sitaxsentan at a high dose. Both STRIDE I and STRIDE II have indicated a low risk (lower than that associated with bosentan) of hepatotoxicity with sitaxsentan at the 100-mg dose.
Another study, STRIDE-2, has enrolled 240 patients with class II, III, or IV symptoms and 6MWD distance of ≤ 450 meters (Table 4).[79] Patients in this study were randomized to placebo, 50-mg, or 100-mg doses of sitaxsentan and were also compared to an open-label group of patients receiving bosentan 125 mg twice daily. The results of this study have not yet been subject to the process of peer review associated with publication; however, early reports indicate that 6MWD distance improved by 24.2 meters over baseline in the group receiving 50 mg of sitaxsentan (P = NS), 31.4 meters over baseline in the group receiving 100 mg of sitaxsentan (P = .04), and 29.5 meters in the group receiving bosentan. Statistically significant improvement in functional class was seen only in the group receiving 100 mg of sitaxsentan (P = .04). The most frequently reported side effect is an elevated INR (when the drug is used concomitantly with warfarin). This can be managed by adjusting the warfarin dose to achieve the desired INR. Ambrisentan is under investigation in a phase 3 trial for which the results have not been released. More information on both ETA antagonists will be forthcoming.
Phosphodiesterase Inhibitors
Cyclic guanosine 3'-5' monophosphate (cGMP) plays a critical role in the regulation of vascular smooth muscle tone by acting as a catalyst in a series of intracellular reactions that mediate vasodilatation. Phosphodiesterases rapidly degrade cGMP thereby limiting nitric oxide-mediated pulmonary vasodilation. Phosphodiesterase type 5 (PDE5), while normally strongly expressed in the lung, has been shown to be present at higher levels than normal in chronic PH.[34] PDE5 inhibitors such as sildenafil or tadalafil can block the effects of PDE5, thereby increasing cGMP levels and potentiating nitric oxide-mediated vasodilatation.
Sildenafil, a potent inhibitor of phosphodiesterase type 5, increases intracellular levels of cGMP and thus causes vasodilatation.[9] Many small, nonrandomized, open-label trials have suggested that administration of sildenafil to patients with PAH improves hemodynamics, 6MWD, and functional class.[80,81] Results of the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER-1) trial were recently presented at the ACCP meeting in October 2004 and at the American thoracic Society meeting in May 2005 (Table 4). This was a randomized, double-blind, placebo-controlled, 12-week trial comparing 3 doses (20 mg, 40 mg, or 80 mg 3 times daily) of sildenafil to placebo in 278 patients with NYHA Class II, III, or IV PAH.[82] Evidence presented showed that all 3 doses of sildenafil improved 6MWD over placebo with a 45-meter improvement in the 20-mg group (P < .001), a 46-meter improvement in the 40-mg group (P < 0.001), and a 50-meter improvement in the 80-mg group (P < .001). Mean pulmonary artery pressure decreased by 2.7 mmHg in the 20-mg group (P = .04), 3 mmHg in the 40-mg group (P = .01), and 5.1 mmHg in the 80-mg group (P < .001). Placebo-corrected cardiac output increased by 0.5 L/min in the 20-mg group (P = .04), 0.5 L/min in the 40-mg group (P = .03), and 0.8 L/min in the 80-mg group (P = .001). Placebo-corrected pulmonary vascular resistance improved by 171 dyne*cm*sec-5 in the 20-mg group (P = .01), 192 dyne*cm*sec-5 in the 40-mg group (P = .006), and 310 dyne*cm*sec-5 in the 80-mg group (P = .001). Time to clinical worsening was not significantly different in the 80-mg sildenafil group vs placebo and by protocol was not statistically evaluated in the other groups. This study is currently undergoing peer review in consideration for publication.
Patients who completed the SUPER-1 study had the option of enrolling in the extension, open-label SUPER-2 study where all patients were transitioned to a dose of 80 mg 3 times a day. Preliminary results from the SUPER-2 study[83] were presented at the American Thoracic Society meeting in May 2005. Data presented were suggestive of sustained benefit in 6MW and NYHA functional class at 12 months, and only 6% of patients required additional therapy. The observed mortality in the group treated with sildenafil was 96% at 1 year, much lower than expected survival of 71% as estimated based on the NIH Registry prediction equation.[33]
On the basis of the results of the SUPER-1 study, the FDA approved sildenafil for use in patients with PAH at a dose of 20 mg 3 times daily with no NYHA functional class restriction. On the basis of previously mentioned nonrandomized, open-label studies, many patients have already been placed on sildenafil doses of up to 75 to 100 mg 3 times daily. Systemic hypotension is the most serious side effect, and some people taking high doses report vision changes including blurred vision and color change. There have also been recent reports of visual loss that appear to be dose related and a class effect.
Nitric oxide, while not a phosphodiesterase inhibitor, does augment and sustain intracellular levels of cGMP, and administration of nitric oxide has been shown to cause reductions in pulmonary artery pressure and pulmonary vascular resistance. Nitric oxide has been used in vasoreactivity challenges for many years, but the experience with its use in the long-term treatment of PAH is very limited.[9,34] One open-label study that included only 5 patients with PAH demonstrated that nitric oxide can be delivered effectively using a nasal cannula and a gas pulsing device.[84] Follow-up RHC at 12 weeks showed improvement in pulmonary artery pressure and cardiac output in 3 of these patients; however, the long-term use of this medication is limited by the difficult delivery system and the lack of published data regarding its efficacy and safety.
L-arginine is the sole substrate for nitric oxide synthase, the enzyme responsible for generating nitric oxide. Studies examining the short-term intravenous administration of L-arginine on hemodynamics have been mixed; however, one small study in which oral L-arginine was compared with placebo showed improvement in hemodynamics and exercise capacity after 1 week of treatment.[85] No large, rigorous trials of L-arginine have yet been published; therefore, at this time the role of L-arginine in the treatment of PAH is not clear.
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Animal models suggest that HMG-CoA reductase inhibitors may slow or inhibit vascular remodeling and improve hemodynamics in rat models of PAH.[86] A case series has recently been published in which therapy with an HMG-CoA reductase inhibitor improved 6MWD and hemodynamics.[87] Further studies need to be done to confirm these findings.
Combination Therapy
Given the mechanisms of action for the 3 main classes of medications used to treat PAH, it would seem that these different medicines would complement each other and achieve a greater effect when given together rather than alone.
Several small studies have provided preliminary, encouraging data about the potential usefulness of combination therapy in patients declining on monotherapy.[88,89] A case series of 9 patients published by Hoeper and colleagues[90] suggests that sildenafil improves 6MWD and maximum oxygen uptake in patients who have worsened while on bosentan therapy alone.
As many of these medicines have only recently been approved, there are more questions than answers regarding the validity of the concept of combination therapy. These questions include the proper combinations of medicines, the appropriate timing to institute combination therapy, the "acceptable" level of benefit, and the identification of patients in whom combination therapy is appropriate. These questions can only be answered via well-designed, prospective trials showing added efficacy, safety, and survival benefit.
Interventional and Surgical Therapy
The presence of a patent foramen ovale has been shown to confer a survival advantage in patients with severe IPAH awaiting lung transplantation.[91] Atrial septostomy (AS), by creating a right-to-left intra-atrial shunt, decompresses the right ventricle and has been shown to immediately improve symptoms of right ventricular function and exercise capacity,[92] and has also been shown to increase cardiac index anywhere from 15% to 58%.[93,94]
Pulmonary thromboendarterectomy[95] has been shown to improve hemodynamics, functional status, and survival in patients with chronic thromboembolic PAH; however, there are few well-controlled trials in this area so the magnitude of benefit is difficult to precisely define.[95] It is accepted that pulmonary thromboendarterectomy is the treatment of choice in patients with operable chronic thromboembolic PH.[96] Patients with inoperable PH from chronic thromboemboli and those with significant residual PH after surgery should be treated with medical therapy used in PAH patients.
Lung transplantation has been performed for patients with PAH for 2 decades; however, with the advances made in the treatment of PAH, lung transplantation should only be considered after medical therapy has failed.[9] Current recommendations state that patients with class III or IV symptoms at presentation should be referred to a transplant center for evaluation so that if the response to therapy is insufficient, evaluation and listing for lung transplantation may be expedited.[96,97] According to the United Network for Organ Sharing database, the survival in patients with PH undergoing LT at 1 year is 73% and at 3 years is 56%.[98]
Prognosis
The prognosis of untreated PAH is poor; however, with therapy the expected survival and quality of life have improved dramatically.[99] The prognosis of treated patients with PAH depends on many factors, and it is still not certain which factors carry the most prognostic significance and which factors should be used to guide decisions regarding escalation of therapy and referral for lung transplant evaluation.[97] Survival in PAH may vary depending on presence or absence of underlying disease and etiology of the underlying disease if present.[99-103] Echocardiographic parameters,[99] the 6MWD,[20] bicycle ergometry,[23] plasma atrial natriuretic peptide and BNP,[104] elevated uric acid levels,[105] baseline exercise tolerance and the degree of improvement in exercise tolerance at 3 months and 1 year after initiation of epoprostenol therapy[46,47] have all been shown to correlate with survival in patients with PAH. Treatment with prostanoids, endothelin receptor antagonists, and phosphodiesterase inhibitors has been shown to prolong survival among patients with PAH.[46,47,75,83]
Conclusion
The past 3 decades have seen great advances in our understanding of the genetics and pathogenesis of PAH. With this understanding has come the development of new treatments that have significantly improved the life span and lifestyle of these patients. New insights into the best way to screen for, monitor, and care for patients with PAH, as well as the development of novel therapies, will hopefully allow us to continue to improve the care that these patients receive.
Supported by an independent educational grant from Actelion.
References
1. Mughal MM, Mandell B, James K, Stelmach K, Minai OA. Implementing a shared-care approach to improve the management of patients with pulmonary arterial hypertension. Cleve Clin J Med. 2003;70:S28-S33.
2. Simmoneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43:10S.
3. Rubin LJ. Diagnosis and management of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:7S-10S.
4. Eddahibi S, Humbert M, Fadel E, et al. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest. 2001;108:1141-1150.
5. McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:14S-34S.
6. Grunig E, Janssen B, Mereles D, et al. Abnormal pulmonary artery pressure response in asymptomatic carriers of primary pulmonary hypertension gene. Circulation. 2000;102:1145-1150.
7. Galie 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;25:2243-2278.
8. Galie N, Manes A, Branzi A. Evaluation of pulmonary arterial hypertension. Curr Opin Cardiol. 2004;19:575-581.
9. Gildea TR, Arroliga AC, Minai OA. Treatments and strategies to optimize the comprehensive management of patients with pulmonary arterial hypertension. Cleve Clin J Med. 2004;70:S18-S27.
10. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med. 1987;107:216-223.
11. McGoon M. The assessment of pulmonary hypertension. Clin Chest Med. 2001;22:493-508.
12. Budev MM, Arroliga AC, Jennings CA. Diagnosis and evaluation of pulmonary hypertension. Cleve Clin J Med. 2003;70:S9-S17.
13. Vasamreddy CR, Jayam V, Bluemke DA, Calkins H. Pulmonary vein occlusion: an unanticipated complication of catheter ablation of atrial fibrillation using the anatomic circumferential approach. Heart Rhythm. 2004;1:78-81.
14. Lupi E, Dumont C, Tehada VM, et al. A radiologic index of pulmonary arterial hypertension. Chest. 1975;68:28-31.
15. D'Alonzo GE, Bower JS, Dantzker DR. Differentiation of patients with primary and thromboembolic pulmonary hypertension. Chest. 1984;85:457-461.
16. Bergin CJ, Hauschildt J, Rios G, Belezzuoli EV, Huynh T, Channick RN. Accuracy of MR angiography compared with radionuclide scanning in identifying the cause of pulmonary arterial hypertension. Am J Roentgenol. 1997;168:1549-1555.
17. Worsley DF, Palevsky HI, Alavi A. Ventilation-perfusion lung scanning in the evaluation of pulmonary hypertension. J Nucl Med. 1994;35:793-796.
18. Steen VD, Graham G, Conte C, et al. Isolated diffusing capacity reduction in systemic sclerosis. Arthritis Rheum. 1992;35:765-770.
19. Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:40S-47S.
20. 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;161:487-492.
21. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension: the primary pulmonary hypertension study group. N Engl J Med. 1996;334:296-302.
22. Paciocco G, Martinez F, Bossone E, Pielsticker E, Gillespie B, Rubenfire M. Oxygen desaturation on the six-minute walk test and mortality in untreated primary pulmonary hypertension. Eur Respir J. 2001;17:647-652.
23. Wensel R, Opitz CF, Anker SD, et al. Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise testing. Circulation. 2002;106:319-324.
24. Hinderliter AL, Willis PW, Barst RJ, et al. Effects of long-term infusion of prostacyclin (epoprostenol) on echocardiographic measures of right ventricular structure and function in primary pulmonary hypertension: Primary Pulmonary Hypertension Study Group. Circulation. 1997;95:1479-1486.
25. Chan KL, Currie PJ, Seward JB, et al. Comparison of three Doppler ultrasound methods in the prediction of pulmonary artery pressure. J Am Coll Cardiol. 1987;9:549-554.
26. Yock PG, Popp RL. Noninvasive estimation of right ventricular systolic pressure by Doppler ultrasound in patients with tricuspid regurgitation. Circulation. 1984;70:657-662.
27. Kim WR, Krowka MJ, Plevak DJ, et al. Accuracy of Doppler echocardiography in the assessment of pulmonary hypertension in liver transplant candidates. Liver Transpl. 2000;6:453-458.
28. Denton CP, Cailes JB, Phillips GD, et al. Comparison of Doppler echocardiography and right heart catheterization to assess pulmonary hypertension in systemic sclerosis. Br J Rheumatol. 1997;36:239-243.
29. Hinderliter AL, Willis PW, Barst RJ, et al. Effects of long-term infusion of prostacyclin (epoprostenol) on echocardiographic measures of right ventricular structure and function in primary pulmonary hypertension: primary pulmonary hypertension study group. Circulation. 1997;95:1479-1486.
30. Bossone E, Duong-Wagner TH, Paciocco G, et al. Echocardiographic features of primary pulmonary hypertension. J Am Soc Echocardiogr. 1999;12:655-662.
31. Penning S, Robinson KD, Major CA, et al. A comparison of echocardiography and pulmonary artery catheterization for evaluation of pulmonary artery pressures in pregnant patients with suspected pulmonary hypertension. Am J Obstet Gynecol. 2001;184:1568-1570.
32. Naeije R, Torbicki A. More on the noninvasive diagnosis of pulmonary hypertension: Doppler echocardiography revisited. Eur Respir J. 1995;8:1445-1449.
33. D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med. 1991;115:343-349.
34. Badesch DB, Abman SH, Ahearn GS, et al. Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:35S-62S.
35. Sitbon O, Humbert M, Ioos V, et al. Who benefits from long-term calcium-channel blocker therapy in primary pulmonary hypertension? [abstract]. Am J Respir Crit Care Med. 2003;167:A440.
36. Galie N, Seeger W, Naeije R, et al. Comparative analysis of clinical trials and evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:81S-88S.
37. Venkateshiah SB, Arroliga AC, Mehta AC, et al. Safety of surgery in patients with pulmonary arterial hypertension (Abstr). Am J Respir Crit Care Med. 2002;165:B53.
38. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425-1436.
39. 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;327:76-81.
40. Fuster V, Steele PM, Edwards WD, et al. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation. 1984;70:580-587.
41. Groves BM, Badesch DB, Turkevich D, et al. Correlation of acute prostacyclin response in primary (unexplained) pulmonary hypertension with efficacy of treatment with calcium channel blockers and survival. In: Weir K, ed. Ion Flux in Pulmonary Vascular Control. New York, NY: Plenum Press; 1993: 317-330.
42. Sitbon O, Brenot F, Denjean A, et al. Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension: a dose-response study and comparison with prostacyclin. Am J Respir Crit Care Med. 1995;151:384-389.
43. Pavelsky HI, Schloo BL, Pietra GG, et al. Primary pulmonary hypertension: vascular structure, morphometry, and responsiveness to vasodilator agents. Circulation. 1989;80:1207-1221.
44. Sitbon O, Humbert M, Jagot JL, et al. Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium-channel blockers in primary pulmonary hypertension. Eur Respir J. 1998;12:265-270.
45. Galie N, Manes A, Branzi A. Emerging medical therapies for pulmonary arterial hypertension. Prog Cardiovasc Dis. 2002;45:213-224.
46. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002;106:1477-1482.
47. 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;40:780-788.
48. Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med. 1990;112:485-491.
49. Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease: a randomized, controlled trial. Ann Intern Med. 2000;132:425-434.
50. Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation. 1999;99:1858-1865.
51. Robbins IM, Gaine SP, Schilz R, et al. Epoprostenol for treatment of pulmonary hypertension in patients with systemic lupus erythematosus. Chest. 2000;117:14-18.
52. Aguilar RV, Farber HW. Epoprostenol (prostacyclin) therapy in HIV-associated pulmonary hypertension. Am J Respir Crit Care Med. 2000;162:1846-1850.
53. Bakst AE, Gaine SP, Rubin LJ. Continuous intravenous epoprostenol therapy for pulmonary hypertension n Gaucher's disease. Chest. 1999;116:1127-1129.
54. Kuo PC, Johnson LB, Plotkin JS, et al. Continuous intravenous infusion of epoprostenol for the treatment of portopulmonary hypertension. Transplantation. 1997;63:604-606.
55. Barst RJ, Maislin G, Fishman AP. Vasodilator therapy for primary pulmonary hypertension in children. Circulation. 1999;99:1197-1208.
56. Ivy DD, Doran A, Claussen L, Bingaman D, Yetman A. Weaning and discontinuation of epoprostenol in children with idiopathic pulmonary arterial hypertension receiving concomitant bosentan. Am J Cardiol. 2004;93:943-946.
57. Kim NH, Channick RN, Rubin LJ. Successful withdrawal of long-term epoprostenol therapy for pulmonary arterial hypertension. Chest. 2003;124:1612-1615.
58. Suleman N, Frost AE. Transition from epoprostenol and treprostinil to the oral endothelin receptor antagonist bosentan in patients with pulmonary hypertension. Chest. 2004;126:808-815.
59. McLaughlin VV, Gaine SP, Barst RJ, et al. Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension. J Cardiovasc Pharmacol. 2003;41:293-299.
60. Simmonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analog, in patients with pulmonary arterial hypertension: a double-blind randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002;165:800-804.
61. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001;358:119-123.
62. Galie N, Humbert M, Vachiery JL, et al. Effects of beraprost sodium, an oral prostacyclin analog, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2002;39:1496-1502.
63. Barst RJ, McGoon M, McLaughlin V, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2003;4:2119-2125.
64. Olschewski H, Simmonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002;347:322-329.
65. MacLean MR. Endothelin-1: a mediator of pulmonary hypertension? Pulm Pharmacol Ther. 1998;11:125-132.
66. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328:1732-1739.
67. Galie N, Grigion F, Bacchi-Raggiani L, et al. Relation of endothelin-1 to survival in patients with primary pulmonary hypertension. Eur J Clin Invest. 1996;26:273.
68. Pearl JM, Wellman SA, Mcnamara JL, et al. Bosentan prevents hypoxia-reoxygenation-induced pulmonary hypertension and improves pulmonary function. Ann Thorac Surg. 1999;68:1714-1721.
69. Chen SJ, Chen YF, Meng QC, et al. Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats. J Appl Physiol. 1995;79:2122-2131.
70. Hill NS, Warburton RR, Pietras L, et al. Nonspecific endothelin-receptor antagonist blunts monocrotaline-induced pulmonary hypertension in rats. J Appl Physiol. 1997;83:1209-1215.
71. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896-903.
72. Galie N, Hinderliter AL, Torbicki A, et al. Effects of the oral endothelin-receptor antagonist bosentan on echocardiographic and Doppler measures in patients with pulmonary arterial hypertension. J Am Coll Cardiol. 2003;41:1380-1386.
73. 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;170:1212-1217.
74. Fattinger K, Funk C, Pantze M, et al. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther. 2001;69:223-231.
75. McLaughlin VV, Sitbon O, Badesch DB, et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J. 2005;25:244-249.
76. Sitbon O, McLaughlin V, Badesch D, et al. Comparison of two treatment strategies, first-line bosentan or epoprostenol, on survival in class III idiopathic pulmonary arterial hypertension [abstract]. Am J Respir Crit Care Med. 2004;169:A442.
77. Barst RJ, Langleben D, Frost A, et al. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004;169:441-447.
78. Langleben D, Hirsch AM, Shalit E, Lesenko L, Barst RJ. Sustained symptomatic, functional, and hemodynamic benefit with the selective endothelin-A receptor antagonist, sitaxsentan, in patients with pulmonary arterial hypertension. Chest. 2004;126:1377-1381.
79. Barst RJ, Langleben D, Badesch D, et al. The STRIDE-2 Trial: Does Selectivity Matter in Endothelin Antagonism for PAH? American Thoracic Society - 2005 - Mini-Symposium. Abstract: A300.
80. Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation. 2002;105:2398-2403.
81. Zimmerman AT, Calvert AF, Veitch EM. Sildenafil improves right-ventricular parameters and quality of life in primary pulmonary hypertension. Intern Med J. 2002;32:424-426.
82. Badesch D, Burgess G, Parpia T, Torbicki A; and the SUPER-1 team. Sildenafil Citrate in Patients with Pulmonary Arterial Hypertension (PAH): Results of a Multicenter, Multinational, Randomized, Double-Blind, Placebo-Controlled Trial by WHO Functional Class (FC). American Thoracic Society, 2005 Thematic Poster Session (Poster: K93, Abstract: A206).
83. Rubin L, Burgess G, Parpia T, Simonneau G, and the SUPER-1 team. Effects of Sildenafil on 6-Minute Walk Distance (6MWD) and WHO Functional Class (FC) after 1 Year of Treatment. American Thoracic Society - 2005 Mini-Symposium (Abstract: A299).
84. Channick RN, Yung GL. Long-term use of inhaled nitric oxide for pulmonary hypertension. Resp Care. 1999;44:212-219.
85. Nagaya N, Uematsu M, Oya H, et al. Short-term oral administration of L-arginine improves hemodynamics and exercise capacity in patients with precapillary pulmonary hypertension. Am J Respir Crit Care Med. 2001;163:887-891.
86. Girgis RE, Li D, Zhan X, et al. Attenuation of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol. 2003;285:H938-945.
87. Kao PN. Simvastatin treatment of pulmonary hypertension. Chest. 2005;127:1446-1452.
88. Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J. 2004;24:353-359.
89. Gomberg-Maitland M, McLaughlin VV, Gulati M, Rich S. Efficacy and safety of sildenafil and atorvastatin added to bosentan as therapy for pulmonary arterial hypertension [abstract]. Am J Respir Crit Care Med. 2005 Sep 8; [Epub ahead of print].
90. Hoeper MM, Faulenbach C, Golpon H, et al. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J. 2004;24:1007-1010.
91. Glanville A, Burke C, Theodore J, et al. Primary pulmonary hypertension: length of survival in patients referred for heart-lung transplantation. Chest. 1987;91:675-681.
92. Klepetko W, Mayer E, Sandoval J, et al. Interventional and surgical modalities of treatment for pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:73S-80S.
93. Nihill MR, O'Laughlin MP, Mullins CE. Effects of atrial septostomy in patients with terminal cor pulmonale due to pulmonary vascular disease. Cathet Cardiovasc Diagn. 1991;24:166-172.
94. Sandoval J, Gaspar J, Pulido T, et al. Graded balloon dilation atrial septostomy in severe primary pulmonary hypertension: a therapeutic alternative for patients unresponsive to vasodilator treatment. J Am Coll Cardiol. 1998;32:297-304.
95. Doyle RL, McCrory K, Channick RN, et al. Surgical treatments/interventions for pulmonary arterial hypertension. ACCP evidence-based clinical practice guidelines. Chest. 2004;126:63S-71S.
96. Moser KM, Auger WR, Fedullo PF, et al. Chronic thromboembolic hypertension: clinical picture and surgical treatment. Eur Respir J. 1992;5:334-342.
97. Minai OA, Budev MM. Referral for lung transplantation: a moving target. Chest. 2005;127:705-707.
98. United Network for Organ Sharing. Available at: . Accessed September 4, 2003.
99. McLaughlin VV, Presberg KW, Doyle RL, et al. Prognosis of pulmonary arterial hypertension. ACCP evidence-based clinical practice guidelines. Chest 2004;126:78S-92S.
100. Koh ET, Lee P, Gladman DD, Abu-Shakra M. Pulmonary hypertension in systemic sclerosis: an analysis of 17 patients. Br J Rheumatol 1996;35:989-993.
101. Stupi AM, Steen VD, Owens GR, et al. Pulmonary hypertension in the CREST syndrome variant of systemic sclerosis. Arthritis Rheum 1986;29:515-24.
102. Opravil M, Pechere M, Speich R, et al. HIV-associated primary pulmonary hypertension: a case controlled study. Swiss HIV cohort study. Am J Respir Crit Care Med. 1997;155:990-995.
103. Hopkins WE, Ochoa LL, Richardson GW, et al. Comparison of the hemodynamics and survival of adults with severe primary pulmonary hypertension or Eisenmenger syndrome. J Heart Lung Transplant. 1996;15:100-105.
104. Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation. 2000;102:865-870.
105. Nagaya N, Uematsu M, Satho T, et al. Serum uric acid levels correlate with the severity and the mortality of primary pulmonary hypertension. Am J Respir Crit Care Med. 1999;160:487-492.
................
................
In order to avoid copyright disputes, this page is only a partial summary.
To fulfill the demand for quickly locating and searching documents.
It is intelligent file search solution for home and business.
Related searches
- pulmonary hypertension and leg swelling
- pulmonary hypertension life expectancy
- pulmonary hypertension severe end stage
- pulmonary hypertension prognosis
- is mild pulmonary hypertension dangerous
- pulmonary hypertension stages and prognosis
- end stage pulmonary hypertension symptoms
- pulmonary hypertension symptoms
- pulmonary hypertension symptom in men
- symptoms of pulmonary hypertension symptoms
- end stage pulmonary hypertension treatment
- pulmonary hypertension stage 3