Download 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)
1. Pulmonary arterial hypertension (PAH)
o
o
o
1.1. Idiopathic (IPAH)
1.2. Familial (FPAH)
1.3. Associated with (APAH):






o
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)
2. Pulmonary hypertension with left heart disease
o
o
2.1. Left-sided atrial or ventricular heart disease
2.2. Left-sided valvular heart disease
3. Pulmonary hypertension associated with lung disease and/or hypoxemia
o
o
o
o
o
o
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
4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease
o
o
o
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)
5. Miscellaneous
o
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 evidencebased 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).
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.
Figure 2. Chest radiograph of a patient with PAH showing central enlargement of pulmonary arteries
bilaterally with peripheral "pruning."
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 MVO 2 < 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 VO 2
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]
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 evidencebased 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 longterm 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
Epoprostenol
Pilot
Epoprostenol
Pivotal
First Author, Journal,
Year
Patients
Duration
(wks)
Rubin, Ann Intern Med,
1990
23
8
Barst, NEJM, 1998
81
12
Epoprostenol
CTD
Badesch, Ann Intern Med,
2000
111
12
Pivotal
Simmoneau, AJRCCM,
2002
469
12
AIR
Olschewsi, NEJM, 2002
203
12
Beraprost
ALPHABET
Galie, JACC, 2002
130
12
Bosentan
Pilot
Channick, Lancet, 2001
33
12
Bosentan
BREATHE1
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
(%)8
NYHA
Functional
Class (%)*
6MWD
(m)#
Hemodynamic
Improvement
Clinical
Parameters
IPAH
(100)
II (9)
45
Yes
Improved
47
Yes
Improved
94
Yes
No Change
1688
Yes
Improved
36
Yes†
Improved
25
No
No Change
III (100)
76
Yes
Improved
III (91)
44
Yes^
Improved
Treprostinil
Iloprost
Epoprostenol
III (65)
IV (26)
Epoprostenol
Epoprostenol
IPAH
(100)
CTD
(100)
III (75)
IV (25)
II (5)
III (78)
IV (17)
Treprostinil
Iloprost
Beraprost
IPAH (58)
II (11)
CHD (24)
III (82)
CTD (19)
IV (7)
IPAH (54)
III (59)
CTD (17)
IV (41)
IPAH (48)
II (49)
CHD (21)
III (51)
Po-PH
(16)
CTD (7)
HIV (7)
Bosentan
IPAH (85)
CTD (15)
Bosentan
IPAH (70)
Sitaxsentan
Sitaxsentan
Sildenafil
CTD (30)
IV (9)
IPAH (53)
II (33)
CTD (24)
III (66)
CHD (24)
IV (1)
IPAH (59)
II (38)
CTD (30)
III (59)
CHD (11)
IV (4)
IPAH (63)
34
Yes
Improved
31
N/A
Yes
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
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 46meter 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] portopulmonary 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]
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 ET B 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]
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.
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 ET B 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 80mg 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). Placebocorrected 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 longterm 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.
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