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CHEST
A consensus panel convened by the American College of Chest Physicians developed guidelines
for the treatment of pulmonary arterial hypertension (PAH) that were published in 2004.
Subsequently, several important clinical trials have been published, and new treatments have
received regulatory approval. In addition, add-on and combination therapy are being explored,
which promise to open new therapeutic avenues. This article, taking into consideration studies
published prior to September 1, 2006, provides an update to the previously published guidelines.
The original guidelines have been summarized, a discussion of new studies has been added, and
the treatment algorithm has been revised to take into account recent developments in therapy.
This update provides evidence-based treatment recommendations for physicians involved in the
care of patients with PAH. Due to the complexity of the diagnostic evaluation required and the
treatment options available, referral of patients with PAH to a specialized center continues to be
strongly recommended.
(CHEST 2007; 131:19171928)
Key words: anticoagulation; arginine; beraprost; bosentan; calcium-channel blockers; endothelin; endothelin receptor
antagonist; epoprostenol; idiopathic pulmonary arterial hypertension; iloprost; medical therapy; oxygen; primary
pulmonary hypertension; prostacyclin; pulmonary arterial hypertension; pulmonary hypertension; secondary pulmonary
hypertension; sildenafil; therapy; treatment; treprostinil; vasoreactivity; warfarin
Abbreviations: ACCP American College of Chest Physicians; CCB calcium-channel blockers; FDA Food and
Drug Administration; IPAH idiopathic pulmonary arterial hypertension; 6MW 6-min walk; NYHA New York
Heart Association; PAH pulmonary arterial hypertension; PAPm mean pulmonary arterial pressure;
PH pulmonary hypertension; PVR pulmonary vascular resistance; RCT randomized clinical trial
www.chestjournal.org
research laboratory. Recognizing the need to educate physicians on the diagnosis and management of
PAH, the American College of Chest Physicians
(ACCP) convened a multidisciplinary panel of experts from 2003 to 2004 to formulate guidelines for
the approach to management of this complex condition. These evidence-based guidelines, including a
comprehensive overview of treatment,1 were published as a supplement to CHEST in 2004.1 8 The
guidelines from this original publication are presented in Table 1.
The pace of developments in the treatment for
PAH has quickened, with several important clinical
trials having been published over the past 2 years
that have led to regulatory approval of newer drugs
and experience with combinations of existing drugs.
These advances are likely to impact on the way
physicians should now approach the treatment of
CHEST / 131 / 6 / JUNE, 2007
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PAH. Accordingly, the ACCP impaneled a subcommittee of the original panel to develop an update to
the treatment guidelines based on these recent
developments. As before, these guidelines are evidence based and the subcommittee employed the
same criteria for inclusion and recommendation as
were used in the previous work.
Update of Treatment Guidelines
A consensus panel convened by the ACCP developed guidelines for the diagnosis and treatment of
PAH that were published in 2004.9 Subsequently,
several important clinical trials have been published
and new treatments have received regulatory approval. In addition, add-on and combination therapy
are being explored, which promise to open new
therapeutic avenues.
Therefore, the Health and Science Policy Com*From the University of Colorado Health Sciences Center (Dr.
Badesch), Denver, CO; The Childrens Hospital (Dr. Abman),
Denver, CO; Hopital Antoine Becle`re (Dr. Simonneau), Clamart,
France; University of California, San Diego (Dr. Rubin), San
Diego, CA; and University of Michigan (Dr. McLaughlin), Ann
Arbor, MI.
Dr. Badesch has received grant monies from the National
Institutes of Health. He has received grant monies from GlaxoSmithKline, United Therapeutics/LungRx, Actelion, Lilly/ICOS,
Encysive, Pfizer, Myogen/Gilead, and CoTherix. He has received
consultant fees from GlaxoSmithKline, Actelion, Myogen/Gilead,
CoTherix, Pfizer, United Therapeutics, Mondo-Biotech, Biogen
IDEC, PR Pharmaceuticals, Forrests Labs, Scios, Amgen, Biovale Pharmaceuticals/Clarus Health, and Johnson & Johnson. He
has served on the speakers bureau for GlaxoSmithKline, Actelion, Myogen/Gilead, Encysive, CoTherix, Pfizer, United Therapeutics, Mondo-Biotech, and Biogen IDEC. He has served on
the board of directors for the Pulmonary Hypertension Association and the American Thoracic Society.
Dr. Abman has served as a scientific advisor for INO Therapeutics.
Dr. Simonneau has received grant monies from, served on the
speakers bureau for, and served on the advisory committees for
Actelion, Pfizer, Schering, United Therapeutics, and GlaxoSmithKline.
Dr. Rubin has received university grant monies from the National
Heart, Lung, and Blood Institute. He has received grant monies
from Actelion, Pfizer, United Therapeutics, Mondo-Biotech, MD
Primer, and Gilead. He is a shareholder in LungRx. He has
received consultant fees from the National Heart, Lung, and
Blood Institute; Actelion; Pfizer; United Therapeutics; ProQuest;
Bayer Schering; and Mondo-Biotech. He is on the advisory
committees for Actelion, Pfizer, LungRx, MD Primer, and
Encysive.
Dr. McLaughlin has received grant monies from Actelion, Encysive, LungRx, Pfizer, and United Technologies. She has served
on the speakers bureau and advisory committees for Actelion,
Gilead, and Pfizer.
Manuscript received November 1, 2006; revision accepted February 9, 2007.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: David B. Badesch, MD, FCCP, University of
Colorado Health Sciences Center, Box C-272, 4200 E. Ninth Ave,
Denver, CO 80262; e-mail: David.Badesch@UCHSC.edu
DOI: 10.1378/chest.06-2674
Calcium-Channel Antagonists
A small number of patients with IPAH, who
demonstrate a favorable response to acute vasodilator testing at the time of cardiac catheterization,
will do well with calcium-channel blocker (CCB)
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Recommendations
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Patients with IPAH should undergo acute vasoreactivity testing using a short-acting
agent such as IV epoprostenol, adenosine, or inhaled nitric oxide.
Patients with PAH associated with underlying processes, such as scleroderma or
congenital heart disease, should undergo acute vasoreactivity testing.
Patients with PAH should undergo vasoreactivity testing by a physician experienced in
the management of pulmonary vascular disease.
Patients with IPAH, in the absence of right-heart failure, demonstrating a favorable
acute response to vasodilator (defined as a fall in PAPm of at least 10 mm Hg to 40
mm Hg, with an increased or unchanged cardiac output), should be considered
candidates for a trial therapy with an oral calcium-channel antagonist.
Patients with PAH associated with underlying processes such as scleroderma or
congenital heart disease, in the absence of right-heart failure, demonstrating a
favorable acute response to vasodilator (defined as a fall in pulmonary artery pressure
of at least 10 mm Hg to 40 mm Hg, with an increased or unchanged cardiac
output), should be considered candidates for a trial of therapy with an oral calciumchannel antagonist.
In patients with PAH, CCBs should not be used empirically to treat PH in the absence
of demonstrated acute vasoreactivity.
Patients with IPAH should receive anticoagulation with warfarin.
In patients with PAH occurring in association with other underlying processes, such as
scleroderma or congenital heart disease, anticoagulation should be considered.
In patients with PAH, supplemental oxygen should be used as necessary to maintain
oxygen saturations at 90% at all times.
Children with PAH:
With right-heart failure or with hypercoagulable state, administer anticoagulation with
warfarin.
Without right-heart failure or with hypercoagulable state, administer anticoagulation with
warfarin; for children 5 years of age, lower target international normalized ratios are
recommended.
In patients with PAH, pregnancy should be avoided, or termination recommended.
Grading
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Table 1Continued
Guideline No.
Surgical treatments/interventions for
PAH
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2
3
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PAH and sleep-disordered breathing
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2
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Prognosis of PAH
1
Recommendations
Grading
Elevated PAPm.
Low Vo2max and low peak exercise systolic and diastolic BP as determined by
cardiopulmonary exercise testing.
ECG findings of increased P wave amplitude in lead II, qR pattern in lead V1, and
World Health Organization criteria for right ventricular hypertrophy.
Elevated brain natriuretic peptide ( 180 pg/mL).
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In patients with IPAH treated with epoprostenol, persistence of NYHA functional class
III or IV status after at least 3 mo of therapy may be used to predict a worse
prognosis.
In patients with scleroderma associated PAH, reduced Dlco ( 45% of predicted) may
be used to predict a worse prognosis.
In pediatric IPAH patients, younger age at diagnosis may be used to predict a worse
prognosis.
*CTEPH chronic thromboembolic PH; Dlco diffusion capacity of the lung for carbon monoxide; HLT heart-lung transplant;
OSA obstructive sleep apnea; Vo2max maximum oxygen uptake.
Recommendation designations are defined in Table 2.
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Description
Net benefit
Substantial
Intermediate
Small/weak
None
Conflicting
Negative
Strength of recommendation
A
B
C
D
I
E/A
E/B
E/C
E/D
Strong recommendation
Moderate recommendation
Weak recommendation
Negative recommendation
No recommendation possible (inconclusive)
Strong recommendation based on expert opinion only
Moderate recommendation based on expert opinion only
Weak recommendation based on expert opinion only
Negative recommendation based on expert opinion only
Prostanoids
Epoprostenol
In a 12-week, prospective, multicenter, randomized,
controlled, open-label trial,11 continuously IV infused
epoprostenol plus conventional therapy (including oral
vasodilators [CCBs], anticoagulation, diuretic, digoxin, and
oxygen) was compared to conventional therapy alone in 81
patients with severe IPAH (NYHA class III or IV).
Exercise capacity improved in the 41 patients treated with
epoprostenol (median 6 min walk [6MW] distance, 362 m
at 12 weeks, vs 315 m at baseline), and decreased in the 40
patients treated with conventional therapy alone (204 m at
12 weeks vs 270 m at baseline; p 0.002 for the comparison of the treatment groups). There were also improvements in indexes of the quality of life, hemodynamics, and
Table 3Relationship of Strength of the Recommendations Scale to Quality of Evidence and Net Benefits*
Net Benefit
Quality of Evidence
Good
Fair
Low
Expert opinion
Substantial
Intermediate
Small/Weak
None
Conflicting
Negative
A
A
B
E/A
A
B
C
E/B
B
C
C
E/C
D
D
I
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I
I
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D
D
D
E/D
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Endothelin Antagonists
Bosentan
The first randomized, double-blind, placebo-controlled, multicenter study22 of bosentan demonstrated an improvement in the 6MW distance of
70 m (from 360 19 m at baseline to 430 14 m at
week 12; p 0.05), whereas no improvement was
seen with placebo (355 25 m at baseline and
349 44 m at week 12). Treatment with bosentan
also improved cardiopulmonary hemodynamics and
functional class. Asymptomatic increases in hepatic
aminotransferases were observed in two bosentantreated patients. In a second double-blind, placebocontrolled study (the Bosentan Randomized Trial of
Endothelin Antagonist Therapy for Pulmonary Hypertension-1 Study23), bosentan (125 or 250 mg bid)
was evaluated in 213 patients with functional class
III and IV PAH (either primary or associated with
connective tissue disease), for a minimum of 16
weeks (62.5 mg bid for 4 weeks then target dose).
Bosentan improved the 6MW distance by 36 m,
whereas deterioration ( 8 m) was seen with placebo.
The difference between treatment groups in the
mean change in 6MW distance was 44 m in favor of
bosentan (95% confidence interval, 21 to 67 m;
p 0.0002). The risk of clinical worsening was
reduced by bosentan compared to placebo
(p 0.0015, log-rank test). Abnormal hepatic function test findings, syncope, and flushing occurred
more frequently in the bosentan group.
Two important articles describing longer-term
outcomes with bosentan therapy have been recently
published. In the first, McLaughlin et al24 found that
first-line therapy with bosentan, with the subsequent
addition or transition to other therapy as necessary,
resulted in Kaplan-Meier survival estimates of 96%
at 12 months and 89% at 24 months. In contrast,
predicted survival rates from the National Institutes
of Health Registry formula are 69% and 57%, respectively. In addition, at the end of 12 months and
24 months, 85% and 70% of patients, respectively,
remained alive and receiving bosentan monotherapy.
Factors that predicted a worse outcome included
World Health Organization functional class IV and
6MW distance below the median (358 m) at baseline. In the second study, Sitbon et al25 compared
survival in patients with functional class III IPAH
treated with bosentan with historical data from simwww.chestjournal.org
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Figure 1. Treatment algorithm for PAH. The recommended therapies presented in this algorithm have
been evaluated mainly in those with IPAH, or PAH associated with connective tissue disease or anorexigen
use. Extrapolation to other forms of PAH should be made with caution. Country-specific regulatory agency
approval status and functional class indications for PAH medications vary. (1) Anticoagulation should be
considered for patients with IPAH, and patients with an indwelling catheter for the administration of an IV
prostanoid, in the absence of contraindications. Diuretics and oxygen should be added as necessary. (2) A
positive acute vasodilator response is defined as a fall in PAPm 10 mm Hg to 40 mm Hg, with an
unchanged or increased cardiac output when challenged with inhaled nitric oxide, IV epoprostenol, or IV
adenosine. (3) Consideration should be given to using a PAH-specific medication such as a phosphodiesterase 5 inhibitor, endothelin receptor antagonist, or prostanoid as first-line treatment instead of a CCB in
patients with PAH that is not IPAH or PAH associated with anorexigen use, or in those in an advanced
functional class (FC) given the exceedingly low long-term response rate to CCB monotherapy in the former
and poor prognosis in the latter. (4) Sustained response to CCB therapy is defined as being in functional
class I or II with normal or near-normal hemodynamics after several months of treatment. (5) The risks and
benefits of treatment in early PAH should be considered. (6) First-line therapy for functional class III
includes bosentan, sildenafil, epoprostenol, inhaled (inh) iloprost, and treprostinil (see text for details). (7)
Most experts recommend IV epoprostenol as first-line treatment for unstable patients in functional class IV.
(8) RCTs studying add-on combination treatment regimens are underway. Designators [A], [B], [C], [D],
and [E/A], [E/C] [E/B] are defined in Table 2. *Not in order of preference. SC subcutaneous.
Summary
The paradigm for treatment of PAH continues to
advance rapidly. Multicenter randomized clinical trials
(RCTs) have provided a basis for evidence-based pracwww.chestjournal.org
tice. The treatment algorithm provided (Fig 1) attempts to summarize the current approach to therapy
for PAH. The following brief overview, organized by
functional class, is intended to facilitate clinical application of the algorithm. It should be noted that funcCHEST / 131 / 6 / JUNE, 2007
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Description
Subcutaneous treprostinil
IV treprostinil
Recommendations
Inhaled iloprost
Subcutaneous treprostinil
IV treprostinil
Functional class IV
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Inhaled iloprost
Subcutaneous treprostinil
Sildenafil
IV treprostinil
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*Refer to Table 1 for recommendations that have not changed since the 2004 guidelines.
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References
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