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Advances in
Pulmonary Hypertension
Off icial Journal of the Pulmonary Hypertension Association
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Advances in
Pulmonary Hypertension
Vol 12, No 3; 2013
The Current Status
of WHO Group 3
Pulmonary
Hypertension
Off icial Journal of the Pulmonary Hypertension Association
Pulmonary Hypertension and Chronic Obstructive
Pulmonary Disease: When Is it Out of Proportion?
Sonja Bartolome, MD, FCCP
Pulmonary Hypertension in Idiopathic
Pulmonary Fibrosis
Belinda N. Rivera-Lebron, MD, MSCE
Hypoxic Pulmonary Vasoconstriction and
Chronic Lung Disease
Erik R. Swenson, MD
Pulmonary Hypertension Roundtable: COPD, IPF, and
Pulmonary Hypertension: A clinician’s dilemma
PHPN: O2 Trials and Tribulations
Tonya Zeiger, RRT, CPFT
Ask the Expert: When Is Testing Beyond Overnight
Oximetry Indicated for Assessment of Sleep-Disordered
Breathing in Pulmonary Arterial Hypertension?
Alison S. Kole, MD, MPH, FCCP
Editorial Advisory Board
Editor-in-Chief
Myung Park, MD
Associate Professor of Medicine
Director, Pulmonary Vascular Diseases
Program
Division of Cardiology
University of Maryland School of
Medicine
Baltimore, Maryland
Immediate Past Editor-in-Chief
Erika Berman Rosenzweig, MD
Associate Professor of Clinical Pediatrics
in Medicine
Director, Pulmonary Hypertension Center
Columbia University College of
Physicians and Surgeons
Morgan Stanley Children’s Hospital of
New York
New York, New York
Editor-in-Chief Elect
Charles Burger, MD
Professor of Medicine
Mayo Clinic College of Medicine
Medical Director, PH Clinic
Mayo Clinic Florida
Jacksonville, Florida
Associate Editors
Harrison Farber, MD
Professor of Medicine
Director, Pulmonary Hypertension Center
Boston University/Boston Medical Center
Boston, Massachusetts
Deborah Jo Levine, MD
Associate Professor
Pulmonary and Critical Care Medicine
Lung Transplant Pulmonologist
Director of Pulmonary Hypertension Center
Division of Cardiothoracic Surgery
University of Texas Health Science
Center at San Antonio
San Antonio, Texas
Section Editor
Omar A. Minai, MD
Department of Pulmonary, Allergy and
Critical Care Medicine
Cleveland Clinic
Cleveland, Ohio
Fernando Torres, MD
Director, Pulmonary Hypertension Clinic
University of Texas Southwestern Medical
Center
Dallas, Texas
International Editor
Editorial Board
Lynette M. Brown, MD
Assistant Professor of Medicine
University of Utah School of Medicine
Murray, Utah
Kelly Chin, MD
Assistant Professor of Medicine
University of Texas Southwestern Medical
Center
Dallas, Texas
Section Editor
Curt Daniels, MD
Director, Adult Congenital Heart Disease
and Pulmonary Hypertension Program
Nationwide Children’s Hospital
The Ohio State University
Columbus, Ohio
Jeffrey D. Edelman, MD
Associate Professor of Medicine
Pulmonary and Critical Care Division
University of Washington
VA Puget Sound Health Care System
Seattle, Washington
Paul Forfia, MD
Associate Professor of Medicine
Medical Director, Pulmonary
Hypertension Program and Right
Heart Failure
Temple Heart and Vascular Center
Temple University School of Medicine
Philadelphia, Pennsylvania
Sean Gaine, MD, PhD
Director, National Pulmonary
Hypertension Unit
Mater Misericordiae University Hospital
University College Dublin
Dublin, Ireland
Dunbar Ivy, MD
Professor of Pediatrics
University of Colorado
Denver Health Sciences Center
Denver, Colorado
Richard Krasuski, MD
Director of Adult Congenital Heart
Disease Services
Cleveland Clinic
Cleveland, Ohio
Ioana Preston, MD
Co-Director, Pulmonary Hypertension
Center
Tufts Medical Center
Boston, Massachusetts
Section Editor
Sean M. Studer, MD, MSc
Chief of Medicine
Woodhull Medical Center
New York University
New York, New York
Section Editor
Program Description
The mission of Advances in Pulmonary Hypertension is to serve as the premiere forum
for state of the art information regarding
diagnosis, pathophysiology, and treatment
of pulmonary hypertension. The 2008 Dana
Point revision of the World Health Organization Classification serves as a guide to
categories of pulmonary hypertension addressed in Advances in Pulmonary Hypertension. While focusing on WHO Group 1
PAH, the other categories (Group 2, pulmonary venous hypertension; Group 3, associated with chronic lung disease and/or
hypoxemia; Group 4, pulmonary embolic
hypertension; Group 5, miscellaneous) are
also addressed. This mission is achieved by
a combination of invited review articles,
roundtable discussions with panels consisting of international experts in PH, and original contributions.
Objectives
Provide up-to-date information regarding diagnosis, pathophysiology, and treatment of pulmonary hypertension.
● Serve as a forum for presentation and
discussion of important issues in the field,
including new paradigms of disease understanding and investigational trial
design.
●
Mary Bartlett, MS, RN, CS, FNP
Coordinator, Winthrop University
Hospital
Pulmonary Hypertension Center
Mineola, New York
PHPN Section Editor
The Scientific Leadership Council of the Pulmonary Hypertension Association
The scientific program of the Pulmonary Hypertension Association is guided by the association’s Scientific Leadership Council. The Council includes the following health care professionals.
Richard Channick, MD
Chair, SLC
Harvard Medical School
Boston, Massachusetts
James Klinger, MD
The Warren Alpert Medical School of
Brown University
Providence, Rhode Island
Karen A. Fagan, MD
Chair Elect, SLC
University of South Alabama
Mobile, Alabama
Irene M. Lang, MD
Medical University of Vienna
Vienna, Austria
Vallerie V. McLaughlin, MD
Immediate Past Chair, SLC
University of Michigan
Ann Arbor, Michigan
Charles Burger, MD
Mayo Clinic College of Medicine
Jacksonville, Florida
Murali Chakinala, MD
Washington University School of
Medicine
St. Louis, Missouri
Serpil Erzurum, MD
Chair, Research Committee
Cleveland Clinic Lerner College of
Medicine of Case Western Reserve
University
Cleveland, Ohio
Marc Humbert, PhD, MD
Hopital Antoine Beclere
Clamart, France
Dunbar Ivy, MD
University of Colorado Denver Health
Sciences Center
Denver, Colorado
Zhi-Cheng Jing, MD
Fu Wai Heart Hospital
Shanghai, China
Dinesh Khanna, MBBS, MSc
University of Michigan
Ann Arbor, Michigan
Stephen C. Mathai, MD, MHS
Johns Hopkins University
Baltimore, Maryland
Michael Mathier, MD
Chair, PHA Online University
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania
John Newman, MD
Vanderbilt University School of Medicine
Nashville, Tennessee
Ronald J. Oudiz, MD
Chair, Insurance and Advocacy Committee
UCLA School of Medicine
Torrance, California
Myung Park, MD
Editor-in-Chief, Advances in Pulmonary
Hypertension
University of Maryland Medical Center
Baltimore, Maryland
Ioana Preston, MD
Tufts Medical Center
Boston, Massachusetts
Tomas Pulido, MD
National Heart Institute
Mexico City, Mexico
Erika Berman Rosenzweig, MD
Columbia University
New York, New York
Robert Schilz, DO, PhD
Chair, SLC Education Committee
Case Western Reserve University School
of Medicine
Cleveland, Ohio
Virginia Steen, MD
Georgetown University Medical Center
Washington, DC
Duncan Stewart, MD
The Ottawa Hospital
Ottawa, ON, Canada
Sean Studer, MD, MSc
New York University
New York, New York
Fernando Torres, MD
UT Southwestern Medical Center
Dallas, Texas
Terence Trow, MD
Yale School of Medicine
New Haven, Connecticut
Joel A. Wirth, MD
Tufts University School of Medicine
Boston, Massachusetts
Roham Zamanian, MD
Stanford School of Medicine
Stanford, California
Liaisons
Traci Stewart, RN, MSN
Chair, PH Professional Network
University of Iowa Hospitals and Clinics
Iowa City, Iowa
Melisa Wilson, ARNP, ACNP-BC
Chair-elect, PH Professional Network
Orlando Heart Center Downtown
Orlando, Florida
Rita Orth, RN
PHA Board Member
Danville, California
SLC Distinguished Advisors
David B. Badesch, MD
University of Colorado Health Sciences
Center
Aurora, Colorado
Bruce H. Brundage, MD
David Geffen School of Medicine at
UCLA, emeritus
Palm Desert, California
C. Gregory Elliott, MD
University of Utah School of Medicine
Murray, Utah
Michael D. McGoon, MD
Mayo Clinic
Rochester, Minnesota
The mission of the Scientific Leadership
Council is to provide medical and scientific
guidance and support to the PHA for:
●
●
●
Developing and disseminating knowledge
for diagnosing and treating pulmonary
hypertension.
Advocating for patients with pulmonary
hypertension.
Increasing involvement of basic and clinical researchers and practitioners.
More information on PHA’s Scientific
Leadership Council and associated committees can be found at www.PHAssociation.
org/SLC/
Advances in
Pulmonary Hypertension
Official Journal of the Pulmonary Hypertension Association
P UBLISHER
Pulmonary Hypertension Association
Vallerie McLaughlin, MD, Board Chair
Rino Aldrighetti, President and CEO
PHA OFFICE
Pulmonary Hypertension Association
801 Roeder Road, Ste 1000
Silver Spring, MD 20910
301-565-3004; 301-565-3994 (fax)
PUBLISHING OPERATIONS
Deborah L. McBride,
Managing Editor
McBride Strategic Services
[email protected]
Copyright ©2013 by Pulmonary Hypertension
Association. All rights reserved. None of the
contents may be reproduced in any form
whatsoever without the written permission of
PHA.
Advances in Pulmonary Hypertension is available
online at www.PHAOnlineUniv.org/journal
Advances in Pulmonary Hypertension is
circulated to cardiologists, pulmonologists,
rheumatologists, and other selected healthcare
professionals by the Pulmonary Hypertension
Association. The contents of the articles are
independently determined by the Editor-inChief and the Editorial Advisory Board.
CONTENTS
106 Editor’s Memo
Myung H. Park, MD
106 Guest Editor’s Memo
Jeffrey D. Edelman, MD
116 Ask the Expert: When Is Testing Beyond Overnight Oximetry Indicated for
Assessment of Sleep-Disordered Breathing in Pulmonary Arterial Hypertension?
Alison S. Kole, MD, MPH, FCCP
118 Clinical Trials Update
Fernando Torres, MD
122 Pulmonary Hypertension and Chronic Obstructive Pulmonary Disease: When Is
It Out of Proportion?
Sonja Bartolome, MD, FCCP
127 Pulmonary Hypertension in Idiopathic Pulmonary Fibrosis
Belinda N. Rivera-Lebron, MD, MSCE
135 Hypoxic Pulmonary Vasoconstriction and Chronic Lung Disease
Erik R. Swenson, MD
145 Pulmonary Hypertension Roundtable: COPD, IPF, and Pulmonary
Hypertension: A Clinician’s Dilemma
Jeffrey Edelman, MD, Deborah J. Levine, MD, James Klinger, MD,
and Robert Schilz, DO, PhD
152 PHPN: O2 Trials and Tribulations
Tonya Zeiger, RRT, CPFT
158 News to Use
Advances in Pulmonary Hypertension: Author Guidelines
General Information
Advances in Pulmonary Hypertension: Official Journal of the
Pulmonary Hypertension Association is a quarterly publication directed by an editorial board of renowned experts
with the oversight of the Association’s Scientific Leadership Council. Its mission is to help physicians in their
clinical decision making by informing them of important
trends affecting their practice and providing an analysis of
the impact of new findings and current information in the
peer-reviewed literature. Each article is reviewed and
approved by members of the Editorial Advisory Board.
While most articles are invited by the editorial board, the
following submissions will be considered for publication:
• Reviews that summarize and synthesize peer-reviewed
literature to date on relevant topics
• Letters to the Editor
• Clinical case studies
Submitted manuscripts are reviewed by the editorial board
and other experts in the field. Acceptance of manuscripts
is determined by factors such as quality, relevance, and
perceived value to clinical decision making.
Manuscript Preparation and Submission Process
Submissions should be sent via e-mail as an attached
Word document to the Editor-in-Chief, Myung Park,
MD, at [email protected] Manuscripts
should be double-spaced and follow AMA style. Fulllength manuscripts should not exceed 4,000 words
including references. References should be limited to 50
entries. No more than 5 figures should accompany the
manuscript. Acceptable file formats are .gif, .tif, and .jpg.
Each figure should be a separate file and figure legends
should appear at the end of the manuscript. Each figure
should be cited by number in the manuscript. Tables
should be self-explanatory and details of the table should
not be repeated in the manuscript. Tables should be prepared as part of the Word document. No more than 3
tables should be included with the manuscript. References
should conform to AMA style and be numbered consecutively in the text. Reference numbers should be placed in
parentheses at the end of the relevant sentence.
Accepted manuscripts will be edited for clarity, spelling,
punctuation, grammar, and consistency with AMA style.
Copyright
Authors must confirm they have rights to all material submitted by including a copyright release form with the
manuscript. The form can be downloaded from the PHA
Web site, www.PHAssociation.org. Authors acknowledge
the material has not been previously published nor is being
considered for publication elsewhere simultaneously with
consideration by Advances in Pulmonary Hypertension.
Any previously published figures, tables, etc. must contain
a full credit-line from the copyright owner. Authors are
responsible for obtaining permission to reproduce such
material and must provide that material in reproducible
form.
Manuscripts are accepted for exclusive publication in
Advances in Pulmonary Hypertension and will be copyrighted by the Pulmonary Hypertension Association.
Conflict of Interest Disclosures
A statement of any and all grant, contract, and industrial
support or proprietary interests of the author(s) related to
the subject matter must be submitted with the manuscript.
Checklist
Authors should be certain to include the following with
the manuscript:
1. Title page listing all authors with their academic
degree(s) and affiliations.
2. Corresponding author contact information including
e-mail and phone number.
3. Copyright release form signed by all authors
4. Conflict of Interest forms for all authors
5. List of approximately 5 key words for indexing
purposes
6. Summary of the paper not exceeding 250 words in the
format of Background; Objectives; Summary/Conclusions
Advances in Pulmonary Hypertension
Volume 12, Number 3; 2013
105
ED IT OR’ S M E M O
Pulmonary Hypertension Due to
Lung Disease: Between a Rock
and a Hard Place
Pulmonary hypertension due to lung
disease (Group 3 PH) represents one of
the most challenging subsets of PH
patients to evaluate and manage. Being
afflicted by progressive severe lung
disease compounded by PH places 3
strikes against the patient with dysfunctions in parenchyma and/or airway,
pulmonary vasculature, and right heart
function. Thus, we often hear desperation in the voices of patients struggling
with severe Group 3 PH, when each
breath taken becomes an act of labor.
These patients are often referred to
PH centers in the hopes that pulmonary
arterial hypertension (PAH) therapies
can help them to improve the quality of
their lives. Unfortunately, the presence of
significant lung disease often poses both
diagnostic and therapeutic challenges. It
has been well established that echocardiograms are not very reliable as
screening tools in patients with lung
disease. Furthermore, accurate interpretation of hemodynamics with right heart
catheterization usually requires additional
scrutiny due to the effects from wide
intrathoracic pressure changes.
As for treatment considerations, there
is a strong desire to see if a patient
would benefit from “off-label” use of
pulmonary vasodilators. However, this
group of patients is challenged because
pulmonary vasodilators can worsen their
hypoxia and clinical status due to underlying lung disease, and for many, there
are no effective disease modifying treatments for most chronic pulmonary
disorders. On the other hand, there are
reports of carefully selected patients with
significant pulmonary arterial vasculopathy and right heart dysfunction in
the presence of lung disease responding
to PAH treatments, causing us to
question whether this disease process is a
single or separate entity.
So it is with sincere pleasure that I
present this issue of Advances, which
focuses on the current status of Group 3
PH: covering questions yet to be
answered, and pitfalls to avoid. I am
sincerely grateful to our guest editor
Dr Jeffrey Edelman for proposing the
topic of Group 3 PH for this issue, and
bringing together a distinguished group
of experts to share their insights on this
disease state—from an in-depth discussion of the pathophysiology of
hypoxic pulmonary vascular disease to
the impact of PH with underlying lung
diseases such as COPD and pulmonary
fibrosis. The Roundtable participants,
led by Dr Edelman and joined by
Drs Klinger, Levine, and Schilz,
accurately articulate the difficulties in
managing Group 3 PH. I hope you find
the information in this issue helpful in
caring for your patients.
of patients with advanced disease manifest mild PH and 1% to 3% have
moderate to severe PH.2 IPF prevalence
estimates in the United States range
from 14-63/100,000 adults and PH has
been reported
in 20% to 46% of
3,4
patients. Thus, it can be inferred that
there is a substantial population of
COPD and IPF patients with PH or
potential to develop PH, and therefore a
substantial population that could benefit
from future studies.
In general, treatment for WHO
Group 3 patients consists of treatment of
the underlying condition and treatment
of hypoxia. The impact of this approach
on the course of disease is not well
defined. We currently do not have
effective therapy for IPF, and COPD
treatments other than smoking cessation
do little to prevent or reverse disease
progression. While the survival benefit of
oxygen therapy has been demonstrated
for hypoxic COPD patients, the impact
of hypoxia treatment on the course of
PH in COPD or other Group 3 patients
is not clear. The mechanisms underlying
hypoxic pulmonary vasoconstriction and
its potential contribution to PH development are discussed by Dr Swenson in
the third article of this issue.
“Off-label” use of PH drugs for
Group 3 patients is frequently considered, but this approach must be
tempered by the lack of demonstrated
benefit, the associated costs, and the
potential for harm. Twenty-two percent
of patients who met the definition for
WHO Group 1 PAH in the Registry to
Evaluate Early And Long-term pulmonary arterial hypertension disease
management (REVEAL) also had
obstructive airways disease5 and conversely, it may be argued that some
Myung H. Park, MD
Associate Professor of Medicine
Director, Pulmonary Vascular Disease
Program
University of Maryland School of Medicine
GU E S T E D IT OR’S M E M O
Over the last 2 decades we have seen
tremendous progress in the understanding and treatment of World Health
Organization (WHO) Group 1 pulmonary arterial hypertension (PAH).
Sadly, the same is not true for WHO
Group 3 PH. Despite an ever-expanding
array of treatments for Group 1 patients,
effective therapy for Group 3 patients is
lacking, as is our understanding of how
and why pulmonary hypertension (PH)
develops in these patients.
In the first 2 articles of this issue of
Advances in Pulmonary Hypertension Drs
Bartolome and Rivera-Lebron focus on
Group 3 PH patients with chronic
obstructive pulmonary disease (COPD)
and idiopathic pulmonary fibrosis (IPF).
In the United States, prevalence of
COPD in adults is estimated to be 6.3%
(approximately 15 million US adults).1
While PH is relatively uncommon in
COPD patients, its incidence increases
as disease progresses. Approximately half
106
Advances in Pulmonary Hypertension
Volume 12, Number 3; 2013
(Continued on page 158)
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For additional important risk and use information, please see brief
summary of full Prescribing Information on adjacent page.
Adempas (riociguat) tablets, for oral use
Initial U.S. Approval: 2013
BRIEF SUMMARY of prescribing information
CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION
WARNING: EMBRYO-FETAL TOXICITY
Do not administer Adempas to a pregnant female because it may cause fetal
harm [see Contraindications (4) and Use in Speciﬁc Populations (8.1)].
Females of reproductive potential: Exclude pregnancy before the start of
treatment, monthly during treatment, and 1 month after stopping treatment.
Prevent pregnancy during treatment and for one month after stopping
treatment by using acceptable methods of contraception [see use in Special
Populations (8.6)].
For all female patients, Adempas is available only through a restricted
program called the Adempas Risk Evaluation and Mitigation Strategy
(REMS) Program [see Warnings and Precautions (5.2)].
inhibitors [see Drug Interactions (7.2), Clinical Pharmacology (12.3)]. Consider
a dose reduction if patient develops signs or symptoms of hypotension.
5.4 Bleeding
In the placebo-controlled clinical trials program, serious bleeding occurred
in 2.4% of patients taking Adempas compared to 0% of placebo patients.
Serious hemoptysis occurred in 5 (1%) patients taking Adempas compared
to 0 placebo patients, including one event with fatal outcome. Serious
hemorrhagic events also included 2 patients with vaginal hemorrhage,
2 with catheter site hemorrhage, and 1 each with subdural hematoma,
hematemesis, and intra-abdominal hemorrhage.
5.5 Pulmonary Veno-Occlusive Disease
Pulmonary vasodilators may signiﬁcantly worsen the cardiovascular status
of patients with pulmonary veno-occlusive disease (PVOD). Therefore,
administration of Adempas to such patients is not recommended. Should
signs of pulmonary edema occur, the possibility of associated PVOD should
be considered and, if conﬁrmed, discontinue treatment with Adempas.
1
INDICATIONS AND USAGE
1.1 Chronic-Thromboembolic Pulmonary Hypertension
Adempas is indicated for the treatment of adults with persistent/recurrent
chronic thromboembolic pulmonary hypertension (CTEPH), (WHO Group 4)
after surgical treatment, or inoperable CTEPH, to improve exercise capacity
and WHO functional class [see Clinical Studies (14.1)].
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the
labeling:
Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)]
Hypotension [see Warnings and Precautions (5.3)]
Bleeding [see Warnings and Precautions (5.4)]
1.2 Pulmonary Arterial Hypertension
Adempas is indicated for the treatment of adults with pulmonary arterial
hypertension (PAH), (WHO Group 1), to improve exercise capacity, WHO
functional class and to delay clinical worsening.
Efﬁcacy was shown in patients on Adempas monotherapy or in combination
with endothelin receptor antagonists or prostanoids. Studies establishing
effectiveness included predominately patients with WHO functional class
II–III and etiologies of idiopathic or heritable PAH (61%) or PAH associated
with connective tissue diseases (25%) [see Clinical Studies (14.2)].
4
CONTRAINDICATIONS
4.1 Pregnancy
Adempas may cause fetal harm when administered to a pregnant woman.
Adempas is contraindicated in females who are pregnant. Adempas was
consistently shown to have teratogenic effects when administered to animals.
If this drug is used during pregnancy, or if the patient becomes pregnant
while taking this drug, the patient should be apprised of the potential hazard
to the fetus [see Use in Speciﬁc Populations (8.1)].
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions,
adverse reaction rates observed in the clinical trials of a drug cannot be
directly compared to rates in the clinical trials of another drug and may not
reﬂect the rates observed in practice.
The safety data described below reﬂect exposure to Adempas in two,
randomized, double blind, placebo-controlled trials in patients with
inoperable or recurrent/persistent CTEPH (CHEST-1) and treatment naive or
pre-treated PAH patients (PATENT-1). The population (Adempas: n = 490;
Placebo: n = 214) was between the age of 18 and 80 years [See Clinical
Studies (14.1, 14.2)].
The safety proﬁle of Adempas in patients with inoperable or recurrent/
persistent CTEPH (CHEST 1) and treatment naive or pre-treated PAH (PATENT
1) were similar. Therefore, adverse drug reactions (ADRs) identiﬁed from the
12 and 16 week placebo-controlled trials for PAH and CTEPH respectively
were pooled, and those occurring more frequently on Adempas than placebo
(≥3%) are displayed in Table 1 below. Most adverse events in Table 1 can be
ascribed to the vasodilatory mechanism of action of Adempas.
The overall rates of discontinuation due to an adverse event in the pivotal
placebo-controlled trials were 2.9% for Adempas and 5.1% for placebo
(pooled data).
Table 1: Adverse Reactions Occurring More Frequently (≥3%) on Adempas
than Placebo
(Pooled from CHEST 1 and PATENT 1)
4.2 Nitrates and Nitric Oxide Donors
Co-administration of Adempas with nitrates or nitric oxide donors (such
as amyl nitrite) in any form is contraindicated [see Drug Interactions (7.1),
Clinical Pharmacology (12.2)].
4.3 Phosphodiesterase Inhibitors
Concomitant administration of Adempas with phosphodiesterase (PDE)
inhibitors, including speciﬁc PDE-5 inhibitors (such as sildenaﬁl, tadalaﬁl,
or vardenaﬁl) or nonspeciﬁc PDE inhibitors (such as dipyridamole or
theophylline) is contraindicated [see Drug Interactions (7.1), Clinical
Pharmacology (12.2)].
5
WARNINGS AND PRECAUTIONS
5.1 Embryo-Fetal Toxicity
Adempas may cause fetal harm when administered during pregnancy
and is contraindicated for use in women who are pregnant. In females of
reproductive potential, exclude pregnancy prior to initiation of therapy,
advise use of acceptable contraception and obtain monthly pregnancy
tests. For females, Adempas is only available through a restricted program
under the Adempas REMS Program [see Dosage and Administration (2.3),
Warnings and Precautions (5.2) and Use in Speciﬁc Populations (8.1, 8.6)].
5.2 Adempas REMS Program
Females can only receive Adempas through the Adempas REMS Program, a
restricted distribution program [see Warnings and Precautions (5.1)].
Important requirements of the Adempas REMS Program include the following:
Prescribers must be certiﬁed with the program by enrolling and completing
training.
All females, regardless of reproductive potential, must enroll in the
Adempas REMS Program prior to initiating Adempas. Male patients are
not enrolled in the Adempas REMS Program.
Female patients of reproductive potential must comply with the pregnancy
testing and contraception requirements [see Use in Speciﬁc Populations (8.6)].
Pharmacies must be certiﬁed with the program and must only dispense to
patients who are authorized to receive Adempas.
Further information, including a list of certiﬁed pharmacies, is available at
www.AdempasREMS.com or 1-855-4 ADEMPAS.
5.3 Hypotension
Adempas reduces blood pressure. Consider the potential for symptomatic
hypotension or ischemia in patients with hypovolemia, severe left ventricular
outﬂow obstruction, resting hypotension, autonomic dysfunction, or
concomitant treatment with antihypertensives or strong CYP and P-gp/BCRP
Adverse Reactions
Adempas % Placebo %
(n=490)
(n=214)
Headache
27
18
Dyspepsia and Gastritis
21
8
Dizziness
20
13
Nausea
14
11
Diarrhea
12
8
Hypotension
10
4
Vomiting
10
7
Anemia (including laboratory parameters)
7
2
Gastroesophageal reﬂux disease
5
2
Constipation
5
1
Other events that were seen more frequently in riociguat compared to placebo
and potentially related to treatment were: palpitations, nasal congestion,
epistaxis, dysphagia, abdominal distension and peripheral edema. With
longer observation in uncontrolled long-term extension studies the safety
proﬁle was similar to that observed in the placebo controlled phase 3 trials.
7 DRUG INTERACTIONS
7.1 Pharmacodynamic Interactions with Adempas
Nitrates: Co-administration of Adempas with nitrates or nitric oxide donors
(such as amyl nitrite) in any form is contraindicated because of hypotension
[see Contraindications (4.1), Clinical Pharmacology (12.2)].
PDE Inhibitors: Co-administration of Adempas with phosphodiesterase
(PDE) inhibitors, including speciﬁc PDE-5 inhibitors (such as sildenaﬁl,
tadalaﬁl, or vardenaﬁl) and nonspeciﬁc PDE inhibitors (such as dipyridamole
or theophylline), is contraindicated because of hypotension [see
Contraindications (4.3), Clinical Pharmacology (12.2)].
7.2 Pharmacokinetic Interactions with Adempas
Smoking: Plasma concentrations in smokers are reduced by 50-60%
compared to nonsmokers. Based on pharmacokinetic modeling, for patients
who are smokers, doses higher than 2.5 mg three times a day may be
considered in order to match exposure seen in nonsmoking patients.
Safety and effectiveness of Adempas doses higher than 2.5 mg three times
a day have not been established. A dose reduction should be considered
in patients who stop smoking [see Dosage and Administration (2.4) and
Clinical Pharmacology (12.3)].
Strong CYP and P-gp/BCRP inhibitors: Concomitant use of riociguat
with strong cytochrome CYP inhibitors and P-gp/BCRP inhibitors such
as azole antimycotics (for example, ketoconazole, itraconazole) or HIV
protease inhibitors (such as ritonavir) increase riociguat exposure and may
result in hypotension. Consider a starting dose of 0.5 mg 3 times a day
when initiating Adempas in patients receiving strong CYP and P-gp/BCRP
inhibitors. Monitor for signs and symptoms of hypotension on initiation and
on treatment with strong CYP and P-gp/BCRP inhibitors. A dose reduction
should be considered in patients who may not tolerate the hypotensive effect
of riociguat [see Dosage and Administration (2.5), Warnings and Precautions
(5.3) and Clinical Pharmacology (12.3)].
Strong CYP3A inducers: Strong inducers of CYP3A (for example, rifampin,
phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may
signiﬁcantly reduce riociguat exposure. Data are not available to guide
dosing of riociguat when strong CYP3A inducers are co-administered [see
Clinical Pharmacology (12.3)].
Antacids: Antacids such as aluminum hydroxide/magnesium hydroxide
decrease riociguat absorption and should not be taken within 1 hour of
taking Adempas [see Clinical Pharmacology (12.3)].
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category X
Risk Summary
Adempas may cause fetal harm when administered to a pregnant woman
and is contraindicated during pregnancy. Adempas was teratogenic and
embryotoxic in rats at doses with exposures approximately 3 times the
human exposure. In rabbits, riociguat led to abortions at 5 times the
human exposure and fetal toxicity at doses with exposures approximately
15 times the human exposure. If Adempas is used in pregnancy, or if the
patient becomes pregnant while taking this drug, apprise the patient of the
potential hazard to the fetus [see Contraindications (4.1)].
Animal Data
In rats administered riociguat orally (1, 5, 25 mg/kg/day) throughout
organogenesis, an increased rate of cardiac ventricular-septal defect was
observed at the highest dose tested. The highest dose produced evidence
of maternal toxicity (reduced body weight). Post-implantation loss was
statistically signiﬁcantly increased from the mid-dose of 5 mg/kg/day.
Plasma exposure at the lowest dose is approximately 0.15 times that in
humans at the maximally recommended human dose (MRHD) of 2.5 mg
three times a day based on area under the time-concentration curve (AUC).
Plasma exposure at the highest dose is approximately 3 times that in
humans at the MRHD while exposure at the mid-dose is approximately 0.5
times that in humans at the MRHD. In rabbits given doses of 0.5, 1.5 and 5
mg/kg/day, an increase in spontaneous abortions was observed starting at
the middle dose of 1.5 mg/kg, and an increase in resorptions was observed
at 5 mg/kg/day. Plasma exposures at these doses were 5 times and 15 times
the human dose at MRHD respectively.
8.3 Nursing Mothers
It is not known if Adempas is present in human milk. Riociguat or its
metabolites were present in the milk of rats. Because many drugs are present
in human milk and because of the potential for serious adverse reactions in
nursing infants from riociguat, discontinue nursing or Adempas.
8.4 Pediatric Use
Safety and effectiveness of Adempas in pediatric patients have not been
established.
8.5 Geriatric Use
Of the total number of subjects in clinical studies of Adempas, 23% were 65
and over, and 6% were 75 and over [see Clinical Studies (14)]. No overall
differences in safety or effectiveness were observed between these subjects
and younger subjects, and other reported clinical experience has not identiﬁed
differences in responses between the elderly and younger patients, but greater
sensitivity of some older individuals cannot be ruled out.
Elderly patients showed a higher exposure to Adempas [see Clinical
Pharmacology (12.3)].
8.6 Females and Males of Reproductive Potential
Pregnancy Testing: Female patients of reproductive potential must have a
negative pregnancy test prior to starting treatment with Adempas, monthly
during treatment, and one month after discontinuation of treatment with
Adempas. Advise patients to contact their health care provider if they become
pregnant or suspect they may be pregnant. Counsel patients on the risk to the
fetus [see Boxed Warning and Dosage and Administration (2.2)].
Contraception: Female patients of reproductive potential must use acceptable
methods of contraception during treatment with Adempas and for 1 month
after treatment with Adempas. Patients may choose one highly effective form
of contraception (intrauterine devices [IUD], contraceptive implants or tubal
sterilization) or a combination of methods (hormone method with a barrier
method or two barrier methods). If a partner’s vasectomy is the chosen method
of contraception, a hormone or barrier method must be used along with this
method. Counsel patients on pregnancy planning and prevention, including
emergency contraception, or designate counseling by another healthcare
provider trained in contraceptive counseling [See Boxed Warning].
8.7 Renal Impairment
Safety and efﬁcacy have not been demonstrated in patients with creatinine
clearance <15 mL/min or on dialysis [see Clinical Pharmacology (12.3).]
8.8 Hepatic Impairment
Safety and efﬁcacy have not been demonstrated in patients with severe
hepatic impairment (Child Pugh C) [see Clinical Pharmacology (12.3)].
10 OVERDOSAGE
In cases of overdose, blood pressure should be closely monitored and
supported as appropriate. Based on extensive plasma protein binding,
riociguat is not expected to be dialyzable.
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Medication Guide).
Embryo-Fetal Toxicity
Instruct patients on the risk of fetal harm when Adempas is used during
pregnancy [see Warnings and Precautions (5.1) and Use in Speciﬁc
Populations (8.1)]. Instruct females of reproductive potential to use effective
contraception and to contact her physician immediately if they suspect
they may be pregnant. Female patients must enroll in the Adempas REMS
Program.
Adempas REMS Program
For female patients, Adempas is available only through a restricted program
called the Adempas REMS Program [see Warnings and Precautions (5.2)].
Male patients are not enrolled in the Adempas REMS Program.
Inform female patients (and their guardians, if applicable) of the following
important requirements:
All female patients must sign an enrollment form.
Advise female patients of reproductive potential that she must comply
with the pregnancy testing and contraception requirements [see Use in
Speciﬁc Populations (8.6)].
Educate and counsel females of reproductive potential on the use of
emergency contraception in the event of unprotected sex or contraceptive
failure.
Advise pre-pubertal females to report any changes in their reproductive
status immediately to her prescriber.
Review the Medication Guide and REMS educational materials with female
patients.
Other Risks Associated with Adempas
Inform patients of the contraindication of Adempas with nitrates or nitric
oxide donors or PDE-5 inhibitors.
Advise patients about the potential risks/signs of hemoptysis and to report
any potential signs of hemoptysis to their physicians.
Instruct patients on the dosing, titration, and maintenance of Adempas.
Advise patients regarding activities that may impact the pharmacology of
Adempas (strong multi pathway CYP inhibitors and P-gp/BCRP inhibitors
and smoking). Patients should report all current medications and new
medications to their physician.
Advise patients that antacids should not be taken within 1 hour of taking
Adempas.
Inform patients that Adempas can cause dizziness, which can affect the
ability to drive and use machines [see Adverse Reactions (6.1)]. They
should be aware of how they react to Adempas, before driving or operating
machinery and if needed, consult their physician.
Manufactured for:
Bayer HealthCare Pharmaceuticals Inc.
Whippany, NJ 07981
Manufactured in Germany
Issued October 2013
©2013 Bayer HealthCare Pharmaceuticals Inc.
6710500BS
2014
PHA’s International PH Conference and Scientific Sessions
RACING TOWARD A CURE
June 20 - 22, 2014
JW Marriott Indianapolis
Indianapolis, Ind., U.S.A.
Registration opens January 2014
www.PHAssociation.org/Conference
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2014
PHA’s International PH Conference and Scientific Sessions
Research Room: Applications Now Accepted
PHA is accepting applications from researchers and institutions wishing to
conduct research (patient surveys, cheek swabs, blood draws, etc.) during
Conference. This event gives researchers the rare opportunity to collect data
from the largest gathering of pulmonary hypertension patients in the world. At
the last Conference in 2012, 180 attendees participated in the Research Room.
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RACING TOWARD A CURE
June 20 - 22, 2014
JW Marriott Indianap
polis
Questions? Contact [email protected] or 301-565-3004 x 770.
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Building Medical Education in PH
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Building Medical Education in PH (BME) events are
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March 27–29, 2014
San Francisco, Calif.
The Alfred P. Fishman Symposium: New Treatment
Approaches to Pulmonary Hypertension
April 26, 2014
Philadelphia, Pa.
1st Annual Drug Discovery and Development for
Pulmonary Hypertension Symposium
%"&'*&+-/3&'
Bethesda, Md.
To view a full list of educational opportunities for medical
professionals, visit: www.PHAOnlineUniv.org/Calendar
ADCIRCA® (tadalafil) tablets is a phosphodiesterase 5 inhibitor (PDE-5i) indicated for the treatment of pulmonary arterial hypertension (PAH)
(WHO Group 1) to improve exercise ability. Studies establishing effectiveness included predominately patients with NYHA Functional Class II–III
symptoms and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (23%).
ADCIRCA (tadalaﬁl) ONCE-DAILY
CAN GIVE YOUR PATIENTS
A SOLID FOUNDATION
A first-line PDE-5 inhibitor that can
help improve exercise ability
•
The only once-daily PDE-5 inhibitor for PAH1
•
33-meter placebo-adjusted mean improvement in 6MWD at 16 weeks1
•
The most common adverse event with ADCIRCA (tadalafil) 40 mg is
headache (42% ADCIRCA vs 15% placebo). Other common adverse events
(reported by ≥9% of patients on ADCIRCA and more frequent than
placebo by 2%) include myalgia (14% vs 4%), nasopharyngitis (13% vs 7%),
flushing (13% vs 2%), respiratory tract infection (13% vs 6%), extremity
pain (11% vs 2%), nausea (11% vs 6%), back pain (10% vs 6%),
dyspepsia (10% vs 2%), and nasal congestion (9% vs 1%)1
•
A $20 co-pay for eligible patients on commercial/private insurance plans*
*Patients must meet certain eligibility criteria to qualify for assistance. Patients receiving
reimbursement under Medicare, Medicaid, VA, DoD (TRICARE), Indian Health Services, or similar federal
or state programs, may not be eligible for some assistance. Some portion of this patient assistance may
be administered by Caring Voice Coalition (CVC), an independent national nonprofit organization.
•
Important Safety Information
CONTRAINDICATIONS
• Nitrates: ADCIRCA should not be used in patients taking medicines
that contain nitrates, as the combination could cause a sudden,
unsafe drop in blood pressure
• Hypersensitivity Reactions: Patients with a known serious
hypersensitivity to tadalafil should not take ADCIRCA
WARNINGS AND PRECAUTIONS
• Cardiovascular: Patients who experience anginal chest pain after
taking ADCIRCA should seek immediate medical attention
• Cardiovascular: Phosphodiesterase 5 inhibitors (PDE-5is), including
tadalafil, have mild systemic vasodilatory properties that may result in
transient decreases in blood pressure. Before prescribing ADCIRCA,
physicians should carefully consider whether their patients with
underlying cardiovascular disease could be adversely affected by
such actions. Pulmonary vasodilators may significantly worsen the
cardiovascular status of patients with pulmonary veno-occlusive
disease (PVOD) and administration of ADCIRCA to these patients is
not recommended
• Cardiovascular: The use of ADCIRCA with alpha blockers, blood pressure
medications, or alcohol may lower blood pressure significantly and may
lead to symptomatic hypotension (light-headedness or fainting)
• Potential Drug Interactions: Tadalafil is metabolized predominately
by CYP3A in the liver. Use of ADCIRCA with potent CYP3A inhibitors,
such as ketoconazole and itraconazole, should be avoided. For patients
on ADCIRCA therapy that require treatment with ritonavir, ADCIRCA
should be discontinued at least 24 hours prior to starting ritonavir.
For patients on ritonavir therapy that require treatment with ADCIRCA,
start ADCIRCA at 20 mg once a day. Use of ADCIRCA with potent
inducers of CYP3A, such as rifampin, should be avoided
ADCIRCA and Cialis are registered trademarks of Eli Lilly and Company, 2013.
Reference: 1. ADCIRCA [package insert]. Indianapolis, IN: Eli Lilly and Company; 2013.
Special Populations: The use of ADCIRCA is not recommended for
patients with severe renal or hepatic impairment. Please see Full
Prescribing Information for dosing recommendations for patients
with mild to moderate renal or hepatic impairment
• Potential Drug Interactions: ADCIRCA contains the same ingredient
(tadalafil) as Cialis®, which is used to treat erectile dysfunction (ED)
and the signs and symptoms of benign prostatic hyperplasia (BPH).
The safety and efficacy of combinations of ADCIRCA with Cialis or
other PDE-5is have not been studied. Therefore, the use of such
combinations is not recommended
• Vision/Hearing: Patients who experience a sudden loss of vision in
one or both eyes, which could be a sign of non-arteritic anterior
ischemic optic neuropathy (NAION), or sudden decrease or loss of
hearing after taking ADCIRCA should seek immediate medical attention
• Prolonged Erection: In rare instances, men taking PDE-5is (including
tadalafil) for ED reported an erection lasting more than four hours.
Male patients who experience a prolonged erection should seek
immediate medical attention
ADVERSE REACTIONS
• Adverse Reactions: The most common adverse event with ADCIRCA
is headache (42% ADCIRCA vs 15% placebo). Other common adverse
events (reported by ≥9% of patients on ADCIRCA and more frequent
than placebo by 2%) include myalgia (14% vs 4%), nasopharyngitis
(13% vs 7%), flushing (13% vs 2%), respiratory tract infection (13% vs
6%), extremity pain (11% vs 2%), nausea (11% vs 6%), back pain
(10% vs 6%), dyspepsia (10% vs 2%), and nasal congestion (9% vs 1%)
ISI.HCP.KCGLUNGLLC-4-70.v1
Please see brief summary of
Full Prescribing Information on
following page. Please see Full
Prescribing Information and
Patient Information available
at www.adcirca.com, or call
1-800-545-5979.
www.adcirca.com
1-877-UNITHER
See how Lung LLC is making strides in pulmonary medicine at www.lungllc.com
© 2013 Lung LLC
All rights reserved.
US/ADC/APR13/114(1)
ADCIRCA® (tadalaﬁl) tablets
BRIEF SUMMARY
The following is a brief summary of the full prescribing
information on ADCIRCA (tadalaﬁl). Please review the full
prescribing information prior to prescribing ADCIRCA.
INDICATIONS AND USAGE
Pulmonary Arterial Hypertension: ADCIRCA is indicated
for the treatment of pulmonary arterial hypertension (PAH)
(WHO Group 1) to improve exercise ability. Studies
establishing effectiveness included predominately patients
with NYHA Functional Class II–III symptoms and etiologies
of idiopathic or heritable PAH (61%) or PAH associated with
connective tissue diseases (23%).
CONTRAINDICATIONS
Concomitant Organic Nitrates: Do not use ADCIRCA in
patients who are using any form of organic nitrate, either
regularly or intermittently. ADCIRCA potentiates the
hypotensive effect of nitrates. This potentiation is thought to
result from the combined effects of nitrates and ADCIRCA
on the nitric oxide/cGMP pathway. Hypersensitivity
Reactions: ADCIRCA is contraindicated in patients with a
known serious hypersensitivity to tadalaﬁl (ADCIRCA or
CIALIS). Hypersensitivity reactions have been reported,
including Stevens-Johnson syndrome and exfoliative dermatitis.
WARNINGS AND PRECAUTIONS
Cardiovascular Effects: Discuss with patients the
appropriate action to take in the event that they experience
anginal chest pain requiring nitroglycerin following intake of
ADCIRCA. At least 48 hours should elapse after the last dose of
ADCIRCA before taking nitrates. If a patient has taken
ADCIRCA within 48 hours, administer nitrates under close
medical supervision with appropriate hemodynamic
monitoring. Patients who experience anginal chest pain
after taking ADCIRCA should seek immediate medical
attention. PDE5 inhibitors, including tadalaﬁl, have mild
systemic vasodilatory properties that may result in transient
decreases in blood pressure. Prior to prescribing ADCIRCA,
carefully consider whether patients with underlying
cardiovascular disease could be affected adversely by
such vasodilatory effects. Patients with severely impaired
autonomic control of blood pressure or with left ventricular
outﬂow obstruction, (e.g., aortic stenosis and idiopathic
hypertrophic subaortic stenosis) may be particularly
sensitive to the actions of vasodilators, including PDE5
inhibitors. Pulmonary vasodilators may signiﬁcantly worsen
the cardiovascular status of patients with pulmonary
veno-occlusive disease (PVOD). Since there are no
clinical data on administration of ADCIRCA to patients
with veno-occlusive disease, administration of
ADCIRCA to such patients is not recommended. Should
signs of pulmonary edema occur when ADCIRCA is
administered, the possibility of associated PVOD should be
considered. There is a lack of data on safety and efﬁcacy in the
following groups who were speciﬁcally excluded from the PAH
clinical trials:
• Patients with clinically
• Patients with life-threatening
arrhythmias
signiﬁcant aortic and
mitral valve disease
• Patients with symptomatic
coronary artery disease
• Patients with pericardial
constriction
• Patients with hypotension
(<90/50 mm Hg) or
• Patients with restrictive or
congestive cardiomyopathy uncontrolled hypertension
• Patients with signiﬁcant
left ventricular dysfunction
Use with Alpha Blockers and Antihypertensives — PDE5
inhibitors, including ADCIRCA, and alpha–adrenergic blocking
agents are vasodilators with blood pressure-lowering effects.
When vasodilators are used in combination, an additive effect
on blood pressure may be anticipated. In some patients,
concomitant use of these two drug classes can lower blood
pressure signiﬁcantly, which may lead to symptomatic
hypotension (e.g., fainting). Safety of combined use of PDE5
inhibitors and alpha blockers may be affected by other
variables, including intravascular volume depletion and use of
other antihypertensive drugs. Use with Alcohol — Both alcohol
and tadalaﬁl are mild vasodilators. When mild vasodilators are
taken in combination, blood pressure-lowering effects are
increased. Use with Potent CYP3A Inhibitors or Inducers:
Co-administration of ADCIRCA in Patients on Ritonavir — In
patients receiving ritonavir for at least one week, start
ADCIRCA at 20 mg once daily. Increase to 40 mg once daily
based upon individual tolerability. Co-administration of
Ritonavir in Patients on ADCIRCA — Avoid use of ADCIRCA
during the initiation of ritonavir. Stop ADCIRCA at least 24
hours prior to starting ritonavir. After at least one week
following the initiation of ritonavir, resume ADCIRCA at 20 mg
once daily. Increase to 40 mg once daily based upon individual
tolerability. Other Potent Inhibitors of CYP3A — Tadalaﬁl is
metabolized predominantly by CYP3A in the liver. In patients
taking potent inhibitors of CYP3A such as ketoconazole
and itraconazole, avoid use of ADCIRCA. Potent Inducers of
CYP3A — For patients chronically taking potent inducers of
CYP3A, such as rifampin, avoid use of ADCIRCA. Use in Renal
Impairment: In patients with mild or moderate renal
impairment — Start dosing at 20 mg once daily. Increase the
dose to 40 mg once daily based upon individual tolerability. In
patients with severe renal impairment — Avoid use of
ADCIRCA because of increased tadalaﬁl exposure (AUC),
limited clinical experience, and the lack of ability to inﬂuence
clearance by dialysis. Use in Hepatic Impairment: In patients
with mild to moderate hepatic cirrhosis (Child-Pugh Class A
and B) — Because of limited clinical experience in patients
with mild to moderate hepatic cirrhosis, consider a starting
dose of 20 mg once daily ADCIRCA. In patients with severe
hepatic cirrhosis (Child-Pugh Class C) — Patients with severe
hepatic cirrhosis have not been studied. Avoid use of
ADCIRCA. Effects on the Eye: Physicians should advise
patients to seek immediate medical attention in the event of a
sudden loss of vision in one or both eyes. Such an event may
be a sign of non–arteritic anterior ischemic optic neuropathy
(NAION), a cause of decreased vision, including permanent
loss of vision that has been reported rarely postmarketing in
temporal association with the use of all PDE5 inhibitors.
It is not possible to determine whether these events are related
directly to the use of PDE5 inhibitors or other factors.
Physicians should also discuss with patients the increased risk
of NAION in individuals who have already experienced NAION
in one eye, including whether such individuals could be
adversely affected by use of vasodilators such as PDE5
inhibitors. Patients with known hereditary degenerative retinal
disorders, including retinitis pigmentosa, were not included
in the clinical trials, and use in these patients is not
recommended. Hearing Impairment: Physicians should
advise patients to seek immediate medical attention in the
event of sudden decrease or loss of hearing. These events,
which may be accompanied by tinnitus and dizziness, have
been reported in temporal association to the intake of PDE5
inhibitors, including ADCIRCA. It is not possible to determine
whether these events are related directly to the use of PDE5
inhibitors or to other factors. Combination with Other PDE5
Inhibitors: Tadalaﬁl is also marketed as CIALIS. The safety
and efﬁcacy of taking ADCIRCA together with CIALIS or other
PDE5 inhibitors have not been studied. Inform patients
taking ADCIRCA not to take CIALIS or other PDE5 inhibitors.
Prolonged Erection: There have been rare reports of
prolonged erections greater than 4 hours and priapism (painful
erections greater than 6 hours in duration) for this class of
compounds. Priapism, if not treated promptly, can result in
irreversible damage to the erectile tissue. Patients who have
an erection lasting greater than 4 hours, whether painful or
not, should seek emergency medical attention. ADCIRCA
should be used with caution in patients who have conditions
that might predispose them to priapism (such as sickle cell
anemia, multiple myeloma, or leukemia), or in patients with
anatomical deformation of the penis (such as angulation,
cavernosal ﬁbrosis, or Peyronie’s disease). Effects on
Bleeding: PDE5 is found in platelets. When administered in
combination with aspirin, tadalaﬁl 20 mg did not prolong
bleeding time, relative to aspirin alone. ADCIRCA has not been
administered to patients with bleeding disorders or signiﬁcant
active peptic ulceration. Although ADCIRCA has not been
shown to increase bleeding times in healthy subjects, use in
patients with bleeding disorders or signiﬁcant active peptic
ulceration should be based upon a careful risk-beneﬁt
assessment.
ADVERSE REACTIONS
The following serious adverse reactions are discussed
elsewhere in the labeling:
• Hypotension • Vision loss • Hearing loss • Priapism
Clinical Trials Experience: Because clinical trials are
conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly
compared to rates in the clinical trials of another drug and may
not reﬂect the rates observed in practice. Tadalaﬁl was
administered to 398 patients with PAH during clinical trials
worldwide. In trials of ADCIRCA, a total of 311 and 251
subjects have been treated for at least 182 days and 360 days,
respectively. The overall rates of discontinuation because of an
adverse event (AE) in the placebo-controlled trial were 9% for
ADCIRCA 40 mg and 15% for placebo. The rates of
discontinuation because of AEs, other than those related to
worsening of PAH, in patients treated with ADCIRCA 40 mg
was 4% compared to 5% in placebo-treated patients. In the
placebo-controlled study, the most common AEs were
generally transient and mild to moderate in intensity. Table 1
presents treatment-emergent adverse events reported by
≥9% of patients in the ADCIRCA 40 mg group and occurring
more frequently than with placebo.
TABLE 1: Treatment-Emergent Adverse Events
Reported by ≥9% of Patients in ADCIRCA and More
Frequent than Placebo by 2%
ADCIRCA
ADCIRCA
Placebo (%) 20 mg (%)
40 mg (%)
EVENT
(N=82)
(N=82)
(N=79)
Headache
15
32
42
Myalgia
4
9
14
Nasopharyngitis
7
2
13
Flushing
2
6
13
Respiratory Tract
Infection (Upper
6
7
13
and Lower)
Pain in Extremity
2
5
11
Nausea
6
10
11
Back Pain
6
12
10
Dyspepsia
2
13
10
Nasal Congestion
(Including sinus
1
0
9
congestion)
Postmarketing Experience: The following adverse reactions
have been identiﬁed during post-approval use of tadalaﬁl.
These events have been chosen for inclusion either because of
their seriousness, reporting frequency, lack of clear alternative
causation, or a combination of these factors. Because these
reactions are reported voluntarily from a population of uncertain
size, it is not always possible to estimate reliably their frequency
or establish a causal relationship to drug exposure. The list does
not include adverse events that are reported from clinical trials
and that are listed elsewhere in this section. Cardiovascular and
cerebrovascular — Serious cardiovascular events, including
myocardial infarction, sudden cardiac death, stroke, chest
pain, palpitations, and tachycardia, have been reported
postmarketing in temporal association with the use of tadalaﬁl.
Most, but not all, of these patients had preexisting
cardiovascular risk factors. Many of these events were reported
to occur during or shortly after sexual activity, and a few were
reported to occur shortly after the use of tadalaﬁl without sexual
activity. Others were reported to have occurred hours to days
after the use of tadalaﬁl and sexual activity. It is not possible to
determine whether these events are related directly to tadalaﬁl,
to sexual activity, to the patient’s underlying cardiovascular
disease, to a combination of these factors, or to other factors.
Body as a whole — Hypersensitivity reactions including
urticaria, Stevens–Johnson syndrome, and exfoliative
dermatitis. Nervous — Migraine, seizure and seizure
recurrence, and transient global amnesia. Ophthalmologic —
Visual ﬁeld defect, retinal vein occlusion, and retinal
artery occlusion. Non–arteritic anterior ischemic optic
neuropathy (NAION), a cause of decreased vision including
permanent loss of vision, has been reported rarely
postmarketing in temporal association with the use of PDE5
inhibitors, including tadalaﬁl. Most, but not all, of these patients
had underlying anatomic or vascular risk factors for
development of NAION, including but not necessarily limited to:
low cup to disc ratio (“crowded disc”), age over 50, diabetes,
hypertension, coronary artery disease, hyperlipidemia, and
smoking. It is not possible to determine whether these events
are related directly to the use of PDE5 inhibitors, to the patient’s
underlying vascular risk factors or anatomical defects, to a
combination of these factors, or to other factors. Otologic —
Cases of sudden decrease or loss of hearing have been
reported postmarketing in temporal association with the use of
PDE5 inhibitors, including tadalaﬁl. In some of the cases,
medical conditions and other factors were reported that may
have also played a role in the otologic adverse events. In many
cases, medical follow-up information was limited. It is not
possible to determine whether these reported events are
related directly to the use of tadalaﬁl, to the patient’s underlying
risk factors for hearing loss, a combination of these factors, or
to other factors. Urogenital — Priapism.
DRUG INTERACTIONS
Potential for Pharmacodynamic Interactions with
ADCIRCA: Nitrates — Do not use ADCIRCA in patients who
are using any form of organic nitrate. In clinical pharmacology
studies ADCIRCA potentiated the hypotensive effect of
nitrates. In a patient who has taken ADCIRCA, where nitrate
administration is deemed medically necessary in a
life–threatening situation, at least 48 hours should elapse after
the last dose of ADCIRCA before nitrate administration is
considered. In such circumstances, nitrates should still only
be administered under close medical supervision with
appropriate hemodynamic monitoring. Alpha-Blockers —
PDE5 inhibitors, including ADCIRCA, and alpha–adrenergic
blocking agents are both vasodilators with bloodpressure-lowering effects. When vasodilators are used in
combination, an additive effect on blood pressure may
be anticipated. Clinical pharmacology studies have been
conducted with coadministration of tadalaﬁl with doxazosin,
alfuzosin or tamsulosin. Antihypertensives — PDE5 inhibitors,
including ADCIRCA, are mild systemic vasodilators. Clinical
pharmacology studies were conducted to assess the effect of
tadalaﬁl on the potentiation of the blood–pressure–lowering
effects of selected antihypertensive medications (amlodipine,
angiotensin II receptor blockers, bendroﬂumethiazide,
enalapril, and metoprolol). Small reductions in blood pressure
occurred following coadministration of tadalaﬁl with these
agents compared with placebo. Alcohol — Both alcohol and
tadalaﬁl, a PDE5 inhibitor, act as mild vasodilators. When
mild vasodilators are taken in combination, blood
pressure–lowering effects of each individual compound may
be increased. Substantial consumption of alcohol (e.g., 5 units
or greater) in combination with ADCIRCA can increase
the potential for orthostatic signs and symptoms, including
increase in heart rate, decrease in standing blood pressure,
dizziness, and headache. Tadalaﬁl (10 mg or 20 mg) did not
affect alcohol plasma concentrations and alcohol did not affect
tadalaﬁl plasma concentrations. Potential for Other Drugs to
Affect ADCIRCA: Ritonavir — Ritonavir initially inhibits and
later induces CYP3A, the enzyme involved in the metabolism
of tadalaﬁl. At steady state of ritonavir (about 1 week), the
exposure to tadalaﬁl is similar as in the absence of ritonavir.
Other Potent Inhibitors of CYP3A — Tadalaﬁl is metabolized
predominantly by CYP3A in the liver. In patients taking potent
inhibitors of CYP3A such as ketoconazole, and itraconazole,
avoid use of ADCIRCA. Potent Inducers of CYP3A — For
patients chronically taking potent inducers of CYP3A, such as
rifampin, avoid use of ADCIRCA. Potential for ADCIRCA to
Affect Other Drugs: Cytochrome P450 Substrates —
Tadalaﬁl is not expected to cause clinically signiﬁcant inhibition
or induction of the clearance of drugs metabolized by
cytochrome P450 (CYP) isoforms (e.g., theophylline, warfarin,
midazolam, lovastatin, bosentan). Aspirin — Tadalaﬁl (10 mg
and 20 mg once daily) does not potentiate the increase in
bleeding time caused by aspirin. P-glycoprotein (e.g.,
digoxin) — Coadministration of tadalaﬁl (40 mg once daily) for
10 days did not signiﬁcantly alter digoxin pharmacokinetics in
healthy subjects.
USE IN SPECIFIC POPULATIONS
Pregnancy: Pregnancy Category B — Animal reproduction
studies in rats and mice revealed no evidence of fetal harm.
There are, however, no adequate and well-controlled studies of
tadalaﬁl in pregnant women. Because animal reproduction
studies are not always predictive of human response, tadalaﬁl
should be used during pregnancy only if clearly needed.
Non–teratogenic effects — Animal reproduction studies
showed no evidence of teratogenicity, embryotoxicity, or
fetotoxicity when tadalaﬁl was given to pregnant rats or mice
at unbound tadalaﬁl exposures up to 7 times the maximum
recommended human dose (MRHD) of 40 mg/day
during organogenesis. In one of two perinatal/postnatal
developmental studies in rats, postnatal pup survival
decreased following maternal exposure to unbound tadalaﬁl
concentrations greater than 5 times the MRHD based on AUC.
Signs of maternal toxicity occurred at doses greater than 8
times the MRHD based on AUC. Surviving offspring had
normal development and reproductive performance.
Nursing Mothers: It is not known whether tadalaﬁl is
excreted into human milk. While tadalaﬁl or some metabolite of
tadalaﬁl was excreted into rat milk, drug levels in animal breast
Treatment delays? Suggestions
for a specialty pharmacy?
Let PHA Know.
milk may not accurately predict levels of drug in human breast
milk. Because many drugs are excreted in human milk, caution
should be exercised when ADCIRCA is administered to a
nursing woman. Pediatric Use: Safety and effectiveness of
ADCIRCA in pediatric patients have not been established.
Geriatric Use: Of the total number of subjects in the clinical
study of tadalaﬁl for pulmonary arterial hypertension, 28
percent were 65 and over, while 8 percent were 75 and over.
No overall differences in safety were observed between
subjects over 65 years of age compared to younger subjects or
those over 75 years of age. No dose adjustment is warranted
based on age alone; however, a greater sensitivity to
medications in some older individuals should be considered.
Renal Impairment: For patients with mild or moderate renal
impairment, start ADCIRCA at 20 mg once daily. Increase the
dose to 40 mg once daily based upon individual tolerability. In
patients with severe renal impairment, avoid use of ADCIRCA
because of increased tadalaﬁl exposure (AUC), limited clinical
experience, and the lack of ability to inﬂuence clearance by
dialysis. Hepatic Impairment: Because of limited clinical
experience in patients with mild to moderate hepatic cirrhosis
(Child-Pugh Class A or B), consider a starting dose of ADCIRCA
20 mg once daily. Patients with severe hepatic cirrhosis
(Child-Pugh Class C) have not been studied, thus avoid use of
ADCIRCA in such patients.
OVERDOSAGE
Single doses up to 500 mg have been given to healthy male
subjects, and multiple daily doses up to 100 mg have been
given to male patients with erectile dysfunction. Adverse
reactions were similar to those seen at lower doses. Doses
greater than 40 mg have not been studied in patients with
pulmonary arterial hypertension. In cases of overdose,
standard supportive measures should be adopted as needed.
Hemodialysis contributes negligibly to tadalaﬁl elimination.
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BS.HCP.KCGLUNGLLC-4-72.v1
The Specialty Pharmacy Advisory Board
wants to hear from you!
The Specialty Pharmacy Advisory Board involves a cross
section of the pulmonary hypertension community, including
patients and their loved ones, as well as specialty pharmacy
Are your pulmonary hypertension patients facing treatment
representatives. A collaboration between the Pulmonary
delays that originate with their specialty pharmacy? Do you
Hypertension Association and the Caring Voice
have an outstanding specialty pharmacy relationship that
Coalition, we’re dedicated to gathering feedback about how
\RXZLVKRWKHUVLQWKH¿HOGZRXOGUHSOLFDWH"
well specialty pharmacies are serving PH patients and using
that feedback to promote improved service.
Submit your comments at
www.PHAssociation.org/SpecialtyPharmacyResponseForm
or by calling 301-565-3004 x773
ASK T HE E X P E R T
When Is Testing Beyond Overnight Oximetry Indicated for
Assessment of Sleep-Disordered Breathing in Pulmonary
Arterial Hypertension?
Section Editor
Sean Studer, MD, MSc, FCCP
New York University
New York, NY
Alison S. Kole, MD, MPH, FCCP
Pulmonary, Critical Care & Sleep Medicine
Englewood Medical Center
Englewood, NJ
Sleep-disordered breathing (SDB) is an
overarching term encompassing several
medical conditions in which breathing
diminishes or ceases during sleep, often
resulting in daytime sleepiness and
reduced quality of life.1 Obesity is
strongly associated with SDB and both
conditions are increasing in prevalence in
the United States.2,3 The pathophysiologic relationship between obesity, SDB,
and pulmonary hypertension (PH)
appears to be complex, although
treatment approaches including weight
loss and limiting intermittent hypoxemia
have received the most attention as measures to improve PH. Clinical consensus
recommendations state that treatment of
PH in the setting of SDB may be
appropriate when PH persists despite
adequate therapy for SDB.4 Current
clinical research is also investigating the
possibility that pulmonary arterial hypertension (PAH) may actually worsen or
cause SDB,5 a reversal of the traditional
paradigm that SDB produces PH.4
However, before a clinician may consider
the ideal treatment approach for an individual patient with PH, it is imperative
that SDB is either excluded or diagnosed
and characterized.
Consensus statements have recommended the use of overnight oximetry as
the initial pivotal test for SDB screening,
with an overnight polysomnography
(PSG) performed as a contingent test
when necessary.4 Two questions that
follow include: (1) When is overnight
oximetry considered sufficiently
abnormal to warrant further investi-
gation? and (2) Are there circumstances
when pretest probability is high enough
to proceed directly to PSG?
There is no universally accepted definition of oxygen desaturation in SDB. A
study reviewing overnight oximetry
results showed that the mean lowest
oxygen saturation in 350 normal subjects
was 90.4% (⫾3.1%) vs 65.9% (⫾22.6%)
in 25 subjects with obstructive sleep
apnea, demonstrating not only the differences between groups but also
significant variability within patients with
SDB.6 The most commonly published
definition of oxygen desaturation in SDB
is a decrease of ⱖ4% from baseline. Calculating the oxygen desaturation index
(ODI), however, which is the number of
desaturations per hour of sleep, may
more closely correlate with the apneahypopnea index obtained from PSG
testing. The threshold for an abnormal
ODI has been studied at ⱖ5, ⱖ10, and
ⱖ15 desaturations per hour with little
evidence to suggest one of these cutoffs
as the most valid.7 Overnight oximetry
reports may not always contain detailed
data that are conducive to waveform
analysis and, since they are unmonitored,
they are also subject to repeated artifacts,
which may limit accurate interpretation.
While overnight oximetry is accessible
and relatively inexpensive, the results are
only valuable when they are interpreted
correctly and may benefit from a universal definition of desaturation in
relation to ODI.
Compared to oximetry as a single test
measurement, the typical PSG monitors
Correspondence: [email protected]
116
Advances in Pulmonary Hypertension
Volume 12, Number 3; 2013
approximately a dozen parameters (of
which oximetry is just one) suggesting
that the PSG is better suited to characterize SDB. However, a traditional
overnight sleep laboratory-based PSG is
an expensive test with limited availability
in many areas. An argument can be
made against screening all PH patients
with PSG for several reasons: it is costly,
labor intensive, time consuming, and
requires an overnight stay at a sleep
center. Furthermore, limited access in
some regions may result in long wait
times and delays in treatment, which
may contribute to clinical worsening in
PH.
However, PH patients with a high
pretest probability of SDB may benefit
from a screening approach that begins
with a nocturnal PSG in lieu of nocturnal oximetry. Utilizing a clinical
prediction assessment for SDB can help
identify those who warrant initial PSG
screening. For example, Flemons and
colleagues developed a clinical prediction
model for SDB based on increasing neck
circumference, hypertension, habitual
snoring, and bed partner reports of nocturnal gasping or choking.8 Table 1
contains the major risk factors to consider in your clinical assessment.
Ambulatory diagnosis of SDB with
home sleep testing (HST) is an increasingly attractive option that may offer an
efficient compromise between the limited
data obtained from overnight oximetry
and the cost, time, and scheduling
requirements of a laboratory-based PSG.
Home sleep testing is becoming increasingly popular and is covered by most
insurance plans. Recent studies com-
Table 1. Risk factors for sleep apnea that
increase the likelihood that a PSG will be
necessary during the PH evaluation
•
•
•
•
•
Male gender
Postmenopausal state
Excess body weight (BMI ⬎30)
Increasing age (especially after age 60)
Race (risk higher with non-Caucasian
races)
• Craniofacial anatomy (especially higher
Mallampati score, retrognathia)
• Familial and genetic predisposition
Modified from Young et al.10
paring clinical outcomes support the use
of HST for patients with high pretest
probability of SDB, though widespread
utility is limited by inadequate standardization and paucity of data that
convincingly demonstrate its cost effectiveness.9
In summary, the current evaluation
algorithm for evaluating SDB in patients
with PH recommends that patients
receive initial testing with overnight
oximetry and those with abnormal results
undergo nocturnal PSG testing. An
oximetry result demonstrating on ODI
of ⱖ5 to ⱖ15 events per hour may represent a prudent cutoff for proceeding
to PSG testing. However, patients with
sufficient risk factors for SDB may be
appropriate for proceeding directly to
initial testing with PSG (Table 1). A
sleep laboratory-based PSG remains the
established standard; however, HST
may be a sufficient alternative in some
patients. Consultation with a sleep
specialist to help facilitate diagnosis
and treatment of SDB and monitor
treatment compliance in PH patients is
recommended.
References
1. National Center on Sleep Disorders Research.
http://www.nhlbi.nih.gov/health/prof/sleep/res_
plan/section5/section5a.html. Accessed October 25,
2013.
2. Peppard PE, Young T, Palta M, Dempsey J,
Skatrud J. Longitudinal study of moderate weight
change and sleep disordered breathing. JAMA.
2000;284(23):3015-3021.
3. Tishler PV, Larkin EK, Schluchter MD,
Redline S. Incidence of sleep-disordered breathing
in an urban adult population: the relative importance of risk factors in the development of sleepdisordered breathing. JAMA. 2003;289(17):22302237.
4. McLaughlin VV, Archer SL, Badesch DB, et
al. ACCF/AHA 2009 expert consensus document
on pulmonary hypertension a report of the
American College of Cardiology Foundation Task
Force on Expert Consensus Documents and the
American Heart Association developed in collaboration with the American College of Chest
Physicians; American Thoracic Society, Inc.; and
the Pulmonary Hypertension Association. J Am
Coll Cardiol. 2009;53(17):1573-1619.
5. Effect of Pulmonary Arterial Hypertension
Treatment on Obstructive Sleep Apnea. Ongoing
clinical trial. http://clinicaltrials.gov/show/
NCT01835080. Accessed October 25, 2013.
6. Gries RE, Brooks LJ. Normal oxyhemoglobin
saturation during sleep. How low does it go? Chest.
1996;110(6):1489-1492.
7. Netzer N, Eliasson AH, Netzer C, Kristo DA.
Overnight pulse oximetry for sleep-disordered
breathing in adults: a review. Chest. 2001;120(2):
625-633.
8. Flemons WW, Whitelaw WA, Brant R,
Remmers JE. Likelihood ratios for a sleep apnea
clinical prediction rule. Am J Respir Crit Care Med.
1994;150(5 Pt 1):1279-1285.
9. Sunwoo B, Kuna ST. Ambulatory management of patients with sleep apnea: is there a
place for portable monitor testing? Clin Chest Med.
2010;31(2):299-308.
10. Young T, Skatruc J, Peppard PE. Risk
factors for obstructive sleep apnea in adults. JAMA.
2004;291(16):2013-2016.
Advances in Pulmonary Hypertension
Volume 12, Number 3; 2013
117
CLINICA L T RIA L S U P DA T E
A Study to Test the Effects of Riociguat in Patients With
Pulmonary Hypertension Associated With Left Ventricular
Systolic Dysfunction (LEPHT)
Section Editor
Fernando Torres, MD
The Clinical Trials Update highlights new and ongoing research trials that are evaluating therapies for PAH. In this issue, Fernando Torres, MD, examines a study on
patients with pulmonary hypertension associated with left ventricular systolic
dysfunction.
Pulmonary hypertension (PH) associated
with left heart disease has been a challenge for the PH community. Though
most of us have concentrated our efforts
on managing the patients who have PH
with normal systolic heart function, there
is another population of patients with
PH with decreased left ventricular heart
function who also are at risk of poor
survival. It is known that patients with
high mean pulmonary arterial pressure
(mPAP)
and left ventricular ejection fraction
(LVEF) less than 45% carry a high
mortality compared to those with normal
mPAP. Thus, finding new therapies
for this population would be advantageous.
In 2009, a single-dose study with
riociguat was found to decrease the
mPAP, wedge, and pulmonary vascular
resistance (PVR) of patients with high
mPAP and left heart failure. This then
prompted the design and completion of
LEPHT.
LEPHT enrolled about 200 patients
worldwide. All patients had a screening
right heart catheterization in which the
mPAP was higher than 25 mm Hg, and
all had an LVEF ⬍45% at inclusion to
the study. They were all maximally medically treated, and their heart failure
medications could not have changed in
the month prior, with the exception of
diuretics, which could have been changed
up to a week prior to randomization. The
patients were randomized to placebo or
riociguat of 0.5, 1, or 2 mg TID in four
parallel arms. After 16 weeks, the patients
had a repeat right heart catheterization
and the primary endpoint of decrease in
mPAP was evaluated. Secondary endpoints included other hemodynamic
parameters, 6-minute walk distance
(6MWD), N-terminal pro-brain natriuretic peptide (NT-proBNP) as well as
quality of life questionnaire.
The results of the trial were presented
recently at the American Heart Association annual meeting in Dallas and
118
Advances in Pulmonary Hypertension
Volume 12, Number 3; 2013
showed a decrease in the mPAP that
was not statistically significant. The
change in cardiac index, systemic
vascular resistance, and PVR showed
statistically significant improvements.
Quality of life markers also were
positive and the medication was tolerated
well.
Though the primary endpoint was not
achieved, there were some markers in
the hemodynamics that were favorable.
Thus, there is still hope that riociguat
may have a role in the treatment of PH
associated with left heart disease. A large
multicenter clinical trial is now being
planned to look at the efficacy and safety
of using riociguat for the treatment of
patients with PH and preserved LVEF
(HFpEF). DILATE is another smaller
study finished in Austria with 39
patients looking at the effects of
riociguat for the treatment of PH with
left heart diastolic dysfunction. The
results of these trials are anticipated in
the near future.
Now approved
Please see Brief Summary of Prescribing Information, including
BOXED WARNING for embryo-fetal toxicity, on adjacent pages.
® OPSUMIT is a registered trademark of Actelion Pharmaceuticals, Ltd.
© 2013 Actelion Pharmaceuticals US, Inc. All rights reserved. MAC-00041 1113
OPSUMIT® (macitentan)
Hepatotoxicity
Other ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver
failure. The incidence of elevated aminotransferases in the study of OPSUMIT in PAH
is shown in Table 1.
Table 1: Incidence of Elevated Aminotransferases in the SERAPHIN Study
OPSUMIT 10 mg
(N=242)
Placebo
(N=249)
>3 × ULN
3.4%
4.5%
>8 × ULN
2.1%
0.4%
Rx only
BRIEF SUMMARY
The following is a brief summary of the full Prescribing Information for OPSUMIT®
(macitentan). Please review the full Prescribing Information prior to prescribing
OPSUMIT.
WARNING: EMBRYO-FETAL TOXICITY
• Do not administer OPSUMIT to a pregnant female because it may cause
fetal harm [see Contraindications (Pregnancy), Warnings and Precautions
(Embryo-fetal Toxicity), Use in Speciﬁc Populations (Pregnancy)].
• Females of reproductive potential: Exclude pregnancy before the start
of treatment, monthly during treatment, and 1 month after stopping
treatment. Prevent pregnancy during treatment and for one month after
stopping treatment by using acceptable methods of contraception [see
Use in Special Populations (Females and Males of Reproductive Potential)].
• For all female patients, OPSUMIT is available only through a restricted
program called the OPSUMIT Risk Evaluation and Mitigation Strategy
(REMS) [see Warnings and Precautions (OPSUMIT REMS Program)].
INDICATIONS AND USAGE
Pulmonary Arterial Hypertension
OPSUMIT® is an endothelin receptor antagonist (ERA) indicated for the treatment of
pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression.
Disease progression included: death, initiation of intravenous (IV) or subcutaneous
prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance,
worsened PAH symptoms and need for additional PAH treatment). OPSUMIT also
reduced hospitalization for PAH.
Effectiveness was established in a long-term study in PAH patients with predominantly
WHO Functional Class II-III symptoms treated for an average of 2 years. Patients were
treated with OPSUMIT monotherapy or in combination with phosphodiesterase-5
inhibitors or inhaled prostanoids. Patients had idiopathic and heritable PAH (57%),
PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart
disease with repaired shunts (8%).
CONTRAINDICATIONS
Pregnancy
OPSUMIT may cause fetal harm when administered to a pregnant woman. OPSUMIT
is contraindicated in females who are pregnant. OPSUMIT was consistently shown to
have teratogenic effects when administered to animals. If OPSUMIT is used during
pregnancy, apprise the patient of the potential hazard to a fetus [see Warnings and
Precautions (Embryo-fetal Toxicity) and Use in Speciﬁc Populations (Pregnancy)].
WARNINGS AND PRECAUTIONS
Embryo-fetal Toxicity
OPSUMIT may cause fetal harm when administered during pregnancy and is
contraindicated for use in females who are pregnant. In females of reproductive
potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable
contraceptive methods and obtain monthly pregnancy tests [see Dosage and
Administration section 2.2 in full Prescribing Information and Use in Speciﬁc Populations
(Pregnancy, Females and Males of Reproductive Potential)].
OPSUMIT is available for females through the OPSUMIT REMS Program, a restricted
distribution program [see Warnings and Precautions (OPSUMIT REMS Program)].
OPSUMIT REMS Program
For all females, OPSUMIT is available only through a restricted program called
the OPSUMIT REMS Program, because of the risk of embryo-fetal toxicity [see
Contraindications (Pregnancy), Warnings and Precautions (Embryo-fetal Toxicity), and
Use in Speciﬁc Populations (Pregnancy, Females and Males of Reproductive Potential)].
Notable requirements of the OPSUMIT REMS Program include the following:
• Prescribers must be certiﬁed with the program by enrolling and completing training.
• All females, regardless of reproductive potential, must enroll in the OPSUMIT REMS
Program prior to initiating OPSUMIT. Male patients are not enrolled in the REMS.
• Females of reproductive potential must comply with the pregnancy testing and
contraception requirements [see Use in Speciﬁc Populations (Females and Males
of Reproductive Potential)].
• Pharmacies must be certiﬁed with the program and must only dispense to patients
who are authorized to receive OPSUMIT.
Further information is available at www.OPSUMITREMS.com or 1-866-228-3546.
Information on OPSUMIT certiﬁed pharmacies or wholesale distributors is available
through Actelion Pathways at 1-866-228-3546.
In the placebo-controlled study of OPSUMIT, discontinuations for hepatic adverse events
were 3.3% in the OPSUMIT 10 mg group vs. 1.6% for placebo. Obtain liver enzyme
tests prior to initiation of OPSUMIT and repeat during treatment as clinically indicated.
Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting,
right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching). If
clinically relevant aminotransferase elevations occur, or if elevations are accompanied
by an increase in bilirubin >2 × ULN, or by clinical symptoms of hepatotoxicity,
discontinue OPSUMIT. Consider re-initiation of OPSUMIT when hepatic enzyme levels
normalize in patients who have not experienced clinical symptoms of hepatotoxicity.
Hemoglobin Decrease
Decreases in hemoglobin concentration and hematocrit have occurred following
administration of other ERAs and were observed in clinical studies with OPSUMIT.
These decreases occurred early and stabilized thereafter. In the placebo-controlled
study of OPSUMIT in PAH, OPSUMIT 10 mg caused a mean decrease in hemoglobin
from baseline to up to 18 months of about 1.0 g/dL compared to no change in the
placebo group. A decrease in hemoglobin to below 10.0 g/dL was reported in 8.7% of
the OPSUMIT 10 mg group and in 3.4% of the placebo group. Decreases in hemoglobin
seldom require transfusion. Initiation of OPSUMIT is not recommended in patients with
severe anemia. Measure hemoglobin prior to initiation of treatment and repeat during
treatment as clinically indicated [see Adverse Reactions (Clinical Trial Experience) ].
Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD)
Should signs of pulmonary edema occur, consider the possibility of associated PVOD.
If conﬁrmed, discontinue OPSUMIT.
Decreased Sperm Counts
Other ERAs have caused adverse effects on spermatogenesis. Counsel men about
potential effects on fertility [see Use in Speciﬁc Populations (Females and Males
of Reproductive Potential) and Nonclinical Toxicology (Carcinogenesis, Mutagenesis,
Impairment of Fertility) ].
ADVERSE REACTIONS
Clinically signiﬁcant adverse reactions that appear in other sections of the labeling
include:
• Embryo-fetal Toxicity [see Warnings and Precautions (Embryo-fetal Toxicity) ]
• Hepatotoxicity [see Warnings and Precautions (Hepatotoxicity)]
• Decrease in Hemoglobin [see Warnings and Precautions (Hemoglobin Decrease)]
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reﬂect the rates observed in clinical practice.
Safety data for OPSUMIT were obtained primarily from one placebo-controlled clinical
study in 742 patients with PAH (SERAPHIN study). The exposure to OPSUMIT in this
trial was up to 3.6 years with a median exposure of about 2 years (N=542 for 1 year;
N=429 for 2 years; and N=98 for more than 3 years). The overall incidence of treatment
discontinuations because of adverse events was similar across OPSUMIT 10 mg and
placebo treatment groups (approximately 11%).
Table 2 presents adverse reactions more frequent on OPSUMIT than on placebo by ≥3%.
Table 2: Adverse Reactions
Adverse Reaction
OPSUMIT 10 mg
(N=242)
Placebo
(N=249)
Anemia
13%
3%
Nasopharyngitis/pharyngitis
20%
13%
Bronchitis
12%
6%
Headache
14%
9%
Inﬂuenza
6%
2%
Urinary tract infection
9%
6%
DRUG INTERACTIONS
Strong CYP3A4 Inducers
Strong inducers of CYP3A4 such as rifampin signiﬁcantly reduce macitentan exposure.
Concomitant use of OPSUMIT with strong CYP3A4 inducers should be avoided [see
Clinical Pharmacology (Pharmacokinetics)].
OPSUMIT® (macitentan)
OPSUMIT® (macitentan)
Strong CYP3A4 Inhibitors
Concomitant use of strong CYP3A4 inhibitors like ketoconazole approximately double
macitentan exposure. Many HIV drugs like ritonavir are strong inhibitors of CYP3A4.
Avoid concomitant use of OPSUMIT with strong CYP3A4 inhibitors [see Clinical
Pharmacology (Pharmacokinetics)]. Use other PAH treatment options when strong
CYP3A4 inhibitors are needed as part of HIV treatment [see Clinical Pharmacology
(Pharmacokinetics)].
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category X.
Risk Summary
OPSUMIT may cause fetal harm when administered to a pregnant woman and is
contraindicated during pregnancy. Macitentan was teratogenic in rabbits and rats at
all doses tested. A no-effect dose was not established in either species. If this drug
is used during pregnancy, or if the patient becomes pregnant while taking this drug,
advise the patient of the potential hazard to a fetus [see Contraindications (Pregnancy)].
Animal Data
In both rabbits and rats, there were cardiovascular and mandibular arch fusion
abnormalities. Administration of macitentan to female rats from late pregnancy
through lactation caused reduced pup survival and impairment of the male fertility
of the offspring at all dose levels tested.
Nursing Mothers
It is not known whether OPSUMIT is present in human milk. Macitentan and its
metabolites were present in the milk of lactating rats. Because many drugs are
present in human milk and because of the potential for serious adverse reactions
from macitentan in nursing infants, nursing mothers should discontinue nursing or
discontinue OPSUMIT.
Pediatric use
The safety and efﬁcacy of OPSUMIT in children have not been established.
Geriatric use
Of the total number of subjects in the clinical study of OPSUMIT for PAH, 14% were 65
and over. No overall differences in safety or effectiveness were observed between these
subjects and younger subjects.
Females and Males of Reproductive Potential
Females
Pregnancy Testing: Female patients of reproductive potential must have a negative
pregnancy test prior to starting treatment with OPSUMIT and monthly pregnancy tests
during treatment with OPSUMIT. Advise patients to contact their health care provider
if they become pregnant or suspect they may be pregnant. Perform a pregnancy test if
pregnancy is suspected for any reason. For positive pregnancy tests, counsel patients
on the potential risk to the fetus [see Boxed Warning and Dosage and Administration
section 2.2 in full Prescribing Information].
Contraception: Female patients of reproductive potential must use acceptable methods
of contraception during treatment with OPSUMIT and for 1 month after treatment with
OPSUMIT. Patients may choose one highly effective form of contraception (intrauterine
devices (IUD), contraceptive implants or tubal sterilization) or a combination of
methods (hormone method with a barrier method or two barrier methods). If a
partner’s vasectomy is the chosen method of contraception, a hormone or barrier
method must be used along with this method. Counsel patients on pregnancy planning
and prevention, including emergency contraception, or designate counseling by
another healthcare provider trained in contraceptive counseling [see Boxed Warning].
Males
Testicular effects: Like other endothelin receptor antagonists, OPSUMIT may have
an adverse effect on spermatogenesis [see Warnings and Precautions (Decreased
Sperm Counts) and Nonclinical Toxicology (Carcinogenesis, Mutagenesis, Impairment
of Fertility ].
OVERDOSAGE
OPSUMIT has been administered as a single dose of up to and including 600 mg to
healthy subjects (60 times the approved dosage). Adverse reactions of headache,
nausea and vomiting were observed. In the event of an overdose, standard supportive
measures should be taken, as required. Dialysis is unlikely to be effective because
macitentan is highly protein-bound.
CLINICAL PHARMACOLOGY
Pharmacokinetics
Special Populations
There are no clinically relevant effects of age, sex, or race on the pharmacokinetics
of macitentan and its active metabolite.
Renal impairment : Exposure to macitentan and its active metabolite in patients with
severe renal impairment (CrCl 15-29 mL/min) compared to healthy subjects was increased
by 30% and 60%, respectively. This increase is not considered clinically relevant.
Hepatic impairment: Exposure to macitentan was decreased by 21%, 34%, and 6% and
exposure to the active metabolite was decreased by 20%, 25%, and 25% in subjects
with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, and C),
respectively. This decrease is not considered clinically relevant.
Drug Interactions
In vitro studies
At plasma levels obtained with dosing at 10 mg once daily, macitentan has no relevant
inhibitory or inducing effects on CYP enzymes, and is neither a substrate nor an
inhibitor of the multi-drug resistance protein (P-gp, MDR-1). Macitentan and its active
metabolite are neither substrates nor inhibitors of the organic anion transporting
polypeptides (OATP1B1 and OATP1B3) and do not significantly interact with proteins
involved in hepatic bile salt transport, i.e., the bile salt export pump (BSEP) and the
sodium-dependent taurocholate co-transporting polypeptide (NTCP).
In vivo studies
Effect of other drugs on macitentan: The effect of other drugs on macitentan and its
active metabolite are studied in healthy subjects and are shown in Figure 1 below.
Figure 1
Interacting drug
Macitentan
Active metabolite
Point estimate and 90% CI
Point estimate and 90% CI
Recommendation
AUCtau
Cmax
No dose adjustment
AUCtau
No dose adjustment
Ketoconazole
AUCinf
Cmax
Avoid
Rifampin
AUCtau
Ctrough
Sildenaﬁl
Cyclosporine-A C
trough
0.0
Avoid
0.5
1.0
1.5
2.0
Change relative to macitentan alone
2.5 0.0
0.5
1.0
1.5
Change relative to macitentan alone
Effects of other strong CYP3A4 inhibitors such as ritonavir on macitentan were
not studied, but are likely to result in an increase in macitentan exposure at steady
state similar to that seen with ketoconazole [see Drug Interactions (Strong CYP3A4
Inhibitors)].
Effect of macitentan on other drugs
Warfarin: Macitentan once daily dosing did not alter the exposure to R- and S-warfarin
or their effect on international normalized ratio (INR).
Sildenafil: At steady-state, the exposure to sildenafil 20 mg t.i.d. increased by 15%
during concomitant administration of macitentan 10 mg once daily. This change is not
considered clinically relevant.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Carcinogenicity studies of 2 years’ duration did not reveal any
carcinogenic potential at exposures 75-fold and 140-fold the human exposure (based
on AUC) in male and female mice, respectively, and 8.3- and 42-fold in male and
female rats, respectively.
Mutagenesis: Macitentan was not genotoxic in a standard battery of in vitro and in vivo
assays that included a bacterial reverse mutation assay, an assay for gene mutations
in mouse lymphoma cells, a chromosome aberration test in human lymphocytes, and
an in vivo micronucleus test in rats.
Impairment of Fertility: Treatment of juvenile rats from postnatal Day 4 to Day 114 led
to reduced body weight gain and testicular tubular atrophy at exposures 7-fold the
human exposure. Fertility was not affected.
Reversible testicular tubular dilatation was observed in chronic toxicity studies at
exposures greater than 7-fold and 23-fold the human exposure in rats and dogs,
respectively. After 2 years of treatment, tubular atrophy was seen in rats at 4-fold
the human exposure. Macitentan did not affect male or female fertility at exposures
ranging from 19- to 44-fold the human exposure, respectively, and had no effect on
sperm count, motility, and morphology in male rats. No testicular ﬁndings were noted
in mice after treatment up to 2 years.
Animal Toxicology
In dogs, macitentan decreased blood pressure at exposures similar to the therapeutic
human exposure. Intimal thickening of coronary arteries was observed at 17-fold
the human exposure after 4 to 39 weeks of treatment. Due to the species-speciﬁc
sensitivity and the safety margin, this ﬁnding is considered not relevant for humans.
There were no adverse liver findings in long-term studies conducted in mice, rats, and
dogs at exposures of 12- to 116-fold the human exposure.
Manufactured for:
Actelion Pharmaceuticals US, Inc.
5000 Shoreline Court, Ste. 200
South San Francisco, CA 94080, USA
ACT20131018
Reference: 1. OPSUMIT full Prescribing Information. Actelion Pharmaceuticals
US, Inc. October 2013.
®
OPSUMIT is a registered trademark of Actelion Pharmaceuticals, Ltd.
© 2013 Actelion Pharmaceuticals US, Inc. All rights reserved. MAC-00217 1013
Pulmonary Hypertension and Chronic Obstructive Pulmonary
Disease: When Is It Out of Proportion?
Sonja Bartolome, MD, FCCP
Associate Professor
Associate Director, Pulmonary
Hypertension Program
UT Southwestern Medical Center
Dallas, TX
Patients with chronic obstructive pulmonary disease (COPD) often present with mild
pulmonary hypertension (PH). This finding has been attributed to hypoxic pulmonary vasoconstriction. However, a small proportion of COPD patients will present
with moderate or severe elevations in their pulmonary artery pressure (PAP), and
these patients appear to have worsened symptoms and survival when compared to
patients with milder elevations in PAP. The diagnosis of PH in COPD may be difficult, due to inaccuracies in the echocardiographic estimates of PAP in these
patients. Additionally, many patients with COPD will also have comorbid conditions
such as diastolic heart failure, systolic heart failure, or obstructive sleep apnea, which
may cause increased pulmonary pressures through other mechanisms. Clinical trials
investigating the effect of PH-specific therapy for patients with PH and COPD have
been small, with mixed results. A careful evaluation for other causes of PH and
hemodynamic evaluation will help guide medical therapy for this group of patients.
The diagnostic evaluation of a new
patient with suspected pulmonary hypertension (PH) must be done methodically
to ensure the correct diagnosis and
treatment plan is assigned. An essential
part of the evaluation of a patient with
suspected PH is to correctly categorize
their disease in the World Health Organization (WHO) classification system for
PH. This system groups patients
together on the basis of the underlying
physiology of their pulmonary pressure
elevation and possible response to
therapy. Over the past 20 years, the
characterization of patients with Group
1 pulmonary arterial hypertension
(PAH) and development of therapy for
those patients has progressed substantially. This allows for an increasingly
data-driven approach to the treatment
plan for these patients. However, the
characterization of some of the other
types of PH has not progressed as
quickly. This leaves providers reaching
for guidelines on the management of
these patients who are also presenting
with significant symptoms and morbidity. One of these more poorly
characterized groups of patients is WHO
Group 3: PH related to respiratory
disease/hypoxia. In this article, we will
review the current characterization of
and data regarding a subgroup of these
patients—those with chronic obstructive
pulmonary disease (COPD) and PH.
PREVALENCE AND
EPIDEMIOLOGY OF PH IN
COPD
The prevalence of COPD in the US
adult population is 6%, and it is estimated that at least 15 million Americans
have a COPD diagnosis.1 The true prevalence of PH in the COPD population
is unknown, because it is difficult to
diagnose. Echocardiography is unreliable
in the COPD population, leaving one
without a noninvasive way to accurately
obtain this information in populationbased studies.2 However, information
does exist regarding the prevalence of
PH in patients with severe COPD who
underwent right heart catheterization
(RHC) as part of the evaluation for
either lung volume reduction surgery or
lung transplantation. Vizza et al
described the hemodynamics of 156
patients referred for lung transplantation
in the early 1990s. The mean pulmonary
artery pressure (mPAP) of these patients
was 25.6 mm Hg, consistent with mild
PH.3 Fifty-nine percent of these patients
also had significant right ventricular dysfunction with a right ventricular ejection
Key Words—COPD, pulmonary arterial hypertension, hypoxemia, hypoxic pulmonary vasoconstriction
Correspondence: [email protected]
Disclosures: None reported.
122
Advances in Pulmonary Hypertension
Volume 12, Number 3; 2013
fraction ⬍45%. Scharf et al reported
RHC results in patients screened for the
National Emphysema Treatment Trial
(NETT). Of 120 patients who
underwent RHC, 91% had mild PH
with mPAP ⬎20 mm Hg. However,
only 5% had severe PH (mPAP ⬎35).4
Thabut et al reported a retrospective
review of 215 patients who underwent
RHC and were referred for lung volume
reduction surgery or lung transplantation.
These patients had severe COPD, with
a mean FEV1 of 23.9% of the predicted
value. Most patients had mild PH with
mPAP of 26.9 mm Hg (Figure 1). Pulmonary hypertension as defined by the
traditional definition (mPAP ⬎25 mm
Hg) was present in 50.2% of the cohort.
Severe PH (mPAP ⬎45 mm Hg) was a
Figure 1: Pulmonary Artery Pressures in
COPD Patients. Pulmonary artery pressures
of patients with severe COPD, referred for
lung volume reduction surgery or lung transplantation. Thabut et al. Chest. 2005;127(5):
1531-1536.
rare event, occurring in only 3.7% of
patients. Further, a subgroup of patients
(7.4%) was identified by cluster analysis,
with less impairment of their pulmonary
function (FEV1 48.5% predicted) but
severe PH (average mPAP 39.8 mm
Hg). It was postulated that this subgroup of patients may have PH out of
proportion to their COPD and may
benefit from pulmonary vasodilator
therapy.5 Lastly, Cuttica et al retrospectively reviewed RHC findings in 4930
COPD patients listed for lung transplantation between 1997 and 2006. In
this group, 48% had mPAP ⱖ25 while
30% had both mPAP ⱖ25 and pulmonary artery occlusion pressure ⱕ15.
Less than 1% of patients had mPAP
⬎35.6
All of these patients were selected
from a population referred for intervention (lung volume reduction or lung
transplantation); therefore, an inherent
selection bias exists. In 2005, Chaouat
reported a retrospective review of 998
patients referred to their department for
chronic respiratory failure management
(not a surgery) and who underwent
RHC as part of the evaluation. Only 27
patients had severe PH with mPAP
⬎40 mm Hg. Of those 27, 16 had
another identifiable risk factor for PH,
while 11 had only COPD as an identifiable risk factor.7
Thus, in COPD patients with chronic
respiratory failure or those referred for
surgery mild PH is fairly common, but
severe PH remains rare.
Pathophysiology
The pathophysiology of PH in patients
with COPD is complex and likely
involves the combination of hypoxic pulmonary vasoconstriction, vascular
inflammation, and loss of alveolar capillary units. Hypoxic pulmonary
vasoconstriction (discussed in detail in
another article in this issue) is a welldescribed phenomenon that preserves
ventilation/perfusion matching by constricting pulmonary blood vessels in areas
of lung with localized hypoxia, therefore
sending blood to healthier areas of lung.
However, when local hypoxia becomes
more widespread, this process can
produce a sustained elevation in pulmonary vascular resistance. When this
process becomes chronic, pulmonary vascular remodeling ensues.8 Autopsy
specimens from COPD patients reveal
muscularization of the small pulmonary
arteries, proliferation of the medial and
intimal layers, and inflammatory cells in
the vascular wall.9 Additionally, a
reduction in the total number of pulmonary vessels in patients with COPD
has been noted on both pathology specimens and angiographic studies.8
Clinical Course
In most patients with COPD, the
degree of PH is mild and its progression
is slow. The natural history of this population was described by Weitzenblum
and colleagues in 1979. They reported
the hemodynamics of 84 patients with
COPD and arterial hypoxemia. Patients
underwent 2 RHCs at least 3 years
apart, each measure taken at a time of
disease stability. Hemodynamic measurement revealed that 34 of 84 patients
had mPAP greater than 20 mm Hg at
baseline, and at follow-up their mPAP
had increased about 0.5 to 0.6 mm Hg.
Only 28 of 84 patients increased their
mPAP by 5 mm Hg or more, and those
who did also exhibited more hypoxemia
and hypercarbia than patients with more
stable hemodynamics.10
Conversely, as described in the epidemiology section, a small percentage of
patients with COPD exhibit moderate
to severe PH at baseline.5 These patients
do not have the same disease stability as
those patients with mild baseline disease.
Oswald-Mammosser and colleagues
examined a cohort of 82 patients with
COPD requiring oxygen therapy and
sought to describe prognostic indicators
for this group. On final analysis, the
5-year survival of COPD patients with a
baseline mPAP of 25 mm Hg or less
was 62.2%, vs 36.6% for those patients
with PH (Figure 2). Multivariate
analysis revealed that PAP was a better
prognostic indicator than FEV1, or the
degree of hypoxemia or hypercapnea.11
In the previously referenced 2005 study
by Chaouat et al, the 27 out of 998
(2.7%) COPD patients with severe PH
(mPAP ⬎40) had a significantly reduced
survival when compared to the rest of
the COPD cohort.7 Therefore, while the
presence of more severe PH is rare in
Figure 2: Survival in Patients With COPD and
PH. Survival of patients with both COPD
and PH, divided by degree of PH. OswaldMammosser et al. Chest. 1995;107(5):11931198.
patients with COPD, it is associated
with increased mortality.
PITFALLS IN THE DIAGNOSIS
OF PH IN COPD PATIENTS
Because of the prognostic significance of
PH in COPD patients, it seems clinically important to identify its presence;
however, making the diagnosis can be a
difficult endeavor. Echocardiography, the
most common screening tool for PH in
the general population, is less accurate in
those with COPD. Arcasoy and colleagues compared the accuracy of
echocardiographic estimates of PAP to
RHC measurements in 374 lung transplant candidates, the majority of which
had obstructive lung disease. Fifty-two
percent of pressure estimates were inaccurate (varied by more than 10 mm Hg)
and 48% of patients were misclassified as
having PH by echocardiography when
they did not. The sensitivity and specificity of echocardiography for the
presence of PH in this population were
85% and 55%, respectively (Figure 3).2
Therefore, if PH is suspected, RHC is
required for confirmation and correct
classification of the diagnosis. But, the
RHC itself also contains diagnostic pitfalls in the COPD population. Patients
with pulmonary parenchymal disease
may exhibit significant negative swings
in pleural pressure with inspiration,
which may increase both the PAP and
the left ventricular afterload. Therefore,
in these patients in particular, it is
important that all measurements be
taken at end expiration.12 Even at end
expiration, hyperinflation with alveolar
distension and increased intrathoracic
Advances in Pulmonary Hypertension
Volume 12, Number 3; 2013
123
Figure 3: Echocardiographic Estimates of
PAP in COPD Patients. The accuracy of
echocardiographic estimates of PAP when
compared to RHC. The PH-negative group
includes those without PH on RHC and the
PH-positive group shows elevations of PAP
on RHC. Arcasoy et al. Am J Respir Crit Care
Med. 2003;167(5):735-740.
pressure can contribute to elevation in
mPAP and pulmonary vascular resistance. Finally, it is important that
COPD patients have hemodynamics
measured at their baseline lung function
because PAP may rise up to 20% during
a COPD exacerbation, only to fall again
after resolution of the exacerbation.10,13
COMPLICATING PROBLEMS
The presence of concomitant conditions
that may affect the PAP further complicates the diagnostic evaluation of PH in
COPD patients. These comorbidities
include sleep apnea, venous thromboembolism (VTE), systolic or diastolic left
heart failure, and pulmonary fibrosis.
Historically, it was thought that COPD
patients exhibited higher rates of sleep
apnea than the general population, with
rates up to 15% quoted.14 However, the
population-based Sleep Heart Health
Study, in which 1138 patients with mild
COPD were studied, revealed that sleep
apnea-hypopnea syndrome (SAHS) is
present in approximately 5% of the
general adult population, and its prevalence in the COPD population appears
to be the same.15 Patients with SAHS
and COPD exhibit more significant
hypoxemia than those with SAHS
alone.14 Further, patients with overlap
syndrome not treated with CPAP
therapy had a higher mortality and were
more likely to be hospitalized for a
COPD exacerbation than patients with
COPD alone. Treatment with CPAP
therapy, however, ameliorated this risk
and these treated patients had no greater
124
Advances in Pulmonary Hypertension
risk for hospitalization or mortality than
those with COPD alone.16,17 The investigation of and treatment for both
SAHS and nighttime hypoxemia in
patients with COPD will help eliminate
reversible hypoxic pulmonary vasoconstriction as a cause of increased
pulmonary pressures.
Patients with COPD may also be at
increased risk for VTE and pulmonary
emboli, which can be a cause of
increased dyspnea, hypoxemia, and elevated PAP. Therefore, evaluation for
VTE is recommended in patients with
COPD and worsening dyspnea.18,19
Additionally, in an aging population,
COPD and either systolic or diastolic
left heart failure often overlap in the
same patient and can contribute to
dyspnea, increased pulmonary pressures,
and morbidity.20,21 A careful evaluation
of left sided filling pressures during heart
catheterization will help identify this
confounder and direct management
toward appropriate therapy.
Finally, patients with the combined
pulmonary fibrosis emphysema syndrome
(CPFE) may initially present with
breathlessness and a diagnosis of COPD.
This entity has no consensus definition,
but this characterization has been proposed: a history of smoking, severe
dyspnea, primarily upper lobe
emphysema, primarily lower lobe pulmonary fibrosis, a severely reduced
diffusing capacity for carbon monoxide
and unexpectedly preserved spirometry
values.22 In some reports, these patients
exhibit markedly increased rates of severe
PH (50% to 90% of patients) and a very
poor 5-year survival rate of 25%.23-25
Specific treatment trials have not been
done for this group. However, given the
severity of the PH in these patients and
data that suggest the PH may drive
mortality, early referral for lung transplantation should be considered and
future studies might address the role of
PH-specific treatments for this group.
WHO GROUP 1 PAH AND COPD
COPD patients with more severe elevation in PH represent a unique group,
and it is likely that conditions other than
COPD may underlie PH in this setting.
This is an important consideration, particularly in patients with PH and mild
Volume 12, Number 3; 2013
COPD. In the Registry to EValuate
Early And Long-term PAH disease
management (REVEAL), 17% of
patients classified as having PAH
(WHO Group 1) had COPD listed as a
comorbid condition. These patients had
mild COPD with a mean FEV1 of 69%
of predicted. Pulmonary hemodynamics
and the distribution of PAH etiologies—
idiopathic (50%), connective tissue
disease (28%), congenital heart disease
(11%), and portopulmonary hypertension
(5%)—were similar for COPD patients
and the overall registry population.
When compared to patients without
comorbid conditions, COPD patients
had a greater incidence likelihood of
New York Heart Association functional
class III or IV (odds ratio 2.19,
P⬍0.001), lower 6-minute walk distance
(304.5 vs 400 m), and lower 3-year survival (64.7% vs 77.4%, P⬍0.001).26
TREATMENT
As the previously mentioned studies
demonstrate, mild PH (mPAP ⬍30) is
relatively common in the COPD population and is thought to be related to
hypoxic pulmonary vasoconstriction.
Therefore, the mainstays of treatment
for these patients remain long-term
oxygen therapy, smoking cessation,
inhaled bronchodilators, and inhaled
corticosteroids. However, the debate
about treatment of PH in COPD surrounds those patients with mPAP ⬎35,
or the so-called “PH out of proportion
to COPD” patients. The argument for
treatment centers on their increased
symptomatology and poorer outcomes
compared with patients with COPD and
milder increases in pulmonary pressures.
Data are confined to a few small trials
and case reports, and no large trial has
specifically enrolled this “out-ofproportion” group. Thus, the debate on
treatment continues.
The phosphodiesterase type 5
inhibitor sildenafil has been investigated
for this group of patients in a couple of
small trials. Acutely, sildenafil caused
hemodynamic improvements over 1 hour
in patients with COPD and PH, but
this improvement was accompanied by
worsened hypoxemia. This hypoxemia is
likely due to obliteration of hypoxic pulmonary vasoconstriction in more
diseased areas of lung with worsening of
ventilation/perfusion mismatch.27,28
Small trials of outpatient use of sildenafil
in these patients have yielded conflicting
results, with one trial showing an
improvement in exercise capacity and
hemodynamics and other trials reporting
no improvement after 3 months of
therapy.29,30
The endothelin receptor antagonist
(ERA) bosentan was investigated in a
small (30 patients), 12-week, placebocontrolled trial in subjects with COPD
and PH. There was no improvement in
exercise capacity or pulmonary pressures,
and oxygenation and quality of life scores
decreased on therapy.31 Other small
trials and case reports have shown
improvement on ERA therapy.32 A
larger trial is needed to definitively elucidate the role of ERA therapy in
patients with COPD and PH.
Inhaled prostacyclins are a theoretically attractive option for this group of
patients, because the inhaled drug will
likely be preferentially delivered to
better-ventilated areas of lung, perhaps
offering a less deleterious effect on
ventilation perfusion matching. Inhaled
iloprost was investigated in patients
with COPD and echocardiographic
evidence of PH. Treatment acutely
improved gas exchange and walk
distance.33
Treatment trials with other agents,
such as tadalafil, sildenafil, udenafil,
riociguat, inhaled nitric oxide, inhaled
treprostinil, and inhaled iloprost, are
ongoing. As these results become
available, the effect of PH-specific
therapy on COPD patients should
become clearer. In the interim, the
decision of when to consider treatment
may hinge on the clinical assessment of
whether or not COPD represents the
cause of PH as opposed to a comorbidity
seen in association with treatable WHO
Group 1 PAH. In the absence of established guidelines, this requires
consideration of COPD vs PH severity
as well as assessment for other associated
comorbidities.
CONCLUSION
Mild PH is relatively common in
patients with COPD. However, a small
subgroup of patients may present with
COPD and moderate-severe elevations
in their PAP. Whether the pathophysiology involved in this severe PH is
different from those with milder PH is
unclear. In this setting, a diligent search
for other contributing conditions should
be undertaken. Given the high prevalence of COPD, some patients will have
more than one condition contributing to
PH, and those with mild COPD and
more severe PH might still be categorized into WHO Group 1. Patients with
severe PH and COPD have increased
morbidity and mortality when compared
with the milder patients. This observation spurs clinicians to consider PH
treatment for patients with COPD and
PH. Currently, data confirming both the
safety and efficacy of PH therapy for
such patients is lacking and it is hoped
that future studies will lead to identification of new, effective treatments as
well as subgroups of patients with
COPD-associated PH more likely to
respond to therapy.
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2. Arcasoy SM, Christie JD, Ferrari VA, et al.
Echocardiographic assessment of pulmonary
hypertension in patients with advanced lung
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735-740.
3. Vizza CD, Lynch JP, Ochoa LL, Richardson
G, Trulock EP. Right and left ventricular dysfunction in patients with severe pulmonary disease.
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4. Scharf SM, Iqbal M, Keller C, Criner G,
Lee S, Fessler HE; National Emphysema
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5. Thabut G, Dauriat G, Stern JB, et al. Pulmonary hemodynamics in advanced COPD candidates for lung volume reduction surgery or lung
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6. Cuttica MJ, Kalhan R, Shlobin OA, et al.
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7. Chaouat A, Bugnet AS, Kadaoui N, et al.
Severe pulmonary hypertension and chronic
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8. Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in COPD. Eur Respir J.
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605-609.
10. Weitzenblum E, Loiseau A, Hirth C,
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obstructive pulmonary disease. Chest. 1979;75(6):
656-662.
11. Oswald-Mammosser M, Weitzenblum E,
Quoix E, et al. Prognostic factors in COPD
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12. MacNee W. Pathophysiology of cor pulmonale in chronic obstructive pulmonary disease.
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13. Abraham AS, Cole RB, Green ID,
Hedworth-Whitty RB, Clarke SW, Bishop JM.
Factors contributing to the reversible pulmonary
hypertension of patients with acute respiratory
failure studies by serial observations during
recovery. Circ Res. 1969;24(1):51-60.
14. Chaouat A, Weitzenblum E, Krieger J,
Ifoundza T, Oswald M, Kessler R. Association of
chronic obstructive pulmonary disease and sleep
apnea syndrome. Am J Respir Crit Care Med. 1995;
151(1):82-86.
15. Sanders MH, Newman AB, Haggerty CL,
et al. Sleep and sleep-disordered breathing in
adults with predominantly mild obstructive airway
disease. Am J Respir Crit Care Med. 2003;167(1):
7-14.
16. Machado MC, Vollmer WM, Togeiro SM,
et al. CPAP and survival in moderate-to-severe
obstructive sleep apnoea syndrome and hypoxaemic
COPD. Eur Respir J. 2010;35(1):132-137.
17. Marin JM, Soriano JB, Carrizo SJ, et al.
Outcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea: the
overlap syndrome. Am J Respir Crit Car Med.
2010;182(3):325-331.
18. Tillie-Leblond I, Marquette CH, Perez T,
et al. Pulmonary embolism in patients with unexplained exacerbation of chronic obstructive
pulmonary disease: prevalence and risk factors. Ann
Intern Med. 2006;144(6):390-396.
19. Ambrosetti M, Ageno W, Spanevello A,
Salerno M, Pedretti RF. Prevalence and prevention
of venous thromboembolism in patients with acute
exacerbations of COPD. Thromb Res. 2003;112(4):
203-207.
20. Rutten FH, Cramer MJ, Zuithoff NP, et al.
Comparison of B-type natriuretic peptide assays for
identifying heart failure in stable elderly patients
with a clinical diagnosis of chronic obstructive pulmonary disease. Eur J Heart Fail. 2007;9(6-7):
651-659.
21. Le Jemtel TH, Padeletti M, Jelic S. Diagnostic and therapeutic challenges in patients with
coexistent chronic obstructive pulmonary disease
and chronic heart failure. J Am Coll Cardiol. 2007;
49(2):171-180.
22. Cottin V, Le Pavec J, Prevot G, et al. Pulmonary hypertension in patients with combined
pulmonary fibrosis and emphysema syndrome. Eur
Respir J. 2010;35(1):105-111.
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23. Cottin V, Nunes H, Brillet PY, et al. Combined pulmonary fibrosis and emphysema: a
distinct underrecognised entity. Eur Respir J. 2005;
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LA, McGoon MD. Comorbid conditions and outcomes in patients with pulmonary arterial
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27. Holverda S, Rietema H, Bogaard HJ, et al.
Acute effects of sildenafil on exercise pulmonary
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558-564.
28. Blanco I, Gimeno E, Munoz PA, et al.
Hemodynamic and gas exchange effects of
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pulmonary disease and pulmonary hypertension.
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Sildenafil improves hemodynamic parameters in
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Sildenafil treatment in COPD does not affect
stroke volume or exercise capacity. Eur Respir J.
2008;31(4):759-764.
31. Stolz D, Rasch H, Linka A, et al. A randomised, controlled trial of bosentan in severe
COPD. Eur Respir J. 2008;32(3):619-628.
32. Valerio G, Bracciale P, Grazia D’Agostino
A. Effect of bosentan upon pulmonary hypertension in chronic obstructive pulmonary disease.
Ther Adv Respir Dis. 2009;3(1):15-21.
33. Dernaika TA, Beavin M, Kinasewitz
GT. Iloprost improves gas exchange and
exercise tolerance in patients with pulmonary hypertension and chronic obstructive pulmonary disease. Respiration. 2010;79(5):
377-382.
Pulmonary Hypertension in Idiopathic Pulmonary Fibrosis
Belinda N. Rivera-Lebron, MD,
MSCE
Department of Medicine
University of Pittsburgh
Pittsburgh, PA
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with a variable natural
history. Pulmonary hypertension (PH) is frequently found in patients with IPF and
is associated with an almost 3-fold increase in the risk of death. Pulmonary hypoxic
vasoconstriction plays an important role in the pathogenesis of PH in IPF (PHIPF), although it has become clear that it is not the only mechanism involved.
While invasive right heart catheterization is the gold standard modality of hemodynamic assessment, there has been increasing interest in noninvasive testing, such as
Doppler echocardiogram, as complementary methods of assessing right ventricular
function in these patients. While the expanding array of pharmacologic options for
the treatment of pulmonary arterial hypertension has engendered increased interest
in the application of these therapies for PH-IPF, supportive evidence for benefit is
lacking.
Idiopathic pulmonary fibrosis (IPF) is a
chronic, progressive fibrosing interstitial
pneumonia of unknown etiology, limited
to the lungs and associated with the histopathologic and/or radiographic pattern
of usual interstitial pneumonia.1,2 IPF is
the most common idiopathic interstitial
pneumonia with an incidence of 7 to 16
per 100,000 cases and a prevalence of 14
to 43 per 100,000 persons.3,4 IPF is a
fatal lung disease with a variable natural
history and a median survival of 2.5 to 5
years.5,6 Pulmonary hypertension (PH) is
a well recognized complication of IPF,
and when present, it is associated with
an almost 3-fold increase in the risk of
death.7,8 This review will summarize the
current knowledge of the epidemiology,
pathophysiology, diagnostic methods,
clinical implications, and possible treatments of PH in IPF.
(RHC). PH should be differentiated
from pulmonary arterial hypertension
(PAH), hemodynamically defined as
mPAP of ⱖ25 mm Hg in the presence
of a normal pulmonary capillary wedge
pressure (PCWP) on resting RHC.9 It
has not been established which hemodynamic definition is suitable for patients
with PH-IPF. In a series of 70 patients
with IPF, a receiver operating curve
(ROC) analysis suggested mPAP cutoff
of 17 was the best predictor for mortality10; however, this has not been
validated in another cohort.
There have been several publications
on the incidence of PH-IPF, reporting
ranges from 20% to 42% (Table 1).
Several factors account for this wide
incidence range. The first factor is the
lack of a standardized definition for
PH-IPF. Some studies used the criteria
for PH and others the PAH definition.
The second factor is the diagnostic
method used for the PH diagnosis.
While most studies used hemodynamic
measurement as assessed by RHC, some
included patients with PH defined by
pulmonary artery systolic pressure
(PASP) on echocardiograms. Finally,
most studies were performed in patients
being worked up for lung transplantation, since these patients routinely
undergo RHC as part of their transplant
DEFINITION AND
EPIDEMIOLOGY
The Fifth Symposium on PH held in
2013 in Nice, France, classifies PH associated with IPF in “Group 3: Pulmonary
hypertension due to lung disease and/or
hypoxemia,” differentiating this from
other etiologies of PH.9 PH is defined
as resting mean pulmonary arterial
pressure (mPAP) of ⱖ25 mm Hg as
assessed by right heart catheterization
Key Words—pulmonary fibrosis, idiopathic pulmonary fibrosis, pulmonary hypertension, pulmonary vascular disease, interstitial lung disease
Correspondence: [email protected]
Disclosures: Dr Rivera-Lebron reported no conflicts.
evaluation. Although lung transplant is
the only treatment available for IPF, the
selected subgroup that receives evaluation
is not representative of the overall IPF
population. Using cohorts that consist of
a younger IPF population with fewer
comorbidities might underestimate the
“true” incidence of PH-IPF. Furthermore, the timing of evaluation for
PH-IPF may affect the prevalence. It
has been shown that at an earlier IPF
stage hemodynamics might be normal or
just mildly abnormal. Use of data from
patients with more advanced disease
undergoing transplant evaluation may
overestimate the incidence of PH-IPF,
and even in the setting of advanced
disease PH progression is ongoing. A
study of IPF patients awaiting lung
transplantation using serial RHC data
showed progressive development of PH
from time of initial transplant evaluation
(38.6%) to time of transplant (86.4%).11
When PH is present in patients with
IPF, it is generally mild to moderate. In
a retrospective study of 135 patients with
IPF, those with PH-IPF (defined by
mPAP ⱖ25 mm Hg and PCWP ⬍15
mm Hg) had mPAP of 31⫾6 mm Hg
and mean pulmonary vascular resistance
(PVR) of 5⫾2 Wood units.12 Fourteen
patients (11%) had moderate to severe
right ventricular (RV) dysfunction on
echocardiogram.12 However, a minority
of patients with advanced lung disease
have severe PH, in which the PAP is
higher than expected, and those are
sometimes referred to as “out of pro-
Advances in Pulmonary Hypertension
Volume 12, Number 3; 2013
127
Table 1. Prevalence of Pulmonary Hypertension in Idiopathic Pulmonary Fibrosis
Author
Year
n
Leuchte et al
Zisman et al22
Patel et al8
2004
2007
2007
Shorr et al53
Nathan et al11
Song et al54
Rivera-Lebron et al12
28
Diagnosis
PH Definition
Prevalence, %
28
65
41
RHC
RHC
RHC
21.4
41.5
20
2007
2008
2525
118
RHC
RHC
2009
2013
131
135
Echo
RHC
mPAP ⬎35 mm Hg
mPAP ⬎25 mm Hg
mPAP ⬎25 mm Hg &
PCWP ⱕ15 mm Hg
mPAP ⬎25 mm Hg
mPAP ⬎25 mm Hg
mPAP ⬎25 mm Hg &
PCWP ⬍15 mm Hg
sPAP ⬎40 mm Hg
mPAP ⱖ25 mm Hg &
PCWP ⬍15 mm Hg
46.1
40.7
36.4
25
29
Adapted from Nathan, 2009.55
portion” PH.13 A definition for “out of
proportion” PH has not yet been established or included in the diagnostic
criteria for Group 3 PH.
PATHOGENESIS
The histopathologic hallmark of IPF
includes heterogeneous areas of fibrosis
with architectural distortion.1 The
fibrotic zones are composed mainly of
dense collagen, with scattered subepithelial foci of proliferating fibroblasts
and myofibroblasts (fibroblast foci).1
Progressive parenchymal fibrosis then
leads to pulmonary vascular destruction,
the initial pathologic mechanism of
PH-IPF (Figure 1, top left, A, and top
right, B). Vessel ablation in areas of
dense fibrosis contributes to reduction of
capillary density, impaired gas exchange,
and elevated PVR.14 However, occlusive
venopathy and vascular remodeling have
been found in nonfibrotic lung areas,15
suggesting mechanisms other than
extension of fibrosis and vascular obliteration contribute to the development of
PH-IPF (Figure 1, bottom left, C, and
bottom right, D).
Chronic alveolar hypoxia leads to subsequent pulmonary vascular remodeling
and pulmonary artery (PA) vasoconstriction, also playing a major role in the
development of PH-IPF. Vessels show
intimal proliferation and medial thickening of muscular pulmonary arteries
and pulmonary veins.16 This leads to
neovascularization and a redistribution of
microvessels within the pulmonary interstitium.14 New vessels differ
morphologically from normal arteries
and arterioles by lacking an elastin
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Advances in Pulmonary Hypertension
layer,14 which reduces vascular compliance.17
Further vascular remodeling is due to
overexpression of inflammatory mediators (cytokines and growth factors). In
general, leukotrienes promote fibrosis,
whereas prostaglandin E2 (PGE2)
opposes fibrogenic responses. There is an
imbalance of these factors in IPF, which
favors the production of 5-lipoxygenase
(a profibrotic leukotriene), and upregulation of tumor necrosis factor (TNF)-␣,
platelet-derived growth factor (PDGF),
and fibroblast growth factor, all of which
mediate lung fibrosis and vascular
remodeling.17,18 There is also evidence
of decreased levels of PGE2 in bronchoalveolar lavage in patients with IPF.18
Decreased levels of PGE2 may increase
expression of TNF-␣ and transforming
growth factor (TGF)-␤, responsible for
collagen deposition.17 Finally, genetic
overexpression of the vasoconstrictor
endothelin-1 (ET-1) causes pulmonary
fibrosis in mice.19 ET-1 is highly
expressed in lung tissue, bronchoalveolar
lavage fluid, and serum from patients
with IPF and concomitant PH.18,19 This
evidence provided the rationale for performing clinical trials using prostacyclin
Figure 1. Pulmonary Artery in 2 Patients With Pulmonary Hypertension in Idiopathic Pulmonary
Fibrosis. Top left, A (hematoxylin-eosin, original ⫻ 25): Pulmonary artery branch (with adjacent
airway) is seen in an area of dense fibrosis. Top right, B (original ⫻ 100): Higher magnification
of this vessel shows medial thickening and significant intimal proliferation. Bottom left, C
(original ⫻ 25): A pulmonary artery/arteriole with adjacent small airway in a lobule of relatively
nonfibrotic lung tissue. Bottom right, D (original ⫻ 100): Higher magnification of this vessel
shows marked medial thickening. Adapted from Patel, et al. 2007.8
Volume 12, Number 3; 2013
Figure 2. Pathophysiology of Pulmonary Hypertension in Idiopathic Pulmonary Fibrosis.
Adapted from King and Nathan, 2013.20
and endothelin receptor antagonists in
patients with IPF-PH.
Comorbidities, both pulmonary and
nonpulmonary, frequently exist in IPF
(Figure 2). These comorbidities, such as
coronary artery disease, systolic or diastolic left ventricular dysfunction,
obstructive sleep apnea, and recurrent
venous thromboembolic events may contribute to the development of PH in
patients with IPF.20 When present, they
may contribute to increased mortality
and should be addressed therapeutically
as indicated.
DIAGNOSIS
PH-IPF symptoms are nonspecific and
overlap with symptoms of IPF, making
the diagnosis extremely challenging.
These include resting or exertional
shortness of breath, fatigue, weakness,
palpitations, chest discomfort, and lightheadedness or syncope. Cardiac
examination may reveal an accentuated
or loud P2 component of the second
heart sound, a fixed split of the second
heart sound (consistent with pulmonic
insufficiency), and a holosystolic tricuspid regurgitation murmur. Other
physical examination signs may include
RV heave, jugular venous distention, and
pedal edema. These findings represent
progressive RV dilation and hypertrophy
leading to increased right atrial pressure,
and are consistent with a more advanced
disease stage.
Clinical suspicion for PH-IPF should be
high in the setting of progressive exercise
limitation despite stable pulmonary function
testing and/or parenchymal fibrosis on a
chest computed tomography (CT) scan.
Once other etiologies have been ruled out
(such as pulmonary embolism), these
symptoms should alert a physician to possible presence of PH-IPF and may justify
pursuing further diagnostic testing.
Imaging
Chest radiography (CXR) may reveal
cardiomegaly and enlargement of the
pulmonary arteries. Although these
findings might indicate presence of PH,
they are nonspecific, and normal radiographic findings do not rule out PH.13
Chest CT findings suggestive of PH
include enlargement of the pulmonary
trunk (PA diameter ⬎29 mm), RV
dilation, and ratio of the main PA to
ascending aorta diameter (ratio ⬎1).21
However, a study of 65 patients with
IPF failed to demonstrate a correlation
between mPAP on RHC and main PA
diameter or fibrosis score on CT scan.22
Pulmonary Function Testing
Pulmonary function test (PFT) values
are fundamental in establishing the diagnosis and severity of IPF. A restrictive
pattern is typically seen in PFTs of IPF
patients. There is no significant difference in the forced vital capacity
(FVC) and total lung capacity (TLC) of
IPF patients with and without PH.7,23
However, percentage of predicted lung
diffusion capacity for carbon monoxide
(DLCO %) is significantly lower in
those with PH-IPF (31⫾10% vs
38⫾11%; P⫽0.04).7 A DLCO ⬍30%
has been shown to be associated with a
2-fold higher prevalence of PH-IPF.23
Similarly, a FVC %/DLCO % ratio
⬎1.5 was associated with an almost
2-fold increased risk of PH-IPF.23 The
combination of DLCO ⬍40% together
with the need for supplemental oxygen
predicted presence of PH-IPF with a
sensitivity and specificity of 65% and
94.1%, respectively.7 However, none of
these associations has been sufficiently
robust to serve as a diagnostic predictor
of PH-IPF.
Exercise Capacity
Performance on a 6-minute walk test
(6MWT) is a key component in the
evaluation of IPF. Mean distance walked
(144⫾66 vs 366⫾82 m; P⬍0.001) and
the pulse oximetry saturation (SpO2)
nadir (80⫾4% vs 88⫾4%; P⬍0.001)
during the 6MWT was found to be significantly lower in PH-IPF in a recent
study of patients with advanced IPF.7
Exercise desaturation to ⬍85% had a
sensitivity and specificity of 100% and
61.9%, respectively, for associated PH.24
Also, failure of the heart rate to fall 1
minute after a 6MWT was found to
predict presence of PH in patients with
IPF (OR 4.0, 95% 1.17-13.69,
P⫽0.02).25
The impact of PH on gas exchange
and exercise capacity was evaluated in a
study of patients with pulmonary fibrosis
undergoing cardiopulmonary exercise
testing.26 Patients with PH showed a
significantly impaired exercise tolerance,
worsened ventilatory efficiency, and
increased dyspnea.
Biomarkers
Circulating levels of B-type natriuretic
peptide (BNP) have been used as a
prognostic biomarker for PAH.27 It has
been shown that plasma BNP levels are
higher in patients with fibrotic lung
Advances in Pulmonary Hypertension
Volume 12, Number 3; 2013
129
disease and mPAP ⬎35 mm Hg.28 Elevated BNP concentrations identified
significant PH with a sensitivity of 85%
and specificity of 88%.29 However, the
usefulness of BNP as a diagnostic tool is
limited since elevated BNP is also
present in other cardiovascular disorders
such as left ventricular failure, and a
normal value does not exclude PH.13,29
Echocardiogram
Doppler echocardiogram (DE) is a
useful, noninvasive method of assessing
RV function and PH. Indications for
echocardiography to evaluate patients
with chronic lung diseases include: confirmation or exclusion of PH,
clarification of concomitant left heart
disease, and the selection of patients for
RHC necessary for the conclusive diagnosis of PH.13
There has been substantial reliance on
echocardiographic estimation of PASP
for the evaluation of PH. PASP calculation depends on the measurement of
the peak velocity of the tricuspid regurgitation jet (Vmax). The modified
Bernoulli equation is applied to calculate
the given pressure (PASP ⫽ 4*Vmax2 ⫹
RAP, where RAP ⫽ right atrial pressure
estimation determined by the variation
in the size of the inferior vena cava
during inspiration). In a study of patients
with advanced lung disease, PASP
assessed by DE had a modest correlation
compared with RHC measurement
(r⫽0.69; P⬍0.0001).30 However, in
those with interstitial lung disease
(ILD), estimation of PASP by DE was
only possible in 54% of the patients, and
when obtained, it was inaccurate in 37%
of cases, with a discordance of greater
than 10 mm Hg.30 Results were similar
in a group of patients with IPF, showing
that measurement of PASP was possible
in 54.5% of the DE, with 40% accuracy
between estimated PASP by DE and
measured PASP by RHC.24
Another echocardiographic measurement used in the evaluation of PAH
is the tricuspid annular plane systolic
excursion (TAPSE). TAPSE is the longitudinal systolic displacement of the RV
base toward the RV apex and has been
shown to correlate strongly with RV
ejection fraction.31 In normal subjects,
the mean TAPSE varies between 2.3
130
Advances in Pulmonary Hypertension
and 2.6 cm, with a TAPSE of 2.0 cm
likely representing the lowest acceptable
normal value.32 In PAH, a TAPSE
⬍1.8 cm was associated with greater RV
dysfunction, lower cardiac index, and
higher mortality.33 In 134 patients with
IPF, the mean TAPSE was 2.1 cm with
a significantly lower TAPSE (1.8 cm vs
2.1 cm; P⫽0.01) in those with moderate
to severe RV dysfunction.12 TAPSE was
associated with stroke volume and
inversely associated with PVR, independent of age, sex, race, height, weight,
and FVC.12
Dilation of the RV in presence of
normal size left ventricle (LV) strongly
suggests increased RV afterload. Direct
measurement of the RV-to-LV diameter
ratio (RV:LV) assesses the relationship
between the RV and the LV, and has
been used to indicate presence of PH. In
IPF patients, the mean RV:LV diameter
ratio was 0.9⫾0.3 and a ratio ⱖ1 was
significantly correlated with increased
PVR, independent of age, sex, race,
height, weight, and FVC.12
Therefore, echocardiographic measures
of RV structure and function, particularly presence of RV dilation, RV
dysfunction, and RV:LV diameter ratio
⬎1, may suggest presence of PH-IPF
and strong consideration should be given
to pursue RHC.
Right Heart Catheterization
RHC is the gold standard modality for
hemodynamic assessment of PH-IPF. It
will confirm the diagnosis and establish
its severity. At this time, RHC is not
routinely recommended in patients with
IPF. Current indications for RHC in
chronic lung disease include: proper
diagnosis of PH in candidates for transplantation; suspected “out of proportion”
PH, potentially amenable to be enrolled
in randomized controlled clinical trials
with PAH drug therapy; frequent episodes of RV failure; and inconclusive
echocardiographic study in cases with a
high level of suspicion.13,34 RHC can
also demonstrate presence of diastolic
dysfunction, which can frequently cause
PH and imparts different implications in
management (aggressive diuresis, blood
pressure control, etc). Moreover, RHC
can provide important prognostic information that can be used in patient
counseling and possibly other therapeutic
considerations for a disease with no
current available treatment.
CLINICAL IMPLICATIONS
IPF has a median survival of 2.5 to 5
years.5,6 Presence of PH-IPF is a poor
prognostic factor and is associated with a
3-fold increased risk of death, independent of age, race, FVC percentage,
6-minute walk distance (6MWD), and
other covariates, (HR 3.6; 95% CI
1.8-7.1; P⫽0.0004).8 In one study, PH
was present in 52.4% of IPF nonsurvivors compared to only 24.1% of
survivors (P⫽0.008).7 The 1-year mortality rate of IPF patients with PH was
28% compared to 5.5% in those without
PH (P⫽0.002) (Figure 3).7
In one study, DLCO ⬍40% predicted
mortality in IPF patients (RR 2.70; 95%
Figure 3. Pulmonary Hypertension As Predictor of Survival in Idiopathic Pulmonary Fibrosis.
Adapted from Lettieri, et al. 2006.
Volume 12, Number 3; 2013
Table 2. Cox Proportional Hazards Models for Echocardiographic and Hemodynamic Predictors of Mortality in Idiopathic Pulmonary Fibrosis
Variables
Echocardiogram
RV:LV ⱖ1
TAPSE ⬍1.6 cm
Moderate to severe right atrial dilation
Moderate to severe RV dilation
Moderate to severe RV dysfunction
PASP, for 5 mm Hg increase
Hemodynamics
Right atrial pressure, for 1 mm Hg increase
mPAP, for 10 mm Hg increase
PVR, for 1 Wood unit increase
Cardiac output, for 1 L/min decrease
Stroke volume, for 10 mL decrease
Unadjusted Model
P
HR
95% CI
Value
Adjusted Model*
HR
95% CI
3.8
2.0
2.4
2.6
4.9
1.1
1.5,
1.0,
1.2,
1.4,
2.5,
1.1,
9.7
3.7
4.7
4.6
9.6
1.2
0.006
0.05
0.009
0.001
⬍0.001
⬍0.001
4.5
1.9
2.9
2.7
5.5
1.2
1.7,
1.0,
1.4,
1.4,
2.6,
1.1,
11.9
3.7
5.9
5.4
11.5
1.3
0.9
1.3
1.3
1.1
1.1
0.9,
1.0,
1.1,
0.9,
1.0,
1.0
1.7
1.4
1.4
1.2
0.34
0.06
⬍0.001
0.31
0.18
0.9
1.3
1.3
1.2
1.1
0.9,
1.0,
1.1,
0.9,
0.9,
1.0
1.8
1.5
1.5
1.3
P
Value
Censored at Lung
Transplantation†
P
HR
95% CI
Value
0.003
0.06
0.004
0.004
⬍0.001
⬍0.001
5.6
1.5
3.0
3.2
7.5
1.2
1.6,
0.7,
1.2,
1.4,
2.7,
1.1,
19.8
3.5
7.8
7.8
20.8
1.4
0.008
0.31
0.02
0.008
⬍0.001
0.002
0.48
0.06
0.001
0.23
0.19
1.0
2.4
1.4
1.4
1.2
0.9,
1.4,
1.2,
0.9,
0.9,
1.1
3.9
1.7
2.0
1.5
0.74
0.001
⬍0.001
0.10
0.09
*Adjusted for age, sex, race/ethnicity, height, weight, FVC, and transplant status
†
Adjusted for age, sex, race/ethnicity, height, weight, FVC
Adapted from Rivera-Lebron et al, 2013.12
CI 1.46-4.99).10 However, in another
study, while FVC and DLCO were
lower in nonsurvivors, they did not independently predict outcomes,7 suggesting
that rapid clinical deterioration with
right heart failure may occur unrelated to
progression of underlying parenchymal
process. In IPF, 6MWD was a better
predictor of mortality than FVC,35 and a
6MWD ⬍207 m was associated with a
greater than 4-fold mortality rate (RR
4.7; 95% CI 2.5-8.9; P⬍0.0001).35 Similarly, heart rate recovery after 6MWT
was found to predict survival in patients
with IPF without PH.36 In addition,
BNP has also been identified as a risk
factor for death independent of lung
functional impairment or hypoxemia in
IPF patients.29
We have shown that increasing
RV:LV diameter ratio, moderate to
severe right atrial and RV dilation and
moderate to severe RV dysfunction
detected by DE were associated with an
increased risk of death, independent of
covariates (including age, sex, race,
height, weight, and FVC) in patients
with IPF being evaluated for lung transplantation (Table 2).12 Moreover,
RV:LV diameter ratio and RV dysfunction predicted adverse outcomes
independently of the presence of
PH-IPF or the level of the PVR.12 The
presence of an increased RV:LV
diameter ratio might represent an early
anatomical change in response to higher
PVR prior to the development of frank
RV failure, and could directly contribute
to adverse outcome. This suggests that
right sided heart structure and function
may provide complementary information
in identifying a population of patients
with IPF who are at increased risk of
death.12
Focusing on hemodynamics, Lettieri
et al7 showed a linear correlation
between mPAP and outcomes, with
higher pressures associated with a greater
risk of mortality (HR 1.09; CI 1.021.16). In our study, higher mPAP was
also possibly associated with reduced
survival but did not reach statistical significance.12 Higher PVR was associated
with 30% increased risk for overall mortality (HR per 1 Wood unit ⫽ 1.3; 95%
CI 1.1-1.5; P⫽0.001).12 Right atrial
pressure, cardiac output, and stroke
volume were not associated with the risk
of death (Table 2).12 Preoperative
mPAP ⬎35 mm Hg has also been associated with increased mortality at 3
months after lung transplantation.37
MANAGEMENT
There are limited data on the treatment
of PH-IPF. Oxygen therapy for correction of hypoxemia decreases mortality
in chronic obstructive pulmonary
disease,38 but such findings have not
been demonstrated or systematically
evaluated in IPF.39 However, given that
hypoxic vasoconstriction plays an
important role in the pathogenesis of
PH-IPF, the use of oxygen to maintain
resting and exertional arterial oxygen
saturation above 90% is recommended.
There is a growing interest in the
potential benefit of PAH-specific therapies in PH-IPF (Table 3). Olschewski
et al40 investigated the acute effects of
inhaled nitric oxide (iNO), inhaled and
intravenous prostacyclin (epoprostenol
and iloprost, respectively), and calcium
channel blockers (CCB) in a pilot, openlabel study of patients with pulmonary
fibrosis of various causes with associated
PH (1 had IPF). All 4 drugs decreased
mPAP and PVR; epoprostenol worsened
oxygenation by increasing the
ventilation/perfusion (V/Q) mismatch;
and epoprostenol and CCB caused
hypotension. Similarly, Ghofrani et al41
examined the acute effects of a single
dose of iNO, epoprostenol, or sildenafil
in 16 patients with PH associated with
pulmonary fibrosis (7 with IPF). All
improved PVR, while only epoprostenol
affected V/Q mismatch and worsened
hypoxemia. The largest prospective prostacyclin study in PH-IPF was published
in abstract form, included 51 patients
with PH-IPF, and showed no difference
Advances in Pulmonary Hypertension
Volume 12, Number 3; 2013
131
Table 3. Trials of Therapy for Pulmonary Hypertension in Idiopathic Pulmonary Fibrosis
Author/
Journal/
Year
40
Olschewski,
AJRCCM 1999
Ghofrani,41 Lancet
2002
Drug
Group
iNO, IV epoprostenol,
inhaled Iloprost,
CCB
iNO, IV epoprostenol
or sildenafil
Pulm fibrosis
Pulm fibrosis
PH
Definition
PASP ⬎50
or
mPAP ⬎30
mPAP ⱖ35
N
Study
Type
8 (IPF⫽1)
Open label
16 (IPF⫽7)
Open label
PASP ⱖ35
or
mPAP ⱖ25
n/a
51
DB-RCT
158
DB-RCT
IPF mild, biopsy
proven
n/a
616
DB-RCT
Ambrisentan
IPF
n/a
494
DB-RCT
Collard,47 Chest
2007
Sildenafil
IPF
14
Open label-RCT
IPFnet,48 NEJM
2010 STEP-IPF
Sildenafil
IPF
mPAP ⱖ25
or
PASP ⱖ35
n/a
180
DB-RCT
Han,49 Chest 2013
(STEP-IPF posthoc analysis)
Sildenafil
IPF
119
DB-RCT
Krowka,42 Chest
[abstract] 2007
Inhaled iloprost
IPF
King,43 AJRCCM
2008 BUILD-1
Bosentan
IPF
King,44 AJRCCM
2011 BUILD-3
Bosentan
Raghu,45 Annals
2013 ARTEMISIPF
Echo with RV
dysfunction
Outcome
All 2 PVR, mPAP
Epo 2 O2
CCB 2BP
All 2 PVR,
Epo 2 O2
Sildenafil 1 O2
No change in 6MWT,
exercise O2, WHO
class in 12 weeks
No change in 6MWD
at 12 months. Trend
toward delaying
time to death or
disease progression
No delay in time to
death or disease
progression
Stopped early for lack
of efficacy and
possible 1 risk of
disease progression
57% improved 6MWD
of 20% at 3 months
Did not meet 20%
change in 6MWD at
12 or 24 weeks.
Improvement in sob
and QoL
Improved preservation
of 6MWD
Adapted from Nathan, 2009.55
in the 6MWD or oxygenation with 12
weeks of inhaled iloprost.42
Endothelin receptor blockers have also
been studied in IPF. Bosentan Use in
Interstitial Lung Disease-1 (BUILD1),43 a double-blind placebo-controlled
trial, investigated the use of bosentan in
158 IPF patients. No significant
improvement in 6MWD was observed
after 12 months; however, there was a
trend toward delaying time to death or
disease progression with therapy. Subsequently, BUILD-344 evaluated 616
patients with mild, biopsy-proven IPF,
but did not show delay in time to death
or disease progression. Most recently,
ARTEMIS-IPF45 examined the use of
ambrisentan in IPF. This study was terminated early for futility, as ambrisentan
was not effective in treating IPF and
may have been associated with an
increased risk of disease progression and
132
Advances in Pulmonary Hypertension
respiratory hospitalizations. It is
important to note that these 3 studies
were not designed to study patients with
PH-IPF, as their inclusion criteria were
based on presence of IPF. A subset of
21 patients with PH associated with
ILD in ARIES-346 demonstrated no
improvement in 6MWD.
Collard et al47 performed an openlabel study of 14 patients with PH-IPF,
and demonstrated a significant
improvement in 6MWD after 3 months
of the phosphodiesterase inhibitor sildenafil. The Sildenafil Trial of Exercise
Performance in IPF (STEP-IPF),48 a
placebo-controlled trial of sildenafil in
180 patients with IPF without hemodynamically diagnosed PH, failed to meet
its primary endpoint of a greater than
20% improvement in 6MWD at 12 and
24 weeks. It did show improvement in
dyspnea and quality of life. Interestingly,
Volume 12, Number 3; 2013
a recent post-hoc analysis of STEP-IPF
showed that the subgroup of patients
with echocardiographic evidence of RV
dysfunction had better preservation of
exercise capacity, while subjects without
RV dysfunction did not respond to
therapy.49 This might indicate that subjects with RV dysfunction have a greater
degree of circulatory limitation to
exercise, and are thus apt to functionally
improve in response to RV afterload
reducing treatment. To determine the
effect of PAH therapies on patients with
PH-IPF, future studies of PH therapy
may need to be focused on IPF subgroups with the combination of
significantly elevated PVR and RV dysfunction, as these subjects may have
greater capacity to improve.
Riociguat is the first member of a new
class of vasodilating agents known as
soluble guanylate cyclase stimulators that
cause vasodilation in both nitric oxidedependent and independent pathways.
Riociguat was investigated in a pilot,
open-label study of 22 ILD-associated
PH subjects (13 with IPF) with the
primary endpoints of safety and tolerability.50 In this study, patients had
mPAP ⬎30 mm Hg (mean ⫾ SD
40⫾10 mm Hg) and PVR ⬎400
dyn䡠s䡠cm⫺5 (mean ⫾ SD 656⫾201
dyn䡠s䡠cm⫺5). It showed improvement in
6MWD, cardiac output, and PVR, and
no change in mPAP at 12 weeks.
Arterial partial pressure of oxygen
(PaO2) decreased by 7⫾12 mm Hg at
12 weeks, suggesting presence of V/Q
mismatch.
In summary, these studies present
conflicting results with the use of PAHspecific agents in this population. Several
factors may account for this. Some
studies included patients with various
diffuse fibrotic lung diseases, and
response to PAH-specific therapy may
differ between different groups. Other
studies did not require PH for
enrollment or relied on echocardiographic estimates of PASP as a surrogate
for PH definition. Moreover, specific
IPF patient subgroups most likely to
benefit from vasodilator therapy have not
been properly identified and studied.
Finally, appropriate trial design and endpoints have not been determined for this
entity.
Current guidelines discourage the use
of PAH-specific therapy in IPF
patients.1,13,34 Benefit of PAH-specific
drugs in patients with PH-IPF has not
been proven. Prospective, randomized,
placebo-controlled trials evaluating IPF
patients with hemodynamically proven
PH and/or evidence of right heart failure
by echocardiogram need to be completed
before these therapies can be universally
endorsed and adopted. Appropriate
patient subgroups will need to be identified and targeted (eg, disproportionate
PH), in whom PH likely contributes
significantly to exercise limitation and
morbidity. Moreover, appropriate trial
endpoints will need to be agreed upon.
Finally, lung transplantation should be
considered in the appropriate IPF
patients with progressive lung disease.
Five-year post-transplantation survival in
IPF patients is estimated to be at 50% to
56%.1 Presence of PH does not preclude
lung transplantation and is associated
with increased mortality while awaiting
transplantation. The current Lung Allocation Scoring system of the United
Network for Organ Sharing increases
priority for patients with PH in the
setting of parenchymal lung disease.51
However, presence of PH also affects
post-transplant outcomes with increased
risk of primary graft dysfunction,52 perioperative mortality, and postoperative
mortality.37
CONCLUSION
In conclusion, PH is a common complication of IPF. The diagnosis of PH-IPF
is challenging, as symptoms are nonspecific. Presence of clinical deterioration
without progression of underlying parenchymal lung disease justifies further
diagnostic testing. Echocardiographic
findings of RV dysfunction, RV dilation,
and increased RV:LV diameter ratio may
suggest presence of PH-IPF. RHC is
the gold standard for the diagnosis of
PH-IPF, and should be considered when
it is likely to influence clinical decision
making. Presence of PH-IPF is associated with increased risk of mortality
and worse outcome. Therapeutic considerations may include treatment of
hypoxemia, treatment of underlying
comorbid conditions, and lung transplantation. The application of PAHspecific therapies for PH-IPF is of
uncertain benefit and needs further evaluation.
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14. Renzoni EA, Walsh DA, Salmon M, et al.
Interstitial vascularity in fibrosing alveolitis. Am J
Respir Crit Care Med. 2003;167(3):438-443.
15. Colombat M, Mal H, Groussard O, et al.
Pulmonary vascular lesions in end-stage idiopathic
pulmonary fibrosis: Histopathologic study on lung
explant specimens and correlations with pulmonary
hemodynamics. Hum Pathol. 2007;38(1):60-65.
16. Naeije R, Barbera JA. Pulmonary hypertension associated with COPD. Crit Care. 2001;
5(6):286-289.
17. Nathan SD, Noble PW, Tuder RM. Idiopathic pulmonary fibrosis and pulmonary
hypertension: connecting the dots. Am J Respir Crit
Care Med. 2007;175(9):875-880.
18. Charbeneau RP, Peters-Golden M. Eicosanoids: mediators and therapeutic targets in
fibrotic lung disease. Clin Sci (Lond). 2005;108(6):
479-491.
19. Hocher B, Schwarz A, Fagan KA, et al. Pulmonary fibrosis and chronic lung inflammation in
ET-1 transgenic mice. Am J Respir Cell Mol Biol.
2000;23(1):19-26.
20. King C, Nathan SD. Identification and
treatment of comorbidities in idiopathic pulmonary
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fibrosis and other fibrotic lung diseases. Curr Opin
Pulm Med. 2013;19(5):466-473.
21. Ng CS, Wells AU, Padley SP. A CT sign of
chronic pulmonary arterial hypertension: the ratio
of main pulmonary artery to aortic diameter.
J Thorac Imaging. 1999;14(4):270-278.
22. Zisman DA, Karlamangla AS, Ross DJ, et al.
High-resolution chest CT findings do not predict
the presence of pulmonary hypertension in
advanced idiopathic pulmonary fibrosis. Chest.
2007;132(3):773-779.
23. Nathan SD, Shlobin OA, Ahmad S,
Urbanek S, Barnett SD. Pulmonary hypertension
and pulmonary function testing in idiopathic pulmonary fibrosis. Chest. 2007;131(3):657-663.
24. Nathan SD, Shlobin OA, Barnett SD, et al.
Right ventricular systolic pressure by echocardiography as a predictor of pulmonary hypertension in
idiopathic pulmonary fibrosis. Respir Med. 2008;
102(9):1305-1310.
25. Swigris JJ, Olson AL, Shlobin OA, Ahmad
S, Brown KK, Nathan SD. Heart rate recovery
after six-minute walk test predicts pulmonary
hypertension in patients with idiopathic pulmonary
fibrosis. Respirology. 2011;16(3):439-445.
26. Glaser S, Noga O, Koch B, et al. Impact of
pulmonary hypertension on gas exchange and
exercise capacity in patients with pulmonary
fibrosis. Respir Med. 2009;103(2):317-324.
27. 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(8):865-870.
28. Leuchte HH, Neurohr C, Baumgartner R, et
al. Brain natriuretic peptide and exercise capacity in
lung fibrosis and pulmonary hypertension. Am J
Respir Crit Care Med. 2004;170(4):360-365.
29. Leuchte HH, Baumgartner RA, Nounou
ME, et al. Brain natriuretic peptide is a prognostic
parameter in chronic lung disease. Am J Respir Crit
Care Med. 2006;173(7):744-750.
30. Arcasoy SM, Christie JD, Ferrari VA, et al.
Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease.
Am J Respir Crit Care Med. 2003;167(5):735-740.
31. Kaul S, Tei C, Hopkins JM, Shah PM.
Assessment of right ventricular function using twodimensional echocardiography. Am Heart J. 1984;
107(3):526-531.
32. Forfia PR, Vachiery JL. Echocardiography in
pulmonary arterial hypertension. Am J Cardiol.
2012;110(6 Suppl):16S-24S.
33. Forfia PR, Fisher MR, Mathai SC, et al.
Tricuspid annular displacement predicts survival in
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pulmonary hypertension. Am J Respir Crit Care
Med. 2006;174(9):1034-1041.
34. Galie N, Hoeper MM, Humbert M, et al;
ESC Committee for Practice Guidelines (CPG).
Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the
Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology
(ESC) and the European Respiratory Society
(ERS), endorsed by the International Society of
Heart and Lung Transplantation (ISHLT). Eur
Heart J. 2009;30(20):2493-2537.
35. Lederer DJ, Arcasoy SM, Wilt JS, D’Ovidio
F, Sonett JR, Kawut SM. Six-minute-walk distance predicts waiting list survival in idiopathic
pulmonary fibrosis. Am J Respir Crit Care Med.
2006;174(6):659-664.
36. Swigris JJ, Swick J, Wamboldt FS, et al.
Heart rate recovery after 6-min walk test predicts
survival in patients with idiopathic pulmonary
fibrosis. Chest. 2009;136(3):841-848.
37. Whelan TP, Dunitz JM, Kelly RF, et al.
Effect of preoperative pulmonary artery pressure on
early survival after lung transplantation for idiopathic pulmonary fibrosis. J Heart Lung Transplant.
2005;24(9):1269-1274.
38. Zielinski J, Tobiasz M, Hawrylkiewicz I, Sliwinski P, Palasiewicz G. Effects of long-term
oxygen therapy on pulmonary hemodynamics in
COPD patients: a 6-year prospective study. Chest.
1998;113(1):65-70.
39. Crockett AJ, Cranston JM, Antic N. Domiciliary oxygen for interstitial lung disease. Cochrane
Database Syst Rev. 2001(3):CD002883.
40. Olschewski H, Ghofrani HA, Walmrath D,
et al. Inhaled prostacyclin and iloprost in severe
pulmonary hypertension secondary to lung fibrosis.
Am J Respir Crit Care Med. 1999;160(2):600-607.
41. Ghofrani HA, Wiedemann R, Rose F, et al.
Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial.
Lancet. 2002;360(9337):895-900.
42. Krowka MJ, Ahmad S, Andrade JA. A randomized, double-blind, placebo-controlled study to
evaluate the safety and efficacy of iloprost inhalation in adults with abnormal pulmonary arterial
pressure and exercise limitation associated with
idiopathic pulmonay fibrosis [abstract]. Chest. 2007;
132(633S).
43. King TE Jr, Behr J, Brown KK, et al.
BUILD-1: a randomized placebo-controlled trial of
bosentan in idiopathic pulmonary fibrosis. Am J
Respir Crit Care Med. 2008;177(1):75-81.
44. King TE Jr, Brown KK, Raghu G, et al.
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BUILD-3: a randomized, controlled trial of
bosentan in idiopathic pulmonary fibrosis. Am J
Respir Crit Care Med. 2011;184(1):92-99.
45. Raghu G, Behr J, Brown KK, et al;
ARTEMIS-IPF Investigators. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a
parallel, randomized trial. Ann Intern Med. 2013;
158(9):641-649.
46. Badesch DB, Feldman J, Keogh A, et al;
ARIES-3 Study Group. ARIES-3: ambrisentan
therapy in a diverse population of patients with
pulmonary hypertension. Cardiovasc Ther. 2012;
30(2):93-99.
47. Collard HR, Anstrom KJ, Schwarz MI,
Zisman DA. Sildenafil improves walk distance in
idiopathic pulmonary fibrosis. Chest. 2007;131(3):
897-899.
48. Idiopathic Pulmonary Fibrosis Clinical
Research Network, Zisman DA, Schwarz M,
Anstrom KJ, Collard HR, Flaherty KR, Hunninghake GW. A controlled trial of sildenafil in
advanced idiopathic pulmonary fibrosis. N Engl
J Med. 2010;363(7):620-628.
49. Han MK, Bach DS, Hagan PG, et al;
IPFnet Investigators. Sildenafil preserves exercise
capacity in patients with idiopathic pulmonary
fibrosis and right-sided ventricular dysfunction.
Chest. 2013;143(6):1699-1708.
50. Hoeper MM, Halank M, Wilkens H, et al.
Riociguat for interstitial lung disease and pulmonary hypertension: a pilot trial. Eur Respir J.
2013;41(4):853-860.
51. Egan TM, Murray S, Bustami RT, et al.
Development of the new lung allocation system in
the United States. Am J Transplant. 2006;6(5 Pt
2):1212-1227.
52. Diamond JM, Lee JC, Kawut SM, et al;
Lung Transplant Outcomes Group. Clinical risk
factors for primary graft dysfunction after lung
transplantation. Am J Respir Crit Care Med. 2013;
187(5):527-534.
53. Shorr AF, Wainright JL, Cors CS,
Lettieri CJ, Nathan SD. Pulmonary hypertension
in patients with pulmonary fibrosis awaiting
lung transplant. Eur Respir J. 2007;30(4):
715-721.
54. Song JW, Song JK, Kim DS. Echocardiography and brain natriuretic peptide as prognostic
indicators in idiopathic pulmonary fibrosis. Respir
Med. 2009;103(2):180-186.
55. Nathan SD. Idiopathic Pulmonary Fibrosis
and Pulmonary Hypertension: A Review. Chest
PCCSU. 2009;23.
Hypoxic Pulmonary Vasoconstriction and
Chronic Lung Disease
Erik R. Swenson, MD
Departments of Medicine and Physiology
and Biophysics
University of Washington
VA Puget Sound Health Care System
Seattle, WA
Hypoxic vasoconstriction in the lung is a unique and fundamental characteristic of
the pulmonary circulation. It functions in health and disease states to better preserve
ventilation-perfusion matching by diverting blood flow to better ventilated regions
when local ventilation is compromised. As more areas of lung become hypoxic either
with high altitude or global lung disease, then hypoxic pulmonary vasoconstriction
(HPV) becomes less effective in ventilation-perfusion matching and can lead to pulmonary hypertension. HPV is intrinsic to the vascular smooth muscle and its
mechanisms remain poorly understood. In addition, the pulmonary vascular endothelium, red cells, lung innervation, and numerous circulating vasoactive agents also
affect the strength of HPV. This review will discuss the pathophysiology of HPV
and address its role in pulmonary hypertension associated with World Health Organization Group 3 diseases. When sustained beyond many hours, HPV may initiate
pulmonary vascular remodeling and lead to more fixed and less oxygen-responsive
pulmonary hypertension if the hypoxic stimulus is maintained.
Hypoxic pulmonary vasoconstriction
(HPV) is a fundamental attribute of the
pulmonary circulation, which has fascinated cardiopulmonary physiologists and
clinicians since its definitive description
in the cat in 19461 and in humans 1 year
later.2 It was immediately appreciated
that this response to local alveolar
hypoxia and hypercapnia, either alone or
in combination generally occurring as
result of regional hypoventilation, acts to
redirect pulmonary blood flow to areas of
better ventilation with their higher
alveolar PO2 and lower PCO2. In this
fashion, HPV and hypercapnic pulmonary vasoconstriction (HCPV) are
potent mechanisms to better match
regional perfusion (Q) to alveolar ventilation (VA) and so enhance gas exchange
efficiency. If an area of regional
hypoventilation is small in relation to the
total pulmonary vascular bed, there is
little to no increase in pulmonary artery
(PA) pressure.3 When there is more
global alveolar hypoxia, such as at high
altitude or more extensive hypoxia with
or without hypercapnia in diffuse parenchymal and airways disease, HPV still
operates to optimize VA/Q matching.
However, with more of the vasculature
undergoing constriction it is less effective
in this function and results in increased
pulmonary vascular resistance (PVR) and
pulmonary hypertension (PH).3
The presence and contribution of
HPV to VA/Q matching and PH in
chronic lung diseases (World Health
Organization [WHO] Group 3) and the
extent to which it might be modified as
part of treatment in this setting is not
easily assessed. This is due to the fact
that other changes in the vasculature in
these conditions also increase vascular
resistance. Depending on the disease and
its duration and severity, these include
physical destruction and loss of vascular
bed with a decrease in total perfused
cross-sectional area, hyperinflation such
as with emphysema, reduction in local
tonic vasodilator generation and/or
increase in vasoconstrictor mediator production, and remodeling of existing
vessels with increased smooth muscle
mass and perivascular thickening leading
to luminal narrowing.
In this review, the present understanding of HPV in the normal and
diseased lung will be discussed with the
goal of understanding its contribution to
WHO Group 3 PH and its potential to
be targeted therapeutically or be altered
by treatments for these conditions.
Key Words—arterial hypoxemia, high altitude, hypercapnia, hypoxia, normoxia
Correspondence: [email protected]
Disclosures: Dr Swenson reports financial relationships with Cardeas, Boehringer Ingelheim, and Novartis.
CHARACTERIZATION OF HPV
Increases in PVR and PA pressure on
ascent to high altitude or exposure to
normobaric hypoxia universally occur in
humans and other mammals. HPV can
be detected with elevations in altitude as
low as 1600-2500 m or with reductions
in FIO2 to 0.15-0.18.4,5 The magnitude
of HPV (Figure 1) can vary almost
5-fold among healthy individuals,6 and
among species (Figure 2) in part related
to total pulmonary vascular smooth
muscle6,7 and with duration of hypoxia
(Figure 3) from minutes to several
days.7-9 HPV is the earliest mechanism
that elevates PA pressure and PVR with
hypoxic or high-altitude exposure. Ultimately, other mechanisms (perhaps
partly in reaction to the first elevation of
pressure initiated by HPV along with
greater cardiac output) such as activation
of pressure-independent hypoxiasensitive inflammatory and proliferative
pathways10 may contribute to sustained
PVR elevation and vascular remodeling.
The process of remodeling is initiated
as early as several hours at the level of
new gene transcription, such as for collagen and other growth factors,11 and
is generally established within days
to weeks of continuous alveolar
hypoxia.12-14
The ability to reverse the acute effects
of HPV by restoration of normoxia progressively diminishes with sustained
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135
patients, and the impact of aging on
HPV is also unknown.
The critical PO2 at the level of the
pulmonary arteriolar smooth muscle
which initiates HPV in a lung region or
the whole lung is a summation of the
effects of alveolar PO2 as set by inspired
PO2 and the ventilation-perfusion
(VA/Q) ratio, the bronchial arterial PO2,
and the mixed venous PO2.3 Because the
bronchial arterial circulation perfuses the
vaso vasorum of the pulmonary arteries
and arterioles, systemic arterial PO2 will
also influence HPV. Separate perfusion
of the bronchial artery in the sheep with
deoxygenated blood, while alveolar PO2
and systemic PO2 were held constant,
led to an increase in PA pressure.19 In
animal studies in which it is possible to
control and hold systemic arterial and
alveolar PO2 constant, reductions in
mixed venous PO2 sensed in the PA
cause vasoconstriction.20,21 The importance of mixed venous PO2 as a factor in
HPV may be magnified with exercise,
when mixed venous PO2 falls to very
low tensions as a result of high tissue
oxygen extraction and greater arterial
hypoxemia than at rest, but of the 3
contributions mixed venous PO2 likely
has the least influence.
Figure 1. HPV variability as assessed by PA systolic pressure response in normal humans to 4
hours of moderate hypoxia. Subjects noted by solid lines are subjects susceptible to HAPE
and show exaggerated HPV, while subjects without HAPE susceptibility (interrupted lines) have
lower HPV. (Grunig et al. J Am Coll Cardiol, 2000.)
hypoxic exposure. This decline in reversibility has been demonstrated as early as
8 hours9 and progressing through 1 to 3
days,15,16 (Figure 4) and becomes more
pronounced after 1 to several weeks of
hypoxic exposure.8,17,18 Although
changes in inspired oxygen remain
widely used to assess HPV, changes in
arterial oxygenation and acid-base status
always follow an alteration in inspired
oxygen, so that systemic effects such as
changes in central nervous system (CNS)
and autonomic nervous activity might
also contribute to the final pulmonary
vascular response. It would be useful to
employ a truly selective HPV inhibitor
or stimulator in vivo rather than use
changes in inspired oxygen, but all
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Advances in Pulmonary Hypertension
available pulmonary vasoactive agents
have actions elsewhere in the circulation
and brain, making them less than ideal
for this purpose.
Lowland species with stronger acute
HPV tend to develop greater PH with
chronic hypoxia than animals with
weaker HPV.12 Whether humans with
stronger HPV develop greater PH with
chronic hypoxia or other conditions predisposing to PH has never been studied,
but such a characteristic might underlie
those often labeled as having “out-ofproportion” hypertension in the face of
subsequent development of obstructive
sleep apnea, heart failure, emphysema,
and fibrotic lung disease. These conditions are more prevalent in older
Volume 12, Number 3; 2013
MECHANISMS OF ACUTE HPV
HPV is a complex process with elements
of its expression arising from multiple
points in the neuro-cardiopulmonary axis,
with variation in intensity and mechanisms over time.22 In addition to the
intrinsic hypoxic response of the pulmonary vasculature that can be elicited in
isolated pulmonary vascular smooth
muscle cells and vessels, there are
numerous extrinsic modulating influences
sensitive to oxygen in vivo that include
the vascular endothelial cells, red cells,
chemoreceptors, autonomic nervous
system, and lung innervation. The pulmonary circulation response to hypoxia is
characterized by contraction of smooth
muscle cells of the small pulmonary arterioles and veins of diameter less than
900 ␮m; the veins account for approximately 20% of the total increase in
PVR.23,24 At a regional level within the
lung vasculature the magnitude of HPV
may not be equivalent in all areas or static
over time.25-28 As a consequence of this
unevenness of regional HPV, some areas
of the vasculature may be more perfused
than others if they have a lower HPV
response. This appears to be the case
in those with a stronger global HPV
response and susceptibility to high
altitude pulmonary edema (HAPE).26,27
Although it is not generally thought that
hypoxia acts at the microvascular or acinar
level, pulmonary capillary endothelial
cells respond to hypoxia with membrane
depolarization,29 and this signal is propagated upstream and possibly downstream
to resistance arterioles and venules. As
yet, no evidence has been found for
capillary constriction with hypoxia,30
despite evidence that other vasoconstrictors are active at this level and in
surrounding parenchymal perivascular
cells that contain actin and myosin
microfilaments.31
HPV in intact animals and humans
appears to be fully expressed within 6 to
8 hours and has several temporal components. The first occurs within 5 minutes
with a half-time of about 30-90
seconds.32-35 A second phase of greater
pressure elevation (almost double) is
evident in humans and plateaus at 2
hours.35 In animal studies, further elevation of pressure develops over the next
6 to 8 hours.32 This has been confirmed
in studies of isolated pulmonary arteries,
lungs, or vascular smooth muscle cells
showing a third phase taking upward of
8 hours.36 The mechanisms behind these
differing time phases and differences
between in vivo and isolated lung and
vessel investigations have not been well
studied, but the isolated vessel studies
suggest the first phase is intrinsic calciumdependent smooth muscle contraction,
with the later phases representing the
summation of numerous other modulating influences acting on the smooth
muscle22,36 in a calcium concentrationindependent fashion as discussed below.
All of these differing hypoxic responses
are fully and immediately reversible with
return to normoxia if hypoxia is not
extended beyond several hours.
HPV at the Level of the Vascular Smooth
Muscle
There are several mechanisms involved
in HPV that are activated in parallel or
sequentially, leading to a critical increase
Figure 2. HPV in a variety of mammals showing baseline differences in normoxic mean PA
pressure and increases with acute hypoxia. (Reeves et al. Int Rev Physiol, 1979.)
of intracellular calcium and/or an
enhanced calcium sensitivity of the actinmyosin that initiates contraction,13,22 a
response opposite to that which occurs
in the systemic vasculature. Intracellular
calcium concentration is increased by
hypoxia-mediated inhibition of several
potassium channels, leading to membrane depolarization and extracellular
calcium entry through L-type channels,
and a release of calcium from the sarcoplasmic reticulum (SR), with further
influx through store-operated calcium
channels (SOCC), receptor-operated
calcium channels (ROCC), and transient
receptor potential channel 6 (TRPC6).
Figure 5 depicts the very complicated
multiple pathways by which intracellular
calcium in pulmonary vascular smooth
muscle is quickly altered by hypoxia to
initiate HPV. In addition, sensitivity to
calcium of the contractile elements is
enhanced via a hypoxia-induced increase
in Rho-kinase activity.37 The change in
oxygen tension that stimulates these
components of HPV is signaled by an
alteration in the redox status of the
smooth muscle cells.13,38 Whether an
increase or a decrease of reactive oxygen
species (ROS) is responsible for HPV
signal transduction is still under debate,
but a stronger case is emerging that
hypoxia increases mitochondrial ROS
generation as an upstream signal for
HPV.38 It is clear that high-altitude
exposure increases stable circulating
markers of ROS production, and persons
with higher HPV appear to generate
more ROS and less bioactive vasodilating nitric oxide (NO) species across
the lung.39
Endothelium-Dependent Modulation of
HPV
The pulmonary vascular endothelium
generates a variety of vasoactive medi-
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137
Figure 3. Species variability in severity of PH during exposure to chronic hypoxia. (Reeves et
al. Int Rev Physiol, 1979.)
ators that act in a paracrine fashion on
the surrounding vascular smooth muscle
cells. These include NO and prostacyclin
as vasodilators, and endothelin-1 acting
as a vasoconstrictor via binding to
endothelin-A receptors and a vasodilator
by binding to endothelin-B receptors
causing NO release.36 Isolated human
PA endothelial cells exposed to 3%
oxygen produce more hydrogen peroxide
and thus may also be a source for ROS
that initiate HPV.40 The endothelium
also produces carbon monoxide (CO) via
heme-oxygenase-2,41 which is upregulated by hypoxia.42,43 CO dilates vessels
by activating guanylate cyclase to generate cyclic guanosine monophosphate
(GMP) in a manner similar to NO.
Hydrogen sulfide (H2S), a strong
reducing agent, generated in hypoxia is
vasoconstricting in the pulmonary circulation by several not yet fully quantified
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Advances in Pulmonary Hypertension
mechanisms.44 It should be noted that
many of these “gaso-transmitters” alter
the concentrations of each other, making
it difficult to assess the contribution of
each to HPV modulation.45,46
Erythrocyte-Dependent Modulation of
HPV
Red cells may contribute to HPV and
pulmonary pressures in several ways.
Although hypoxia-mediated decrease in
deformability might reduce flow and
increase measured vascular resistance,47,48
direct measurements of human and other
mammalian red cells over a range of
PO2 from 120 to 47 mm Hg show no
evidence of significant deformability
changes.49 With elevations in hematocrit
with altitude, pulmonary vascular pressures increase. This is partly due to
increased blood viscosity and direct
increases in lung vascular resistance as
Volume 12, Number 3; 2013
shown by hemodilution studies at high
altitude in patients with chronic
mountain sickness50 and in animal
studies.51 Red cell-mediated changes in
PVR with hypoxia represent a balance
between those effects that are vasodilating and others that are
vasoconstricting. Direct endothelial cell
NO scavenging by oxyhemoglobin52 and
ROS generation by hypoxic red cells53
will enhance HPV. In contrast, the oxygenation dependent behavior of red cells
and hemoglobin that lead to
s-nitrosothiol release54 and NO generation from nitrite
with hemoglobin
55
desaturation will blunt HPV. Additionally, deoxygenated red cells also
release adenosine triphosphate (ATP),
which activates endothelial cell NO production via purinergic receptor binding56
and so act in a vasodilating fashion.
Finally, recent evidence that red cells
themselves express the endothelial
isozyme of nitric oxide synthase (eNOS)
and are able generate NO that escapes
intracellular hemoglobin binding57
needs to be considered. Similar to the
various and sometimes competing interactions of endothelial cell vasoactive
mediators on HPV, the contribution of
red cells is similarly complicated and
the net result on PVR may vary
depending on the degree and duration of
hypoxia.
Neurohumoral-Dependent Modulation of
HPV
The lung vasculature is innervated by
sympathetic noradrenergic fibers from
the large conduit arteries and veins down
to 50 ␮m vessels in larger species such as
man and dogs, but much less so in
smaller species.58 In addition to release
of norepinephrine with sympathetic activation causing vasoconstriction via
alpha-1 adrenergic receptors on vascular
smooth muscle, there is release of other
opposing vasodilating neurotransmitters
such as neuropeptide Y and vasoactive
intestinal peptide.58 Additionally, there is
opposing NO-dependent vasodilating
parasympathetic innervation.59 Arterial
PO2 is gauged by the peripheral chemoreceptors, which project afferents to the
medullary cardiovascular control areas in
the brain stem in addition to the respiratory control center, activating both
parasympathetic and sympathetic outflow
to the lung. Denervation of the carotid
bodies and loss of afferent input from
the peripheral chemoreceptors increases
HPV.60,61 The efferent arc of this
response is not well defined but is conveyed by the vagus nerve. Vagotomy
reduces HPV.62,63 Studies using atropine
and propranolol suggest that vasodilating
parasympathetic activity is more dominant than sympathetic activity in HPV
inhibition.63,64 Other data suggest a
stronger sympathetic contribution.65
In regard to neurohumoral mediation
of HPV, susceptibility to HAPE is characterized by a very exaggerated HPV66
and a much greater generalized sympathetic nervous system activation to
hypoxia.67,68 However, not all studies
find evidence for neural modulation of
HPV.69 The reason for this discrepancy
is not clear, but those studies finding no
effect on HPV have employed receptor
blocking drugs rather than neural
pathway interruption. It is entirely possible that peripheral chemoreceptormediated modulation of HPV may
involve other neurotransmitter release via
the lung innervation besides catecholaminergic or cholinergic agonists as
described above. In humans, the association of stronger hypoxic ventilatory
response (HVR), which is almost wholly
a peripheral chemoreceptor mediated
response, with weaker HPV supports the
majority of the animal work.70
The pulmonary vasculature expresses
adrenergic and cholinergic receptors, as
well as other receptors, including those
for thyroxine, angiotensin II, adenosine,
natriuretic peptides, and estrogen. Thus
it can respond to circulating vasoactive
mediators with dilation by epinephrine
via beta-2 receptors,58 estrogens71 and
natriuretic peptides,72 and constriction
with angiotensin,73 adenosine,74 and thyroxine.75 The full neurohumoral
component of the lung vascular response
to hypoxia is often neglected in discussions of HPV.
Other Modulating Influences on HPV
Individual genetic background76-78 and
a history of familial susceptibility to
HAPE or PH79-81 also contribute to the
strength of HPV. Acid-base status and
carbon dioxide have a considerable
Figure 4. Time course in PA pressure (systolic, mean, and diastolic) and wedge pressure in
humans with acute hypoxia showing lack of complete resolution of HPV with return to normoxia after 8 hours. (Dorrington et al. J Appl Physiol, 1997.)
influence on HPV, with alkalosis and
hypocapnia both diminishing HPV and
hypercapnia increasing HPV.82,83 Thus
subjects with stronger ventilatory
responses to hypoxia will not only
maintain higher alveolar PO2, but also
will have less HPV due to their greater
hypocapnic alkalemia at any given
altitude or FIO2. Increasing lung volume
by positive end-expiratory pressure in the
range of 8-10 cmH2O does not reduce
HPV.84 Pre-existing high arterial wall
tension also diminishes HPV.85 Lastly,
animal studies with low-grade infection
or inflammation show that circulating
and locally produced inflammatory leukotrienes, thromboxanes and cytokines,
(ie, tumor necrosis factor, interleukin6),86-89 or activation of their receptors in
the vasculature90 appear to modulate
HPV (both negatively and positively).
Hypoxia-Regulated Gene Transcription
Factors and HPV
The study of HPV continues to identify
new sensing, signaling, and effector
mechanisms and pathways. The most
recent are the hypoxia-inducible factors
(HIFs), transcription factors that alter
the gene expression over 1000 genes
involved in promoting tolerance to
hypoxia.91 Additionally, HIF activates
a number of inflammatory signaling
molecules such as nuclear factor kappa
beta.10 In this fashion, hypoxia and
inflammation may be inextricably
linked in chronic lung diseases. In 2 rat
strains with differing pulmonary hypoxic
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139
reduce and increase HPV respectively,98,99 possibly via altered HIF
metabolism100 involving prolyl hydroxylases, the O2-sensitive enzymes that
degrade HIF and require iron. HIFmediated gene transcription also drives
much of the longer-term remodeling of
the vasculature.14
Figure 5. Diagram of pulmonary arterial smooth muscle cell intracellular calcium ([Ca2⫹]i)
pathways with acute hypoxia. Pathways that increase ([Ca2⫹]i are shown on the left, while
those that decrease ([Ca2⫹]i are on the right. Hypoxia can activate (green) or inhibit (red) these
pathways. Whether these effects are probable, possible, or speculative is indicated by solid,
dashed, and dotted lines, respectively, as shown in the key at the bottom. With respect to
plasma membrane and associated cytosolic signals, TASK-1 is TWIK-related acid-sensitive
channel-1;VOCC, KV, ClCa, SOCC, NSCC, and ROCC indicate voltage-operated Ca2⫹, voltagedependent K⫹, calcium-dependent Cl, store-operated Ca2⫹, nonselective cation, and receptoroperated Ca2⫹ channels, respectively. NCX, Na-Ca exchanger; A, agonist; R, receptor; PLC,
phospholipase C; PIP2, phosphatidylinositol 4,5-bisphosphate; IP3, inositol 1,4,5-trisphosphate;
DAG, diacylglycerol; PKC, protein kinase C; PMCA, plasma membrane Ca2_-ATPase. With
respect to sarcoplasmic reticulum (SR) and associated cytosolic signals, SERCA is
sarcoplasmic-endoplasmic reticulum ATPase, IP3R is IP3 receptor, RyR is ryanodine receptor,
STIM1 is stromal interaction molecule 1, and cADPR is cyclic ADP ribose. With respect to
lysosome-like organelles (LLO) and associated cytosolic signals, NAADP is nicotinic acid
adenine dinucleotide phosphate, HCX is H-Ca exchanger, and HA is H⫹-ATPase. Mito, mitochondria. (Sylvester et al. Physiol Rev, 2012.)
responses, HIF-1 activity and HIFmediated protein expression were higher
in the strain with greater PH.92 In contrast, mice with heterozygous HIF-1
alpha deficiency have weaker acute and
chronic hypoxic responses in isolated
pulmonary vascular smooth myocytes
and pulmonary vessels than wild-type
mice.93,94 Further supporting pharmacological evidence for HIF-1 alpha
mediation of HPV was demonstrated in
mice by reduction in hypoxic PH95 with
140
Advances in Pulmonary Hypertension
digoxin, a known inhibitor of HIF-1
alpha transcriptional activity.96 At
present it is not fully clear how HIFdependent gene transcription affects
HPV, but it likely involves upregulation
of TRPC on the vascular smooth
muscle cell membrane97 and alterations
in pulmonary vascular smooth muscle
calcium signaling.95 Iron is emerging as
a critical element in HPV and pulmonary vascular changes with hypoxia.
Iron supplementation and iron chelation
Volume 12, Number 3; 2013
RELEVANCE OF HPV IN
HEALTH
At low altitudes where humans evolved,
it would appear that the sensitivity to
oxygen of the lung vasculature evolved
along with HCPV as mechanisms101 to
shift blood flow from poorly or nonventilated lung regions with localized airway
or airspace pathology in post-fetal life to
better ventilated and healthy areas as
elegantly advanced by von Euler and
Liljestrand1 in their landmark paper.
Based on whole lung pulmonary vascular
responses to changes in alveolar PO2 and
PCO2, Dorrington et al101 modelled
that improvements in VA/Q matching
and gas exchange by HPV are most
important in the lower range of VA/Q
(0.01 to 1.0), and that HCPV has its
greatest impact in the VA/Q ratio of 1
to 100. The ability of both HPV and
HCPV to divert blood flow and minimally raise PA pressure are more
effective when the area of VA/Q mismatching is smaller.3 From an
evolutionary perspective, HPV may have
conferred a survival (and ultimately a
reproductive) advantage for individuals
with severe pneumonia or thoracic
trauma with acute pneumothorax by limiting the degree of severe life threatening
shunt-induced hypoxemia. This may still
be the case even in the modern clinical
era of effective antibiotics and surgery
before patients can be treated.102
Alternatively, others have argued it may
be simply a vestige of fetal existence. In
this regard, HPV maintains a high vascular resistance to limit blood flow in the
nonventilated lung (in combination with a
patent ductus arteriosis and foramen
ovale) to allow an 80% to 90% right to
left shunt to provide more blood flow to
the placenta and better oxygenated blood
to the developing brain.103 However,
many other aspects of the fetal lung also
contribute to higher PVR, including its
liquid-filled nonventilated high volume
state, lack of surfactant, relative hypercapnia and acidosis, a limited slower
growing vascular bed relative to the faster
growing airway and parenchymal
structure, lesser endothelial vasodilator
generation, greater endothelial vasoconstrictor production, and lack of bronchial
epithelial NO generation.103,104 In fact,
HPV in the fetal lung does not appear
until the middle of the third trimester of
gestation. Thus, it would appear to reduce
PVR and prepare the pulmonary circulation to accommodating the entire
cardiac output at birth as the ductus arteriosis closes and the lungs are ventilated
and assume gas exchange duties from the
placenta.104 In this sense, HPV should
perhaps more correctly be renamed
“oxygen-dependent vasodilation.” If
strong HPV is an evolutionary advantage
in utero, then one might predict a fetal
survival disadvantage in Tibetans, who
have much lower HPV as adults than
other populations.105 Yet, birth rates and
neonatal survival in this population exceed
those of newcomers to high altitude.106
RELEVANCE OF HPV IN
CHRONIC LUNG DISEASE
In the setting of chronic lung diseases,
several questions regarding HPV are
relevant. The first is whether it is present
and what is its magnitude. The second is
how useful is HPV in maintaining as
optimal state of gas exchange as possible.
The third is what benefit or harm is
realized with therapies that either
directly alter HPV or alter it as a consequence of targeting some other aspect of
the disease.
In answering the first and second
questions, if the model of chronic global
hypoxia107,108 such as that occurring
with long-term high-altitude exposure is
any answer, then the finding that after
several weeks at high altitude there is
little pulmonary vasodilation with
breathing oxygen would suggest HPV
should not be present to any great extent
in chronic hypoxic lung diseases.8,105
Some patients with chronic obstructive
pulmonary disease (COPD) and chronic
bronchitis given high levels of inspired
oxygen acutely show deterioration in
VA/Q matching suggestive of inhibition
of HPV,109 but this has not been shown
in every case.110 Although these data
and data from other studies have been
used to support the idea that HPV is
contributing to the high vascular tone, in
studies with right heart catheterization
there is minimal reduction in PH with
supplemental oxygen therapy either
acutely or chronically in most patients.112
This apparent paradox might be
explained either by there being only
small regions of lung having any HPV,
such that gas exchange deterioration still
takes place, but reduction in overall PA
pressure is minimal. A second possibility
is that simultaneous increase in local
carbon dioxide brought about by an
increase in blood flow with release of
HPV113 in these areas leads to counteracting HCPV and limits the fall of
pulmonary artery pressure. Despite the
equivocal salutary effects of short-term
oxygen, it is clearly established that
chronic supplemental oxygen extends life
in hypoxemic COPD patients and that
this is associated with a mild
improvement in pulmonary hemodynamics in those using continuous
oxygen.114 In patients exhibiting a significant drop in mean PA pressure of
⬎5 mm Hg the benefits were
greatest.115 The benefits of oxygen
therapy are multiple and stem largely
from improvements in systemic oxygenation. However, the pulmonary vascular
effects of oxygen in the long run may be
related to HPV in much the same way
that all models of chronic hypoxic PH in
animals and in humans relocating from
high altitude to sea level ultimately show
regression of PH after return to normoxia.107,108
In interstitial lung disease the story is
different. Two studies have shown no
significant vasodilator response or change
in VA/Q matching with 100%
oxygen,116,117 and chronic home oxygen
administration does not alter mortality in
fibrotic lung diseases.118 Therefore, from
these data it appears that HPV does not
contribute greatly to PH in interstitial
lung disease.119
HPV can be decreased for treatment
purposes by a variety of pharmacological
agents that act on many of the endothelial cell-derived modulators of PVR,
signal transduction pathways, and gene
transcription discussed above, including
NO, nitrates, calcium channel blockers,
phosphodiesterase 5 inhibitors, endothelin receptor blockers, prostacyclin
analogs, soluble guanylate cyclase (sGC)
activators, angiotensin converting
enzyme inhibitors, and some carbonic
anhydrase inhibitors, such as acetazolamide.22 While these drugs certainly
inhibit HPV at high altitude and some
are quite useful to prevent and treat
HAPE and high-altitude PH,66 it
must be appreciated that none of
these agents are truly specific HPV
inhibitors, except perhaps for acetazolamide.120 Their pressure-lowering
effects act on intracellular calcium signaling, mediator release, or receptor
engagement, some of which may be
common to HPV.
Several of these drugs that have been
tested in patients with COPD and idiopathic pulmonary fibrosis (IPF) (as will
be discussed in the 2 accompanying
articles in this issue) may impair gas
exchange efficiency by inhibiting HPV
and/or by general vasodilation more in
areas of shunt or low VA/Q. For
instance, with oral sildenafil in COPD,
PA pressure is lowered at equivalent
exercise intensity,121 but in some arterial
PO2 falls. In those that derive an
exercise and pressure-lowering effect, the
drop in oxygenation could be likely prevented by small increases in their
supplemental oxygen flow rate. Whether
this is a tenable approach and might
increase exercise capacity requires formal
testing. (Note added in proof: A recent
study by Blanco et al. (Eur Respir J.
2013;42:982-99) showed no benefit of
sildenafil to a comprehensive pulmonary
rehabilitation program in exercise
endurance or quality of life.)
Lastly, the adverse effect of giving
these agents orally might be mitigated by
giving them by inhalation in order to
vasodilate preferentially in the better
ventilated regions and not worsen VA/Q
mismatch such as with iloprost.122,123
CONCLUSION
The search for more potent and selective
vasodilators for the treatment of nonhypoxic forms of PH grows apace, and it is
likely that most will have the ability to
inhibit HPV. It may be useful in
selected patients without an obvious ventilatory limitation at maximal exercise to
Advances in Pulmonary Hypertension
Volume 12, Number 3; 2013
141
measure how much both oxygen and
medications lower PA pressure and
restrict their use to those with reductions
in PVR associated with increased functional capacity or decreased dyspnea
while adding or increasing supplemental
oxygen as needed to maintain acceptable
arterial oxygenation levels.
There is considerable diversity among
WHO Group 3 PH patients and within
the individual diagnostic subsets comprising this group. While HPV may play
a variable role in the pathogenesis of PH
in Group 3 patients, and treatment of
hypoxia remains an important therapeutic consideration, the heterogeneity of
this population poses significant challenges for development of effective
treatment.
Multiple pathways associated with
HPV, HCPV, other VA/Q matching
mechanisms, hyperinflation, inflammation, vascular remodeling, and
parenchymal loss contribute to the development of PH and pose significant
challenges for identification and evaluation of potential therapeutic agents.
Understanding these mechanisms and
identifying patient groups where similar
pathways predominate is a critical component in the evolution of treatment for
WHO Group 3 PH.
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e52248.
PULM ONA RY HY P E R T E N S I O N R O U N DT A B LE
COPD, IPF, and Pulmonary Hypertension: A Clinician’s
Dilemma
On October 9, 2013, a group of experts met by telephone to discuss PH in the setting of COPD and IPF. The group consisting
of guest editor of this issue Jeffrey Edelman, MD, Head, Lung Transplant Program VA Puget Sound Health System, University
of Washington; Deborah J. Levine, MD, Director, Pulmonary Hypertension Center, University of Texas Health Science Center
at San Antonio; James Klinger, MD, Director, Rhode Island Hospital Pulmonary Hypertension Center; and Robert Schilz, DO,
PhD, Director of Pulmonary Vascular Disease and Lung Transplantation, University Hospitals, Case Medical Center; provided
perspective and insight into how clinicians can approach these patients most effectively.
Dr Edelman: I thought it would be reasonable to discuss: when to consider PH
in COPD and IPF; the approach to
evaluation (such as when to obtain right
heart catheterization); and other comorbidities to consider when PH is present
in the setting of these conditions as well
as the impact of coexistent COPD with
pulmonary fibrosis. Additionally, we
shall discuss whether or not PH is, in
and of itself, an indication for treatment
or more of an indicator of prognosis in
these patients.
Dr Schilz: This topic was discussed in
depth at the World Symposium for Pulmonary Hypertension in Nice, France
this year, summarizing this topic in a
way that a lot of us think about WHO
Group 3 disease. I think that we know
that there are a lot of data and information on what typical elevations of
pulmonary pressures are in the major
diseases that comprise Class 3, especially
COPD, IPF, and sleep apnea. And in
the grand scheme of things, those pressures are typically pretty modest if you
go back and look at a number of the
very key and important studies.
Dr Edelman: Knowing that these
patients are at risk for pulmonary hypertension and knowing the size of these
populations, I’d like to start by asking
when you think about pulmonary hypertension in this population.
Dr Schilz: I think we can take a lot of
lessons from the literature in helping us
understand about PH and COPD. A
widely quoted study by Chaouat, sampling almost 1,000 patients consistently
reported that mean pulmonary pressures
were generally less than 20, even in
patients with advanced COPD and
respiratory failure. And only about 3
percent of patients had means that typically were over 35. And even less than
that had means that were typically in the
40 to 50 range or greater than we usually
see in PAH patients. Similarly, findings
are reported in transplant or lung volume
reduction patient populations. . . So in
general, significant elevation in pulmonary pressures, which usually
characterize our PAH patients, are typically not seen in COPD.
Dr Klinger: I think that’s an important
point to focus on. One of the ways to
put it in perspective is that if we look at
the average mean PA pressure in registries of people that have Group 1
pulmonary arterial hypertension, we’re
usually talking about values in the 50 to
55 mm Hg range. Usually in the chronic
lung diseases, people get excited or at
least interested in pulmonary arterial
pressures when we’re seeing systolic PA
pressures that are 55 to 60 mm Hg,
which gives them a mean PA pressure,
as Bob was saying, around 25 or 30. So
they’re really kind of separate groups.
Disclosures: Drs Edelman and Levine report no conflicts of interest. Dr Klinger has disclosed financial
relationships with Actelion, Bayer, Gilead, Ikaria, and United Therapeutics. Dr Schilz has disclosed
financial relationships with Actelion, Bayer, Boehringer Ingelheim, GeNo, Gilead, GlaxoSmithKline,
Ikaria, and United Therapeutics.
That is to say, most of the PH that we
see associated with chronic lung disease
is right at the borderline of the cutoff for
a definition of pulmonary hypertension,
whereas most of the pulmonary hypertension we see in Group 1 is twice as
high as the mean cutoff level for pulmonary hypertension.
Dr Levine: I agree, Jim. However, when
you look at patients with end-stage lung
disease (more with ILD than COPD)
when they come for lung transplant evaluation, there is a small proportion who
come with very, very high mean pulmonary artery pressures. Most of them
have mild or even moderate pressures as
you are alluding to, but this small but
significant portion of patients have severe
pulmonary hypertension. This group of
patients is one group that can really be
separated out from the other patients
with end-stage lung disease and we may
treat them differently based on that.
Dr Schilz: It is interesting, however,
that in spite of that, historical epidemiology continues to underscore the fact
that even modest amounts of elevations
of pressure in the lung, when associated
with advanced COPD or IPF are associated with worse outcomes.
Dr Levine: Absolutely.
Dr Schilz: The existing data summarized point to 2 important trends. First,
that patients with COPD and PH
appear to comprise 2 different populations: one with very modest (by PAH
standards) pressures and one with mean
Advances in Pulmonary Hypertension
Volume 12, Number 3; 2013
145
pulmonary pressures approaching that
typically seen in PAH populations.
Second, that having elevated blood pressures in the lung, in the presence of
COPD seems to be associated with a
worse outcome. I think the latter has
driven therapeutic trials in this area to
date that have been tried in these groups
so far, quite honestly, unsuccessfully.
Dr Edelman: I think we all see enriched
populations of patients with more
advanced disease. But if you’re treating
patients outside of the context of a PH
program or a transplant program or an
ILD program, which patients should you
think about evaluating for pulmonary
hypertension and how? I mean, are there
red flags that would lead one to say,
“Hey, I should start and get an echo for
this person,” or do we get them for all
patients? How do we decide when to
start thinking about PH in these
patients?
Dr Levine: We can use pulmonary
function tests to help us in this regard.
One of the values we can look at in
these patients is the DLCO. If there is a
disproportionate decrease in the DLCO
(as compared to the rest of their pulmonary function tests) and they are
more hypoxemic than you feel they
should be based on other indices (CT
scan, lung volumes, VQ scan), it may
trigger you to consider the pulmonary
vascular disease playing a more significant role.
Dr Schilz: Yes, I think that’s a great
point and suggests another topic that I
wanted to add—that was the entity that
all of us have seen over time that seems
to find its way into pulmonary hypertension clinics—the fibrotic COPD
patient— described in a systematic way
in Chest by Mejı´a et al. in 2009. These
patients have abnormally low DLCO,
profound parenchymal destruction and
significantly elevated pulmonary pressures with a modestly affected FEV1.
From my perspective these patients are
disabled more than I think they ought to
be, based on their FEV1s, based on their
conditioning, and so forth. They appear
much more like a patient with PAH. To
answer your question directly, if someone
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Advances in Pulmonary Hypertension
is more dyspneic than you think they
ought to, they perhaps deserve a different look.
Dr Klinger: I think that’s the key that
we would want to get out as a message.
That is to say, the time to evaluate the
patient is not so much dependent on
their echocardiogram or even their estimates of their PA pressure, but rather
how those numbers correlate with their
performance. Patients with mild lung
disease and high PA pressures that are
associated with dyspnea that’s difficult to
explain are the ones that we really get
concerned about. The issue often is
whether the pulmonary hypertension is
part of the chronic lung disease, or an
independent disease process, or as I
think most of us are coming around to,
an exaggerated pulmonary hypertensive
response to an underlying lung disease.
We ask ourselves, do those people have
the ability to be improved upon if we
treat their pulmonary hypertension.
When their dyspnea becomes out of proportion to their underlying lung disease,
I think that’s when most of us start
looking for secondary causes and frequently pulmonary hypertensive disease.
Dr Schilz: Jim, I couldn’t agree more.
Another factor that draws my attention
in this population is an abnormal right
ventricle. But certainly, we all know the
importance of the right ventricle. And
any right ventricle that starts getting
dilated gets my attention, as well. And
again, that’s not a common finding in
most COPD patients, even with
advanced COPD. So a patient with a
performance status that is not explained
by their FEV1, coupled with an enlarged
RV, in my mind should make us think
about pulmonary hypertension.
Dr Klinger: Yes, I think that’s very
important. We frequently look for cor
pulmonale and if we see it, we get much
more concerned about either chronic
CO2 retention or nocturnal hypoxemia
or other forms of hypoxia that are not
well-appreciated. Frequently, we see this
in combination with polycythemia or at
least elevated hemoglobin levels. That
combination really needs to be looked at
carefully in such a way that if we can
Volume 12, Number 3; 2013
reverse the hypoxia, the hypercapnia, and
the underlying polycythemia, a lot of
that cor pulmonale and pulmonary
hypertension will improve on its own.
Dr Edelman: So one issue there that
you’ve touched on is that the first
response to seeing evidence of pulmonary hypertension is to think about
what other comorbidities may be contributing. These may include, hypoxia,
hypercapnia, chronic thromboembolic
disease, left heart disease, collagen vascular disease, sleep disordered breathing,
and if the patient is still smoking,
perhaps carboxyhemoglobinemia. Bob,
you also used the term “fibrotic COPD.”
I think about that as COPD coexisting
with pulmonary fibrosis, particularly that
setting where you may have upper lobe
emphysema and lower lobe pulmonary
fibrosis. In effect you have different hits
to the pulmonary vascular bed with “offsetting” impact on lung compliance, so
that your spirometry numbers and your
lung volume numbers may look relatively
normal, but the telling factor is the
hypoxemia, the low DLCO, and the
poor exercise tolerance.
Dr Klinger: Yeah, this is a very interesting group of patients. Just by
coincidence, I literally saw this guy yesterday in the office who had worked out
for a professional football team nearly 50
years ago but now is extremely limited.
We haven’t had a chance to get all his
records yet, but by report, he’s got
normal PFTs. His FEV1, FVC, and
TLC are all within 95 to 105 percent of
predicted. He has no obstructive defect
at all, but he has fibrosis and emphysema
on his high res CT scan and his DLCO
is 8% of predicted. His RV systolic
pressure on echocardiogram is estimated
to be 89 mm Hg and, interestingly
enough, he’s got a preserved right ventricle.
I think he is kind of a poster child
of this disease that has been characterized somewhat as a new entity and
that is referred to as combined pulmonary fibrosis and emphysema. This is
an unfortunate progression of disease in
somebody that’s got underlying
emphysema that results in fibrosis of the
healthy parenchyma and then, of course,
continued destruction by emphysema of
the rest of the parenchyma, leaving
essentially very little gas exchange surface
and probably very little pulmonary circulation for the blood flow to go through,
so they’re really in a very bad situation
with very little respiratory reserve.
Dr Schilz: These can be very ill
patients. But they tend to show up in
our clinic just as you and Jim have
pointed out. Their PFTs are often modestly down. I see a lot of FEV1s in this
group of 60 –70%. But as you say, when
you look at the CT scan they demonstrate profound parenchymal damage and
distortion, and when you look at their
performance on exercise and their
desaturation with exercise, they’re often
very hypoxic as well. I think this is a
very interesting and unique group, but I
think an important group to talk about.
It has been characterized and they do
tend to show up in specialty pulmonary
hypertension clinics.
Dr Klinger: Yes, absolutely.
Dr Schilz: Everyone has brought up
several concepts that, I think, may guide
the next phase of our discussion. We all
understand that typical levels of pulmonary hypertension that accompany
pulmonary disease tend to be modest at
best, but small subpopulations can
achieve presssures typically seen in PAH.
Some of these patients may have profound parenchymal lung destruction.
This suggests a possible separation of
these populations into logical groups
based on high vs low mean PAP and
significant vs modest parenchymal lung
disease.
We all go through the exercise of
separating comorbidity from cause in our
PAH patients. We know that the
importance of separating out coexisting
disease with true idiopathic patients is
something that we need to do in the
setting of PAH. Let us consider the following theoretical COPD patient (not
one of these fibrotic COPD patients): a
patient with an FEV1 of 70%; no significant emphysema on imaging; expected
DLCO; absence of profound exercise
desaturation; and a mean pulmonary
arterial pressure of 50 or 55 mm Hg. In
the absence of left heart disease I think
that most of us would suggest that this
patient has two diseases: PAH and
COPD. This type of discussion comprised at least part of the discussion in
the World PAH Symposium. We all
recognize that comorbidities can exist
and that by definition, part of our
patient population, if they share risk
factors and demographics, will have
COPD or ILD, even though they have
truly IPAH as well.
Dr Klinger: Yes. I think that’s a point
worth discussing. In the REVEAL
Registry, for example, where patients
are referred in from pulmonary hypertension centers, about 18% were reported
to have COPD as a comorbidity. So it’s
definitely out there. I think in the
general population, the incidence of
COPD is about the same, it’s around
12% or so.
Dr Schilz: Exactly.
Dr Klinger: It’s possible that there is a
higher incidence of COPD comorbidity
in Group 1 PAH, although we probably
don’t have the data to say that. But I
think it bears keeping in mind that at
least, 1 out of 5 or 6 patients with pulmonary hypertension is going to have
COPD. So we are frequently faced with
the task of deciphering whether we are
seeing a PAH patient with COPD or a
COPD patient that has pulmonary
hypertension.
Dr Levine: And this may be where
these patients with end-stage lung
disease and very high pressures come in.
They have Group 3 disease, but still
have very high pressures. So this is what
this special population may be.
Dr Schilz: Yes I agree. These concepts
formed the basis of significant discussion
at the most recent World Pulmonary
Hypertension Symposium in Nice.
The literature-based discussion identified groups with very severe lung disease
and very high mean PAP as an “out
of proportion” group versus an “inproportion” group (pardon my
grammar), and then explored the
concept of mild comorbidities in the
setting of what truly may be IPAH. This
structure led to a very productive discussion, in my opinion.
Dr Levine: It is very important to
everyone treating all three types of
patients: ILD, COPD, and PAH
patients. In terms of evaluation, as well
as management, the possibilities of therapies are going to be quite different. So
I think it will be very interesting to hear
how that discussion at the World Symposium proceeded.
Dr Schilz: The World Symposium consensus statement will be forthcoming
and I believe will be useful in this
regard. I’d like to turn to a survey, which
a number of us filled out, and that was
ultimately brought forward in Respiratory
Medicine in 2010, by one of our colleagues, Omar Minai. And if you’ll
remember, this was a survey of PH and
lung disease. There was a general
opinion that PH in the setting of lung
disease carried a poorer prognosis. Most
people felt that oxygen was important in
hypoxic patients. It was interesting that
the thought, at least among people who
treated PAH, was that there certainly
would be some groups that they felt
deserved closer evaluation or perhaps
deserved treatment.
Dr Levine: It would be very interesting
to know the numbers in that, in terms of
what people called out of proportion
PH. Was that issue brought up in the
survey?
Dr Schilz: Yes, it was. And so of the
responders, the question paraphrased
was, when would you consider prescribing PAH medicines? Obviously this
may represent off-label prescription.
About 30 – 40% of people said they
would when they had very severe pulmonary hypertension, persistent
pulmonary hypertension in spite of
oxygen administration, significant functional limitation, or “out of proportion
PH” without an obvious qualifier on the
degree of PH.
Dr Levine: I think one of the questions
is “Do we have a definition for ‘out of
proportion’ PH?”
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147
Dr Schilz: Perhaps with the publication
of new consensus statements in the
upcoming months.
Dr Levine: Okay.
Dr Edelman: I think that’s easier to
conceptualize, but harder to define by
numeric criteria. But I think it will be
important to have that going forward,
as it may help to define patients for
inclusion in clinical trials, so we can
start to evaluate whether there are subpopulations that may benefit from
treatment.
Dr Schilz: I think that thresholds as you
mention are critical for defining investigation and may be possible utilizing
current literature and distributions of
pulmonary pressure elevations in the
setting of parenchymal lung disease.
Resting pressures of less than 25 mm
Hg at this time can be excluded as
normal. (Note that I have chosen not to
discuss exercise pressures, which represent yet another discussion). Jim, you
brought up before that mean PAPs of
50 mm Hg or more are unusual but
serious. If we start stepping back—a
mean of 45, probably significant—a
mean of 40 . . . and if we get down to a
mean of 35, that’s when you start getting
the tail end of the normal distribution of
what would be expected in the normal
end-stage patient with severe ILD or
COPD. These are the kinds of issues
that were discussed at the Worlds. And
so drawing the line somewhere below 50
but certainly in that 35, 40, or 45 range,
I think makes some deal of sense when
we know the normal distribution of elevations of pressures that have been seen
in the literature.
Dr Levine: But I think that’s definitely
progress from where we were previously.
If we have at least established a baseline
which most people call normal, then this
work toward standardization is going in
the right direction.
Dr Klinger: I would just caution that
there is a very slippery slope here to
believe that there is a kind of a cutoff
level or a threshold where the pulmonary
hypertension is out of proportion and
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Advances in Pulmonary Hypertension
should be thought of as a separate
disease. You still have a very high
number of patients in that chronic
disease population that would fit that
threshold and absolutely no data anywhere, at least that I’m aware of, to say
that there are situations where you can
actually make people better by treating
their pulmonary hypertension when
it’s associated with chronic lung
disease.
Dr Schilz: Jim, that’s a great point. I
think ultimately, before we’re done, we
should talk a bit about the attempts of
treating so far.
Dr Edelman: Before we move to
treatment, I want to ask about one other
line to draw, so to speak. We talked
about mean pulmonary artery pressures
quite a bit in thinking about different
populations. And a mean pulmonary
artery pressure implies that you’ve had a
right heart cath. And so in these patient
groups, when do we move to right heart
catheterization? It may not be everybody
and it may not be everybody with an
abnormal echo. The question is: are we
going to identify patients where there’s
going to be some kind of alteration in
our approach as a result of a right heart
catheterization?
Dr Schilz: Those are great, great questions, Jeffrey. I see a number of patients
for advanced surgical options for
advanced parenchymal lung disease
either transplant or LVRS. These
patients in general are cathed because
an alteration in the approach may be
dictated by elevated pulmonary pressures.
It is a routine part of that evaluation.
Clearly just the presence of parenchymal
lung disease does not justify RHC in
all patients. I consider right heart cath
when I can’t explain disability and I’m
looking for alternate factors— usually in
a patient that has an abnormal RV. A
lot of these patients may also have
multiple risk factors, at least in COPD,
for coronary disease. I know that each
and every one of you have likely
obtained right and left heart catheterization and found 90% LAD occlusions
or heart failure that you didn’t expect.
These issues can be effectively treated.
Volume 12, Number 3; 2013
Dr Klinger: Bob, that’s a really interesting issue. Normally in our approach
to right heart cath for PH, the idea is
we’re doing the right heart catheterization with the expectation that when
we rule out other causes of elevated PA
pressure we’re going to start treatment
for PAH. But in the patient with fairly
advanced or moderate underlying lung
disease, we’re not sure if we’re going to
treat the PAH, even if it’s really there on
right heart cath.
Dr Schilz: No, you’re right.
Dr Klinger: There is, of course, something else that we might find on the
right heart cath, such as diastolic dysfunction, or other diseases that we think
would be amenable to other treatments
or an explanation for their underlying
pulmonary hypertension.
Dr Levine: I agree. We know that in
many patients with lung disease, the
echo is far off when compared to the
right heart catheterization. Remember
Dr. Selim Arcasoy’s study on ILD
patients at transplant, comparing the
echo findings to those with right heart
catheterization? The echo pressure was
higher in some patients and lower in
other patients. So you may use the RHC
to not only rule in PH, but also to say,
“Hey, there really is no PH here, so we
may need to look elsewhere for causes of
their severe dyspnea or hypoxemia.”
Dr Schilz: Prognostically, you do have
information that says that even if you
get PH which is “expected,” that implies
a worse course for a patient. That may
change your timing on transplant or
other interventions, or your perspective
on LVRS and so forth. Data from the
studies that we’ve done so far do not
appear to support the use of PAH drugs
in these patients. Patients with very
high pulmonary pressures and parenchymal lung disease represent a
population that has not been studied
rigorously but one that really most
urgently deserves careful investigation.
Interestingly, some of the experimental
initial phases of inhaled nitric oxide are
starting to include some of these populations right now.
Dr Edelman: I think in the context of
this discussion, one important point is
that when we’re talking about
PH-directed treatment in these groups,
what we’re really talking about is trying
to think about populations for whom
clinical trials would be appropriate.
We don’t really have evidence supporting
PH-directed therapy in these population
groups at this point. I’m wondering
also what the approach is in clinical
practice right now. What do we do
when we find these patients who we
think have PH that’s “out of proportion”? We do a diligent search for
other comorbidities and associated conditions. We think about transplant. Do
we have a discussion about prognosis?
Do we consider PAH drugs or do we
look at the evidence and say, “there’s
not a whole lot of evidence base for
treatment.”? There’s not much in the
way of consensus in clinical practice. I
think if you look even at the most
recent guidelines for treatment of IPF,
there is still a little wiggle room left
and there’s a statement that PH
treatment may be appropriate for a
minority of patients. And the focus is
largely on PDE-5 inhibitors, particularly
sildenafil based on recently reported
results of the STEP-IPF trial. And
then the last thing to think about is in
the absence of evidence or consensus, do
we do empiric trials of treatment for
individual patients or is that fair to
patients?
Dr Klinger: Yes, so probably not. Not
only do we have little information to
suggest that most of our therapies are
not helpful, but we actually have
accruing information to suggest that
most of the pulmonary vasodilators that
are available now to treat pulmonary
hypertension when applied to people
that have chronic lung disease are
capable of doing harm, both in terms of
worsening oxygenation and decreasing
quality of life. In fact, there are some
fascinating data that’s coming out of the
recently published ambrisentan for pulmonary fibrosis study suggesting that
those people who were treated with
ambrisentan actually had worsening of
lung function and more frequent hospitalizations. There’s just the reality
that not only are we unable to improve
our patients with these treatments, but
that we can actually make them worse
by trying to treat their pulmonary
hypertension. So the approach really
has to be, I believe, convincing yourself
that the person’s pulmonary hypertension
is not due to their underlying lung
disease, and that you really have 2 diseases going on and you’re going to
treat them separately. That means for
patients with mild pulmonary hypertension in association with moderate
to severe lung disease, we really
should be looking away from trying to
treat these patients’ pulmonary hypertension.
Dr Schilz: I agree. I agree 1,000%, Jim.
And just to take that ambrisentan data
one step further, that study also generated the black box warning on
ambrisentan.
Dr Klinger: Right.
Dr Schilz: I think Jim has summed
things up nicely. Some patients clearly
seem to have 2 diseases. That patient
with FEV1 of 75%, their CT isn’t bad,
their DLCO isn’t bad, and they’ve got
mean pulmonary pressures of 55 mm
Hg, and they smoked for 15 years: we
think that this may represent 2 disease
processes and that many of us would
treat this as a PAH patient with a
comorbidity. A second group was mild
PH—the PH which is expected in
ILD or COPD has been studied already.
The results suggested either no benefit
or, as Jim pointed out, potential harm in
some patient populations. I think the
last patient population, which is the big
question mark, is clearly an ill group of
patients, one greatly in need of RCTs,
and perhaps that group which Jim has
mentioned: the patient who displays
pressures comparable to PAH patients,
well out of proportion to what you’d
expect, even considering possible significant parenchymal disease. Maybe this
population has 2 diseases, maybe an
unusual variant of PAH causing such
profound hemodynamic and functional
compromise. I think that this group in
particular needs to be looked at more
carefully.
Dr Levine: But I think the fact when
you’re talking about management, you’re
also talking about management of the
diseases in terms of further therapy, even
beyond pharmacotherapy. And so when
you’re looking at treating patients with
these severe diseases and with the fact
that they do have pulmonary hypertension, whether it be super high or even
moderate, that their survival is less, and
that you might want to refer them
earlier for a different form of therapy, for
example, LVRS or transplant. So when
you talk about therapy, knowing that
they have PH is also very important in
the next step you take.
Dr Schilz: No, absolutely. And again,
optimizing those sorts of therapies.
Obviously, LVRS has a relative contraindication of performance in higher
pulmonary pressures. These types of
patients certainly need to be seen by
centers that have expertise in advanced
lung disease, transplantation, advanced
therapies, perhaps experimental therapies, as well as the management and
evaluation of pulmonary hypertension,
which I think is a clear message that we
ought to bring out, as well.
Dr Klinger: Jeff, you brought up an
interesting topic and that is the discussion of new entry criteria for clinical
trials going forward. I’m not sure if that’s
an issue that you want to discuss in this
issue, but there are a lot of different
opinions about which patients should be
targeted and which patients should be
studied for a variety of different information. We can certainly discuss that,
but I think it may open up a lot of questions that the practitioner who is trying
to treat the patient would not necessarily
be looking at. That is to say, some
parties may try to design a study that
would have the greatest chance of
achieving a positive result, but may not
answer the question of when do you
treat patients that have pulmonary
hypertension and underlying lung
disease.
Dr Edelman: Yes, I think the context
that I brought that up was with the
notion of sort of defining patient groups,
where the PH was greater than expected
Advances in Pulmonary Hypertension
Volume 12, Number 3; 2013
149
and I think one of the main reasons to
define those groups would be then to
say, well, this might be the group that
we would study. But I agree, once you
sort of pick an enriched population and
study it, you’re always left with the
question of how broadly applicable the
data are to other patient subsets.
Dr Klinger: If we’re looking for a
figure that defines these subgroups, you
can plot PA pressure on the ordinate
and FEV1 or other functions of PFTs
on the abscissa and divide patients into
four basic quadrants: low PFTs and low
PA pressures, low PFTs and high PA
pressures, high PFTs and low PA pressures, and then the quadrant that’s up
and to the right is those people that
have essentially high PFTs, meaning
close to normal percentage predicted
or mild lung disease and high PA pressures. And that’s where you see most of
the mortality—in that mild lung disease,
but high PA pressure group. There’s
been some suggestion that that’s the
group that ought to be focused on.
We did a small trial here years ago,
where we simply looked at mortality in
our COPD admissions based on their
echocardiographic estimates of PA
pressure, and found the same trend.
High 1 year mortality in COPD
patients admitted with acute exacerbation who also have pulmonary
hypertension and the group that had the
worst survival were those patients who
had the highest PA pressures but near
normal PFTs.
Dr Schilz: Yeah. It’s also worthwhile,
Jim, to extend your data, that also those
same patients are ones with COPD
that re-exacerbate more frequently,
as well.
Dr Klinger: Right.
Dr Schilz: I think we need about 3
more hours of discussion on this.
(Laughter) I think few things have
been subject to more discussion without
concrete resolution than the issues of
elevated blood pressures of the lungs
in this context of parenchymal lung
disease. I do think that perhaps we’re
starting to get a more useful structure
150
Advances in Pulmonary Hypertension
upon which to base future discussion
and, more importantly, investigation.
Dr Edelman: It will be a very thick
issue of Advances. But I agree, there’s
certainly much more here than could be
covered in 45 minutes or 3 hours or even
more time. But I also think that among
this panel today, we do seem to have
fairly good consensus as to when to
think about PH in patients with COPD
and IPF; how we evaluate these patients;
and also on the lack of data for
PH-directed therapy and the fact that
not only is there a lack of evidence in
favor of therapy, but there’s some evidence suggesting that some of the drugs
that are used may be harmful as well.
And another important point therefore is
to think about when we identify PH in
these patient populations, that it may be
more of an indicator of prognosis. It
may be an indicator for transplant consideration. And it’s certainly an indicator
for a diligent search for other associated
treatable comorbidities. So making sure
we’re aggressive about treating hypoxia,
encouraging and assisting with smoking
cessation, considering pulmonary rehabilitation, and looking for left heart disease,
sleep-disordered breathing, collagen vascular disease and thromboembolic
disease.
Dr Schilz: Jeffrey, it is interesting that
you bring up the hypoxia part of it.
We know that one important treatment
in hypoxic COPD patients that has
been shown to help is oxygen. But
interestingly, that oxygen improved morbidity without changing pulmonary
pressures.
Dr Klinger: Yes, but you have to be
careful because, the P-value there was
0.07. So it got very, very close to
bringing down PA pressure.
Dr Schilz: That study was not designed
to look and answer that specific
question.
Dr Klinger: Right.
Dr Schilz: It is often important to
optimize treatment. But it may be that
simply changing the pulmonary pressures
Volume 12, Number 3; 2013
may not be all that helpful if it’s just a
marker of advanced disease and poor
outcome.
Dr Klinger: Yes. I agree completely.
The other thing we didn’t get a chance
to discuss much is this interesting phenomena of being able to improve
oxygenation by using inhaled pulmonary
vasodilators. Once upon a time, the idea
of continuous inhaled pulmonary vasodilator therapy was just kind of pie in
the sky, but with the advent of the
inhaled prostacyclins and ongoing trials
of inhaled nitric oxide, there are more
patients out there who are using these
kinds of medications for that indication.
It’s hard to tell whether or not we’re
actually achieving improvement, but you
can’t argue with the fact that your
patient’s oxygen saturation will go from
the 80s, or I even have a patient in the
70s now, back to the 90s following
their inhaled prostacyclin. It doesn’t last
very long, but it allows them to get up
and walk around and do their chores
and whatnot. We should probably consider discussing when those types of
therapies are most appropriate and which
patients might potentially benefit from
them.
Dr Edelman: I think we’re somewhat
time limited there. But are you perhaps
suggesting again that this might be a
good focus for a clinical trial going
forward, as well? Because we’re looking
at manifestations of short-term
improvement, without really knowing
what the long-term impact of those
inhaled therapies might be in this
patient group.
Dr Klinger: Yes, absolutely.
Dr Schilz: Perhaps again with a different target, of augmenting oxygenation,
rather than changing pulmonary pressures, per se.
Dr Klinger: Right.
Dr Edelman: Well, does anyone else
have any other closing or summary
remarks? If not, I think I will conclude
by thanking everyone for participating in
this very interesting discussion for what
really amounts to be a fairly common
problem in a large population of
patients.
Dr Klinger: Jeff, I did have just one last
thing to add, kind of an overall perspective. I think group 3 PH is really
different from the other types of pulmonary hypertension and associated
diseases. We have tried for so long to
really beat the bushes for early diagnosis
and, finding patients who have Group 1
pulmonary hypertension, to get them on
treatment. And now, in a sense, we’ve
kind of created a huge interest in people
that have pulmonary hypertension of
other etiologies. I know the practitioners,
particularly the modern-day pulmonologists and cardiologists who have made a
practice seeing patients with pulmonary
hypertensive diseases, are under a lot of
pressure with referrals, trying to do
something to help these people. But
group 3 PH is an area where rather
than saying, “Make sure you don’t miss a
case of pulmonary hypertension that
could have been treated with a pulmonary vasodilator,” we’re really kind
of saying, I think collectively, “Be
careful who it is that you choose for
treatment. And it’s really okay to see
somebody and put them through a lot
of diagnostic tests and admit that they
have pulmonary hypertension associated
with their lung disease, but in this particular case, it’s better not to do
something for them.” That’s a different
approach that we’ve had toward treating
pulmonary hypertensive diseases than
we’ve had with some of the other PH
groups.
Dr Edelman: And it also points to the
way we, as physicians, are sometimes
wired in that we tend to think of diseases as conditions for which we always
need to offer treatment. And so we
then also need to step back and say,
“Well, this condition is present and
maybe I don’t have a treatment.” That’s
sometimes a very tough position to
be in as a physician. It’s often harder
to offer no treatment than it is to
offer treatment, particularly in the
context of a patient/physician
interaction.
Dr Schilz: Jeffrey, that’s exactly true.
Occasionally the most difficult but best
thing to do may be not treating PH
directly in many Group 3 patients—at
least according to the data we have to
date.
Dr Edelman: I agree and again I want
to thank everyone for their participation and input in our discussion of this
fascinating and challenging group of
patients.
Advances in Pulmonary Hypertension
Volume 12, Number 3; 2013
151
PH P ROF E S S IO NA L N E T W O R K
O2 Trials and Tribulations
Section Editor
Mary Bartlett, MS, RN, CS, FNP
Tonya Zeiger, RRT, CPFT
Pulmonary Hypertension Coordinator
Associate in Pulmonary Medicine
Mayo Clinic Florida
Jacksonville, FL
Many caregivers are regularly challenged
with questions regarding portable
oxygen. There are more options available
than ever and one would assume that
would simplify things. However, there is
more mainstream marketing directed at
patients, and some systems are simply
not sufficient for patients’ needs.
conserver, the solenoid of the conserver
opens every time the sensor signals. The
length of time it remains open depends
on the pulse setting. The higher the
pulse setting, the longer the solenoid
remains open, thereby increasing the
flow. The volume of the pulse is based
on the number on the dial, which manufacturers compare to liters per minute
(lpm), but it is actually not delivering
lpm when in pulse mode. Instead, it is
delivering milliliters per breath.
The intermittent-breath conserver
senses the breath initiation and fires
based on its setting. If the device is set
at number 1, it will deliver 1 pulse of a
fixed volume of oxygen for every 4
breaths sensed; number 2 will deliver a
pulse of oxygen every other breath;
number 3 would deliver a pulse of
oxygen on 3 out of 4 sensed breaths; and
number 4 would deliver it every breath.
A pneumatic conserver senses the
initial negative pressure then delivers a
fixed pulse of oxygen followed by continuous flow until it senses the beginning
of exhalation. For that reason, some
pneumatic conservers have a dual
cannula (one is attached to the “sensing”
port and the other to the “oxygen” port).
Oxygen suppliers stock a variety of
systems and it would be very difficult to
keep up with the newest developments.
When a patient inquires about the eligibility of a conserving device (or a smaller
tank), one option is to write a prescription to “titrate and evaluate a
patient for a conserver device.” The
oxygen company would then assess the
patient with the conserver that they
supply. After documentation is received
LOOKING BACK
Forty years ago the only existing “home
oxygen” option available was when an
industrial supplier of medical gases
would deliver a series of “H” cylinders
(with brass regulators) to a patient’s
home. Times have changed. Today’s
choices include home oxygen concentrators, portable oxygen concentrators
(POCs), aluminum portable (lighter and
smaller) tanks, oxygen conserver
(demand) devices, portable liquid oxygen
(LOX), and “self-fill” home systems. In
this article, we will briefly discuss some
of the newer systems and how they
work.
DEMAND AND PULSE OXYGEN
CONSERVER
While conservers were initially introduced as a way for portable oxygen tanks
to last longer, manufacturers have added
this technology to some liquid delivery
systems and portable concentrators, as
well. The basic operating systems of
these conservers are either electric or
pneumatic.
Electric conservers can operate on an
intermittent-breath or every-breath basis.
The “smart” technology senses the negative pressure generated at the beginning
of inhalation. With an “every-breath”
Correspondence: [email protected]
152
Advances in Pulmonary Hypertension
Volume 12, Number 3; 2013
identifying the patient’s precise oxygen
saturations on that device, the conserver
prescription can be approved or denied.
A recurrent challenge with “pulse”
dosing is that a patient (when short of
breath) will sometimes breathe through
their mouth to “catch up.” While
“mouth breathing,” the sensor does not
always recognize the inspiration and
therefore will not fire. Lack of oxygen
flow further decreases a patient’s oxygen
level and increases shortness of breath
(thereby perpetuating the problem). The
same may be true at night when a
patient does not generate sufficient
pressure to trigger the demand device.8
Each conserver has specific pros and
cons. Instructing the home oxygen
company to test the patient on the actual
conserver provided is the safest option.
CONSERVER TECHNOLOGY
HAS BEEN INTEGRATED WITH
VARIOUS CURRENT OXYGEN
OPTIONS
Liquid Oxygen
Liquid oxygen (LOX) is one of the only
viable home oxygen options for patients
on liter flows greater than 10 lpm. There
are several variations of setups for highflow patients. Some patients utilize a
concentrator for their home and LOX
for portability. If a patient requires a
flow between 10 and 15 lpm, patients
can receive their home flow from a flowmeter attached to a liquid reservoir. The
major drawback to LOX is cost and
storage of the refill reservoirs. Each
standard home reservoir holds about
20 liters of LOX and weighs between
100 and 160 pounds. Smaller reservoirs
hold 10 liters and are usually less than
60 pounds (full). The smaller units are
the perfect size for travel and can easily
Advances in Pulmonary Hypertension
Volume 12, Number 3; 2013
153
FAA Approval
Maximum altitude (see
note #1)
Oxygen concentration
Oxygen output pressure
Max. Hose length (see
note #3)
Maximum oxygen
capacity
Maximum Breaths/minute
3,000 ml/minute
3,000 ml / min
35
87-95.6%
12.0 psig
7 P 25C
91% ⫾ 3%
35P 50 C
Yes
10,000ft
Yes
13,123 ft
30
90% ⫹ 3%
4 psi
Yes
10,000 ft
41-44 dBa
35-42 dBa
38-40 dBa
17 pounds
SeQual
Eclipse 2
setting 6
72 ml
setting 2
24 ml
3 hrs
setting 1
12 ml
2000 ml/min
86% to 97%
3 psi
30 ft
Yes
10,000 ft
43 dB @ setting 2
11.5H-10W-6D
10.0 lbs
12.25 lbs /w
battery
96 ml
96 ml
37 min
48 ml
48 ml
53 min
16 ml
16 ml
1.2 hrs
1, 2 & 3 lpm
1 lmp
1.1 hrs
2 lpm
45 min
3 lpm
30 minutes
16, 32, 48, 64,
80, 96 ml
Sequal
SAROS
4.4 pounds
5.8 pounds
2 hours
setting 3
2.5 hours
setting 2
3.5 hours
setting 1
1 to 3
Airsep
Freestyle
setting 1
8.75ml ⫹/ 15%
3 hours-up to 7
hours with
optional Air
Belt
setting 3
26.5ml ⫹/ 10%
1.5 hours-up to
3.3 hours with
optional Air
Belt
setting 5
43.75ml ⫹/ 10%
1 hour-up to 2.3
hours with
optional Air
Belt
5.8 lbs
add .53 lb/
battery
1.8 lb AirBelt
(opt)
1 to 5
Airsep
Freestyle 5
1.75lb ⫹ .53lb
per battery
1.8 lb AirBelt
(opt)
3 hours (1.5
hours per
battery-2
included)
A single pulse
setting (equiv
of 2LPM)
Airsep Focus
9.75 poumds
50 minutes (3.25
hours with 3
batteries in
powerpack)
setting 2
1 to 5
Airsep Lifestyle
3,000 ml /
minute
40
90% ⫾ 3%
5.0 psig
7 P 50C
40 dB @ 3.0
pulse-48dB @
3.0 LP
continuous
Yes
13,123 ft
31 to 40 (9616 p)
93% ⫹/ 3%
4.0 psig
Yes
18,000 ft
⬍59 dB
90% ⫾ 3%
Yes
12,000 ft
38-44 dBa
90% ⫹5.5%-3%
Yes
12,000 ft
41 dBA at setting
2
7 ft
90%-⫹5.5/-3%
Yes
10,000 ft
Yes
12,000 ft
50 dBa
18H-12.3W-7.1D 26.80H-4.375 dia 8.6H-6.1W-3.6D 10.5H-6.4W-4.4D 6.4H-4.8W-2.5D 5.5H-7.25W-6.31D
19 pounds
14.5 lbs
18 pounds
setting 6
96 ml
1.8 hours
setting 2
32 ml
3.5 hours
setting 1
16 ml
5 hours
0.5, 1, 1.5, 2 LPM .5 to 3.0 LPM
.5 LPM
4.4 hours
2 LPM
1.8 hours
2 lpm
3 LPM
.9 hours
1.3 hours
1 to 6
.5 to 6.0 (0.5
increments)
Respironics
SimplyGo
11.85 pound 10 lbs w/battery
14.85 pounds
16.55H-11W-8D 12H-8W-8D
17 pounds
19.9 pounds
setting 6
96 ml
1.8 hours
15H-11W-8D
15.5 pounds
19 pounds
Weight
1 battery
setting 6
80 ml
2.5 hours
setting 2
32 ml
3 hours
setting 1
16 ml
4.5 hours
3 LPM
1 Hour
1 to 6
1 to 3 LPM
OxLife
Independence
22 pounds
setting 6
96 ml
3 hours
Maximum delivery at
Oxygen output
Battery life
setting 2
32 ml
3.5 hours
setting 1
16 ml
4.5 hours
.5 to 3.0 LPM
.5 LPM
4.5 hours
2.0 LPM
2.5 hours
3.0 LPM
1.5 hours
1 to 5
Invacare
SOLO2
20 pounds
setting 2
32 ml
4.8 hours
Average delivery at
Oxygen output
Battery life
1 battery & shoulder
bag
1 battery & cart
2 battery & shoulder
bag
Size (Height X Width X
Depth)
Sound level
setting 1
16 ml
6 hours
1.0 to 3.0 LPM
1.0 LPM
4 hours
2 LPM
2.4 hours
3 LPM
1.6 hours
1.0 to 6.0
Minimum delivery at
Oxygen output
Battery life
Continuous settings
Minimum delivery
Battery life
Average delivery
Battery life
Maximum delivery
Battery life
Pulse settings
DeVilbiss iGo
Table. Personal Oxygen Concentrators
154
Advances in Pulmonary Hypertension
Volume 12, Number 3; 2013
Maximum Breaths /minute
FAA Approval
Maximum altitude (note #1)
Oxygen concentration
Oxygen output pressure
Max. Hose length (note #3)
Maximum oxygen capacity
1 battery & shoulder bag
1 battery & cart
2 battery & shoulder bag
Size (Height X Width X
Depth)
Sound level
1 battery
Yes
10,000 ft
90%-3%, ⫹6%
900 ml/minute
750 ml/minute
38 dBa
37-40 dBa
Yes
10,000 ft
90% ⫾ 3%
9.5H-10.7W-3.9D
7 lbs.
setting 6
37 ml
1 hours
12.4H-11.6W-6D
Maximum delivery at
Oxygen output
Battery life
setting 2
15 ml
12 pounds
13 pounds
setting 6
37 ml
1 hours
Average delivery at
Oxygen output
Battery life
1 to 5 plus a
“satellite”
setting
setting 1
7.5 ml
4 hours on single
battery-8 hrs
on double
battery
Inogen One G2
12 pounds
13 pounds
setting 2
15 ml
2.5 hours
Minimum delivery at
Oxygen output
Battery life
Weight
1 to 5 plus a
“satellite”
setting
setting 1
7.5 ml
3 hours
Continuous settings
Minimum delivery
Battery life
Average delivery
Battery life
Maximum delivery
Battery life
Pulse settings
Inogen One
Table. Personal Oxygen Concentrators (Continued)
9 ft
25 ft (w/ high flow)
900 ml/min
Yes
10,000 ft
90% ⫾ 3%
⬍ 50 dBa
Yes
10000 ft
90% ⫾ 3%
44-46 dBa
9H-7W-4D
setting 5
58 ml
1 hours
setting 2
23 ml
2.5 hours
setting 1
13 ml
3 hours
1 to 5
Invacare
XPO2
6 pounds
10 pounds
7.5 pounds
10H-7W-4D
add 1 lb for
external
battery
4.9 lbs
setting 1
1 LPM
2⫹ hours on
Internal battery
on all settings
(add 3 hrs with
battery)
setting 2
2 LPM
additional 3
hours with
external
battery
setting 3
3LPM
1 to 3
pulse only-has
sleep mode
technology for
24/7 use
Yes
10,000 ft
90%-3% /⫹ 6%
42 dBA at setting 2
7.25H-8.75W-3.0D
4.8 lbs with 1
battery
setting 4 @ 20 bpm
36.0ml ⫹/ 10%
setting 2 @ 20 bpm
18.0ml ⫹/ 10%
setting 1 @ 20 bpm
9.0ml ⫹/ 10%
up to 4.5 hrs single
battery up to 9
hrs double
battery
1 to 4
Inogen One G3
International
Biophysics
Corporation
LifeChoice
41 db at setting 1
46 dB at setting 3
Yes
10,000 ft
90% (⫹/ 3%)
7.875H-9.05W-4.38D
setting 3
30 ml
5 hrs (internal
battery) ⫹2 hrs for
external battery
4.83 lbs
setting 2
20 ml
6 hrs (internal
battery) ⫹3 hrs for
external battery
setting 1
10 ml
12 hrs /w internal
battery add 3 hrs
for external battery
1 to 3
Inova Labs
LifeChoice Activox
925 ml/minute
sustained- 1200ml
for short periods
30
90% ⫾ 3%
Yes
7.4W-4.6-11.6H
9.8 pounds
3 hours at 15 BPM
setting 2
1 to 5
Oxus RS00400 /
Delphi RS00400
1050 ml/
minute
Yes
8,000 ft
90% ⫾ 3%
3 psi
42-44 dBa
8.5 pounds
12 pounds
9.9 pounds
8.5H-12W-6D
setting 6
52 ml
2 hours-per
battery
setting 2
23 ml
4 hours-per
battery
setting 1
12 ml
5 hours-per
battery
1 to 6
Respironics
EverGo
35
7 ft
Yes
9.000 ft
87% to 95%
44 dBA
10.1H-6.5W-4.5D
6.8 lbs
setting 5
42 ml ⫾ 15%
1.5 hrs
2.5 hrs
setting 3
setting 1
13 ml ⫾ 15%
4.5 hrs
1 to 5
Precision Medical
Easy Pulse
be transported in mid- to large-sized
automobiles (as long as the home oxygen
company will allow it). How often the
oxygen company refills the patient’s reservoir depends on liter flow and the rate
of evaporation. Consider LOX if your
patient requires high flows.
Self-Fill Systems
In recent years reimbursement for home
oxygen has decreased, and it has become
more fiscally challenging for oxygen
companies. With home oxygen companies trying to find more ways to
deliver care with fewer deliveries and less
upkeep, a new product was developed in
2000, enabling home oxygen patients to
fill their own portable gas cylinders from
their oxygen concentrator. The key with
this system is that a cylinder filled with a
concentrator will not contain 100%
oxygen. A properly functioning concentrator can produce an oxygen
concentration as low as 88%; therefore,
that would be the percentage of oxygen
filling the patient’s portable tank. While
there have been studies citing this as
clinically inconsequential, it should be
noted, particularly if your patient needs
liter flows ⬎4 lpm.
Portable Oxygen Concentrator
The newest addition to the oxygen
world is the POC. There are several
factors to consider with each option,
keeping in mind all of the particulars
discussed previously. Since the 2005
landmark decision by the Federal Aviation Administration to allow POCs on
commercial aircraft,1 there have been a
host of new POCs introduced. While 5
portable concentrators have the ability to
provide continuous flow and they are
limited to a maximum of 3 lpm, the
majority of POCs deliver oxygen by
pulse flow only. Considerations for
selection of a POC include: weight, size,
battery life, maximum oxygen capacity,
sound level, and oxygen hose length.
POC weights with a single battery range
from 2.3 to 19.9 pounds. In general,
lighter units have shorter battery life and
lower maximum oxygen capacities.
Battery life varies by POC unit and flow
rate used, ranging from ⬍1 hour to 6
hours. Utilizing extra batteries can
extend the time between charges.5 The
more details we learn about how portable concentrators work, the more we
can appropriately gauge which patients
may benefit most from this technology.
Different options are constantly
emerging.
When initiating oxygen therapy, it is
wise to discuss the patient’s expectations
and lifestyle. Some patients have frequent travel plans and should select a
company that can and will accommodate
those needs. The world of oxygen
systems is ever changing and new developments must be addressed. The focus
should center on developing individualized patient oxygen therapy plans as
new options emerge.
An important tool in the arena of
patient self-monitoring is the portable
pulse oximeter. In recent years, the portable pulse oximeter has become
increasingly affordable. While it is not a
perfect tool, a home pulse oximeter can
be very helpful for a patient to report
their oxygenation while in the home
setting. This is especially true in monitoring patients with exercise-related
dyspnea and for titrating oxygen flow for
patients on long-term oxygen therapy,
provided their disease is stable and they
have good circulation. In general, the
goal should be to maintain oxygen saturation ⬎90% during all activities.
Pulse oximeters can overestimate
oxygen saturation, particularly in those
with darkly pigmented skin. Additional
cautions should be noted if the patient
has:
• Poor perfusion due to systemic hypotension, Raynaud’s, hypovolemic shock,
cold environment, or cardiac failure—
it may result in the machine not providing a reading (or an inaccurate
reading)
• Anemia— oxygen delivery to tissues is
inadequate due to lack of hemoglobin
for oxygen to bind to, but oxygen saturation is normal
• Carbon monoxide poisoning— carbon
monoxide binds to hemoglobin,
resulting in inadequate oxygen
transport despite normal pulse oximeter readings. The pulse oximeter
cannot distinguish what gas is binding
to the hemoglobin (only that a gas is
attached).
• Movement, shivering patient, heart
arrhythmias— oximeter may not be
able to identify an adequate pulse
signal due to movement intolerance
• Nail polish, dirt, artificial nails— can
cause false low readings or prevent
readings altogether
It is difficult to predict whether a patient
will be appropriately oxygenated with a
particular system, but by working closely
with patients and home oxygen providers, patients can truly live life to its
fullest.
References
1. Special Federal Aviation Regulation. Use of
Certain Portable Oxygen Concentrator Devices
Onboard Aircraft. 14 CFR Parts 11 and 121,
[Docket No. FAA-2004-18596; SFAR No. 106];
RIN 2120-AI30.
2. Apria Healthcare Web site. Patient Instructions: Oxygen Conserving Devices. http://www.
apria.com/wps/wcm/connect/7df32ae7–
d8ef-4e9a-b242– 49246aacd4be/RES-2007⫹
Oxygen⫹Conserving⫹Devices.PDF?MOD
⫽AJPERES. Accessed June 3, 2010.
3. Lewarski J. A clinical comparison of portable
oxygen systems: continuous flow compressed gas
vs. oxygen concentrator gas delivered with an
oxygen conserving device. Respir Care. 2003;48(11):
1115.
4. Liquid Oxygen. Portable Oxygen: A User’s
Perspective. http://www.portableoxygen.org/
liquido2.html. Accessed November 19, 2013.
5. Wilson PM. PortableOxygen.org. Personal
Oxygen Concentrators comparison chart.
http://www.portableoxygen.org/2pagePOC
comparisonchart.pdf. Accessed November 19,
2013.
6. Chatburn RL, Lewarski JS, McCoy RW.
Nocturnal oxygenation using a pulsed-dose oxygenconserving device compared to continuous flow.
Respir Care. 2006;51(3):252-256.
7. McCoy RR. Oxygen-conserving techniques
and devices. Respir Care. 2000;45(1):95-103.
8. Wyka K. The current and future status of portable oxygen concentrators. FOCUS: J Respir Care
Sleep Med. 2009.
Advances in Pulmonary Hypertension
Volume 12, Number 3; 2013
155
For PAH (WHO Group 1) patients on oral monotherapy
MORE
TO DO MORE
ADD MORE to your treatment strategy
+ PAH may be progressing even if patients seem stable1,2
+ Many patients plateau on oral therapy (PDE-5 inhibitor or ERA) within 12 weeks3,4
ADD MORE: Tyvaso is the only PAH treatment approved as an add-on to oral therapy5
+ After 1.7 years (mean) on oral monotherapy, adding Tyvaso for 12 weeks improved median
6MWD by 20 m (P<0.001)5,6
COULD YOUR
STABLE PATIENTS
ON ORAL MONOTHERAPY
BENEFIT FROM ADD-ON
THERAPY WITH TYVASO?
+ 4X daily dosing with short treatment sessions (2-3 minutes) approximately every 4 hours5,7
Study design: TRIUMPH I was a 12-week, randomized, double-blind, placebo-controlled, multicenter study of patients (N=235) with PAH who were receiving a stable dose of bosentan or sildenafil for 3 months
before study initiation. Patients were administered either placebo or Tyvaso in 4 daily treatment sessions with a target dose of 9 breaths (54 mcg) per session over the course of the 12-week study. Primary
endpoint was change in 6MWD at 12 weeks. Secondary endpoints included time to clinical worsening, Borg dyspnea score, NYHA functional class, trough 6MWD at week 12 (obtained at least 4 hours after
study drug administration), peak 6MWD at 6 weeks, quality of life as measured by the MLWHF questionnaire, and PAH signs and symptoms.5,8
INDICATION
Tyvaso is a prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve
exercise ability. Studies establishing effectiveness included predominately patients with NYHA Functional Class III symptoms and etiologies
of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%).
The effects diminish over the minimum recommended dosing interval of 4 hours; treatment timing can be adjusted for planned activities.
While there are long-term data on use of treprostinil by other routes of administration, nearly all controlled clinical experience with inhaled
treprostinil has been on a background of bosentan (an endothelin receptor antagonist) or sildenafil (a phosphodiesterase type 5 inhibitor).
The controlled clinical experience was limited to 12 weeks in duration.
IMPORTANT SAFETY INFORMATION
+ Tyvaso is intended for oral inhalation only. Tyvaso is approved
+
+
+
+
for use only with the Tyvaso Inhalation System
The safety and efficacy of Tyvaso have not been established in
patients with significant underlying lung disease (such as asthma
or chronic obstructive pulmonary disease) and in patients under
18 years of age. Patients with acute pulmonary infections should be
carefully monitored to detect any worsening of lung disease and
loss of drug effect
Tyvaso may increase the risk of bleeding, particularly in patients
receiving anticoagulants
In patients with low systemic arterial pressure, Tyvaso may cause
symptomatic hypotension. The concomitant use of Tyvaso with
diuretics, antihypertensives, or other vasodilators may increase the
risk of symptomatic hypotension
Hepatic or renal insufficiency may increase exposure to Tyvaso and
decrease tolerability. Tyvaso dosage adjustments may be necessary
if inhibitors of CYP2C8 such as gemfibrozil or inducers such as
rifampin are added or withdrawn
www.tyvaso.com 1-877-UNITHER
Request a visit from a Tyvaso
sales representative by
scanning this QR code with
your smartphone or by visiting
www.tyvasorep.com.
Tyvaso is a registered trademark of United Therapeutics Corporation.
All other trademarks and registered trademarks are the property of their respective owners.
© 2013. United Therapeutics Corporation, Inc. All rights reserved. US/TYV/JAN13/188
+ The most common adverse events seen with Tyvaso in ≥4% of PAH
+
patients and more than 3% greater than placebo in the placebocontrolled clinical study were cough (54% vs 29%), headache (41% vs
23%), throat irritation/pharyngolaryngeal pain (25% vs 14%), nausea
(19% vs 11%), flushing (15% vs <1%), and syncope (6% vs <1%)
Tyvaso should be used in pregnancy only if clearly needed. Caution
should be exercised when Tyvaso is administered to nursing women
Please see brief summary of Full Prescribing
Information on following page. For more information,
please see Full Prescribing Information, Patient
Package Insert, and the Tyvaso Inhalation System
Instructions for Use manual. These items are available
at www.tyvaso.com.
6MWD=6-minute walk distance. MLWHF=Minnesota Living With Heart Failure. NYHA=New York
Heart Association. PAH=pulmonary arterial hypertension. WHO=World Health Organization.
References: 1. Barst R. How has epoprostenol changed the outcome for patients with pulmonary
arterial hypertension? Int J Clin Pract. 2010;64(suppl 168):23-32. 2. Voelkel NF, Quaife RA, Leinwand LA,
et al. Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working
group on cellular and molecular mechanisms of right heart failure. Circulation. 2006;114(17):1883-1891.
3. Galiè N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension.
N Engl J Med. 2005;353(20):2148-2157. 4. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for
pulmonary arterial hypertension. N Engl J Med. 2002;346(12):896-903. 5. Tyvaso [package insert].
Research Triangle Park, NC: United Therapeutics Corporation; 2011. 6. Data on file. United Therapeutics
Corporation. Research Triangle Park, NC 27709. June 2008. 7. Tyvaso [patient package insert].
Research Triangle Park, NC: United Therapeutics Corporation; 2011. 8. McLaughlin VV, Benza RL,
Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a
randomized controlled clinical trial. J Am Coll Cardiol. 2010;55(18):1915-1922.
BRIEF SUMMARY
The following is a brief summary of the full prescribing information
for TYVASO® (treprostinil) Inhalation Solution. Please review the full
prescribing information prior to prescribing TYVASO.
INDICATIONS AND USAGE
TYVASO is a prostacyclin vasodilator indicated for the treatment of
pulmonary arterial hypertension (PAH) (WHO Group 1) to improve
exercise ability. Studies establishing effectiveness included
predominately patients with NYHA Functional Class III symptoms
and etiologies of idiopathic or heritable PAH (56%) or PAH associated
with connective tissue diseases (33%). The effects diminish over the
minimum recommended dosing interval of 4 hours; treatment timing
can be adjusted for planned activities. While there are long-term
data on use of treprostinil by other routes of administration, nearly
all controlled clinical experience with inhaled treprostinil has been
on a background of bosentan (an endothelin receptor antagonist)
or sildenaﬁl (a phosphodiesterase type 5 inhibitor). The controlled
clinical experience was limited to 12 weeks in duration.
CONTRAINDICATIONS
None.
WARNINGS AND PRECAUTIONS
Patients with Pulmonary Disease or Pulmonary Infections–The
safety and efficacy of TYVASO have not been established in patients
with signiﬁcant underlying lung disease (e.g., asthma or chronic
obstructive pulmonary disease). Patients with acute pulmonary
infections should be carefully monitored to detect any worsening of
lung disease and loss of drug effect.
Risk of Symptomatic Hypotension– Treprostinil is a pulmonary and
systemic vasodilator. In patients with low systemic arterial pressure,
treatment with TYVASO may produce symptomatic hypotension.
Patients with Hepatic or Renal Insufficiency–Titrate slowly in patients
with hepatic or renal insufficiency, because such patients will likely
be exposed to greater systemic concentrations relative to patients
with normal hepatic or renal function.
Risk of Bleeding–Since TYVASO inhibits platelet aggregation, there
may be an increased risk of bleeding, particularly among patients
receiving anticoagulant therapy.
Effect of Other Drugs on Treprostinil–Co-administration of a
cytochrome P450 (CYP) 2C8 enzyme inhibitor (e.g., gemﬁbrozil)
may increase exposure (both Cmax and AUC) to treprostinil.
Co-administration of a CYP2C8 enzyme inducer (e.g., rifampin) may
decrease exposure to treprostinil. Increased exposure is likely to
increase adverse events associated with treprostinil administration,
whereas decreased exposure is likely to reduce clinical effectiveness.
ADVERSE REACTIONS
The following potential adverse reactions are described in Warnings
and Precautions:
I0.=0,>049>D>?084.-7::/;=0>>@=0I700/492
Adverse Reactions Identiﬁed in Clinical Trials–Because clinical
trials are conducted under widely varying conditions, adverse
reaction rates observed in the clinical trials of a drug cannot be
directly compared to rates in the clinical trials of another drug
and may not reﬂect the rates observed in practice. In a 12-week
placebo-controlled study (TRIUMPH I) of 235 patients with PAH (WHO
Group 1 and nearly all NYHA Functional Class III), the most commonly
reported adverse reactions to TYVASO included: cough and throat
irritation; headache, gastrointestinal effects, muscle, jaw or bone
pain, ﬂushing and syncope. Table 1 lists the adverse reactions that
occurred at a rate of at least 4% and were more frequent in patients
treated with TYVASO than with placebo.
Manufactured for: United Therapeutics Corporation
Research Triangle Park, NC 27709
Rx only February 2011
www.tyvaso.com
Table 1: Adverse Events in ≥4% of PAH Patients Receiving TYVASO and More Frequent* than Placebo
Adverse Event
Treatment n (%)
TYVASO
Placebo
n = 115
n = 120
Cough
62 (54)
35 (29)
Headache
Throat Irritation/
Pharyngolaryngeal Pain
Nausea
Flushing
Syncope
*More than 3% greater than placebo
47 (41)
27 (23)
29 (25)
17 (14)
22 (19)
13 (11)
17 (15)
7 (6)
1 (<1)
1 (<1)
The safety of TYVASO was also studied in a long-term, open-label
extension study in which 206 patients were dosed for a mean
duration of one year. The adverse events during this chronic dosing
study were qualitatively similar to those observed in the 12-week
placebo controlled trial. Adverse Events Associated with Route
of Administration–Adverse events in the treated group during
the double-blind and open-label phase reﬂecting irritation to the
respiratory tract included: cough, throat irritation, pharyngeal pain,
epistaxis, hemoptysis and wheezing. Serious adverse events during
the open-label portion of the study included pneumonia in 8 subjects.
There were three serious episodes of hemoptysis (one fatal) noted
during the open-label experience.
DRUG INTERACTIONS
Pharmacokinetic/pharmacodynamic interaction studies have
not been conducted with inhaled treprostinil (TYVASO); however,
some of such studies have been conducted with orally (treprostinil
diethanolamine) and subcutaneously administered treprostinil
(Remodulin®).
Pharmacodynamics–Antihypertensive Agents or Other Vasodilators–
Concomitant administration of TYVASO with diuretics,
antihypertensive agents or other vasodilators may increase the
risk of symptomatic hypotension. Anticoagulants–Since treprostinil
inhibits platelet aggregation, there may be an increased risk of
bleeding, particularly among patients receiving anticoagulants.
Pharmacokinetics–Bosentan–In a human pharmacokinetic study
conducted with bosentan (250 mg/day) and an oral formulation
of treprostinil (treprostinil diethanolamine), no pharmacokinetic
interactions between treprostinil and bosentan were observed.
Sildenaﬁl–In a human pharmacokinetic study conducted with
sildenaﬁl (60 mg/day) and an oral formulation of treprostinil
(treprostinil diethanolamine), no pharmacokinetic interactions
between treprostinil and sildenaﬁl were observed. Effect of
Cytochrome P450 Inhibitors and Inducers–In vitro studies of
human hepatic microsomes showed that treprostinil does not inhibit
cytochrome P450 (CYP) isoenzymes CYP1A2, CYP2A6, CYP2C8,
CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A. Additionally,
treprostinil does not induce cytochrome P450 isoenzymes CYP1A2,
CYP2B6, CYP2C9, CYP2C19, and CYP3A. Human pharmacokinetic
studies with an oral formulation of treprostinil (treprostinil
diethanolamine) indicated that co-administration of the cytochrome
P450 (CYP) 2C8 enzyme inhibitor gemﬁbrozil increases exposure
(both Cmax and AUC) to treprostinil. Co-administration of the CYP2C8
enzyme inducer rifampin decreases exposure to treprostinil. It is
unclear if the safety and efficacy of treprostinil by the inhalation
route are altered by inhibitors or inducers of CYP2C8. Effect of Other
Drugs on Treprostinil–Drug interaction studies have been carried
out with treprostinil (oral or subcutaneous) co-administered with
acetaminophen (4 g/day), warfarin (25 mg/day), and ﬂuconazole
(200 mg/day), respectively in healthy volunteers. These studies
did not show a clinically signiﬁcant effect on the pharmacokinetics
of treprostinil. Treprostinil does not affect the pharmacokinetics or
pharmacodynamics of warfarin. The pharmacokinetics of R- and
S-warfarin and the INR in healthy subjects given a single 25 mg dose
of warfarin were unaffected by continuous subcutaneous infusion of
treprostinil at an infusion rate of 10 ng/kg/min.
USE IN SPECIFIC POPULATIONS
Pregnancy—Pregnancy Category B–There are no adequate and
well controlled studies with TYVASO in pregnant women. Animal
reproduction studies have not been conducted with treprostinil
administered by the inhalation route. However, studies in pregnant
rabbits using continuous subcutaneous (sc) infusions of treprostinil
sodium at infusion rates higher than the recommended human sc
infusion rate resulted in an increased incidence of fetal skeletal
variations associated with maternal toxicity. Animal reproduction
studies are not always predictive of human response; TYVASO should
be used during pregnancy only if clearly needed.
Labor and Delivery–No treprostinil treatment-related effects
on labor and delivery were seen in animal studies. The effect of
treprostinil on labor and delivery in humans is unknown.
Nursing Mothers–It is not known whether treprostinil is excreted
in human milk. Because many drugs are excreted in human milk,
caution should be exercised when treprostinil is administered to
nursing women.
Pediatric Use–Safety and effectiveness in pediatric patients have not
been established. Clinical studies of TYVASO did not include patients
younger than 18 years to determine whether they respond differently
from older patients.
Geriatric Use–Clinical studies of TYVASO did not include sufficient
numbers of patients aged 65 years and over to determine whether
they respond differently from younger patients. In general, dose
selection for an elderly patient should be cautious, reﬂecting the
greater frequency of hepatic, renal, or cardiac dysfunction, and of
concomitant diseases or other drug therapy.
Patients with Hepatic Insufficiency–Plasma clearance of treprostinil,
delivered subcutaneously, was reduced up to 80% in subjects with
mild-to-moderate hepatic insufficiency. Uptitrate slowly when
treating patients with hepatic insufficiency because of the risk of
an increase in systemic exposure which may lead to an increase in
dose-dependent adverse effects. Treprostinil has not been studied in
patients with severe hepatic insufficiency.
Patients with Renal Insufficiency–No studies have been performed
in patients with renal insufficiency. Since treprostinil and its
metabolites are excreted mainly through the urinary route, patients
with renal insufficiency may have decreased clearance of the
drug and its metabolites and consequently, dose-related adverse
outcomes may be more frequent.
OVERDOSAGE
In general, symptoms of overdose with TYVASO include ﬂushing,
headache, hypotension, nausea, vomiting, and diarrhea.
Provide general supportive care until the symptoms of overdose
have resolved.
NEWS T O US E
PHA Classroom
PHA Classroom hosts and archives live
e-learning events targeted toward
patients and caregivers that cover a wide
array of topics to help improve their
lives. Recent recordings include:
• Pulmonary Hypertension in Chronic
Obstructive Pulmonary Disease
• Surviving Survivor’s Guilt
• Chronic Thromboembolic Pulmonary
Hypertension—What You Need to
Know
• Exercise-Induced Pulmonary
Hypertension—What Is It and What
Do We Do About It?
You and your patients can view recent
recordings and upcoming live e-learning
events at www.PHAssociation.org/
Classroom.
PHA Resources for Patients
PHA offers ongoing education and
information for patients and caregivers
at every stage of their PH journeys.
We now provide resources to help your
patients and caregivers cope with the
mental, emotional and social impacts of
living with PH. Order your Coping
Guides Postcards to point patients and
caregivers to these resources at
www.PHAssociation.org/ForYourPatients
PHA Online University
View new releases of medical education
courses on PHA Online University.
Recent additions include:
• Sickle Cell Disease and PH
Roberto Machado, MD, University of
Illinois College of Medicine at
Chicago, Chicago, IL
Nov. 2013
View this course at
www.PHAOnlineUniv.org/
SickleCellDisease
• PAH in Systemic Lupus Erythematosus
Atiya Dhala, MD, FACP, Private
Practice, Mesa, AZ
Nov. 2013
View this course at
www.PHAOnlineUniv.org/PAHSLE
Join Team PHenomenal Hope
UPMC PH-treating pulmonologist,
Dr Patty George, and her cycling team,
Team PHenomenal Hope, will be
competing in the ultra-endurance “Race
Across America” cycling race in June
2014 to raise funds in the fight against
pulmonary hypertension. Join Dr George
and PHA on Saturday, April 14 to cover
a PHenomenal Mile wherever you live in
solidarity with the team. Lace up your
sneakers, get on your bike, and grab your
colleagues to support this extraordinary
doctor’s efforts. Go the extra mile and
donate online to the Race of Our Lives
campaign. For more info visit: http://
www.phassociation.org/RaceOfOurLives
GU E S T E D IT OR’S M E M O
(co nt inue d fr o m p a g e 1 0 6 )
patients (perhaps among those with “out
of proportion PH”) may have more than
one disease process and therefore could
potentially benefit from PH directed
treatment.
Success in our present understanding
of Group 1 PAH rests on foundations of
basic science, prospective registries, and
focused clinical trials. A reiteration of
this approach for Group 3 and other PH
groups should be fostered. While reading
this issue, consider how to plot a course
to advance knowledge in the realm of
Group 3 PH.
158
Advances in Pulmonary Hypertension
Jeffrey D. Edelman, MD
Associate Professor of Medicine
Pulmonary and Critical Care Division
University of Washington
VA Puget Sound Health Care System
Seattle, Washington
References
1. Centers for Disease Control and Prevention
(CDC). Chronic obstructive pulmonary disease
among adults – United States, 2011. MMWR
Morb Mortal Wkly Rep. 2012;61(46):938-943.
2. Chaouat A, Bugnet AS, Kadaoui N, et al.
Severe pulmonary hypertension and chronic
Volume 12, Number 3; 2013
obstructive pulmonary disease. Am J Respir Crit
Care Med. 2005;172(2):189-194.
3. Nalysnyk L, Cid-Ruzafa J, Rotella P, Esser D.
Incidence and prevalence of idiopathic pulmonary
fibrosis: review of the literature. Eur Respir Rev.
2012;21(126):355-361.
4. Nathan SD. Idiopathic pulmonary fibrosis and
pulmonary hypertension: a review. Chest PCCSU.
2009;23.
5. Badesch DB, Raskob GE, Elliott CG, et al.
Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;
137(2):376-387.
Lisa P.
Letairis patient
The goals that matter to you
matter to patients
Go to www.letairis.com to learn more.
Please see accompanying brief summary of full Prescribing Information, including Boxed WARNING on the risk of embryo-fetal toxicity.
© 2013 Gilead Sciences, Inc. All rights reserved. LETP0058 September 2013
Letairis is a registered trademark of Gilead Sciences, Inc. Gilead and the Gilead logo are trademarks of Gilead Sciences, Inc.
Letairis®(ambrisentan) 5 mg and 10 mg Tablets, for oral use
Brief summary of full prescribing information. See full prescribing information. Rx only.
BOXED WARNING: EMBRYOFETAL TOXICITY
Do not administer Letairis to a pregnant female because it may cause fetal harm.
Letairis is very likely to produce serious birth defects if used by pregnant female,
as this eﬀect has been seen consistently when it is administered to animals
[see Contraindications, Use in Speciﬁc Populations].
Exclude pregnancy before the initiation of treatment with Letairis. Females of
Reproductive Potential must use acceptable methods of contraception during
treatment with Letairis and for one month after treatment. Obtain monthly
pregnancy tests during treatment and 1 month after discontinuation of treatment
[see Use in Special Populations].
Because of the risk of embryo-fetal toxicity, females can only receive Letairis
through a restricted program called the Letairis REMS Program [see Warnings and
Precautions].
INDICATIONS AND USAGE: Letairis is indicated for the treatment of pulmonary arterial
hypertension (PAH) (WHO Group 1) to improve exercise ability and delay clinical worsening. Studies
establishing eﬀectiveness included predominantly patients with WHO Functional Class II-III
symptoms and etiologies of idiopathic or heritable PAH (64%) or PAH associated with connective
tissue diseases (32%).
DOSAGE AND ADMINISTRATION: Adult Dosage: Initiate treatment at 5 mg once daily, and consider
increasing the dose to 10 mg once daily if 5 mg is tolerated. Tablets may be administered with or
without food. Tablets should not be split, crushed, or chewed. Doses higher than 10 mg once daily have
not been studied in patients with pulmonary arterial hypertension (PAH). Pregnancy Testing in
Females of Reproductive Potential: Initiate treatment with Letairis in Females of Reproductive
Potential only after a negative pregnancy test. Obtain monthly tests during treatment [see Use in
Speciﬁc Populations].
CONTRAINDICATIONS: Pregnancy: Letairis may cause fetal harm when administered to a pregnant
female. Letairis was consistently shown to have teratogenic eﬀects when administered to animals.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug,
the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions,
Use in Speciﬁc Populations]. Idiopathic Pulmonary Fibrosis: Letairis is contraindicated in patients
with Idiopathic Pulmonary Fibrosis (IPF) including IPF patients with pulmonary hypertension
(WHO Group 3) [see Clinical Studies].
WARNINGS AND PRECAUTIONS: Letairis REMS Program: For all females, Letairis is available only
through a restricted program called the Letairis REMS, because of risk of embryo-fetal toxicity [see
Contraindications, Warnings and Precautions, Use in Speciﬁc Populations]. Notable requirements of the
Letairis REMS Program include that the Prescribers must be certiﬁed with the program by enrolling
and completing training. All females, regardless of reproductive potential, must enroll in the Letairis
REMS Program prior to initiating Letairis. Male patients are not enrolled in the REMS. Females of
Reproductive Potential must comply with the pregnancy testing and contraception requirements [see
Use in Speciﬁc Populations]. Pharmacies that dispense Letairis must be certiﬁed with the program and
must dispense to female patients who are authorized to receive Letairis. Further information is
available at www.letairisrems.com or 1-866-664-5327. Fluid Retention: Peripheral edema is a
known class eﬀect of endothelin receptor antagonists, and is also a clinical consequence of PAH and
worsening PAH. In the placebo controlled studies, there was an increased incidence of peripheral
edema in patients treated with doses of 5 or 10 mg Letairis compared to placebo [see Adverse Reactions].
Most edema was mild to moderate in severity, and it occurred with greater frequency and severity in
elderly patients. In addition, there have been post-marketing reports of ﬂuid retention in patients with
pulmonary hypertension, occurring within weeks after starting Letairis. Patients required intervention
with a diuretic, ﬂuid management, or, in some cases, hospitalization for decompensating heart failure.
If clinically signiﬁcant ﬂuid retention develops, with or without associated weight gain, further
evaluation should be undertaken to determine the cause, such as Letairis or underlying heart failure,
and the possible need for speciﬁc treatment or discontinuation of Letairis therapy. Pulmonary Venoocclusive Disease: If patients develop acute pulmonary edema during initiation of therapy with
vasodilating agents such as Letairis, the possibility of pulmonary veno-occlusive disease should be
considered, and if conﬁrmed Letairis should be discontinued. Decreased Sperm Counts: Decreased
sperm counts have been observed in human and animal studies with another endothelin receptor
antagonist and in animal fertility studies with ambrisentan. Letairis may have an adverse eﬀect on
spermatogenesis. Counsel patients about potential eﬀects on fertility [see Speciﬁc Populations,
Nonclinical Toxicology]. Hematological Changes: Decreases in hemoglobin concentration and
hematocrit have followed administration of other endothelin receptor antagonists and were observed
in clinical studies with Letairis. These decreases were observed within the ﬁrst few weeks of treatment
with Letairis, and stabilized thereafter. The mean decrease in hemoglobin from baseline to end of
treatment for those patients receiving Letairis in the 12 week placebo controlled studies was 0.8 g/dL.
Marked decreases in hemoglobin (>15% decrease from baseline resulting in a value below the lower
limit of normal) were observed in 7% of all patients receiving Letairis (and 10% of patients receiving
10 mg) compared to 4% of patients receiving placebo. The cause of the decrease in hemoglobin is
unknown, but it does not appear to result from hemorrhage or hemolysis. In the long-term open-label
extension of the two pivotal clinical studies, mean decreases from baseline (ranging from 0.9 to
1.2 g/dL) in hemoglobin concentrations persisted for up to 4 years of treatment. There have been
postmarketing reports of decreases in hemoglobin concentration and hematocrit that have resulted in
anemia requiring transfusion. Measure hemoglobin prior to initiation of Letairis, at one month, and
periodically thereafter. Initiation of Letairis therapy is not recommended for patients with clinically
signiﬁcant anemia. If a clinically signiﬁcant decrease in hemoglobin is observed and other causes have
been excluded, consider discontinuing Letairis.
ADVERSE REACTIONS: Clinically signiﬁcant adverse reactions that appear in other sections of the
labeling include: Embryo-fetal toxicity [see Warnings and Precautions, Use in Speciﬁc Populations] Fluid
Retention [see Warnings and Precautions] Pulmonary Edema with PVOD [see Warnings and Precautions]
Decreased Sperm Count [see Warnings and Precautions] Hematologic changes [see Warnings and
Precautions]. Clinical Trials Experience: Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared
to rates in the clinical trials of another drug and may not reﬂect the rates observed in practice. Safety
data for Letairis were obtained from two 12 week, placebo controlled studies in patients with
pulmonary arterial hypertension (PAH) (ARIES-1 and ARIES-2) and four nonplacebo controlled studies
in 483 patients with PAH who were treated with doses of 1, 2.5, 5, or 10 mg once daily. The exposure to
Letairis in these studies ranged from 1 day to 4 years (N=418 for at least 6 months and N=343 for at
least 1 year). In ARIES-1 and ARIES-2, a total of 261 patients received Letairis at doses of 2.5, 5, or 10 mg
once daily and 132 patients received placebo. The adverse reactions that occurred in >3% more
patients receiving Letairis than receiving placebo are shown in Table 1.
Table 1 Adverse Reactions with Placebo-Adjusted Rates >3%
Placebo (N=132)
Letairis (N=261)
Adverse reaction
n (%)
n (%)
Placebo-adjusted (%)
Peripheral edema
14 (11)
45 (17)
6
Nasal congestion
2 (2)
15 (6)
4
Sinusitis
0 (0)
8 (3)
3
Flushing
1 (1)
10 (4)
3
Most adverse drug reactions were mild to moderate and only nasal congestion was dose dependent.
Few notable diﬀerences in the incidence of adverse reactions were observed for patients by age or
sex. Peripheral edema was similar in younger patients (<65 years) receiving Letairis (14%; 29/205) or
placebo (13%; 13/104), and was greater in elderly patients (≥65 years) receiving Letairis (29%; 16/56)
compared to placebo (4%; 1/28). The results of such subgroup analyses must be interpreted
cautiously. The incidence of treatment discontinuations due to adverse events other than those
related to PAH during the clinical trials in patients with PAH was similar for Letairis (2%; 5/261
patients) and placebo (2%; 3/132 patients). The incidence of patients with serious adverse events
other than those related to PAH during the clinical trials in patients with PAH was similar for placebo
(7%; 9/132 patients) and for Letairis (5%; 13/261 patients). During 12-week controlled clinical trials,
the incidence of aminotransferase elevations >3x upper limit of normal (ULN) were 0% on Letairis
and 2.3% on placebo. In practice, cases of hepatic injury should be carefully evaluated for cause. Use
in Patients with Prior Endothelin Receptor Antagonist (ERA) Related Serum Liver Enzyme
Abnormalities: In an uncontrolled, open label study, 36 patients who had previously discontinued
endothelin receptor antagonists (ERAs: bosentan, an investigational drug, or both) due to
aminotransferase elevations >3x ULN were treated with Letairis. Prior elevations were
predominantly moderate, with 64% of the ALT elevations <5x ULN, but 9 patients had elevations
>8 x ULN. Eight patients had been re-challenged with bosentan and/or the investigational ERA and
all eight had a recurrence of aminotransferase abnormalities that required discontinuation of ERA
therapy. All patients had to have normal aminotransferase levels on entry to this study. Twenty-ﬁve
of the 36 patients were also receiving prostanoid and/or phosphodiesterase type 5 (PDE5) inhibitor
therapy. Two patients discontinued early (including one of the patients with a prior 8x ULN elevation).
Of the remaining 34 patients, one patient experienced a mild aminotransferase elevation at 12 weeks
on Letairis 5 mg that resolved with decreasing the dosage to 2.5 mg, and that did not recur with later
escalations to 10 mg. With a median follow-up of 13 months and with 50% of patients increasing the
dose of Letairis to 10 mg, no patients were discontinued for aminotransferase elevations. While the
uncontrolled study design does not provide information about what would have occurred with
re-administration of previously used ERAs or show that Letairis led to fewer aminotransferase
elevations than would have been seen with those drugs, the study indicates that Letairis may be tried
in patients who have experienced asymptomatic aminotransferase elevations on other ERAs after
aminotransferase levels have returned to normal. Postmarketing Experience: The following
adverse reactions were identiﬁed during postapproval use of Letairis. Because these reactions
were reported voluntarily from a population of uncertain size, it is not possible to estimate reliably
the frequency or to establish a causal relationship to drug exposure: anemia [see Warnings and
Precautions], ﬂuid retention [see Warnings and Precautions], heart failure (associated with ﬂuid
retention), hypersensitivity (e.g., angioedema, rash), nausea, and vomiting. Elevations of liver
aminotransferases (ALT, AST) have been reported with Letairis use; in most cases alternative causes
of the liver injury could be identiﬁed (heart failure, hepatic congestion, hepatitis, alcohol use,
hepatotoxic medications). Other endothelin receptor antagonists have been associated with
elevations of aminotransferases, hepatotoxicity, and cases of liver failure [see Adverse Reactions].
DRUG INTERACTIONS: Multiple dose co-administration of ambrisentan and cyclosporine resulted in an
approximately 2-fold increase in ambrisentan exposure in healthy volunteers; therefore, limit the dose
of ambrisentan to 5 mg once daily when co-administered with cyclosporine [see Clinical Pharmacology].
USE IN SPECIFIC POPULATIONS: Pregnancy Category X: Risk Summary: Letairis may cause fetal
harm when administered to a pregnant woman and is contraindicated during pregnancy. Letairis was
teratogenic in rats and rabbits at doses which resulted in exposures of 3.5 and 1.7 times respectively
the human dose of 10 mg per day. If this drug is used during pregnancy, or if the patient becomes
pregnant while taking this drug, advise the patient of the potential hazard to a fetus [see
Contraindications, Warnings and Precautions]. Animal Data: Letairis was teratogenic at oral doses of
≥15 mg/kg/day (AUC 51.7 h•μg/mL) in rats and ≥7 mg/kg/day (24.7 h•μg/mL) in rabbits; it was not
studied at lower doses. These doses are of 3.5 and 1.7 times respectively the human dose of 10 mg per
day (14.8 h•μg/mL) based on AUC. In both species, there were abnormalities of the lower jaw and hard
and soft palate, malformation of the heart and great vessels, and failure of formation of the thymus
and thyroid. A preclinical study in rats has shown decreased survival of newborn pups (mid and high
doses) and eﬀects on testicle size and fertility of pups (high dose) following maternal treatment with
ambrisentan from late gestation through weaning. Doses tested were 17x, 51x, and 170x (on a
mg/kg:mg/m2 basis) the maximum oral human dose of 10 mg and an average adult body weight of 70 kg.
Nursing Mothers: It is not known whether ambrisentan is present in human milk. Because many
drugs are present in human milk and because of the potential for serious adverse reactions in nursing
infants from Letairis, a decision should be made whether to discontinue nursing or discontinue Letairis,
taking into account the importance of the drug to the mother. Pediatric Use: Safety and eﬀectiveness
of Letairis in pediatric patients have not been established. Geriatric Use: In the two placebo controlled
clinical studies of Letairis, 21% of patients were ≥65 years old and 5% were ≥75 years old. The elderly
(age ≥65 years) showed less improvement in walk distances with Letairis than younger patients did, but
the results of such subgroup analyses must be interpreted cautiously. Peripheral edema was more
common in the elderly than in younger patients. Females and Males of Reproductive Potential:
Pregnancy Testing: Female patients of reproductive potential must have a negative pregnancy test prior
to initiation of treatment, monthly pregnancy test during treatment, and 1 month after stopping
treatment with Letairis. Advise patients to contact their health care provider if they become pregnant or
suspect they may be pregnant. Perform a pregnancy test if pregnancy is suspected for any reason. For
positive pregnancy tests, counsel patient on the potential risk to the fetus and patient options [see Boxed
Warning and Dosage and Administration]. Contraception: Female patients of reproductive potential must
use acceptable methods of contraception during treatment with Letairis and for 1 month after stopping
treatment with Letairis. Patients may choose one highly eﬀective form of contraception (intrauterine
devices (IUD), contraceptive implants, or tubal sterilization) or a combination of methods (hormone
method with a barrier method or two barrier methods). If a partner’s vasectomy is the chosen method
of contraception, a hormone or barrier method must be used along with this method. Counsel patients
on pregnancy planning and prevention, including emergency contraception, or designate counseling by
another healthcare provider trained in contraceptive counseling [see Boxed Warning]. Infertility: Males In
a 6-month study of another endothelin receptor antagonist, bosentan, 25 male patients with WHO
functional class III and IV PAH and normal baseline sperm count were evaluated for eﬀects on testicular
function. There was a decline in sperm count of at least 50% in 25% of the patients after 3 or 6 months
of treatment with bosentan. One patient developed marked oligospermia at 3 months and the sperm
count remained low with 2 follow-up measurements over the subsequent 6 weeks. Bosentan was
discontinued and after 2 months the sperm count had returned to baseline levels. In 22 patients who
completed 6 months of treatment, sperm count remained within the normal range and no changes in
sperm morphology, sperm motility, or hormone levels were observed. Based on these ﬁndings and
preclinical data [see Nonclinical Toxicology] from endothelin receptor antagonists, it cannot be excluded
that endothelin receptor antagonists such as Letairis have an adverse eﬀect on spermatogenesis.
Counsel patients about the potential eﬀects on fertility [see Warnings and Precautions]. Renal
Impairment: The impact of renal impairment on the pharmacokinetics of ambrisentan has been
examined using a population pharmacokinetic approach in PAH patients with creatinine clearances
ranging between 20 and 150 mL/min. There was no signiﬁcant impact of mild or moderate renal
impairment on exposure to ambrisentan [see Clinical Pharmacology]. Dose adjustment of Letairis in
patients with mild or moderate renal impairment is therefore not required. There is no information on
the exposure to ambrisentan in patients with severe renal impairment. The impact of hemodialysis on
the disposition of ambrisentan has not been investigated. Hepatic Impairment: Pre-existing
hepatic impairment: The inﬂuence of pre-existing hepatic impairment on the pharmacokinetics of
ambrisentan has not been evaluated. Because there is in vitro and in vivo evidence of signiﬁcant
metabolic and biliary contribution to the elimination of ambrisentan, hepatic impairment would be
expected to have signiﬁcant eﬀects on the pharmacokinetics of ambrisentan [see Clinical Pharmacology].
Letairis is not recommended in patients with moderate or severe hepatic impairment. There is no
information on the use of Letairis in patients with mild pre-existing impaired liver function; however,
exposure to ambrisentan may be increased in these patients. Elevation of Liver Transaminases:
Other endothelin receptor antagonists (ERAs) have been associated with aminotransferase (AST, ALT)
elevations, hepatotoxicity, and cases of liver failure [see Adverse Reactions]. In patients who develop
hepatic impairment after Letairis initiation, the cause of liver injury should be fully investigated.
Discontinue Letairis if aminotransferase elevations >5x ULN or if elevations are accompanied by
bilirubin >2x ULN, or by signs or symptoms of liver dysfunction and other causes are excluded.
OVERDOSAGE: There is no experience with overdosage of Letairis. The highest single dose of Letairis
administered to healthy volunteers was 100 mg and the highest daily dose administered to patients with
PAH was 10 mg once daily. In healthy volunteers, single doses of 50 mg and 100 mg (5 to 10 times the
maximum recommended dose) were associated with headache, ﬂushing, dizziness, nausea, and nasal
congestion. Massive overdosage could potentially result in hypotension that may require intervention.
PATIENT COUNSELING INFORMATION: See FDA-approved patient labeling (Medication Guide).
Embryo-fetal toxicity: Instruct patients on the risk of fetal harm when Letairis is used in pregnancy
[see Warnings and Precautions; Use in Special Populations]. Female patients must enroll in
the Letairis REMS Program. Instruct Females of Reproductive Potential to immediately contact their
physician if they suspect they may be pregnant. Letairis REMS Program: For female patients,
Letairis is only available through a restricted program called the Letairis REMS [see Contraindications,
Warnings and Precautions]. Male patients are not enrolled in the Letairis REMS. Inform female patients
(and their guardians, if applicable) of the following notable requirements: All female patients must
sign an enrollment form. Advise female patients of reproductive potential that they must comply with
the pregnancy testing and contraception requirements [see Use in Speciﬁc Populations]. Educate and
counsel Females of Reproductive Potential on the use of emergency contraception in the event of
unprotected sex or known or suspected contraceptive failure. Advise pre-pubertal females to report
any changes in their reproductive status immediately to their prescriber. Review the Letairis
Medication Guide and REMS educational material with female patients. A limited number of
pharmacies are certiﬁed to dispense Letairis. Therefore, provide patients with the telephone number
and website for information on how to obtain the product. Hepatic Eﬀects: Some members of this
pharmacological class are hepatotoxic. Patients should be educated on the symptoms of potential liver
injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant abdominal
discomfort, jaundice, dark urine or itching) and instructed to report any of these symptoms to their
physician. Hematological Change: Patients should be advised of the importance of hemoglobin
testing. Administration: Patients should be advised not to split, crush, or chew tablets.
GS22-081-012
For detailed information, please see full Prescribing Information.
To learn more: call 1-800-GILEAD-5 (Option 2) or visit www.letairis.com.
Manufactured and marketed by: Gilead Sciences, Inc., Foster City, CA 94404, USA
© 2013 Gilead Sciences, Inc. All rights reserved. LETP0055 August 2013
Letairis is a registered trademark of Gilead Sciences, Inc.
Gilead and the Gilead logo are trademarks of Gilead Sciences, Inc.
Other brands noted herein are the property of their respective owners.
STAY SHARP
WITH YOUR PAH
KNOWLEDGE
The PHA Medical Education On-Demand Program
is designed to improve competence, performance
and patient care practices by instructing clinicians
in the highest quality of care for patients with
pulmonary arterial hypertension (PAH). At the
conclusion of this CME program, participants
should be able to:
Accurately diagnose patients through
comprehensive screening and early
recognition of symptoms
Evaluate the patient’s condition and
prescribe long-term optimal management
Medical professionals can also request an OnDemand Program designed to meet your medical
team’s PAH educational needs.
Washington University designates this live activity for a
maximum of 1.5 AMA PRA Category 1 Credits™
For a full listing of On-Demand Program
events or to request your own program, visit:
www.PHAssociation.org/
OnDemand
Advances in
Pulmonary Hypertension
NON-PROFIT ORG.
US POSTAGE
PAID
Lancaster, PA
Permit #161
Pulmonary Hypertension Association
801 Roeder Road, Suite 1000
Silver Spring, MD 20910-4496
To order additional copies, call or contact PHA at 1-866-474-4742 or www.PHAssociation.org.
All issues of Advances in Pulmonary Hypertension are also available online at www.PHAOnlineUniv.org/Journal
Program Announcement:
New Application Deadline: June 12, 2014
New Application Deadline: October 12, 2014
Pulmonary Hypertension
Association (PHA)
Resubmission Deadline: March 12, 2014
Resubmission Deadline: July 12, 2014
National Heart, Lung, and
Blood Institute (NHLBI)
Jointly Sponsored
Mentored Clinical Scientist Development Award (K08) &
Mentored Patient-Oriented Research Career Development Award (K23)
PURPOSE: K08
• To support the development of outstanding clinician research
scientists in the area of pulmonary hypertension.
• To provide specialized study for clinically trained professionals
who are committed to a career in research in pulmonary
hypertension and have the potential to develop into independent
investigators.
• To support a 3 to 5 year period of supervised research experience that integrates didactic studies with laboratory or clinically
based research.
• To support research that has both intrinsic research importance
and merit as a vehicle for learning the methodology, theories,
and conceptualizations necessary for a well-trained independent
researcher.
MECHANISM:
Awards in response to the program announcement will use the
National Institutes of Health (NIH) K08 or the K23 mechanism.
FUNDING:*
The award will be funded by PHA and NHLBI and the K08
and/or the K23 will be awarded in 2013.
PURPOSE: K23
• To support career development of investigators who have
made a commitment to focus their research endeavors on
patient-oriented research.
• To support a 3 to 5 year period of supervised study and
research for clinically trained professionals who have the
potential to develop into productive, clinical investigators
focusing on patient-oriented research in pulmonary hypertension.
• To support patient-oriented research, which is deÀned as
research conducted with human subjects (or on material of
human origin, such as tissues, specimens, and cognitive
phenomena) for which an investigator directly interacts with
human subjects.
• To support areas of research that include: 1) mechanisms of
human disease; 2) therapeutic interventions; 3) clinical trials;
and 4) development of new technologies.
FOR MORE INFORMATION:
Visit: www.PHAssociation.org/MedicalProfessionals/Research
* Restrictions apply. Please see complete announcement
at the website listed above.
Advances in
Pulmonary Hypertension
NON-PROFIT ORG.
US POSTAGE
PAID
Lancaster, PA
Permit #161
Pulmonary Hypertension Association
801 Roeder Road, Suite 1000
Silver Spring, MD 20910-4496
To order additional copies, call or contact PHA at 1-866-474-4742 or www.PHAssociation.org.
All issues of Advances in Pulmonary Hypertension are also available online at www.PHAOnlineUniv.org/Journal
Program Announcement:
New Application Deadline: June 12, 2014
New Application Deadline: October 12, 2014
Pulmonary Hypertension
Association (PHA)
Resubmission Deadline: March 12, 2014
Resubmission Deadline: July 12, 2014
National Heart, Lung, and
Blood Institute (NHLBI)
Jointly Sponsored
Mentored Clinical Scientist Development Award (K08) &
Mentored Patient-Oriented Research Career Development Award (K23)
PURPOSE: K08
• To support the development of outstanding clinician research
scientists in the area of pulmonary hypertension.
• To provide specialized study for clinically trained professionals
who are committed to a career in research in pulmonary
hypertension and have the potential to develop into independent
investigators.
• To support a 3 to 5 year period of supervised research experience that integrates didactic studies with laboratory or clinically
based research.
• To support research that has both intrinsic research importance
and merit as a vehicle for learning the methodology, theories,
and conceptualizations necessary for a well-trained independent
researcher.
MECHANISM:
Awards in response to the program announcement will use the
National Institutes of Health (NIH) K08 or the K23 mechanism.
FUNDING:*
The award will be funded by PHA and NHLBI and the K08
and/or the K23 will be awarded in 2013.
PURPOSE: K23
• To support career development of investigators who have
made a commitment to focus their research endeavors on
patient-oriented research.
• To support a 3 to 5 year period of supervised study and
research for clinically trained professionals who have the
potential to develop into productive, clinical investigators
focusing on patient-oriented research in pulmonary hypertension.
• To support patient-oriented research, which is deÀned as
research conducted with human subjects (or on material of
human origin, such as tissues, specimens, and cognitive
phenomena) for which an investigator directly interacts with
human subjects.
• To support areas of research that include: 1) mechanisms of
human disease; 2) therapeutic interventions; 3) clinical trials;
and 4) development of new technologies.
FOR MORE INFORMATION:
Visit: www.PHAssociation.org/MedicalProfessionals/Research
* Restrictions apply. Please see complete announcement
at the website listed above.