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Pulmonary HypertensionOff icial Journal of the Pulmonary Hypertension Association

Advances in

Just as the Pulmonary Hypertension Association is the only organization devoted

solely to finding ways to prevent and cure pulmonary hypertension, and to provide

hope for the pulmonary hypertension community through support, education,

research, advocacy and awareness, Advances in Pulmonary Hypertension, the official

journal of the Pulmonary Hypertension Association, is the only publication

directed solely to clinicians involved with PH patients.

Advances in Pulmonary Hypertension’s mission is to serve as the premier forum

for state-of-the-art information regarding diagnosis, pathophysiology, and

treatment of patients with pulmonary hypertension.

The quarterly, theme-based issues of Advances in Pulmonary Hypertension

provide an unparalleled forum for knowledge you need for your patients. Each

issue includes a combination of

Guided by a global editorial board, internationally-known researchers and

practitioners provide comprehensive reviews on topics related to the care of PH

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Vol 12, No 2; 2013

ISSN 1933-088X

Pulmonary HypertensionOff icial Journal of the Pulmonary Hypertension Association

Advances in

Preoperative Assessment and Management of Liver Transplant Candidates With Portopulmonary Hypertension Rodrigo Cartin-Ceba, MD Michael J. Krowka, MD

Perioperative Evaluation and Management of Patients With Portopulmonary Hypertension Aiming for Orthotopic Liver Transplantation José L. Díaz-Gómez, MD; Pablo Moreno Franco, MD; Juan M. Canabal, MD; Samuel Irefin, MD; Charles D. Burger, MD

Pulmonary Hypertension in Patients With Chronic Kidney Disease: Noninvasive Strategies for Patient Phenotyping and Risk Assessment Amresh Raina, MD

Hemodynamic Evaluation of Pulmonary Hypertension in Chronic Kidney Disease Ryan J. Tedford, MD Paul R. Forfia, MD

Pulmonary Hypertension Roundtable: The Challenging Spectrum of PH in Liver and Kidney Transplantation Patients

PHPN: Drug Interactions of Current Pulmonary Arterial Hypertension Therapies in Abdominal Organ Transplant Recipients Patricia A. Uber, BS, PharmD

Ask the Expert: Nutritional Assessment in Patients With Pulmonary Arterial Hypertension Facing Transplantation Beth Coplan, RD, CDE

Evaluation and Management of Pulmonary Hypertension in Patients with End-Stage Renal or Liver Disease

ISSN 1933-088X

Editorial Advisory Board

Editor-in-ChiefMyung Park, MDAssociate Professor of MedicineDirector, Pulmonary Vascular Diseases

ProgramDivision of CardiologyUniversity of Maryland School of

MedicineBaltimore, Maryland

Immediate Past Editor-in-ChiefErika Berman Rosenzweig, MDAssociate Professor of Clinical Pediatrics

in MedicineDirector, Pulmonary Hypertension CenterColumbia University College of

Physicians and SurgeonsMorgan Stanley Children’s Hospital of

New YorkNew York, New York

Editor-in-Chief ElectCharles Burger, MDProfessor of MedicineMayo Clinic College of MedicineMedical Director, PH ClinicMayo Clinic FloridaJacksonville, Florida

Associate EditorsHarrison Farber, MDProfessor of MedicineDirector, Pulmonary Hypertension CenterBoston University/Boston Medical CenterBoston, Massachusetts

Deborah Jo Levine, MDAssociate ProfessorPulmonary and Critical Care MedicineLung Transplant PulmonologistDirector of Pulmonary Hypertension CenterDivision of Cardiothoracic SurgeryUniversity of Texas Health Science

Center at San AntonioSan Antonio, TexasSection Editor

Omar A. Minai, MDDepartment of Pulmonary, Allergy and

Critical Care MedicineCleveland ClinicCleveland, Ohio

Fernando Torres, MDDirector, Pulmonary Hypertension ClinicUniversity of Texas Southwestern Medical

CenterDallas, TexasInternational Editor

Editorial BoardLynette M. Brown, MDAssistant Professor of MedicineUniversity of Utah School of MedicineMurray, Utah

Kelly Chin, MDAssistant Professor of MedicineUniversity of Texas Southwestern Medical

CenterDallas, TexasSection Editor

Curt Daniels, MDDirector, Adult Congenital Heart Disease

and Pulmonary Hypertension ProgramNationwide Children’s HospitalThe Ohio State UniversityColumbus, Ohio

Jeffrey D. Edelman, MDAssociate Professor of MedicinePulmonary and Critical Care DivisionUniversity of WashingtonVA Puget Sound Health Care SystemSeattle, Washington

Paul Forfia, MDAssociate Professor of MedicineMedical Director, Pulmonary

Hypertension Program and RightHeart Failure

Temple Heart and Vascular CenterTemple University School of MedicinePhiladelphia, Pennsylvania

Sean Gaine, MD, PhDDirector, National Pulmonary

Hypertension UnitMater Misericordiae University HospitalUniversity College DublinDublin, Ireland

Dunbar Ivy, MDProfessor of PediatricsUniversity of ColoradoDenver Health Sciences CenterDenver, Colorado

Richard Krasuski, MDDirector of Adult Congenital Heart

Disease ServicesCleveland ClinicCleveland, Ohio

Ioana Preston, MDCo-Director, Pulmonary Hypertension

CenterTufts Medical CenterBoston, MassachusettsSection Editor

Sean M. Studer, MD, MScChief of MedicineWoodhull Medical CenterNew York UniversityNew York, New YorkSection Editor

Mary Bartlett, MS, RN, CS, FNPCoordinator, Winthrop University

HospitalPulmonary Hypertension CenterMineola, New YorkPHPN Section Editor

Program DescriptionThe mission of Advances in Pulmonary Hy-pertension is to serve as the premiere forumfor state of the art information regardingdiagnosis, pathophysiology, and treatmentof pulmonary hypertension. The 2008 DanaPoint revision of the World Health Orga-nization Classification serves as a guide tocategories of pulmonary hypertension ad-dressed in Advances in Pulmonary Hyperten-sion. While focusing on WHO Group 1PAH, the other categories (Group 2, pul-monary venous hypertension; Group 3, as-sociated with chronic lung disease and/orhypoxemia; Group 4, pulmonary embolichypertension; Group 5, miscellaneous) arealso addressed. This mission is achieved bya combination of invited review articles,roundtable discussions with panels consist-ing of international experts in PH, and orig-inal contributions.

Objectives● Provide up-to-date information regard-

ing diagnosis, pathophysiology, and treat-ment of pulmonary hypertension.

● Serve as a forum for presentation anddiscussion of important issues in the field,including new paradigms of disease un-derstanding and investigational trialdesign.

The Scientific Leadership Council of the Pulmonary Hypertension AssociationThe 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, MDChair, SLCHarvard Medical SchoolBoston, Massachusetts

Karen A. Fagan, MDChair Elect, SLCUniversity of South AlabamaMobile, Alabama

Vallerie V. McLaughlin, MDImmediate Past Chair, SLCUniversity of MichiganAnn Arbor, Michigan

Charles Burger, MDMayo Clinic College of MedicineJacksonville, Florida

Murali Chakinala, MDWashington University School of

MedicineSt. Louis, Missouri

Serpil Erzurum, MDChair, Research CommitteeCleveland Clinic Lerner College of

Medicine of Case Western ReserveUniversity

Cleveland, OhioMarc Humbert, PhD, MDHopital Antoine BeclereClamart, France

Dunbar Ivy, MDUniversity of Colorado Denver Health

Sciences CenterDenver, ColoradoZhi-Cheng Jing, MDFu Wai Heart HospitalShanghai, China

Dinesh Khanna, MBBS, MScUniversity of MichiganAnn Arbor, Michigan

James Klinger, MDThe Warren Alpert Medical School of

Brown UniversityProvidence, Rhode Island

Irene M. Lang, MDMedical University of ViennaVienna, Austria

Stephen C. Mathai, MD, MHSJohns Hopkins UniversityBaltimore, Maryland

Michael Mathier, MDChair, PHA Online UniversityUniversity of Pittsburgh Medical CenterPittsburgh, Pennsylvania

John Newman, MDVanderbilt University School of MedicineNashville, Tennessee

Ronald J. Oudiz, MDChair, Insurance and Advocacy CommitteeUCLA School of MedicineTorrance, California

Myung Park, MDEditor-in-Chief, Advances in Pulmonary

HypertensionUniversity of Maryland Medical CenterBaltimore, Maryland

Ioana Preston, MDTufts Medical CenterBoston, Massachusetts

Tomas Pulido, MDNational Heart InstituteMexico City, Mexico

Erika Berman Rosenzweig, MDColumbia UniversityNew York, New York

Robert Schilz, DO, PhDChair, SLC Education CommitteeCase Western Reserve University School

of MedicineCleveland, Ohio

Virginia Steen, MDGeorgetown University Medical CenterWashington, DC

Duncan Stewart, MDThe Ottawa HospitalOttawa, ON, Canada

Sean Studer, MD, MScNew York UniversityNew York, New YorkFernando Torres, MDUT Southwestern Medical CenterDallas, TexasTerence Trow, MDYale School of MedicineNew Haven, ConnecticutJoel A. Wirth, MDTufts University School of MedicineBoston, Massachusetts

Roham Zamanian, MDStanford School of MedicineStanford, CaliforniaLiaisonsTraci Stewart, RN, MSNChair, PH Professional NetworkUniversity of Iowa Hospitals and ClinicsIowa City, IowaMelisa Wilson, ARNP, ACNP-BCChair-elect, PH Professional NetworkOrlando Heart Center DowntownOrlando, Florida

Rita Orth, RNPHA Board MemberDanville, California

SLC Distinguished AdvisorsDavid B. Badesch, MDUniversity of Colorado Health Sciences

CenterAurora, Colorado

Bruce H. Brundage, MDDavid Geffen School of Medicine at

UCLA, emeritusPalm Desert, California

C. Gregory Elliott, MDUniversity of Utah School of MedicineMurray, Utah

Michael D. McGoon, MDMayo ClinicRochester, Minnesota

The mission of the Scientific LeadershipCouncil is to provide medical and scientificguidance and support to the PHA for:

● Developing and disseminating knowledgefor diagnosing and treating pulmonaryhypertension.

● Advocating for patients with pulmonaryhypertension.

● Increasing involvement of basic and clin-ical researchers and practitioners.

More information on PHA’s ScientificLeadership Council and associated commit-tees can be found at www.PHAssociation.org/SLC/

50 Editor’s MemoMyung H. Park, MD

50 Guest Editor’s MemoCharles D. Burger, MD; Paul R. Forfia, MD

53 Clinical Trials Update55 Article Reviews60 Preoperative Assessment and Management of Liver Transplant Candidates

With Portopulmonary HypertensionRodrigo Cartin-Ceba, MD; Michael J. Krowka, MD

68 Perioperative Evaluation and Management of Patients With PortopulmonaryHypertension Aiming for Orthotopic Liver TransplantationJose L. Diaz-Gomez, MD; Pablo Moreno Franco, MD; Juan M. Canabal, MD;Samuel Irefin, MD; Charles D. Burger, MD

75 Clinical Case Studies in Renal Transplantation76 Pulmonary Hypertension in Patients With Chronic Kidney Disease:

Noninvasive Strategies for Patient Phenotyping and Risk AssessmentAmresh Raina, MD

82 Hemodynamic Evaluation of Pulmonary Hypertension in Chronic KidneyDiseaseRyan J. Tedford, MD; Paul R. Forfia, MD

88 Pulmonary Hypertension Roundtable: The Challenging Spectrum of PH inLiver and Kidney Transplantation PatientsCharles D. Burger, MD; Paul R. Forfia, MD; Michael Krowka, MD;Jose Diaz-Gomez, MD; Anna Hemnes, MD; Michael Mathier, MD

94 PHPN: Drug Interactions of Current Pulmonary Arterial HypertensionTherapies in Abdominal Organ Transplant RecipientsPatricia A. Uber, BS, PharmD

96 Ask the Expert: Nutritional Assessment in Patients With Pulmonary ArterialHypertension Facing TransplantationBeth Coplan, RD, CDE

102 News to Use

Advances inPulmonary HypertensionOfficial Journal of the Pulmonary Hypertension Association

CONTENTSPUBLISHERPulmonary Hypertension AssociationVallerie McLaughlin, MD, Board ChairRino Aldrighetti, President and CEO

PHA OFFICEPulmonary Hypertension Association801 Roeder Road, Ste 1000Silver Spring, MD 20910301-565-3004; 301-565-3994 (fax)

PUBLISHING OPERATIONSDeborah L. McBride,Managing EditorMcBride Strategic [email protected]

Copyright ©2013 by Pulmonary HypertensionAssociation. All rights reserved. None of thecontents may be reproduced in any formwhatsoever without the written permission ofPHA.

Advances in Pulmonary Hypertension is availableonline at www.PHAOnlineUniv.org/journal

Advances in Pulmonary Hypertension iscirculated to cardiologists, pulmonologists,rheumatologists, and other selected healthcareprofessionals by the Pulmonary HypertensionAssociation. The contents of the articles areindependently determined by the Editor-in-Chief and the Editorial Advisory Board.

Advances in Pulmonary Hypertension: Author Guidelines

General InformationAdvances in Pulmonary Hypertension: Official Journal of thePulmonary Hypertension Association is a quarterly publi-cation directed by an editorial board of renowned expertswith the oversight of the Association’s Scientific Lead-ership Council. Its mission is to help physicians in theirclinical decision making by informing them of importanttrends affecting their practice and providing an analysis ofthe impact of new findings and current information in thepeer-reviewed literature. Each article is reviewed andapproved by members of the Editorial Advisory Board.

While most articles are invited by the editorial board, thefollowing submissions will be considered for publication:

• Reviews that summarize and synthesize peer-reviewedliterature to date on relevant topics

• Letters to the Editor• Clinical case studies

Submitted manuscripts are reviewed by the editorial boardand other experts in the field. Acceptance of manuscriptsis determined by factors such as quality, relevance, andperceived value to clinical decision making.

Manuscript Preparation and Submission ProcessSubmissions should be sent via e-mail as an attachedWord document to the Editor-in-Chief, Myung Park,

MD, at [email protected] Manuscriptsshould be double-spaced and follow AMA style. Full-length manuscripts should not exceed 4,000 wordsincluding references. References should be limited to 50entries. No more than 5 figures should accompany themanuscript. Acceptable file formats are .gif, .tif, and .jpg.Each figure should be a separate file and figure legendsshould appear at the end of the manuscript. Each figureshould be cited by number in the manuscript. Tablesshould be self-explanatory and details of the table shouldnot be repeated in the manuscript. Tables should be pre-pared as part of the Word document. No more than 3tables should be included with the manuscript. Referencesshould conform to AMA style and be numbered consecu-tively in the text. Reference numbers should be placed inparentheses at the end of the relevant sentence.

Accepted manuscripts will be edited for clarity, spelling,punctuation, grammar, and consistency with AMA style.

CopyrightAuthors must confirm they have rights to all material sub-mitted by including a copyright release form with themanuscript. The form can be downloaded from the PHAWeb site, www.PHAssociation.org. Authors acknowledgethe material has not been previously published nor is beingconsidered for publication elsewhere simultaneously withconsideration by Advances in Pulmonary Hypertension.

Any previously published figures, tables, etc. must containa full credit-line from the copyright owner. Authors areresponsible for obtaining permission to reproduce suchmaterial and must provide that material in reproducibleform.

Manuscripts are accepted for exclusive publication inAdvances in Pulmonary Hypertension and will be copy-righted by the Pulmonary Hypertension Association.

Conflict of Interest DisclosuresA statement of any and all grant, contract, and industrialsupport or proprietary interests of the author(s) related tothe subject matter must be submitted with the manuscript.

ChecklistAuthors should be certain to include the following withthe manuscript:

1. Title page listing all authors with their academicdegree(s) and affiliations.

2. Corresponding author contact information includinge-mail and phone number.

3. Copyright release form signed by all authors4. Conflict of Interest forms for all authors5. List of approximately 5 key words for indexing

purposes6. Summary of the paper not exceeding 250 words in the

format of Background; Objectives; Summary/Conclusions

49Advances in Pulmonary Hypertension Volume 12, Number 2; 2013

EDITOR’S MEMO

Kidney and Liver Transplantand Pulmonary Hypertension:Navigating Through theObstacle Course

Facing the news of needing kidney orliver transplant is a daunting prospectthat many of our patients face. Indeed,according to the latest census by theOrgan Procurement Transplant Network(OPTN) database, there are 15,841patients on the waiting list for livertransplant and 97,511 for the kidneytransplant. Among these, 6,256 liver and16,485 kidney transplants were per-formed in U.S. in 2012. For those withend stage liver and kidney disease, trans-plant offers a second chance at life.

So being told by your physician thatyour echocardiogram shows pulmonaryhypertension and that evaluation has tobe on hold until further input can be

obtained is devastating news. This ishow patients are often referred to us, inthe midst of confusion and dread hopingthat we will be able to tell them that “allis well” and that they can proceed withthe transplant that they desperately need.As any clinician who has been consultedfor this reason can attest, this is a verydifficult situation. On one hand, you donot wish to take away the chance for alife-saving measure but you also wish toavoid the prospect of a poor outcome foryour patient as well as wasting a valuableresource.

Having experienced this difficultdilemma many times myself, it is mysincere pleasure to present to you thisissue which focuses on evaluating andmanaging patients with portopulmonaryhypertension and end stage kidneydisease with PH who require a trans-plant. I am very grateful to our GuestEditors, Dr. Charles Burger and Dr.

Paul Forfia, who have assembled arenowned group of experts to helpanswer the difficult questions that oftenarise such as: how do you managepatients with portopulmonary hyper-tension who have elevated pulmonaryartery pressure and yet, normal pul-monary vascular resistance? how do youinterpret hemodynamics in patients onhemodialysis with fistula? These ques-tions and much more are discussed inthe articles with lively and compellingdialogue in the Roundtable section.

I sincerely hope that you find thisissue helpful the next time you are asked“I think this patient has PH. Can theyundergo transplant?”

Myung H. Park, MDAssociate Professor of MedicineDirector, Pulmonary Vascular DiseaseProgramUniversity of Maryland School of Medicine

GUEST EDITOR’S MEMO

We are excited about the current issue ofAdvances, as the authors have done anexcellent job reviewing the challengesfaced by patients with pulmonary hyper-tension (PH) in the setting of end-stagehepatic or renal disease. The selection ofthis topic is a result of the many chal-lenges presented by these patient types,but also the need to contrast the differ-ences between the 2 disease states—notonly for our PH community but also forour transplant colleagues. The 4 primaryarticles have been designated to reviewthe pretransplant evaluation and care ofeach disease state, followed by a reviewof the peri- and postoperative man-agement, respectively.

Determination of the exact cause ofthe PH in patients with liver disease iscritical, as the clinical implications andapproach to treatment vary with the eti-ology. Drs Cartin-Ceba and Krowkahave produced an outstanding update forthe pretransplant evaluation, emphasizingan algorithmic approach and utilizingscreening echocardiogram with diag-nostic right heart catheterization. Thepriority is to maximize the patient’sopportunity for safe transplantation;therefore, goal-directed pharmacologicaltreatment for portopulmonary hyper-tension is reviewed. The immediate

perioperative and postoperative care ofportopulmonary hypertension can beequally if not more challenging and isnicely reviewed by Dr Diaz-Gomez andhis colleagues. A multidisciplinary teamapproach to care, utilization of bedsideand intraoperative echocardiography, andcurrent treatment experience are empha-sized.

It is equally important to determinethe cause of PH in patients with chronickidney disease, as the implications, inter-ventions, and impact of PH ontransplant candidacy varies considerably.Simply diagnosing a patient with “pul-monary hypertension” does not suffice,as this diagnosis does not provide nearlysufficient detail to appropriately addresspatient management and transplant can-didacy. Dr Raina provides an excellentdiscussion on the approach to patientswith PH and chronic kidney diseasebased on noninvasive assessment, withan emphasis on how to optimally use theecho-Doppler examination to determinethe hemodynamic basis of the PHreliably and prior to invasive evaluation.Dr Tedford explores the invasive hemo-dynamic evaluation of the patient withPH and chronic kidney disease, with asophisticated discussion of PH hemody-namics and how to consider unique

aspects of PH in this setting, ie, the roleof an arteriovenous fistula in a patientwith PH and end-stage renal disease.

In both the liver and renal diseasearticles, the authors appropriatelyemphasize the importance of the com-bined assessment of pulmonary vascularload (ie, pulmonary vascular resistance)and right heart function in order to gainthe most insight into the impact of PHon any individual patient. We hope thatthis series of articles provides perspectiveand practical information about PH inthe setting of advanced liver and kidneydisease so that providers may be betterinformed on how to approach thesecomplex patients.

Charles D. Burger, MDAssociate Professor of MedicineMedical Director, PH ClinicMayo Clinic FloridaJacksonville, Florida

and

Paul R. Forfia, MDAssociate Professor of MedicineMedical Director, Pulmonary HypertensionProgram and Right Heart FailureTemple University School of MedicinePhiladelphia, Pennsylvania

50 Advances in Pulmonary Hypertension Volume 12, Number 2; 2013

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

IMPORTANT SAFETY INFORMATION + Tyvaso is intended for oral inhalation only. Tyvaso is approved

for use only with the Tyvaso Inhalation System

+ The safety and effi cacy of Tyvaso have not been established in

patients with signifi cant 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 eff ect

+ 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 insuffi ciency may increase exposure to Tyvaso and

decrease tolerability. Tyvaso dosage adjustments may be necessary

if inhibitors of CYP2C8 such as gemfi brozil or inducers such as

rifampin are added or withdrawn

+ The most common adverse events seen with Tyvaso in ≥4% of PAH

patients and more than 3% greater than placebo in the placebo-

controlled clinical study were cough (54% vs 29%), headache (41% vs

23%), throat irritation/pharyngolaryngeal pain (25% vs 14%), nausea

(19% vs 11%), fl ushing (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.

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

+ 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 sildenafi l 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

INDICATIONTyvaso is a prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability. Studies establishing eff ectiveness 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 eff ects 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 sildenafi l (a phosphodiesterase type 5 inhibitor). The controlled clinical experience was limited to 12 weeks in duration.

Request a visit from a Tyvaso sales representative by scanning this QR code with your smartphone or by visiting www.tyvasorep.com.

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. Sildenafi l 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 fi le. 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.

www.tyvaso.com 1-877-UNITHER

COULD YOURSTABLE PATIENTSON ORAL MONOTHERAPYBENEFIT FROM ADD-ONTHERAPY WITH TYVASO?

MORETO DO MORE

For PAH (WHO Group 1) patients on oral monotherapy

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:

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.

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.

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 n = 115

Placebo n = 120

Cough 62 (54) 35 (29)

Headache 47 (41) 27 (23)

Throat Irritation/ Pharyngolaryngeal Pain 29 (25) 17 (14)

Nausea 22 (19) 13 (11)

Flushing 17 (15) 1 (<1)

Syncope 7 (6) 1 (<1)

*More than 3% greater than placebo

CLINICAL TRIALS UPDATE

Recent Phase 3 Results

Section EditorsDeborah J. Levine, MDFernando Torres, MD

The Clinical Trials Update highlights new and ongoing research trials that are evalu-ating therapies for PAH. In this issue, Deborah Levine, MD, examines thePATENT-1 study results, findings from CHEST-1, and outcomes of theSERAPHIN trial.

Three important Phase 3 clinical trialfindings have recently been publishedregarding treatment of pulmonary hyper-tension (PH): PATENT-1 described theresults of treating patients with riociguatfor pulmonary arterial hypertension(PAH); CHEST-1 reported findings onthe treatment of chronic thromboem-bolic pulmonary hypertension (CTEPH)with riociguat; and SERAPHIN dis-cussed using macitentan for PAH.1-4

Riociguat is a soluble guanylase cyclase(sGC) stimulator that, when bound tonitric oxide (NO), enhances synthesis ofcyclic guanosine monophosphate(cGMP), which promotes vasodilatationand decreases proliferation, fibrosis, andinflammation. Riociguat has a dual modeof action: it sensitizes sGC to endog-enous NO by stabilizing the NO-sGCbinding and it also directly stimulatessGC via a different binding site, inde-pendently of NO. Macitentan is a dualendothelin-receptor antagonist (ERA)that was developed by modifying thestructure of bosentan to increase efficacyand safety. It is characterized byenhanced tissue penetration and receptorbinding capability.

PATENT-1PATENT (Pulmonary Arterial Hyper-tension sGC-Stimulator Trial) is a12-week, double blind, randomized,placebo-controlled international multi-center trial. The inclusion criteria listedwere: pulmonary vascular resistance(PVR) �300 dyn/sec/cm5, mean pul-monary artery pressure (mPAP) �25mm Hg, and a 6-minute walk distance(6MWD) of 150-450 m. Patients wereincluded if they had either beenreceiving no other PAH therapy or ifthey were receiving either ERAs or non-intravenous prostanoids for PAH (50%

of patients were receiving no othertherapy, 44% were receiving an ERA,and 6% of patients were receiving nonin-travenous prostanoids). Patients wererequired to be on these medications atstable doses for at least 90 days. A totalof 443 patients were randomly assignedto receive riociguat 3 times daily (TID)with dose titration to 2.5 mg TID,placebo TID, or riociguat TID withcapped titration at 1.5 mg TID. Thepatients receiving the dose capped at1.5 mg TID were not included in theefficacy analysis.

The primary endpoint was change inthe 6MWD from baseline until the endof the study (12 weeks). Secondary end-points included changes in the PVR,N-terminal pro-brain natriuretic peptide(NT-proBNP), World Health Organi-zation (WHO) functional class, time toclinical worsening, Borg scores, andquality of life scores.

There was a statistically significantimprovement in 6MWD at Week 12 inthe riociguat group (�30 m) comparedwith the placebo group (-6m), for a totalchange of 36 meters. This effect wasseen across both patients on and not onprior PAH therapy. Both PVR andNT-proBNP levels decreased signifi-cantly. The time to clinical worseningwas increased and the Borg scoreimproved in the riociguat group. Thesebenefits of the riociguat group weremaintained at 24 weeks, seen in thelong-term extension study(PATENT-2). There was no increasedfrequency of adverse events or discon-tinuations in the riociguat group ascompared to placebo.

These results reflect patients who wereboth on prior PAH therapy and thosewho were receiving no other therapy. Inthose patients not on prior therapy, the

increase in 6MWD may be consideredmodest. However, in patients on priortherapy, improvements were similar tothose in other trials (ie, PHIRST andBREATHE-1). The results also reflectthat riociguat appears to be a safetherapy with a novel mechanism ofaction to add to the armamentarium oftherapies for patients with PAH.

CHEST-1CHEST-1 (A Study to EvaluateEfficacy and Safety of OralBAY63-2521 in Patients WithCTEPH) was a 16-week, multicenter,randomized, double blind, placebo-controlled international trial to evaluateriociguat in patients with CTEPH(Group 4 PH). Patients with eithertechnically inoperable CTEPH orpatients who had undergone pulmonaryendarterectomy but had persistent orrecurrent PH were included in the trial.

Inclusion criteria were: PVR �300dyn/sec/cm5, mPAP �25 mm Hg, anda 6MWD of 150-450 m. Patients wereexcluded if they had received an ERA,phosphodiesterase type 5 (PDE-5)inhibitor, or NO donor 3 months priorto the study. The primary and secondaryendpoints were identical to thePATENT-1 trial. A total of 261patients (173 riociguat, 88 placebo) wererandomly assigned to receive eitherplacebo or riociguat (1, 1.5, 2, or 2.5mg) TID, and the dose was titrated overthe course of 8 weeks.

There was a statistically significantimprovement in 6MWD at 16 weeks inthe riociguat group compared to placebo(46 m difference). PVR and otherhemodynamic parameters (mPAP,cardiac output) improved significantlywhen compared to placebo, as well assignificant decrease in the level of


NT-proBNP, and improvements inWHO functional class. There was nosignificant difference in the incidence ofclinical-worsening events between theriociguat and placebo groups (2% vs 6%;P�0.17).

CHEST-1 demonstrates that riociguatappears to be a safe oral therapy forpatients with inoperable CTEPH andfor those with persistent PH after endar-terectomy. Keeping in mind that patientsshould always be evaluated for CTEPHand that surgery must be the first optionwhenever possible, it would be awelcome additional treatment for thesepatients.

SERAPHINThe SERAPHIN (Study with an Endo-thelin Receptor Antagonist inPulmonary arterial Hypertension toImprove cliNical outcome) trial is thepivotal Phase 3 study designed toevaluate the efficacy and safety ofmacitentan. To date, SERAPHIN is thelargest and longest conducted ran-domized, controlled study in PAHpatients. SERAPHIN is unique amongPAH trials in that it included a clearlydefined primary endpoint of morbidityand all cause-mortality of treatment vsplacebo, making it the first event-drivenPhase 3 trial in PAH.

The primary endpoint was a com-posite endpoint from the time ofinitiation of treatment to the first occur-rence of death, atrial septostomy, lungtransplantation, initiation of treatmentwith intravenous (IV) or subcutaneous(SC) prostanoids, or worsening of PAH.Secondary endpoints includedimprovement in the 6MWD andimprovement in WHO functional class

at 6 months, death due to PAH or hos-pitalization for PAH up to the end oftreatment, and death from any cause upto the end of treatment and up to theend of the study. Laboratory data wereassessed at Months 3 and 6, and 6months after until the end of treatment.

Seven hundred forty-two patients wererandomized 1:1:1 into 1 of 3 treatmentgroups: placebo, 3 mg, and 10 mg a dayof oral macitentan. Use of PDE-5 inhib-itors, oral or inhaled prostanoids, calciumchannel blockers, or L-arginine were allallowed. Any of these therapies had tobe at a stable dose for at least 3 months.Any SC or IV prostanoids wereexcluded. Inclusion criteria were: patients12 years of age and older who had idio-pathic PAH, heritable PAH, or PAHrelated to connective tissue disease,repaired congenital systemic to pul-monary shunts, HIV, or drug or toxinexposure; 6MWD of 50 m or more, andin WHO functional class II, III, or IV.

In this study, macitentan showed asignificant decrease in the morbidity andmortality endpoint. The composite end-point of death due to PAH orhospitalization showed a significanttreatment effect with macitentan (mostlydriven by lower hospitalization in themacitentan groups). A trend in favor ofthe 10 mg dose was noted in all-causemortality. The worsening of PAH wasthe most frequent primary endpointevent. The effect of macitentan on thisendpoint was observed regardless ofbackground therapy for PAH. The sec-ondary endpoints, change from baselineto Month 6 in 6MWD, and WHOfunctional class were statistically signif-icant at both dosages. Macitentan waswell tolerated in the study. The overall

incidence of adverse events reported andtreatment discontinuations was similaracross all groups. The incidence ofserious adverse events was lower inpatients treated with macitentan com-pared to placebo. Compared to placebo,a higher proportion of macitentan-treated patients had nasopharyngitis,headache, and anemia. There were nodifferences in liver function test abnor-malities compared to placebo. Inaddition, no difference in edema wasobserved between macitentan andplacebo.

This study is novel in its morbidity/mortality endpoint. The design, theduration of the study, and the resultsbring up the important issue of whetherthis trial establishes a new baseline ofhow we evaluate new therapies forchronically progressive diseases such asPAH.

All 3 of these important trials werepublished in the last 2 months in theNew England Journal of Medicine. TheFDA is currently reviewing the results ofthese studies for consideration forapproval for treatment of PH.

References1. Ghofrani HA, Galie N, Grimminger F, et al;PATENT-1 Study Group. Riociguat for thetreatment of pulmonary arterial hypertension.N Engl J Med. 2013;369(4):330-340.2. Ghofrani HA, D’Armini AM, Grimminger F,et al; CHEST-1 Study Group. Riociguat for thetreatment of chronic thromboembolic pulmonaryhypertension. N Engl J Med. 2013;369(4):319-329.3. Archer SL. Riociguat for pulmonaryhypertension—a glass half full. N Engl J Med.2013;369(4):386-388.4. Pulido T, Adzerikho I, Channick RN, et al;SERAPHIN Investigators. Macitentan and mor-bidity and mortality in pulmonary arterialhypertension. N Engl J Med. 2013;369(9):809-818.


ARTICLE REVIEWS

Medication and Drug Exposure in PH Patients

Section EditorKelly Chin, MD

Summaries and commentaries from the section editors and invited reviewers presenta clinical context for practitioners’ application of the latest published research relevantto the care of patients with pulmonary hypertension. In this issue Kelly Chin, MD,,discusses 2 recently published articles regarding medication and drug exposures in PHpatients.

Montani D, Bergot E, Gunther S, etal. Pulmonary arterial hypertension inpatients treated by dasatinib. Circu-lation. 2012;125(17):2128-2137.In this French pulmonary hypertension(PH) registry study,1 Montani and col-leagues describe cases of dasatinib-associated PH among their cohort ofpatients. Patients were included in thestudy if they were diagnosed withcatheterization-confirmed PH in thesetting of either (or both) a diagnosis ofchronic myeloid leukemia (CML) ortreatment with dasatinib, imatinib, ornilotinib between 2006 and 2010. NinePH patients met these criteria, all ofwhom had received long-term treatmentwith dasatinib over a median of 34months (range 8-48 months); nopatients receiving imatinib or nilotinibdeveloped PH. Hemodynamics wereconsistent with precapillary PH (normalwedge pressure) with variable severity,including several patients who had evi-dence of right heart failure. Nosecondary causes of PH were identified,including left heart disease, lung disease,or chronic pulmonary embolism.Treatment included an endothelin-1receptor antagonist in 2 patients and acalcium channel blocker in 1 patient whoresponded to a vasodilator challenge, anddasatinib was discontinued in all 9 cases.Some improvement in hemodynamicswas seen in most patients, but none ofthose who underwent follow-up cathe-terization had normalized theirpulmonary arterial pressures.

In the same paper but using a com-bined dataset, Montani and colleaguesalso estimated the PH incidence rateamong dasatinib-exposed patients. Inaddition to their 9 cases, 5 cases of PHassociated with dasatinib were reported

to the French pharmacovigilance agency,resulting in a total of at least 13 cases ofPH over the study period. This was outof 2900 patients receiving dasatinibduring these years, resulting in anincident rate of 0.45% among exposedindividuals. Based on this and otherreports, the French, European, and USdrug agencies have published a warningon the risk of PH in patients treatedwith dasatinib. These results suggest thatdasatinib is capable of causing pulmonaryarterial hypertension (PAH), at least in asubset of patients, and that increasedawareness and close follow-up ofexposed patients is indicated. Strengthsof this study include the comprehensiveclinical and hemodynamic evaluation, thelong-term follow-up, and the use ofmultiple data sources to identify caseswithin France. Montani and colleaguesalso provide a nice overview of thetyrosine kinase inhibitors and theirvarious kinase and nonkinase targets,including future targets that they suggestare worth exploring in PH.

Karch SB, Mari F, Bartolini V, BertolE. Aminorex poisoning in cocaineabusers. Int J Cardiol. 2012;158(3):344-346.Cocaine has been suspected of causingPAH, based on case reports and oninconclusive results from diet-pill andother case-control studies.2-4 However,the mechanism through which this couldoccur has not been definitively deter-mined, particularly because cocaine, as amonoamine reuptake inhibitor, is dif-ferent mechanistically from the diet pillsand other stimulants that have beenassociated with PAH.5 In this reviewarticle by Karch and colleagues,6 an

alternative potential link between cocaineand PAH is described, based on recentwork from their own laboratory. Theypropose that cocaine could be associatedwith PAH because it is often adulteratedwith levamisole, a drug whose metabo-lites include aminorex. Aminorex wasassociated with an epidemic of PH inEurope in the 1960s.

This unexpected metabolite was firstidentified after several dozen racehorsestested positive for aminorex, a bannedstimulant in racing, and it was ultimatelylinked to the use of levamisole as ananthelminthic.7 Follow-up studies con-firmed that levamisole could beconverted to aminorex in both horsesand humans.8,9 In their own recentwork, Karch and colleagues report iden-tifying levamisole and aminorex in overhalf of all cocaine-positive urine samples(62 of 154). Levamisole has also beenidentified in a majority of cocaine seizedin the United States in recent years, andin many samples of cocaine in othercountries. As a result, these authors raisea very valid concern: could aminorexexposure from cocaine lead to PAH?

They conclude their review by statingthat: “The key issue to be addressed nowis not whether humans convertlevamisole to aminorex (we know theycan), or whether aminorex can cause[PAH] (it does). The question thaturgently requires answering is whetherchronic users of levamisole-taintedcocaine actually convert enoughlevamisole into aminorex to cause[PAH]”. This does appear to be the keyquestion, but unfortunately, it is not onethat is going to be easy to answer, bothbecause it is not clear what minimumlevels of aminorex exposure might berequired to cause PAH, and because of


the widely varying dose and compositionof drugs taken illicitly.

In summary, these 2 articles suggestthat medication and drug exposures inPH patients are not just concerns of aprior era, but should remain a focus ofboth clinical assessment and futureresearch in PH.References1. Montani D, Bergot E, Gunther S, et al. Pul-monary arterial hypertension in patients treated bydasatinib. Circulation. 2012;125(17):2128-2137.2. Collazos J, Martinez E, Fernandez A, Mayo J.Acute, reversible pulmonary hypertension associatedwith cocaine use. Respir Med. 1996;90(3):171-174.

3. Chin KM, Channick RN, Rubin LJ. Is meth-amphetamine use associated with idiopathicpulmonary arterial hypertension? Chest. 2006;130(6):1657-1663.4. Abenhaim L, Moride Y, Brenot F, et al.Appetite-suppressant drugs and the risk of primarypulmonary hypertension. International PrimaryPulmonary Hypertension Study Group. N EnglJ Med. 1996;335(9):609-616.5. Rothman RB, Ayestas MA, Dersch CM,Baumann MH. Aminorex, fenfluramine, andchlorphentermine are serotonin transporter sub-strates. Implications for primary pulmonaryhypertension. Circulation. 1999;100(8):869-875.6. Karch SB, Mari F, Bartolini V, Bertol E.Aminorex poisoning in cocaine abusers. IntJ Cardiol. 2012;158(3):344-346.

7. Barker SA. The formation of aminorex inracehorses following levamisole administration. Aquantitative and chiral analysis following syntheticaminorex or levamisole administration vs.aminorex-positive samples from the field: a prelim-inary report. J Vet Pharmacol Ther. 2009;32(2):160-166.8. Bertol E, Mari F, Milia MG, Politi L, Fur-lanetto S, Karch SB. Determination of aminorex inhuman urine samples by GC-MS after use oflevamisole. J Pharm Biomed Anal. 2011;55(5):1186-1189.9. Hess C, Ritke N, Broecker S, Madea B,Musshoff F. Metabolism of levamisole and kineticsof levamisole and aminorex in urine by means ofLC-QTOF-HRMS and LC-QqQ-MS. AnalBioanal Chem. 2013;405(12):4077-4088.


Go to www.letairis.com to learn more.

Please see accompanying brief summary of full Prescribing Information, including BOXED WARNING on the risk of serious birth defects.

© 2013 Gilead Sciences, Inc. All rights reserved. LETP0005 April 2013LETAIRIS is a registered trademark of Gilead Sciences, Inc. Gilead and the Gilead logo are trademarks of Gilead Sciences, Inc.

The goals that matter to you matter to patients

goals

Lisa PowellLETAIRIS patient

LETAIRIS® (ambrisentan) tablets, for oral useBrief Summary of full Prescribing Information. See full Prescribing Information. Rx only.

BOXED WARNING: CONTRAINDICATED IN PREGNANCYDo not administer LETAIRIS to a pregnant woman because it may cause fetal harm. LETAIRIS is very likely to produce serious birth defects if used by pregnant women, as this effect has been seen consistently when it is administered to animals[see Contraindications]. Pregnancy must therefore be excluded before the initiationof treatment with LETAIRIS and prevented during treatment and for one month after stopping treatment by the use of two acceptable methods of contraception unless the patient has had a tubal sterilization or chooses to use a Copper T 380A IUD or LNg 20 IUS, in which case no additional contraception is needed. Obtain monthly pregnancy tests [see Warnings and Precautions]. Because of the risk of birth defects,LETAIRIS is available only through a restricted program under a Risk Evaluation andMitigation Strategy (REMS) called the LETAIRIS Education and Access Program(LEAP). As a component of the LETAIRIS REMS, prescribers, patients, and pharmacies must enroll in the 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 andetiologies of idiopathic or heritable PAH (64%) or PAH associated with connective tissue diseases (32%).

DOSAGE AND ADMINISTRATION: Healthcare professionals who prescribe LETAIRIS must enroll in the restricted program called LEAP and must comply with the required monitoring to ensure safe use of LETAIRIS [see Warnings and Precautions]. ]] 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 dailyhave not been studied in patients with pulmonary arterial hypertension (PAH). Women of Childbearing Potential: Initiate treatment with LETAIRIS in women of childbearing potential only after a negative pregnancy test [see Contraindications, Warnings and Precautions]. ]]

CONTRAINDICATIONS: Pregnancy: LETAIRIS may cause fetal harm when administered to a pregnant woman. Ambrisentan was teratogenic at oral doses of ≥15 mg/kg/day in rats and ≥7 mg/kg/day in rabbits; it was not studied at lower doses. In both species, there were abnormalities of the lower jawand hard and soft palate, malformation of the heart and great vessels, and failure of formation of the thymus and thyroid. Teratogenicity is a class effect of endothelin receptor antagonists. There are nodata on the use of LETAIRIS in pregnant women. LETAIRIS is contraindicated in women who are or may become pregnant. 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. Pregnancy must be excluded before the initiation of treatment with LETAIRIS and prevented during treatment and for one month after stopping treatment [see Dosage and Administration, Warnings and Precautions]. ]] Idiopathic Pulmonary Fibrosis: LETAIRIS is contraindicated in patients with Idiopathic Pulmonary Fibrosis (IPF) including IPF patients with pulmonary hypertension (WHO Group 3).

WARNINGSWW AND PRECAUTIONS: LETAIRIS Education and Access Program (LEAP): Because of the risk of birth defects, LETAIRIS is available only through a restricted program called the LETAIRIS Education and Access Program (LEAP). Required components of LEAP: Healthcare professionals whoprescribe LETAIRIS must complete the LEAP Prescriber Enrollment and Agreement Form, enroll in the program, and comply with the REMS requirements. To receive LETAIRIS, all patients must complete apatient enrollment form and be re-enrolled annually by their prescriber. For women of childbearing potential, (1) a pregnancy test must be ordered and reviewed by the prescriber prior to initiation of LETAIRIS treatment and monthly during treatment, (2) she must agree to be contacted prior to each shipment to confirm that a pregnancy test was completed, (3) she must agree to be counseled on the requirements of the REMS program and the risks of LETAIRIS, and (4) she must agree to be contactedby Gilead if she becomes pregnant while on LETAIRIS or within 30 days of treatment discontinuation.Pharmacies that dispense LETAIRIS must enroll in the program and agree to comply with the REMSrequirements. Further information is available at www.letairisrems.com or 1-866-664-LEAP (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 anincreased 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 somecases, 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 Veno-occlusive Disease: If patientsdevelop 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: In a 6-month study of anotherendothelin 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 withbosentan. 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 discontinuedand 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 preclinicaldata from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as LETAIRIS have an adverse effect on spermatogenesis. Hematological Changes: Decreases inhemoglobin concentration and hematocrit have followed administration of other endothelin

receptor antagonists and were observed in clinical studies with LETAIRIS (ambrisentan). These decreases were observed within the first few weeks of treatment with LETAIRIS, and stabilizedthereafter. The mean decrease in hemoglobin from baseline to end of treatment for those patientsreceiving LETAIRIS in the 12 week placebo-controlled studies was 0.8 g/dL. Marked decreases inhemoglobin (>15% decrease from baseline resulting in a value below the lower limit of normal) wereobserved in 7% of all patients receiving LETAIRIS (and 10% of patients receiving 10 mg) compared to4% 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 twopivotal 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 periodicallythereafter. 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 beenexcluded, consider discontinuing LETAIRIS.

ADVERSE REACTIONS: See Warnings and Precautions for discussion of hematological changes. sClinical 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 forLETAIRIS were obtained from two 12-week, placebo-controlled studies in patients with pulmonaryarterial 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 TT 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) 6Nasal congestion 2 (2) 15 (6) 4Sinusitis 0 (0) 8 (3) 3Flushing 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 clinicaltrials, 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 forcause. 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 elevationswere 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 alleight 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 laterescalations 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 occurredwith 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 ERAsafter 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],]]asthenia, dizziness, fatigue, 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 alternativecauses 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 thedose of ambrisentan to 5 mg once daily when co-administered with cyclosporine.

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. LETP0011 April 2013LETAIRIS 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.

USE IN SPECIFIC POPULATIONS: Pregnancy Category X [see Contraindications]:]] Treat women of childbearing potential only after a negative pregnancy test and treat only women who are using acceptable methods of contraception. Pregnancy tests should be obtained monthly in women of childbearing potential taking LETAIRIS (ambrisentan) [see Warnings and Precautions]. ]] NursingMothers: It is not known whether ambrisentan is excreted in human milk. Breastfeeding whilereceiving LETAIRIS is not recommended. 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 (low, mid, high dose, respectively) the maximum oral human dose of 10 mg on a mg/mm2 basis. 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 suchsubgroup analyses must be interpreted cautiously. Peripheral edema was more common in the elderly than in younger patients. Renal Impairment: The impact of renal impairment on the pharmacokinetics of ambrisentan has been examined using a population pharmacokinetic approachin 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. 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 eliminationof ambrisentan, hepatic impairment would be expected to have significant effects on thepharmacokinetics of ambrisentan. 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 [seeAdverse Reactions]. In patients who develop hepatic impairment after LETAIRIS initiation, the cause of ]]liver injury should be fully investigated. Discontinue LETAIRIS if aminotransferase elevations >5xULN 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 themaximum 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). LETAIRIS Education and Access Program (LEAP): Advise the patient that LETAIRIS is available onlythrough a restricted program called LEAP. As a component of LEAP, prescribers must review the contents of the LETAIRIS Medication Guide and the LETAIRIS Patient Enrollment Guide before initiatingtreatment with LETAIRIS. Inform the patient that LETAIRIS is available only from Certified Specialty Pharmacies enrolled in LEAP. Provide patients with a list of Certified Specialty Pharmacies. As a component of LEAP, Certified Specialty Pharmacies must provide a copy of the Medication Guide to patients or caregivers each time LETAIRIS is dispensed. Patients must be instructed to read theMedication Guide each time they receive LETAIRIS because new information may be available. Inaddition, Certified Specialty Pharmacies must contact patients before each shipment to confirm thatthe patient will be available to receive the LETAIRIS shipment, and, in the case of women of childbearing potential, to confirm that a pregnancy test has been completed. Patients must complete a patient enrollment form and be re-enrolled annually by their prescribers using the LEAP Patient Enrollmentand Consent form to confirm that they understand the risks of LETAIRIS. Patients may be asked to participate in a survey to evaluate the effectiveness of LEAP. Pregnancy: Instruct patients that therisks associated with LETAIRIS include serious birth defects if used by pregnant women: Educate and counsel women of childbearing potential to use highly reliable contraception during LETAIRIStreatment and for one month after stopping treatment. If the patient has had a tubal sterilization or chooses to use a Copper T 380A IUD or LNg 20 IUS for pregnancy prevention, no additional contraception is needed. Women who do not choose one of these methods should always use two acceptable formsof contraception: one hormone method and one barrier method, or two barrier methods where one method is the male condom. Acceptable hormone methods include: progesterone injectables, progesterone implants, combination oral contraceptives, transdermal patch, and vaginal ring. Acceptable barrier methods include: diaphragm (with spermicide), cervical cap (with spermicide), and the male condom. Partner’s vasectomy must be used along with a hormone method or a barriermethod. Educate and counsel women of childbearing potential on the use of emergency contraception in the event of unprotected sex or known or suspected contraceptive failure [see Boxed Warning, Contraindications]. Instruct patient to immediately contact their physician if they suspect they may be ]]pregnant. Hematological Change: Patients should be advised of the importance of hemoglobintesting. Administration: Patients should be advised not to split, crush, or chew tablets.

GS22-081-010

A SAMPLING OF UPCOMING

ON-DEMAND PROGRAM EVENTS:

Nov. 5, 2013 Boston, Mass.

Nov. 6, 2013 San Antonio, Texas

Nov. 12, 2013 Austin, Texas

Nov. 12, 2013 San Diego, Calif.

Nov. 12, 2013 Westfield, Mass.

STAY SHARP WITH YOUR PAH

KNOWLEDGE

For a full listing of On-Demand Program events or to request your own program, visit:

www.PHAssociation.org/OnDemand

The PHA Medical Education On-Demand Programis 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 compre-hensive screening and early recognition of symp-toms

�� Evaluate the patient’s condition and prescribe long-term optimal management

Medical professionals can also request an On-Demand 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™

Preoperative Assessment and Management of Liver TransplantCandidates With Portopulmonary Hypertension

Rodrigo Cartin-Ceba, MDAssistant Professor of MedicineDivision of Pulmonary and Critical CareMedicineMayo ClinicRochester, MN

Michael J. Krowka, MDProfessor of MedicineDivision of Pulmonary and Critical CareMedicineMayo ClinicRochester, MN

Pulmonary artery hypertension (PAH) that occurs as a consequence of portal hyper-tension is termed portopulmonary hypertension (POPH) and is associated withsignificant morbidity and mortality. Among liver transplant (LT) candidates, reportedincidence rates of POPH range from 4.5% to 8.5%. The severity of POPH is unre-lated to the severity of portal hypertension or the liver disease. In LT patients,intraoperative death and immediate post-LT mortality are feared clinical events whentransplantation is attempted in the setting of untreated, moderate to severe POPH.Specific pulmonary artery vasodilator medications (PAH-specific therapy) appeareffective in reducing pulmonary artery pressures, improving right ventricular (RV)function and survival. Thus, screening for and accurately diagnosing POPH prior toLT has become a standard of care. The post-LT course of patients with moderatePOPH is unpredictable, but most patients can be weaned from PAH-specific therapyover time. In this article, we present an overview of the preoperative assessment ofPOPH with an emphasis on risk assessment for transplant and the most recentmedical treatment options.

Portopulmonary hypertension (POPH) isdocumented in 4.5% to 8.5% of livertransplant (LT) candidates,1 and it is awell-recognized relationship of pul-monary artery hypertension (PAH) thatevolves as a consequence of portal hyper-tension.2 According to the 2008 DanaPoint classification of PAH, POPH isincluded within the Group 1 of the clas-sification.2 The first description of whatwe now know as POPH was providedby Mantz and Craige in 1951.3 Theseauthors described necropsy results of a53-year-old female with spontaneousportocaval shunt (due to a probable con-genital portal vein narrowing) thatoriginated at the confluence of theportal, splenic, and mesenteric veins andcoursed through to mediastinum. Theshunt was lined by varying amounts ofthrombus thought to have embolized viathe innominate vein into the right heartand pulmonary arteries. In addition toembolized small pulmonary arteries, anextreme endothelial proliferation andrecanalization process was documented.3

Over the last 30 years, enhanced recog-nition and renewed importance ofPOPH has evolved with the evolution of

LT and potential outcomes associatedwith POPH. Specific screening recom-mendations and diagnostic criteria arenow clearly defined for this entity.Despite the lack of randomized con-trolled trials for pulmonary arteryvasodilator medications (PAH-specifictherapy), extrapolation of the therapeuticadvances in treating PAH with beneficialeffects in POPH has stimulated ongoinginterest and importance in this syn-drome. This article summarizes the mostrecent advances in the comprehensivepreoperative management of POPHpatients undergoing LT.

HOW IS POPH DEFINED?Given the various pulmonary hemody-namic patterns that complicate advancedliver disease,4,5 POPH should be clearlydefined and recognized; therefore, theimportance of accurate interpretation ofhemodynamics obtained by right heartcatheterization (RHC) cannot be under-estimated. The vascular pathology thatcharacterizes POPH includes obstructionto arterial flow due to vasoconstriction,endothelial and smooth muscle prolifer-ation, in-situ thrombosis, and plexogenic

arteriopathy.6,7 These changes increasethe resistance to pulmonary arterialblood flow, which is the main mech-anism of the disease. In the presence ofportal hypertension, POPH is thereforedefined as a mean pulmonary arterypressure (MPAP) �25 mm Hg asso-ciated with pulmonary vascular resistance(PVR) �240 dynes/sec/cm-5 and pul-monary capillary wedge pressure(PCWP) �15 mm Hg based on RHC(Table 1). It is also very important torecognize the 3 main abnormal hemody-namic patterns that can be presentduring RHC in patients with portalhypertension (Figure 1); distinguishingthese patterns is of paramount importantfor the adequate management and treat-ment: a) hyperdynamic circulatory stateinduced by liver dysfunction; b) excesspulmonary venous volume due to dia-stolic dysfunction and/or renalinsufficiency (pulmonary venous hyper-tension); and c) PAH due to vascularobstruction (POPH).6

It is important to mention thatPOPH should be distinguished from theother major pulmonary vascular conse-quence of liver disease, namelyhepatopulmonary syndrome (HPS).4,8 InHPS, arterial hypoxemia is caused byintrapulmonary vascular dilatations(exactly opposite to the vascular obstruc-tions documented in POPH) that form

Key Words—portopulmonary hypertension, cirrhosis, liver transplant, portal hypertension, pulmonaryhypertensionCorrespondence: [email protected]: The authors did not provide disclosures.


as a remodeling process due to factorsyet to be identified. In addition, the pul-monary hemodynamics associated withHPS reflect a normal PVR and usually ahigh flow state characterized by anincreased cardiac output (CO). The dis-tinction between these 2 syndromes isvery important, especially if LT is to beconsidered because of the differences inrisk, treatment options, and outcomesbetween these syndromes.8

HOW IS THE SCREENINGPROCESS FOR POPHPERFORMED?Transthoracic echocardiography (TTE)has been the most practical screeningmethod to detect POPH.9-11 Byassessing the tricuspid regurgitant peakvelocity (TR), estimating the right atrialpressure by inferior vena cava changeswith inspiration, and using the modifiedBernoulli equation, an estimate of rightventricle systolic pressure (RVSP) can bedetermined in �80% of patients withportal hypertension.9 This quantitativeapproach allows one to decide whichpatients should proceed to RHC for thedefinitive characterization of pulmonaryhemodynamics. In our current practice atMayo Clinic, the presence of RVSP�50 mm Hg has been the cutoff criteriato proceed to RHC in a clinical algo-rithm followed since 1996.5 Rarely,immeasurable TR with abnormal quali-tative RV size or function results inRHC. TTE has been noted to have a97% sensitivity and 77% specificity to

detect moderate to severe PAH prior toLT.9

Current policy adopted by theAmerican Association for the Study ofLiver Diseases calls for screening TTEto detect pulmonary hypertension (PH)in every patient considered for LT in theUnited States.12 This policy originated,in part, from documentation that POPHwas first diagnosed in the operatingroom in 65% of patients (28/43 patientsin 18 peer-reviewed studies) reported ina literature review with a 35% mortalityin patients subsequently transplanted. Ofparticular note, pre-LT MPAP �35mm Hg (untreated) was associated withhigher mortality.13 Studies by Castro etal,14 Starkel et al,15 and Saner et al16

reported first diagnosing POPH in theoperating room after anesthesiainduction (in the era prior to currentPAH-specific therapy), noting that mildto moderate POPH patients (MPAP�35 mm Hg) do quite well withoutpre-LT PAH-specific therapy. The goalof screening is to identify and treat thosewho have the highest risk of cardiopul-monary adversity during and after LT.Pulmonary hemodynamics in LT candi-dates may change over time, so repetitivescreening (every 12 months) is recom-mended.17

WHAT IS KNOWN ABOUT THEEPIDEMIOLOGY AND NATURALHISTORY OF POPH?Yoshida et al appear to be the firstauthors to use the term POPH in 1993,

as they described the first successful caseof POPH to undergo successful LT (39-year-old male with long-standing chronicactive hepatitis).18 In the same paper,the authors also described long-termfailure of single lung transplant to sta-bilize POPH in the setting of continuedportal hypertension. Subsequently,several small series and case reports withautopsy results have described pulmonaryarterial obstruction and pulmonaryplexogenic arteriopathy with and withoutthromboemboli.7,19-22 Two distinct pul-monary vascular obstructive patternscausing PAH in association with portalhypertension are well described: 1)chronic pulmonary emboli from sponta-neous or surgical portocaval shunts,in-situ thrombus, and/or platelet aggre-gates; and 2) a vasoconstrictive,proliferative endothelial/smooth muscleprocess due to circulating mediators thatbypassed normal hepatic metabolism dueto flow patterns of portal hypertension.

Large series have confirmed the coex-istence of these portal and pulmonaryvascular abnormalities and have shownthat the association is not coincidental.An unselected series of 17,901 autopsiesrevealed that PAH was 5 times morelikely in cirrhotic patients than thosewithout liver disease.23 Within the1981-1987 National Institutes of Health(NIH) registry of “primary” PH from 32centers reported by Rich et al,24 addi-tional analyses by Groves et al concludedthat 8.3% likely had POPH (17/204;187 had primary PH).25 Hadenguereported the largest prospective study ofpatients with portal hypertension(n�507) in which portopulmonaryhemodynamic measurements concludedthat 2% had POPH.26

More recently, prospective studieshave focused on the frequency of POPHin clinic settings, including national reg-istries and individual transplant centerexperiences. In the French PH registryexperience over a 12-month period(2002-2003), Humbert reported a 10.4%frequency of POPH (70/674) from 17university hospitals.27 In the UnitedStates, the REVEAL (Registry toEvaluate Early And Long-term pul-monary arterial hypertension diseasemanagement) registry documented a5.3% POPH frequency (174/3525) in

Table 1. Diagnostic and Severity Criteria for POPH

Variable Criterion

Portal hypertension Clinical diagnosis (ascites, varices, splenomegaly)

Mean pulmonary artery pressure(MPAP)

�25 mm Hg; and

Pulmonary vascular resistance (PVR)a � 240 dynes/s/cm-5

Pulmonary capillary wedge pressure(PCWP)

�15 mm Hg

Transpulmonary gradient (TPG)b �12 mm Hg

Degree of severity

Mild �25 MPAP �35 mm Hg

Moderate �35 MPAP �45 mm Hg

Severe �45 mm Hg MPAP

aPVR � (MPAP-PCWP) x 80/cardiac output.bIn the case where PCWP is �15 mm Hg (abnormal), an abnormal TPG (MPAP-PCWP) may distinguish between simple volume excess causing increased MPAP andthe pulmonary artery vasculopathy that characterizes POPH.


which there were 68% prevalent and32% incident cases, satisfying the criteriathat MPAP �25 mm Hg and PVR�240 dynes/s/cm-5 with PCWP �15mm Hg.28 Following slightly differentPVR diagnostic criteria as part of outpa-tient RHC diagnostic assessments, thelargest POPH-LT center experiencesreported to date are as follows: 8.5%(Baylor 102/1205; PVR �120 dynes/s/cm-5), 6.1% (Clichy, France 10/165;PVR �120 dynes/s/cm-5), and 5.3%(Mayo Clinic 66/1235; PVR �240dynes/s/cm-5).5,17,29

The natural history of POPH has

been difficult to characterize and hasbeen confounded by small series prior tothe availability of current PAH-specifictherapy. Robalino and Moodie reporteda dismal 5-year survival of 4% (n�78)prior to the availability of continuousintravenous prostacyclin infusion.30

Swanson et al reported a 14% 5-yearsurvival in POPH patients (n�19)denied LT and not treated with any ofthe current PAH-specific therapies.31

From the French National Center forPAH (n�154 over a 20-year span until2004), Le Pavec described 1-, 3-, and5-year survivals of 88%, 75%, and 68%

respectively for POPH patients (majorityChilds A and alcoholic cirrhotics).1 Onlyone-third had been treated with PAH-specific therapies with severity ofcirrhosis and reduced CO identified aspoor prognostic factors. Causes of deathin all series mentioned herein wereequally distributed between right heartfailure due to POPH and direct compli-cations of liver disease (bleeding, sepsis,hepatocellular carcinoma).

From the REVEAL registry, 2important POPH observations werereported.28 First, POPH treatment pat-terns reported in the REVEAL registrydemonstrated that the use of any PAH-specific therapy for POPH was delayedcompared to patients diagnosed withidiopathic PAH (IPAH). Specifically, atthe time of entry into the registry only25% were on PAH-specific therapy andat 12 months follow-up 74% were ontreatment. Second, although baselinehemodynamics in POPH (MPAP andPVR) were significantly better thanthose with IPAH, the 1- and 3-yearsurvivals were worse. The 5-year survivalfor all POPH patients was 40% com-pared to 64% for IPAH. Liver diseaseetiologies and causes of death were notdetermined in the registry and survivalwas not analyzed by the type of PAH-specific therapy.

Two caveats are important in charac-terizing the natural history of POPH.First, with the advent of PAH-specifictherapies, every controlled randomizedstudy has excluded POPH patients. Thisuniversal exclusion in the United Statesfurther complicated the understanding ofPOPH outcomes compared to otherPAH disorders. Second, beginning in2002 a higher priority for LT was anoption for highly selected patients withPOPH in the United States.32 Formal-ization of higher priority pulmonaryhemodynamic criteria were put forth in2006, and standardized in 2010. Onlypatients with moderate to severe POPH(MPAP �35 mm Hg) who attainedsignificant hemodynamic improvementwith PAH-specific therapy (MPAP �35mm Hg and PVR �400 dynes/s/cm-5)were granted higher priority for LT.From 2002 through 2010, 155 POPHpatients were granted such priority andtransplanted by regional review boards.33

Figure 1. A: Pulmonary hemodynamic patterns documented by right heart catheterization inadvanced liver disease. B: Three LT candidates with abnormal screening TTE (RVSP �50 mmHg); all 3 patients had elevated MPAP. However, only patient C had POPH.TTE: transthoracic echocardiography; RVSP: right ventricular systolic pressure; LT: liver trans-plantation; MPAP: mean pulmonary artery pressure (normal �25 mm Hg); PVR: pulmonaryvascular resistance (normal �240 dyne/s/cm-5 [or 3 Wood units]); PCWP, pulmonary capillarywedge pressure; CO, cardiac output; POPH: portopulmonary hypertension.


HOW TO TREAT AND MANAGEPOPH IN LT CANDIDATESIn Figure 2, we summarize the clinicalalgorithm followed at our institutionbased on RHC results: deciding whichpatients indeed have POPH, decidingwho needs PAH-specific therapy basedon severity, and determining the risksand timing for potential LT are themost important clinical questions.POPH patients with MPAP �35 mmHg are particularly vulnerable to pooroutcomes with attempted LT, especiallyif there is no attempt to treat the POPHwith current PAH-specific medications.With current treatments, POPH out-comes are variable, yet in highly selectedPOPH patients with aggressivetreatment and successful LT, pulmonaryhemodynamics may completely nor-malize. RV size and function normalizesand liberation from PAH-specific medi-cations may be allowed.

The immediate goal in the man-agement and treatment of POPH is toimprove pulmonary hemodynamics byreducing the obstruction to pulmonaryarterial flow. This can be accomplishedby medications that result in vasodi-lation, antiplatelet aggregation, andantiproliferative effects.34 This goal maybe attained by augmenting the lack ofpulmonary endothelial prostacyclin syn-thase deficiency (prostacyclin infusion),blocking circulating endothelin-1 effects(endothelin receptor antagonists), and

enhancing local nitric oxide vasodila-tation effects (phosphodiesteraseinhibitors).34 The ultimate goal, inaddition to favorably affecting pulmonaryhemodynamics (decreased MPAP,decreased PVR, and increased CO), is tostabilize, improve, and/or normalize RVfunction.

Uncontrolled small series and recentcase reports have demonstrated thatPAH-specific therapies used for othertypes of PAH could be beneficial forpatients with POPH (Table 2).35-52 It isimportant to stress that improvements inboth MPAP and PVR are the idealgoals in treating POPH. However,MPAP may not decrease as much asdesired, as increases in CO associatedwith reduced obstruction to flow (mea-sured by decreased PVR) will result inhigher flow (and increased pressure).

Role of Prostacyclins in POPHThe most dramatic PAH-specifictherapy effects in POPH have been withthe use of continuous prostacyclininfusion via a central catheter and oralendothelin receptor antagonists. In asummary of 48 patients treated withintravenous epoprostenol from 5 studies,MPAP decreased by 25% (48336 mmHg), PVR decreased by 52% (5503262dynes/s/cm-5), and CO increased by 38%(6.338.7 L/min, all P�0.01).13,46-50

Other prostacyclins (intravenous trepros-tinil and inhaled iloprost) have resulted

in significant pulmonary hemodynamicimprovement in POPH.44,48,50

Role of Endothelin Receptor Antagonistsin POPHRegarding the use of endothelin receptorantagonists, Hoeper et al documented 1-and 3-year survival of 94% and 89% in18 patients with POPH and Childs Aseverity liver disease using the nonse-lective endothelin antagonist bosentan.43

No liver toxicity was noted. However,Eriksson et al have correctly warnedabout potential liver toxicity with the useof bosentan, occurring in up to 10% ofpatients without documented POPH.37

Although Kahler et al have reportedsuccess in POPH with the use of aselective endothelin receptor antagonistsitaxsentan, this medication has not beenapproved in the United States and hasbeen associated with fatal hepaticfailure.45 Cartin-Ceba et al reported 13POPH patients using the endothelinreceptor antagonist ambrisentan (10 mgdaily) and documented at 1-yearimprovement in each of 8 POPHpatients (MPAP 58341 mm Hg andPVR 4453174 dynes/s/cm-5; P�0.004).Of note, 5 of the 8 patients normalizedtheir PVR.36 In further support ofambrisentan in POPH, Halank et aldescribed significant improvement inboth exercise capacity and symptoms in14 POPH patients.40 Importantly,neither of the uncontrolled ambrisentanstudies was associated with hepatic tox-icity. This may be due to the differencesin chemical structure (ambrisentan-propionic acid; bosentan and sitaxsentan-sulfa base) and distinct hepatic metabolicpathways.42 More recently, Savale et aldescribed 34 patients with POPH(Childs A or B severity of liver disease)treated with bosentan documenting sig-nificant hemodynamic improvement(more so in the Childs B subgroup), andevent-free survival estimates were 82%,63%, and 47% at 1, 2, and 3 yearsrespectively.53

Role of Phosphodiesterase-5 (PDE-5)Inhibitors in POPHPDE-5 inhibitors prevent the breakdownof cyclic guanosine monophosphate, themediator of nitric oxide-induced vasodi-lation. The use of phosphodiesterase

Figure 2. Current POPH screening evaluation and treatment algorithm used at the Mayo Clinic.RVSP: right ventricular systolic pressure; MPAP: mean pulmonary artery pressure (normal �25mm Hg); PVR: pulmonary vascular resistance (normal �240 dyne/s/cm-5 [or 3 Wood units]); LT:liver transplantation 3 Yes: risk to proceed with LT is minimal; RX: PAH-specific therapyadvised prior to LT; NR: never reported; contraindicated: high risk of intraoperative event atgraft reperfusion.


inhibition (sildenafil) to enhance nitricoxide vasodilating effect, either alone orin combination with other PAH-specifictherapies, has successfully improvedPOPH pulmonary hemodynamics andfacilitated successful LT. Most of thepublished experiences have been inpatients with less severe POPH.39,41,49

Role of Other Therapies and Interventionsin POPHIn a single case report, a dramatichemodynamic improvement wasobserved with the 6-week addition ofimatinib 400 mg daily (a tyrosine kinaseinhibitor) to pre-LT intravenousepoprostenol and post-LT bosentantherapy, resulting in liberation of allPAH-specific medications and normal-ization of RV function 1 year post-LT.This observation suggests a possiblefourth pathway of PAH-specific therapyeffectiveness (blocking platelet-derivedgrowth factor receptors) in treatingPOPH.54

The use of beta blockers or tran-sjugular intrahepatic portosystemicshunting (TIPS) in the setting ofPOPH may be problematic. Theformer, used to prevent gastrointestinalbleeding by reducing the degree ofportal hypertension, may impair neededRV function. In moderate to severePOPH (n�10; mean MPAP � 52 mmHg), withdrawal of beta blockadeincreased CO by 28%, decreased PVRby 19% with no change in MPAP, andincreased 6-minute walk by 79meters.55 TIPS, as a treatment foruncontrollable gastrointestinal bleedingor refractory ascites, can temporarilyincrease MPAP, CO, and PVR. In astudy of 16 cirrhotic patients withoutPH, the increase in MPAP was greaterthan that noted in CO, suggesting anincrease in the PVR after TIPS.56 Suchchanges remained for at least 30 dayspost-TIPS and reflected neurohumoraleffects as opposed to increased preload.A significant increase in RV work was

documented and the potential effect onRV function could be deleterious inpatients with preexisting POPH.57

WHAT IS THE ROLE OF LT INPOPH PATIENTS?The majority of patients with POPHhave cirrhosis and LT is a potentiallycurative intervention, at least from ahemodynamic perspective. In the UnitedStates, a total of 5805 liver transplantswere accomplished in 2011. As of mid-2013, there were approximately 16,482patients on the wait list in over 120United States LT centers.58 Assumingup to 8.5% of LT candidates havePOPH, at any point in time there maybe approximately 1300 POPH-LT can-didates.1 The outcome of POPHfollowing LT remains unpredictabledespite screening, careful patient selection,higher priority for LT, and advances insingle and combination PAH-specifictherapies (Table 3).14-16,59-65 EffectivePAH-specific therapy has resulted in

Table 2. PAH-Specific Therapy Use in POPH

Study first author (medication)Number of

patients Comments

ENDOTHELIN RECEPTOR ANTAGONISTS

Hoeper43 (bosentan) 18 1- and 3-year survivals 94% and 89%, respectively

Cartin-Ceba36(ambrisentan) 13 At 1 year, MPAP and PVR improved in 8/8; PVRnormalized in 5

Savale53 (bosentan) 34 Event-free survival estimates were 82%, 63%, and 47%at 1, 2, and 3 years, respectively

PHOSPHODIESTERASE INHIBITORS

Reichenberger49 (sildenafil) 12 Improvement at 3 months; not sustained at 1 year

Gough39 (sildenafil) 11 PVR decreased in all at first RHC follow-up

Hemnes41 (sildenafil) 10 At 1-year MPAP and PVR decreased in 3/5 patients

PROSTACYCLINS

Kuo47 (IV epoprostenol) 4 MPAP and PVR improved

Krowka46 (IV epoprostenol) 15 15 MPAP and PVR improved

Ashfaq35 (IV epoprostenol) 16 Successful LT in 11 patients; 5-year survival 67%

Fix38 (IV epoprostenol) 19 PVR improved in 14/14; MPAP improved in 11/14

Sussman51 (IV epoprostenol) 8 MPAP and PVR improved in 7/8

Sakai50 (IV treprostinil) 3 Successful LT in 2 patients (moderate POPH)

Hoeper43 (inhaled iloprost) 13 1- and 3-year survivals 77% and 46%, respectively

Melgosa48 (inhaled iloprost) 21 Acute, but no long-term hemodynamic improvement

COMBINATION THERAPY

Hollatz44 (sildenafil alone or combined with prostacyclinsin 9 patients)

11 MPAP and PVR improved in all patients, all underwentLT and 7/11 are off PAH-specific therapy

Raevens52 (6 patients combined therapy with sildenafiland bosentan; 1 patient only on prostacyclins)

7 MPAP and PVR improved in the 5/6 patients treatedwith combination of sildenafil and bosentan; 2underwent LT

MPAP: mean pulmonary artery pressure; PVR: pulmonary vascular resistance; LT: liver transplantation; IV: intravenous; POPH:portopulmonary hypertension.


successful LT and subsequent liberationfrom pre-LT PAH-specific therapy(Table 3). Importantly, reperfusionduring the LT procedure represents acritical time when preload can increase,cytokines may be released, thrombi maymigrate into the pulmonary circulation,and intraoperative death follows fromacute right heart failure.66

Although supporting data are limited,LT programs in the United States nowallow higher priority to conduct LT ifpulmonary hemodynamics can be signifi-cantly improved and meet standardizedModel of End-Stage Liver Disease(MELD) exception guidelines. Currenttreatment targets for POPH MELDexception in the United States are shownin Table 4. The goal and results of suchrecent policy in US LT programs hasbeen to interrupt the natural history ofPOPH (reduce waitlist death) and alsoimprove post-LT survival with liberationfrom PAH-specific therapy after suc-cessful LT once pulmonaryhemodynamics have normalized (Table3). However, failure to reduce MPAPbelow 50 mm Hg is considered by mostcenters to be a contraindication to LTor, if discovered at the time of the oper-ation, grounds to cancel the LTprocedure prior to the abdominal

incision. Despite limited experience, atthis time it seems logical that similarpulmonary hemodynamic guidelinesshould be followed when living-donorPOPH transplants are considered.60,67

Although the role of LT in thesetting of POPH is evolving with expe-rience, the recognition that severePOPH (measured hemodynamically andqualitatively by echocardiography) canresolve post-LT with aggressive pre-LTPAH therapy is quite remarkable.Although preliminary observations areencouraging, the normalization of pul-monary hemodynamics post-LT doesnot necessarily equate to pulmonary vas-cular pathology resolution or long-termstability. Finally, it should be noted thatclinically significant PAH could developde novo following LT (ie, normal pul-monary hemodynamics are noted at thetime of LT) for reasons that are clearlynot understood.68

FUTURE CONSIDERATIONSAND FINAL REMARKSFrom the current evidence available fromobservational studies, moderate to severePOPH is curable in some cases with acombination of LT and PAH-specificmedications. There are 2 important,pressing issues regarding the MELD

exception rules that are important todiscuss. The first issue has to do withthe MELD exception not being grantedunder current US policy if the MPAPremains �35 mm Hg despite normal-ization of PVR and RV function withpre-LT therapy. In such patients, theelevation in MPAP reflects a change inphysiology and is the result of pul-monary vasoactive therapy increasing theexisting high flow state, and decreasingthe PVR to flow. We consider that inthose patients where there is normal-ization of RV function and PVR,MELD exception should be granteddespite the “abnormal MPAP.” Based onobservational data, it is hypothesized thatfor those individuals, cure of POPHafter LT can be obtained. Admittedly, itis unknown whether pulmonary hemo-dynamic normalization post-LT reflectsa pathologic pulmonary vascular cure. Inaddition, in most post-LT patients thathave clinical improvement and echocar-diographic normalization of RVfunction, size, and RVSP; RHC is notroutinely performed to corroborate thenormalization of the hemodynamics.The second pressing issue deals with theadoption of the standard MELDexception for POPH. Even though those

Table 4. MELD Exception Criteria for POPH

1. Moderate to severe POPH diagnosisconfirmed by right heart catheterization

a. MPAP �35 mm Hg

b. PVR �240 dynes/sec/cm-5

c. PCWP �15 mm Hg

2. PAH-specific therapy initiated;improvement documented

a. MPAP �35 mm Hg

b. PVR �400 dynes/sec/cm-5a

c. Satisfactory right ventricularfunction by transthoracicechocardiography

3. MELD exception updated (additional10% MELD points) every 3 months

a. Give additional MELD exceptionif RHC data satisfies criteria # 2

aIf PVR is normal, higher MPAP may beallowed and reconsidered due to physi-ology that is now high flow rather thanobstruction to flow due to the therapy.POPH: portopulmonary hypertension;MPAP: mean pulmonary artery pressure;PVR: pulmonary vascular resistance;PCWP: pulmonary capillary wedge pres-sure; RHC: right heart catheterization;MELD: Model End-Stage Liver Disease.

Table 3. Liver Transplant Outcomes in the Setting of POPH

Outcome References

POPH Wait-list mortality 17,38,39,51

POPH MELD exception pre-LT 33,51

Case canceled in operating room 13,29,47,61

Intraoperative death 1,13,29,31,33,63

Transplant hospitalization death 13,15,16,29,33,35,52,62,63,65

POPH Post-LT

Resolved; PAH-specific therapy discontinued 33,35,36,38,39,44,50,51,54,60a

Resolved/stable without PAH-specific therapy 14,15,17,18,35

Improved/stabilized/PAH-specific therapycontinued

33,38,41,44,49-52,59b

Progressive despite PAH-specific therapy 29

Late death not due to POPH 29,31,35

Late death due to POPH 1,29

Multiorgan (H-Lu-Lv; Lu-Lv transplant)c 64

De novo PAH post-LTd 68

aLiving donor liver transplant (3 patients)bCombined PAH-specific therapy usecH-Lu-Lv: heart, double lung, liver; Lu-Lv- double lung, liver transplants. It is notedthat multiorgan transplants have been reported in the literature for cystic fibrosis,alpha-1 antitrypsin deficiency, and sarcoidosis, but these entities also affect lungparenchyma and many cases were accomplished in the era prior to current PAH-specific medications, therefore were not included herein.dPAH – pulmonary artery hypertension; a literature review of 13 such cases.


individuals can be tracked in terms ofgeneral survival, no data are availableregarding PAH-specific therapy man-agement after LT. Unfortunately, thereis lack of understanding about the mostappropriate post-LT management inorder to optimize outcomes. A multi-center survival registry collectingcomprehensive information should beperformed in POPH patients thatundergo LT.

In conclusion, POPH is anuncommon and serious yet treatable pul-monary vascular consequence of portalhypertension that can lead to right heartfailure and death if untreated. Due tothe different spectrum of pulmonaryhemodynamic changes associated withhepatic dysfunction, screening by TTEand confirmation by RHC is necessaryfor accurate diagnosis and therapeuticconsiderations. Despite the lack of con-trolled studies, PAH-specific therapies inPOPH can significantly improve pul-monary hemodynamics and RV function.The potential to “cure” POPH, at leasthemodynamically, with a combination ofPAH-specific therapy and LT appears tobe an attainable goal in a cohort ofPOPH patients yet to be optimally char-acterized. Controlled, multicenter studiesand long-term follow-up post-LT areneeded.

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Perioperative Evaluation and Management of Patients WithPortopulmonary Hypertension Aiming for Orthotopic LiverTransplantation

Jose L. Dıaz-Gomez, MDDepartment of Critical Care andDepartment of AnesthesiologyMayo ClinicJacksonville, FL

Pablo Moreno Franco, MDDepartment of Critical Care andDepartment of TransplantationMayo ClinicJacksonville, FL

Juan M. Canabal, MDDepartment of Critical Care andDepartment of TransplantationMayo ClinicJacksonville, FL

Samuel Irefin, MDDepartment of General AnesthesiologyAnesthesiology InstituteCleveland ClinicCleveland, OH

Charles D. Burger, MDDepartment of Critical Care andDepartment of Pulmonary MedicineMayo ClinicJacksonville, FL

Background: Portopulmonary hypertension (POPH) is defined as pulmonary arterialhypertension (PAH) in the context of portal hypertension. Severe POPH has beenconsidered an absolute contraindication of orthotopic liver transplantation (OLT).Objective: Since there are no definitive guidelines for the immediate preoperative,intraoperative, and postoperative evaluation and treatment of POPH patients, wehave used published literature along with our experience to review current knowledgein this area.Summary: Moderate-to-severe POPH has important consequences in the perioper-ative management of candidates for OLT. Adequate right ventricular function iscritical to survive the hemodynamic burden of OLT. Immediate preoperativeassessment of hemodynamics; careful intraoperative monitoring and management ofvolume status, pressure changes, and ventricular function; and postoperative transi-tions of PAH-specific therapy are key components to successful OLT. We emphasizethe advantages of the echocardiogram during all of these phases and stress the impor-tance of a team approach to plan care and respond to the multiple challenges ofOLT in POPH.

Initially described in 1951, the coexis-tence of pulmonary arterial hypertension(PAH) and hepatic dysfunction has beenwell documented.1 During the 4thWorld Symposium held at Dana Pointin 2008, the previous clinical classifi-cation of portopulmonary hypertension(POPH) as a well-recognized cause ofPAH was upheld.2 Patients with liverdisease can present with a continuum ofpulmonary vascular resistance profiles,from the characteristic vasodilatation ofhepatopulmonary syndrome to increasedresistance to pulmonary blood flow inthe setting of POPH. The focus of this

review is the immediate perioperativeassessment and management of patientswith POPH undergoing orthotopic livertransplant (OLT).

PREOPERATIVE PERIODA methodical diagnostic approach is ofthe utmost importance in patients withportal hypertension undergoing standardpretransplant evaluation. Transthoracicechocardiography (TTE) plays anintegral role in the evaluation of end-stage liver disease (ESLD) patients.Noninvasive screening of elevated rightventricular systolic pressures (RVSP) is

the main role of Doppler TTE in thepreoperative evaluation of patients withPOPH undergoing OLT. However,TTE alone cannot characterize theseverity of POPH.3 In fact, echocardio-graphically estimated RVSP andmeasurements by right heart catheter-ization (RHC) may disagree, particularlyat higher estimated RVSP.4 It isassumed that RVSP equates with systolicpulmonary artery pressure (SPAP). Inour practice, we also use echocardio-graphically measured mean pulmonaryartery pressure (MPAP), which appearsto correlate well with MPAP measuredby RHC.5,6

Two recent studies described thecutoff value of RVSP by TTE as anindication for RHC. Krowka et al used a

Key Words—portopulmonary hypertension, pulmonary hypertension, liver transplantationCorrespondence: [email protected]: The authors have no conflicts related to this manuscript.


cutoff of 50 mm Hg to proceed withRHC (see accompanying manuscript byCartin-Ceba and Krowka in this issue).A lower threshold was used by Raevenset al, who demonstrated that increasingthe cutoff from 30 mm Hg to 38 mmHg safely reduces the number of patientswho need RHC (specificity 82%; neg-ative predictive value of 100%).7

An elevated RVSP by TTE does notequate to a diagnosis of POPH, as up to20% of ESLD patients have a hyperdy-namic circulatory state with a directcorrelation between pulmonary arterypressure (PAP) and cardiac output(CO). The high-flow hemodynamicprofile is as follows: MPAP �25 mmHg, high CO, and low pulmonary vas-cular resistance (PVR).8,9 Even ifdiscovered in the immediate preoperativeassessment, this group of patients withpulmonary hypertension (PH) fromhigh-flow state may safely proceed withOLT.

In contrast, “true” POPH documentedby RHC in the immediate preoperativeperiod (ie, not previously diagnosed)requires careful assessment and may pre-clude proceeding with OLT. Ourpreoperative approach of patients withPOPH is shown in Figure 1.

Often volume overload is present inpatients with ESLD, complicating theinterpretation of an elevated RVSP byTTE. Carefully monitored diuresis toachieve “dry weight” is recommended.At this point, the echocardiographicevaluation should be repeated. If TTEagain reveals PH, an RHC should beperformed. In those patients with ele-vated serum creatinine, it may benecessary to evaluate and treat as inpa-tients. Our practice is to admit forpulmonary artery catheterization withintravenous administration of loop-inhibiting diuretics to achieve “normal”left-heart pressures, ie, pulmonary arteryocclusion pressure (PAOP) �15 mmHg. Rarely in those patients with moresevere renal disease, renal replacementtherapy is used to achieve normal intra-vascular volume status. Reassessment ofthe hemodynamic profile is diagnostic ofPOPH if the MPAP �25 mm Hg,PAOP �15 mm Hg, and PVR �240dyne s cm�5 (3 Wood units) as outlinedin Figure 1.10 With hemodynamic con-

firmation of the POPH, the mostappropriate PAH-specific therapy isdetermined.

The mortality of patients with mod-erate POPH with MPAP 35-45 mmHg and PVR �250 dyne s cm-5 hasbeen reported to be about 50%-80%,11,12

while the mortality when MPAP �50mm Hg has been found to be near100%.11,13 Long-term prognosis ofpatients with POPH remains poor, butintraoperative and immediate perioper-ative mortality is certainly the majorconcern in patients with MPAP �50mm Hg. Indeed, the Registry toEvaluate Early and Long-term pul-monary arterial hypertension diseasemanagement (REVEAL) demonstratedthat POPH had significantly poorer sur-vival and all-cause hospitalization ratescompared with idiopathic PAH, despitehaving better hemodynamics at diag-nosis.14

Prognostication and the decision toproceed with OLT are commonly com-plicated by 1 of 2 scenarios. In the firstscenario, the severity of POPH does notnecessarily correlate with the severity ofliver disease. In that case, UnitedNetwork for Organ Sharing hasapproved Model for End-Stage LiverDisease (MELD) exception points forpatients with POPH, thereby enhancingthe likelihood of earlier OLT (seeaccompanying manuscript byCartin-Ceba and Krowka in this issue).12

In the second scenario, the patient mayexperience clinical deterioration due tothe failing liver but has hemodynamicsthat are considered borderline eligible forOLT.10 It is unknown whether theincreased risk of OLT should be con-sidered acceptable in this circumstance.We advocate a multidisciplinary dis-cussion, including the hepatologist,transplant surgeon, anesthesiologist,critical care physician, and PH specialist,to discuss the individualized circum-stances influencing the decision toproceed with OLT. A team approachmarshals the relevant expertise in all sub-specialties to provide the mostappropriate decision.

PAH-specific therapies are designedto improve or normalize right ventricular(RV) function while reducing theMPAP and PVR to a range considered

safe for transplantation.10 A detaileddiscussion of these therapies for the out-patient pre-OLT period is detailed inthe companion article. This review willaddress the use of appropriate PAHtherapy in the immediate pre-OLT timeframe, as well as intraoperative and post-operative time courses. Important clinicalconsiderations include the patient’s out-patient medical regimen, hemodynamicprofile at the time of OLT, conversionto dose delivery systems permissibleunder anesthesia and during the periop-erative period. A list of applicable PAHmedications is shown in Table 1.

While case series of improved hemo-dynamics and outcome in POPH havebeen published with outpatient use,limited evidence is available to definetheir role on patient outcome in theperioperative period.

In the immediate pre-OLT period,reassessment with RHC and transesoph-ageal echocardiography (TEE) isstrongly advised. Generally, any currentPAH-specific therapy (Table 1) is con-tinued whenever feasible in order tomaintain hemodynamic stability andavoid rebound PH. Certainly for thosepatients who are already receiving con-tinuous intravenous infusion or inhaledtreatments, the therapy should be con-tinued and titrated based on thehemodynamic goals as previously dis-cussed.

Oral PAH-specific medications canand should be administered until thepatient is no longer taking oral medica-tions in preparation for surgery.Sildenafil has an intravenous formulationthat can be substituted for the oral ifneeded. The 10 mg intravenous dose isroughly equivalent to the 20 mg oraldose; nonetheless, when administeringvasodilators by the intravenous route,careful monitoring of the systemic bloodpressure is warranted.

Practical considerations for bothinhaled and infusion therapy includeexperience with the various PAH-specific therapies and ease/cost ofdelivery systems. For example, amongthe inhaled delivery options, the deliverysystem and dosing for nitric oxide (NO)offers simplicity and convenience but isexpensive compared to inhaled epopros-tenol, which is more difficult to


Figure 1. Evaluation of POPH in Patients With ESLD.


administer. The availability of propri-etary inhaled agents (iloprost andtreprostinil) often depends on insuranceand formulary coverage.

The protocols for initiation andtitration of inhaled and intravenoustherapy vary among OLT centers.Inhaled NO can be delivered via afacemask or into the inspiratory limb ofa ventilator circuit. Generally, the dose isstarted at 5 ppm with subsequent dou-bling to desired effect (eg, 10, 20, 40, 80ppm). Methemoglobinemia is a sideeffect that requires daily monitoring.Inhaled epoprostenol requires the use ofthe brand FLOLAN® (epoprostenolsodium). Various dose strengths can becreated using different concentrations ofthe 0.5 mg vial and proprietaryFLOLAN diluent. Dose concentrationsare generally 2500 to 20,000 ng/mL.The resulting solution is nebulized at 8mL/hour into the ventilatory circuit. Thesolution must be protected from lightand degrades after 8 hours at room tem-perature. The glycine buffer may causethe FLOLAN to precipitate and accu-mulate in the circuit, requiring closemonitoring and filter changes as indi-cated.

Intravenous epoprostenol therapy iscommonly initiated in the hospital (2ng/kg/min) and titrated up by 1-2ng/kg/min (recommendation on fre-quency of increase varies from every 30

minutes to every 1-2 hours) to achievethe required hemodynamic effect or untillimited by common side effects(headache, nausea, flushing, myalgia,diarrhea, jaw pain, or systemic hypo-tension). The initial “plateau” dose rarelyexceeds 12 ng/kg/min, but thereafter canbe increased more slowly if needed.Pharmacologic treatment of side effectsmay be required to promote tolerance.Treprostinil, a prostacyclin analogue, isan alternative to epoprostenol. Thelogistics of initiating therapy are similarto epoprostenol. In contrast to epopros-tenol, it can be administeredsubcutaneously with reported 100% bio-availability. Nonetheless, the cachexiaassociated with ESLD and abdominaldistension from ascites raise concernsabout the tolerability and absorption inthis setting. Initial dosing of treprostinilin patients with mild to moderatehepatic dysfunction is half that ofpatients without liver disease, with astarting dose of 0.625 ng/kg/min.Limited data are available for use inpatients with severe liver dysfunction.

Of specific note, long-term complica-tions of intravenous prostacyclins includethrombocytopenia, systemic hypotension,central line infection, post-insertionbleeding, and progressive splenomegaly(which may worsen thrombocytopeniaand produce leukopenia). Since the goalis to continue the PAH-specific therapy

until the postoperative period followingOLT, clinicians must appreciate thenuances of medication administration,hemodynamic goals, and unusual sideeffect profile of these medications.15,16

Some authors have published casereports describing the successful use ofcombined therapies to maximize thebenefit from pulmonary vasodilation.17

In many centers, combination treatmentis often utilized to obtain the goal ofMPAP �35 mm Hg for OLT can-didacy. Although this may be a plausibleoption, there are limited data regardingthe best combination or sequence oftherapy.

INTRAOPERATIVE PERIODUtilization of IntraoperativeTransesophageal Echocardiography DuringOLTIn addition to routine monitoring forOLT, TEE may be of added value inmanaging patients with POPH.18 Inrecent years, preexisting esophagealvarices are no longer considered anabsolute contraindication for TEEduring OLT. Often, esophageal bleedingis self-limited and mild to moderate inseverity. The TEE examination can beperformed using limited views andavoiding excessive manipulations of theprobe. However, intraoperative exami-nation should be performed withimmediate availability of a gastroenter-

Table 1. PAH Medications Used for POPH in the Perioperative Period for OLT

CLASS MEDICATION PERIOPERATIVE USE in POPH

PDE-5 Inhibitor Sildenafil IV form 10 mg tid Case series with improved hemodynamics

Tadalafil No IV formulation Reduce dose to 20 mg daily in Child-Pugh class Aor B; avoid for class C

Endothelin Blocker Ambrisentan Oral onlyShould not be crushed

Case series published with improved hemodynamicsand no hepatoxicity; multicenter open label trialongoing

Bosentan Oral only Hepatotoxicity a concern but has been used in caseseries

Prostacyclin Iloprost Inhaled every 2 hours Case series with improved hemodynamics; intervalbetween dose may be increased to 3 to 4 hours inliver disease

Treprostinil Continuous infusion either IV orsubcutaneous; inhaled every4 to 6 hours

Limited data; initial dosing reduced by half to 0.625ng/kg/min; no data for inhaled formulation

Epoprostenol Continuous IV Case series with improved hemodynamics

Inhaled continuously Case reports only

Nitric Oxide Nitric Oxide Inhaled 5 to 80 ppm Case reports only

A comparison of the medications used to manage POPH in patients undergoing OLT. Key: PDE-5 � phosphodiesterase-5, IV �intravenous.


ology specialist to address any severebleeding. The main intraoperative goalof managing hemodynamics for patientswith POPH is to maintain optimalmechanical matching between the RVfunction and pulmonary circulation.

There are several intraoperative phasesin which the patient is at risk for severesystemic arterial hypotension: during thedissection phase, the manipulation of theliver, drainage of large ascites, andclamping of the inferior vena cava (IVC)(if the “piggy-back” technique is notused) and/or portal vein. It is advised tohave immediate availability of continuousinfusions of vasopressor and inotropicagents for the treatment of shock. Con-tinuous assessment of volume status iscritical intraoperatively. Left ventricularend diastolic area (�5.5 cm/m2 surfacearea) in the transgastric short axis viewby TEE is suggestive of hypovolemia.19

Other applications of TEE includeplacement of venovenous bypass cannula(again not an issue with the “piggy-back”technique), identification of hemody-namically significant thrombosis of theIVC, intracardiac thrombus, complica-tions of transjugular intrahepaticportosystemic shunts, and managementof patients with underlying valvular heartdisease, coronary artery disease, or car-diomyopathy (eg, alcohol-induced,hemochromatosis, or amyloidosis).20-23

During the anhepatic phase, there arepredictable hemodynamic changesincluding decreased systemic vascularresistance and increased CO, MPAP,and PVR. The TEE assessment shouldbe focused on determining ventriculardysfunction and volume status.

The reperfusion phase is perhaps themost important period of TEE evalu-ation during OLT. Post-reperfusionsyndrome is the hallmark of this hemo-dynamic disturbance.24 It is manifest as avasodilatory state with worsening POPHand RV function. Thus, the mostimportant signs to confirm RV failureare dilation and dysfunction of the RV,as well as septal dyskinesia. Airembolism is an under-recognized con-dition that can aggravate or precipitateRV failure. The RV is compromised dueto the anterior anatomic position of theright coronary artery. Finally, it isimportant to note that hypovolemia,

tachycardia, and overutilization of ino-tropic support can all lead to a systolicanterior motion of the mitral valve withsubsequent dynamic obstruction of theleft ventricular outflow tract.

Therapeutic strategies. Preoperative useof intravenous epoprostenol is usuallycontinued intraoperatively. Inhaled NOmay be used as an adjunct inhalationagent to optimize RV function and mit-igate elevated MPAP. Intraoperativefluid management should be adequate toachieve euvolemic state and ensure ade-quate RV preload. Inhaled NO isgenerally quite easy to transition fromthe intraoperative to the postoperativesetting, a distinct advantage for theperi-OLT management of POPH.Phosphodiesterase-3 inhibition withintravenous milrinone reduces PVR andassists in managing MPAP; however,care must be taken not to compromisesystemic pressures when this agent isused. Several vasodilator therapies byinhalation route as previously discussedmay be administered intraoperatively tomanage patients with POPH whopresent for OLT. These agents offerunique advantages since they can bedelivered directly to the alveoli. Conse-quently, the ventilated areas may giverise to a decrease in the pulmonary shuntand improved oxygenation wheneverthese agents are administered.25

Rarely, a patient may develop or berecognized as having POHP in the oper-ating room (OR) suite. Intravenousepoprostenol can be initiated in the OR,but hemodynamic changes and respon-siveness can be variable and challenging.Inhaled agents like iloprost and trepros-tinil cannot be administered in the OR.Inhaled epoprostenol or NO are alterna-tives for treatment of POPH. Milrinonehas also been used and can be continuedboth intra- and postoperatively. Occa-sionally, anesthesiologists have used itbefore the anhepatic/reperfusion phase inanticipation of known hemodynamicalterations that occur during reperfusion.Furthermore, the duration of coldischemic time may play a role in PAHtherapy selection; therefore, an agentthat is reliable with rapid onset and iseasily and accurately titratable needs tobe used (eg, intravenous epoprostenol).

Initiation of intravenous epoprostenolintraoperatively is essentially no differentthan in the pretransplant environmentfor a POPH patient who requirestreatment but is still appropriate toproceed with OLT. For the most part,the hemodynamic contraindication forOLD, and hence the need to cancelsurgery, is the finding of MPAP �50mm Hg from RHC. Treatment may beattempted in the OR to reduce theMPAP to a range of 40-49 mm Hg iftime allows, whereas MPAP 36-39 mmHg may warrant consideration fortreatment after careful interpretation ofhemodynamic profile to differentiate“volume-induced,” “hyperdynamic-induced,” or true POHP.Hyperdynamic-induced PH is usuallywell tolerated at this range (MPAP36-39 mm Hg). However, both of thesehemodynamic interpretations are bestdone in conjunction with TEE evalua-tions to assess RV size and function inorder to make the decision regardingproceeding with OLT.

POSTOPERATIVE PERIODThe resolution of POPH after OLT isunpredictable. Most of the studies reportthat up to 76% of the patients improveor resolve POPH following OLT.26

However, this improvement varies (up to27 months).27

It is a common practice in our insti-tution to continue the PAH-specifictherapy that was used in the pre- andintraoperative periods. All patients withknown POPH, or de novo POPH, areadmitted to the intensive care unit(ICU) after OLT. We attempt earlypostoperative extubation in all patientswith postsurgical optimization. If inhaledNO was used intraoperatively, it is dis-continued if possible during the weaningfrom mechanical ventilation; however,some patients may need longer supportwith gradual weaning postextubation.Routine post-OLT care is provided withspecial considerations and attentiongiven to avoiding/minimizing rapidvolume infusions, need for vasopressors,use of appropriate PAH-specific therapy,and evidence of postoperative RV failure.Infrequently, the use of milrinone infu-sions has been either continued from theoperating room or started in the ICU


due to its vasodilatory action and ino-tropic effects, provided that adequate andstable systemic blood pressure is present.In the case that multiple agents are usedsimultaneously, careful titration is man-datory. Agents not used preoperativelywill usually be discontinued first (eg,milrinone and inhaled NO). Postoper-ative use and transition of PAH-specifictherapy depends on whether the patientwas on such therapy preoperatively andthe clinical status of the patient. Infu-sions of intravenous epoprostenol thatwere initiated perioperatively often canbe transitioned to oral PAH-specifictherapy within 2-4 days. We maintainthe RHC in place while titrating care ortransitioning medications. Once there isdocumented stability in pressures on oraland/or inhaled agents, the RHC can bediscontinued. If the patient has been onlong-standing PAH-specific therapy,that therapy will be continued postopera-tively and slowly tapered over weeks tomonths as an outpatient.

Careful clinical observation forsudden or progressive changes in pul-monary status or central venous pressuremeasurements are important clues topossible RV failure. Postoperative dete-rioration of POPH is anticipated in theimmediate postoperative period due tomultiple factors (eg, post-reperfusionsyndrome, blood product transfusions,hypothermia, pain, etc).13 Thus, wecontinue infusion of intravenousepoprostenol, and administer the oralagents via a nasogastric tube if possible.We taper intravenous epoprostenolinfusion in decrements of 1-2ng/kg/min if started perioperatively, andits subsequent dose depends on theinvasive hemodynamic monitoringand/or pulmonary pressure estimates onTTE examination. Patients requiringcontinuous epoprostenol presurgery aremaintained on that dose (or higher ifneeded). The decision to titrate off theinfusion is made as an outpatient aftercareful follow-up evaluation. Likewise,chronic oral or inhaled PAH-specifictherapy is continued into the dischargefollow-up period. The duration ofPAH-specific therapy after OLT isvariable and depends on regularfollow-up and TTE and/or RHC evalu-ations. The weaning process after OLT

can often be achieved over severalweeks. Some patients can be weaned offall vasodilators, revealing that the pro-cedure itself can rapidly improve andresolve POPH.

Postoperative Follow-Up of Patients WithPOPH and OLTRight ventricular dysfunction is one ofthe most important conditions the cli-nician will face in the postoperativeperiod. There are 4 hemodynamic prin-ciples that frame the understanding ofthis devastating complication. First, PVRis the main factor that affects the RVafterload. Second, it is the RV afterloadand not the MPAP that precipitates RVfailure. Third, the appearance of RVdilatation, RV dysfunction, and septaldyskinesia are the most valuably eval-uated echocardiography signs. Fourth,the RV outflow tract (RVOT) is a keyphysiological element in the interactionbetween the RV and the pulmonaryartery.28 Perioperative Doppler TTE iscrucial in the assessment of this inter-action. Patients with evidence of RVdysfunction and “notching” in Dopplerimaging envelope in the RVOT are con-sidered dependent on RV afterload.29 Inorder to obtain an adequate imaging ofthe RVOT, parasternal short-axis viewat heart base level (TTE) or transgastriclong axis view at 135 degrees are recom-mended.28

Once the patient is transferred to therecovery ward, there is usually notitration of medications. A pre-dischargeTTE and b-type natriuretic peptide(BNP) are recommended for documen-tation, as well as close follow-up at theoutpatient clinic at 1 week with theOLT team. Specific instructions are pro-vided to call or come to the emergencydepartment with any symptoms of dete-rioration. Otherwise, our practice hasbeen a 1-month follow-up with a TTEwith the intention to formulate a sen-sible plan for weaning medications. Amultidisciplinary discussion between spe-cialists in transplant and PH iswarranted. It is possible to safelywithdraw medications in a matter ofmonths, depending on the severity ofpersistent elevated MPAP or thepresence of RV dilation on TTE. Subse-quent follow-up visits at our center are

anywhere from 2 to 6 months post-OLTand include functional class, BNP,6-minute walk test, and TTE to assessthe clinical status. There are someaccounts of medication titrations takingmore than a year to complete. Somepatients may need medication for anindefinite amount of time (or lifelong),perhaps pointing to possible undetectedprimary causes besides portal hyper-tension or to irreversible vascularremodeling. Reevaluation with RHCmay be necessary if TTE reveals absenceor incomplete tricuspid regurgitant (TR)jet, which precludes assessment of rightheart pressures. For patients on con-tinuous infusion prostacyclin therapy,RHC may be needed for safe transitionto oral therapy. Lastly, repeat RHC maybe indicated if the clinical information isdisparate or there is consideration ofescalation of PAH-specific therapy.

CONCLUSIONThe management of POPH in patientsundergoing OLT involves an immediatepretransplant assessment with RHC andoften TTE. With that information inhand, a multidisciplinary approach todetermine the best PAH-specifictreatment plan is recommended.

References1. Krowka MJ. Hepatopulmonary syndromeversus portopulmonary hypertension: distinctionsand dilemmas. Hepatology. 1997;25(5):1282-1284.2. Simonneau G, Robbins IM, Beghetti M, et al.Updated clinical classification of pulmonary hyper-tension. J Am Coll Cardiol. 2009 30;54(1 Suppl):S43–S54.3. Krowka MJ, Swanson KL, Frantz RP,McGoon MD, Wiesner RH. Portopulmonaryhypertension: Results from a 10-year screeningalgorithm. Hepatology. 2006;44(6):1502-1510.4. Garg A, Armstrong WF. Echocardiography inliver transplant candidates. JACC CardiovascImaging. 2013;6(1):105-119.5. Aduen JF, Castello R, Lozano MM, et al. Analternative echocardiographic method to estimatemean pulmonary artery pressure: diagnostic andclinical implications. J Am Soc Echocardiogr. 2009;22(7):814-819.6. Auden JF, Castello R, Daniels JT, et al.Accuracy and precision of three echocardiographicmethods for estimating mean pulmonary arterypressure. Chest. 2011;139:347-352.7. Raevens S, Colle I, Reyntjens K, et al. Echo-cardiography for the detection of portopulmonaryhypertension in liver transplant candidates: ananalysis of cutoff values. Liver Transpl. 2013;19(6):602-610.


8. Castro M, Krowka MJ, Schroeder DR, et al.Frequency and clinical implications of increasedpulmonary artery pressures in liver transplantpatients. Mayo Clin Proc. 1996;71(6):543-551.9. Kuo PC, Vagelos RH, Alfrey EJ, Garcia G,Dafoe DC. Liver transplant candidates exhibitvolume-mediated pulmonary hypertension[abstract]. Hepatology. 1994;20:124A.10. Safdar Z, Bartolome S, Sussman N. Por-topulmonary hypertension: an update. LiverTranspl. 2012;18(8):881-891.11. Krowka MJ, Plevak DJ, Findlay JY, RosenCB, Wiesner RH, Krom RA. Pulmonary hemody-namics and perioperative cardiopulmonary-relatedmortality in patients with portopulmonary hyper-tension undergoing liver transplantation. LiverTranspl. 2000;6(4):443-450.12. Krowka MJ, Fallon MB, Mulligan DC, GishRG. Model for end-stage liver disease (MELD)exception for portopulmonary hypertension. LiverTranspl. 2006;12(12 Suppl 3):S114–S116.13. Ramsay MA, Simpson BR, Nguyen AT,Ramsay KJ, East C, Klintmalm GB. Severe pul-monary hypertension in liver transplant candidates.Liver Transpl Surg. 1997;3(5):494-500.14. Krowka MJ, Miller DP, Barst RJ, et al. Por-topulmonary hypertension: a report from theUS-based REVEAL Registry. Chest. 2012;141(4):906-915.15. Findlay JY, Plevak DJ, Krowka MJ, SackEM, Porayko MK. Progressive splenomegaly afterepoprostenol therapy in portopulmonary hyper-

tension. Liver Transpl Surg. 1999;5(5):362-365.16. Touma W, Nayak RP, Hussain Z, BaconBR, Kudva GC. Epoprostenol-induced hyper-splenism in portopulmonary hypertension. Am JMed Sci. 2012;344(5):345-349.17. Austin MJ, McDougall NI, Wendon JA, etal. Safety and efficacy of combined use of sildenafil,bosentan, and iloprost before and after liver trans-plantation in severe portopulmonary hypertension.Liver Transpl. 2008;14(3):287-291.18. Mahmood F, Christie A, Matyal R. Trans-esophageal echocardiography and noncardiacsurgery. Semin Cardiothorac Vasc Anesth. 2008;12(4):265-289.19. Leung JM, Levine EH. Left ventricular end-systolic cavity obliteration as an estimate ofintraoperative hypovolemia. Anesthesiology. 1994;81(5):1102-1109.20. Burtenshaw AJ, Isaac JL. The role of trans-oesophageal echocardiography for perioperativecardiovascular monitoring during orthotopic livertransplantation. Liver Transpl. 2006;12(11):1577-1583.21. Aubuchon J, Maynard E, Lakshmina-rasimhachar A, Chapman W, Kangrga I.Intraoperative transesophageal echocardiographyreveals thrombotic stenosis of inferior vena cavaduring orthotopic liver transplantation. LiverTranspl. 2013;19(2):232-234.22. Sibulesky L, Peiris P, Taner CB, Kramer DJ,Canabal JM, Nguyen JH. Intraoperative intra-cardiac thrombosis in a liver transplant patient.

World J Hepatol. 2010;2(5):198-200.23. Vannucci A, Johnston J, Earl TM, Doyle M,Kangrga IM. Intraoperative transesophageal echo-cardiography guides liver transplant surgery in apatient with thrombosed transjugular intrahepaticportosystemic shunt. Anesthesiology. 2011;115(6):1389-1391.24. Robertson AC, Eagle SS. TransesophagealEchocardiography During Orthotopic Liver Trans-plantation: Maximizing Information Without theDistraction. J Cardiothorac Vasc Anesth. 2013 Apr30. [Epub ahead of print]25. Walmrath D, Schermuly R, Pilch J, Grim-minger F, Seeger W. Effects of inhaled versusintravenous vasodilators in experimental pulmonaryhypertension. Eur Respir J. 1997;10(5):1084-1092.26. Minder S, Fischler M, Muellhaupt B, et al.Intravenous iloprost bridging to orthotopic livertransplantation in portopulmonary hypertension.Eur Respir J. 2004;24(4):703-707.27. Levy MT, Torzillo P, Bookallil M, SheilAG, McCaughan GW. Case report: delayed reso-lution of severe pulmonary hypertension afterisolated liver transplantation in a patient with cir-rhosis. J Gastroenterol Hepatol. 1996;11(8):734-737.28. Otto CM. Textbook of Clinical Echocardiog-raphy. 5th ed. Philadelphia: Elsevier Saunders; 2013.29. Arkles JS, Opotowsky AR, Ojeda J, et al.Shape of the right ventricular Doppler envelopepredicts hemodynamics and right heart function inpulmonary hypertension. Am J Respir Crit CareMed. 2011;183(2):268-276.


Clinical Case Studies in Renal Transplantation

The case studies below are referred to in the articles “Pulmonary Hypertension inPatients with Chronic Kidney Disease: Noninvasive Strategies for Patient Pheno-typing and Risk Assessment” by Amresh Raina, MD, and “HemodynamicEvaluation of Pulmonary Hypertension in Chronic Kidney Disease” by RyanTedford, MD, and Paul Forfia, MD, on the following pages.

Clinical Case 1A 69-year-old man presents for preoper-ative evaluation prior to consideration ofrenal transplantation. He has a long-standing history of systemichypertension, type 2 diabetes mellitus,obesity, and obstructive sleep apnea. Hedeveloped end-stage renal disease as aresult of diabetic nephropathy and hasbeen on hemodialysis via right subclaviantunneled catheter for the last 3 years.

Over the past few months, the patientreports worsening dyspnea with mild to

moderate exertion and multiple episodesof paroxysmal nocturnal dyspnea overthe past 6 months. He has alsodeveloped 2 pillow orthopnea andbilateral lower extremity. He denies chestdiscomfort, angina, palpitations, syncope,or presyncope. He has bilateral pleuraleffusions noted on chest x-ray.

Ventilation-perfusion scan is lowprobability for pulmonary embolism.Lower extremity Doppler studies arenegative for deep venous thrombosis.

Chest CT reveals no evidence ofemphysema or interstitial lung disease,but does reveal a large right pleuraleffusion.

A screening pretransplant transtho-racic echocardiogram showed normal leftand right ventricular size and systolicfunction, with estimated pulmonaryartery pressure of 60 mm Hg. He istherefore referred for further evaluationof his pulmonary hypertension in consid-eration of transplant.

Clinical Case 2A 74-year-old man presents for evalu-ation of dyspnea. He has a long-standinghistory of systemic hypertension andhypertensive nephropathy. He hadrequired hemodialysis 3 times weekly viaa right upper extremity arteriovenous(AV) fistula for several years, and ulti-mately underwent successful cadavericrenal transplantation 3 years ago. Hisright heart catheterization just prior torenal transplant revealed a right atrialpressure of 2 mm Hg, mean pulmonaryarterial pressure of 35 mm Hg, pul-

monary capillary wedge pressure of 11mm Hg, and an elevated cardiac outputof 8.8 L/ min (cardiac index 4.3L/min/m2). His AV fistula was nottaken down post-transplant.

He initially did well after transplantbut presented to the pulmonary hyper-tension clinic after a progressive declinein exercise tolerance over the past 6months, now limited even when walkingshort distances. To date, evaluation forischemic disease has been negative, a

ventilation/perfusion scan was low prob-ability for pulmonary embolism, and aCT scan of the chest showedenlargement of the pulmonary arteriesbut no evidence of parenchymal lungdisease.

A transthoracic echocardiogram isperformed, which reveals normal leftventricular and right ventricular (RV)systolic function with significant RVdilatation and estimated pulmonaryartery systolic pressure of 80 mm Hg.

Clinical Case 3A 47-year-old man with long-standingtype 1 diabetes mellitus, systemic hyper-tension, and chronic kidney diseaserelated to diabetic nephropathyunderwent combined renal and pan-creatic transplant 13 years ago.Subsequently, he had renal allograftfailure leading to dialysis for 10 years viaan arteriovenous (AV) fistula. Threeyears ago, he received another successfulrenal transplant and is now being con-

sidered for a repeat renal transplant. HisAV fistula remains functional.

On interview he reports mild lowerextremity edema, which has beenchronic, and mild dyspnea with mod-erate activity. He denies orthopnea orparoxysmal nocturnal dyspnea. A venti-lation perfusion scan shows no evidenceof pulmonary embolism. A CT scan ofthe chest shows dilated central pul-monary arteries consistent withpulmonary hypertension (PH), but no

evidence of parenchymal lung disease.Pulmonary function tests showed amildly reduced diffusion lung capacityfor carbon monoxide.

However, on a screening pretransplantechocardiogram, he was noted to have adilated right ventricle with RV dys-function, with an estimated pulmonaryartery systolic pressure of 105 mm Hg.He is therefore referred for further eval-uation of his PH.


Pulmonary Hypertension in Patients With Chronic KidneyDisease: Noninvasive Strategies for Patient Phenotyping andRisk Assessment

Amresh Raina, MDCardiovascular InstituteAllegheny General HospitalPittsburgh, PA

Pulmonary hypertension (PH) is relatively common among patients with chronickidney disease (CKD). PH is most prevalent in patients undergoing hemodialysis,ranging from 32%-58%, depending on the definition of PH used. The reported inci-dence of PH is less frequent for patients receiving peritoneal dialysis (12%-42%), andrenal transplant recipients are typically the least likely to have PH than either of thesedialysis cohorts.1-6

An important distinction must be madebetween PH, which is simply defined asmean pulmonary artery (PA) pressure�25 mm Hg or systolic PA pressure�35 mm Hg vs pulmonary arterialhypertension (PAH), which includesPA occlusive pressure �15 mm Hg, achronic, progressive condition of pul-monary vascular remodeling, leading toright heart failure and ultimately deathif left untreated.7

The etiology of PH in CKD patientsis typically associated with left heartdisease (WHO Group 2), as PAH(WHO Group 1) is rare in this patientpopulation.4 Moreover, in general,patients with CKD often have a varietyof risk factors predisposing them towardpulmonary venous congestion, includingsystemic hypertension, left ventricularhypertrophy (LVH), ischemic heartdisease, and left ventricular (LV) dia-stolic dysfunction.8,9 Although purepulmonary vascular disease (PVD)-basedPH (high pulmonary vascular resistance[PVR], noncompliant conduit pulmonaryarteries) is relatively rare in end-stagerenal disease (ESRD), not infrequently a“mixed” phenotype of PVD with pul-monary venous hypertension is seen inthis population.

PH in CKD patients is important torecognize for 3 major reasons. The firstis that several studies have indicated thatPH is an independent predictor of mor-tality in CKD patients, especially thosereceiving renal replacement therapy.5,10,11

Second, many CKD patients are eval-uated for renal transplantation. Ingeneral, significant PH is felt to be arelative contraindication to renal trans-plantation in patients with CKD. Inretrospective studies, PH has been asso-ciated with increased early renal allograftdysfunction in these patients,12 and isalso associated with reduced patient sur-vival after renal transplantation.13

Whether the PH is the direct, causalexplanation for these differences inoutcome is debatable and somewhat con-troversial. Nevertheless, in many centers,patients with significant PH are charac-terized as not being acceptablecandidates for renal transplantation.

Perhaps most importantly from aclinical perspective, many patients withCKD present to their treating physicianswith dyspnea. PH is often picked up ondiagnostic echocardiograms in thesepatients, and not infrequently PH isinvoked as a potential etiology ofdyspnea and targeted with pulmonaryvasodilating medications. However, theclinical phenotype of PH can be quitevaried within this broad categorization,ranging from patients with “simple” dia-stolic heart failure and secondary PH, tothose with severe reactive PVD, rightventricular (RV) dysfunction, and aclinical syndrome resembling PAH. Thekey physiologic differences in thesesubsets of patients warrant appropriatediscussion and attention not only interms of identifying patients who are

appropriate candidates for renal trans-plantation, but also in terms ofidentifying in which of these patientsPH is the major cause of symptoms, vsothers for whom PH is a marker ofother underlying disease processes.

Though PH in CKD patients war-rants a comprehensive evaluation oftenincluding invasive hemodynamicassessment, the first step in evaluation ofthese patients is typically a noninvasiveassessment with physical examinationand a transthoracic echocardiogram.Careful attention to the physical exami-nation and the echo-Doppler assessmentcan provide clues to the underlying phys-iology of PH in these patients and caninform decisions regarding furtherassessment and treatment strategies,including appropriate maneuvers duringinvasive hemodynamic assessment.

From the 2-dimensional echocar-diogram, LVH and left atrialenlargement suggest the presence of LVdiastolic dysfunction and left atrial con-gestion. However, grade 2 or grade 3LV diastolic dysfunction based ontransmitral Doppler imaging will bepresent in many CKD patients withPH.8,9 Therefore, echocardiographicassessment of PH in these patientsshould also focus carefully on evaluatingRV size, structure, and function andevaluating for direct and indirect evi-dence of elevated PVR with detailedDoppler hemodynamic assessment.14

This approach to the noninvasiveassessment of PH in CKD patients ishighlighted in the 3 case studies thatreference the associated clinical his-tories.

Key Words—chronic kidney disease, end-stage renal disease, noninvasive assessment, pulmonary vasculardisease, renal transplantationCorrespondence: [email protected]: The author provided no disclosures.


CASE 1Recap: A 69-year-old man with obesity,hypertension, diabetes, and obstructivesleep apnea with ESRD on hemodialysisbeing evaluated for renal transplant.

Physical ExaminationOn examination, blood pressure is178/60, pulse is 64 beats per minute,respiratory rate is 12 breaths per minute,and oxygen saturation is 90% on roomair. There is a square-wave response insystolic blood pressure to Valsalvamaneuver. In general, the patient is amildly obese, well-appearing man in noapparent distress. Jugular venous pressureis 12 cm of water with normal venouscontours. On cardiac examination, S1and S2 are normal with normal P2intensity. There is a 2/6 holosystolicmurmur at the right upper sternalborder. LV apical impulse is normal andnondisplaced. There is no RV heave.Lung auscultation showed diminishedbreath sounds at the right base upthrough the mid-right lung field.Abdomen is soft and nondistended.There is mild hepatojugular reflux noted.Extremities revealed 2-3� bilateralpitting edema to the upper shins.

EchocardiogramA transthoracic echocardiogram is per-formed and representative parasternallong and short axis views and apical 4chamber views are shown. In addition,pulsed wave Doppler in the RV outflowtract and transmitral Doppler profiles areshown. LV systolic function is normal at55%. Mitral regurgitation is noted asmoderate (not shown). There is nomitral stenosis.

The parasternal long axis view (panelA) confirms normal LV size with signif-icant LVH. The parasternal short axisviews (panels B and C) reveal a notableabsence of septal flattening in systole ordiastole with a convexed septal profile.The apical 4 chamber view (panel D)illustrates significant left atrialenlargement, while RV size is mildlydilated with RV:LV ratio of roughly 1.0.Notably, the RV apical angle is relativelyacute, does not form or share the apex ofthe heart, and there is minimal rightventricular hypertrophy (RVH). These2-dimensional findings do not supportthe presence of PVD.

On hemodynamic assessment, pulsewave Doppler in the right ventricularoutflow tract (RVOT) (panel E) reveals

a normal parabolic profile without“notching.” The RVOT accelerationtime is low normal at 110 ms. Thesefindings together strongly suggest anormal PVR. The velocity time integral(VTI) in the RVOT is in the normalrange (14 cm), implying normal RVstroke volume. Transmitral pulse waveDoppler (panel F) shows a restrictiveinflow pattern, consistent with high leftatrial pressure. Lastly, tricuspid annularplane systolic excursion (TAPSE) per-formed via M-mode (panel G) confirmsnormal RV function with TAPSE of 23mm.

In this case, the findings on historyand physical examination combined withthe echocardiographic findings stronglysuggest a hemodynamic phenotype ofheart failure with preserved ejectionfraction and secondary PH, without con-comitant PVD. The patient presentswith several symptoms consistent withmarked left heart congestion includingorthopnea and paroxysmal nocturnaldyspnea (PND). In addition, there areobjective signs on physical examinationof elevated left atrial pressure, includingsquare wave systolic blood pressureresponse to Valsalva and right pleuraleffusion.15

The echocardiogram in this casestrongly points toward a left heart originof PH. There is marked LVH, left atrialenlargement, and restrictive transmitralfilling consistent with severe LV diastolicdysfunction and elevated left atrialpressure. Though the RV is mildly

Figure 1A

Figure 1


dilated, RV function is preserved as evi-denced by normal TAPSE and normalRVOT VTI. Lastly, there is no evidenceof significantly elevated PVR as evi-denced by the absence of septalflattening or notching of the pulse waveDoppler profile in the RVOT and rela-tively preserved RVOT accelerationtime.16,17

Given the preserved RV function anda phenotype consistent with left sideddiastolic heart failure, this patient wouldbe considered an acceptable candidate forrenal transplantation once volume statuswas optimized by volume removal withultrafiltration and with blood pressureunder better control; repeat evaluationwith right heart catheterization may beneeded. In the invasive hemodynamicassessment of such patients, it is notuncommon to find a top normal or onlymildly elevated resting wedge pressure.In such cases, saline fluid challenge orexercise should be considered.

CASE 2Recap: A 74-year-old man with systemichypertension, ESRD, previously onhemodialysis via arteriovenous (AV)fistula, now with progressive dyspnea andexercise intolerance post renal transplant.

Physical ExaminationOn examination, blood pressure is142/64. Pulse is 83 beats per minute andregular. Respiration is 18 breaths/minuteand oxygen saturation is 92% on roomair. There is a slow decay in systolicblood pressure with Valsalva. In general,the patient is an elderly appearing manin no apparent distress. Jugular venouspressure was 14 cm of water with prom-inent V wave. Arterial pulses are stiffand hyperdynamic with rapid upstroke.Point of maximum impulse (PMI) isnondisplaced and is hyperdynamic. S1and S2 are normal with normal P2intensity. A soft S4 is audible. There is a3/4 systolic murmur at the left uppersternal border. Abdomen is soft; there ismild hepatojugular reflux. Extremitieshave no edema. There is a large rightbrachial AV fistula with palpable thrill.

EchocardiogramA transthoracic echocardiogram is per-formed. Parasternal long and short axisand apical 4 chamber views are illus-trated below. In addition, pulse waveDoppler in the RVOT and transmitralDoppler profiles are shown. LV systolicfunction is normal with left ventricularejection fraction (LVEF) of 70%. There

is no mitral regurgitation or mitral ste-nosis.

The parasternal long axis view (panelA) reveals normal LV size with mildLVH with mitral annular calcification, acommon finding in CKD. The para-sternal short axis views (panels B and C)reveal mild diastolic and systolic septalflattening. The apical 4 chamber view(panel D) reveals a mildly dilated RVwith RV:LV ratio of roughly 1.0, andthe RV shares the apex with the LV.There is mild RVH.

On hemodynamic assessment, pulsedwave Doppler in the RVOT reveals alate systolic notch and an RVOT accel-eration time that is mildly reduced at 90ms. These findings suggest top normalor mildly elevated PVR. The VTI in theRVOT is high (22 cm), suggesting highRV stroke volume. Transmitral pulsewave Doppler (panel F) shows a“pseudonormal” inflow pattern, con-sistent with increased left atrial pressure.Lastly, TAPSE performed via M-mode(panel G) suggests normal to hyperdy-namic RV function with TAPSE of 28mm.

This patient presents with theinsidious onset of progressive dyspneaseveral years after renal transplantation.On physical examination, he has severalfeatures that suggest underlying left heartstiffness and left atrial congestion such asan S4 gallop and slow decay in systolicblood pressure in response to Valsalvamaneuver. However, there are alsoseveral findings suggesting high cardiac

Figure 2

Figure 2A


output state, including hyperdynamicarterial pulses and PMI. The echocar-diogram in this instance suggests amixed picture of left sided congestion,high cardiac output, and mildly elevatedPVR.

The RV is mildly dilated and in thiscase shares the apex of the heart withmild RVH. RVH function is nearhyperdynamic with TAPSE of 28 mm.This is confirmed by pulse wave Dopplerassessment of the RVOT with highRVOT VTI, suggesting high RV strokevolume.

Thus, the noninvasive assessmentstrongly suggests a high cardiac outputsyndrome due to the large brachial AVfistula with moderate left heart con-gestion, coupled with mild PVD andstiff, sclerotic central pulmonary arteries.In this case, hemodynamic assessment isclearly warranted, preferably with pro-vocative maneuvers such as temporaryfistula occlusion to assess the contri-bution of the fistula to cardiac output,left heart congestion, and PH (see articleby Dr Tedford in this issue).

CASE 3Recap: A 47-year-old man with type 1diabetes mellitus, prior renal and pan-creatic transplant, renal allograft failure,

being evaluated for repeat renal trans-plant.

Physical ExaminationOn examination, blood pressure is128/68, pulse is 57 beats per minute andregular. Respiratory rate is 16 breaths perminute. Oxygen saturation on room airis 91%. There is slow decay in systolicblood pressure in response to Valsalvamaneuver. In general this is a well-appearing man in no apparent distress.Jugular venous pressure is 12 cm ofwater with normal venous contours.Arterial pulses are narrow, lowamplitude. On cardiac examination, S1is normal. S2 is normal with accentuatedP2 component. There is a prominent S4gallop audible. No murmurs or rubs areappreciated. LV apical impulse is non-displaced. There is a shallow RV heave.Lungs are clear to auscultation bilaterallywithout rales, rhonchi, or wheezing.Abdomen is soft and nontender. Thereis an old midline surgical scar that iswell healed. There is no hepatojugularreflux. Extremities are well perfusedbilaterally. There is trace bilateral lowerextremity edema. There is a left upperextremity AV graft with palpable thrilland audible bruit.

EchocardiogramA transthoracic echocardiogram isobtained and representative parasternallong and short axis and apical 4 chamberimages are shown below. LV size andsystolic function are normal, with LVEFof 65%. Mitral regurgitation is mild (notshown). There is no mitral stenosis.

The parasternal long axis view (panelA) again reveals normal LV size, mildLVH, and moderate left atrialenlargement. The parasternal short axisviews (panels B and C) and apical 4chamber view (panel D) reveal signif-icant septal flattening in systole�diastole. The apical 4 chamber view alsoreveals a moderately dilated RV withRV:LV ratio of 1.2, and the RV sharesthe apex with the LV. There is moderateRVH.

On hemodynamic assessment, pulsedwave Doppler in the RVOT reveals amidsystolic notch pattern consistent witha PVR �5 Wood units. RVOT acceler-ation time is very short at 60 ms. TheVTI in the RVOT is normal (16 cm),suggesting normal RV stroke volume.Transmitral pulse wave Doppler (panelF) shows an impaired relaxation pattern,also referred to as grade 1 diastolic dys-function. Lastly, TAPSE performed viaM-mode (panel G) suggests moderateRV dysfunction with TAPSE of 16 mm.

This patient has several features sug-gesting the etiology of his PH hascontributions from left sided heartdisease, including slow decay in systolicblood pressure response to Valsalva andS4 gallop. However, other elements of

Figure 3a

Figure 3


his examination and his echocardiogramsuggest a more “right sided” phenotypewith narrow, low amplitude pulses,accentuated P2, and RV heave.

Although the echocardiogram demon-strates LVH and left atrial enlargement,it also shows marked RV enlargement,systolic septal flattening, and moderateRV dysfunction, all of which indicateright heart dysfunction on the basis ofincreased pulmonary arterial afterload.Most notably, there are several featuressuggesting significant PVD including amidsystolic notch profile in the RVOT,very short RVOT acceleration time, andpredominant systolic septal flat-tening.14,16,17 Notably, transmitralDoppler shows an impaired-relaxationpattern, implying a normal or at mostmildly elevated left atrial pressure.

Based on the above assessment, wecan conclude that this patient hasdeveloped significant PVD secondary tochronic left heart congestion and nowhas a predominantly “right sided” phe-notype with RV enlargement and RVdysfunction rather than classic signs orsymptoms of left heart congestion. Thisis a more complex situation, where thePH is not simply a marker of high leftatrial pressure or high cardiac output,but instead is of major hemodynamicimport with manifest and clinically sig-nificant right heart dysfunction. Thispatient would be at much higher risk foradverse events with renal transplantationthan the patient in Case 1, and likelywould not be a candidate withoutaddressing the manifest PVD. Chronicthromboembolic disease must also beexcluded by ventilation-perfusion scintig-raphy. Certainly, invasive hemodynamicassessment is warranted prior to consid-eration of elective surgery.

DISCUSSIONPH in CKD patients is associated with avaried pathophysiology, of which 3 dis-crete phenotypes are illustrated in thecases above. In clinical practice, there isoften considerable overlap between fea-tures of each of the phenotypesdescribed, and the purpose of this reviewis not to describe every scenario ofpatients with CKD and PH. In addition,there are rare cases of idiopathic PAH orconnective tissue disease-associated PAH

with associated CKD, but the physiologyof these patients is typically driven pri-marily by PVD more so thanpathophysiologic features unique toCKD. Indeed, some features arecommon to many patients with PHassociated with CKD, includingimpaired salt and water handling, sys-temic hypertension, LV diastolicdysfunction, and left heart congestion.

In addition, patients with CKD andin particular those with long-standingdiabetes and hemodialysis patients oftendevelop a diffuse arteriosclerotic processinvolving large arteries including conduitpulmonary arteries, leading to increasedarterial stiffness and diminished arterialcompliance, which has been associatedwith adverse cardiovascular mortality.18,19

Some CKD patients may also developlarge stroke volumes and high cardiacoutput syndromes secondary to long-standing systemic shunts such as largedialysis AV fistulas. Although there isdebate as to whether an AV fistula alonecan lead to PH, it is clear from clinicalobservation and physiologic rationale(mean PA pressure � cardiac output *PVR � left atrial pressure) that couplingan inappropriately high cardiac outputwith a noncompliant, hypertrophied leftheart will lead to left heart congestion,with PH being an inevitableconsequence.20-22

Lastly, patients with chronic left heartcongestion can develop significant PVD,which may be severe enough to manifestas a clinical syndrome similar to PAH,particularly when right heart dysfunctionresults. Noninvasive assessment usinghistory, physical examination, and anecho-Doppler examination forms thecornerstone of the initial evaluation ofpatients with CKD and suspected PH,not just because these are typically thefirst tests obtained, but also becausemuch information can be gleaned fromthese initial tests that can guide subse-quent invasive evaluations.

At the bedside, using blood pressureresponse to Valsalva maneuver canprovide a simple estimation of elevatedleft atrial pressure and provide clues inthe clinic to the hemodynamic basis ofPH.15 Similarly, a simple echo-Dopplerscoring system can help to differentiate apulmonary vascular from a pulmonary

venous etiology of PH.14 In CKDpatients, the PH clinician must take thisassessment a step further in that many ifnot most patients with CKD will havesome stigmata of left heart disease onphysical examination or echo-Dopplerassessment.

The keys to noninvasive assessment ofPH in these patients rest in theassessment of RV structure and function,to evaluate for high cardiac output syn-dromes, and to evaluate carefully forevidence of elevated PVR using athorough assessment of the pulsed waveDoppler signal in the RVOT.14,23 Usingthis type of comprehensive physicalexamination and echo-Dopplerassessment should provide the PH cli-nician with an overall impression of thehemodynamic basis of PH in themajority of patients presenting withdyspnea even prior to cardiac catheter-ization.

References1. Abedini M, Sadeghi M, Naini AE, AtapourA, Golshahi J. Pulmonary hypertension amongpatients on dialysis and kidney transplant recip-ients. Ren Fail. 2013;35(4):560-565.2. Agarwal R. Prevalence, determinants andprognosis of pulmonary hypertension amonghemodialysis patients. Nephrol Dial Transplant.2012;27(10):3908-3914.3. Bozbas SS, Akcay S, Altin C, et al. Pulmonaryhypertension in patients with end-stage renaldisease undergoing renal transplantation. Trans-plant Proc. 2009;41(7):2753-2756.4. Pabst S, Hammerstingl C, Hundt F, et al.Pulmonary hypertension in patients with chronickidney disease on dialysis and without dialysis:results of the PEPPER-study. PLoS One. 2012;7(4):e35310.5. Ramasubbu K, Deswal A, Herdejurgen C,Aguilar D, Frost AE. A prospective echocardio-graphic evaluation of pulmonary hypertension inchronic hemodialysis patients in the United States:prevalence and clinical significance. Int J Gen Med.2010;3:279-286.6. Yigla M, Nakhoul F, Sabag A, et al. Pul-monary hypertension in patients with end-stagerenal disease. Chest. 2003;123(5):1577-1582.7. Galie N, Hoeper MM, Humbert M, et al.Guidelines for the diagnosis and treatment of pul-monary hypertension: the Task Force for theDiagnosis and Treatment of Pulmonary Hyper-tension of the European Society of Cardiology(ESC) and the European Respiratory Society(ERS), endorsed by the International Society ofHeart and Lung Transplantation (ISHLT). EurHeart J. 2009;30(20):2493-2537.8. Hayashi SY, Rohani M, Lindholm B, et al.Left ventricular function in patients with chronickidney disease evaluated by colour tissue Doppler


velocity imaging. Nephrol Dial Transplant. 2006;21(1):125-132.9. Miyazato J, Horio T, Takiuchi S, et al. Leftventricular diastolic dysfunction in patients withchronic renal failure: impact of diabetes mellitus.Diabet Med. 2005;22(6):730-736.10. Stallworthy EJ, Pilmore HL, Webster MW,et al. Do echocardiographic parameters predictmortality in patients with end-stage renal disease?Transplantation. 2013;95(10):1225-1232.11. Yigla M, Fruchter O, Aharonson D, et al.Pulmonary hypertension is an independent pre-dictor of mortality in hemodialysis patients. KidneyInt. 2009;75(9):969-975.12. Zlotnick DM, Axelrod DA, Chobanian MC,et al. Non-invasive detection of pulmonary hyper-tension prior to renal transplantation is a predictorof increased risk for early graft dysfunction. NephrolDial Transplant. 2010;25(9):3090-3096.13. Issa N, Krowka MJ, Griffin MD, HicksonLJ, Stegall MD, Cosio FG. Pulmonary hyper-tension is associated with reduced patient survivalafter kidney transplantation. Transplantation. 2008;86(10):1384-1388.

14. Opotowsky AR, Ojeda J, Rogers F, et al. Asimple echocardiographic prediction rule for hemo-dynamics in pulmonary hypertension. CircCardiovasc Imaging. 2012;5(6):765-775.15. Opotowsky AR, Ojeda J, Rogers F, Arkles J,Liu T, Forfia PR. Blood pressure response to thevalsalva maneuver. A simple bedside test todetermine the hemodynamic basis of pulmonaryhypertension. J Am Coll Cardiol. 2010;56(16):1352-1353.16. Arkles JS, Opotowsky AR, Ojeda J, et al.Shape of the right ventricular Doppler envelopepredicts hemodynamics and right heart function inpulmonary hypertension. Am J Respir Crit CareMed. 2011;183(2):268-276.17. Yared K, Noseworthy P, Weyman AE,McCabe E, Picard MH, Baggish AL. Pulmonaryartery acceleration time provides an accurateestimate of systolic pulmonary arterial pressureduring transthoracic echocardiography. J Am SocEchocardiogr. 2011;24(6):687-692.18. Blacher J, Guerin AP, Pannier B, MarchaisSJ, Safar ME, London GM. Impact of aorticstiffness on survival in end-stage renal disease. Cir-

culation. 1999;99(18):2434-2439.19. Sipahioglu MH, Kucuk H, Unal A, et al.Impact of arterial stiffness on adverse cardiovas-cular outcomes and mortality in peritoneal dialysispatients. Perit Dial Int. 2012;32(1):73-80.20. Beigi AA, Sadeghi AM, Khosravi AR,Karami M, Masoudpour H. Effects of the arterio-venous fistula on pulmonary artery pressure andcardiac output in patients with chronic renalfailure. J Vasc Access. 2009;10(3):160-166.21. Malhotra K, Dhawan V, Dalal P, et al.Decompensated high-output congestive heartfailure in a patient with AVF and the role of rightheart catheterization: a case study. Hemodial Int.2012;16 Suppl 1:S58–S61.22. Unal A, Tasdemir K, Oymak S, et al. Thelong-term effects of arteriovenous fistula creationon the development of pulmonary hypertension inhemodialysis patients. Hemodial Int. 2010;14(4):398-402.23. Opotowsky AR, Clair M, Afilalo J, et al. ASimple Echocardiographic Method to EstimatePulmonary Vascular Resistance. Am J Cardiol. 2013Jun 1. [Epub ahead of print]


Hemodynamic Evaluation of Pulmonary Hypertension inChronic Kidney Disease

Ryan J. Tedford, MDDepartment of MedicineDivision of CardiologyJohns Hopkins School of MedicineBaltimore, MD

Paul R. Forfia, MDAssociate Professor of MedicineDirector, Pulmonary Hypertension and

Right Heart Failure ProgramTemple University HospitalPhiladelphia, PA

Chronic kidney disease (CKD) is a common condition and its prevalence isincreasing.1,2 Likewise, the number of patients reaching end-stage renal disease(ESRD) continues to rise. In the United States in 2010, there were 413,275 patientson dialysis and 179,361 patients with a functioning renal transplant, bringing the rateof prevalent ESRD cases to 1752 per million population.2 Pulmonary hypertension(PH) is a commonly encountered comorbidity of patients with CKD and those whohave progressed to ESRD. Although the true prevalence of PH in these populationsis unknown, several small, single-center analyses using varied cutoffs for echocardio-graphically estimated pulmonary pressures have reported estimates as high as 56%.3-7

The factors that likely contribute to thedevelopment of PH in ESRD arenumerous and have been well describedin a recent review by Kawar et al.5 Theseinclude persistent passive congestionfrom volume overload, decreased leftventricular compliance and/or systolicdysfunction, endothelial dysfunction,anemia, metabolic and hormonalderangements leading to pulmonaryvasoconstriction, and the long-termeffects of arteriovenous (AV) fistulas.While the latter’s contribution to thedevelopment of PH remains contro-versial, it is clear that in the rightscenario, an AV shunt can cause highoutput heart failure.8 Creation of a sys-temic AV shunt leads to an increasedcardiac output (CO) by several mecha-nisms. First, it decreases total peripheralresistance, leading to increased venousreturn to the right heart. This increase inpreload leads to enhanced stroke volumevia the Starling mechanism. Also, thereduced peripheral resistance activatessympathetic cardiovascular reflexes,increasing both heart rate and contrac-tility. These combined mechanismscontribute to CO augmentation andincrease the work done by both ven-tricles.9,10 The severity appears related tosize of the shunt.11 Lastly, AV shuntsmay also increase total blood volume,

which further increases preload.12

Patients with already stiff ventricles mayhave difficulty accommodating theincreased preload, and the increasedworkload may lead to more maladaptivehypertrophy over time.13 More recently,Paneni and colleagues compared echoparameters of right ventricular (RV) sys-tolic and diastolic function in controls,patients undergoing peritoneal dialysis(PD), and those undergoing hemodi-alysis via radial or brachial AV fistulas.When adjusted for confounding factors,patients with an AV fistula had anincreased risk of RV dysfunction whencompared to the PD group (OR 6.3;P�0.001).14

Despite advances in noninvasiveimaging, full hemodynamic character-ization of PH requires invasivelydetermined hemodynamics. Pulmonaryarterial hypertension (PAH, WorldHealth Organization [WHO] Group 1)requires normal left sided filling pres-sures (pulmonary capillary wedgepressure [PCWP] �15 mm Hg) inaddition to the elevated mean pulmonaryarterial pressure (MPAP). Group 1PAH is rare, with an overall prevalenceestimated at 6.6 cases per million.15 Inkeeping, Group 1 PAH is also rare inpatients with ESRD. WHO Group 2PH, ie, PH secondary to left heart

disease, is diagnosed when the PCWP is�15 mm Hg. It is the most commoncause of PH worldwide,16,17 and is alsothe most common cause of PH in theESRD population. WHO Group 2 PHcan be further subcategorized. “Passive”PH is usually defined as PCWP �15mm Hg but a normal transpulmonarygradient (TPG) �12-15 mm Hg and/orpulmonary vascular resistance (PVR) �3Wood units. Those with an elevatedTPG �12-15 mm Hg and/or PVR �3Wood units have been referred to as“mixed,” “reactive,” or “out of pro-portion” PH in the literature as there isno consensus terminology.

The aim of this review is to providean overview of the hemodynamicassessment of patients with PH andCKD, with a particular focus on renaltransplantation. We will consider 3 casesto illustrate these points, with the cathe-terization data serving as the invasivehemodynamic follow-up information forthe same subjects discussed in the com-panion article by Dr Raina. As such, thehemodynamic information shoulddovetail with the corresponding echo-Doppler data discussed in thenoninvasive article.

CASE 1Initial review of the patient’s hemody-namic report (Table 1) suggests adiagnosis of heart failure with preservedejection fraction (HFpEF) with mixedPH. Even without the hemodynamic

Key Words—chronic kidney disease, end-stage renal disease, hemodynamics, pulmonary hypertension,renal transplantationCorrespondence: [email protected]: The authors did not provide disclosures.


assessment, it should be noted that thepatient’s clinical characteristics suggestpulmonary venous hypertension (PVH)rather than WHO Group 1 PAH. Fea-tures of the metabolic syndrome, as seenin this patient, are more commonly asso-ciated with PVH (ie, HFpEF)18 as isolder age and associated renal insuffi-ciency.19

In this case, the PCWP value isreported to be mildly elevated, but noticethe discrepancy between the PCWP andthe more markedly elevated left ven-tricular end diastolic pressure (LVEDP),obtained during simultaneous left heart

catheterization. Discrepancy between thePCWP and the LVEDP has beenreported previously; however, morerecently it has been suggested that alarge portion of this difference may beexplained by operators reporting thesoftware-generated or digitized “mean”PCWP values across the respiratory cyclerather than that measured manually atend expiration.20,21 This is particularlyimportant in situations where swings inpleural pressure are more exaggerated, asis the case in the obese and in patientswith significant lung disease (Figure 1).Although not present in this case,

incomplete balloon occlusion of the pul-monary artery can lead to significantoverestimation of the PCWP—ie, pul-monary artery pressures blend into thePCWP waveform (Figure 2)—leading tohemodynamic misclassification of PH.When there is a question as to theaccuracy of the PCWP, proceduralistsshould confirm the PCWP position bychecking the oxygen saturation to verifythat the sample is consistent with oxy-genated, pulmonary venous blood(PCWP saturation).

The patient in this case has manysymptoms of left sided heart failure

Table 1. Initial Hemodynamics

Case 1 Case 2 Case 3

Heart rate (bpm) 64 80 68

Right atrial pressure (mm Hg) 14 13 14

Pulmonary pressures – systolic/diastolic (mean) (mm Hg) 60/30 (40) 78/30 (46) 93/26 (49)

Pulmonary capillary wedge pressure (mm Hg) 16* (LVEDP 26) 27 (v waves to 40) 16

Transpulmonary gradient (mm Hg) 24 (14) 19 33

DPAP-PCWP gradient (mm Hg) 14 (4) 3 10

Cardiac output (L/min) 6.0 10.7 6.4

Cardiac index (L/min/m2) 2.9 5.4 3.5

PVR (Wood units) 4.0 (2.3) 1.8 5.2

SVR (Wood units) 13.3 7.4 14.3

*Note discrepancy between PCWP and LVEDP. This difference suggests an error in the hemodynamic recordings (see text).Transpulmonary gradient, diastolic gradient, and pulmonary vascular resistance values using the LVEDP are shown in paren-theses.

Figure 1. Marked respiratory variation is seen on both tracings: pulmonary capillary wedge pressure (PCWP, upper panel) and pulmonary arterypressure (PAP, lower panel). Digitized mean PCWP across the respiratory cycle underestimates the true wedge pressure at end expiration.Using the underestimated PCWP in this case leads to an overestimation of PVR. The correct diagnosis is WHO Group 2 pulmonary hyper-tension.


(orthopnea, paroxysmal nocturnaldyspnea [PND], pleural effusions), sug-gesting the mildly elevated PCWP maybe inaccurate. Moreover, the echo-Doppler information presented in thecompanion article by Dr Raina stronglysuggests markedly elevated left heartfilling pressures and a PVR that isnormal. By combining the informationfrom echo-Doppler imaging with thehemodynamics, the clinician has aheightened sense of what the hemody-namics “should” be, thus making it morelikely that pitfalls in the hemodynamicassessment (as seen here) are easily iden-tified and avoided. Using the LVEDPinstead of PCWP in the PVR calcu-lation yields a value �3 Wood units,supporting the notion that a largeportion of the PH is due to left heartfailure, passive congestion, and normal tohigh CO.

Although it has been demonstratedthat an elevated TPG (and “mixed” PH)

portends a worse prognosis in heartfailure,22 it is important to rememberthat factors other than pulmonary vas-cular remodeling affect this parameter.Elevations in left atrial pressure directlyaffect the TPG. As pressures in the leftatrium increase, this pressure is passivelytransmitted back to the pulmonary vas-culature, resulting in elevation of thediastolic pulmonary artery pressure(DPAP). However, this increased venouspressure also leads to more pulmonaryvascular stiffness (or lower vascular com-pliance) than one would predict based onthe PVR alone.23 The lower complianceleads to enhanced pulmonary arterialwave reflections, which raise the systolicpulmonary artery pressure (SPAP) andMPAP, and in turn the TPG. PVR isalso raised by these effects, given TPG isin the numerator of its calculation. Bothparameters may also be affected by COas elegantly described by Naeije and col-leagues.24 Importantly, the enhanced

pulsatile loading that serves to amplifythe SPAP and MPAP does not affectthe DPAP. Hence, emerging evidencesuggests that the DPAP to PCWP gra-dient may be a better indicator ofpulmonary vascular remodeling,24,25 andhow “proportionate” any degree ofMPAP elevation is relative to left atrialpressure.26-29

In this patient, the correct measure ofleft heart filling pressure was 26 mm Hg(in this case, from LVEDP), and thus,correctly calculated PVR was only 2.3Wood units. Further inspection of thehemodynamics reveals a relatively lowratio of right to left heart filling pressure(right atrial pressure [RAP]/LVEDP,0.54) and PVR/systemic vascular resis-tance (SVR) ratio (0.17), furthersupporting a relatively “pure” case ofPVH, or PH related to left heart con-gestion.

In HFpEF patients as shown in thiscase, renal transplantation should allow

Figure 2. Upper panel is an example of tracing recorded during inadequate pulmonary capillary wedge pressure (PCWP) occlusion. Lower panelis from the same patient with proper wedging, confirmed by PCWP oxygen saturation. In this case, the patient would have been diagnosed withWHO Group 2 pulmonary hypertension if the inadequate PCWP tracing was used, although WHO Group 1 pulmonary arterial hypertension wasthe correct diagnosis.


for better volume regulation and systemicblood pressure control, which are themainstays of current therapy. One small,retrospective study has even suggestedimprovements in both systolic and dia-stolic function after renal transplantationalong with improvements in parametersof left ventricular remodeling andreduction in echo-estimated pulmonarypressures.30

This patient’s volume status was opti-mized and ultimately underwent renaltransplantation. Post-transplant thepatient did quite well with robustimprovements in exercise tolerance andhad no diuretic requirement.

CASE 2The patient’s hemodynamics (Table 1)are consistent with high output heartfailure leading to left heart congestionand passive PH, as suggested by theimaging findings discussed in the com-panion article by Dr Raina. The rightheart catheterization (RHC) data furtherreveal that the PVR is normal, as are theRAP/pulmonary artery wedge pressure(PAWP) and PVR/SVR ratio. The mostobvious culprit is his persistent func-tioning left upper extremity AV fistula,which was not taken down after trans-plantation. An intracardiac oximetry runwas negative for an intracardiac shunt,although the oxygen saturation in thesuperior vena cava (SVC) was higherthan his pulmonary artery saturation.The “step-down” in saturation from theSVC to pulmonary artery is supportiveof a shunt in the upper extremity, astypically the SVC saturation is lower dueto cerebral oxygen extraction. Repeatinghemodynamics during compression ofthe fistula is often helpful in determining

the contribution to overall output.8,9

Although some have argued that a shuntoutput to CO ratio of more than 30%should raise concern, it is likely that no“set” amount of flow through an AVfistula clearly defines a range that ispathologic.8 Instead, the hemodynamicand clinical significance of any givenshunt relates to the interaction betweenthe size of the shunt and the degree towhich the heart can accommodate theextra venous return. A patient withsevere hypertensive heart disease anddiastolic dysfunction may be highlyintolerant to the excess flow provided viaan AV fistula, whereas a patient withoutstructural heart disease may accom-modate a very large shunt withoutuntoward clinical or hemodynamiceffects. In this case, 1 minute of manualfistula occlusion led to a 2-liter reductionin the CO, and thus 2 liters of shuntflow at rest (not shown in Table 1).Taking all factors of this case into con-sideration, the patient was referred forsurgical ligation of the AV fistula.

Following closure of the AV fistula,the patient’s symptoms resolved. RepeatRHC revealed essentially normal hemo-dynamics with a right atrium 4 mm Hg,MPAP 20 mm Hg, PCWP 11 mm Hg,and CO 5.9 L/min (index 2.8L/min/m2).

CASE 3Review of the initial hemodynamic data(Table 1) is consistent with HFpEFwith mixed PH. These findings are con-sistent with the patient’s echo-Dopplerexamination discussed in the companionarticle by Dr Raina, which showed evi-dence of both left heart congestion andRV morphologic and Doppler evidence

that strongly suggested an increasedPVR. His TPG is quite elevated incomparison to the mildly elevatedPCWP, as is the DPAP-PCWP gra-dient. Even with the open fistula, hisCO is in the “normal” range, consistentwith restricted pulmonary blood flow viaafterload-dependent RV dysfunction. Amuch larger proportion of this patient’sPH is arising from pulmonary vasculardisease than was observed in the patientshighlighted in cases 1 and 2. The patientwas lost to follow-up and returned a yearlater for a repeat evaluation (Table 2).There has been an interval worsening ofhemodynamics. CO has fallen alongwith an increase in pulmonary pressures.The PVR/SVR ratio is close to 0.5, anindication of more severe pulmonaryvascular disease. RAP and PCWP areboth elevated and almost equal, with aratio near 1, a finding associated withhigher PVR, RV dysfunction, and worseoutcomes in heart failure.31 Occlusion ofthe AV fistula lowered CO (Table 2) asexpected, but right and left heart con-gestion did not improve, nor did thepulmonary pressures. The PVR actuallyincreased, which reflects a flow-relatedderecruitment of the pulmonary circu-lation. These hemodynamic findingswere supported by repeat echocar-diogram showing more marked RVdilation and lower tricuspid annularplane systolic excursion (TAPSE). Giventhe high-risk features of this case, hewas not deemed a candidate for renaltransplantation. Although the benefits ofsuch therapy have not been evaluatedsystematically in large randomized trials,phosphodiesterase 5 inhibitor treatmentmight be beneficial in this more welldefined HFpEF-PH phenotype and may

Table 2. Case 3 Repeat Hemodynamics

Case 3 Baseline AV fistula compression

Heart rate (bpm) 77 74

Right atrial pressure (mm Hg) 24 22

Pulmonary pressures – systolic/diastolic (mean) (mm Hg) 119/45 (70) 118/43 (69)

Pulmonary capillary wedge pressure (mm Hg) 28 26

Transpulmonary gradient (mm Hg) 42 43

DPAP-PCWP gradient (mm Hg) 17 17

Cardiac output (L/min) 5.5 4.8

Cardiac index (L/min/m2) 3.1 2.3

PVR (Wood units) 7.6 9.0

SVR (Wood units) 16.2 17.1


be useful to test for reversibility of thePH.32 Caution should be used, however,given the negative results of the RELAXstudy, which enrolled a more heteroge-neous HFpEF population.33 Moreover,in relation to this case, pharmacologiclowering of the PVR here may lead toan increase in pulmonary blood flow,and in turn lead to worsening left heartcongestion. Thus, caution must be exer-cised in treating pulmonary vasculardisease in this setting, particularly recog-nizing that the AV fistula represents anadditional flow reservoir that may bemore fully “appreciated” clinically in thispatient once the PVR is lowered.

DISCUSSIONThere are little existing data to guide theclinician when considering the risk asso-ciated with renal transplantation inindividuals with PH. Although onestudy has suggested increased post-transplant mortality in patients with aright ventricular systolic pressure (RVSP)�50 mm Hg, the retrospective nature,small number of patients (and deaths),and lack of adjustment for comorbidconditions make it difficult to drawmeaningful conclusions from the data.34

It is curious that despite the fact thatsome 30%-50% of patients with ESRDhave PH, patient and renal allograft sur-vival at most transplant centers isoutstanding. This observation suggeststhat PH itself is not the direct causallink to changes in outcome post renaltransplant, or that factors that contributeto PH in ESRD are positively impactedby renal transplantation. It is alsoimportant to note that in PAH, pul-monary pressures alone are not robustpredictors of survival35,36; rather, prog-nosis is more closely related to RVdysfunction.37-40 RV function is also astrong predictor of prognosis in left heartfailure.41,42 Therefore, measures of RVfunction and the integration of RVfunction with RV afterload (ie, PVR) arelikely the best indicators of prognosis inpatients being considered for renal trans-plantation.

CONCLUSIONIn summary, PH is common in theCKD and ESRD disease populations.Proper hemodynamic assessment along

with noninvasive imaging studies shouldbe used in concert when evaluating a PHpatient. These techniques can giveimportant insight into the contributionsof volume overload, systolic and diastolicdysfunction, and CO to PH as well asthe degree of pulmonary vascular diseaseand RV dysfunction. Elevated pul-monary pressures alone should notnecessarily exclude a patient from renaltransplantation, especially when RVfunction is well preserved.

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PULMONARY HYPERTENSION ROUNDTABLE

The Challenging Spectrum of PH in Liver and KidneyTransplantation Patients

On August 16, 2013, a group of physicians with clinical expertise related to management of pulmonary hypertension (PH)patients who are undergoing evaluation for or having liver or kidney transplantation was convened by telephone to discuss thischallenging topic. These complex patients represent a spectrum of clinical types of PH and require complete evaluations utilizinga team-oriented and multidisciplinary approach to ensure appropriate treatment and safe transplantation. Facilitated by the guesteditors of this issue, Charles Burger, MD, and Paul Forfia, MD, discussants included Michael Krowka, MD, Professor of Med-icine, Pulmonary Division, Mayo Clinic, Rochester, Minnesota; Jose Diaz-Gomez, MD, Medical Director-ICU, Departments ofAnesthesiology and Critical Care, Mayo Clinic, Jacksonville, Florida; Anna Hemnes, MD, Assistant Professor, Assistant Director,Pulmonary Vascular Disease Program Vanderbilt University Medical Center, Nashville, Tennessee; and Michael Mathier, MD,Assistant Professor of Medicine, Director, Pulmonary Hypertension Program, and Associate Director, Cardiovascular FellowshipProgram of the University of Pittsburgh Medical Center.

Dr Burger: One of the issues that hascome up fairly regularly in addressinghepatic cirrhosis patients who are beingconsidered for liver transplant has beenthose patients who progress with theirliver disease and have what we wouldconsider marginal hemodynamic profilesfor purposes of clearing them for a safetransplant. From a personal perspective,I struggle with that patient. In the inter-actions with the hepatologists and mytransplant colleagues, I often ask, “Is itappropriate to move ahead with thetransplant, despite the fact that we don’thave the hemodynamic criteria exactlywhere we might prefer it to be?” I wouldask Dr. Krowka to weigh in on thisclinical scenario, which I’m sure he faceson a regular basis.

Dr Krowka: Well, it is a problem. Andthe main problem is that of the indi-viduals that have pulmonary arteryhypertension complicating their liverdisease. Most liver transplant centersthat I’m aware of do screen for pul-monary hypertension withechocardiography. And centers do havetheir own criteria for who goes on toright heart catheterization. As you know,there are criteria that exist now to allowpatients to have a higher priority for livertransplant, as long as their treatment forthe portopulmonary hypertension, as we

know it, reaches a certain satisfactorylevel in terms of measuring mean pul-monary artery pressure and pulmonaryvascular resistance. We do run into theseindividuals that, despite our treatment,they are borderline in terms of satisfyingthese acceptable criteria. A commonproblem that we’ve run into is that apatient will be treated for their portopul-monary hypertension with any one of avariety of pulmonary vasodilator optionsand their mean pulmonary arterypressure remains above this acceptablecutoff of 35 mm Hg, yet their pul-monary vascular resistance has markedlyimproved and their cardiac output hasmarkedly improved. So what do weadvise for these individuals? In my expe-rience, this is where theechocardiography comes into play. If wehave seen changes where the right ven-tricle is now significantly improved, withnormal size and normal function, I ammuch more comfortable letting thosepatients go onto liver transplant.Whether or not they’ll get a higher pri-ority for transplant or not, I’m a littlemore reassured that they can at least getthrough the procedure. I do believe thatthe individuals that have normalizedtheir right ventricle with treatment havethe greatest likelihood of coming offpulmonary vasodilator after a successfulliver transplant.

Dr Burger: So to that end, it seems likethe hemodynamic guidelines are justthat, “guidelines.” They help us, I think,put together a construct for approachingthe patients. But with the more modernera of options for treating pulmonaryvascular disease and the availability ofmethodologies to evaluate the right ven-tricle, as you said, echocardiography,MRI, whatever it might be in a par-ticular institution, how valid do youthink the older transplant hemodynamicguidelines really are for 2013?

Dr Krowka: That’s an excellent point,because those hemodynamic criteria werebased on two retrospective studies anddatabases several years ago. There’s beenno prospective study to look at whatwould be the optimal or favorable hemo-dynamics overall. And I think thatwould be a very important contribution.So right now, we’re basing our judg-ments on data that’s close to ten yearsold and clinical experience in everyone’sindividual centers.

Dr Forfia: What’s interesting about theway that the mean pulmonary pressureof 35 cutoff is utilized in real life is thatthe resistance aspect of the equation isignored. And actually in the seminalpaper (Krowka MJ, Plevak DJ, FindlayJY, et al., Pulmonary hemodynamics andperioperative cardiopulmonary-relatedmortality in patients with portopul-monary hypertension undergoing liver

Disclosures: Drs Burger, Forfia, Krowka, Diaz-Gomez, and Mathier indicated no conflicts. Dr Hemneshas disclosed current financial relationships with Pfizer, United Therapeutics, and Annamometer.


transplantation. LiverTransplanta-tion,2000; 6 (4):443-450), in the patientswith a mean pulmonary pressurebetween 35 and 50, only those with aPVR greater than 240 were at higherrisk. And we’ve had this conversationwith our own liver transplant team manytimes. And so to Mike’s point, when thepatient has a mean pulmonary pressurethat’s still elevated, but yet their PVRhas normalized, it seems that the livertransplant community has not embracedthat group of patients; those whosemean pulmonary pressure is still highbut their PVR is low. In that paper,those with a mean PA pressure between35 and 50 and a PVR less than 240 didwell. Also, to underscore Mike’s point, ifyou have a PVR that’s less than 240 andnormal RV size and function in thecontext of persistently elevated mean PApressure, we do feel this is an optimizedgroup where referral for liver transplantis reasonable.

Dr Krowka: You raise a very good pointregarding educating the liver communityregarding these observations. And Ithink that was noted in that paper.Perhaps we’ve not done as good a job aswe could. We are in communicationwith the OPTN/UNOS liver and intes-tinal transplant committee to relook andpossibly revise the Model for EndstageLiver Disease (MELD) exception cri-teria. I suspect the committee will wantto see some supportive and/or pro-spective data. Unfortunately, we don’thave a good handle on that right nowand we don’t have those data to show.But I would totally agree, our clinicalexperience has been favorable. Hopefullyover time, we’ll be able to see thisadjusted.

Dr Hemnes: I would echo that what Ithink we’re all getting around is thatmean pulmonary artery pressure reallydoesn’t give you any particular infor-mation as to what the underlyingpathology or pathobiology is. And if youunderstand what’s driving that increasein mean pulmonary artery pressure, thenyou can make a more informed decisionabout whether or not somebody is or isnot suitable for liver transplantation orhas unacceptable outcomes afterward. So

I think use of mean pulmonary arterypressure as a sole decision maker forwhether somebody can or cannotundergo liver transplantation may misspatients who could tolerate transplan-tation. That’s sort of how we approach ithere, using hemodynamics and rightventricular function together todetermine etiology of pulmonary hyper-tension and suitability fortransplantation.

Dr Mathier: I’ll just expand on that inmaybe the other direction. It’s not onlywhat is driving the elevation in meanpulmonary pressure but, as has beenpointed out, what effect has thatpressure overload had on RV perfor-mance? And if the RV performance byour current technologies looks favorable,then I think that that has to be factoredinto a decision making process morethan it often is.

Dr Burger: It just seems that there’s ageneral consensus among the participantsthat we haven’t perhaps pushed theenvelope as much as we could in thosewhose PVRs have normalized withtherapy. So I would just ask for the par-ticipants to comment on the additionalcomponent of assessing RV size andfunction. Is echocardiography adequate?Or are there other imaging modalities,in this particular setting, pre-liver trans-plant with portopulmonary hypertension,which you would favor?

Dr Diaz-Gomez: I would like to pointout as a practicing anesthesiologist andintensivist that the current advances intransthoracic echocardiography for evalu-ation of patients with POPH facilitate abetter assessment of the right ventricularfunction. For instance, I would like tohighlight the article by Arkles et al. pub-lished in the blue journal in 2011(Arkles JS, Alexander R, Opotowsky JO,et al. Shape of the right ventricularDoppler envelope predicts hemody-namics and right heart function inpulmonary hypertension. Am J RespCrit Care 2011; 183:268-276) Theauthors described a method that actuallyprovides a different insight of the inter-action between the pulmonary circulationand the right heart function. Indeed,

they aimed to assess the coupling effectbetween the two components: the rightventricular function and pulmonary vas-cular resistance. Thus, if the rightventricular outflow tract Doppler flowvelocity envelope presents a notch, itmeans the patient has more severe vas-cular disease and right ventriculardysfunction. I think right now we have abetter capability in the OR to assess thisvaluable hemodynamics evaluation withechocardiography, even in the postoper-ative period. Some patients will come tothe OR and even they have borderlinePAP readings. After the intubation, wecan find with the TEE evaluation thatthe PAP are higher than expected. Inthis case we have the ability to provideadequate depth of anesthesia, acid base,and intravascular volume status. Theseare common causes of increased PAPreadings. Subsequently, we can reassessthe patient, and determine the beststrategy to intervene further theincreased PAP. In conclusion, I wouldprobably put a lot of weight on perioper-ative echocardiography in the assessmentof this patient population.

Dr Forfia: Mike, I just want to say thatI did not call him ahead of time and askhim to say that. (laughter)

Dr Hemnes: I don’t believe you, Paul.

Dr Burger: Does anyone else have acomment on the best way to image? Iwould agree completely with Dr. Diaz-Gomez’s comment about the wholebusiness of the coupling and certainly,you know, Dr. Forfia has made a pointof this in many presentations. We can’tseparate out each of these individualmeasurements in the hemodynamicprofile from that of the right ventricle’sability to handle the challenge of there-perfused blood volume once the newliver is transplanted. That’s really thechallenge!

Dr Mathier: I don’t know that I wouldsay that I favor any kind of differentapproach, except that I think it’s worthemphasizing that we have to have as fullan understanding of RV performance aspossible. So that in many patients, echo-cardiography combined with


hemodynamics is adequate for that. Butin some, when the echo windows aren’tacceptable, you may need to move ontoMRI or you may need to rely moreheavily on serial hemodynamic data. ButI think the main take home point has tobe that a really full understanding ofright heart performance is what’simportant. And how you get it is goingto vary from patient to patient.

Dr Krowka: I agree and I think there isa lot to be learned by the evolvingmethods to look at that right ventricle.The sequential studies are veryimportant. One group of patients thatI’ve found that are very worrisome arethose that have, just with a simple elec-trocardiogram, T-wave inversions in V1through let’s say V4, V5. That tells me,everything else being all right, thatthere’s still a lot of stress and straingoing on affecting that right ventricle.And we pay a lot of attention to theimprovement in just the basic electrocar-diogram to give us another piece ofinformation that perhaps we’re takingsome stress and strain off the right heart.

Dr Diaz-Gomez: I absolutely agreewith you, Dr Krowka. I think we canmaximize the understanding of the rightventricular function if we use wisely allthe technology we have in place, startingwith the EKG. I will add, for example,the utilization of continuous cardiacoutput monitoring and mixed venoussaturation. The trend of the mixedvenous saturation, or the limitation atthe time of its interpretation in thesetting of severe underlying hypoxemia isvalid, as well. Other clinically used sur-rogates, such as lactate, are helpfulguiding the management of patientswith perioperative right ventricularfailure. So if you have a patient who isimproving his or her hyperlactatemia,the mixed venous is persistently better,and the hemodynamics looks good, thatwould suffice to have a good informationabout the patient’s current status, even ifyou have limited echo windows and youcannot have a very desirable echocardio-graphic assessment.

Dr Hemnes: The only thing that Iwould add is that although the echo and

MRI may be useful, a lot of times at thebedside you can even tell when you’vemade an improvement. As you all know,of course, you can look at right atrialpressure, feel for RV heave, and thosecan be early and relatively reasonablepredictors of hemodynamic response andRV function after changes in or additionof therapy for portopulmonary disease.

Dr Burger: So in that vein, what do theparticipants think is the best strategy forcontinued pharmacologic treatment aftera successful orthotopic liver transplant?Both in that more immediate perioper-ative period and then beyond thehospitalization?

Dr Mathier: I’ll tell you what ourpractice is. It’s again variable frompatient to patient. If I had a patient withportopulmonary hypertension whorequired intravenous epoprostenol toachieve the hemodynamic benchmarkswe look for, I typically will continue thatdrug postoperatively, at least for a blockof time that ranges from several weeks toseveral months, before I begin to reassessthe patient’s need for the drug. Thattypically is a clinical assessment, followedby an echocardiogram. And if the signsare favorable that the drug can be atleast weaned, I always start with a rightheart catheterization to ensure that Iknow exactly what the hemodynamicsare before I begin. If instead it’s apatient who had more modest portopul-monary hypertension and I was able toreach my hemodynamic benchmarkswith a PDE-5 inhibitor alone, I’ll typi-cally do something relatively similar. Butdepending on how the echocardiogramlooks, I may or may not proceed with ahemodynamic assessment, if it reallylooks favorable for weaning or discon-tinuing that drug. So I try toindividualize it according to the patient.I tend to not like the idea of removingPAH therapy in the immediate postop-erative setting, unless there is a lot ofdifficulty with systemic hypotension oranother indication to do so.

Dr Diaz-Gomez: I absolutely agreewith that practice. Spending some timein the operating room, I would say thatsometimes it’s easier for us to use nitric

oxide in that setting. Although we havethe capability of actually continuing withthe face mask and nebulize it away inthe postop period, I absolutely agreewith the weaning has to be extremelycautious, especially during the first week.So sometimes we have used intravenousepoprostenol in the acute setting, if wedon’t have favorable numbers. It may beafter the TEE and the same. We will dothe weaning the way you describe it. SoI don’t think there is any unique way todo it. But probably, the most twopopular alternatives that we have at thispoint is even IV epoprostenol or nitricoxide.

Dr Krowka: I would agree with Mike’sapproach, also. It’s variable by individual.We proceed slowly. What I do like todo, regardless of the method that we’veused to get them through, whether it’sIV preparations or oral medications, justbefore they’re dismissed from the hos-pital, I do get a baseline echo. Wegenerally would bring them back atabout 12 weeks for a reevaluation oftheir whole posttransplant status. I govery slowly with weaning them off of anIV preparation and an oral preparation.It may take weeks and months.Depending again on factors like whatdid that echo look like pretransplantwith our successful management, if I didget to a normal RV size and functionand everything looked good, I’m a littlebit more comfortable that, well, maybe Ican move a little more quickly, weeksafter the transplant. But the other thingI’d like to stress is that when you thinkabout this, this is one of the few timeswe potentially can cure, at least hemody-namically, pulmonary arteryhypertension; what we know as por-topulmonary hypertension. So there arefolks that have severe hemodynamicimpairment before their liver transplant;we treat them, get them through theirtransplant, and we can get them off ofthese medications at a certain point lateron. And we see this sustained success.The echo looks almost normal, if notnormal. We have essentially created ahemodynamic cure, at least in myopinion.

Dr Forfia: We set out to tackle pul-


monary hypertension in advanced liverdisease, which it seems is the area withthe most data, relatively speaking, com-pared to renal disease-associated PH.And, of course, it’s also the condition,endstage liver disease, where true group1 disease is a significant complication ofportal hypertension. Endstage renaldisease, of course, is a different matter,where there’s a tremendous burden ofleft heart disease in the background, aswell as heterogeneity of the hemody-namic presentation. There is also apaucity of data in the background tosupport treatment and managementdecisions. Nevertheless, there does exist afear of the presence of pulmonary hyper-tension in patients with endstage renaldisease in the context of transplant that Ithink we’ve all encountered. So, that setsup our first question for the panel.Which is, how do you approach apatient prior to renal transplant, whosebeen referred to you with evidence ofpulmonary hypertension, on an echocar-diogram? So we’ll start with that becausethis is, of course, by far the mostcommon scenario that we all encounter.

Dr Mathier: I’ll tell you what we do. Soas you pointed out, Paul, pulmonaryhypertension in a patient with endstagerenal disease is both common andcomplex. It can be on the basis of anynumber of factors, either individually orin combination. These folks often have adiastolic abnormality of the left heart,with elevated left heart filling pressures.They often have volume overload. Theyoften have high cardiac output related toAV fistulas, or even in the absence of alarge fistula. And they, at least some ofthe time, have pulmonary vasculardisease. They also often have a comor-bidity profile that can contribute topulmonary vascular disease in an indirectway, whether that’s intrinsic lung diseaseor sleep apnea or something else. So it’simperative in my mind that no assump-tions be made when you have a patientwith advanced kidney disease, who hasevidence of pulmonary hypertension onecho. Even if that echo is very con-vincing for its being a group 2 type ofphysiology, with a very large left atrium,hypertrophied ventricle, and Dopplerprofiles consistent with significant dia-

stolic dysfunction, I still think we’reobligated to perform a very carefulhemodynamic study. I often insist thatthis be both a right and left heart cathe-terization, because I think it’s reallyimperative that we understand left heartfilling pressure without any uncertaintyrelated to whether the wedge pressure isaccurate or not. And so it’s reallybecome my routine to do very carefulhemodynamic assessment as the nextstep.

Dr Krowka: I totally agree with that. Ithink we’ve probably been lax in ourkidney transplant program, in terms ofevaluating these patients beyond echo-cardiography. We are trying to changeour algorithm at this point, because thereare so many other subtleties that dooccur; and I would also agree, I think it’sunusual to see pure pulmonary arteryhypertension in these folks. It doesoccur. More often than not, we aretaking people off of pulmonary vasodi-lator medications when they’re referredto us, because I think they’re being mis-treated in that sense. The othercomment I would make, and the issuethat’s come up from our kidney spe-cialists on several occasions, has beenwhat is the real impact of these largeAV fistulas that have been placed? Howmuch of their contribution is reallycausing a lot of difficulties? And again, Ithink that’s where it’s very important toproceed to a good hemodynamicassessment by right and left heart cathe-terization, so we fully understand what’sgoing on in terms of the possible backpressure that’s going to affect kidneyoutflow and these other cardiac issues.

Dr Mathier: Do any of you guys askthat your catheterizers do temporaryocclusion of the fistula to try to assess itsimpact on either flow or pressure?

Dr Hemnes: Yes, I was just going tobring that up. We routinely do that,regardless of really the size of the fistula.Although lately, it seems like many ofthe patients who have been referred tous have really large, longstanding fistulae.But yes, specifically when we talk abouta careful hemodynamic assessment inthis population, I agree a left heart cath-

eterization is almost always useful andinformative, in addition to the rightheart catheterization. But we usually doit with and without occlusion of thefistula.

Dr Mathier: Is there a protocol for howlong you occlude?

Dr Hemnes: I don’t think you need toocclude for very long. We usually do itfor a few minutes, at most.

Dr Forfia: We do the same thing. I dothe caths myself. And we’ll do baselinehemodynamics and then we’ll do amanual occlusion of the fistula, typicallyfor two minutes, and repeat the hemody-namics. If I could also just share I thinka clinical pearl, that after having nowfairly extensive experience with dealingwith fistula-associated dyspnea and pul-monary hypertension or heart failure, isthe location of the fistula is veryimportant in predicting its hemodynamicsignificance. If you really dig through thedata from published literature, it’s fairlyclear that proximal fistulas are muchmore common to do this. For example,in the upper extremity, it’s the brachialfistula, so it’s above the elbow whereyou’re much more likely to have a highflow. We’ve also seen this with the rareoccasion of a fistula in the femoralartery-vein. But either way, it’s aproximal vessel. We have not seen verymuch in the way of high output withgrafts, although that’s possible, or withfistulas that are at the level of the wrist.And, Anna also alluded to the fact ofthe duration of fistula, which is relevant.Because the longer that the fistula hasbeen in, typically the larger it gets. Andso when we see a brachial fistula that’sbeen in place for many years, thatpatient is the setup for a high outputsituation, where our pretest probabilityfor a very high flow is quite high.

Dr Hemnes: But, of course, the otherthing to notice though is that pulmonaryhypertension is common in people whoare getting dialysis through a catheterand also a peritoneal dialysis. So, youknow, the Israeli group has done a nicejob of characterizing these patients andhas suggested that endothelin or poor


clearance of endothelin may underliepulmonary hypertension in this group.So while the fistulas may play a role insome patients, patients that don’t havefistulas are at risk, as well.

Dr Burger: While I don’t disagree withthe catheterization for the hemodynamicprofile, almost all of these patients willhave elevated left heart pressures. So thequestion is, what do you do with thatinformation vis-a-vis transpulmonarygradient, diastolic pulmonary gradient,attempts to lower the left heart pressureand then see what happens to the hemo-dynamics?

Dr Mathier: Charlie, as you pointedout, these patients will nearly alwayshave elevated left-sided filling pressure,but also, elevated right-sided filling pres-sures are common. I’ll try to give somefeedback to the dialysis team and, youknow, try to have them incorporate thehemodynamic data into how they set adry weight and how the patient on theirown works to manage their volumestatus. And then the other thing is thata lot of times these folks have very-difficult-to-control systemic hypertensionand that will be directly influencingfilling pressures. And so you can use thehemodynamic data to also advocate for amore aggressive approach to systemicblood pressure control. And those thingscan have a very substantial impact onpulmonary pressures. And I think they’reimportant, because without optimizingvolume and systemic pressure, you’re notgoing to really stand much of a chanceof improving the pulmonary pressures.

Dr Forfia: If I may jump in just for asecond and go back to our first question,which was how to approach the patientprior to renal transplant, with evidenceof PH on an echo. Mike, you made agreat point about how you’re going tohave a low threshold to refer that patientfor a right heart catheterization. But if Icould get you guys to comment brieflyon how you use the echo to start tomake distinctions between the types ofpulmonary hypertension prior to invasiveassessment. So what does one echo in apatient with PH and endstage renaldisease look like versus another? For

example, a pure diastolic heart failurepatient versus a patient who seems tohave evidence of pulmonary vasculardisease, How do you make those distinc-tions?

Dr Krowka: At our institution, I thinkthe echoes have been very helpful in thesense that if we look at, for example, theleft atrial volume index, if that’s huge,that certainly gives us more of a clue,along with these other indirect measuresof diastolic dysfunction that our echofolks give us, you know, would certainlylean more toward the fact that, alright,we’re going to probably be dealing withthe volume and the diastolic dysfunctionissue here, rather than, you know, a pul-monary artery hypertension scenario,which again is probably uncommon. Ithink the timing of when some of thesestudies are done is very important. Sothe nephrologist will call and say, “Well,I have an echo. Take a look at this.”Well, it’s done the day before or themorning of dialysis. Getting data afterthe dialysis is probably where we’ve gonenow, rather than trying to select arandom set of measurements from echo-cardiography to decide what our nextstep is going to be.

Dr Forfia: If I could underscore that asimilar approach in the use of echo inendstage liver disease can be advocatedin patients with endstage renal disease.So specifically, Mike Mathier and MikeKrowka had emphasized the importanceof looking at right ventricular size andfunction in the context of pulmonaryhypertension in endstage liver disease, I’dlike to hear what everyone has to sayabout how they incorporate right ven-tricular size and function informationinto the echocardiogram read in thepatient prior to renal transplant.

Dr Burger: I think it makes a big dif-ference. I mean, just yesterday, we sawtwo end-stage renal patients with ele-vated right heart pressures onechocardiogram. One had the classicgrade 3 restrictive left ventricular fillingon echocardiogram, with all of the signsand symptoms of restrictive cardiomy-opathy in the setting in volume overload.The other patient, had elevated right

heart pressures but the diastolic relax-ation didn’t look bad. The E/e’ ratio alsolooked okay. The pressures were onlymildly elevated. The RV looked pristine.And so that creates a situation whereone has to use judgment about nextsteps. In the second case, we made everyeffort to go over all the things that havebeen mentioned about maximizing theimpact of the systemic blood pressure,normalizing the intra-vascular volume,making sure that they’re compliant withsodium and fluid restriction, wearingtheir oxygen, etc., before moving aheadwith a catheterization. Because even ifthey moved quickly to renal transplant, Ithink that patient’s ability to survive anddo very well with the transplant is quitegood. I think all of those things comeinto play for your judgment in thisregard. And I think you’re exactly right,Paul, the integrity of the right ventricleis very important.

Dr Diaz-Gomez: A quick commentabout a relatively common condition aspatients with advanced chronic kidneydisease may have dual pathology, due tohigh prevalence of systolic as well as dia-stolic cardiac dysfunction. In addition,the presence of the cardiac dysfunctiondoes not automatically exclude coexis-tence with pulmonary arterialhypertension. So I think we probablyneed to be more rigorous and precisewith the echocardiography assessment incomparison with the liver transplantpatient population. So, just keep inmind, that both diastolic and systolicdysfunction can be present in patientswith end stage kidney disease.

Dr Mathier: I’d like to agree with that.We often see patients who have, in thissetting on hemodynamic study, elevatedleft heart filling pressures, but very hightranspulmonary gradients and very highpulmonary vascular resistance, or at leastmoderately high, in excess of 5 or 6units. And so you’re left with one ofthese mixed profiles and they’re verychallenging in terms of really knowinghow to attack it. And also, I’d go backto something that I think Paul said rightat the beginning of the discussion of theadvanced kidney disease patient. We’renot really 100 percent sure what the


impact of the pulmonary hemodynamicderangement is on clinical course and onoutcomes with kidney transplant. Thetransplant group at our facility hasgotten concerned that these patients arehigher risk. And they cite some less thanideal outcomes in terms of graft functionand graft survival in patients who hadpulmonary hypertension before trans-plant. So I think it’s a population thatwe really need to try to get a betterhandle on through careful study in thenear term. Because it’s a very commonclinical scenario, at least in what we’vebeen seeing.

Dr Hemnes: I completely agree withyou. And the most common scenario ofthe patients referred to us is one of wefound pulmonary hypertension on anecho and this person who has endstagerenal disease who is being evaluated for atransplant, can they survive transplant?And I feel like the data isn’t out there toreally know definitively what the answeris to that question. We have our ownpersonal practice patterns and I tend torely on the RV function, what I thinkthe underlying etiology of the pulmonaryhypertension is, etc. But in the absenceof any data, that’s a very hard questionto answer right now.

Dr Forfia: I would say that we can usesome epidemiologic data to get at someof these answers. It’s estimated that 30to 50 percent of patients at the time ofrenal transplant have pulmonary hyper-tension. And I would say it’s closer to50. In that context, patient survival andrenal allograft survival at most renaltransplant centers is outstanding. And sothat’s interesting. What that suggests tome is that in many of our patients withendstage renal disease who have pul-monary hypertension, the pulmonaryhypertension itself is not what is con-ferring the risk. And that whatever ismaking up the pulmonary hypertension,which many of us feel is the combinedeffects of fluid overload, high cardiacoutput, and systemic hypertension, areactually significantly alleviated with renaltransplant. So now, that is not to say

that there is not a subset of patients withpulmonary hypertension and endstagerenal disease where the PH is actually areal risk factor for perioperative outcome.With that in mind, I just have this lastquestion, which I don’t think will takevery long to answer. And it is, who isthe renal transplant patient who youwould consider PH being a relative con-traindication, or at least where PHtherapy should be attempted prior toreevaluation for renal transplant? Whichof these PH patients with endstage renaldisease really gives you pause, whereyou’re going to stop and really carefullydelve into this and/or treat their PH, butnot agree that they are ready to be listedfor kidney transplant?

Dr Mathier: I would say high PVR andevidence of significant right heart dys-function.

Dr Krowka: I would agree. That’swhere the hemodynamic right heartstudy really is crucial in these folks. AndI would agree with that picture of whoI’d be strongly concerned about.

Dr Burger: I would also add any strongrisk factor for pulmonary arterial vascu-lopathy such as HIV or collagen vasculardisease; that is something else thatwould make you think that the risk ofactual pulmonary arterial hypertension ishigher, in conjunction with any evidencethat the RV is dilated or hypokinetic.

Dr Hemnes: I would agree with all ofthose things. And the only other sort ofpatient category that I’d add is that it’swell-described that patients who havehad multiple angioplasties of their fis-tulas are at risk for chronicthromboembolic pulmonary hyper-tension. So, a patient who’s had multipleangioplasties and evidence for chronicthromboembolic disease also gives mepause.

Dr Krowka: I would like to also seesome prospective data that characterizeswho does have graft failure. What arethose criteria for renal graft failure and

what are the characteristics of those indi-viduals hemodynamically that perhapswould shed some light on the dilemma.

Dr Forfia: Right. And I think that’s thetype of study that needs to be done.Because retrospective studies that citeevidence of pulmonary hypertension onan echo, and then without any furtherinformation, associate pretransplant pul-monary hypertension on an echo withtransplant outcome, are quite prob-lematic. Given hat there is such a hugeamount of colinearity between many ofthe comorbidities that the patients sufferfrom prerenal transplant and their PH.For example, their body mass index,their systemic hypertension, the size oftheir fistula, the duration of time ondialysis, the degree of left ventricularhypertrophy, the degree of left ven-tricular systolic and diastolic dysfunction.These factors cannot really be properlyparsed out when someone is doing anassociation between PH and outcomepost kidney transplant. So, it seemslikely that PH has to a certain extentbeen blamed for less optimal outcomeswhen, in fact, more careful analysis mayreveal that the PH itself was not thedirect cause of adverse events in many ofthose patients.

Dr Burger: I’d like to thank the pan-elists for a very educational andinformative discussion and for the timeaway from their busy days for partici-pating.

Dr Forfia: Yes, I’d like to thankeveryone, as well. And I feel it is worthemphasizing that our ability to assesspulmonary hypertension in any indi-vidual patient, pointed out from everymember of the panel during this dis-cussion, involved the assessment ofvarying hemodynamics in combinationwith an evaluation of right heart size andfunction. We agree that pairing pul-monary vascular load with right heartsize and function is seemingly the bestway to gain insight into the significanceof pulmonary hypertension in any indi-vidual person.


PH PROFESSIONAL NETWORK

Drug Interactions of Current Pulmonary Arterial HypertensionTherapies in Abdominal Organ Transplant Recipients

Section EditorMary Barrett, MS, RN, CS, FNP

Patricia A. Uber, BS, PharmDAssociate Professor of MedicineUniversity of MarylandBaltimore, MD

The incidence of echo-derived pul-monary arterial hypertension (PAH) inpatients undergoing renal or liver trans-plant evaluation is reported as high as30%-60% and 25%, respectively.1,2 Notall of these patients will continue to havethe diagnosis of PAH or requiretreatment following the organ transplant.However, if therapy is warranted, themedical team will need to be mindful ofthe potential drug-drug interactions withthe currently available agents to treatPAH and medications used followingtransplantation (immunosuppression,antifungal agents, etc). The 2 types ofdrug-drug interactions important toPAH medications and agents used fol-lowing transplantation arepharmacokinetic or pharmacodynamicinteractions. Pharmacokinetic drug inter-actions are those in which one or moremedications interfere with the metab-olism or clearance of another agent,leading to either an increase or decreasein plasma concentration. Pharmacody-namic interactions consist of the effect ofthe drug on the body, including adversereactions, and may be enhanced whenused in combination with other of medi-cations.

At this time, the 3 different classes ofdrugs approved for the treatment ofPAH are prostacyclin derivatives, endo-thelin antagonists (ERAs), andphosphodiesterase type 5 (PDE5) inhib-itors. There are very fewpharmacokinetic drug interactionsencountered with epoprostenol, trepros-tinil, or iloprost. Treprostinil is

substantially metabolized by the liver,mostly via the cytochrome (CYP) P4502C8 enzymatic pathway, leading to thepotential for an increase in treprostinilconcentrations when combined withgemfibrozil or a decrease in treprostinilconcentrations when given withrifampin.3 The main concern with pros-tacyclin derivatives is the risk of bleedingand interactions with medications thataffect platelet aggregation.

Both commercially available ERAs aremetabolized by the liver, but they havesignificantly different potentials for phar-macokinetic drug interactions. Bosentan’selimination is dependent on hepaticmetabolism via CYP3A4, CYP2C9, andCYP2C19.4 This drug is both a sub-strate and an inducer for these enzymaticpathways and therefore significantlyincreases its own metabolism withrepeated administration, leading to areduction in plasma concentrations.Combining bosentan with inhibitors ofCYP enzymes often used in a transplantpopulation like antifungal azoles (eg,voriconazole, itraconazole, posiconazole,ketoconazole), clarithromycin, erythro-mycin, protease inhibitors, and diltiazemmay lead to an increase in plasma con-centrations. Conversely, CYP inducerssuch as rifampicin, phenytoin, and carba-mazepine may cause a decrease in plasmaconcentrations.

Bosentan is also a substrate of thehuman organic anion transporting poly-peptides (OATPs) OATP1B1 andOATP1B3, found in the liver, and isresponsible for hepatic uptake of many

drugs.5 Induction or inhibition of thistransporter system will effectively alterthe rate of metabolism and plasma con-centration of drugs. Cyclosporine is aninhibitor of OATP1B1 and when com-bined with bosentan can result in asignificant and potentially dangerousincrease in plasma concentrations ofbosentan, making the combination ofthese 2 drugs contraindicated. Clarithro-mycin and erythromycin are inhibitors ofOATP1B1 and should be used withcaution with bosentan.

Ambrisentan is metabolized via theliver by uridine diphosphate glucurono-syltransferases (UGTs).6 The CYA3A4and 2C19 pathways are responsible for20% or less of its metabolism, and sinceambrisentan is only a substrate for thesepathways, it does not interfere with itsown metabolism or that of other drugs.As seen with bosentan, OATPs areinvolved in the hepatic uptake ofambrisentan and caution is advised whenadministering with agents that inhibitthis pathway. A small study evaluatingthe effects of cyclosporine onambrisentan pharmacokinetics revealed amarked elevation in ambrisentan plasmaconcentrations, accompanied by anincrease in reported side effects such ashypotension and gastrointestinal com-plaints.7 Therefore, the dose ofambrisentan should not exceed 5 mgdaily when prescribed in combinationwith cyclosporine.

Sildenafil and tadalafil are the PDE5inhibitors currently used in the treatmentof PAH. Both agents are metabolizedvia the CYP3A4 pathway and are subjectto many drug-drug interactions by medi-cations that either induce or inhibit thispathway.8,9 For example, when used in

Correspondence: [email protected] Uber has no financial relationships to disclose.


combination with bosentan, a CYP3A4inducer, both sildenafil and tadalafil con-centrations are decreased by about 50%.Drugs like phenytoin and rifampin maydecrease the drug effectiveness due to anincrease in clearance, whereas agents likecyclosporine, azoles, and clarithromycinmay increase PDE5 inhibitors’ concen-tration and lead to more side effects.There is some evidence that sildenafilinhibits the OATP1B transporters andtherefore may have more drug-druginteractions than tadalafil, which doesnot appear to affect these transporters.10

In the solid organ transplant, additionof therapy to treat PAH must be donewith careful consideration of the currentmedical regimen and pharmacokineticprofiles of the currently available PAHmedications. Close monitoring for sideeffects encountered with an increase in

drug exposure and therefore a potentialfor an increase in vasodilation (hypo-tension, gastrointestinal effects,headache) or for a decrease in drugexposure and potentially worsening PAHsymptoms (volume overload, edema,shortness of breath) is warranted.

References1. Kawar B, Ellam T, Jackson C, Kiely DG. Pul-monary hypertension in renal disease:epidemiology, potential mechanisms and implica-tions. Am J Nephrol. 2013;37(3):281-290.2. Harinstein ME, Iyer S, Mathier MA, et al.Role of baseline echocardiography in the preoper-ative management of liver transplant candidates.Am J Cardiol. 2012;110(12):1852-1855.3. Remodulin [package insert]. Research TrianglePark, NC: United Therapeutics Corp; 2011.4. Venitz J, Zack J, Gillies H, Allard M, Reg-nault J, Dufton C. Clinical pharmacokinetics anddrug-drug interactions of endothelin receptorantagonists in pulmonary arterial hypertension.J Clin Pharmacol. 2012;52(12):1784-1805.

5. Shitara Y. Clinical importance of OATP1B1and OATP1B3 in drug-drug interactions. DrugMetab Pharmacokinet. 2011;26(3):220-227.6. Croxtall JD, Keam SJ. Ambrisentan. Drugs.2008;68(15):2195-2204.7. Spence R, Mandagere A, Richards DB, MageeMH, Dufton C, Boinpally R. Potential for phar-macokinetic interactions between ambrisentan andcyclosporine. Clin Pharmacol Ther. 2010;88(4):513-520.8. Warrington JS, Shader RI, von Moltke LL,Greenblatt DJ. In vitro biotransformation of silde-nafil (Viagra): identification of human cytochromesand potential drug interactions. Drug Metab Dispos.2000;28(4):392-397.9. Croxtall JD, Lyseng-Williamson KA. Tada-lafil: in pulmonary arterial hypertension. Drugs.2010;70(4):479-488.10. Weiss J, Theile D, Spalwisz A, Burhenne J,Riedel KD, Haefeli WE. Influence of sildenafiland tadalafil on the enzyme- and transporter-inducing effects of bosentan and ambrisentan inLS180 cells. Biochem Pharmacol. 2013;85(2):265-273.


ASK THE EXPERT

Nutritional Assessment in Patients With Pulmonary ArterialHypertension Facing Transplantation

Section EditorSean Studer, MD, MSc

Beth Coplan, RD, CDETransplant DietitianNewark Beth Israel Medical CenterNewark, NJ

Obesity is epidemic in the UnitedStates,1,2 and a recent analysis of patientsenrolled in the Registry to EvaluateEarly and Long-term PAH DiseaseManagement (REVEAL) demonstratedsignificantly more underweight (definedas body mass index [BMI] �18.5) andobese (defined as BMI �30) than age-and sex-matched controls from theNational Health and Nutrition Exami-nation Survey (NHANES).3 Specifically,idiopathic PAH (IPAH) and drugs andtoxins-associated pulmonary arterialhypertension (PAH) were more likely tobe obese, and those individuals withconnective tissue disease-associated PAHand congenital heart disease-associatedPAH were more likely to be under-weight.3 These data suggest thatclinicians treating patients with PAH arevery likely to encounter patients who areobese or underweight. Historically, lungor heart-lung transplant has been atreatment option facing many of thesepatients with life-threatening right ven-tricular (RV) failure. With effectivemedical therapies for PAH, patients whomight have died from RV failure maysuccumb to comorbidities instead,4 andsubgroups of PAH patients with por-topulmonary hypertension present agrowing population of potentialabdominal organ transplant candidates.

The ideal approach to managingpatients who are underweight or obeseto optimize their candidacy forabdominal organ transplant is far fromclear. There is a paucity of dataregarding optimal nutritional strategiesin patients with PAH; most of the

guidance regarding nutritional screeningin patients who are potential solid-organtransplant candidates is derived from thegeneral transplant medical literature,which suggests that obesity and under-weight affect post-transplantoutcomes.5-8

To address the potential nutritionalrisks, dietitians often set goals thatinclude maintaining the weight and leanmuscle mass of patients with adequatenutritional status, promoting weight andmuscle gain in underweight patients, anddeveloping strategies for weight loss inobese individuals. The resulting goal-oriented diet and exercise plans aredeveloped with the interdisciplinary careteam, which includes dietitians alongwith active participation of physicians,nursing professionals, physical therapists/exercise physiologists, psychologists, andrespiratory therapists. The processemphasizes promoting an overall healthymetabolism, which (for example)includes normalizing blood sugars andmanaging patients’ symptoms.9

While the assessment of patients isindividualized, it generally begins with acalculation of BMI, assessment ofpattern adiposity for those who areobese, measurement of lean muscle mass(eg, triceps skin fold and mid-armmuscle circumference), a detailed dietaryintake, and a comprehensive assessmentof laboratory values—emphasizing pre-albumin levels. Attempts to standardizesome anthropometric assessments todetermine lean muscle mass, such as bio-electrical impedance analysis and dual-energy x-ray absorptiometry (DEXA),

have been hampered by the variable fluidstatus in patients with cirrhosis and renalfailure. The importance of an overallclinical assessment of these chronically illpatients is recognized.9

When the initial assessment has beencompleted and compared with the eligi-bility criteria of a specific organtransplant program, a plan is oftendeveloped focusing on maintenance,repletion, or reduction in weight.9-11

The nutritional plan will likely focus onreaching a specific goal weight, deter-mining the appropriate daily calorie,protein (and fluid) requirements, andthorough dietary counseling, which mayinclude the review of adequate portionsizes, food and beverage choices, mealpattern/consistency, and the importanceof staying active. The success of the planwill likely be affected by the patient’sseverity of illness, commitment to theplan, and the degree of involvement ofthe interdisciplinary team. As one mightexpect, a patient’s personality and/orchanging illness may necessitate changesto the initial nutritional plan, makingflexibility and adaptation other keyingredients to success. The safety andefficacy of weight-loss medications, espe-cially in view of the data regardingcertain anorexigens and the risk in devel-opment of PAH and of weight-losssurgery have yet to be determined. Thisdoes not exclude consideration of suchapproaches in the future as the indica-tions for bariatric surgery in patientswith PAH continues to evolve.12

In summary, an increasing number ofobese and underweight patients withPAH are likely to require abdominalorgan transplant. Optimizing theirweight and nutritional status may beCorrespondence: [email protected]


required for them to become, or remain,transplant candidates. A set of nutritionevaluation questions are relevant to amajority of these patients (see box),although the points of emphasis andspecific BMI or metabolic goals mayvary based on the proposed type of organtransplant and individual transplantprogram criteria. A cooperative andcomprehensive interdisciplinary approachwith early intervention is an achievablegoal and will likely optimize the out-

comes for patients with PAHundergoing transplantation.

References1. Catenacci VA, Hill JO, Wyatt HR. Theobesity epidemic. Clin Chest Med. 2009;30(3):415-444, vii.2. Ogden CL, Yanovski SZ, Carroll MD, FlegalKM. The epidemiology of obesity. Gastroenterology.2007;132(6):2087-2102.3. Burger CD, Foreman AJ, Miller AP, SaffordRE, McGoon MD, Badesch DB. Comparison ofbody habitus in patients with pulmonary arterial

hypertension enrolled in the Registry to EvaluateEarly and Long-term PAH Disease Managementwith normative values from the National Healthand Nutrition Examination Survey. Mayo ClinProc. 2011;86(2):105-112.4. Oudiz R. Death in pulmonary arterial hyper-tension. Am J Respir Crit Care Med. 2013;188(3):269-270.5. Lederer DJ, Wilt JS, D’Ovidio F, et al.Obesity and underweight are associated with anincreased risk of death after lung transplantation.Am J Respir Crit Care Med. 2009;180(9):887-895.6. Hasse J. Pre-transplant obesity: a weighty issueaffecting transplant candidacy and outcomes. NutrClin Pract. 2007;22(5):494-504.7. Moreira TR, Bassani T, de Souza G, ManfroRC, Goncalves LF. Obesity in kidney transplantrecipients: association with decline in glomerularfiltration rate. Ren Fail. 2013 Aug 1. [Epub aheadof print]8. Killackey MT. Transplantation in the obesepatient. Mt Sinai J Med. 2012;79(3):388-396.9. Weseman RA. Nutritional Requirements ofAdults Before Transplantation. http://emedicine.medscape.com/article/431031. AccessedSeptember 6, 2013.10. DiCecco SR. Medical weight loss treatmentoptions in obese solid-organ transplant candidates.Nutr Clin Pract. 2007;22(5):505-511.11. Killackey M, Zhang R, Sparks K, ParameshA, Slakey D, Florman S. Challenges of abdominalorgan transplant in obesity. South Med J. 2010;103(6):532-540.12. Studer SM, Mathier M, Mcglothlin D,Levine D, Ramanathan R. Pulmonary Roundtable– Bariatric Surgery and the PAH Patient. Adv Pul-monary Hypertens. 2013;12(1):31-37.

Nutritional assessment questions for evaluating patients’ readiness for transplant

1. Is BMI within organ-specific transplant guidelines? Underweight or obesity concernsmust be addressed with a goal-oriented plan.

2. If patient is overweight/obese, where is the extra body fat distributed? Pattern of fatdistribution (eg, gluteo-femoral vs android/central) has implications regarding surgicaland post-transplant risk.

3. Is pre-albumin normal? Low pre-albumin may adversely affect healing potential aftertransplantation.

4. Is this patient compliant with dietary recommendations (eg, low sodium)? Adherencemay affect post-transplant outcomes.

5. Is blood sugar control optimal (eg, normal HgbA1C)? This may affect healing aftertransplantation. It may also amplify the effects that post-transplant medications willhave on pretransplant hyperglycemia.

6. Is there adequate lean muscle mass? Assess if patient is physically conditioned and ifprotein intake is adequate.

7. Is the patient experiencing malabsorption that adversely affects optimal vitamin andcalorie intake?

8. Are there any eating issues/symptoms such as dyspnea while eating, nausea,vomiting, diarrhea, difficulty chewing or swallowing that affect nutrition and potentiallypost-transplant medications?


Signifi cant progress has been made in PAH treatment over the past 2 decades, yet patient

morbidity and mortality remain high.1 There is limited information on the long-term eff ects of

PAH-specifi c therapies, and many patients continue to experience death, hospitalizations, and

the need for additional therapies.1,2

Now is the time for a new perspective in PAH. Experts are calling for future PAH studies to

deliver data on the long-term eff ect of therapy on clinical outcomes, such as hospitalizations

and mortality.1-3 Actelion is committed to investigating this evolving perspective in PAH.

Despite advances, patients’ long-term outcomes remain poor

Have we come far enough in PAH patient outcomes?

References: 1. Galiè N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani M, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension.

Eur Heart J. 2009;30:394-403. 2. Gomberg-Maitland M, Dufton C, Oudiz RJ, Benza RL. Compelling evidence of long-term outcomes in pulmonary arterial hypertension?

J Am Coll Cardiol. 2011;57:1053-1061. 3. McLaughlin VV, Badesch DB, Delcroix M, et al. End points and clinical trial design in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S97-S107. 4. Thenappan T, Shah SJ, Rich S, Gomberg-Maitland M. A USA-based registry for pulmonary arterial hypertension: 1982-2006. Eur Respir J.

2007;30:1103-1110. 5. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry.

Ann Intern Med. 1991;115:343-349.

© 2013 Actelion Pharmaceuticals US, Inc. All rights reserved. ACT-00252

Advertisement

CHANG IVE

Survival in PAH, 1988 and 2006*4,5

*Survival observed over periods from 1981-1988 and 1982-2006, respectively.

PERSPECT

Chronic Thromboembolic Pulmonary Hypertension

Scan for it, for the chance to surgically cure it.

CTEPH is designated as WHO Group 4 and is an under-recognized type of PH1,2

Estimates suggest that the cumulative incidence of CTEPH in patients who survive pulmonary embolism is from 0.57 to 3.8%3

The V/Q scan is a pivotal test in the diagnostic work-up of CTEPH and is the preferred imaging tool for the initial assessment of patients with suspected CTEPH4,5

PEA surgery can be curative and should be considered in all eligible patients with CTEPH6,7

Some patients are not operable candidates or suffer from persistent or residual pulmonary hypertension after PEA surgery3,6

References: 1. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classifi cation of pulmonary hypertension. J Am Coll Cardiol. 2009;54(1)(suppl S):S43-S54. 2. Piazza G, Goldhaber SZ. Chronic thromboembolic pulmonary hypertension. N Engl J Med. 2011;364(4):351-360. 3. Fedullo P, Kerr KM, Kim NH, Auger WR. Chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med. 2011;183(12):1605-1613. 4. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30(20):2493-2537. 5. Tunariu N, Gibbs SJR, Zarni W, et al. Ventilation–perfusion scintigraphy is more sensitive than multidetector CTPA in detecting chronic thromboembolic pulmonary disease as a treatable cause of pulmonary hypertension. J Nucl Med. 2007;48(5):680-684. 6. Keogh AM, Mayer E, Benza RL, et al. Interventional and surgical modalities of treatment in pulmonary hypertension. J Am Coll Cardiol. 2009;54(1)(suppl S):S67-S77. 7. Jamieson SW, Kapelanski DP, Sakakibara N, et al. Pulmonary endarterectomy: experience and lessons learned in 1,500 cases. Ann Thorac Surg. 2003;76(5):1457-1464.

CTEPH=chronic thromboembolic pulmonary hypertension; PEA=pulmonary endarterectomy; PH=pulmonary hypertension; V/Q=ventilation/perfusion scintigraphy; WHO=World Health Organization.

For more information on PH, visit the Pulmonary Hypertension Association at phassociation.org, and for more information on WHO Group 4 (CTEPH), visit ctephawareness.com.

Bayer HealthCare Pharmaceuticals100 Bayer Boulevard, Whippany, NJ 07981 USA©2013 Bayer HealthCare Inc. Whippany, NJ456-10-0002-13 August 2013

CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION:ONE OF THE 5 DISTINCT TYPES OF PH

Contributing to the scientifi c discussion of PH.

Science For A Better Life

Even a Physician With PulmonaryHypertension Can Be Misdiagnosed

By Lynn Brown, MD, Campaign Chair

Diagnosing pulmonary hypertension (PH)is often so tricky that even a patientpracticing pulmonology can experiencedelayed diagnosis. That’s what happenedto Bonnie Hudak, MD, a new memberof the Sometimes it’s PH early diagnosiscampaign’s Education Committee.

Dr Hudak is a pediatric pul-monologist at Nemours Children’sClinic in Jacksonville, Florida, where sheoften treats asthma and cystic fibrosis.Yet her path to diagnosis parallels thatof many other PH patients, particularlymiddle-age women.

Dr Hudak had long been treated forscleroderma and Reynaud’s disease. Herrheumatologist knew of the associationbetween PH and scleroderma. DrHudak maintained a healthy weight,exercising regularly while practicingmedicine and raising children. In her40s, exercising became more difficult,but with her busy life she says she paidthis little attention. Then while hiking in2004, Dr Hudak discovered that ataltitude she could not walk uphill.

In Jacksonville she underwent anechocardiogram, an EKG, and a chestx-ray. Her doctor called the results“maybe slightly abnormal.” He was reas-sured and attributed her symptoms toperimenopause and deconditioning. Hereported that the cardiologist had con-sidered her echocardiogram normal.“They were happy with normal, and Iwas, too,” Dr Hudak said.

Still, Saturday morning tennis gamesleft her tired all weekend. Once, at aneighborhood party, she was chattingwith a cardiologist friend. He told herfirmly, “Anyone with scleroderma andshortness of breath with exercise has PHunless proven otherwise.” Two weeks later

she was diagnosed by right heart catheter-ization and referred to a PH specialtycenter.

Dr Hudak’s experience at Mayo Clinicin Jacksonville under the care of CharlesBurger, MD, highlights the importanceof referral to specialty centers, a keyelement of the Sometimes it’s PH cam-paign. In a single day she receivedcomprehensive testing, including a moredetailed echocardiogram, which success-fully measured tricuspid regurgitationvelocity. Those administering these testspursued results doggedly.

Dr Burger also admitted Dr Hudak tothe hospital for a right heart catheter-ization that included a vasodilatorchallenge. Without that thorough pro-cedure and all of the necessary testing,Dr Hudak’s vasoreactive type of PHwould not have been discovered. DrHudak has remained on nifedipine asher sole PH treatment and has improvedfrom Class III to Class I. She has alsoparticipated in a clinical trial.

In her practice Dr Hudak now looksfor a few more zebras among the horses.She also looks more carefully at the dataused to interpret studies. She wouldadvise other physicians to be more vig-ilant with a patient who has anunderlying condition associated with PHand to work up minimal symptoms thatmay be due to PH. She also suggestsfurther evaluation if existing results don’tmake sense in the clinical setting.

Dr Hudak’s experience illustrates thatboth patients and professionals must bemore active in questioning the data andthe decisions that drive diagnosis. Herunique insights will be an asset as PHAworks to enhance primary and specialtycare professionals’ ability to diagnose andtreat PH promptly and correctly.

To find out more about Sometimes it’sPH, visit www.SometimesItsPH.org.

NEWS TO USE

Connect Patients With SupportResourcesPHA offers ongoing education andinformation for patients and caregivers atevery stage of their PH journey. Wenow provide resources to help yourpatients and caregivers cope with themental, emotional, social, and spiritualcomponents of living with PH. Todownload your free guide, visitwww.PHAssociation.org/Coping.

Newest Survival Guide Hits the Shelves“The Survival Guide is one of inestimablevalue for patients, families, nurses, physi-cians, and anybody else who has anythingto do with this disease. . . . Our practicebuys it in bulk and provides it to ourpatients, their families, and caregivers.”— Bruce Brundage, MD, former Chair,

PHA Scientific Leadership Council

The fifth edition, 2013 revision of Pul-monary Hypertension: A Patient’s SurvivalGuide is now available. Eight of the 17chapters, plus the glossary and appen-dices, were updated for this latest versionof the 300-page book, covering survivaloutcomes, insurance coverage, newresources, as well as conventional, drug,and surgical treatments. For the first time,PHA is offering this valuable resource asboth a paperback and an e-book.

Order copies for your patientsand medical team now at www.PHAssociation.org/SurvivalGuide.


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 and Cialis are registered trademarks of Eli Lilly and Company, 2013.Reference: 1. ADCIRCA [package insert]. Indianapolis, IN: Eli Lilly and Company; 2013.

Important Safety InformationCONTRAINDICATIONS• 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

• 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.v1Please 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

• 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.

ADCIRCA (tadalafil) ONCE-DAILYCAN GIVE YOUR PATIENTS

A SOLID FOUNDATIONA first-line PDE-5 inhibitor that can

help improve exercise ability

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) tabletsBRIEF SUMMARYThe 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 USAGEPulmonary 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%).CONTRAINDICATIONSConcomitant 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 PRECAUTIONSCardiovascular 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:

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-benefitassessment.ADVERSE REACTIONSThe following serious adverse reactions are discussed elsewhere in the labeling: • Hypotension • Vision loss • Hearing loss • PriapismClinical 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%

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 reportedpostmarketing in temporal association with the use of tadalafil. Most, but not all, of these patients had preexistingcardiovascular 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 includingurticaria, Stevens–Johnson syndrome, and exfoliativedermatitis. Nervous — Migraine, seizure and seizurerecurrence, and transient global amnesia. Ophthalmologic — Visual field defect, retinal vein occlusion, and retinalartery occlusion. Non–arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarelypostmarketing 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 INTERACTIONSPotential for Pharmacodynamic Interactions with ADCIRCA: Nitrates — Do not use ADCIRCA in patients who

• Patients with clinically significant aortic and mitral valve disease

• Patients with pericardial constriction

• Patients with restrictive or congestive cardiomyopathy

• Patients with significant left ventricular dysfunction

• Patients with life-threatening arrhythmias

• Patients with symptomatic coronary artery disease

• Patients with hypotension (<90/50 mm Hg) or uncontrolled hypertension

ADCIRCA ADCIRCA Placebo (%) 20 mg (%) 40 mg (%)EVENT (N=82) (N=82) (N=79)Headache 15 32 42Myalgia 4 9 14Nasopharyngitis 7 2 13Flushing 2 6 13Respiratory Tract Infection (Upper 6 7 13and Lower)Pain in Extremity 2 5 11Nausea 6 10 11Back Pain 6 12 10Dyspepsia 2 13 10Nasal Congestion (Including sinus 1 0 9congestion)

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.OVERDOSAGESingle 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.

Marketed by: Lung LLC, a wholly-owned subsidiary ofUnited Therapeutics CorporationRx only www.adcirca.comBS.HCP.KCGLUNGLLC-4-72.v1

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 blood-pressure-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 dur ing 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

These day-long, highly interactive events are available at no cost. The PHA Preceptorship Program builds links among community PH specialists, non-specialists and clinicians at PH centers. The program creates new avenues for communication and more comprehensive, state-of-the-art diagnosis, initial treatment and long-term management of patients with PH.

It is designed to improve competence, performance and patient care practices by instructing front-line clinicians in the highest quality of care for patients with PH.

Washington University designates this live activity for a maximum of 5 AMA PRA Category 1 CreditsTM

UPCOMING PRECEPTORSHIP PROGRAM EVENTS:

Nov. 8, 2013 Houston, Texas

Dec. 6, 2013 Chicago, Ill.

Dec. 6, 2013 Philadelphia, Pa.

Register for a PHA Preceptorship Program event at:

www.PHAssociation.org/Preceptorship

STAY SHARP WITH YOUR PAH KNOWLEDGE

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

Advances in Pulmonary HypertensionPulmonary Hypertension Association801 Roeder Road, Suite Silver Spring, MD 20910-4496

NON-PROFIT ORG.US POSTAGEPAIDLancaster, PAPermit #161

Jointly SponsoredMentored Clinical Scientist Development Award (K08) &

Mentored Patient-Oriented Research Career Development Award (K23)

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 201 .

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 hyper-tension.

• To support patient-oriented research, which is defined as research conducted with human subjects (or on material ofhuman origin, such as tissues, specimens, and cognitive phenomena) for which an investigator directly interacts withhuman subjects.

• To support areas of research that include: 1) mechanisms ofhuman disease; 2) therapeutic interventions; 3) clinical trials;and 4) development of new technologies.

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 independentinvestigators.

• To support a 3 to 5 year period of supervised research experi-ence that integrates didactic studies with laboratory or clinicallybased research.

• To support research that has both intrinsic research importanceand merit as a vehicle for learning the methodology, theories,and conceptualizations necessary for a well-trained independentresearcher.

Pulmonary HypertensionAssociation (PHA)

National Heart, Lung, andBlood Institute (NHLBI)

Program Announcement:

FOR MORE INFORMATION:Visit: www.PHAssociation.org/MedicalProfessionals/Research

* Restrictions apply. Please see complete announcement at the website listed above.

1000

3

New Application Deadline: October 12, 2013New Application Deadline: February 12, 2014

Resubmission Deadline: November 12, 2013Resubmission Deadline: March 12, 2014

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