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PulmonaryHypertension

Advances inWinter 2002 Vol 1, No 3

Official Journal of the Pulmonary Hypertension Association

Editorial MissionAdvances in Pulmonary Hypertension is committed to help physicians in their clinical decision making byinforming them of important trends affecting their practice. Analyzing the impact of new findings and covering current information in the peer-reviewed litera-ture, Advances in Pulmonary Hypertension is publishedfour times a year. Advances in Pulmonary Hypertensionis the official journal of the Pulmonary HypertensionAssociation.

Each article in this journal has been reviewed andapproved by members of the Editorial Advisory Board.

Editorial Advisory Board

Editor-in-ChiefVictor F. Tapson, MDAssociate Professor of MedicineDivision of Pulmonary and Critical Care MedicineDuke University Medical CenterDurham, North Carolina

Sean Gaine, MD, PhDDirector, Pulmonary Hypertension UnitMater Misericordiae HospitalUniversity CollegeDublin, Ireland

Vallerie V. McLaughlin, MDAssociate Professor of MedicineAssociate DirectorCenter for Pulmonary Heart DiseaseCoronary Heart Disease Detection

and Treatment CenterRush Heart Institute Rush Presbyterian-St. Luke’s Medical CenterChicago, Illinois

Ivan M. Robbins, MDDirector, Pulmonary Hypertension CenterVanderbilt UniversityNashville, Tennessee

PublisherPulmonary Hypertension AssociationBruce Brundage, MD, PresidentRino Aldrighetti, Executive Director

Publishing StaffStu Chapman, Executive EditorSusan Chapman, Managing EditorHeidi Green, Associate EditorGloria Catalano, Production DirectorMichael McClain, Design Director

PHA OfficePulmonary Hypertension Association850 Sligo Avenue, Suite 800Silver Spring, MD 20910301-565-3004, 301-565-3994 (fax)www.phassociation.org

Provided through an unrestricted educational grant from Actelion Pharmaceuticals, U.S., Inc. and Accredo Therapeutics.

© 2002 by Pulmonary Hypertension Association andDataMedica. All rights reserved. None of the contentsmay be reproduced in any form whatsoever without thewritten permission of the executive editor.

Editorial OfficesAdvances in Pulmonary Hypertension, DataMedica, 424 Dune Road, Westhampton Beach, NY 11978 Tel (631) 288-4702

Advances in Pulmonary Hypertension is circulated to cardiologists, pulmonologists, rheumatologists and other selected physicians by the PulmonaryHypertension Association. The contents are independently determined by the Editor and the Editorial Advisory Board.

Cover Photo: Color enhanced electron beam CT of the heart, before (upper panel) and after (lower panel) treatmentwith epoprostenol. The straight line marks the interventricular septum and is rotated counterclockwise after treatment, indicating a decrease in the size of the right ventricle.(Courtesy of Bruce Brundage, MD)

Printed on recycled paper.

The Scientific LeadershipCouncil of the PulmonaryHypertension AssociationThe scientific program of the PulmonaryHypertension Association is guided by theassociation’s Scientific Leadership Council.The Council includes the following healthcare professionals:

Michael McGoon, MDSLC ChairPulmonary Hypertension ClinicMayo ClinicRochester, Minnesota

Robyn Barst, MDSLC Vice-ChairColumbia Presbyterian Medical CenterBabies HospitalNew York, New York

David B. Badesch, MDChair, SLC Nominations CommitteeUniversity of Colorado

Health Sciences CenterDenver, Colorado

Joy Beckmann, RN, MSNPulmonary Hypertension ProgramHarbor-UCLA Medical CenterTorrance, California

C. Gregory Elliott, MDChair, SLC Publications CommitteeLDS HospitalUniversity of Utah

School of MedicineSalt Lake City, Utah

Adaani Frost, MDBaylor College of MedicineHouston, Texas

Sean Gaine, MD, PhDMater Misericordiae HospitalDublin, Ireland

Nazzareno Galiè, MDIstituto di Malattie dell’ Apparato

CardiovascolareUniversita di BolognaBologna, Italy

Marc Humbert, MD, PhDHospital Antoine BeclereClamart, France

Abby Krichman, RRTDivision of Pulmonary and

Critical Care MedicineDuke University Medical CenterDurham, North Carolina

David Langleben, MDJewish General HospitalMontreal, Quebec, Canada

James E. Loyd, MDPulmonary and Critical Care MedicineVanderbilt University Medical CenterNashville, Tennessee

Vallerie V. McLaughlin, MDRush Presbyterian-St. Lukes

Medical CenterChicago, Illinois

John H. Newman, MDNashville VA HospitalNashville, Tennessee

Horst Olschewski, MDJustus Liebig UniversityGiessen, Germany

Harold I. Palevsky, MDUniversity of Pennsylvania

School of MedicinePresbyterian Medical CenterPhiladelphia, Pennsylvania

Marlene Rabinovitch, MDStanford University

School of MedicineStanford, CA

Stuart Rich, MDVice-Chair, SLC Research CommitteeRush Heart Institute-Center for Pulmonary Heart DiseaseChicago, Illinois

Ivan M. Robbins, MDChair, SLC Consensus CommitteeVanderbilt UniversityNashville, Tennessee

Lewis J. Rubin, MDChair, SLC Research CommitteeUniversity of California at San DiegoSan Diego, California

Cathy J. Severson, RN, BSNPulmonary Hypertension ClinicMayo ClinicRochester, Minnesota

Victor F. Tapson, MDDivision of Pulmonary and Critical

Care MedicineDuke University Medical CenterDurham, North Carolina

Allison Widlitz, PAPediatric CardiologyNew York Presbyterian HospitalNew York, New York

Carol E. Vreim, PhD NHLBI LiaisonDeputy DirectorDivision of Lung Diseases, NHBLIBethesda, Maryland

EmeritusBruce H. Brundage, MDHeart Institute of the CascadesBend, Oregon

Alfred P. Fishman, MDUniversity of Pennsylvania

Health SystemPhiladelphia, Pennsylvania

Advances in Pulmonary Hypertension 3

Editor’s Memo

The Prostacyclin Story: FromDiscovery to Future Directions

Until recent years, the concept of treatingpulmonary arterial hypertension through avariety of mediators and mechanisms seemedbeyond our grasp. As much as it is routinelydone in other illnesses, the possibility ofapplying this concept in pulmonary hyperten-sion was remote. This picture has radicallychanged, however, with the introduction of

new agents that may be used in conjunction with prostacyclinand its analogs. The revolution in therapy started with theman profiled in this issue, Sir John Vane, a Nobel Prize win-ner recognized for his work in prostaglandin research.

Perhaps the theme of this issue should be that the revolu-tion continues. After paying a debt of gratitude to Dr Vane,

our story about prostacyclin continues throughout this issue.We explore the need to develop prostacyclin analogs to over-come the limitations of the epoprostenol delivery system,elaborate on the intriguing work with inhaled iloprost, andround it up with a roundtable discussion ranging across thespectrum of issues involving prostacyclin. We are also grate-ful to Bruce Brundage, MD, president of the PulmonaryHypertension Association, who provided the images forthis issue's cover.

Slowly, but with encouraging progress, we are getting tothe point where we will better understand how to treat pul-monary arterial hypertension through a variety of mediatorsand mechanisms. There is still much to be discovered aboutprostacyclin—for example, how precisely does the medicationwork? When we discover its true mechanisms and determinehow it can be used in combination with other treatments, perhaps the revolution in therapy will have achieved its goals.

Vic Tapson, MDEditor-in-Chief

Profiles in Pulmonary Hypertension

A Nobel Prize Winner Who Triggered a Revolution in Therapy

Winner of the Nobel Prize in medi-cine. The researcher who discoveredprostacyclin, the most widely pre-scribed drug in pulmonary hyperten-sion. The pioneer who uncovered themode of action of aspirin. Knightedin 1984 for his contributions tomedical research. These achieve-ments of Sir John Vane and the

accolades received for them tend to dwarf those of eventhe most highly respected investigators in pulmonaryhypertension.

It’s been 20 years since Dr Vane shared the NobelPrize for his studies of prostaglandins, and his discoveryof one of them, prostacyclin, eventually ushered in a newera in the treatment of pulmonary hypertension. Ironical-ly, the initial research involving the drug took a differentdirection.

“The first clinical trials on prostacyclin were not inpulmonary hypertension. They were in peripheral vasculardisease,” recalled Dr Vane during a recent interview fromhis office in the United Kingdom. Dr Vane was cited bythe Nobel committee for his “discovery of the pros-taglandin known as prostacyclin in 1976, and for analyz-

ing its biological effects and function.” Yet it was yearsbefore the drug epoprostenol (Flolan) was first used inpulmonary hypertension after Timothy Higenbottam, MD,documented its efficacy in the disease in 1987. Initially,however, Polish researchers who spent time with Dr Vanein his UK laboratory took a different track with prostacy-clin when they returned to Poland.

“They reported striking and prolonged benefits follow-ing intra-arterial infusion of prostacyclin in five patientswith advanced atherosclerotic lower-limb peripheral vas-cular disease. Rest pain disappeared, previously refractoryulcers healed, and muscle blood flow as measured byXenon133 clearance was significantly increased for at least 6 weeks after prostacyclin infusion. They laterreported striking improvements in some of 55 patientswith advanced peripheral artery disease of the lowerextremities.”

With the benefits also observed in pulmonary hyper-tension and Dr Vane later serving as Group Research andDevelopment Director of the Wellcome Foundation, thepath was cleared for the introduction of Flolan. Since theintroduction of the drug, longer lasting analogs have beenintroduced, but no one has produced a compound with ahalf-life of more than 2 hours and this remains a barrierstill to be overcome with the use of such agents.

Addressing this problem, Dr Vane said, “the answermust be that the prostacyclin molecule is unstable, andno matter what you do to it to try to add stability, youcan’t add all that much. Since the analogs have to bebased on the original structure of prostaglandin, they aregoing to have relatively short half-lives.”

Dr Vane’s research on other medications are also mile-stones in the development of more effective treatment fora wide range of disorders. These include his discovery of

(continued on page 20)

4 Advances in Pulmonary Hypertension

Continuous intravenous epoprostenol sodium (Flolan®) is along-term, complex, and expensive therapy. Its pivotal role inthe management of pulmonary arterial hypertension (PAH) isbased on randomized studies that clearly established clinicalefficacy. Subsequent studies have confirmed its benefits withregard to symptomatic and functional improvement, sustainedhemodynamic effect, and enhanced survival. Initial studiesdemonstrated both acute (Figure 1A) and short-term (Figure1B) hemodynamic improvement.1,2 Exercise capacity inepoprostenol-treated patients, as measured by 6-minute walk test distance, improved during 12 weeks of follow-upcompared with conventionally treated patients (Figure 2).2

Improved exercise capacity, as assessed by improvement inpeak oxygen consumption, has also been documented (Figure3).3 Importantly, increased survival has recently been report-ed in two large case series of patients with PAH (Figure 4).4,5

Although the US Food and Drug Administration (FDA) hasrecently approved alternative subcutaneous and oral drugs,intravenous epoprostenol remains the most effective agent inthe therapeutic armamentarium for PAH patients with WorldHealth Organization (WHO) Class III or IV symptoms.

Despite its proved efficacy and cumulative experiencesince the commercial availability of epoprostenol in 1996,intravenous epoprostenol remains a complicated and poten-tially dangerous therapy. With the approval of additional thera-pies for advanced PAH, the selection of appropriate candi-dates for epoprostenol treatment has become particularlychallenging. Health care providers must assess the potentialrisks and benefits of epoprostenol therapy compared withalternative treatment for each patient. This assessment shouldconsider the patient’s medical diagnosis, comorbidities, psychosocial status, support structure, financial resources,and stability.

Providers should also consider the available resources intheir own facility to provide the comprehensive and intensivemanagement that these patients require. Importantly, althoughepoprostenol therapy can be life-saving when used appropri-ately, it can potentially complicate, and in some cases worsen,symptoms with catastrophic results if it is incorrectly initiated,administered, or managed over the long term. Careful atten-tion to four aspects of treatment is required when consider-ing long-term use of epoprostenol: (1) patient eligibility, (2) patient education, (3) drug initiation, and (4) treatmentmaintenance and follow-up.

PATIENT ELIGIBILITY

The decision about whether a patient should be treated with

epoprostenol requires consideration of a number of issues: • Does the patient have appropriate clinical indications?• Are there clinical contraindications?• Are alternative medications more suitable?• Have issues of medical coverage been defined?

Continuous Intravenous Epoprostenol for Pulmonary ArterialHypertension: Highlighting Practical Issues, Special Considerations

Cathy J. Severson, RN, BSNPulmonary Hypertension ClinicMayo ClinicRochester, Minnesota

Michael D. McGoon, MDPulmonary Hypertension ClinicMayo ClinicRochester, Minnesota

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Fig. 1—(A, top). Acute hemodynamic response to intravenousepoprostenol in 23 patients1 and in 81 patients2 with PPH studied inthe two original randomized efficacy studies. Although the change inmean pulmonary arterial pressure (PAm) was minimal, cardiac index(CI) increased and pulmonary vascular resistance (Rp) decreased (*P < .0003). (B, bottom). After 8 to 12 weeks of follow-up, hemo-dynamic benefit was maintained in patients treated with epoprostenoland was significantly better than in patients receiving conventionaltherapy (*P < .03 compared with baseline).


• Is the patient able and willing to learn and comply withthe regimen?

• Can adequate follow-up be assured?

Clinical indicationsEpoprostenol is currently FDA-approved for patients withsymptomatic (WHO Class III or IV) primary pulmonary hyper-tension (PPH) or PAH associated with collagen-vascular dis-ease (the scleroderma-spectrum of diseases). At present, thereare no controlled data demonstrating its efficacy in patientswith HIV infection, congenital heart disease, or portopul-monary hypertension. Because these indications are similar to those for oral bosentan (Tracleer®) and subcutaneous tre-prostinil (Remodulin®), additional considerations should beweighed in selecting epoprostenol over these other agents.

Patients with very advanced or rapidly progressive symp-toms should be considered for early treatment withepoprostenol since it has proved to be the most effective med-

ical therapy and improved mortality has been demonstratedwith its use.2 Epoprostenol can be added to the medical regimen of patients whose condition has failed to adequatelyrespond or who have not tolerated other medications. Thisdrug should not be used in those with pulmonary venoushypertension as no benefit has been demonstrated and thereis potential for worsening.6,7 Central venous access is essentialfor placement of a permanent catheter. The presence of supe-rior vena cava or bilateral subclavian vein obstruction (usuallyin the setting of previous central catheters or pacemakerleads) may be a relative contraindication.

Medical coverageEpoprostenol is far more expensive than most drugs, its usesometimes exceeding $100,000 per year. If prescribed forappropriate indications (WHO Class III and IV PPH and PAHassociated with the scleroderma-spectrum of diseases), med-ical coverage is usually available. Prior insurance authorizationis necessary and can be facilitated by the distributors of themedication. Awareness of reimbursement issues by caregiversis mandatory, and coordination between the patient and thedistributor is a vital role of an active pulmonary hypertensionclinic.

Patient capability and complianceAlthough purely clinical issues regarding treatment selectionare pivotal, other factors may take precedence in matchingthe patient to appropriate epoprostenol treatment. Despite thedesire to provide optimal clinically indicated therapy to allpatients, not all are safe candidates. In addition, health care

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Fig. 3—Effect of epoprostenol on exercise in 16 patients with PPH.At epoprostenol initiation, peak oxygen consumption (VO2) haddeclined compared with a previous measurement 6 ± 3.2 months earlier (*P < .05 vs previous measurement). Following initiation ofdrug, peak VO2 and 6-minute walk distance both increased (†P < .05 and ‡P < .001 vs initiation, respectively).3

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provider time is a valuable resource; care of one marginallycompliant or competent patient may adversely affect the careof others. Thus, careful consideration of factors related to apatient’s willingness and ability to undergo therapy as well as the level of family and social support should be addressedbefore initiation. These factors are best explored by an expe-rienced and sensitive nursing staff with specialization in themanagement of PAH patients.

Nursing interviews should be conducted with both thepatient and a significant other who will assist and support thepatient at the outset. A number of issues should be exploredwith careful questioning. Responses to these questions do not necessarily preclude therapy, but are extremely useful inplanning for future patient and staff needs.

Questions to ask after therapy has been explained include:

• Are there physical limitations, such as digital loss becauseof collagen vascular disease or visual problems or hearingimpairment, that may hinder the ability to manipulatesyringes, operate the pump, or hear warning alarms?

• Are there problems with the home environment that may

preclude safe drug administration and follow-up, such asabsence of satisfactory plumbing, poor home sanitation,or lack of access to a telephone?

• Is there a reliable family or social support person to helpprepare the medication and manage the infusion pump?

• Are the patient and support persons committed to takingthe time each day (approximately 1 to 1.5 hours) to per-form necessary procedures?

Questions practitioners should ask themselves about the patient include:

• Is the patient sufficiently at ease to be a receptive learnerabout a complex treatment strategy, or does stress andagitation warrant deferring?

• Has the patient demonstrated compliance and initiativeby keeping scheduled clinic visits and following currenttreatment recommendations?

• Does the patient actively participate in his or her owncare or allow a significant other to manage it?

• Does the patient have a history of substance abuse ormental illness, including depression, that has requiredmedication or hospitalization, which would be risky in thesetting of long-term complex intravenous medication infu-sion?

PATIENT EDUCATION

This process is important and should proceed in an orderlyand compulsive fashion. Information for the patient mustinclude the following components:

• Introduction to the concept of long-term drug infusion• Discussion of realistic expectations• Education about technical aspects of epoprostenol use• Potential adverse effects of epoprostenol

Introduction to therapyPrior to making the decision to proceed with epoprostenoltherapy, patients should be shown the actual delivery system,have all procedures demonstrated, and ideally have an oppor-tunity to meet another epoprostenol patient. This may dramat-ically reduce the anxiety associated with starting long-termintravenous therapy. Patients may be more likely to benefit ifthey have the opportunity to meet someone of the same sex,disease substrate, and age range. Patients can be given infor-mation about the Pulmonary Hypertension Association (PHA),which may assist them in locating another patient in theirarea.

With the advent of new drug therapy, it is feasible thatsome patients may ultimately be weaned from epoprostenol,but they should understand that it is very likely going to bepart of their daily routine forever, unless they undergo lung or heart-lung transplantation. In our experience, patients must have control over the decision-making process to learnand properly care for the delivery system. To ensure success,written and visual (videotape or compact disc) material toreview at home can be offered to supplement face-to-faceteaching prior to making a final decision regardingepoprostenol therapy.

Fig. 5—Infusion apparatus for epoprostenol administration consists of a portable infusion pump and single lumen central venous catheter(generally a Hickman catheter). Note that the catheter exit site ispositioned where it is accessible to the patient for self-care.


Realistic outlook Patients should have realistic perceptions about the drug.Although epoprostenol has the potential for making a signifi-cant difference in quality of life and for improving survival, ithas not proved to be a cure for PAH. It is inconvenient, hasside effects, and has associated risks. Patients must realizethat there may not be immediate improvement in symptoms.

Although the majority of patients improve, it is impossibleto predict the magnitude or duration of the therapeutic re-sponse. Patients have to understand that initial improvementin symptoms does not guarantee continued improvement orpreclude eventual decline. While it is essential to hear thisinformation from the pulmonary hypertension center providers,patients also may benefit from discussion with other patientsand caregivers through support groups. They should not, how-ever, base their expectations on results of therapy in otherpatients.

Technical educationAlthough the approach to education and drug initiation differsamong large centers based on experience and resources, thereare some common practices. Patients should be taught byexperienced health care providers and ideally by the samepeople who will be following their care over the long term. At the Mayo Clinic, patients are provided with preprinted step-by-step directions in a manual that covers pump operation,drug reconstitution, and cassette and tubing change. They areencouraged to share a copy of this information with their localphysician. Teaching should occur in intensive blocks beforeand during the actual initiation of the drug. Whether the infu-sion is initiated on an inpatient or an outpatient basis, it must be done in a monitored setting with immediate access to emergency equipment and care. Long-term epoprostenolinfusion should be initiated using CADD I or Legacy pumps.

The process of reconstituting epoprostenol and all facetsof pump operation and catheter care must be fully explainedand demonstrated. Patients and support persons should beable to demonstrate their proficiency in all phases ofepoprostenol administration before they can be consideredadequately trained. This ensures that the patient always has a back-up person trained, which reduces patient stress.

Adverse effectsPatients should also be aware of common potential sideeffects, including jaw pain, headache, hypotension, nausea,diarrhea, and flushing. More long-term side effects mayinclude leg and foot pain, and skin rash. Others, such as highcardiac output failure, anemia, thrombocytopenia, pancytope-nia, or weight loss, may be recognized by the clinician withcareful follow-up over time. Some of the latter effects mayalso, however, be due to other underlying disease. Finally, certain adverse effects may be related to the delivery system,including catheter-related infection or sepsis, catheter-relatedthrombosis, pump failure, and rebound symptoms or deathdue to sudden discontinuation of epoprostenol.

DRUG INITIATION

A 6 or 9 French single-lumen tunneled central venouscatheter in the subclavian or internal jugular vein is the pre-

ferred approach for long-term epoprostenol therapy. The central venous catheter should be tunneled to an exit site that will allow the patient to see the site in order to care for it independently. Sutures should be removed after 4 weeks.Catheters are changed only when they become dysfunctionalor infected. Many patients maintain the same catheter formany years. If a tunneled catheter must be removed for aperiod of time (for example, because of infection) a short-termdedicated catheter, such as a percutaneous intravenous cen-tral catheter (PICC) or midline catheter, is appropriate forshort-term use. Such catheters have limited stability and aredifficult to care for using only one hand.

Epoprostenol infusion through the catheter is typicallystarted in a monitored setting at an infusion rate of 2 to 3 ng/kg/min. Vital signs are obtained before and at least every half hour for at least 2 to 3 hours after drug initiation.Teaching sessions occur on a daily basis until patients andsupport persons demonstrate proficiency in the techniques ofsterile preparation of the medication, operation of the infusionpump, and care of the central venous catheter. At the time of discharge, patients are provided with detailed contact infor-mation. Patients are instructed to see their local physicianswithin the first month of returning home, offering them theopportunity to become familiar with their current status, andto assist with their assessment and monitoring, including anticoagulation.

A proactive approach has been successful with this pa-tient population. Once the patient is fairly comfortable withthe procedures and has minimal jaw pain, mild diarrhea, orheadache, the epoprostenol dosage is increased by 1 to 2 ng/kg/min. The patient is called or instructed to call withinthe next week or sooner if dyspnea decreases or the sideeffects cause discomfort.

TREATMENT MAINTENANCE AND FOLLOW-UP

Important issues in long-term management include:• Communication• Dose modification• Interaction with the referring physician• Follow-up at the clinic• Emergencies

CommunicationWhile large pulmonary hypertension centers have differentcommunication protocols, virtually all include telephone con-tact as part of management. At the Mayo Clinic, patients areinstructed to call at least every two weeks. The following infor-mation is always obtained:

• Verification of current pump rate• Number and type of vials that are being mixed• Current weight• Interim change in symptoms (including functional status)

or side effects, and relationship to dose changes• Verification of prothrombin time monitoring, including

recent international normalized ratio (INR)

Dose adjustmentWhen epoprostenol was FDA-approved, experienced cliniciansfelt that frequent and consistent dose escalations were advis-


able in order to “stay ahead” of symptoms, rather than to tryto catch up once they recurred or worsened. As a conse-quence of this dosing strategy and because of extendedpatient survival, substantial numbers of patients began toreceive epoprostenol infusion rates of 100 ng/kg/min andhigher. Over time, it became apparent that the consequencesof high epoprostenol doses in some patients included highoutput states and fatigue.5

Epoprostenol dosing should be individualized to thepatient, taking into consideration severity of symptoms, side effects, and underlying disease. Some patients who experience improvement in symptoms during initiation ofepoprostenol in the hospital or monitored outpatient settingwill report increased symptoms on returning home to a morephysically challenging environment. Thus, close regular contact with these patients is imperative.

Role of referring physiciansLocal medical providers, including primary care physicians,specialists, and emergency personnel, should be informedabout patients’ need for epoprostenol and its implications.Patients’ current symptoms, medications and doses, the target range for the INR, potential complications, and plan for the future should be provided to primary care and otherlocal practitioners. Local providers should also know how andwhen to contact the pulmonary hypertension center, particu-larly for problems that occur after clinic hours. Laminatedinstruction cards inserted into the pump pack are useful inemergency situations.

Clinic follow-upPatients are generally seen for follow-up examination in theclinic 1 month after initiation and then every 3 to 6 months,depending on response to treatment. They are called oradvised to call every 2 to 4 weeks to report symptoms andside effects, or sooner if problems arise. The frequency ofcontact depends on the stability of the patient, side effects,and overall comfort level.

During follow-up telephone surveillance, new or worseningsymptoms should prompt a visit to the clinic for evaluation.Many centers repeat hemodynamic assessment after 1 year of therapy. Right-heart catheterization is the gold standard forassessment of pulmonary hemodynamics. The expectation at1 year should be improvement in pulmonary hemodynamicsbut not normalization of them. Echocardiographic evaluationafter approximately 3 to 6 months of treatment can provideuseful interim estimation of pulmonary hemodynamics.

EmergenciesAll potential emergency situations and proper responsesshould be discussed and “role-played” with patients duringinitial teaching. Ideally, local emergency rooms or emergencymedical staff should be informed about PAH and its treatmentand emergency requirements. Patients sometimes take on thisresponsibility themselves. If necessary, a letter can be provid-

ed to emergency services about the importance of maintainingthe infusion at all times and even via a peripheral vein if necessary. Stickers located on the infusion pump show thecurrent dose of epoprostenol as well as warn that the pumpcannot be turned off for any reason. Patients are also encour-aged to wear a medic alert bracelet or carry a laminated cardlisting their health problems as well as pump warnings.Urgent situations include central catheters being inadvertentlypulled out, a torn or leaking catheter, pump malfunction, andcentral line infection (particularly tunnel infection or sepsis).Patients need to call 911 or proceed to an emergency roomand be certain that the ambulance or emergency personnelare aware that interrupted epoprostenol delivery constitutes an emergency and that intravenous access must be estab-lished immediately. The pulmonary hypertension center shouldbe contacted for further instructions if at all possible. A back-up medication cassette and supplies should be brought to thehospital. Infections related to long-term indwelling centrallines can be minimized by strict attention to aseptic care.

References1. Rubin LJ, Mendoza J, Hood M, McGoon M, Barst R, Williams WB, etal. Treatment of primary pulmonary hypertension with continuous intra-venous prostacyclin (epoprostenol): results of a randomized trial. AnnIntern Med 1990;112(7):485-91.2. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, etal. A comparison of continuous intravenous epoprostenol (prostacyclin)with conventional therapy for primary pulmonary hypertension. N Engl JMed 1996;334(5):296-302.3. Wax D, Garofano R, Barst RJ. Effects of long-term infusion of prosta-cyclin on exercise performance in patients with primary pulmonary hyper-tension. Chest 1999;116(4):914-20. 4. Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Herve P, et al.Long-term intravenous epoprostenol infusion in primary pulmonary hyper-tension: prognostic factors and survival. J Am Coll Cardiol 2002;40(4):780-8.5. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonaryhypertension: the impact of epoprostenol therapy. Circulation 2002;106(12):1477-82.6. Califf RM, Adams KF, McKenna WJ, Gheorghiade M, Uretsky BF,McNulty SE, et al. A randomized controlled trial of epoprostenol (prosta-cyclin) therapy for severe congestive heart failure: the Flolan internationalrandomized survival trial (FIRST). Am Heart J 1997;134(1):44-54.7. Palmer SM, Robinson LJ, Wang A, Gossage JR, Bashore T, Tapson VF,et al. Massive pulmonary edema and death after prostacyclin infusion ina patient with pulmonary veno-occlusive disease. Chest1998;113(1):237-240.8. Rich S, McLaughlin VV. The effects of chronic prostacyclin therapy oncardiac output and symptoms in primary pulmonary hypertension. J AmColl Cardiol 1999;34(4):1184-7.9. Shapiro SM, Oudiz RJ, Cao T, Romano MA, Beckman XJ, Georgiou D,et al. Primary pulmonary hypertension: improved long-term effects andsurvival with continuous intravenous epoprostenol infusion. J Am CollCardiol 1997;30(12):343-9.10. Barst RJ, Rubin LJ, McGoon MD, Caldwell EJ, Long WA, Levy PS, etal. Survival in primary pulmonary hypertension with long-term continuousintravenous prostacyclin. Ann Intern Med 1994;121(6):409-15.11. D’ Alonzo GE, Barst RJ, Ayers SM, Bergofsky EH, Brundage BH,Detre KM, et al. Survival in patients with primary pulmonary hyperten-sion: results from a national prospective registry. Ann Intern Med 1991;115(5):343-9.

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Canterbury:pick up from

first issue

Epoprostenol therapy has revolutionized the treatment of pulmonary arterial hypertension (PAH).1-3 Patients realized animprovement in quality of life, hemodynamics, and survivaland this therapy has offered hope to patients with advanceddisease.1,4 However, these attributes must be balancedagainst the complicated nature of the intravenous delivery system. Infections may range in severity from local exit-siteinfections easily treated with oral antibiotics to life-threaten-ing sepsis. Because of the short half-life of epoprostenol,interruptions in therapy related to catheter displacement orpump malfunction may be life-threatening. Rare adverseevents associated with the delivery system include pneumoth-orax, deep venous thrombosis, and paradoxical embolus.Additionally, the patient’s life is radically changed by the needto mix the medication on a daily basis, store the medicationunder refrigerated conditions, and carry a mechanical pump.The success of epoprostenol coupled with the limitations ofthe delivery system has provided the impetus to developprostacyclin analogs with alternative routes of delivery. Thisarticle will focus on the analogs beraprost and treprostinil (theanalog iloprost is discussed in another article in this issue).

BeraprostBeraprost sodium is an orally administered prostacyclin ana-log. When taken with food the half-life is approximately 3 to31⁄2 hours, requiring dosing four times daily. Enthusiasm forthe treatment of PAH with beraprost arose from the initialexperience in Japan and subsequent experience in Europe.

In 1999 Nagaya and colleagues reported the benefit ofberaprost on survival in patients with primary pulmonaryhypertension (PPH).5 They followed 58 consecutive patientswith PPH between 1981 and 1997. The 34 patients diag-nosed before December 1992 were treated with conventionaltherapy alone, and the 24 patients diagnosed after January1993 were treated with beraprost in addition to conventionaltherapy. Oral beraprost was initiated at a rate of 60 mcg perday and increased by increments of 60 mcg per day over 1 to2 weeks to the highest tolerated dosage. Survival was estimat-ed from the date of initial diagnosis until the conclusion ofthe study in November 1998. Of the 34 patients in the con-ventional therapy group, 27 patients died of cardiopulmonary

causes after a mean follow-up of 44 ± 45 months. In con-trast, only 4 of the patients in the beraprost group died of cardiopulmonary causes during a mean follow-up of 30 ±20 months. Kaplan-Meier survival curves demonstrated the 1-, 2-, and 3-year survival rates in the beraprost group to be96%, 86%, and 76%, respectively, compared with 77%,47%, and 44%, respectively, in the conventional therapygroup, differences that were statistically significant.

A subgroup of 15 patients treated with beraprost under-went repeat cardiac catheterization after receiving therapy fora mean of 53 days. There was a reduction in mean pulmonaryartery pressure of 13% and in total pulmonary resistance of25% as well as an increase of 17% in cardiac output. Sixty-seven percent of the patients treated with beraprost demon-strated an improvement in New York Heart Association(NYHA) Functional Class. Although these results suggested animprovement in survival with beraprost therapy, several limita-tions of the study bear mention. These include the small sizeof the cohort and retrospective analysis. Other medical thera-pies were not controlled and there was a significant differencein the use of calcium channel blockers and digitalis betweenthe conventional therapy group and the beraprost group. Themean follow-up was substantially longer in the conventionaltherapy group than in the beraprost group. Additionally, a larger proportion of the patients in the beraprost group wenton to treatment with intravenous epoprostenol.

More recently Vissa and colleagues reported their results of long-term treatment of PAH with beraprost.6 They studied13 patients, 9 with PPH, 3 with thromboembolic pulmonaryhypertension, and 1 with PAH related to congenital heart dis-ease. The mean daily dose of beraprost was 116 ± 24 mcgafter the first month of treatment and 193 ± 74 mcg at theend of 12 months. One patient died at 40 days of treatmentand 1 patient was lost to follow-up. Twelve-month follow-updata were achieved in 11 patients. Patients demonstrated animprovement in NYHA Functional Class from 3.4 ± 0.7 atbaseline to 2.9 ± 0.7 at the end of 1 month (P < .016). Nofurther improvement was noted after a full year of therapy.The 6-minute walk distance increased by 63 ± 47 metersfrom a baseline distance of 213 ± 64 meters. This improve-ment was noted at 1 month and was maintained over the

Oral and Subcutaneous Prostacyclin Analogs:Analyzing the Latest Evidence on Efficacy and Safety

Vallerie V. McLaughlinRush Presbyterian-St. Luke’s Medical CenterChicago, Illinois



12-month period. This prospective uncontrolled trial suggest-ed that beraprost improved symptoms and exercise capacity inpatients with PAH.

The only prospective, double blind, placebo-controlled,randomized study of beraprost in the study of PAH has recent-ly been completed in Europe.7 Galie and colleagues studied130 patients with PAH, including PPH and PAH associatedwith collagen vascular disease, congenital heart disease, por-tal hypertension, and human immunodeficiency virus infec-tion. Patients were randomized to receive the maximal toler-ated dose of beraprost or placebo for 12 weeks. The primaryend point of distance walked in 6 minutes improved by 25.1 meters (P = .036) in the active treatment group. Theyalso noted an improvement in symptoms as measured by the Borg dyspnea index, which decreased by 0.94 in theberaprost group (P = .009). Subgroup analysis demonstratedthat patients with PPH realized the greatest improvement,with a mean change in 6-minute walk distance of 46.1meters. They noted no statistically significant differences incardiopulmonary hemodynamics or NYHA Functional Class.The median dosage of beraprost in the study was 80 mcg four times per day.

The most common side effects of beraprost reported inthese studies were headache, flushing, jaw pain, diarrhea, leg pain, and nausea. Side effects can be minimized when the drug is taken with a meal. Beraprost is currently availablein Japan and may become available in Europe. A placebo-controlled trial with beraprost in the United States was terminated prematurely and this drug will not likely becomecommercially available in the United States. Presumably theearly termination was because of a lack of efficacy estimationby the Data and Safety Monitoring Board.

Treprostinil Treprostinil is a prostacyclin analog with a half-life of 3 hourswhen administered subcutaneously. The drug is stable at roomtemperature. Animal studies suggest that the hemodynamiceffects of treprostinil are similar to those of epoprostenol.8,9

To test this hypothesis in humans, we studied 14 patientswith PPH acutely with intravenous epoprostenol and thenintravenous treprostinil.10 Both drugs had similar effects onhemodynamics. There was no difference in reduction in pul-monary vascular resistance (22% with epoprostenol versus20% with treprostinil).

To then test the alternative subcutaneous delivery method,we compared the effects of intravenous and subcutaneous treprostinil in 25 patients with PPH. In the intravenous tre-prostinil and subcutaneous treprostinil groups there was a 6% and 13% decline in mean pulmonary artery pressure anda 23% and 28% decline in pulmonary vascular resistancerespectively.

Having demonstrated that the drug favorably affects car-diopulmonary hemodynamics when given subcutaneouslyacutely, we embarked on an 8-week, placebo controlled, 2:1, randomized trial of subcutaneous treprostinil. Twenty-sixpatients with PPH were enrolled. Two patients in the trepros-tinil group did not complete the study because of intolerableside effects. The remaining 15 patients randomized to activedrug were receiving a mean dosage of 13.0 ± 3.1 ng/kg/min

of treprostinil, and the 9 patients randomized to placebo were receiving 38.9 ± 6.7 ng/kg/min at the end of the 8-weekperiod. There was an improvement of 37 ± 17 meters in the 6-minute walk distance in patients receiving the active thera-py (from 373 meters to 411 meters) compared with a 6 ± 28meter reduction in those receiving placebo (from 384 metersto 379 meters), which was not statistically significant. Therewas a favorable, but again not statistically significant trend inhemodynamics, with a 20% reduction in pulmonary vascularresistance index over the 8-week period in the group receivingactive treprostinil. Adverse events, including headache, diar-rhea, flushing, jaw pain, and foot pain, were as common inthe treprostinil-treated as in the epoprostenol-treated group.An unexpected adverse effect was pain at the site of the sub-cutaneous infusion. This pain was occasionally severe, wasoften associated with erythema, and occurred in nearly all thepatients undergoing active therapy. This proof-of-concept trialdemonstrated that this novel subcutaneous agent could begiven safely and effectively on an outpatient basis and pavedthe way for a larger pivotal trial.

Subsequently, the largest placebo-controlled randomizedstudy involving PAH patients was an international trial assess-ing the efficacy of subcutaneously delivered treprostinil inpatients with PAH, either primary or associated with collagenvascular disease or congenital systemic-to-pulmonaryshunts.11 Patients were enrolled between November 1998 and October 1999 in 24 centers in North America and 16centers in Europe, Australia, and Israel. Four hundred-seventypatients were randomly assigned to receive either continuoussubcutaneous infusion of treprostinil plus conventional thera-py or continuous infusion of placebo (vehicle solution withouttreprostinil) plus conventional therapy. Because of the infu-sion-site pain and reaction noted in the proof-of-concept trial,the dosing strategy called for lower doses at initiation and amaximal allowable dose at the end of 12 weeks of 22.5ng/kg/min. The primary end point of this trial was exercisecapacity as measured by the 6-minute walk distance, whichimproved in the treprostinil group and was unchanged withplacebo. The median between treatment group difference was16 meters (P = .006). This effect on exercise toleranceappeared to be dose-related. The patients in the lowest twoquartiles of dosing experienced little improvement in 6-minute

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1st Quartile<5.0

2nd Quartile5.0 to <8.2

3rd Quartile8.2 to <13.8

4th Quartile>13.8

Fig. 1—Change in exercise as function of dose.11


Pull-Out Algorithm


walk distance, and patients in the highest quartile of dosing(greater than 13.8 ng/kg/min) demonstrated a mean improve-ment of 36 meters (Figure 1). Secondary end points, includ-ing the dyspnea fatigue rating and the Borg dyspnea scale,confirmed an improvement with treprostinil therapy.Treprostinil also demonstrated a significant improvement inthe hemodynamic parameters of mean right atrial pressure,mean pulmonary artery pressure, cardiac index, pulmonaryvascular resistance, and mixed venous oxygen saturation(Table 1). Common side effects included headache, diarrhea,nausea, rash, and jaw pain. Side effects related to the infu-sion site were common. Eighty-five percent of patients experi-enced infusion site pain and 83% had erythema or indurationat the infusion site. Eight percent of the patients in the activetreatment group were withdrawn from the study because ofsite pain.

Although statistically significant, the 16-meter improve-ment in 6-minute walk distance was relatively modest andless than the improvements demonstrated in the trials withintravenous epoprostenol for both PPH and PAH related to the

scleroderma spectrum of diseases, which demonstra-ted treatment effects of 47 meters and 99 meters,respectively.1,3 The reasonsfor the less impressiveeffects are multifactorial.The entry criteria for the tre-prostinil trial were broaderthan those for either of theepoprostenol trials. Key sub-group analyses are listed inTable 2. The epoprostenoltrials included only patients

who were in NYHA Func-tional Class III or IV. Fifty-threepatients who were in NYHA Functional Class II were enrolledin the treprostinil trial. Their treatment effect in the 6-minutewalk distance was only two meters in the Functional Class IIpatients compared with 17 meters for the 382 patients whowere in Functional Class III and 54 meters for the 34 patientswho were in Functional Class IV. The baseline 6-minute walkdistance in the treprostinil study was 326 ± 5 meters in theactive treprostinil group and 327 ± 6 meters in the placebogroup.

In comparison the baseline 6-minute walk distance in thePPH epoprostenol trial was 315 meters in the epoprostenolplus conventional therapy group versus 270 meters in theconventional therapy group alone.1 In the sclerodermaepoprostenol trial the baseline 6-minute walk distance was272 meters in the epoprostenol plus conventional therapygroup and 240 meters in the group receiving conventionaltherapy alone.3 This demonstrates that the patient populationwas less ill in the treprostinil trial, which may have contri-buted to the less impressive treatment effect.

The treatment effect was also related to the baseline walkdistance in the treprostinil trial (Table 2). Patients who wereable to walk between 351 and 450 meters did not demon-strate a treatment effect at all, whereas those patients whowere able to walk in the lowest category of 50 to 150 metersdemonstrated a treatment effect of 51 meters. The etiology ofPAH was also more broad in the treprostinil trial. In additionto the inclusion of PPH patients and PAH associated with col-lagen vascular disease, PAH associated with congenital heartdisease was included. This group had been untested in thepast and in the treprostinil study did not demonstrate anytreatment effect at all. This may in part be related to thepatients’ long-standing disease and the difficulty of making an impact on such a process over a short 12-week period.

The nemesis of subcutaneous treprostinil has been painand erythema at the infusion site (Figure 2). A variety of ther-apies have been used to control this adverse effect, althoughnone has emerged as uniformly successful. Local remediessuch as topical hot and cold packs, topical analgesics andanti-inflammatory agents have been variably effective. Somepatients also responded to oral analgesics, such as nons-teroidal anti-inflammatory drugs. More recently, a pharmaceu-tical transdermal delivery vehicle, pluronic lecithin organogel,has been compounded with a variety of analgesic and anes-

Table 1—Hemodynamic Response to Subcutaneous Treprostinil

Treprostinil Placebo P Value

Mean right atrial pressure, mmHg -0.5 ± 0.4 +1.4 ± 0.3 .0002

Mean pulmonary artery pressure, mmHg -2.3 ± 0.5 +0.7 ± 0.6 .0003

Cardiac index, L/min/m2 +0.12 ± 0.04 -0.06 ± 0.04 .0001

Pulmonary vascular resistance index, units/m2 -3.5 ± 0.6 +1.2 ± 0.6 .0001

Mixed venous oxygen saturation, % +2.0 ± 0.8 -1.4 ± 0.7 .0001

Adapted from Simonneau et al.11


Table 2—Subgroup Analysis of Treprostinil Trial

NYHA Class Treatment Effect*

II +2 m

III +17 m

IV +54 m

Baseline Walk Treatment Effect

50 – 150 m +51 m

151 – 250 m +33 m

251 – 350 m +16 m

351 – 450 m -2 m

Disease Treatment Effect

Primary pulmonary hypertension +13.0 m

Collagen vascular disease +10.4 m

Congenital heart disease -1.0 m

*Refers to primary end point of 6-minute walk distance.

Clinical Algorithm

Elective Initiationof EpoprostenolIvan Robbins, MDDirectorPulmonary Hypertension CenterVanderbilt UniversityNashville, Tennessee

Abby Krichman, RRTPulmonary Hypertension Coordinator Duke University Medical CenterDurham, North Carolina


Footnotes1. A few large centers initiate epoprostenol therapy in an outpatient

setting; patients stay at local facilities that are provided for by the medical center.

2. These include Hickman and Groshong catheters. In some patients it may be appropriate to start with an antecubital PICC line.Epoprostenol should not be infused through a Mediport—this is not an appropriate catheter for continuous infusions, only for intermittentinfusions, ie, antibiotics, chemotherapy.

3. Rarely, patients may not tolerate this and the dose may have to bedecreased to 1 ng/kg/min.

4. Rarely, patients may not tolerate this and dosage may have to beincreased at a slower rate. Other, sicker patients may warrant moreaggressive titration, ie, 2-3 ng/kg/min dose increases daily.

5. Rarely, patients may not tolerate this and dosage may have to be increased at a slower rate. Other, sicker patients may warrant moreaggressive titration, ie, 2-4 ng/kg/min dose increases weekly.

6. The policy regarding listing for transplantation and moving to inactivelist varies substantially at different centers.

Hospital Admission• Telemetry bed1

• Baseline CBC• Placement of central

venous catheter2

• Start epoprostenol at 2 ng/kg/min3

• Daily increase by 1 ng/kg/min in hospital4

• Daily teaching by qualified individuals

Discharge• Aim for dose of

3-6 ng/kg/min• Initiate warfarin therapy,

if no contraindication• Schedule home-health

visit for following day

Common Side Effectsa. Jaw painb. Diarrheac. Nausea: usually worse with dose increase, persists in

some patientsd. Headache: usually worse with dose increasee. Thrombocytopenia: unclear if related to disease process

or epoprostenol f. Musculoskeletal pain: may substantially limit activity g. Palmar erythema, diffuse erythematous rash:

suggests overdosing

Treatment Optionsa. No specific treatment, if severe consider decreasing

doseb. Almost always controlled with loperamide, rarely

need diphenoxylate/atropine (Lomotil)c. Decrease dose if possible or increase at slower rate

if in early phase; Rx cautiously with antiemetics, consider right heart failure as cause

d. Rx with conventional headache medications (avoid NSAIDs, ASA for regular use)

e. No specific treatment, consider other disorders if severe, ie, myeloma, lupus

f. Consider Rx with COX-2 inhibitors, amitriptyline, gabapentin, rarely narcotics; dose decrease may help

g. Consider repeat catheterization to assess for high output state; if present, decrease dose, otherwise, no specific Rx

Miscellaneous• Once started,

epoprostenol should never be discon-tinued for any reason

• Patients should be given written statementdescribing basic points about epoprostenol

• If central catheter is removed, epoprostenol can be infused through peripheral line for several hours

• Emergency numbers for prescribing physician and epoprostenol provider should be carried by patients at all times

• Patients should carry back-up pump and supplies at all times

Initial OutpatientManagement

• Weekly dose increase by 1-2 ng/k/min5

• Weekly f/u by phone• Return to clinic in

~1 month• Suture removal from

catheter

Long-term OutpatientManagement

• Return to clinic every 3-6 months

• Assessment of clinical/cardiac functionat regular intervals

• Regular f/u by phone(weekly-monthly)

• Assess need forchange in epoprostenol dose at regular intervals

• Decide whether to continue with listing fortransplantation6

Prehospital Education-Facts about disease -Benefits/side effects ofepoprostenol

-Consider preadmissioncounseling


thetic therapies for local application in patients treated withtreprostinil. Initial observations appear promising, althoughthe therapy has yet to be studied in a controlled fashion.

A common observation has been that site pain and erythe-ma improve after several months of therapy. Additionally, thepain is not related to the dose of treprostinil. Given the dose-response relationship, it is important to increase the dose reg-ularly, so that patients realize an improvement in dyspnea.Under such circumstances, patients are more likely to toleratesite discomfort. Some patients have found that moving theinfusion site every 3 days as opposed to every day is useful.The infusion site most commonly used was subcutaneousabdominal fat, although some patients were able to use theouter hips and thighs and underside of the upper arm withsome success.

Because of the longer half-life of treprostinil, interruptionsof drug due to dislodgment of the catheter or pump malfunc-tion are less serious than with epoprostenol. In such instances,either the catheter could be replaced or a backup pump,which all patients had, could be exchanged without any seri-ous consequences. The Mini-Med pump‚ used to administertreprostinil, is smaller than the CADD pump used to adminis-ter epoprostenol and is about the size of a pager. The drugcomes in a premixed-prefilled syringe and therefore patientsneed only to place the syringe in the pump and do not have to mix the medication in a sterile fashion on a daily basis.

The Food and Drug Administration has approved subcuta-

neous treprostinil for patients with Functional Class II, III, and IV PAH. One should consider the use of subcutaneoustreprostinil in patients who are not candidates for or declinetherapy with intravenous epoprostenol, for example someonewith poor venous access or recurrent catheter infections. Inaddition, patients who have contraindications to or transami-nase elevations with the oral endothelin-receptor antagonistbosentan might be candidates for subcutaneous treprostinil.Treprostinil has not been studied in combination with bosen-tan; however, there may be a theoretical benefit to such acombination.

References1. Barst R, Rubin L, Long W, et al. A comparison of continuous intra-venous epoprostenol (prostacyclin) with conventional therapy for primarypulmonary hypertension. N Engl J Med 1996;334:296-301.2. McLaughlin V, Genthner D, Panella M, Rich S. Reduction in pul-monary vascular resistance with long-term epoprostenol (prostacyclin)therapy in primary pulmonary hypertension. N Engl J Med1998;338:273-7.3. Badesch D, Tapson V, McGoon M, et al. Continuous intravenousepoprostenol for pulmonary hypertension due to the scleroderma spec-trum of disease. Ann Intern Med 2000;132: 425-34.4. Shapiro S, Oudiz R, Cao T, et al. Primary pulmonary hypertension:improved long-term effects and survival with continuous intravenousepoprostenol infusion. J Am Coll Cardiol 1997;30:343-9.5. Nagaya N, Uematsu M, Okano Y, et al. Effect of orally active prostacy-clin analogue on survival of outpatients with primary pulmonary hyperten-sion. J Am Coll Cardiol 1999; 34:1188-92.6. Vizza CD, Sciomer S, Morelli S, et al. Long term treatment of pul-monary arterial hypertension with beraprost, an oral prostacyclin ana-logue. Heart 2001;86:661-5.7. Galie N, Humbert M, Vachiery J-L, et al. Effects of beraprost sodium,an oral prostacyclin analogue, in patients with pulmonary arterial hyper-tension: a randomised, double-blind, placebo-controlled trial. J Am CollCardiol 2002;39: 1496-502.8. Steffen RP, de la Mata M. The effects of 15AU81, a chemically stableprostacyclin analog, on the cardiovascular and renin-angiotensin systemsof anesthetized dogs. Prostaglandins Leukot Essent Fatty Acids1991;43:277-86.9. McNulty MJ, Sailstad JM, Steffen RP. The pharmacokinetics and phar-macodynamics of the prostacyclin analog 15AU81 in the anesthetizedbeagle dog. Prostaglandins Leukot Essent Fatty Acids 1993;48:159-66.10. McLaughlin VV, Gaine SP, Barst RJ, et al. Efficacy and safety of tre-prostinil: An epoprostenol analogue for primary pulmonary hypertension.J Cardiovasc Pharmacol (forthcoming).11. Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneousinfusion of treprostinil, a prostacyclin analogue, in patients with pul-monary arterial hypertension. Am J Resp Crit Care Med 2002;165:800-4.

Fig. 2—Subcutaneous treprostinil has been associated with pain and erythema at the infusion site.


Inhaled therapy for pulmonary hypertension is an interestingconcept as it offers selectivity of hemodynamic effects for thelung vasculature, thus avoiding systemic side effects.Selective pulmonary vasodilatation has been described forinhaled nitric oxide (NO) but use of this agent has severaldrawbacks. Most importantly, there are no data demonstratingimproved survival with long-term inhaled NO treatment, andthere is evidence that this agent possesses less vasodilatorpotency than do the prostanoids in primary pulmonary hyper-tension (PPH) patients.1,2 The intravenous prostacyclinepoprostenol (Flolan) has been shown to improve survival,exercise capacity, and hemodynamics in patients with severePPH.3-5 Epoprostenol has been approved for treatment of PPHin the United States and several European countries.

Iloprost, a Stable Prostacyclin AnalogIloprost is a prostacyclin analog that has the same biologicprofile as the natural substance with respect to prostaglandinreceptor binding and cellular effects.6 This explains why dur-ing continuous intravenous use its effects as well as its sideeffects are the same as those of epoprostenol.7 In contrast,the chemical stability is considerably different. Epoprostenolhas to be freshly dissolved, continuously cooled, and protect-ed from light to provide full activity, while iloprost is stable atroom temperature and normal light. Epoprostenol has a half-life in vivo of 3 to 5 minutes, while iloprost has a serum half-life of 20 to 25 minutes.8

For these reasons iloprost has practical advantages fordaily use compared with epoprostenol, and it has beenapproved for treatment of pulmonary arterial hypertension(PAH) in New Zealand. While epoprostenol is available in theUnited States and Europe, iloprost is not approved for use inthe United States.

The dosages used with continuous epoprostenol rangebetween 10 and 50 ng/kg/min, while the dosages for continu-ous intravenous iloprost range between 1 and 5 and rarely upto 10 ng/kg/min. The reasons for this huge difference have notbeen not fully elucidated but probably result from a higherpotency of iloprost (about 5:1) and the different deliverymethod, as well as from more aggressive dosing with intra-venous epoprostenol in the United States compared withEurope.

Prostanoid InhalationPatients receiving prostanoids are prone to side effects suchas headache, jaw pain, leg pain, and diarrhea, and there maybe complications with the delivery system. These findings arewell documented for continuous intravenous epoprostenoltherapy3,9,10 and have also been reported with the subcuta-neous delivery of the prostacyclin preparation treprostinil.11

Inhaled Iloprost for Treatment of Pulmonary Arterial Hypertension

Horst Olschewski, MDJustus Liebig UniversityGiessen, Germany

Fig. 1—Anatomy of precapillary pulmonary arteries. Note that at alllevels the vessels are in close contact with alveolar surfaces anddeposited drug can reach the vessel wall (arrows). Level 1, musculararteries. Level 2, partly muscular arteries. Level 3, intermediate cells.Level 4, partly intermediate cells. Level 5, pericytes surround lungcapillaries.33


Oral application of prostanoids(beraprost) may decrease deliv-ery-associated risks, but thistherapy has not yet provedeffective in severe disease,although in moderately ill PPHpatients there was a significantbenefit in a controlled study.12

In order to selectively treatthe pulmonary vessels in theventilated areas of the lung,inhaled prostacyclin and ilo-prost were ultimately consid-ered as treatment options. Dueto the fact that the intraacinarpulmonary arteries are tightlysurrounded by alveolar surfaces(Figure 1), it is possible tovasodilate these vessels via thealveolar deposition of a prosta-noid. For acute vasodilator test-ing with inhaled prostacyclin or iloprost, a special inhalationdevice with a drug-saving reser-voir for delivery of aerosols isutilized.

For long-term therapy,

Acute testing: prostacyclin (Flolan 25-50 µg/mL, 4-15 min) or iloprost 5-10 µg/mL, 4-15 min

Long-term therapy: iloprost (Ilomedin 5-10 µg/mL, 4-10 min, 6-9/d)

0:00 6:00 12:00 18:00 24:00

Reservoir

Reservoir

Bennett-Raindrop®

Jet-Nebuliser

Compressor PulmoCar-Accu®

ExpirationFilter

ExpirationValve

InspirationValve

Filter

Fig. 2—Inhalation of prostanoids. A schematic of the IloNebTM Device with AerotrapTM Reservoir (NebuTec, Elsenfeld, Germany) is shown to demonstrate prostanoid aerosolization for testing and as therapy for pulmonary hypertension. Alternative devices allow inhalation times as short as 4 minutes. Inhalations are repeated six to nine times a day with an overnight pause.

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mm Hg

ILO

SaO2

MAP

PAP

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CO

0 30 60 90 min

SvO2

0 30 150 330Day

720

Fig. 3—Acute hemodynamic effects of iloprost inhalation. Left: Inhalation of 2.8 µg of iloprost during a 15-minute inhalation time (ILO). SaO2, systemic arterial O2 saturation; MAP, mean systemic arterial pres-sure; PAP, mean pulmonary artery pressure; PVR, pulmonary vascular resistance; CVP, central venous pressure; SvO2, pulmonary artery O2 saturation; CO, cardiac output. Note that inhalation decreases PAP but not MAP. Right: Results of repeat cardiac catheterization in the same patient. Arrows indicate acutechanges induced by iloprost inhalation.14


repetitive inhalations with iloprost, six to nine times per dayare required (Figure 2). Each inhalation takes approximately10 to 15 minutes. With newer devices, it is possible to reducethe inhalation time to about 4 minutes13 and to avoid noisydelivery by using ultrasound energy for nebulization.

In patients with severe PAH, we have demonstrated thatinhalation of aerosolized iloprost results in a substantialdecrease in pulmonary artery pressure and pulmonary vascularresistance. This decrease is concomitant with an increase incardiac output, in the absence of a significant decrease inmean arterial pressure (Figure 3) or worsening ventilation-per-fusion mismatch.14,15

In a statistical comparison of the effects of intravenousepoprostenol and inhaled iloprost, the mean acute effect onpulmonary vascular resistance was equal. However, duringtreatment with inhaled iloprost, pulmonary artery pressuredecreased significantly and systemic artery pressureremained stable, whereas during treatment with intravenous

epoprostenol, systemic pressure decreased significantly andpulmonary artery pressure was minimally changed.14 Theseobservations were consistent with preceding findings inmechanically ventilated patients with acute respiratoryfailure.16-22 In uncontrolled studies, inhaled iloprost was effective in decompensated right heart failure23 and led tofavorable long-term hemodynamic improvement.24

AIR StudyA large randomized double-blind placebo-controlled multicen-ter study in Europe with inhaled iloprost has been performed(Aerosolized Iloprost Randomized, AIR).25 A total of 203patients with PPH or other forms of PAH were enrolled. Theseincluded New York Heart Association (NYHA) Functional ClassIII or IV patients with PAH due to appetite suppressants orcollagen vascular diseases and those with associated or non-operable thromboembolic pulmonary hypertension. In the ilo-prost and placebo groups, about 50% had PPH and 50% hadPAH of other causes. About 60% were in NYHA FunctionalClass III and 40% in Functional Class IV.

The primary end point of the study, defined as an improve-ment in NYHA Functional Class combined with at least 10%improvement in the 6-minute walk test and no prior deteriora-tion or death (combined clinical end point), was reached by3.4 times more patients in the iloprost group compared withthe placebo group (16.8% vs 4.9%; P = .007). Treatmenteffects did not differ between subgroups. This effect wasachieved with a mean inhaled iloprost dosage of 0.37ng/kg/min (Figure 4).

In the 6-minute walk test the treatment effect was 36.4meters in favor of iloprost (P < .004, Figure 5). There was atreatment effect with iloprost on NYHA Functional Class (P < .05), quality of life assessments by means of theEuroQoL visual analogue scale (P < .05), and on the MahlerDyspnea Transition Index (P < .05). Hemodynamics signifi-cantly deteriorated in the placebo group, whereas in the ilo-prost group, although preinhalation values were unchangedcompared with baseline, postinhalation values were signifi-cantly improved. Importantly, the number of patients remain-ing on study medication was significantly higher in the ilo-

AIR StudyIlloprost Dosing

• 6 × 2.5 µg (15 µg)

• 9 × 2.5 µg (22.5 µg)

• 6 × 5.0 µg (30 µg)

• 9 × 5.0 µg (45 µg)

Titration to highest tolerateddosage (first week)

Inhalation frequency: 7.5 ± 1.5 /d

Dose per inhalation: 5 µg (91% of patients)

Daily dosage (mean): 37.5 µg/d (0.37 ng/kg/min)

Fig. 4—Dose titration with inhaled iloprost in AIR study. During the first week of the study, the dose was increased until side effectsappeared or a maximal regimen of 5 µg delivered nine times wasachieved. The majority of patients tolerated 5 µg per inhalation.About 50% of patients inhaled six times per day and 50% inhalednine times daily.

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Fig. 5—Change in 6-minute walk test in AIR study. There was a significant improvement in distance walked in favor of the iloprost-treated group. The difference between groups was 36.4 meters. Forthe subgroup of PPH patients the difference was 59 meters, for theother patients 12 meters.26

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Fig. 6—Likelihood of completing 12-week AIR study. Kaplan-Meiersurvival estimates are shown for patients receiving iloprost vs placebo.Reasons for not completing included death, discontinuation of studymedication, and withdrawal of consent, usually because of clinicaldeterioration.26


the mode of action of aspirin, for example. As a pharma-ceutical consultant, Dr Vane initiated the program ininhibiting angiotensin-converting enzyme (ACE) that led to the development of the ACE inhibitor captopril(Capozide). He also oversaw the development of atracuri-um (Tracrium), acyclovir (Zovirax), and lamotrigine(Lamictal). After achieving knighthood, Dr Vane foundedthe William Harvey Research Institute in 1986 and hasbuilt the Institute to more than 100 members. In 1971Dr Vane and his associates discovered that aspirin andsimilar drugs produced their effects because they inhibitthe biosynthesis of prostaglandins. This paved the way for further discovery implicating the cyclooxygenases asbeing responsible for producing prostaglandins. This, in turn, has led the way for additional research into theCOX-2 inhibitor used to treat such inflammatory diseasesas rheumatoid arthritis.

Dr Vane has also explored other avenues of researchinto the mechanisms of prostaglandin, including its cyto-protective effects. “In models of myocardial infarction, itwill reduce the infarct size. It will reduce oxygen demandand enzyme release from the infarcted areas. Otherprostaglandins also share similar cytoprotective activity,distinct from the activity on platelet aggregation orvasodilatation.”

One of the intriguing questions still unresolved is thepossibly synergistic relationship between prostacyclin—essentially a cyclic AMP agonist—and the phosphodi-esterase inhibitor sildenafil (Viagra). Dr Vane suggestedthat the synergism could be related to the fact that silde-nafil inhibits consumption of both cyclic GMP and cyclicAMP. This could enhance the effect of prostacyclin inpulmonary hypertension.

(Sir John Vane, continued from page 3)

prost than in the placebo group (Figure 6). Over 3 months of therapy, there was no indication of

tachyphylaxis. In the iloprost group, 1 patient (1.0%) diedduring the double-blind study period vs 4 patients (4.0%) inthe placebo group. Overall, iloprost therapy was well tolerated.Cough, headache, and flushing occurred more commonly inthe iloprost group. These adverse events were mild and mostlytransient. Syncope occurring in the iloprost group was moreoften rated as serious, compared with the placebo group, butwas commonly not associated with clinical deterioration. Itcan be concluded from this study that inhalation of iloprost isan effective and safe therapy for patients with severe (NYHAFunctional Class III and IV) PPH and for patients with theother causes of PAH that were studied.

Future PerspectivesIn addition to treatment of PPH, the pulmonary selectivity ofinhaled iloprost provides the chance to safely applyprostanoids in patients who are prone to systemic hypoten-sion, such as patients with portopulmonary hypertension, andin emergency situations. The intrapulmonary selectivity allowsprostanoid application in patients who are prone to intrapul-monary right-to-left shunt, such as patients with pulmonaryfibrosis.15 The inhaled application may be combined withother effective treatments for PAH, although this has not yetbeen studied in a controlled fashion.

A more specific positive interaction is the use of inhalediloprost in combination with phosphodiesterase (PDE)inhibitors. The specific pulmonary vasodilating effects of ilo-prost that may be mediated by an intracellular increase ofcAMP can be increased by blocking the breakdown of thissecond messenger by means of PDE inhibition.26-31 Wenoticed excellent clinical results with the combination ofinhaled iloprost and sildenafil, a specific PDE 5 inhibitor32

and have been successfully using this combination for morethan a year in a considerable number of patients. At present

sildenafil is not approved for use as therapy for PAH, but clin-ical studies are under way. Inhalation intervals could belengthened and pulmonary selectivity could still potentially beachieved with the concominant use of PDE inhibitors. Thisapproach could also lead to simpler delivery methods, such asvia metered dose inhaler, for treatment of PAH.

Conclusions Inhaled iloprost has been shown to be effective for the treat-ment of PAH and may provide an alternative to the use ofintravenous epoprostenol. When the clinical effects of inhalediloprost and intravenous epoprostenol are compared, iloprostinhalation has clear advantages but also certain drawbacks.Most importantly, inhalation provides potent pulmonaryvasodilatation with minimal systemic side effects and no riskof catheter-related complications. Additionally, iloprost couldbe considered as therapy in patients with pre-existent ventila-tion-perfusion mismatch and in those who are prone to devel-op such a mismatch during systemic prostanoid application.The most important disadvantage is the fact that the hemody-namic effects of inhaled iloprost last only 30 to 90 minutes,and that six to nine inhalations are needed to achieve goodclinical results. In addition, sustained hemodynamic improve-ment and long-term survival with long-term use of inhaled ilo-prost have yet to be demonstrated in more than a small num-ber of patients.

References1. Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J.Inhaled nitric oxide as a cause of selective pulmonary vasodilatation inpulmonary hypertension. Lancet 1991;338:1173-1174.2. Hoeper MM, Olschewski H, Ghofrani HA, Wilkens H, Winkler J, BorstMM, et al. A comparison of the acute hemodynamic effects of inhalednitric oxide and aerosolized iloprost in primary pulmonary hypertension.German PPH study group. J Am Coll Cardiol 2000;35:176-182.3. Barst RJ, Rubin LJ, McGoon MD, Caldwell EJ, Long WA, Levy PS.Survival in primary pulmonary hypertension with long-term continuousintravenous prostacyclin. Ann Intern Med 1994;121:409-415.


4. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, etal. A comparison of continuous intravenous epoprostenol (prostacyclin)with conventional therapy for primary pulmonary hypertension. ThePrimary Pulmonary Hypertension Study Group. N Engl J Med1996;334:296-302.5. McLaughlin VV, Genthner DE, Panella MM, Rich S. Reduction in pul-monary vascular resistance with long-term epoprostenol (prostacyclin)therapy in primary pulmonary hypertension. N Engl J Med1998;338:273-277.6. Olschewski H, Olschewski A, Rose F, Schermuly R, Schutte H,Weissmann N, et al. Physiologic basis for the treatment of pulmonaryhypertension. J Lab Clin Med 2001;138:287-297.7. Higenbottam T, Butt AY, McMahon A, Westerbeck R, Sharples L. Long-term intravenous prostaglandin (epoprostenol or iloprost) for treatment ofsevere pulmonary hypertension. Heart 1998;80:151-155.8. Krause W, Krais T. Pharmacokinetics and pharmacodynamics of theprostacyclin analogue iloprost in man. Eur J Clin Pharmacol1986;30:61-68.9. Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Herve P, et al.Long-term intravenous epoprostenol infusion in primary pulmonary hyper-tension: prognostic factors and survival. J Am Coll Cardiol 2002;40:780-788.10. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonaryhypertension: the impact of epoprostenol therapy. Circulation2002;106:1477-1482.11. Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, et al.Continuous subcutaneous infusion of treprostinil, a prostacyclin ana-logue, in patients with pulmonary arterial hypertension. A double-blind,randomized, placebo-controlled trial. Am J Resp Crit Care Med2002;165:800-804.12. Galie N, Humbert M, Vachiery JL, Vizza CD, Kneussl M, Manes A, etal. Effects of beraprost sodium, an oral prostacyclin analogue, in patientswith pulmonary arterial hypertension: a randomized, double-blind, place-bo-controlled trial. J Am Coll Cardiol 2002;39:1496-1502.13. Gessler T, Schmehl T, Hoeper MM, Rose F, Ghofrani HA, OlschewskiH, et al. Ultrasonic versus jet nebulization of iloprost in severe pulmonaryhypertension. Eur Resp J 2001;17:14-19.14. Olschewski H, Walmrath D, Schermuly R, Ghofrani A, Grimminger F,Seeger W. Aerosolized prostacyclin and iloprost in severe pulmonaryhypertension. Ann Intern Med 1996;124:820-824.15. Olschewski H, Ghofrani HA, Walmrath D, Schermuly R, Temmesfeld-Wollbruck B, Grimminger F, et al. Inhaled prostacyclin and iloprost insevere pulmonary hypertension secondary to lung fibrosis. Am J Resp CritCare Med 1999;160:600-607.16. Walmrath D, Schneider T, Pilch J, Grimminger F, Seeger W.Aerosolised prostacyclin in adult respiratory distress syndrome. Lancet1993;342:961-962.17. Walmrath D, Schneider T, Pilch J, Schermuly R, Grimminger F,Seeger W. Effects of aerosolized prostacyclin in severe pneumonia.Impact of fibrosis. Am J Resp Crit Care Med 1995;151(3 Pt 1):724-730.18. Walmrath D, Schneider T, Schermuly R, Olschewski H, GrimmingerF, Seeger W. Direct comparison of inhaled nitric oxide and aerosolizedprostacyclin in acute respiratory distress syndrome. Am J Resp Crit CareMed 1996;153:991-996.19. Putensen C, Hormann C, Kleinsasser A, Putensen-Himmer G.Cardiopulmonary effects of aerosolized prostaglandin E1 and nitric oxide

inhalation in patients with acute respiratory distress syndrome. Am JResp Crit Care Med 1998;157(6 Pt 1):1743-1747.20. Zwissler B, Kemming G, Habler O, Kleen M, Merkel M, Haller M, etal. Inhaled prostacyclin (PGI2) versus inhaled nitric oxide in adult respi-ratory distress syndrome. Am J Resp Crit Care Med 1996;154(6 Pt1):1671-1677.21. Eichelbronner O, Reinelt H, Wiedeck H, Mezody M, Rossaint R,Georgieff M, et al. Aerosolized prostacyclin and inhaled nitric oxide inseptic shock—different effects on splanchnic oxygenation? Intensive CareMed 1996;22:880-887.22. De Jaegere AP, van den Anker JN. Endotracheal instillation of prosta-cyclin in preterm infants with persistent pulmonary hypertension. EurResp J 1998;12:932-934.23. Olschewski H, Ghofrani HA, Schmehl T, Winkler J, Wilkens H, HoperMM, et al. Inhaled iloprost to treat severe pulmonary hypertension. Anuncontrolled trial. German PPH Study Group. Ann Intern Med2000;132:435-443.24. Hoeper MM, Schwarze M, Ehlerding S, Adler-Schuermeyer A,Spiekerkoetter E, Niedermeyer J, et al. Long-term treatment of primarypulmonary hypertension with aerosolized iloprost, a prostacyclin ana-logue. N Engl J Med 2000;342:1866-1870.25. Olschewski H, Simonneau G, Galie N, Higenbottam T, Naeije R,Rubin LJ, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347:322-329.26. Olschewski H, Rose F, Grunig E, Ghofrani HA, Walmrath D, SchulzR, et al. Cellular pathophysiology and therapy of pulmonary hypertension.J Lab Clin Med 2001;138:367-377.27. Schermuly RT, Roehl A, Weissmann N, Ghofrani HA, Leuchte H,Grimminger F, et al. Combination of nonspecific PDE inhibitors withinhaled prostacyclin in experimental pulmonary hypertension. Am JPhysiol Lung Cell Mol Physiol 2001; 281:L1361-L1368.28. Schermuly RT, Ghofrani HA, Enke B, Weissmann N, Grimminger F,Seeger, et al. Low-dose systemic phosphodiesterase inhibitors amplify thepulmonary vasodilatory response to inhaled prostacyclin in experimentalpulmonary hypertension. Am J Resp Crit Care Med 1999;160(5 Pt1):1500-1506.29. Schermuly RT, Roehl A, Weissmann N, Ghofrani HA, Schudt C, TenorH, et al. Subthreshold doses of specific phosphodiesterase type 3 and 4inhibitors enhance the pulmonary vasodilatory response to nebulizedprostacyclin with improvement in gas exchange. J Pharmacol Exp Ther2000; 292:512-520.30. Ghofrani HA, Wiedemann R, Rose F, Olschewski H, Schermuly RT,Weissmann N, et al. Combination therapy with oral sildenafil and inhalediloprost for severe pulmonary hypertension. Ann Intern Med2002;136:515-522.31. Wilkens H, Guth A, Konig J, Forestier N, Cremers B, Hennen B, etal. Effect of inhaled iloprost plus oral sildenafil in patients with primarypulmonary hypertension. Circulation 2001;104:1218-1222.32. Ghofrani HA, Wiedemann R, Rose F, Olschewski H, Schermuly RT,Weissmann N, et al. Combination therapy with oral sildenafil and inhalediloprost for severe pulmonary hypertension. Ann Intern Med2002;136:515-522.33. Jones RC. Role of interstitial fibroblasts and intermediate cells inmicrovascular remodelling in pulmonary artery hypertension. Eur RespRev 1993;3:569-575.


Ivan Robbins, MD, Director, Pulmonary Hyper-tension Center, Vanderbilt University, Nashville,Tennessee, conducted this discussion. The panelincluded David Langleben, MD, Director, Center for Pulmonary Vascular Disease, Jewish GeneralHospital, McGill University, Montreal, Quebec,Canada; Michael McGoon, MD, Consultant inCardiology, Mayo Clinic, Rochester, Minnesota; and Abby Krichman, RRT, Pulmonary Hyperten-sion Coordinator, Duke University Medical Center,Durham, North Carolina.

Dr Robbins: I have always been interested in whyinvestigators decided to try intravenous prostacyclin,or epoprostenol (Flolan), as long-term treatment.

Dr McGoon: It was recognized as a very potentvasodilator, with the additional theoretical benefitsof being one of the most potent endogenous plateletinhibitors. So it made some sense to use it in a dis-ease in which vasoconstriction was felt to be a pre-dominant causal mechanism.

Dr Langleben: It was a serendipitous concurrence of a novel molecule and a pharmaceutical companythat held very basic research in high regard. Prosta-cyclin, as an endogenous vasodilator was initiallydescribed in 1976. The major clinical phase in pul-monary hypertension began later in that decade,extending to the mid-80s. So it took a while to workits way down to clinical use. I think it was its potentvasodilator effect with a probable short duration ofaction that made it very attractive as an acutevasodilator for testing.

Dr McGoon: The other serendipitous aspect of thisdrug is that it came when we were getting disillu-sioned with other vasodilators, most specificallyhydralazine. So the concept of a short-acting pul-monary vasodilating agent, which was actuallyreplacing deficient endogenous production of prostacyclin, made a lot of sense.

Dr Robbins: How did you come up with the dosingscheme?

Dr McGoon: Initially it had been identified duringthe acute-stage dose-ranging studies that precededour involvement. It became clear very soon whenusing epoprostenol that if you gave too big a doseyou were going to get a lot of side effects and youhad to creep up on the dose if you were gong to get

benefit over the long haul. About 2 to 3 ng/kg/minwas the initial starting dosage in the early studiesand is clearly the way to go. Typically, most pa-tients, by the time they were dismissed from our initial care, were receiving around 6 ng/kg/min whenthey went home, and after that point we increment-ed gradually by 1 or 2 ng/kg/min every week or so,particularly if a patient was still symptomatic, whichwas frequently the case. Later, based on conversa-tions with other clinicians nationwide, we evolvedinto more or less routinely increasing the dosageregardless of symptoms. The idea was that we wanted to stay ahead of symptoms preventively and continue to have a vasodilator effect that wouldhopefully impart some vascular remodeling and permanency to the decreased resistance. Eventuallyit was recognized that there was a state in whichsymptoms of high cardiac output could overtake thebenefits of decreased resistance. It has always beenobserved that the predominant effect of administer-ing epoprostenol was to increase cardiac output with modest decreases in pulmonary pressure atbest, resulting in a decrease in calculated pul-monary resistance.

Dr Robbins: Abby, what has the experience been atDuke?

Ms Krichman: Initially, in the early days ofepoprostenol dosing, the prevailing practice was tocontinue increasing dosages on a regular basis andjust tolerate the adverse side effects. We certainlyhave come full circle. Now we try to maintain thelowest dose (of epoprostenol) possible to amelioratesymptoms but also to minimize the side effects.

Dr Langleben: Our practice was exactly as Mikedescribed initially.

Dr Robbins: We were just looking at our 5-yearexperience, and our average dose is probably somewhere around 25 ng/kg/min. We have very fewpeople receiving more than 50 ng/kg/min.

Dr Langleben: Our early patients, the ones who havehad 10 or 11 years of treatment, have reached high-er dosages. Most of the recent patients are not at thatdose level, though. Our average is probably 45 to 60ng/kg/min after many years. After a year of therapymost people are receiving about 20 ng/kg/min.

Dr McGoon: We are all over the board, to be perfect-

Pulmonary Hypertension Roundtable

Bench to Bedside: Principles and Practice ofEpoprostenol Therapy, from Maximizing Benefit to Minimizing Side Effects

Ivan Robbins, MD

David Langleben, MD

Michael McGoon, MD

Abby Krichman, RRT


ly honest. It is such a moving target at this time,when we have the option of combining or transi-tioning to other medications. We can talk aboutaverages, but at least in our case, the standarddeviation of doses at any given time is extremelybroad.

Dr Robbins: Should we talk a bit about combinedtherapy?

Dr McGoon: It is at an early stage. We are still learning aboutit. One pattern we have seen is that when we add anotheragent to epoprostenol, even one that is not a prostenoid, likebosentan, for example, there can be an exacerbation of whatwe would normally call epoprostenol side effects, such asflushing, headache, and gastrointestinal disquietude.

Dr Langleben: The concept of attacking an illness through avariety of mediators and mechanisms is standard for othertypes of illnesses. Perhaps, because of the relative rarity ofpulmonary hypertension or the lack of availability of easy therapy, we have not been able to consider combined therapyuntil now.

Ms Krichman: There are a lot of physicians out there whothink they can just give patients bosentan and completelywean them from epoprostenol. We may be able to accomplishthat in some patients, but with very careful monitoring.

Dr Robbins: You are absolutely right.

Ms Krichman: We ought to make it clear that we are usingcombination therapy to hopefully improve outcomes, not solelyto wean epoprostenol.

Dr Langleben: Would everyone agree that epoprostenolremains our gold standard for the medical treatment ofadvanced functional class III and IV patients?

Dr Robbins: Yes.

Dr Langleben: So, has everyone around the table seen failuresof other therapies already and resorted to epoprostenol?

All: Yes.

Dr McGoon: Our prediction was, and I think it is coming true,that the oral therapy, bosentan, would be used widely, butthat not all hopeful expectations would be met. There hasbeen more recently the feeling that “Well, we haven’t seen allthe benefit we want, so maybe we should think about addingor transitioning to epoprostenol.”

Ms Krichman: At our center, and probably for most of you aswell, when somebody’s more of an early Class III patient, ourpreference is always oral therapy first, but for those with laterClass III symptoms, we are initiating epoprostenol in mostcases.

Dr McGoon: That would be my preference, andthat is what I express to most patients.

Ms Krichman: There are always patients whorefuse epoprostenol and want to try oral therapyfirst. In most cases we’re amenable to a short trial of oral therapy with careful follow-up andmonitoring.

Dr McGoon: The key, particularly if you are going to start withconservative therapy, is the follow-up. The whole process ofthe pulmonary hypertension specialty clinic has to be gearedto establishing communication with the patient about thetreatment options, the pros and cons, and then to very inten-sive follow-up and reevaluation.

Dr Langleben: What are your standards for follow–up?

Dr McGoon: Of course, it varies from patient to patient. Wefollow patients in terms of clinical symptoms with 6-minutewalk testing at intervals of 3 to 6 months and with echocar-diography, usually at 6 months. If there is disparity amongclinical impression, examination, and echocardiographic data,we will do right-heart catheterization.

Dr Langleben: We prospectively follow patients with echocar-diography at least every 6 months. Our population numbersaren’t huge, but we can tell who is doing well on the basis ofthe Doppler echocardiography-derived index of myocardial per-formance (the TEI index)) and how their ventricles are coping.

Dr McGoon: At some centers, some clinicians clearly feel thatregular, periodic right-heart catheterization for hemodynami-cally precise characterization provides additional informationabout cardiac output.

Ms Krichman: I think a lot of centers do that.

Dr McGoon: We don’t do it on everybody because the specificnumber doesn’t really help me too much, compared with theglobal assessment of a patient’s status, which includes manyfactors. I think all of us employ multiple criteria in decidinghow patients are doing and what changes, if any, in therapyshould be attempted.

Dr Langleben: The other thing we pay particular attention toon our echocardiograms is an estimate of cardiac output.

Ms Krichman: What is the prevailing thought about patientswho continue to have severely enlarged right ventricles, butwho symptomatically are doing okay?

Dr Langleben: With those patients, we follow the TEI index. In many of these patients the index is greatly and abnormallyelevated. If the index is slightly improved, despite the factthat they have right ventricular dilatation, we gently increasethe dosage. If the index hasn’t really improved with epo-prostenol, we give them a couple of months, then that is anindicator to list them for early transplantation, regardless of

Now we try to main-tain the lowest dose(of epoprostenol)possible to amelio-rate symptoms butalso to minimize theside effects.


their symptoms. Then we more aggressively increase theepoprostenol dosage to try to buy them time to get their transplant.

Dr Robbins: David, I am just not impressed with aggressivedosing. And by going up on the dose aggressively, we find youget a lot more side effects.

Dr Langleben: We do increase the dose more rapidly than wewould in more stable patients. We don’t get a lot of epopros-tenol side effects beyond jaw pain and a little bit of diarrhea.

Ms Krichman: We see a lot of musculoskeletal pain.

Dr McGoon: The problem is knowing in the individual patientwhether you have reached the optimal dosage. I agree withDavid that if a patient is not doing well, then you don’t knowthat a higher dose won’t work until you have tried. So it doesstimulate a strategy of going up on the dosage. If you find theside effects overwhelm the benefits, or if you really don’t getany additional benefits from the inconvenience or expense ofa higher dosage, then it may make sense to try tapering offagain.

Ms Krichman: I think we should talk about general dosingstrategies for patients who have just started receivingepoprostenol. We usually have a 3- to 4-day hospitalizationwith a goal of sending patients home taking 4 to 6 ng/kg/minof drug, somewhere in that range. For sicker patients we’ll be more aggressive, titrating up during the initiation period. Once they are home, we call patients weekly for at least a month following initiation of therapy and go up 1 or 2 ng/ kg/min a week. Dosing is very individualized, depending on symptoms and side effects. Once symptoms are somewhatunder control, we back off on dose titration, typically to every2 weeks and then every month. When we reach a dosagewhere there is a balance of symptomatic improvement andminimal side effects, we stop going up.

Dr Robbins: That is pretty close to what we do, and what isprobably done in a lot of centers.

Ms Krichman: Except for the very sickest patients, there is noneed to rapidly titrate epoprostenol

Dr McGoon: Oh, I agree.

Dr Robbins: You raised a very good point, Abby, the fact thatthese patients need very close follow-up. You can’t just sendpatients home taking 3 or 4 ng/kg/min and then say, “Okay,we’ll see you back in a month or so.”

Ms Krichman: It doesn’t work well for physicians taking careof epoprostenol patients without some kind of physicianextender. There is clearly a role for health care professionalswho work very closely with physicians and who talk withpatients on a regular basis and see them in clinic periodically.This is not an easy disease to manage.

Dr McGoon: I have no hesitation whatsoever in saying that our pulmonary hypertension clinic was established primarily to have nurses in a setting with focused interest.

Ms Krichman: Yes. And that has to be the message to com-munity physicians or physicians who aren’t at tertiary carecenters.

Dr Robbins: What about infection from the long-term in-dwelling catheters? How do you manage that at your centers?

Dr McGoon: The first step is obviously prevention, and thatcomes with education of the patient about strict aseptic con-trol. But even under the best conditions, the catheter can getinfected. Our response depends on the circumstances. If it isa localized exit-site infection, we will make substantial effortsto preserve the catheter and treat with antibiotics to prevent itfrom getting worse. Certainly if there is any evidence of sys-temic infection, the catheter is out and intravenous antibioticsare given.

Dr Robbins: Education is key. The only time we have hadproblems is with patients who didn’t understand or ignoredthe signs of the problem and then came in and were quite ill.

Ms Krichman: Overall, how many catheters have you had topull because of systemic infection?

Dr McGoon: If I had to guess the percentage of patients who have had that, it would be 3% or 4 % maybe. I havesome patients who have been receiving the drug for more than 10 years who have never had a change in catheter. Butthenthere are others who have had two or three infections in one year.

Dr Robbins: Have the indications for use of prostacyclinchanged over the years for you?

Dr McGoon: Yes, it has evolved to broader indications. As published experience increased with secondary pulmonaryhypertension and randomized studies increased with collagen vascular disease, the labeling expanded our options and wewere able to use the drug more broadly. Now we consider itsuse in nonsurgical thromboembolic disease or interstitial pulmonary fibrosis and so on, in which pulmonary hyperten-sion may be a big component. The more other things you have wrong, the less the beneficial effect.

Dr Langleben: I am not sure their longevity will be the sameas that of primary pulmonary hypertension patients in thesense that the other medical issues related to their principalillness will likely affect survival.

Dr Robbins: Any other issues that anyone feels are importantto bring up?

Dr McGoon: One source of problems for us has been whenpatients unexpectedly see other physicians who don’t knowwhat to do in an urgent situation. You just have to listen to


patients when dealing with epoprostenol. Theyactually know what they are doing.

Ms Krichman: That is an important part of the education of patients and caregivers that some-times does not happen, really taking the time toexplain what a peripheral IV is, when you need toget it put in, and that sort of thing.

Dr Langleben: We give patients a preprinted cardthat they carry with their pumps. It states in bigbold letters, “DO THIS NOW.” Patients areinstructed to go to their nearest hospital emergencyroom if they have a problem with the infusion linesor catheter, and to show the card immediately onarrival. The system works.

Ms Krichman: Another topic we might touch on is the sideeffects of prostacyclin and how we are treating them. The ini-tial approach is to lower the dose of epoprostenol if tolerated.Musculoskeletal pain is a big issue. Mostly we are usinggabapentin (Neurontin).

Dr Robbins: We have used COX-2 inhibitors. They help somepeople, and then we move on to amitriptyline with an occa-sional patient, and then to gabapentin.

Ms Krichman: Is anybody using tramadol (Ultram) or opioids?

Dr McGoon: Not in any routine way. We have a low thresholdfor using gabapentin.

Dr Langleben: What about for diarrhea?

All: Loperamide (Imodium).

Dr McGoon: We sometimes use jaw pain as an index ofwhether patients are getting enough. If they are not havingjaw pain, we have serious concerns whether enough is beingused.

Ms Krichman: We used to do that, and then there were thosepatients who did not have jaw pain but were doing great.

Dr McGoon: If someone is not doing well, we won-der (a) is the patient getting it and (b) if they are,whether it may be at too low a dose.

Dr Robbins: Any other big side effects?

Ms Krichman: One thing I know we have all seenas a side effect is ascites. The important issue isdetermining whether ascites is from worseningheart failure or from epoprostenol. Those seem tobe the most difficult to sort out.

Dr Robbins: We have seen it somewhat, but moreoften we have seen it in the face of severe rightheart failure.

Ms Krichman: We certainly have seen such patients, but nowwe are seeing patients who are not in right heart failure andhave significant ascites.

Dr McGoon: Yes, I agree, Abby. And patients require frequentparacentesis.

Dr McGoon: You know, I think it is a testimonial. To be frank,epoprostenol has never been exposed to what we would con-sider a scientifically rigorous clinical study. There was noplacebo, there was no blinding involved and so on, and yet Ithink most of us are convinced, based on our experience, thatit works. Part of the reason we are convinced is that in spiteof what seem to be fairly horrendous side effects, patients stillfeel they are benefiting from the medication. The other reasonI think it is physiologically beneficial is our experience whensome patients’ infusions have been surreptitiously interrupted.For example, we’ve had a couple of instances when the linewas inadvertently pulled out from the vein but remained sub-cutaneous, so the patient was unknowingly no longer gettingan infusion. The patients felt worse, as though their symptomshad returned until the infusion was resumed. That was my“controlled” study.

One thing I know we have all seen as a side effect isascites. The impor-tant issue is deter-mining whetherascites is fromworsening heartfailure or fromepoprostenol. Those seem to bethe most difficult to sort out.

Advances in Pulmonary HypertensionPulmonary Hypertension Association850 Sligo Avenue, Suite 800Silver Spring, MD 20910

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The Pulmonary Hypertension Association announces the

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$30,000 stipend per year and $5,000 project support per year

Application Deadline: Friday, January 24, 2003Award Notification: May 31, 2003Award Activation: July 1, 2003

Suggested investigation topics include, but are not limited to:

• Genetics of pulmonary hypertension• Molecular biology of pulmonary vascular

endothelium• Development of new pharmacologic agents to

treat PH• Development of innovative techniques for early

diagnosis• Pathophysiology of right heart failure• Epidemiology of risk factors for developing PH

For More Information Visitwww.phassociation.org/support/researchfunding.htm

Visit PHA at www.phassociation.org, PHA’s gateway to the PH community

Patients, family members, physicians, andnurses providing hope, support, and education. Through research programs,PHA seeks better treatments and a cure.

Learn and teach with Pulmonary Hypertension: A Patient’s Guide, now in its second edition.

Among the topics:• What Is PH?• How Do I Know?• Who Gets PH?• PH Treatments• Children & PH• Taking Your Medicine• Living With PH

Also included: Resource Section,Bibliography and Glossary. Available for$25 per copy ($15 for PHA members). Call 301-565-3004 or order online atwww.phassociation.org and click on “How Can I Help?” and then click on“Visit PHA’s Store.”

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