When to Initiate Intravenous Therapy and/or Refer

Hunter C. Champion, MD, PhD, FAHA*

Intravenous (IV) prostacyclin (epoprostanol) and its analogs (iloprost and treprostinil) are

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effective in treating pulmonary artery hypertension (PAH). Although prostacyclins areavailable for inhaled and subcutaneous delivery, IV administration of prostacyclins, some-times in combination with other agents, such as bosentan or sildenafil, is considered the mostaggressive method to manage PAH. This report attempts to help clinicians determine whento initiate IV treatment of PAH and when to refer a patient with PAH to a center fortreatment. IV prostacyclin therapy initiation is suggested when patients exhibit WorldHealth Organization functional class IV symptoms. The Registry to EValuate Early AndLong-term Pulmonary Arterial Hypertension disease management (REVEAL) risk calcu-lator can help determine a patient’s 1-year mortality with PAH and characterize the clinicalcourse, treatment, and predictors of outcomes in patients with PAH. Referring physicianscan screen their patients for PAH and refer even before the diagnosis has been confirmed sothat the center can facilitate the diagnostic process and provide suggestions for initialtherapy selection and provide other collaborative and supportive services. Alternatively, thephysician can diagnose and initiate early therapy with a plan to involve the pulmonaryhypertension center at the need for IV therapy or consideration for transplantation, workingclosely with the patient to ensure stability. Physicians and pulmonary centers must developgood methods of communication to ensure effective diagnosis and management. � 2013Published by Elsevier Inc. (Am J Cardiol 2013;111[suppl]:21Ce24C)

Background of Intravenous Therapy

Intravenous (IV) prostacyclin and its analogs are argu-ably the most effective approach to treating pulmonaryartery hypertension (PAH).1e10 To date, these agents remainthe only therapy with proven benefit in reducing mortality inpatients with PAH compared to conventional therapy.2

Epoprostenol was the first synthetic prostacyclin formu-lation for use in patients with PAH. Since the initial use ofepoprostanol, other more stable analogs (iloprost and tre-prostinil) have been developed and approved for use inPAH. Generally speaking, these drugs have improvedexercise tolerance, breathing, hemodynamic parameters, andsurvival (in the case of epoprostenol).1e7,11,12 Althoughprostacyclins are available for inhaled and subcutaneousdelivery, IV use is considered the most aggressive method tomanage PAH.8e10,13

IV therapy requires the use of a permanent IV catheterand an infusion pump, which can be associated with serious

lmonary, Allergy, and Critical Care Medicine, Depart-, University of Pennsylvania Medical Center Montefiorer Medicine Institute, University of Pittsburgh/UPMC,lvania.this supplement was supported by an educational grantces, Inc.mpletion: To access your Continuing Medical Educationust complete the post-test with a score of �70% andation. To take the post-test for this article you will need.cmeuniversity.com and complete the registration formg process.author disclosure: Please see the Author Disclosuresof this article.eprints: Hunter C. Champion, MD, PhD, FAHA, UPMCal - NW628, 3459 Fifth Avenue, 628 NW, Pittsburgh, PA.: championhc@upmc.edu (H.C. Champion).

see front matter � 2013 Published by Elsevier Inc.0.1016/j.amjcard.2013.01.321

complications such as mechanical malfunction, obstruction,and infection. Although treprostinil has pharmacodynamicssimilar to those of epoprostenol, it can be administeredsubcutaneously or intravenously and has favorable phar-macokinetics, with its longer plasma half-life.1,7,14,15

Although no survival data are available for treprostinil,treatment has been shown to improve New York HeartAssociation/World Health Organization (WHO) functionalclass (FC) in patients with PAH and symptoms as deter-mined by the Borg dyspnea score.1,15e17

Survival data: As noted, IV prostacyclin therapy is theonly treatment of PAH with proven survival benefit in patientswith PAH. In a 12-week, randomized, open-label study, Barstet al2 compared the effects of a continuous IV infusion ofepoprostenol (starting dose 2 ng/kg/min) plus conventionaltherapy (oral vasodilators, anticoagulation) with those ofconventional therapy alone in 81 patients with severe PAH.Compared to conventional therapy alone, the epoprostenolgroup showed significant improvements in the 6-minute walkdistance (6MWD;p¼ 0.002), quality-of-life indexes (p<0.01),and significant reductions in mean pulmonary artery pressure(mPAP; p ¼ 0.002) and pulmonary vascular resistance (p<0.001). Eight patients in the conventional therapy group diedcompared to no deaths in the epoprostenol group during thestudy period (p ¼ 0.003). The primary limitations of the studyand its lack of blinding and placebo control were explained bythe investigators as being necessary for ethical reasons, becauseof the known incidence of sepsis associated with central venouscatheters in control patients and the highly predictable adverseeffects associatedwith long-termepoprostenol therapy (i.e., jawpain, diarrhea). The baseline exercise capacity was slightlypoorer in patients receiving conventional therapy alone than inthe group receiving epoprostenol plus conventional therapy.Although the difference was not statistically significant, it is

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possible that the epoprostenol-treated patients had had lessimpairment before treatment.2

Combination therapy data with IV therapy: Anumberof existing and emerging PAH therapies act by distinct andpotentially complementary mechanisms of action. At least 3mechanistic pathways can be exploited by currently availableFood and Drug Administration-approved agents aimed at thepathobiology of PAH.8e10,13 The rationale for combiningtherapies is rooted in the success of this practice in otherdisease states. The most applicable disease state is heartfailure, in which medications are started in combination andtitrated accordingly. For a number of reasons (i.e., cost, drugdelivery systems, and the stepwise approval by the Food andDrug Administration), the treatment of PAH is almost alwaysstarted with 1 drug, with the advancement of therapy occur-ring by replacing that drug with another. The combination ofthe currently available agents to treat PAH is certainlyattractive and might provide both short-term and long-termbenefits. Several studies noted in the following sections haveattempted to address the efficacy and safety of combinationtherapy for PAH. For this discussion, we have focused on thecombination of prostacyclin therapy with other medications.

The Bosentan Randomized Trial of Endothelin AntagonistTherapy for PAH (BREATHE-2) was the first randomized,double-blind, placebo-controlled trial studying combinationtherapy for PAH and remains the only study published to datethat tested a true combination approach instead of an add-ondesign.17 The study included 33 patients with PAH in NewYork Heart Association FC III or IV who were designated toreceive IV epoprostenol therapy. They were randomized ata 2:1 ratio to either bosentan or placebo combined with epo-prostenol.Although a trend toward improvementwas observedamong the patients receiving combination therapy, no signifi-cant difference was found between the 2 groups in the hemo-dynamics or clinical measures. The total pulmonary resistancedeclined by 41% from baseline to week 16 of treatment (from1,697 � 142 to 1,016 � 78 dyn/s/cm�5) in the bosen-taneepoprostenol group compared to 23% (from 1,628� 154to 1,242 � 153 dyn/s/cm�5) in the placeboeepoprostenolgroup (p ¼ 0.08). The cardiac index increased by 49%in the bosentaneepoprostenol group (vs 38% in theplaceboeepoprostenol group), the mPAP decreased by 9% (vs2%), and the pulmonary vascular resistance declined by 35%(vs 26%). The FC improved in 59% of patients receivingcombination therapy compared to 45% of patients receivingepoprostenol monotherapy. Of potential concern, however,was the occurrence of 2 deaths during the study in the combi-nationgroup and a third death shortly after studywithdrawal forclinicalworsening compared to no deaths or clinicalworseningin the epoprostenol-only arm. In both groups, most of theadverse events were characteristic of epoprostenol infusion,including jaw pain, diarrhea, flushing, and headache. Thebosentaneepoprostenol regimen showed some capacity tolessen the rate of prostanoid side effects: 59% of patientsexperienced jaw pain during bosentaneepoprostenoltherapy compared to 91% of those randomized toplaceboeepoprostenol. Moreover, abnormal hepatic functionwas less frequent in the bosentaneepoprostenol group (9% vs18%). However, lower limb edema (27% vs 9%) and diarrhea(55% vs 27%) were more frequent in the combination group.

Themajor limitation of the studywas that it was not adequatelypowered to show meaningful therapeutic differences.

A retrospective study assessed the utility of adding bosentanto an infused prostanoid therapy in 86 children (BREATHE-3)with PAH.3 These children started treatment with bosentanalone or in addition to pre-existing subcutaneous treprostinil orIV epoprostenol. Of all the patients assessed, the WHO-FCimproved in 46% and stabilized in 44%, and the mPAP (from64 to 57 mm Hg; p ¼ 0.005), and pulmonary vascular resis-tance (from 20 to 15 U/m2; p ¼ 0.01) were improved aftera median of 9 months of therapy. However, the effects ofbosentan were marginal in patients receiving infused prosta-noids: 50% had no change in FC, 35% improved, and 15%deteriorated after a median follow-up of 12 months. Nosignificant changes in hemodynamics were observed.3 Inanother pediatric study, bosentan enabled a reduction in the IVepoprostenol dose, with decreases in prostanoid side effectswithout hemodynamic or clinical compromise in 7 of 8patients. Epoprostenol was successfully discontinued in 3patients in whom the baseline mPAP was normal or nearlynormal. In adult PAH, epoprostenol was successfully transi-tioned to bosentan in 9 of 23 selected patients. In summary,insufficient data are available on the combination of bosentanand IV epoprostenol. Limited clinical evidence is available tosuggest that bosentan has marginal efficacy when given duringor after epoprostenol. In some cases, however, bosentan mightallow for dose reduction or, in patients with near-normalhemodynamics, cessation of epoprostenol.

Sildenafil therapy alone has been suggested to alleviatesymptoms in patients with PAH. In a study from France, thelong-term effects of adding sildenafil to IV therapy withepoprostanol were studied in a 16-week, double-blind trial.Patients with PAH who were receiving IV epoprostanoltherapy (n ¼ 267) were randomly assigned to receive sil-denafil or placebo. The addition of sildenafil improved the6MWD, hemodynamic measurements, and quality of lifebut had no effect on the Borg dyspnea score. Although thecombination of epoprostanol and sildenafil was clinicallyeffective, it produced more headaches and dyspepsia thandid epoprostanol alone.

Registry to Evaluate Early and Long-termPulmonary Arterial Hypertension disease managementdata: The Registry to EValuate Early And Long-termPAH disease management (REVEAL) was established tocharacterize the clinical course, treatment, and predictors ofoutcomes in patients with PAH in the United States.18e21 Inthis, the largest registry of its type involving PAH, it wasobserved that many patients with a PAH diagnosis die fromtheir disease without ever having been treated with IVprostacyclin therapy.22 Although many of the patients hadbeen treated with monotherapy or combination therapy withoral agents, that only 43% of patients were receiving IVprostacyclin therapy at the death is of great concern. Thesedata can be interpreted to mean that worsening PAH/heartfailure was not recognized, and thus, there was no sugges-tion to their physician that advanced therapy was warranted.

When to Initiate IV Therapy

IV prostacyclin therapy initiation has largely been sug-gested when patients exhibit WHO-FC IV symptoms.

Continuing Medical Education/Initiating IV Therapy 23C

Recently, the REVEAL registry proposed a risk calculatorthat can be used at the point of care to determine a patient’s1-year mortality with PAH.19 This prognostic calculator wasdeveloped and validated with data from the REVEALregistry. The calculator provides�19 categories and markersand calculates a risk score ranging from 0 to 22. Thesecategories included the patient’s WHO subgroup, demo-graphics and co-morbidities, functional class, vital signs,6MWD results, brain natriuretic peptide, echocardiographicresults, pulmonary function test results, and hemodynamicdata. Patients with scores of �12 are at the highest estimatedrisk, with a predicted 1-year survival of <70%. With lowerscores, the 1-year mortality risk estimate is less.

Many experts in the field perform this type of calculationsubconsciously. However, with more clinicians treatingPAH, a risk calculator might make them aware of the higherrisk level for a particular patient and might persuade them touse IV therapy earlier in the patient’s treatment. Currently,this calculator is used to validate the response to therapy andshould provide additional evidence for the advancement oftherapy from baseline oral therapies.

Guidelines and Consensus Information

A number of clinical and specialty societies have issuedrecommendations for diagnosing and managing PAH.8e10

In 2009, the European Society of Cardiology set forth theirrecommendations for treating patients with PAH.9 Theclinical, noninvasive, and invasive findings indicated thata patient’s clinical condition can be defined as stable andsatisfactory, stable but not satisfactory, unstable, and dete-riorating. Patients thought to be stable and satisfactorywill fulfill most of the findings associated with a betterprognosis. Specifically, patients who are stable and satis-factory are characterized by an absence of clinical signs ofright ventricular (RV) failure, stable WHO-FC I or IIwithout syncope, a 6MWD >500 m depending on theindividual patient, a peak oxygen consumption >15 mL/min/kg, normal or near normal brain natriuretic peptide/N-terminal probrain natriuretic peptide plasma levels, nopericardial effusion, tricuspid annular plane systolic excur-sion >2.0 cm, right atrial pressure <8 mm Hg, and a cardiacindex >2.5 L/min/m. It has generally been agreed thatpatients with these findings should begin oral or inhaledmonotherapy, with revaluation in 4 to 6 months to determinetreatment success.

To be stable and not satisfactory, a patient would beclinically stable but would not have achieved a status thatthe patient and treating physician would consider desirable.This patient would probably possess some of the featuresdescribed for a stable and satisfactory condition. Thesepatients require frequent re-evaluation (every 1 to 3 months)to evaluate the need for additional therapy. They can startoral or inhaled monotherapy, with the understanding thatfrequent re-evaluation is necessary to address the potentialneed for advancing to combination oral and inhaled therapy.

A patient evaluated de novo and found unstable, or whobecomes unstable because of deterioration, would havefindings consistent with a worse prognosis. In particular, thepatient will be characterized by evidence of progression ofRV failure symptoms and signs, worsening WHO-FC (i.e.,

from II to III or from III to IV), a 6MWD of <300 m, a peakoxygen consumption of <12 mL/min/kg, increasing brainnatriuretic peptide/N-terminal-probrain natriuretic peptideplasma levels or elevated levels from a previous visit,evidence of pericardial effusion, tricuspid annular planesystolic excursion <1.5 cm, right atrial pressure >15 mmHg and increasing, or a cardiac index <2.0 L/min/m2 anddecreasing. The clinical warning signs are increasing edemaand/or the need to escalate diuretic therapy because of RVfailure; new onset or increasing frequency or severity ofangina, which can be a sign of deteriorating RV function;and the onset or increasing frequency of syncope, which isoften a grim prognostic sign and requires immediate atten-tion, because it heralds low output RV failure.

Supraventricular arrhythmias can be seen in thisadvanced condition and can contribute to clinical deterio-ration. In this group of patients, it has been recommendedthat patients be hospitalized for the initiation of IV prosta-cyclin therapy with or without concomitant treatment withoral therapy. If a patient presents in this category or has >3features associated with this category, it would be recom-mended to begin upfront IV prostacyclin therapy.

When to Refer Patients With PAH for AdvancedOptions (Two Approaches)

In the early days of diagnosing and treating PAH, everyfacet was managed at the PAH centers (which tended to belarge academic centers). This was largely because of thelack of understanding of the disease state, the difficulty instarting IV prostaclycins, and the lack of oral therapy at thetime. During the past 15 years, however, the landscape ofPAH has changed, and oral therapies are available to all;more physicians have become familiar with the diseaseitself. PAH is more commonly diagnosed in the communityand therapy routinely offered in the community setting.Although local availability is certainly more convenient forpatients who live at a distance from a pulmonary hyper-tension center, it has also been associated with problems,including a slow response to advancing disease and subse-quent morbidity and mortality; delays in being evaluated forlung or heart/lung transplantation; and not being offeredinclusion into clinical trials.

We believe that involvement with a pulmonary hyper-tension center is very important for both the patient and forsupporting the treating or referring physician. Pulmonaryhypertension centers and community physicians have 2possible options in their partnership for pulmonary hyper-tension diagnosis and treatment: sooner and later.

Early interaction with pulmonary hypertensioncenters: Referring physicians have the option to screentheir patients for PAH and then refer, even before thediagnosis has been confirmed so that the center can facilitatethe diagnostic process. This relationship will (1) helpconfirm the appropriate diagnosis and risk stratification, (2)allow the center to provide suggestions for initial therapyselection, (3) allow the center to have biosamples of thetreatment-naive patient, (4) allow rapid referral to pulmo-nary hypertension centers if the patient’s condition deteri-orates rapidly in the future, and (5) allow evaluation forlung transplant and intervene on relative contraindications

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before the patient’s condition deteriorates. With this, thecommunity physician can interact closely with the center,providing interim care and limit the need for the patient totravel as often to the center.

Later interaction with pulmonary hypertensioncenters: With more community physicians becomingfamiliar with uncomplicated PAH cases, it is not unreasonablefor the physician to diagnose and initiate early therapy witha plan to involve the pulmonary hypertension center at the needfor IV therapy or consideration for transplantation. It is critical,however, that the referring physician work very closely withthe patient to ensure that the patient remains stable.

Working With Centers to Ensure Proper Timing ofReferral for IV Therapy or Transplantation

Regardless of the diagnosis and treatment style desired, itis critical that pulmonary hypertension centers align them-selves with community physicians and groups for a co-management strategy. This will ensure a good line ofcommunication between the two and ensure proper diag-nosis and management.

Acknowledgement

Publication of this supplement was supported by aneducational grant from Gilead Sciences, Inc.

Author Disclosures

The author who contributed to this article has disclosedthe following industry relationships:

Hunter C. Champion, MD, PhD, FAHA, has receivedconsulting fees from Gilead, Bayer, and Pfizer.

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