Updated Treatment Algorithm ofPulmonary Arterial Hypertension

Nazzareno Gali, MD,* Paul A. Corris, MD,y Adaani Frost, MD,z Reda E. Girgis, MD,xJohn Granton, MD,k Zhi Cheng Jing, MD,{ Walter Klepetko, MD,# Michael D. McGoon, MD,**Vallerie V. McLaughlin, MD,yy Ioana R. Preston, MD,zz Lewis J. Rubin, MD,xx Julio Sandoval, MD,kkWerner Seeger, MD,{{ Anne Keogh, MD##Bologna, Italy; Newcastle, England; Houston, Texas; Grand Rapids and Ann Arbor, Michigan;

na;d

y of the treatment algorithm for pulmonary channel blockers (CCBs) for vasoreactive patients, the only

Journal of the American College of Cardiology Vol. 62, No. 25, Suppl D, 2013 2013 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2013.10.031

DownloaPzer, Bayer-Schering, GlaxoSmithKline, and Novartis; has been paid lectures for Eliarterial hypertension (PAH) has progressively increased sincethe 2nd World Symposium on Pulmonary Hypertension(WSPH) in Evian, France in 1998 when, apart from calcium

approved therapywas epoprostenol administered by continuousintravenous infusion (1). Five years later at the 3rdWSPHheldinVenice, Italy, in 2003, the treatment algorithmhad expanded

From the *Department of Experimental, Diagnostic and Specialty Medicine(DIMES), Bologna University Hospital, Bologna, Italy; yInstitute of Cellular Medi-cine Newcastle University and The Newcastle Hospitals NHS Foundation Trust,Newcastle, United Kingdom; zBaylor College of Medicine, Houston, Texas;xMichigan State University, College of Human Medicine, Grand Rapids, Michigan;kDivision of Respirology, University of Toronto, Toronto, Canada; {Fu Wai Hospital& National Center for Cardiovascular Disease Peking Union Medical College andChinese Academy of Medical Science, Beijing, China; #Department of ThoracicSurgery, Medical University Vienna/Vienna General Hospital, Vienna, Austria;**Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota; yyCardiovascularMedicine, The University of Michigan, Ann Arbor, Michigan; zzPulmonary, CriticalCare and Sleep Division, Tufts Medical Center, Tufts University School of Medicine,Boston, Massachusetts; xxMedical School, University of California, San Diego, LaJolla, California; kkClinical Research, National Institute of Cardiology of Mexico,Mexico City, Mexico; {{Max Planck Institute for Heart and Lung Research,Universities of Giessen and Marburg Lung Center, Giessen/Bad Nauheim, Germany;and the ##Heart Transplant Unit, St Vincents Hospital, Sydney, Australia. Dr. Galihas served on the advisory boards of and received paid lectures from Eli Lilly, Actelion,

and Novartis. Dr. Corris has received grant support from Bayer and Actelion; andhonoraria for speaking and chairing meetings for Actelion, Bayer, Pzer, and Glaxo-SmithKline. Dr. Frost has received clinical research grants from Gilead, Actelion,Pzer, GlaxoSmithKline, InterMune, Eli Lilly, United Therapeutics, AIRES,Novartis, Bayer, and IKARIA; has received honoraria for speakers bureau presenta-tions from Actelion, Gilead, United Therapeutics, Bayer, and Pzer; has served on thesteering committee for AIRES, AMBITION (Gilead, GlaxoSmithKline, Eli Lilly);has served on the advisory boards for Bayer, Gilead, and Actelion; has served on thesteering committee for AIRES, IKARIA, Gilead/GlaxoSmithKline, and UnitedTherapeutics/Lung LLC; and has served as a committee member for Entelligence andREVEAL funded by Actelion. Dr. Girgis has served on the speakers bureau for Bayer;and is a consultant for Gilead. Dr. Granton has received support for investigator-ledresearch from Actelion, Bayer, GlaxoSmithKline, Lilly, United Therapeutics, Ikaria,and Pzer; has received honoraria directed to his institution for consultant work fromActelion, Eli Lilly, GlaxoSmithKline, Ikaria, and Bayer; his institution has receivedsupport for their foundation from Actelion, Bayer, and Lilly; and has received unre-stricted support for investigator-led research from Actelion and Pzer/CIHR grant(Canadian Institute for Health Research). Dr. Jing has served as a consultant, memberof scientic advisory boards, and investigator and speaker in trials for Actelion, BayerThe complexitLilly and Compainstitutional grant

ded From: httpconicting. The treatment algorithm usually includes different types of recommendations with varying degrees ofscientic evidence. In addition, the algorithm is required to be comprehensive but not too complex, informative yetsimple and straightforward. The type of information in the treatment algorithm are heterogeneous including clinical,hemodynamic, medical, interventional, pharmacological and regulatory recommendations. Stakeholders (or users)including physicians from various specialties and with variable expertise in PAH, nurses, patients and patientsassociations, healthcare providers, regulatory agencies and industry are often interested in the PAH treatmentalgorithm for different reasons. These are the considerable challenges faced when proposing appropriate updates tothe current evidence-based treatment algorithm.The current treatment algorithm may be divided into 3 main areas:1) general measures, supportive therapy, referral strategy, acute vasoreactivity testing and chronic treatment withcalcium channel blockers; 2) initial therapy with approved PAH drugs; and 3) clinical response to the initial therapy,combination therapy, balloon atrial septostomy, and lung transplantation. All three sections will be revisitedhighlighting information newly available in the past 5 years and proposing updates where appropriate. The EuropeanSociety of Cardiology grades of recommendation and levels of evidence will be adopted to rank the proposedtreatments. (J Am Coll Cardiol 2013;62:D6072) 2013 by the American College of Cardiology FoundationThe demands on a pulmonary arterial hypertension (PAH) treatment algorithm are multiple and in some waysRochester, Minnesota; Toronto, Canada; Beijing, ChiLa Jolla, California; Mexico City, Mexico; Giessen/Bany, Pzer, Bayer-Schering, and GlaxoSmithKline; and receivedsupport from Actelion, Pzer, Bayer-Schering, GlaxoSmithKline,

://content.onlinejacc.org/ on 04/16/2014Vienna, Austria; Boston, Massachusetts;Nauheim, Germany; and Sydney, AustraliaSchering, Pzer, GlaxoSmithKline, and United Therapeutics. Dr. McGoon hasreceived grant support directed at his institution for investigator-led research from

to 5 compounds belonging to 3 pharmacological classes, pro-stanoids, endothelin receptor antagonists (ERA), and phos-phodiesterase type 5 inhibitors (PDE-5i), and included 4different routes of administration (oral, inhaled, subcutaneous,and intravenous) (2). In 2008 the 4thWSPHwas held inDanaPoint, California, and the treatment algorithm included 4additional compounds (1 of them, the ERA sitaxentan, waseventually withdrawn) (3,4). Although this progress in phar-macotherapy has been associated in different meta-analyseswith a reduction of morbidity and mortality (5,6), limitingsymptoms and poor outcome still characterize patients withPAH. Further advances observed in different areas of PAHtreatment in the past 5 years and the evolution of the treatmentalgorithm discussed and updated at the 5th WSPH held in

hat patients should avoids to distressing symptoms,may undertake supervisedbased on a randomizedstrated an improvement inin quality of life in patientsprogram as comparedwithce then, additional uncon-hese data utilizingdifferentwo additional RCTs havened PAHpatients reacheddecreased fatigue severity,

tance (6MWD), cardiore-eported quality of life as14,15). The sample size ofranging from 19 to 183as highly supervised and inn-patient setting. Despitecordance of the results andggest the upgrading of theand exercise training to.

JACC Vol. 62, No. 25, Suppl D, 2013December 24, 2013:D6072

DownloaNice, France, from February 27 to March 1, 2013, will bepresented here.The current treatment algorithm may be divided into 3

main areas: 1) general measures (rehabilitation/exercise andexercise training, psychosocial support, pregnancy, vaccina-tions), supportive therapy (anticoagulants, diuretics, digitalis,oxygen), the roles of referral centers, acute vasoreactivitytesting, and chronic CCB therapy; 2) information about theinitial therapy and includes all drugs approved in any countryaccording to the World Health Organization functionalclass (WHO-FC) of the patients and the grade of recom-mendation and level of evidence of each individual compound;and 3) the clinical response to the initial therapy and in caseof inadequate results, the recommendations/role of combi-nations of approved drugs and additional interventionalprocedures such as balloon atrial septostomy and lungtransplantation.All 3 sections will be revisited, highlighting the new

information collected in the past 5 years and proposingupdates where appropriate.The European Society of Cardiology grades of recom-

mendation and levels of evidence will be adopted to scorethe proposed treatments (Tables 1 and 2) (4).The new proposed treatment algorithm is shown in

Figure 1.

Medtronic and Gilead; has participated in speaking activities for Actelion and Gilead(funded conferences, not speakers bureaus); has served as a consultant to Pharma andActelion; has served as the chair of the REVEAL Registry; on the data adjudicationcommittees for Gilead; and on the advisory committee for Lung LLC and Glaxo-SmithKline. Dr. McLaughlin has served on the speakers bureau for Gilead and UnitedTherapeutics; has served as a consultant or member of the advisory board/steeringcommittee for Actelion, Bayer, Gilead, United Therapeutics; and has received insti-tutional grant/research support from Actelion, Bayer, Lkana, and Novartis. Dr. Prestonhas received research grants from Actelion, Bayer, Gilead, United Therapeutics,Novartis, GeNO, and AIRES; and has served as a consultant for Actelion, Bayer,Gilead, and United Therapeutics. Dr. Rubin has a relationship with United Thera-peutics, Bayer, GeNO, NHLBI, FDA, Actelion, Lung LLC, Gilead, Reata Phar-maceuticals, Arena Pharmaceuticals, and AIRES. Dr. Sandoval has received honorariaand lecture fees from Bayer Schering. Dr. Seeger has received speaker fees from Pzerand Bayer HealthCare; and is a consultant for Bayer Pharma AG. Dr. Keogh has servedas a clinical trialist for Actelion, Aires, Bayer, GlaxoSmithKline, Pzer, Novartis,Arena, and United Therapeutics; has served on the advisory board for Actelion, Bayer,and GlaxoSmithKline; and has served on the speakers bureau for Actelion, Bayer, and

GlaxoSmithKline. All other authors have reported that they have no relationshipsrelevant to the contents of this paper to disclose.Manuscript received October 11, 2013; accepted October 22, 2013.

ded From: http://content.onlinejacc.org/ on 04/16/2014patients should be encouraged tolimits (4). It was recommended texcessive physical activity that leadbut when physically deconditionedexercise rehabilitation. This wascontrolled trial (RCT) that demonexercise and functional capacity andwithPHwho took part in a traininga control untrained group (8). Sintrolled experiences have supported tmodels of exercise training (913). Talso been published reports that traihigher levels of physical activity, hadshowed improved 6-min walk disspiratory function, and patient-rcompared with untrained controls (all these studies is quite small (patients), and all or initial trainingwsome instances conducted in an ithese limitations, however, the conthe overall publication of 3 RCTs surecommendation for rehabilitationClass I with a Level of Evidence: AGeneral Measures,Supportive Therapy,Referral Centers, andVasoreactivity Test

General measures. In thissection new information isprovided for pregnancy, rehabil-itation, and exercise training.

PREGNANCY. Pregnancy remainsassociated with a substantialmortality rate in PAH. However,a recent report indicates that theoutcome of pregnancies in PAHhas improved, at leastwhenPAHiswell controlled and particularly inlong-term responders to CCBs (7).During a 3-year period, the 13participating centers reported 26pregnancies. Three women (12%)died and 1 (4%) developed rightheart failure requiring urgent heart-lung transplantation. There were 8 abortions: 2 spontaneous and6 induced. Sixteen pregnancies (62%) were successful (i.e., thewomen delivered healthy babies without complications). Thesedata must be conrmed by larger series before the generalrecommendation to avoid pregnancy in all patients with PAH isreconsidered (gradeof recommendation I,Level ofEvidence:C).

REHABILITATION AND EXERCISE TRAINING. The 2009pulmonary hypertension (PH) guidelines suggested that PAH

be active within symptom

Abbreviationsand Acronyms

APAH = associated

pulmonary arterial

hypertension

BAS = balloon atrial

septostomy

CCB = calcium channel

blocker

ERA = endothelin receptor

antagonist

PAH = pulmonary arterial

hypertension

PVR = pulmonary vascular

resistance

RCT = randomized controlled

trials

6MWD = 6-min walk

distance

WHO-FC = World Health

Organization Functional

Class

Gali et al.Treatment Algorithm of Pulmonary Arterial Hypertension

D61The limitations of this recommendation are based on thegaps in knowledge of the optimal method, intensity, and

nitionSuggested Wording

to Use

ent that a given treatment orl, effective.

Is recommended,Is indicated

ivergence of opinion aboutgiven treatment

fav

esta

thattive,

JACC Vol. 62, No. 25, Suppl D, 2013December 24, 2013:D6072

Downloaduration of the training. In addition, neither the character-istics of the supervision and the mechanisms for theimprovement of symptoms, exercise, and functional capacitynor the possible effects on prognosis are clear. Exercisetraining programs should be implemented by centers expe-rienced in both PAH patient care and rehabilitation ofcompromised patients.Supportive therapy. No major new information is availableon anticoagulants, diuretics, digitalis, and oxygen, and nochanges in the recommendations are proposed (4). Long-term oxygen therapy is suggested to maintain arterialblood O2 pressure 8 kPa (60 mm Hg).Referral centers and vasoreactivity testing. PAH is a rarechronic progressive condition that is lethal, disabling, costly,and treatable. High-volume specialized centers have beenrecurrently shown to obtain the best outcomes for patientsin different areas of medicine while maintaining greatestpatient satisfaction, lowest complication rates, shortest lengthof hospital stay and best value for healthcare payers (16).Suggestions on possible models of emergency treatments (17)and a survey on PAH care organization in developed coun-tries have been published (18). The recommendation to referpatients after PAH diagnosis to expert centers is maintained.Acute vasoreactivity testing remains mandatory in patients

with idiopathic PAH to identify subjects that will respondfavorably to long-term treatment with high doses ofcalcium-channel blockers. Inhaled nitric oxide (iNO) is thecompound of choice for the acute test and, on the basis of

or procedure.

Class IIa Weight of evidence/opinion is in

Class IIb Usefulness/efcacy is less well

Class III Evidence or general agreementprocedure is not useful/ effecbe harmful.Table 1 Classes of Recommendations

Class ofRecommendations De

Class I Evidence and/or general agreemprocedure is benecial, usefu

Class II Conicting evidence and/or a dthe usefulness/efcacy of the

Gali et al.Treatment Algorithm of Pulmonary Arterial Hypertension

D62previous experience, intravenous epoprostenol or adenosinemay also be used as an alternative (but with a risk of systemicvasodilator effects) (4). More recently, inhaled iloprost hasbeen able to identify patients who may benet from long-term therapy with CCBs (19).

Initial Therapy With PAH-Approved Drugs

Therapy with PAH-approved drugs needs to be initiated inPAH patients who are not vasoreactive or are vasoreactive butnot responding appropriately to CCBs (Fig. 1). For the initialtherapy, drugs are classied according to the grade ofrecommendation (Table 1) and the level of evidence (Table 2)on the basis of published RCTs. In addition, initial drugtherapies are also stratied according to WHO-FC.

ded From: http://content.onlinejacc.org/ on 04/16/2014Individual compounds. A summary of the RCTs per-formed in PAH for each compound is shown in Tables 36on the basis of the related pathobiological pathway. Thetable also includes nonapproved drugs for PAH or drugs stillunder regulatory consideration at the time of this publica-tion. Pharmacological classes and drugs are listed in alpha-betical order. Only compounds approved for PAH or underregulatory approval process are included in the treatmentalgorithm and are listed in alphabetical order (Fig. 1).A brief description of the compounds, according to their

pharmacological class, is provided subsequently.Endothelin pathway. Activation of the endothelin systemhas been demonstrated in the plasma and lung tissue ofPAH patients (20). Although it is not clear if the increasesin endothelin plasma levels are a cause or a consequence ofPH (21), these data support a prominent role for theendothelin system in the pathogenesis of PAH (22).Endothelin receptor antagonists. Endothelin exertsvasoconstrictor and mitogenic effects by binding to 2distinct receptor isoforms in the pulmonary vascular smoothmuscle cells, endothelin-A and -B receptors. Endothelin-Breceptors are also present in endothelial cells, and theiractivation leads to release of vasodilators and antiproliferativesubstances such as NO and prostacyclin that may counter-balance the deleterious effects of endothelin-1. Despitepotential differences in receptor isoform activity, the efcacyin PAH of the dual endothelin-A and -B receptor antago-nist drugs and of the selective endothelin-A receptor

or of usefulness/efcacy. Should be considered

blished by evidence/opinion. May be considered

the given treatment orand in some cases may

Is not recommendedantagonist compounds appear to be comparable.

AMBRISENTAN. Ambrisentan is a nonsulfonamide, propanoicacid class, ERA that is selective for the endothelin-A receptor.Ambrisentan has been evaluated in a pilot study (23) and

Table 2 Levels of Evidence

Level Denition

A Data derived from multiple randomized clinical trials or meta-analyses

B Data derived from a single randomized clinical trial or largenonrandomized studies

C Consensus of opinion of the experts and/or small studies,retrospective studies, registries

Results on the basis of post-hoc and subgroup analyses of clinical trials most often do not meet thecriteria of a level of evidence A.

DownloaJACC Vol. 62, No. 25, Suppl D, 2013December 24, 2013:D6072in 2 large RCTs (ARIES [Ambrisentan in pulmonaryarterial hypertension, Randomized, double-blind, placebo-controlled, multicentre, Efcacy Study]-1 and -2), whichhave demonstrated efcacy on symptoms, exercise capacity,

Figure 1 Evidence-Based Treatment Algorithm

APAH associated pulmonary arterial hypertension; BAS balloon atrial septostomy; CCBguanylate cyclase stimulators; IPAH idiopathic pulmonary arterial hypertension; i.v. iWHO-FC World Health Organization functional class.

ded From: http://content.onlinejacc.org/ on 04/16/2014Gali et al.Treatment Algorithm of Pulmonary Arterial Hypertension

D63hemodynamics, and time to clinical worsening of patientswith idiopathic PAH and PAH associated with connectivetissue disease and human immunodeciency virus infection(24). Ambrisentan has been approved for the treatment of

calcium channel blockers; ERA endothelin receptor antagonist; sGCS solublentravenous; PDE-5i phosphodiesterase type-5 inhibitor; s.c. subcutaneous;

Table 3Characteristics of Randomized Controlled Trials With Pulmonary Arterial Hypertension Drugs Interfering With theEndothelin Pathway (See Text for References)

Drug(s) Tested Study Background Primary Endpoint Outcome (Secondary Endpoint) Duration (weeks) No. of Patients

Ambrisentan ARIES-1 No 6MWD TTCW (NS) 12 202

ARIES-2 No 6MWD TTCW 12 192

Bosentan Study-351 No 6MWD TTCW 12 32

BREATHE-1 No 6MWD TTCW 16 213

BREATHE-2* No PVR d 12 33

EARLY No Sildenal (16%) PVR, 6MWD TTCW 24 185

BREATHE-5 No SaO2, PVR d 12 54

Macitentany SERAPHIN No, PDE5i or Inhal iloprost TTCW Safety 100 742

*Bosentan epoprostenol versus placebo epoprostenol. yApproved by the FDA for PAH patients and has obtained at the time of printing the positive opinion of the Committee for Medicinal Products forHuman Use of the the EMA for this indication.

phod

Gali et al. JACC Vol. 62, No. 25, Suppl D, 2013Treatment Algorithm of Pulmonary Arterial Hypertension December 24, 2013:D6072

D64

DownloaWHO-FC II and III patients. The incidence of abnormalliver function tests range from 0.8% to 3%. No tendency fordevelopment of abnormal liver function tests was observed inpatients who had previously demonstrated abnormalitieswhile on other ERA, andmonthly liver function assessment isnot mandated in the United States (25). An increased inci-dence of peripheral edema has been reported with ambri-sentan use. Ambrisentan is approved for PAH patients.

BOSENTAN. Bosentan is anoral activedual endothelin-Aand -Breceptor antagonist and the rst molecule of its class to besynthesized. Bosentan has been evaluated in PAH (idio-pathic, associated with connective tissue disease and Eisen-mengers syndrome) in 5 RCTs (Study-351, BREATHE[Bosentan Randomised trial of Endothelin AntagonistTHErapy]-1, BREATHE-2, BREATHE-5, and EARLY[Endothelin Antagonist tRial in mildLY symptomaticpulmonary arterial hypertension patients]), which showedimprovement in exercise capacity, functional class, hemody-namics, echocardiographic and Doppler variables, and timeto clinical worsening (2630). Increases in hepatic amino-transferases occurred in approximately 10%of the subjects butwere found to be dose-dependent and reversible after dosereduction or discontinuation. For these reasons, liver function

6MWD 6-min walk distance; inhal inhalation; NS not statistically signicant; PDE5i phosTTCW time to clinical worsening.testing should be performed monthly in patients receivingbosentan. Bosentan is approved for PAH patients.

Table 4Characteristics of Randomized Controlled Trials With PulmoNitric Oxide Pathway (See Text for References)

Drug(s) Tested Study Background Primary Endpoin

Soluble Guanylate Cyc

Riociguat* PATENT No bosentan or prostanoids 6MWD

Phosphodiesterase T

Sildenal SUPER-1 No 6MWD

Sastry No TT

Singh No 6MWD

PACES Epoprostenol 6MWD

Iversen Bosentan 6MWD

Tadalal PHIRST No or bosentan (54%) 6MWD

Vardenaly EVALUATION No 6MWD

*Approved by the FDA for PAH and CTEPH patients and is currently undergoing the regulatory approvalTT treadmill test; other abbreviations as in Table 3.

ded From: http://content.onlinejacc.org/ on 04/16/2014MACITENTAN. The dual ERA macitentan was developedby modifying the structure of bosentan to increase efcacyand safety. Macitentan is characterized by sustained receptorbinding and enhanced tissue penetration. In the event-driven SERAPHIN (Study with an Endothelin ReceptorAntagonist in Pulmonary Arterial Hypertension to ImproveClinical Outcome) study (31), 742 PAH patients weretreated with 3 or 10 mg macitentan as compared withplacebo for an average of 100 weeks. The primary endpointwas the time from the initiation of treatment to the rstoccurrence of a composite endpoint of death, atrial septos-tomy, lung transplantation, initiation of treatment withintravenous or subcutaneous prostanoids, or worsening ofPAH. Macitentan signicantly reduced this compositeendpoint of morbidity and mortality among patients withPAH and also increased exercise capacity. Benets wereshown both for patients who had not received treatmentpreviously and for those receiving background therapy forPAH. While no liver toxicity was shown, reduction in bloodhemoglobin 8 g/dl was observed in 4.3% of patientsreceiving 10 mg of macitentan. Macitentan is approvedby the U.S. Food and Drug Administration (FDA) for PAHpatients and has obtained at the time of printing the positiveopinion of the Committee for Medicinal Products for

iesterase type-5 inhibitors; PVR pulmonary vascular resistance; SaO2 nger oxygen saturation;Human Use of the European Medicines Agency (EMA) forthis indication.

nary Arterial Hypertension Drugs Interfering With the

t Outcome (Secondary Endpoint) Duration (weeks) No. of Patients

lase Stimulators

TTCW 12 443

ype-5 Inhibitors

TTCW (NS) 12 277

d 12 22

d 6 20

TTCW 16 264

d 12 20

TTCW 16 405

TTCW 12 66

process by the EMA for both indications. yNot approved for pulmonary arterial hypertension.

Nitric oxide pathway. Impairment of NO synthesis andsignaling through the NOsoluble guanylate cyclase (sGC)cyclic guanosine monophosphate (cGMP) pathway isinvolved in the pathogenesis of pulmonary hypertension.Soluble guanylate cyclase stimulators. While PDE-5is,such as sildenal, tadalal, and vardenal, enhance theNOcGMP pathway, slowing cGMP degradation, sGCstimulators enhance cGMP production and are potentiallyeffective also in conditions in which endogenous NO is

common serious adverse event in the placebo group andthe 2.5 mg group was syncope (4% and 1%, respectively).The combination of riociguat and PDE-5i is contra-indicated due to hypotension and other relevant side effectsdetected in the open-label phase of the PATENT-plusstudy (34). Riociguat is approved by the FDA for PAHand chronic thromboembolic pulmonary hypertension(CTEPH) patients and is currently undergoing the regu-latory approval process by the EMA for both indications.

lmo

tano

Table 5Characteristics of Randomized Controlled Trials With Pulmonary Arterial Hypertension Drugs Interfering With thePlatelet-Derived Growth Factor Pathway (See Text for References)

Drug(s)Tested Study Background Primary Endpoint

Outcome(Secondary Endpoint)

Duration(weeks)

No. ofPatients

Tyrosine kinase inhibitor imatinib* Phase 2 Bosentan and/or sildenal and/orprostanoids

6MWD (NS) d 24 59

IMPRES Bosentan and/or sildenal and/orprostanoids

6MWD TTCW (NS) 24 202

*Not approved for pulmonary arterial hypertension.Abbreviations as in Table 3.

JACC Vol. 62, No. 25, Suppl D, 2013 Gali et al.December 24, 2013:D6072 Treatment Algorithm of Pulmonary Arterial Hypertension

D65

Downloadepleted (32). Pre-clinical studies with sGC stimulatorshave shown antiproliferative and antiremodeling propertiesin various animal models.

RIOCIGUAT. Riociguat has a dual mode of action, actingin synergy with endogenous NO and also directly stimu-lating sGC independent of NO availability. An RCT(PATENT [Pulmonary Arterial Hypertension SolubleGuanylate CyclaseStimulator Trial]-1) (33) in 443 PAHpatients (44% and 6% on background therapy with ERAor prostanoids, respectively) treated with riociguat up to2.5 mg 3 times daily has shown favorable results on exercisecapacity, hemodynamics, WHO-FC, and time to clinicalworsening. The increase in exercise capacity was alsodemonstrated in patients on background therapy. The most

Table 6Characteristics of Randomized Controlled Trials With PuProstacyclin Pathway (See Text for References)

Drug(s) Tested Study Background

Pros

Beraprost ALPHABET No

Barst No

Epoprostenol Rubin NoBarst No

Badesch No

Iloprost AIR No

STEP Bosentan

COMBI Bosentan

Treprostinil SC- Simonneau No

Inhal TRIUMPH Bosentan or Sildenal

PO- Freedom M No

PO- Freedom C1 Bosentan and/or sildenal

PO- Freedom C2 Bosentan and/or sildenal

Prostacyclin IP-rece

Selexipag* Phase 2 Bosentan and/or sildenal

*Not approved for pulmonary artery hypertension.CW clinical worsening; FC Functional Class; inhal inhalation; PO oral; SC subcutaneous; o

ded From: http://content.onlinejacc.org/ on 04/16/2014PDE-5is. Inhibition of the cyclic guanosine mono-phosphate degrading enzyme PDE-5 results in vasodilationthrough the NO/cGMP pathway at sites expressing thisenzyme. Because the pulmonary vasculature containssubstantial amounts of PDE-5 the potential clinical benetof PDE-5 has been investigated in PAH. In addition,PDE-5i exerts antiproliferative effects (35,36). All 3 PDE-5is approved for the treatment of erectile dysfunction, sil-denal, tadalal, and vardenal cause signicant pulmonaryvasodilation with maximum effects observed after 60, 75 to90, and 40 to 45 min, respectively (37).

SILDENAFIL. Sildenal is an orally active, potent, andselective PDE-5i. Five RCTs in PAH patients treated withsildenal have conrmed favorable results on exercise

nary Arterial Hypertension Drugs Interfering With the

PrimaryEndpoint

Outcome(Secondary Endpoint)

Duration(weeks)

No. ofPatients

ids

6MWD d 12 130

CW (NS) d 52 116

6MWD d 12 236MWD Survival 12 81

6MWD d 12 111

6MWD and FC d 12 203

6MWD TTCW 12 67

6MWD (NS) d 12 40

6MWD d 12 470

6MWD d 12 235

6MWD d 16 185

6MWD (NS) d 16 354

6MWD (NS) d 16 310

ptor Agonists

PVR 6MWD (NS) 17 43

ther abbreviations as in Table 3.

Downloacapacity, symptoms, and/or hemodynamics (3841). ThePACES (Pulmonary Arterial hypertension Combinationstudy of Epoprostenol and Sildenal) trial addressing theeffects of adding sildenal to epoprostenol showedimprovements after 12 weeks in 6MWD and time to clinicalworsening. Of note, 7 deaths occurred in this trial, all in theplacebo group (42). The approved dose of sildenal is 20 mgthree times daily. Most side effects of sildenal are mild tomoderate and mainly related to vasodilation (headache,ushing, epistaxis). On the basis of pharmacokinetic data anintravenous formulation of sildenal (43) has been approvedby the FDA and EMA as a bridge for PAH patients onlong-term oral treatment who are temporarily unable toingest tablets. Sildenal is approved for PAH patients.

TADALAFIL. Tadalal is a once daily dispensed, selectivePDE-5i. An RCT (PHIRST [Pulmonary arterial Hyper-tension and ReSponse to Tadalal] trial) in 406 PAHpatients (53% on background bosentan therapy) treatedwith tadalal 2.5, 10, 20, or 40 mg once daily has shownfavorable results on exercise capacity, symptoms, hemody-namics, and time to clinical worsening at the highest dose(44). The side effect prole was similar to that of sildenal.Tadalal is approved for PAH patients.

VARDENAFIL. Vardenal is a twice daily dispensed PDE-5i.An RCT (EVALUATION [Efcacy and Safety of Varde-nal in the Treatment of Pulmonary Arterial Hypertension])in 66 treatment naive PAH patients treated with vardenal5 mg twice daily has shown favorable results on exercisecapacity, hemodynamics, and time to clinical worsening(45). The side effect prole was similar to that of sildenal.Vardenal is currently not approved for PAH patients.

Table 7Survival After Lung Transplantation in Patients WithPulmonary Arterial Hypertension

1 year 5 years 10 years

Pittsburgh (Toyoda et al., 2008 [74]) 86 75 66

Paris (Fadel et al., 2010 [75]) 79 52 43

Toronto (de Perrot et al., 2012 [76]) 78 60 45

Vienna (Klepetko, unpublisheddata, 2011)

73 71 d

Gali et al.Treatment Algorithm of Pulmonary Arterial Hypertension

D66Platelet-derived growth factor pathway. Proliferation ofendothelial cells and vascular smooth muscle cells withnarrowing or occlusion of the vessel lumen is a histopatho-logical hallmark of the distal pulmonary arteries in PAHpatients. Evidence from animal models and human diseasesuggest that platelet-derived growth factor and c-KITsignaling are important in vascular smooth muscle cellproliferation and hyperplasia.Tyrosine kinase inhibitors. IMATINIB. Imatinib is anantiproliferative agent developed to target the Bcr-Abltyrosine kinase in patients with chronic myeloid leukemia.In addition, the inhibitory effects of imatinib on platelet-derived growth factor receptors and c-KIT suggest that it

ded From: http://content.onlinejacc.org/ on 04/16/2014may be efcacious in PAH. Two RCTs on PAH patientstreated with imatinib (all of them on background therapywith at least 2 PAH-approved drugs) have shown positiveresults on exercise capacity and hemodynamics (data possiblyinuenced by the drop-out rate in the treated group), butfailed to show favorable effects on time to clinical worsening(46,47). In addition, an increased incidence of subduralhematoma was observed in PAH patients treated with bothimatinib and oral anticoagulants. Regulatory considerationof imatinib for the PAH indication has recently been halted.Prostacyclin pathway. Prostacyclin is produced predomi-nantly by endothelial cells and induces potent vasodilation ofall vascular beds and in addition is an inhibitor of plateletaggregation and it also appears to have both cytoprotectiveand antiproliferative activities (48). Dysregulation of theprostacyclin metabolic pathways has been shown in patientswith PAH as assessed by reduction of prostacyclin synthaseexpression in the pulmonary arteries and of urinary metab-olites of prostacyclin (49,50).Prostanoids. The clinical use of prostacyclin in patientswith PAH has been extended by the synthesis of stableanalogues.

BERAPROST. Beraprost is the rst chemically stable andorally active prostacyclin analogue. The RCT ALPHABET(Arterial Pulmonary Hypertension And Beraprost Euro-pean Trial) (51) in Europe and a second study in the UnitedStates (52) with this compound have shown an improvementin exercise capacity, which unfortunately persists only up to3 to 6 months. There were no hemodynamic benets. Themost frequent adverse events were headache, ushing,jaw pain, and diarrhea. Beraprost is approved for PAH inJapan and South Korea.

EPOPROSTENOL. Epoprostenol (synthetic prostacyclin) hasa short half-life (3 to 5 min) and is stable at room temper-ature for only 8 h requiring cooling, continuous adminis-tration by means of an infusion pump and a permanenttunneled catheter. The efcacy of continuous intravenous(IV) administration of epoprostenol has been tested in 3unblinded RCTs in patients with idiopathic PAH (53,54)and in those with PAH associated with the sclerodermaspectrum of diseases (55). Epoprostenol improves symp-toms, exercise capacity, and hemodynamics in both clinicalconditions, and is the only treatment shown to reducemortality in idiopathic PAH in a randomized study (54).The meta-analysis for total mortality of the 3 epoprostenolRCTs (5355) performed with the MantelHaenszel andthe Peto xed-effect methods showed a relative risk(RR) reduction of 70% (z 2.35, p 0.019, heterogeneityp 0.182) and 68% (z 2.52, p 0.012, heterogeneityp 0.153), respectively (Fig. 2). Serious adverse eventsrelated to the delivery system include pump malfunction,local site infection, catheter obstruction, and sepsis. Intra-venous epoprostenol is approved for PAH patients. A

JACC Vol. 62, No. 25, Suppl D, 2013December 24, 2013:D6072thermostable formulation of epoprostenol is approved in theUnited States, Canada, Japan and in most of the European

countries and does not require cooling packs to maintainstability beyond 8 to 12 h.

ILOPROST. Iloprost is a chemically stable prostacyclinanalogue available for intravenous, oral, and inhaledadministration. Inhaled iloprost has been evaluated in 1RCT (AIR [Aerosolized Iloprost Randomized] study) inwhich daily repetitive iloprost inhalations (6 to 9 times, 2.5to 5 mg/inhalation, median 30 mg daily) were comparedwith placebo inhalation in patients with PAH and CTEPH(56). The study showed an increase in exercise capacity andimprovement in symptoms, pulmonary vascular resistance(PVR) and clinical events in enrolled patients. Two addi-tional RCTs (STEP [Safety and pilot efcacy Trial ofinhaled iloprost in combination with bosentan for Evalua-tion in Pulmonary arterial hypertension] and COMBI[COMbination therapy of Bosentan and aerosolized Iloprostin idiopathic pulmonary arterial hypertension]) of patientsalready treated with bosentan have shown conicting resultsof the addition of inhaled iloprost (57,58). Overall, inhalediloprost was well tolerated with ushing and jaw pain beingthe most frequent side effects. Continuous IV administra-tion of iloprost appears to be as effective as epoprostenol ina small uncontrolled series of patients with PAH andCTEPH (59). Inhaled iloprost is approved for PAH. TheIV formulation is approved for PAH in New Zealand.

TREPROSTINIL. Treprostinil is a tricyclic benzidine analogueof epoprostenol, with sufcient chemical stability to beadministered at ambient temperature. These characteristicsallow administration of the compound by the IV as wellas the subcutaneous and oral route. The subcutaneousadministration of treprostinil can be accomplished by amicroinfusion pump and a small subcutaneous catheter.The effects of treprostinil in PAH were studied in an RCTand showed improvements in exercise capacity, hemody-namics, and symptoms (60). Infusion site pain was the mostcommon adverse effect of treprostinil, leading to discon-tinuation of the treatment in 8% of cases on active drug andlimiting dose increase in an additional proportion of patients(60). An RCT was performed with intravenous treprostinilin PAH patients (TRUST [Multicenter, Randomized,Double-Blind, Placebo-Controlled Trial Compared Con-tinuous IV Treprostinil to Placebo in PAH Patients]) butthe enrollment of this trial was closed after 45 (36%) of theplanned 126 patients had been randomized because of safetyconsiderations (61). The data generated from 31 (25%)survivors after the randomized phase (23 active and 8placebo) are not considered reliable and the study is notincluded in Table 6.An RCT (TRIUMPH [inhaled TReprostInil sodiUM

in Patients with severe Pulmonary arterial Hypertension])with inhaled treprostinil in PAH patients on background

iesy M

ive r

JACC Vol. 62, No. 25, Suppl D, 2013 Gali et al.December 24, 2013:D6072 Treatment Algorithm of Pulmonary Arterial Hypertension

D67

DownloaFigure 2Meta-Analysis of Published Randomized Controlled StudWith Epoprostenol in Pulmonary Arterial Hypertension b

The analysis included 215 patients in 3 trials. The gure shows the cumulative relatgroups. An overall reduction of the risk of mortality of 70% (p 0.019) and 68% (o 0.0interval; OR odds ratio.

ded From: http://content.onlinejacc.org/ on 04/16/2014(Identied by First Author and Year of Publication)antelHaenszel and Peto Methods

isk (RR) estimate of death in active treatment groups when compared with control

12) is shown with MantelHaenszel and Peto methods, respectively. CI condence

Downloatherapy with either bosentan or sildenal showed improve-ments in 6MWD by 20 m at peak dose, N-terminal proB-type natriuretic peptide (NT-proBNP) and quality-of-lifemeasures (62).Oral treprostinil has been evaluated in 2 RCTs in PAH

patients on background therapy with bosentan and/or sil-denal (FREEDOM [Multicenter, Double-101 Blind,Randomized, Placebo-Controlled Study of the Efcacy andSafety of Oral treprostinil Sustained Release Tablets inSubjects With Pulmonary Arterial Hypertension] C1 andC2) and in both the primary endpoint 6MWD did not reachstatistical signicance (63,64). An additional RCT in PAHnaive patients showed improvement in 6MWD by 26 m atpeak dose (65). Subcutaneous treprostinil is approved forPAH. Intravenous treprostinil is approved in the UnitedStates and European Union in patients with PAH whocannot tolerate the subcutaneous administration (based onbioequivalence). Inhaled treprostinil is approved for PAH inthe United States. Oral treprostinil is currently not approvedfor PAH.Prostacyclin IP-receptor agonists. SELEXIPAG. Selexipagis an orally available, selective prostacyclin IP receptor agonist.Although selexipag and its metabolite have modes of actionsimilar to that of endogenous prostacyclin (IP receptor ago-nism), they are chemically distinct from prostacyclin witha different pharmacology. In a pilot RCT in PAH patients(receiving stable ERA and/or a PDE-5i therapy) selexipagreduced PVR after 17 weeks (66). A large event-driven phase3 RCT (GRIPHON [Prostocyclin (PGI2) Receptor Agonistin Pulmonary Arterial Hypertension] trial) is currentlyongoing. Selexipag is currently not approved for PAH.

Clinical Response, Combination Therapy,and Interventional Procedures

After initial therapy, the next steps are based on the clinicalresponse, which is usually reassessed at 3 to 6 months aftertreatment start.The clinical response is based on the evaluation of

different parameters including WHO-FC, exercise capacity,cardiac index, right atrial pressure, NT-proBNP plasmalevels, echocardiographic parameters, and perceived needfor additional/change of therapy. The exact denition ofclinical response is addressed in another paper of thissupplement and is beyond the scope of this paper.If the clinical response is considered not adequate,

combination therapy is considered.Combination therapy. Combination therapydusing 2 ormore classes of drugs simultaneouslydhas been usedsuccessfully in the treatment of systemic hypertension andheart failure. It is also an attractive option for the manage-ment of PAH, because 3 separate signaling pathways areknown to be involved in the disease: the prostacyclinpathway, the endothelin pathway, and the NO pathway.

Gali et al.Treatment Algorithm of Pulmonary Arterial Hypertension

D68In Tables 3 to 6, 13 (43%) of the RCTs performed inPAH patients included at least 1 subgroup treated with

ded From: http://content.onlinejacc.org/ on 04/16/2014combination therapy. The experience with combinationtherapy is therefore growing and a recent meta-analysis on 6RCTs with combination therapy including 858 patients hasbeen published (67): compared with the control group,combination therapy reduced the risk of clinical worsening(RR: 0.48; 95% condence interval: 0.26 to 0.91; p 0.023), increased the 6MWD signicantly by 22 m, andreduced mean pulmonary arterial pressure, right atrialpressure, and PVR. The incidence of serious adverse eventswas similar in the 2 groups (RR: 1.17; 95% condenceinterval: 0.40 to 3.42; p 0.77). The reduction on all-causemortality was not statistically signicant. However, theincidence of mortality in RCTs with PAH medications isrelatively low and to achieve statistical signicance a samplesize of several thousands of patients may be required (67).The patterns to apply combination therapy may be

sequential or initial (upfront).Sequential combination therapy is the most widely

utilized strategy both in RCTs (12 of 13 of the RCTs withcombination therapy) (Tables 3 to 6) and in clinical prac-tice: From monotherapy there is addition of a second andthen third drug in cases of inadequate clinical results or incases of deterioration. A structured prospective program toevaluate the adequacy of clinical results is the so-calledgoal-oriented therapy, a treatment strategy that usesknown prognostic indicators as treatment targets. Thetherapy is considered adequate only if the targets are met.The key difference between goal-oriented therapy andnonstructured approaches is that patients who are stabi-lized, or even those who improve slightly, can still receiveadditional therapy if treatment goals are not met. The goal-oriented treatment strategy has been endorsed by recentPAH guidelines proposing different targets includingWHO-FC I or II and the near normalization of restingcardiac index and/or of NT-proBNP plasma levels (4). Arecent study has conrmed a better prognosis in patientsachieving these goals as compared with the patients whodid not (68). Sequential combination therapy has beenallocated a grade of recommendation I and level of evidenceA in PAH patients with inadequate clinical response toinitial monotherapy.The rationale for initial or upfront combination therapy

is based on the known mortality of PAH that is reminiscentof many malignancies and the fact that malignancies andcritical medical illnesses (heart failure, malignant hyperten-sion) are not treated with a stepwise approach to therapybut rather with pre-emptive combination therapy. Theexperience on RCTs with initial combination therapy islimited to the small BREATHE-2 study, which failed todemonstrate any signicant difference between patientstreated initially with the combination epoprostenol andbosentan as compared with epoprostenol alone (28). Ina more recent experience, 23 treatment naive PAH patientswere treated with the initial combination of epoprostenol

JACC Vol. 62, No. 25, Suppl D, 2013December 24, 2013:D6072and bosentan and compared with a matched historicalcontrol group treated with epoprostenol (69). The study

Downloashowed a statistically signicantly greater decrease in PVRin the initial combination therapy group but this hemody-namic benet did not translate into a statistically signicantdifference in survival, or in transplant-free survival. A mul-ticenter, multinational blinded placebo controlled trial(AMBITION [A Randomized, Multicenter Study of First-Line Ambrisentan and Tadalal Combination Therapy inSubjects with Pulmonary Arterial Hypertension]) comparingrst line monotherapy with tadalal, monotherapy withambrisentan and combination therapy with tadalal andambrisentan in de novo WHO-FC II and III PAH patientswas underway at the time of this publication to address theefcacy to safety ratio of initial combination therapy. Initialcombination therapy has been allocated a grade of recom-mendation IIb and level of evidence C in WHO-FC IVPAH patients in case of nonavailability of IV prostanoids.Interventional procedures. LUNG TRANSPLANTATION. Theadvent of disease targeted therapy for severe PAH hasreduced and delayed patients referral for lung transplantprograms (70). The long-term outcomes of medically treatedpatients remain uncertain and transplantation shouldcontinue to be an important option for those who fail onsuch therapy and remain in WHO-FC III or IV (71,72).Delayed referral in combination with the length of thewaiting time, due to the shortage of organ donors, mayincrease the mortality on the waiting list and clinical severityat the time of transplantation.The overall 5-year survival following transplantation for

PAH was considered to be 45% to 50% with evidence ofcontinued good quality of life (73). More recent data showthat survival is increased to 52% to 75% at 5 years and to45% to 66% at 10 years (Table 7) (7476).Considering together the previous information, it seems

reasonable to consider eligibility for lung transplantationafter an inadequate clinical response to the initial mono-therapy and to refer the patient soon after the inadequateclinical response is conrmed on maximal combinationtherapy (Fig. 1).Also the etiology of PAH may help the decision making

because the prognosis varies according to the underlyingcondition. In fact, PAH associated with connective tissuedisease has a worse prognosis than idiopathic PAH evenwhen treated with prostanoids, while patients with PAHassociated with congenital heart disease have a bettersurvival. The worst prognosis is seen in patients with pul-monary veno-occlusive disease and pulmonary capillaryhemangiomatosis because of the lack of effective medicaltreatments and these patients should be listed for trans-plantation at diagnosis.Both heart-lung and double-lung transplantation have

been performed for PAH, although the threshold forunrecoverable right ventricle systolic dysfunction and/or leftventricle diastolic dysfunction is unknown. Currently thevast majority of patients worldwide receive bilateral lungs

JACC Vol. 62, No. 25, Suppl D, 2013December 24, 2013:D6072as evidenced by the International Society for Heart andLung Transplantation Registry gures (77). Patients with

ded From: http://content.onlinejacc.org/ on 04/16/2014Eisenmengers syndrome due to simple shunts have beentreated by isolated lung-transplantation and repair of thecardiac defect or by heart-lung transplantation (73).While registry data initially supported a survival benet of

heart-lung transplantation for patients with pulmonaryhypertension associated with a ventricular septal defects (78)experience with isolated bilateral lung transplantation hasgrown and more recent data supports a role for this approachcombined with repair of the defect (79).Recent reports indicate that venoarterial extracorporeal

membrane oxygenation may be employed in awake end-stage PH patients for bridging to lung transplantation (80).

BALLOONATRIAL SEPTOSTOMY. The creation of an interatrialright-to-left shunt can decompress the right heart chambers,and increase left ventricle pre-load and cardiac output(81,82). In addition, this improves systemic O2 transportdespite arterial O2 desaturation (81) and decreases sympa-thetic hyperactivity. The recommended technique is gradedballoon dilation atrial septostomy, which produces equiva-lent improvements in hemodynamics and symptoms butreduced risk compared with the original blade technique.Other techniques are considered experimental (83).A careful pre-procedure risk assessment ensures reduced

mortality. Balloon atrial septostomy (BAS) should beavoided in end-stage patients presenting with a baselinemean right atrial pressure of >20 mm Hg and O2 satura-tion at rest of

months of treatment.

responders who remain in (or progress to) WHO-FC

ReUn401

REF

Downloa PAH is a rare disease and regulatory agencies mayrequire only 1 RCT with pre-specied characteristics(e.g., size, duration, endpoint, level of statisticalsignicance) to grant the approval for the use. Forthese reasons approved drugs with level of evidence A(more than 1 RCT or meta-analysis) and approveddrugs with Level of Evidence: B (1 RCT) have beengrouped together.

The treatment algorithm does not apply to patients inother clinical groups, and in particular not to patientswith PH associated with left heart disease (group 2) orwith lung diseases (group 3).

Only the compounds ofcially approved for PAH orunder regulatory approval process in at least 1 countryare included. Single compounds are listed by alpha-betical order according with the pharmacologicalname.

As head-to-head comparisons among differentcompounds are not available, no evidence-based rst-line treatment can be proposed. In this case the choiceof the drug may depend on a variety of factorsincluding the approval status, the labeling, the route ofadministration, the side effect prole, patients prefer-ences, physician experience, and the cost.

A 4-level hierarchy for endpoints in RCT has beenproposed by experts according to level of evidenceregarding efcacy (84,85): Level 1 is a true clinicalefcacy measure; Level 2 is a validated surrogate (fora specic disease setting and class of interventions);Level 3 is a nonvalidated surrogate, yet 1 established tobe reasonably likely to predict clinical benet (fora specic disease setting and class of interventions);and Level 4 is a correlate that is a measure of biologicalactivity but that has not been established to be so ata higher level. All-cause death and morbidity andmortality endpoints for PAH have been included inLevel 1 (84) whereas 6MWD is not considereda validated surrogate in PAH (86) and it may beincluded either at Level 3 or 4. According to thishierarchy, drugs with morbidity and mortality asprimary endpoint in RCTs or drugs with demon-strated reduction in all-cause mortality (prospectivelydened) have been highlighted.

DESCRIPTION.

The suggested initial approach after the diagnosis ofPAH is the adoption of the general measures, theinitiation of the supportive therapy, and referral to anexpert center.

Acute vasoreactivity testing should be performed in allpatients with PAH (group 1), although patients withidiopathic PAH, heritable PAH, and PAH associatedwith anorexigen use are the most likely to exhibit anacute positive response and to benet from high-dose

Gali et al.Treatment Algorithm of Pulmonary Arterial Hypertension

D70CCB therapy. Vasoreactive patients should be treatedwith high and optimally tolerated doses of CCBs;

1.

ded From: http://content.onlinejacc.org/ on 04/16/2014III, should be considered candidates for treatmentwith any of the approved PAH drugs.

As head-to-head comparisons among differentcompounds are not available, no evidence-based rst-line treatment can be proposed (see previous) for eitherWHO-FC II or III patients.

Continuous IV epoprostenol is recommended as rst-line therapy for WHO-FC IV PAH patients becauseof the survival benet in this subset. In absence of IVepoprostenol all other compounds may be utilized.

Although ambrisentan, bosentan, and sildenal areapproved in WHO-FC IV patients in the UnitedStates, only a small number of these patients wereincluded in the RCTs of these agents. Accordingly,most experts consider these treatments as a second linein severely ill patients.

In WHO-FC IV patients initial combination therapymay also be considered.

In case of inadequate clinical response, sequentialcombination therapy should be considered. Combi-nation therapy can either include an ERA plusa PDE-5i or a prostanoid plus an ERA or a prostanoidplus a PDE-5i. Upon regulatory approval the sGCstimulator riociguat can be considered as a potentialalternative to PDE-5i in the different types of doublecombinations. The combination of riociguat andPDE-5is is contraindicated.

In case of inadequate clinical response with doublecombination therapy, triple combination therapyshould be attempted.

It seems reasonable to consider eligibility for lungtransplantation after an inadequate clinical response tothe initial monotherapy and to refer the patient forlung transplantation soon after the inadequate clinicalresponse is conrmed on maximal combinationtherapy.

Balloon atrial septostomy should be regarded asa palliative or bridging procedure in patients deterio-rating despite maximal medical therapy.

print requests and correspondence: Dr. Nazzareno Gali,iversity of Bologna, Institute of Cardiology, via Massarenti 9,38-Bologna, Italy. E-mail: nazzareno.galie@unibo.it.

ERENCES Nonresponders to acute vasoreactivity testing who arein WHO-FC II should be treated with an oralcompound.

Nonresponders to acute vasoreactivity testing, oradequate response should be conrmed after 3 to 4

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titlink1Updated Treatment Algorithm of Pulmonary Arterial HypertensionGeneral Measures, Supportive Therapy, Referral Centers, and Vasoreactivity TestGeneral measuresPregnancyRehabilitation and Exercise Training

Supportive therapyReferral centers and vasoreactivity testing

Initial Therapy With PAH-Approved DrugsIndividual compoundsEndothelin pathwayEndothelin receptor antagonistsAmbrisentanBosentanMacitentan

Nitric oxide pathwaySoluble guanylate cyclase stimulatorsRiociguat

PDE-5isSildenafilTadalafilVardenafil

Platelet-derived growth factor pathwayTyrosine kinase inhibitorsImatinib

Prostacyclin pathwayProstanoidsBeraprostEpoprostenolIloprostTreprostinil

Prostacyclin IP-receptor agonistsSelexipag

Clinical Response, Combination Therapy, and Interventional ProceduresCombination therapyInterventional proceduresLung TransplantationBalloon Atrial Septostomy

Treatment algorithm principles and descriptionPrinciplesDescription

References