Screening Diagnosis and Treatment of PAH:
An OverviewKerri Akaya Smith, MD
Wednesday, April 25
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
1
Screening, Diagnosis, and Treatment of
Pulmonary Arterial Hypertension (PAH):
An Overview
New Jersey Association of Osteopathic Physicians & Surgeons
Atlantic City, New Jersey
April 25, 2018
K. Akaya Smith, MDAssistant Professor of Medicine
Perelman School of Medicine at the University of Pennsylvania
Medical Director, Pulmonary Hypertension Program
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania
Faculty Disclosure
• Dr. Smith has received research support/grants from Eiger
BioPharmaceuticals, Inc, Gilead Sciences, Inc., Actelion Pharmaceuticals
US, Inc, and United Therapeutics Corporation.
• Dr. Smith has also served on an advisory committee for United Therapeutics
Corporation.
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
2
The Pulmonary Hypertension Association (PHA)
is the leading non-profit organization for PH research,
public awareness, and services. The organization
has over 12,000 members, including patients, family
members, and medical professionals.
www.PHAssociation.org
Let’s get started . . .
Vascular Pressure in Systemic and Pulmonary Circulations (mm Hg)
PulmonaryCirculation
Systemic Circulation
SystemicArteries
PulmonaryArteries
SystemicVeins Pulmonary
Veins
120/80, mean 93 25/8, mean 14
LAMean
5
RAMean 2-
5
RV25 / 2-5
LV120 / 5-10
Mean 12Mean 30
LungBody
Kovacs G et al. Eur Respir J. 2009;34:888-894.
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
3
5th World Symposium on PH:Classification of PH 1. Pulmonary arterial hypertension
1.1 Idiopathic PAH1.2 Heritable PAH
1.2.1 BMPR21.2.2 ALK1, ENG, SMAD9, CAV1, KCNK31.2.3 Unknown
1.3 Drug- and toxin-induced1.4 Associated with
1.4.1 Connective tissue diseases1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart disease1.4.5 Schistosomiasis
1’. Pulmonary veno-occlusive disease and/orpulmonary capillary hemangiomatosis
1’’. PPHN
2. PH due to LHD2.1 LV systolic dysfunction2.2 LV diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart
inflow/outflow obstruction
3. PH due to lung diseases and/or hypoxia3.1 COPD3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive
and obstructive pattern3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung diseases
4. CTEPH
5. PH with unclear multifactorial mechanisms
5.1 Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy
5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis
5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH
Simonneau G et al. JACC 2013;62:D34-41.
5th World Symposium on PH: Hemodynamic Definition of PH/PAH
PH
PAHMean PAP ≥25 mm Hg plusPAWP ≤15 mm Hg plusPVR >3 Wood units
Mean PAP ≥25 mm Hg at rest during RHC
Hoeper MM et al. J Am Coll Cardiol. 2013;62:D42-D50.
5th World Symposium on PH:Classification of PH 1. Pulmonary arterial hypertension
1.1 Idiopathic PAH1.2 Heritable PAH
1.2.1 BMPR21.2.2 ALK1, ENG, SMAD9, CAV1, KCNK31.2.3 Unknown
1.3 Drug- and toxin-induced1.4 Associated with
1.4.1 Connective tissue diseases1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart disease1.4.5 Schistosomiasis
1’. Pulmonary veno-occlusive disease and/orpulmonary capillary hemangiomatosis
1’’. PPHN
2. PH due to LHD2.1 LV systolic dysfunction2.2 LV diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart
inflow/outflow obstruction
3. PH due to lung diseases and/or hypoxia3.1 COPD3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive
and obstructive pattern3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung diseases
4. CTEPH
5. PH with unclear multifactorial mechanisms
5.1 Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy
5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis
5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH
Simonneau G et al. JACC 2013;62:D34-41.
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
4
Heritable PAH • Autosomal dominant• BMPR2 (bone morphogenetic protein receptor type 2)
is the major predisposing gene• Mutation detection rate for known genes is ≈75% in
familial PAH • Major predisposing gene has a highly variable
penetrance between families• Genetic anticipation
• ALK1 (ACVRL1; activin A receptor type-II-like kinase 1) is major gene when PAH is associated with hereditary hemorrhagic telangiectasia (HHT)
Soubrier F et al. J Am Coll Cardiol. 2013;62:D13-D21.Simonneau G et al. J Am Coll Cardiol. 2013;62:D34-D41.
PAH Related to ConnectiveTissue Disease• Connective tissue diseases
– limited scleroderma (most common)– diffuse scleroderma – mixed connective tissue disease– systemic lupus erythematosus– rheumatoid arthritis– Sjogren’s syndrome
• PH is one of the leading causes of death in scleroderma
• Similar to IPAH pathology• Medical treatment same as for IPAH, but benefits less
than for IPAHHachulla E et al. Rheumatology. 2009;48:304-308.
Prevalence of PAH in Scleroderma
• Prevalence 7.9% in large prospective study (N=599) with confirmatory catheterizations
– excluded severe PFT abnormalities– all underwent Doppler echocardiography – catheterization if VTR >3 m/sec or
2.5–3 m/sec + unexplained dyspnea
• Prevalence of PAH: found in 47 of 599 scleroderma patients
– 29 had known PAH at study entry – 18 patients were newly diagnosed with PAH
Hachulla E et al. Arthritis Rheum. 2005;52:3792-3800.
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
5
Portopulmonary Hypertension
• Prevalence overall: 2-5% by RHC; liver transplant candidate: 4% to 17%
• Dependent on portal HTN, not hepatocellular dysfunction
• Poor prognosis: higher risk of death than IPAH pts
• Liver transplant
– may improve survival with mild to moderate PAH(28-56%, 5 yr)
– significant PAH (mPAP >35 mm Hg) predicts unacceptably high perioperative mortality
Budhiraja R et al. Chest. 2003. Hadengue A et al. Gastroenterology. 1991. Castro M et al. Mayo Clin Proc. 1996. Kawut SM et al. Liver Transpl. 2005. Ramsay MA et al. Liver Transpl Surg. 1997. Krowka MJ et al. Clin Chest Med. 2005. Krowka MJ et al. Liver Transpl. 2004. Swanson KL et al. Hepatology. 2004.
5th World Symposium on PH:Classification of PH 1. Pulmonary arterial hypertension
1.1 Idiopathic PAH1.2 Heritable PAH
1.2.1 BMPR21.2.2 ALK1, ENG, SMAD9, CAV1, KCNK31.2.3 Unknown
1.3 Drug- and toxin-induced1.4 Associated with
1.4.1 Connective tissue diseases1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart disease1.4.5 Schistosomiasis
1’. Pulmonary veno-occlusive disease and/orpulmonary capillary hemangiomatosis
1’’. PPHN
2. PH due to LHD2.1 LV systolic dysfunction2.2 LV diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart
inflow/outflow obstruction
3. PH due to lung diseases and/or hypoxia3.1 COPD3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive
and obstructive pattern3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung diseases
4. CTEPH
5. PH with unclear multifactorial mechanisms5.1 Hematological disorders: chronic hemolytic anemia,
myeloproliferative disorders, splenectomy5.2 Systemic disorders: sarcoidosis, pulmonary
Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis
5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH
Simonneau G et al. JACC 2013;62:D34-41.
Most Common Cause of Elevated PAPs by Echo: Left Heart DiseaseSymptoms
– paroxysmal nocturnal dyspnea
– orthopnea
History– diabetes
– hypertension
– obesity
– coronary artery disease
– metabolic syndrome
ECG– atrial fibrillation
– absence of right axis deviation
Echo– left atrial enlargement
– left ventricular hypertrophy
– normal RA, RV
– abnormal diastolic filling
– mitral or aortic disease
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
6
Percentage of PAH and PVH Patients With All 4 Metabolic Syndrome Factors
*p≤0.005; **p=0.023.Robbins IM et al. Chest. 2009;136:31-36.
0
20
40
60
80
100
Percentof
patients**
*
*
*
PAHPVH
HTN13.7
(1.6-113.0)
Obesity7.1
(1.9-26.8)
DM5.7
(1.6-20.4)
HL4.2
(1.2-15.7)OR
95% CI
5th World Symposium on PH:Classification of PH 1. Pulmonary arterial hypertension
1.1 Idiopathic PAH1.2 Heritable PAH
1.2.1 BMPR21.2.2 ALK1, ENG, SMAD9, CAV1, KCNK31.2.3 Unknown
1.3 Drug- and toxin-induced1.4 Associated with
1.4.1 Connective tissue diseases1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart disease1.4.5 Schistosomiasis
1’. Pulmonary veno-occlusive disease and/orpulmonary capillary hemangiomatosis
1’’. PPHN
2. PH due to LHD2.1 LV systolic dysfunction2.2 LV diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart
inflow/outflow obstruction
3. PH due to lung diseases and/or hypoxia3.1 COPD3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive
and obstructive pattern3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung diseases
4. CTEPH
5. PH with unclear multifactorial mechanisms5.1 Hematological disorders: chronic hemolytic anemia,
myeloproliferative disorders, splenectomy5.2 Systemic disorders: sarcoidosis, pulmonary
Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis
5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH
Simonneau G et al. JACC 2013;62:D34-41.
Chronic Obstructive Pulmonary Disease (COPD) and PH• Retrospective study of 215 COPD patients• 13.5% had a PA mean >35 mm Hg• Correlated best (inversely) with PaO2• A small number had only moderate obstruction: treatable sub-group?
Thabut G et al. Chest. 2005;127:1531-1536. FEV1 (% pred.)
mPAP (mm Hg)
10
20
30
40
60
50
0 20 40 60 80
4
12
3
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
7
5th World Symposium on PH:Classification of PH 1. Pulmonary arterial hypertension
1.1 Idiopathic PAH1.2 Heritable PAH
1.2.1 BMPR21.2.2 ALK1, ENG, SMAD9, CAV1, KCNK31.2.3 Unknown
1.3 Drug- and toxin-induced1.4 Associated with
1.4.1 Connective tissue diseases1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart disease1.4.5 Schistosomiasis
1’. Pulmonary veno-occlusive disease and/orpulmonary capillary hemangiomatosis
1’’. PPHN
2. PH due to LHD2.1 LV systolic dysfunction2.2 LV diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart
inflow/outflow obstruction
3. PH due to lung diseases and/or hypoxia3.1 COPD3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive
and obstructive pattern3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung diseases
4. CTEPH
5. PH with unclear multifactorial mechanisms5.1 Hematological disorders: chronic hemolytic anemia,
myeloproliferative disorders, splenectomy5.2 Systemic disorders: sarcoidosis, pulmonary
Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis
5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH
Simonneau G et al. JACC 2013;62:D34-41.
Incidence of CTEPH
• Approximately 3% to 4% 1-2 yr after acute PE
• USA: 600,000 cases ofacute PE each year
• Only 40% to 50% of CTEPH patients have a history ofprevious episodes of acutePE
• VQ scan identifies old PE better than CTA
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.Pengo V et al. N Engl J Med. 2004;350:2257-2264.Tapson VF, Humbert M. Proc Am Thorac Soc. 2006;3:564-567.
Years
Cum
ulat
ive
inci
denc
e of
CTE
PH
0 1 2 3 4 7 8 9 10 115 60.00
0.01
0.02
0.03
0.04
Pathology of PAH
Gaine S. JAMA. 2000;284:3160-3168.
WHO Group I: Characterized by progressive growth and vasoconstriction of small pulmonary arteries
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
8
PAH: Hemodynamic and Clinical Course
NORMAL
Time
PAP
PVR
CO
INYHA
Adventitia
Media
Intima
Adapted from Gaine S. JAMA. 2000;284:3160-3168.
NORMAL
Adventitia
Media
Intima
REVERSIBLE DISEASE
Time
PAP
PVR
CO
I II IIINYHA
Smooth Muscle Hypertrophy
Early Intimal Thickening
Adapted from Gaine S. JAMA. 2000;284:3160-3168.
PAH: Hemodynamic and Clinical Course
NORMAL
Adventitia
Media
Intima
Smooth Muscle Hypertrophy
Early Intimal Thickening
REVERSIBLE DISEASE
IRREVERSIBLE DISEASE
Plexiform Lesions
Thrombosis
Adventitial, Intimal Proliferation
Smooth Muscle Hypertrophy
Time
PAP
PVR
CO
I II III IVNYHA
PAH: Hemodynamic and Clinical Course
Adapted from Gaine S. JAMA. 2000;284:3160-3168.
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
9
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5
Percent survival
McLaughlin VV et al. Chest. 2004;126:78S-92S.
Congenital heart disease
Portopulmonary
IPAH
CTD
HIV
Years
Survival in PAH
Adapted from: Sitbon O et al. J Am Coll Cardiol. 2002;40:780-788. D’Alonzo GE et al. Ann Intern Med.1991;115:343-349. McLaughlin VV et al. Chest. 2004;126:78S-91S.
Idiopathic PAH: Survival If Untreated
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 50
20
40
60
80
100
Years of follow-up
Perc
enta
ge s
urvi
ving
NIH registrySitbon historical controlACCP estimate
• Incidence: 2-6 cases per million in US
• Poor prognosis in an era lacking therapy
• Therapeutic options and research efforts now offer more hope
French Registry: Kaplan-Meier Survival Estimates in Combined PAH Population vs NIH-predicted
Humbert M et al. Circulation. 2010;122:156-163.
0 12 24 36Time (mo)
Survival (%)
0
40
80
100
60
20
Observed
Predicted (NIH Registry)
No. at risk:All patients 56 98 120 13369 113 127
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
10
REVEAL: Observed 1-year Survival From Time of Enrollment According to Predicted Risk Strata
Benza RL et al. Circulation. 2010;122:164-172.
Months from enrollment
Survival (%)
0
60
100
80
40
0 3 6 9 122 5 8 111 4 7 10
Risk strataLowAverageModerately highHighVery high
No. at risk:LowAverageMod. highHighVery high
1374665280295102
1368659277293100
136465727429196
135965326928489
135664826427781
135264726327074
135164026026372
134662825925569
134162525524761
133661825424159
131160424923855
130460224423352
130359624322549
Key Pathways Implicated in PAH Pathogenesis
Humbert M et al. N Engl J Med. 2004;351:1425-1436.
cGMP
cAMP
Vasoconstriction
and proliferation
Endothelinreceptor A Endothelin
receptor B
Vasodilation
and antiproliferation
Phosphodiesterase type 5
Vasodilation
and antiproliferation
Nitric Oxide
Endothelin-1
Pre-proendothelin
L-arginine
Prostaglandin I2
L-citrulline
Nitric OxidePathway
EndothelinPathway
ProstacyclinPathway
Endothelial cells
Proendothelin
Endothelial cells
Arachidonic acid
Smooth muscle cells
Prostacyclin (prostaglandin I2)
Smooth muscle cells
Case: Jane
• 37-yr-old woman, previously healthy
• Delivered second child 14 mo previously
• Limited exercise tolerance since delivery, attributed to weight gain
• Dyspnea while playing with older child; syncope while walking up an incline
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
11
Jane: Initial Symptoms
• Currently has dyspnea with mild exertion, walks slowly in store
• Exertional light-headedness
• Atypical chest pain
• Occasional palpitations
• Lower extremity edema
Multiple Guidelines, Consistent Message: Comprehensive Diagnostic Evaluation/ Robust PH Specialty Center Collaboration Are Necessary
Follow Basic Steps of American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Consensus Algorithm, With Some Updates• To identify:
– the presence of PH
– which group of PH (WHO I-V)
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.Developed in Collaboration With the American College of Chest Physicians; American Thoracic Society, Inc; and the Pulmonary Hypertension Association
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
12
Echocardiogram
PFT’s
Polysomnography
V/Q Scan
• Sleep Disorder
• Chronic PE
Functional Test(6MWT, CPET)
Overnight Oximetry
HistoryExamCXRECG
HIV
ANA
LFT’s
RH Cath
TEEExercise Echo
Pulmonary AngiographyChest CT AngiogramCoagulopathy Profile
Vasodilator TestExercise RH CathVolume Loading
ABG’s
• Index of Suspicion of PH
• RVE, RAE, RVSP, RV Function
• Left Heart Disease• VHD, CHD
• Ventilatory Function• Gas Exchange
Other CTD Serologies
• HIV Infection
• Scleroderma, SLE, RA
• Portopulmonary Htn
• Establish Baseline• Prognosis
• Confirmation of PH• Hemodynamic Profile• Vasodilator Response
Pivotal Tests Contingent Tests Contribute to Assessment of:
Left Heart CathMcLaughlin VV et al. J Am Coll Cardiol.2009;53:1573-1619.
ACC
F/AH
A D
iagn
ostic
Alg
orith
m
History and Physical Exam Findings Are Insensitive Unless Advanced Disease/RV Failure Present
History Exam (PH) Exam (RV Failure)• Dyspnea (86%)• Fatigue (27%)• Chest pain (22%)• Edema (22%)• Syncope (17%)• Dizziness (15%)• Cough (14%)• Palpitations
(13%)
• Loud P2 (listen at apex)• RV lift (left parasternal –
fingertips)• RV S3, S4• Systolic murmur (TR;
inspiratory augmentation)• Early systolic click• Midsystolic ejection
murmur• Diastolic murmur (PR)
• JVD; increased A wave, V wave; hepatojugular reflex
• Pulsatile liver• Hepatomegaly• Edema• Ascites• Low BP, low PP, cool
extremities
REVEAL. Brown LM et al. Chest. 2011;140:19-26. Adapted from McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Jane: Physical Exam
• HR 90 bpm; BP 130/68 mm Hg; Wt 190 lb; Ht 5'4"
• JVP ~15 cm, reduced carotid upstrokes
• Clear lungs
• Palpable RV heave, RRR, normal S, loud P2,III/VI, TR m
• 2+ LE edema
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
13
Jane: Additional History
• PMH: 2 children, 4 yr and 14 mo
– IBS: diet-controlled
• Meds: none
• Allergies: contrast dye
• FH: PPH in a paternal aunt, CAD, DM, Htn
• SH: rare ETOH, o/w unremarkable
Healthy
Peripheral hypo-vascularity (pruning)
Prominent centralpulmonary artery
Adapted from McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Chest Radiograph May Show Right Heart and Vascular Abnormalities in Advanced Disease
PH
Healthy
RV enlargement into retrosternal clear space
Adapted from McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
PH
Chest Radiograph May Show Right Heart and Vascular Abnormalities in Advanced Disease
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
14
Electrocardiogram May Show Right Heart Abnormalities in Advanced Disease
Right Axis Deviation
Right Atrial Enlargement Right Ventricular Strain
Right Ventricular Hypertrophy
Image courtesy Christopher F. Barnett, MD, MPH
Echocardiogram
PFT’s
Polysomnography
V/Q Scan
• Sleep Disorder
• Chronic Thromboembolic PH
Functional Test(6MWT, CPET)
Overnight Oximetry
HistoryExamCXRECG
HIV
ANA
LFT’s
RH Cath
TEEExercise Echo
Pulmonary AngiographyChest CT AngiogramCoagulopathy Profile
Vasodilator TestExercise RH CathVolume Loading
ABG’s
• Index of Suspicion of PH
• RVE, RAE, RVSP, RV Function
• Left Heart Disease• VHD, CHD
• Ventilatory Function• Gas Exchange
Other CTD Serologies
• HIV Infection
• Scleroderma, SLE, RA
• Portopulmonary Htn
• Establish Baseline• Prognosis
• Confirmation of PH• Hemodynamic Profile• Vasodilator Response
Pivotal Tests Contingent Tests Contribute to Assessment of:
Left Heart CathMcLaughlin VV et al. J Am Coll Cardiol.2009;53:1573-1619.
ACC
F/AH
A D
iagn
ostic
Alg
orith
m
Checklist for Echocardiographic Assessments When PH Is Suspected• Estimate pulmonary artery systolic pressure
• Evaluate severity of TR
• Evaluate right heart size and function
• Exclude left heart valvular disease and systolic dysfunction
• Exclude congenital heart disease
• Differentiate PAH from PH due LHD
• Estimate RA pressure
• Evaluate for pericardial effusion
Adapted from McLaughlin VV et al. J Am Coll Cardiol. 2015;65:1976-1997.
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
15
Barnett C et al. JAMA. 2008;299:324-331.
Modified Bernoulli EquationRVSP= 4(VTR)2 + RAP
PASP Is Estimated Using Tricuspid Regurgitant Jet Velocity
PASP=RVSP in the absence of pulmonic outflow obstruction
B
TR Jet Signal Quality Affects Reliability of Estimated PASP
Poor signal quality Good signal quality
Images courtesy Christopher F. Barnett, MD, MPH
Structural Echocardiographic Findings in Patients With PH
• RV enlargement• RA enlargement• Septal flattening• Pericardial effusion
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
16
Echocardiogram
PFT’s
Polysomnography
V/Q Scan
• Sleep Disorder
• Chronic Thromboembolic PH
Functional Test(6MWT, CPET)
Overnight Oximetry
HistoryExamCXRECG
HIV
ANA
LFT’s
RH Cath
TEEExercise Echo
Pulmonary AngiographyChest CT AngiogramCoagulopathy Profile
Vasodilator TestExercise RH CathVolume Loading
ABG’s
• Index of Suspicion of PH
• RVE, RAE, RVSP, RV Function
• Left Heart Disease• VHD, CHD
• Ventilatory Function• Gas Exchange
Other CTD Serologies
• HIV Infection
• Scleroderma, SLE, RA
• Portopulmonary Htn
• Establish Baseline• Prognosis
• Confirmation of PH• Hemodynamic Profile• Vasodilator Response
Pivotal Tests Contingent Tests Contribute to Assessment of:
Left Heart CathMcLaughlin VV et al. J Am Coll Cardiol.2009;53:1573-1619.
ACC
F/AH
A D
iagn
ostic
Alg
orith
m
Ventilation Perfusion Scan (V/Q): Best Screening Test to Exclude CTEPH• Should never be missed
• Is potentially curable with pulmonary endarterectomy (PEA)
• 3% to 4% of acute PE will develop CTEPH
• Half of those with CTEPH do not have an apparent history of thromboembolism
• Normal V/Q scan excludes CTEPH
• CTEPH may be diagnosed on CT pulmonary angiogram, however, reported sensitivity varies from 50-98%
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619. Fedullo PF et al. N Engl J Med. 2001; 345:1465-72. Reichelt A et al. Eur J Radiol. 2009;71:49-54. Tunariu N et al. J Nucl Med. 2007;48:680-4.
Ventilation Perfusion Scan (V/Q) to Exclude CTEPH
Image courtesy Kelly Chin, MD
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
17
High-Quality Conventional Pulmonary Angiography: Gold Standard Test for CTEPH Diagnosis
PA LateralReproduced with permission from Barnett, CF, in: Yuan JX-J et al, eds, Textbook of Pulmonary Vascular Disease. Springer, 2011.
CTEPH: A Surgical Disease Survival Without Surgery Is Poor
Image courtesy Christopher F. Barnett, MD, MPH
Echocardiogram
PFT’s
Polysomnography
V/Q Scan
• Sleep Disorder
• Chronic Thromboembolic PH
Functional Test(6MWT, CPET)
Overnight Oximetry
HistoryExamCXRECG
HIV
ANA
LFT’s
RH Cath
TEEExercise Echo
Pulmonary AngiographyChest CT AngiogramCoagulopathy Profile
Vasodilator TestExercise RH CathVolume Loading
ABG’s
• Index of Suspicion of PH
• RVE, RAE, RVSP, RV Function
• Left Heart Disease• VHD, CHD
• Ventilatory Function• Gas Exchange
Other CTD Serologies
• HIV Infection
• Scleroderma, SLE, RA
• Portopulmonary Htn
• Establish Baseline• Prognosis
• Confirmation of PH• Hemodynamic Profile• Vasodilator Response
Pivotal Tests Contingent Tests Contribute to Assessment of:
Left Heart CathMcLaughlin VV et al. J Am Coll Cardiol.2009;53:1573-1619.
ACC
F/AH
A D
iagn
ostic
Alg
orith
m
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
18
Presence and Severity of Lung Disease Must Be Assessed • Abnormalities on PFTs may suggest cause of PAH or
reveal PH from lung disease (Group III)
• CT scanning useful in identifying parenchymal lung disease
• 20% have isolated reduction in DLCO
• DLCO mildly reduced(60%-80% predicted NIH registry)
• PVR correlates with reduction in DLCO
IPAH and CTEPH
• 20% have isolated reduction in DLCO
• Severity predicts future PAH
• DLCO correlates inversely with PASP
Systemic Sclerosis
DLCO=diffusing capacity of the lungs for carbon monoxide
Overnight Pulse Oximetry Is a Useful Screening Test for Sleep Disordered Breathing
• Hypoxia may signal underlying sleep apnea
• In patients with obstructive sleep apnea (OSA), PAPs reported to decrease in response to CPAP therapy
• Untreated—response to other treatment likely to be less effective
Somers VK et al. J Am Coll Cardiol. 2008;52:686-717.
Echocardiogram
PFT’s
Polysomnography
V/Q Scan
• Sleep Disorder
• Chronic Thromboembolic PH
Functional Test(6MWT, CPET)
Overnight Oximetry
HistoryExamCXRECG
HIV
ANA
LFT’s
RH Cath
TEEExercise Echo
Pulmonary AngiographyChest CT AngiogramCoagulopathy Profile
Vasodilator TestExercise RH CathVolume Loading
ABG’s
• Index of Suspicion of PH
• RVE, RAE, RVSP, RV Function
• Left Heart Disease• VHD, CHD
• Ventilatory Function• Gas Exchange
Other CTD Serologies
• HIV Infection
• Scleroderma, SLE, RA
• Portopulmonary Htn
• Establish Baseline• Prognosis
• Confirmation of PH• Hemodynamic Profile• Vasodilator Response
Pivotal Tests Contingent Tests Contribute to Assessment of:
Left Heart CathMcLaughlin VV et al. J Am Coll Cardiol.2009;53:1573-1619.
ACC
F/AH
A D
iagn
ostic
Alg
orith
m
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
19
Class Description
I No limitation of physical activity; ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope
IISlight limitation of physical activity; no discomfort at rest; ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope
IIIMarked limitation of physical activity; no discomfort at rest; less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope
IVUnable to carry out any physical activity without symptoms; signs of right-heart failure; dyspnea and/or fatigue may be present at rest; discomfort is increased by any physical activity
Functional Assessment: WHO Functional Class Modified From NYHA Classification
Rubin LJ. Chest. 2004;126:7S-10S.
Jane: Laboratory Studies
• ANA: negative
• Echo: normal LV function, RAE, RVE, RVSP 60 mm Hg, TEE—no shunt found after agitated saline injection
• VQ: normal
• PFTs: normal volumes and flows, DLCO 81%
• 6MWD: 222 m, 99-96%
Echocardiogram
PFT’s
Polysomnography
V/Q Scan
• Sleep Disorder
• Chronic Thromboembolic PH
Functional Test(6MWT, CPET)
Overnight Oximetry
HistoryExamCXRECG
HIV
ANA
LFT’s
RH Cath
TEEExercise Echo
Pulmonary AngiographyChest CT AngiogramCoagulopathy Profile
Vasodilator TestExercise RH CathVolume Loading
ABG’s
• Index of Suspicion of PH
• RVE, RAE, RVSP, RV Function
• Left Heart Disease• VHD, CHD
• Ventilatory Function• Gas Exchange
Other CTD Serologies
• HIV Infection
• Scleroderma, SLE, RA
• Portopulmonary Htn
• Establish Baseline• Prognosis
• Confirmation of PH• Hemodynamic Profile• Vasodilator Response
Pivotal Tests Contingent Tests Contribute to Assessment of:
Left Heart CathMcLaughlin VV et al. J Am Coll Cardiol.2009;53:1573-1619.
ACC
F/AH
A D
iagn
ostic
Alg
orith
m
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
20
Cardiac Catheterization
• Confirm echo findings
• Survey for left heart disease
– measure wedge pressure or LVEDP
• Measure CO; calculate PVR
• Exclude systemic to pulmonary shunts
• Establish severity and prognosis
• Acute vasodilator challenge
Required when PAH is suspected
Assessment of Pressures as the Catheter Passes Through the Heart
Reproduced with permission from Barnett Cf. In: Murray & Nadel’s Textbook of Respiratory Medicine, 6th ed, Elsevier 2016.
PAVC RA RV PVPC
LA LV Ao
Pulmonary venous hypertensionElevated PCWP, normal PVR
PAHPH with respiratory diseaseCTEPHNormal PCWP, elevated PVR
Other:high CO
PH: The Importance of Hemodynamics
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
21
Vasodilator Testing Identifies Patients Who Respond Well Long Term to Treatment With Calcium Channel Blockers
• Vasodilator testing
– Nitric Oxide Inh orepoprostenol IV
– Positive testdefined by:
Drop in mPAP ≥10 mm Hg to a mPAP≤40 mmHg
+ normal CO
Years
Long-term CCB responders*
Long-term CCB failure
38 33 30 22 13 8 3 3 2 119 12 7 4 0
Subjectsat risk, n
Cum
ulat
ive
surv
ival
Responders
Failure
0.0
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 10 12 14 16 18
p=0.0007
*~50% of acute responders or ≤7% of IPAH patients
Sitbon O et al. Circulation. 2005;111:3105-3111.
Jane: Right Heart Cath
1/29/07Baseline
Nitric Oxide20 ppm
RAP (mm Hg) 19 20
PAP (mm Hg) 93/40, mean 63 93/46, mean 64
LVEDP (mm Hg) 10
Oxygen saturation (%)Pulmonary arteryFemoral artery
52.991.4
58.391.7
Cardiac output / Cardiac index(L/min) Fick 2.5/1.3 2.88/1.52
PVR (Wood units) Fick 21.2 15.2
Screening and Diagnosis Summary
• High index of suspicion
• Thorough diagnostic evaluation
• Exclude thromboembolic disease
• Evaluate potential causes/contributing issues
• RHC required prior to initiating PAH therapy
• Baseline functional evaluation
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
22
PAH Treatment Goals
• Fewer/less severe symptoms
• Improved exercise capacity
• Improved hemodynamics
• Prevention of clinical worsening
• Improved quality of life
• Improved survival
McLaughlin VV et al. J Am Coll Cardiol 2013.:62:D73-81.
5th World Symposium on PH Goals of Therapy: Setting the Bar Higher
Functional Class • I or II
Hemodynamics • Normalization of RV function (RAP <8 mm Hg and CI >2.5-3.0 L/min/m2)
Echocardiography/ MRI • Normal/near normal RV size and function
BNP level • ‘Normal’
6MWD • 380-440 m, may not be aggressive enough
CPET • Peak VO2 >15 mL/kg/min• VE/VCO2 @ AT <45
Anticoagulate ± Diuretics ±Oxygen ± Digoxin
Positive
Sustained Response
Oral CCB
Continue CCB
Yes
Negative
What Is the Optimal Treatment Strategy?
Acute Vasoreactivity Testing
No LOWER RISK DETERMINANTS OF RISK HIGHER RISK
No Clinical evidence ofRV failure Yes
Gradual Progression of symptoms Rapid
II, III WHO class IVLonger (>400 m) 6MWD Shorter (<300 m)
Peak VO2 >10.4 mL/kg/min CPET Peak VO2 <10.4 mL/kg/min
Minimal RV dysfunction Echocardiography
Pericardial effusion,significant RV
enlargement/dysfunction;RA enlargement
RAP <10 mm Hg;CI >2.5 L/min/m2 Hemodynamics RAP >20 mm Hg;
CI <2.0 L/min/m2
Minimally elevated BNP Significantly elevated
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619..
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
23
Chronic Adjuvant Therapies in PAHDigoxin• Variable inotropic effect and use• No long-term data; need to balance unproven benefits with known risksOxygen• Use to prevent hypoxic vasoconstriction• Consider exercise, sleep, altitude • Aim for target saturation >90%• May not correct hypoxia with shuntDiuretics• Most need; hypotension not a contraindication (may need BP support)• Renal function and electrolytes must be monitored closelyAnticoagulation• Recommended in IPAH• Observational studies only (2 retrospective, 1 prospective); need to balance
unproven benefits with known risks• INR 1.5 – 2.5Adapted from: Badesch DB et al. Chest. 2004;126:35S-62S. Badesch DB et al. Chest. 2007;131:1917-1928.McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Other Management Issues
• Encourage exercise and activity within the limits of disease and ability to maintain O2 levels
• Consider enrollment in a pulmonary rehabilitation program
• Immunizations
• Contraception
What Is the Optimal Treatment Strategy?
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Anticoagulate ± Diuretics ±Oxygen ± Digoxin
Positive
Sustained Response
Oral CCB
Continue CCB
Yes
Negative
Acute Vasoreactivity Testing
No LOWER RISK DETERMINANTS OF RISK HIGHER RISK
No Clinical evidence ofRV failure Yes
Gradual Progression of symptoms Rapid
II, III WHO class IVLonger (>400 m) 6MWD Shorter (<300 m)
Peak VO2 >10.4 mL/kg/min CPET Peak VO2 <10.4 mL/kg/min
Minimal RV dysfunction Echocardiography
Pericardial effusion,significant RV
enlargement/dysfunction;RA enlargement
RAP <10 mm Hg;CI >2.5 L/min/m2 Hemodynamics RAP >20 mm Hg;
CI <2.0 L/min/m2
Minimally elevated BNP Significantly elevated
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
24
Sitbon O et al. Circulation. 2005;111:3105-3111.
Survival in IPAH:Long-term CCB Responders
Years
Long-term CCB responders (~50% of acute responders or ≤7% of IPAH patients)
Long-term CCB failure
38 33 30 22 13 8 3 3 2 1
19 12 7 4 0Subjectsat risk, n
Cum
ulat
ive
surv
ival
Long-term CCBresponders
Long-term CCBfailure
0.0
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 10 12 14 16 18
p=0.0007
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Revised Definition of Vasodilator Responder
“Vasodilator Response”• Fall in mPAP ≥10 mm Hg• + mPAP (absolute) ≤40 mm Hg• + Normal CO
• Only acute vasodilator responders should be tried on CCB therapy to treat PAH
PAH Determinants of RiskLOWER RISK DETERMINANTS OF RISK HIGHER RISK
No Clinical evidence ofRV failure Yes
Gradual Progression of symptoms Rapid
II, III WHO class IV
Longer (>400 m) 6MWD Shorter (<300 m)
Peak VO2 >10.4 mL/kg/min CPET Peak VO2 <10.4 mL/kg/min
Minimal RV dysfunction Echocardiography
Pericardial effusion,significant RV
enlargement/dysfunction; RA enlargement
RAP <10 mm Hg;CI >2.5 L/min/m2 Hemodynamics RAP >20 mm Hg;
CI <2.0 L/min/m2
Minimally elevated BNP Significantly elevated
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
25
What Is the Optimal Treatment Strategy?
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Anticoagulate ± Diuretics ±Oxygen ± Digoxin
Sustained Response
Continue CCB
Yes
Negative
No LOWER RISK DETERMINANTS OF RISK HIGHER RISKNo Clinical evidence of RV failure Yes
Gradual Progression of symptoms RapidII, III WHO class IV
Longer (>400 m) 6MWD Shorter (<300 m)Peak VO2 >10.4 mL/kg/min CPET Peak VO2 <10.4 mL/kg/min
Minimal RV dysfunction Echocardiography
Pericardial effusion, significant RV
enlargement/dysfunction;RA enlargement
RAP <10 mm Hg;CI >2.5 L/min/m2 Hemodynamics RAP >20 mm Hg;
CI <2.0 L/min/m2
Minimally elevated BNP Significantly elevated
Acute Vasoreactivity TestingPositive
Oral CCB
Approved Therapeutic Targets
Humbert M et al. N Engl J Med. 2004;351:1425-1436.
cGMP
cAMP
Vasoconstriction
and proliferation
Endothelinreceptor A
Endothelin-
receptor
antagonists
Endothelinreceptor B
Phosphodiesterase
type 5 inhibitor
Vasodilation
and antiproliferation
Phosphodiesterase type 5
Vasodilation
and antiproliferation
Prostacyclin
derivatives
Nitric Oxide
Endothelin-1
Pre-proendothelin
L-arginine
Prostaglandin I2
L-citrulline
Nitric OxidePathway
EndothelinPathway
ProstacyclinPathway
Endothelial cells
Proendothelin
Endothelial cells
Arachidonic acid
Smooth muscle cells
Prostacyclin (prostaglandin I2)
Smooth muscle cells
Exogenous
nitric oxide
sGC
stimulator
Approved Therapeutic Targets
Humbert M et al. N Engl J Med. 2004;351:1425-1436.
cGMP
cAMP
Vasoconstriction
and proliferation
Endothelinreceptor A
Endothelin-
receptor
antagonists
Endothelinreceptor B
Phosphodiesterase
type 5 inhibitor
Vasodilation
and antiproliferation
Phosphodiesterase type 5
Vasodilation
and antiproliferation
Prostacyclin
derivatives
Nitric Oxide
Endothelin-1
Pre-proendothelin
L-arginine
Prostaglandin I2
L-citrulline
Nitric OxidePathway
EndothelinPathway
ProstacyclinPathway
Endothelial cells
Proendothelin
Endothelial cells
Arachidonic acid
Smooth muscle cells
Prostacyclin (prostaglandin I2)
Smooth muscle cells
Exogenous
nitric oxide
sGC
stimulator
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
26
Iloprost (Ventavis®)Treprostinil (Tyvaso®)
Prostacyclin Analogues: Intravenous, Subcutaneous, Inhaled, or Oral
WG
Treprostinil (Remodulin®)
Treprostinil (Orenitram®)Selexipag (Uptravi®)
Epoprostenol (Flolan®
or Veletri®)Treprostinil (Remodulin®)
Epoprostenol IV: FC III-IV, 2 ng/kg/min titrated to desired clinical response in 1-2 ng/kg/min increments.Treprostinil IV / SC: FC II-IV, 1.25-2.5 ng/kg/min/wk. IV=diluted. Inhaled: FC III, to 54 mcg, 4 inh/d. Oral: FC II-III, starting at 0.25 mg bid and titrated in 0.25 mg increments as tolerated. Selexipag: FC II-III, starting at 200 mcg bid, and titrated as tolerated up to 1600 mcg bid . Iloprost Inhaled: FC III-IV, 2.5-5 mcg, 6-9 inh/d.
Prostacyclin Analogues: Pivotal Trials for IV and SC Formulations
Study Name / Drug N / Etiol / Class Design Positive Results
IV epoprostenolvs conventional Rx
81IPAH/FPAH
III,IV
Open-label12-week
• 6MWD• Symptoms• Hemodynamics• Survival
IV epoprostenolvs conventional Rx
111APAH SSc
III,IV
Open-label12-week
• 6MWD• Hemodynamics• Symptoms
TRUSTIV treprostinil vs placebo
44PAH
III
Double-blind, placebo-controlled12-week
• 6MWD• Symptoms
SC treprostinil vs SC placebo
470PAHII-IV
Double-blind12-week
• 6MWD• Symptoms• Hemodynamics
Barst RJ et al. N Engl J Med. 1996;334:296-301.Badesch D et al. Ann Intern Med 2000;132:425-432.Hiremath J et al. J Heart Lung Transplant. 2010;29:137-149. Simonneau G et al. Am J Respir Crit Care Med. 2002;165:800-804.
100
80
60
40
20
0Week
Epoprostenol (n=41)
0 2 4 6 8 1210
Conventional therapy (n=40)
Surv
ival
(%)
p=0.003*
*Two-sided, by log-rank test.Barst RJ et al for the PPH Study Group. N Engl J Med. 1996;334:296-301.
Survival Among Patients With IPAH: Epoprostenol vs Conventional Therapy
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
27
Prostacyclin Analogues: Pivotal Trials for Inhaled and Oral FormulationsStudy Name / Drug
N / Etiol / Class Design Positive Results
AIRInhaled iloprost vs placebo
203PH
III-IV
Double-blind12-week
• Composite end point• 6MWD • Symptoms• Hemodynamics
TRIUMPH 1Inhaled treprostinil vsplacebo§
235PAHIII-IV*
Double-blind12-week on
background oral Rx
• 6MWD
FREEDOM-MOral treprostinil vs placebo
228PAHII-III
Double-blind, placebo-controlled
12-week
• 6MWD
GRIPHONOral selexipag vs placebo
1156PAHII-III
Double-blind, naïveor on background
ERA and/or PDE5I,event-driven
morbidity/mortality
• Time to first morbid or mortality event
* Approved for class III only. §Included background therapy with ERA or PDE5-I.Olschewski H et al. N Engl J Med. 2002;347:322-329. McLaughlin VV et al. J Am Coll Cardiol. 2010;55:1915-1922Hiremath J et al. J Heart Lung Transplant. 2010;29:137-149. Jing Z-C et al. Circulation. 2013;127:624-633. Sitbon O et al. NEJM. 2015;373:2522-33.
Prostanoid Side Effects
• Flushing
• Headache
• Diarrhea, nausea, vomiting
• Jaw pain
• Leg pain
• Hypotension
• Dizziness
• Syncope
• Rebound PH if interruption of epoprostenol delivery (due to short half-life)
• Delivery site complications (pain, infection, cough, thrombosis, infusion)
Vary according to drug and route of delivery
cGMP
cAMP
Vasoconstriction
and proliferation
Endothelinreceptor A
Endothelin-
receptor
antagonists
Endothelinreceptor B
Phosphodiesterase
type 5 inhibitor
Vasodilation
and antiproliferation
Phosphodiesterase type 5
Vasodilation
and antiproliferation
Prostacyclin
derivatives
Nitric Oxide
Endothelin-1
Pre-proendothelin
L-arginine
Prostaglandin I2
L-citrulline
Nitric OxidePathway
EndothelinPathway
ProstacyclinPathway
Endothelial cells
Proendothelin
Endothelial cells
Arachidonic acid
Smooth muscle cells
Prostacyclin (prostaglandin I2)
Smooth muscle cells
Exogenous
nitric oxide
sGC
stimulator
Approved Therapeutic Targets
Adapted from Humbert M et al. N Engl J Med. 2004;351:1425-1436.
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
28
Endothelin Receptor Antagonists: Pivotal Trials
Study NameDrug
NEtiology
Class Design PositiveResults
BREATHE-1Oral bosentan* vs placebo
213PAHIII, IV
Double-blind16-week
• 6MWD• Delay clinical worsening• Symptoms
EARLYOral bosentanvs placebo
185PAH
II
Double-blind6-month
• Delay clinical worsening• Hemodynamics
ARIES-1&2Oral ambrisentan§vs placebo
394PAHII, III
Double-blind12-week
• 6MWD• Delay clinical worsening
SERAPHINOral macitentan†
vs placebo
742PAHII,III
Double-blindEvent-driven
morbidity/mortality
• Delay disease progression• 6MWD• Symptoms
Rubin L et al. N Engl J Med. 2002;346:896-903. Channick RN et al. Lancet. 2001;358:1119-1123. Galiè N et al. Lancet. 2008;371:2093-2100. Galiè N et al. Circulation. 2008;117:3010-3019. Pulido T et al. N Engl J Med. 2013;369:809-818.
*Bosentan = Tracleer®. Approved for FC II-IV. 62.5-125 mg po bid.§Ambrisentan = Letairis®. Approved for FC II-III. 5-10 mg po qd†Macitentan = Opsumit®. Approved for FC II-III. 10 mg po qd.
Endothelin Receptor Antagonists: Side Effects• Nasal congestion
• Abnormal hepatic function*
– monthly LFTs required for bosentan
• Anemia
– monitor CBC quarterly
• Edema
– lower extremity edema may require diuretic adjustment
• Teratogenic
– use requires dual contraceptive methods (hormonal plus barrier)
*PHA Scientific Leadership Council recommends LFT testing at onset of all treatments for PAH and periodically thereafter, at prescriber’s discretion.
cGMP
cAMP
Vasoconstriction
and proliferation
Endothelinreceptor A
Endothelin-
receptor
antagonists
Endothelinreceptor B
Phosphodiesterase
type 5 inhibitor
Vasodilation
and antiproliferation
Phosphodiesterase type 5
Vasodilation
and antiproliferation
Prostacyclin
derivatives
Nitric Oxide
Endothelin-1
Pre-proendothelin
L-arginine
Prostaglandin I2
L-citrulline
Nitric OxidePathway
EndothelinPathway
ProstacyclinPathway
Endothelial cells
Proendothelin
Endothelial cells
Arachidonic acid
Smooth muscle cells
Prostacyclin (prostaglandin I2)
Smooth muscle cells
Approved Therapeutic Targets
Humbert M et al. N Engl J Med. 2004;351:1425-1436.
Exogenous
nitric oxide
sGC stimulator
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
29
PDE-5 Inhibitor Pivotal Trials
Study NameDrug
NEtiolClass
Design Positive Results
SUPER-1Oral sildenafil*vs placebo
278PAHI-IV
Double-blind12-week
• 6MWD• Symptoms• Hemodynamics
PHIRST-1Oral tadalafil§vs placebo
405PAHI-IV
Double-blind16-week
• 6MWD• Delay clinical
worsening• Hemodynamics• HRQoL
Galiè N et al. N Engl J Med. 2005:353:2148-2157.Galiè N et al. Circulation. 2009;119;2894-2903.
*Sildenafil = Revatio®. Approved for FC II-III. 20 mg po tid.§Tadalafil = Adcirca®. Approved for FC I-IV. 40 mg po qd.
PDE-5 Side Effects
• Nose bleed
• Headache
• Dyspepsia
• Flushing
• Diarrhea
• Visual changes
Contraindicated with use of nitrate
sGC Stimulator Pivotal Trials
Study NameDrug
NEtiolClass
Design Positive Results
PATENT-1Oral riociguat*vs placebo
443PAHI-IV
Double-blind12-week
• 6MWD• Symptoms• Hemodynamics• Delay clinical worsening
CHEST-1Oral riociguatvs placebo
261CTEPH
I-IV
Double-blind16-week
• 6MWD• Symptoms• Hemodynamics
*Riociguat = Adempas®. Approved for WHO Group 1; persistent CTEPH (WHO Group 4) after surgical treatment, or inoperable CTEPH; titrated to maximum 2.5 mg po tid.
Ghofrani HA et al. N Engl J Med. 2013;369:319-329.Ghofrani HA et al. N Engl J Med. 2013;369:330-340.
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
30
sGC Stimulator Side Effects
• Headache
• Dizziness
• Dyspepsia/gastritis
• Nausea
• Diarrhea
• Hypotension
• Vomiting
• Anemia
• Gastroesophageal reflux
• Constipation
Contraindicated in pregnancy, with use of nitrates or NO donors in any form, or with use of PDE inhibitors
• Supervised exercise training (I-A)• Psycho-social support (I-C)• Avoid strenuous physical activity
(I-C)• Avoid pregnancy (I-C)• Influenza and pneumococcal
immunization (I-C)
• Oral anticoagulants: – IPAH, heritable PAH, and PAH
due to anorexigens (IIa-C)– APAH (Ilb-C)
• Diuretics (I-C)• Oxygen (I-C)• Digoxin (IIb-C)
Continue CCB
WHO FC I-III CCB (I-C)
Sustained response
(WHO FC I-II)
VASOREACTIVE NON-VASOREACTIVE
5th World Symposium on PH:2013 PAH Treatment Algorithm
Galiè N et al. J Am Coll Cardiol. 2013;62:D60-D72.
INITIAL THERAPY WITH PAH-APPROVED DRUGS
YES
NO
Acute vasoreactivity test (I-C for IPAH) (IIb-C for APAH)
Expert Referral (I-C)
General measures and supportive therapy
5th World Symposium on PH:2013 Treatment Algorithm
Galiè N et al. J Am Coll Cardiol. 2013;62:D60-D72.
Sequential CombinationTherapy (I-A)
Referral for LungTransplantation (I-C)
Consider Eligibility for Lung Transplantation
Inadequate ClinicalResponse
on Maximal Therapy
INITIAL THERAPY WITH PAH-APPROVED DRUGS
PDE-5 I orsGCs
ERAs
Prostanoids
++
+
Balloon AtrialSeptostomy (IIa-C)
Inadequate ClinicalResponse
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
31
INITIAL THERAPY WITH PAH-APPROVED DRUGSYELLOW: Morbidity and mortality as primary end point in randomized controlled study or reduction in all-cause mortality (prospectively defined)Level of evidence based on WHO-FC of majority of patients of studies
Evidence WHO FC II WHO FC III WHO FC IV
Rec
omm
enda
tion
I A or B
•Ambrisentan, Bosentan•Macitentan•Riociguat•Sildenafil •Tadalafil
•Ambrisentan, Bosentan, Epoprostenol IV
• Iloprost inh•Macitentan•Riociguat•Sildenafil •Tadalafil•Treprostinil SC, inh
•Epoprostenol IV
IIa C
• Iloprost IV*, TreprostinilIV
•Ambrisentan, Bosentan, Iloprost inh and IV*
•Macitentan•Riociguat•Sildenafil, Tadalafil•Treprostinil SC, IV, Inh*
IIb
B •Beraprost*
C• Initial Combination Therapy
• Initial Combination Therapy
5th World Symposium on PH:2013 PAH Treatment Algorithm
Galiè N et al. J Am Coll Cardiol. 2013;62:D60-D72. *Not approved in US.
Combination Therapy
sGCStimulators Prostanoids
EndothelinReceptor
Antagonists
Phospho-diesteraseInhibitors
TRIUMPHSTEP
SERAPHIN†
GRIPHONγ
TRIUMPHPACES
GRIPHON
PATENT-1*
PATENT-1*
?
?
???
PHIRST*SERAPHIN†
AMBITION
*53% on background ERA for PHIRST, 50% on background ERA or prostanoid for PATENT-1 †64% on background PDE-5I or prostanoid in SERAPHIN. γ84% on background ERA and/or PDE-5I in GRIPHON
Weeks0 1921444824 72 96 168120
Hazard ratio, 0.50 (95% Cl, 0.35-0.72)P<0.001
0
60
100
80
40
20
Combination therapy
Pooled monotherapy
AMBITION: Effect of Ambrisentan Plus Tadalafil Versus Monotherapy on Clinical Worsening*
* Death, hospitalization for worsening PAH, disease progression, unsatisfactory long-term clinical response.Galiè N et al. N Engl J Med. 2015;373:834-44.
Part
icip
ants
with
no
even
t (%
)
No. at risk:Combination therapyPooled monotherapy
229
209
186
155
145
108
106
77
71
49
36
25
4
5
253
247
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
32
Sitbon O et al. N Engl J Med. 2015;373:2522-33.
Selexipag vs placebo: RR 40%; HR=0.60; p<0.0001
No. at RiskPlacebo 582 433 347 220 149 88 28Selexipag 574 455 361 246 171 101 40
Pat
ient
s w
ithou
t an
even
t (%
)
00
20
40
80
60
12 18 24 30 366Months
Placebo
Selexipag
80% on background therapy:- 47% on ERA or PDE5I- 33% on ERA+PDE5I
GRIPHON: Effect of Selexipag on Time to First Morbidity or Mortality Event
SERAPHIN: Effect of Macitentan on Disease Progression
* Worsening of PAH, initiation of treatment with IV or SC prostanoids, lung transplantation or atrial septostomyPulido T et al. N Engl J Med. 2013;369:809-818.
0
40
80
100
60
20
Months
Pat
ient
s w
ithou
t an
even
t re
late
d to
PA
H o
r dea
th fr
om
from
any
cau
se*
(%)
0 6 12 363018 24
No. at risk:PlaceboMacitentan 3 mgMacitentan 10 mg
250250242
188213208
160188187
233241
648091
135166171
122147155
Macitentan 10 mg qdMacitentan 3 mg qdPlacebo
64% on background therapy:- 62% PDE5I- 5% Prostanoid
COMPASS-2: Effect of Sildenafil + BosentanVersus Sildenafil + Placebo on Time to First Morbidity/Mortality Event*
* All-cause death, hospitalization for worsening PAH or IV prostanoid, atrial septostomy, lung transplant, or PAH worsening. McLaughlin VV et al. Eur Respir J. 2015;46:405–413 | DOI: 10.1183/13993003.02044-2014
Patients at risk (n)Placebo 175 154 140 123 118 107 90 76 68 61 55 48 43 36 32 26
Bosentan 159 144 128 114 103 97 88 82 69 57 50 42 32 24 21 15
100
90
80
70
60
50
40
30
20
10
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60
Patie
nts
with
out a
n ev
ent (
%)
Months
Sildenafil + BosentanSildenafil + Placebo
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
33
Combination Therapy Caveats
• Experience evolving
• Most data from ‘add-on’ - ? De novo? Order?
• More drugs available
– more options
– more ways to get it wrong
• More questions than answers
• Costs/expenditures; third-party hurdles
Taichman DB. Ann Intern Med. 2008;149:583-585.
Jane: Initial Management
• Admitted to hospital following cath
• IV diuresis
• IV epoprostenol initiation
On-therapy Prognostic Indicators• Functional class I or II
• 6MWD >380 m
– limiting supporting data; do not use in isolation
• Hemodynamics
– normal cardiac index (>2.2 L/min/m2)
– normal RA pressure
• Positive response to CCB
• BNP <180 pg/mLSitbon O et al. J Am Coll Cardiol. 2002;40:780-788. McLaughlin VV et al. Circulation. 2002;106:1477-1482.Wensel R et al. Circulation. 2002;106:319-324.
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
34
Important Prognostic Variables
Humbert M et al. Circulation. 2010;122:156-163.Benza RL et al. Circulation. 2010;122:164-172.
• Functional class• 6-minute walk• RAP• CO• Age• Gender• Etiology
French Registry
• Functional class• 6-minute walk• PVR, RAP• Vitals• BNP• Pericardial effusion• DLCO• Age• Gender• Etiology
REVEAL Registry
Jane: Return Visits in May & September
• Significantly improved
• No limitations
• Functional class I
• Meds
– epoprostenol 30 ng/kg/min
– warfarin
– furosemide 20 mg
– KCl 10 mEq qd
Jane: Follow-up Physical Exam
• HR 80 bpm; BP 103/59 mm Hg; Wt 144.8 lb
• JVP 6, carotid upstrokes normal
• Clear lungs
• Palpable RV heave, normal S, loud P2, II/VI TR murmur
• No LE edema
Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension
35
Jane: 6MWD
• 222 m: 99-96% in January
• 486 m: 99-97% in May
• 556 m: 99-97% in September
Local Care PH Center
Collaborative Care With PH Centers:
• Diagnostic dilemmas• Diagnostic cath/
vasodilator trial• Fluid management• Acute issues• PAH-specific therapies• Side effects• Hospitalizations • Transplant• Clinical trials
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