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Professor Emerita of PediatricsColumbia University
College of Physicians & SurgeonsNew York, New York
ROBYN BARST, MDROBYN BARST, MD
Consensus Updates in PAH Classification, Screening and Treatment
2
Faculty:Content Development and Training
Robyn J. Barst, MDRobyn J. Barst, MDProfessor Emerita of Pediatrics Professor Emerita of Pediatrics
Columbia University College of Physicians & SurgeonsColumbia University College of Physicians & SurgeonsNew York, New YorkNew York, New York
Vallerie McLaughlin, MDVallerie McLaughlin, MDProfessor of MedicineProfessor of Medicine
Director, Pulmonary Hypertension ProgramDirector, Pulmonary Hypertension ProgramUniversity of MichiganUniversity of MichiganAnn Arbor, MichiganAnn Arbor, Michigan
3
Learning Objectives (CME, CE, CPE)
At the completion of this educational activity, participants should be able to:
#̶ Describe the new classification scheme for pulmonary hypertension
#̶ Discuss important changes in the PH classification scheme and how this impacts patient management
#̶ Discuss the current diagnostic algorithms for PAH
#̶ Report on the updated guidelines regarding initial PAH therapy
Updated Clinical Classification ofPulmonary Arterial Hypertension
(PAH)
5
Updated Definition of PAH
Adapted from Badesch DB, et al. J Am Coll Cardiol. 2009;54(suppl 1):S55–S66Adapted from McLaughlin VV, et al. Circulation. 2009;119(16):2250-2294.
Increased mean pulmonary arterial pressure (mPAP)*
>25 mm Hg at rest
Normal pulmonary capillary wedge pressure (PCWP)
<15 mm Hg
Increased pulmonary vascular resistance (PVR)†
>3 Wood units
Right Heart Catheterization Confirmed
* Normal resting mPAP = 8 – 20 mm Hg. † In ACCP/AHA expert consensus; in 4th World Symposium on PH, increased PVR given without a value. Significance of mPAP from 21 – 24 mm Hg unclear.
6
Updated Hemodynamic Definitions of Pulmonary Hypertension
Adapted from: Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
Definition Characteristics Clinical groupPre-capillary PH Mean PAP ≥25 mm Hg
PWP ≤15 mm Hg
CO normal or reduced
Pulmonary arterial hypertension
PH due to lung disease CTEPH PH with unclear or
multifactorial mechanisms
Post-capillary PH Mean PAP ≥25 mm Hg
PWP >15 mm Hg
CO normal or reduced
Passive = TPG ≤12 mm Hg
Reactive = TPG >12 mm Hg
PH due to left heart disease
CO = cardiac output.
TPG = transpulmonary pressure gradient.
7
2009 Updated Clinical Classification of Pulmonary Hypertension: Group 1
Idiopathic (IPAH) Heritable (PAH)
— BMPR2— ALK1— Endoglin (with or without hereditary hemorrhagic telangiectasia)— Unknown
Drugs and Toxins induced Associated with
— Connective Tissue Diseases— HIV Infection— Portal Hypertension— Congenital Heart Diseases— Schistosomiasis— Chronic hemolytic anemia
Persistent pulmonary hypertension of the newborn
Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.
8
2009 Updated Clinical Classification of Pulmonary Hypertension: Group 1'
Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH)
Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.
9
2009 Updated Clinical Classification of Pulmonary Hypertension: Group 2
Pulmonary hypertension owing to left heart disease— Systolic dysfunction— Diastolic dysfunction— Valvular disease
Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.
10
2009 Updated Clinical Classification of Pulmonary Hypertension: Group 3
Pulmonary hypertension owing to lung diseases and/or hypoxia— Chronic obstructive pulmonary disease— Interstitial lung disease— Other pulmonary diseases with mixed restrictive
and obstructive pattern— Sleep-disordered breathing— Alveolar hypoventilation disorders— Chronic exposure to high altitude— Developmental abnormalities
Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.
11
2009 Updated Clinical Classification of Pulmonary Hypertension: Group 4
Chronic thromboembolic pulmonary hypertension (CTEPH)
Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.
12
2009 Updated Clinical Classification of Pulmonary Hypertension: Group 5
Pulmonary hypertension with unclear multifactorial mechanisms
Hematologic disorders: myeloproliferative disorders, splenectomy
Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis
Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis
Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.
13
Important Changes in Updated Clinical Classification Schema
Change from “familial” to “heritable” PAH— With or without mutations
Classifying PAH due to schistosomiasis as Group 1
PAH due to PVOD and/or PCH in separate Group 1' as a combined subcategory
Separation of CTEPH into separate, single-entity category (Group 4)
Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.
Updated Diagnostic Algorithm for Pulmonary Arterial Hypertension
(PAH)
15
Diagnostic Algorithm for PH
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
History, Symptoms, Signs Suggestive of PH History, Symptoms, Signs Suggestive of PH
16
Diagnostic Algorithm for Pulmonary Hypertension: Clinical Presentation
Symptoms— Breathlessness— Fatigue— Syncope— Weakness— Angina— Abdominal distension
Signs— Accentuated pulmonary
component of second heart sound (P2) at apex
— Early systolic ejection click— Midsystolic ejection murmur— Left parasternal lift— Right ventricle S4 gallop— Prominent jugular “a” wave— Diastolic murmur of pulmonary
regurgitation— Holosystolic murmur of tricuspid
valve regurgitation— Cool extremities
Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.McGoon M, et al. Chest. 2004;126(suppl 1):14S-34S.
17
Other Physical Findings:Differential Diagnosis/PH Etiology
McGoon M, et al. Chest. 2004;126(suppl 1):14S-34S.
Finding Differential Diagnosis/PAH Etiology
Cyanosis Right-to-left shunt
Clubbing Rare in IPAHCongenital heart or pulmonary veno-occlusive disease
Rales, fine rales, abnormal breath sounds
Pulmonary congestion, parenchymal airway disease, PVOD, PCH, etc.
Obesity, kyphoscoliosis, enlarged tonsils
Hypoventilatory disorders
Sclerodermal skin changes, rashes, nail-fold capillary abnormalities
Associated connective tissue disorder
Peripheral venous insufficiency
Venous thrombosis, pulmonary thromboembolic disease
18
REVEAL Database: Most Frequent Symptoms at Diagnosis
Elliott EG, et al. Chest. 2007;132(suppl 4):631S.
Dyspnea at rest
Cough
Dizzy/lightheaded
Presyncope/syncope
Edema
Chest pain/discomfort
Other
Fatigue
Dyspnea on exertion84%
26%
24%
23%
21%
23%
16%
13%
11%
83%
29%
27%
20%
20%
20%
14%
13%
11%
0 25 50 75 100 Incidence (%)
IPAHAPAH
N=1479.
19
Diagnostic Algorithm for PH
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
History, Symptoms, Signs Suggestive of PH History, Symptoms, Signs Suggestive of PH
Consider Common Causes of PHConsider Common Causes of PH
Group 2: Left Heart DiseaseGroup 2: Left Heart Disease Group 3: Lung Diseases and/or Hypoxia
Group 3: Lung Diseases and/or Hypoxia
20
Initial Evaluation of Patients with Suspected PH
ECG Chest X-ray Transthoracic echocardiography Pulmonary function test High-resolution CT scan
Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
21
ECG Associated With Right Axis Deviation (RAD) and Right Ventricular Hypertrophy (RVH)
Image courtesy of Vallerie McLaughlin, MD
22
Electrocardiogram Associated With Right Bundle Branch Block Plus RVH
Image courtesy of Vallerie McLaughlin, MD
23
Chest X-Ray Findings Consistent with PH
Enlarged main and hilar pulmonary artery shadows
“Pruning” of peripheral pulmonary vasculature Right ventricular enlargement Patients may have normal chest x-ray Chest x-ray may reveal underlying causes
of PH
McGoon M, et al. Chest. 2004;126(suppl 1):14S-34S.
24
Chest X-Ray Consistent With PH
Image courtesy of Vallerie McLaughlin, MD
25
Echocardiogram:Parasternal Long Axis
Image courtesy of Vallerie McLaughlin, MD
26
Echocardiogram:Parasternal Short Axis
Image courtesy of Vallerie McLaughlin, MD
27
Echocardiogram: Apical Four Chamber
Image courtesy of Vallerie McLaughlin, MD
28
Echocardiogram: Tricuspid Regurgitation
Modified Bernoulli’s Equation:4 x (V)² + RAP = RVSP (PASP)
V=tricuspid jet velocity (m/s); RAP= right atrial pressure; RVSP=right ventricular systolic pressure; PASP=pulmonary artery systolic pressure.
Image courtesy of Vallerie McLaughlin, MD
29
Accuracy of PH Diagnosis by Echocardiography in Advanced Lung Disease
Cohort study of lung transplant patients (n=374)
All patients— Doppler echo 24 to 48 hours
prior to RHC Prevalence of PH: 25% Echo frequently inaccurate
leading to over diagnosis of pulmonary hypertension in patients with advanced lung disease
Arcasoy SM, et al. Am J Respir Crit Care Med. 2003;167(5):735-740.
0
10
20
30
40
50
60
70
Diagnosis of PH
Stu
die
s (%
)
OverestimationAccurateUnderestimation
NoPulmonary
Hypertension
PulmonaryHypertension
30
Pulmonary Function Tests and Arterial Blood Gases
Findings suggestive of PAH— DLCO 40% - 80% of
expected
— Mild to moderate reduction of lung volumes
— Peripheral airway obstruction
— Arterial O2 tension normal or slightly reduced at rest
— Arterial CO2 is reduced
Findings suggestive of alternate PH diagnoses— Hypoxic PH due to COPD
• Irreversible airway obstruction + increased residual volumes + reduced DLCO + normal or increased CO2 tension
— Interstitial lung disease• Decrease in lung
volume + decreased DLCO
Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
31
Actual Diagnoses of Patients Referred to PH Specialty Clinic
Moghbelli MH, et al. Am J Respir Crit Care Med. 2008;177:A923.
Interstitial Lung Disease
Venous Thromboembolism
Other
Structural Heart Disease
Obstructive Sleep Apnea
LV Dysfunction
Obstructive Lung Disease
All Alternative Diagnoses 85.0%
24.0%
22.0%
19%
13.0%
12.0%
5.0%
5.0%
32
Algorithm for Diagnosing and Rating Severity of PH
Adapted from McLaughlin VV, et al. Circulation. 2009;119(16):2250-2294
History – Physical – CXR - ECGHistory – Physical – CXR - ECG
EchocardiographyEchocardiography
VQ Scan - ABGsVQ Scan - ABGs
Overnight OximetryOvernight Oximetry
HIV – ANA - LFTsHIV – ANA - LFTs
Functional TestingFunctional Testing
Right Heart CatheterizationRight Heart Catheterization
Index of Suspicion – Evaluate for LH & RH
disease
Index of Suspicion – Evaluate for LH & RH
disease
CTEPHCTEPH
OSAOSA
Underlying CausesUnderlying Causes
Functional SeverityFunctional Severity
Confirm DiagnosisConfirm Diagnosis
33
Diagnostic Algorithm for PH
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
History, Symptoms, Signs Suggestive of PH History, Symptoms, Signs Suggestive of PH
Consider Common Causes of PHConsider Common Causes of PH
Group 2: Left Heart DiseaseGroup 2: Left Heart Disease Group 3: Lung Diseases and/or Hypoxia
Group 3: Lung Diseases and/or Hypoxia
NoNo
34
Diagnostic Algorithm for PH
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
YesYes
NoNo
YesYesConsider Group 2 or 3 PHConsider Group 2 or 3 PH
“Out of proportion”PH
“Out of proportion”PH
Perform V/Q ScanPerform V/Q Scan
Segmental Perfusion DefectsSegmental Perfusion Defects
CTEPHCTEPH
PVOD/PCHPVOD/PCH
35
V/Q Scan for Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
Normal V/Q scan makes CTEPH unlikely— Sensitivity: 90% to 100% — Specificity: 94% to 100%
>1 segmental-sized or larger mismatched perfusion defects seen with CTEPH
Spiral CT may underestimate degree of obstruction in chronic CTEPH— ~7% false negative
McGoon M, et al. Chest. 2004;126(suppl 1):14S-34S.
36
Diagnostic Algorithm for PH
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
YesYes
NoNo
YesYesConsider Group 2 or 3 PHConsider Group 2 or 3 PH
“Out of proportion”PH
“Out of proportion”PH
Perform V/Q ScanPerform V/Q Scan
Segmental Perfusion DefectsSegmental Perfusion Defects
NoNo
CTEPHCTEPH
PVOD/PCHPVOD/PCH
Perform RHCPerform RHC
37
Recommended Measurements during Right Heart Catheterization
Systemic artery pressure Pulmonary capillary wedge pressure (or left ventricular
end diastolic pressure if not obtainable) Pulmonary artery pressure Right ventricle pressure Right atrium pressure Left atrium (if entered via a patent foramen ovale or
atrial septal defect) pressure Mixed venous oxygen saturation
— Site dependent if congenital systematic to pulmonary shunt present; if no shunt, SVO2 = PA oxygen saturation
Systemic arterial oxygen saturation
Gibbs JSR, et al. Heart. 2008;94(suppl 1):i1-i41.
38
Measuring Pulmonary Capillary Wedge Pressure
160
140
120
100
80
60
40
20
012
Time (seconds)
Pre
ssu
re (
mm
Hg
)
BalloonOcclusion
0 2 4 6 8 10
ARDSIPAH
Time Steady State is Longer in IPAH than in ARDS
Pulmonary Artery Pressure Decay Curve
ARDS: acute respiratory distress syndrome.
Souza R, et al. Crit Care. 2005;9:R132-R138.
39
Inaccurate Readings of PCWP
PA and RV Recordingsin Patient with PAH
RV Pressure MistakenlyRecorded as PCWP
Oudiz RJ, et al. Advances PAH. 2005;4(3):26-30.
40
Misclassification of PAH Through Reliance on PCWP vs LVEDP
Halpern SD, et al. Chest. 2009;136(1):37-43.
46.5
53.5
0
10
20
30
40
50
60
70
80
90
100
N = 11,523, all patients undergoing LHC and RHC over 10 years at single center.
Per
cen
t (
%)
PCWP ≤15 mm Hg LVEDP >15 mm Hg
PCWP ≤15 mm Hg LVEDP ≤15 mm Hg
41
Diagnostic Algorithm for PAH: Results of RHC
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
NoNo YesYes
Perform RHCPerform RHC
mPAP ≥25 mmHg
PWP ≤15 mmHg
Increased PVR
mPAP ≥25 mmHg
PWP ≤15 mmHg
Increased PVR
Search for other causes
Search for other causes
Specific diagnostic tests for PAH causes:Specific diagnostic tests for PAH causes:
42
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
Evaluating Causes of PAH
mPAP ≥25 mmHgPWP ≤15 mmHgIncreased PVR
mPAP ≥25 mmHgPWP ≤15 mmHgIncreased PVR
CTDCTD
Specific diagnostic tests for PAH causes:Specific diagnostic tests for PAH causes:
43
3-year Incidence of Pulmonary Hypertension in Systemic Sclerosis
Estimated incidence (per 100 patient years)
95% CI
All forms of pulmonary hypertension 1.37 0.74 – 2.00
Pulmonary arterial hypertension 0.61 0.26 – 1.20
PAH in limited cutaneous systemic sclerosis 0.40 0.11 – 1.03
PAH in diffuse cutaneous systemic sclerosis 1.25 0.34 – 3.20
Postcapillary pulmonary hypertension 0.61 0.26 – 1.20
PH secondary to pulmonary fibrosis 0.15 0.02 – 0.55
Hachulla E, et al. Arthritis Rheum. 2009;60(6):1831-1839.
44
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
Evaluating Causes of PAH
CTDCTD Drugs/ToxinsDrugs/Toxins
Specific diagnostic tests for PAH causes:Specific diagnostic tests for PAH causes:
mPAP ≥25 mmHgPWP ≤15 mmHgIncreased PVR
mPAP ≥25 mmHgPWP ≤15 mmHgIncreased PVR
45
PAH Due to Drugs and Toxins
Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.
Definite RiskAminorexFenfluramineDexfenfluramineToxic rapeseed oil
Possible RiskCocainePhenylpropanolamineSt. John’s wortChemotherapeutic agentsSSRI
Likely RiskAmphetaminesL-tryptophanMethamphetamines
Unlikely RiskOral contraceptivesEstrogenCigarette smoking
46
SSRIs in Late Pregnancy and Risk of Persistent Pulmonary Hypertension in the Newborn
Chambers CD, et al. N Engl J Med. 2006;354(6):579–587.
Maternal use of SSRIs
PPHN(N=377)
Matched Controls(N=836)
Adjusted Odds Ratio(95% CI)
P value
Never during pregnancy (%) 361 (95.8) 812 (97.1) 1 NS
Before wk 20 (%) 2 (0.5) 18 (2.2) 0.3 (0.1 - 1.2) 0.08
After wk 20 (%) 14 (3.7) 6 (0.7) 6.1 (2.2 - 16.8) 0.001
47
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
Evaluating Causes of PAH
CTDCTD
HIVHIV
Drugs/ToxinsDrugs/Toxins
Specific diagnostic tests for PAH causes:Specific diagnostic tests for PAH causes:
mPAP ≥25 mmHgPWP ≤15 mmHgIncreased PVR
mPAP ≥25 mmHgPWP ≤15 mmHgIncreased PVR
48
PAH and HIV Disease
Seen in approximately 0.5% of HIV-infected patients
Etiology appears related to HIV itself— No evidence for direct infection of HIV of vascular
endothelium— Higher prevalence among injection drug users
PAH incidence and course unaffected by HIV disease (stage or use of antiretrovirals)— ~66% of mortality related to PAH
Limsukon A, et al. Mt Sinai J Med. 2006;73(7):1037-1044.
49
Prevalence of Methamphetamine Use in HIV-PAH
Lewis JE et al. Am J Respir Crit Care Med. 2008;177:A444.
N = 17 patients with HIV-PAH
29%
41%
18%
12%
Methamphetamine
Methamphetamine + cocaine
Cocaine
Denied stimulant use
50
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
Evaluating Causes of PAH
CTDCTD
HIVHIV
Drugs/ToxinsDrugs/Toxins
Congenital heart disease
Congenital heart disease
Specific diagnostic tests for PAH causes:Specific diagnostic tests for PAH causes:
mPAP ≥25 mmHgPWP ≤15 mmHgIncreased PVR
mPAP ≥25 mmHgPWP ≤15 mmHgIncreased PVR
51
Congenital Heart Disease and PAH
Systemic to pulmonary shunts — Prevalence of PAH associated with shunts
estimated at 1.6 to 12.5 cases per million adults— May result in PAH if not repaired early in life— Eisenmenger Syndrome – severe PAH with reversal
of shunt direction
Post switch repair transposition of the great vessels
Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.
52
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
Evaluating Causes of PAH
CTDCTD
HIVHIV
PortopulmonaryPortopulmonary
Drugs/ToxinsDrugs/Toxins
Congenital heart disease
Congenital heart disease
Specific diagnostic tests for PAH causes:Specific diagnostic tests for PAH causes:
mPAP ≥25 mmHgPWP ≤15 mmHgIncreased PVR
mPAP ≥25 mmHgPWP ≤15 mmHgIncreased PVR
53
Portopulmonary Hypertension (PoPH)
Portal hypertension is main risk— Prevalence is 2% to 6% in this population
Pathologic changes in small arteries appears identical to IPAH
Right heart catheterization mandatory for diagnosing PoPH
Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.
54
Survival in Portopulmonary Hypertension Related to Cirrhosis
Le Pavec J, et al. Am J Respir Crit Care Med. 2008;178(6):637-643.
N = 154.
PoPH without cirrhosis
p = 0.003
PoPH with cirrhosis
0 12 24 36 48 60 72 84 96 108 120
0
0.2
0.4
0.6
0.8
1.0
Cu
mu
lati
ve S
urv
ival
Months
55
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
Evaluating Causes of PAH
CTDCTD
HIVHIV
PortopulmonaryPortopulmonary
Drugs/ToxinsDrugs/Toxins
Congenital heart disease
Congenital heart disease
SchistosomiasisSchistosomiasis
Specific diagnostic tests for PAH causes:Specific diagnostic tests for PAH causes:
mPAP ≥25 mmHgPWP ≤15 mmHgIncreased PVR
mPAP ≥25 mmHgPWP ≤15 mmHgIncreased PVR
56
Schistosomiasis-associated PAH
PH associated with schistosomiasis can have a similar clinical presentation to IPAH— Similar histologic findings
• Development of plexiform lesions
May include PoPH— 200 million people are infected with any of the 3
species of Schistosoma • 4% to 8% of patients will develop hepatosplenic disease
Invasive hemodynamics required for diagnosis— Post-capillary PH also prominent in this population
Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.
57
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
Evaluating Causes of PAH
CTDCTD
HIVHIV
PortopulmonaryPortopulmonary
PVOD/PCHPVOD/PCH
Drugs/ToxinsDrugs/Toxins
Congenital heart disease
Congenital heart disease
SchistosomiasisSchistosomiasis
Specific diagnostic tests for PAH causes:Specific diagnostic tests for PAH causes:
mPAP ≥25 mmHgPWP ≤15 mmHgIncreased PVR
mPAP ≥25 mmHgPWP ≤15 mmHgIncreased PVR
58
Pulmonary Venous Occlusive Disease / Pulmonary Capillary Hemangiomatosis
Shares characteristics of IPAH— Histology— Clinical features— Genetic alterations– familial forms for PVOD/PCH
(with or without identified mutations)
Distinct features— Crackles and clubbing, ground glass opacities,
septal thickening, mediastinal adenopathy, hemosiderin-laden macrophages, lower DLCO and PaO2
— Response to therapy also different• Risk for pulmonary edema with PAH-specific medications
Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.
59
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
Evaluating Causes of PAH
CTDCTD
HIVHIV
PortopulmonaryPortopulmonary
PVOD/PCHPVOD/PCH
Drugs/ToxinsDrugs/Toxins
Congenital heart disease
Congenital heart disease
SchistosomiasisSchistosomiasis
Chronic hemolysis
Chronic hemolysis
Specific diagnostic tests for PAH causes:Specific diagnostic tests for PAH causes:
mPAP ≥25 mmHgPWP ≤15 mmHgIncreased PVR
mPAP ≥25 mmHgPWP ≤15 mmHgIncreased PVR
60
New Group 1 Classification Category: PAH Due to Chronic Hemolytic Anemia
Chronic hemolytic anemias associated with PAH— Sickle cell disease — Thalassemia— Hereditary spherocytosis — Stomatocytosis— Microangiopathic hemolytic anemia
Prevalence not established Mechanism of PAH in this population still not well
understood PH also occurs with hemolytic anemias due to LVDD
with pulmonary venous hypertension PH may also be “mixed” pulmonary vasculopathy with
increased PCWP and increased PVRSimonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.
61
Evaluating Causes of PAH
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
No known cause
No known cause
CTDCTD
HIVHIV
PortopulmonaryPortopulmonary
PVOD/PCHPVOD/PCH
Drugs/ToxinsDrugs/Toxins
Congenital heart disease
Congenital heart disease
SchistosomiasisSchistosomiasis
Chronic hemolysis
Chronic hemolysis
Idiopathic or heritable PAHIdiopathic or heritable PAH
Specific diagnostic tests for PAH causes:Specific diagnostic tests for PAH causes:
mPAP ≥25 mmHgPWP ≤15 mmHgIncreased PVR
mPAP ≥25 mmHgPWP ≤15 mmHgIncreased PVR
Assessment of PAH
63
Prognostic Factors for Risk of PAH Disease Progression
McLaughlin VV, et al. Circulation. 2006;114(13):1417-1431.
Lower Risk Higher Risk
Evidence of RV failure No Yes
Progression Gradual Rapid
WHO Class II, III IV
6-minute walk distance >380 m <325 m
Brain natriuretic peptide <180 pg/mL >180 pg/mL
Echo findings Minimal RV dysfunction
Pericardial effusion; significant RV dysfunction
Hemodynamics Normal/near normal RAP and CI
High RAP, Low CI
64
Assessment of PH Severity: WHO Functional Classification (NYHA Modification for PH)
WHO Class Description
I No limitation of usual activities
II Mild limitation of usual activitiesNo discomfort at restNormal physical activity causes increased dyspnea, fatigue, chest pain, or presyncope
III Marked limitation of physical activityNo discomfort at restLess than ordinary activity causes increased dyspnea, fatigue, chest pain, or presyncope
IV Patient unable to perform any physical activity at rest and may have signs of right ventricular failureDyspnea and/or fatigue and/or syncope/near-syncope may be present at rest, and symptoms are increased by almost any physical activity
Rich S. World Health Organization. 1998.
65
6-Minute Walk Distance Correlates With IPAH Disease Severity
Miyamoto S, et al. Am J Respir Crit Care Med. 2000;161:487-492.
0
100
200
300
400
500
600
700
800
Dis
tan
ce W
alke
d in
6 M
inu
tes
(m)
Control NYHA II
*P<0.05 versus control.†P<0.05 versus NYHA Class II.‡P<0.05 vs NYHA Class III.
NYHA III NYHA IV
*
*†
*†‡
66
Impact of Baseline 6-Minute Walk Distance on Survival in IPAH/HPAH
Barst RJ, et al. N Engl J Med. 1996;334(5):296-302.
6-minute walk distance at baseline was the only independent predictor of survival (P<0.003)
6-MinuteWalk Distance
Survivors(n=73)
305 + 14
Deaths (n=8)
195 + 63
Epoprostenol (n=41)Conventional Therapy (n=40)
100
80
60
40
20
00 2 4 6 8 10 12
Week
Per
cen
t S
urv
iva
l
Epoprostenol Versus Placebo
67
NT-proBNP Elevations Correlate With Right Ventricular Systolic Dysfunction (RVSD) in PH
Blyth KG, et al. Eur Respir J. 2007;29(4):737-744.
0
1000
2000
3000
4000
5000
NT
-pro
BN
P (
ng
/L)
With RVSD
4127
354
Without RVSD
Threshold value RVD detection: 1,685 ng/L-1.Sensitivity for RVD 100%; specificity 94%.
68
Composite Scoring System Predicts Disease Progression in PAH
Anderson D, et al. Am J Respir Crit Care Med. 2008;177:A915.
Time (years)
Composite Score 3-year Survival
0-6
Su
rviv
al (
%) 100
0
75
50
0 1 2 3
25
6-9
9-12
0 1 2 3
Walk (m) 340 260-340 190-260 <190
FC 1 2 3 4
NT-proBNP <2000 >2000
QOL (CAMPHOR) <12 >12
Activity <11 >11
Symptoms <16 >16
^
69
Heritable PAH: Frequency of BMPR2 and ALK1 Mutations
Nakanishi N, et al. Am J Respir Crit Care Med. 2008;177:A256.
N = 222.
92.3
23.8
1.37.7 5.4
1.30
20
40
60
80
100
BMPR2 ALK1
Per
cen
t (%
)
HPAH IPAH APAH
^
Updated Treatment Algorithm For PAH
71
Supportive Therapy and General Measures in PAH
Oral anticoagulants (IPAH/HPAH)— Favorable data primarily from retrospective trials
Diuretics— Standard of care for right-heart failure— Clinician preference on choice of agents
Oxygen— Low-flow supplemental O2 improved outcome in clinical case
series; maintain SaO2 >92%• Not evaluated in randomized controlled trial
Digoxin— Modest increase in cardiac output— No data available on long-term management
Supervised exercise program rehabilitationBarst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.
72
Additional General and Supportive Measures in PAH
Avoid excessive exertion Avoid pregnancy Avoid constipation Appropriately refer to ensure psychological
and social support Provide appropriate training and counseling on
infection prevention— Including, but not limited to, infections related to
infusion/injection-based PAH therapy— Pneumococcal and flu vaccines
Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.
73
When to Initiate PAH-specific Therapy
No data support “wait-and-see” approach to diagnosed PAH
Data suggests that patients assigned to placebo in randomized controlled trials may fail to “catch-up” when enrolled into long-term observational arms
In FC II patients, bosentan improved outcomes consistent with usefulness of early intervention
Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.
74
Bosentan (n=86)
Placebo (n=91)
3Months
6Months
Mea
n C
han
ge
in 6
-Min
ute
Wal
kin
g D
ista
nce
(m
)
30
25
20
15
10
5
0
-5
-10
-15
-20
-25
EARLY: 6MWD Results With Bosentan for NYHA Class II PAH
Galie N, et al Lancet. 2008;371(9630):2093–2100.
Note: 15% of both groups also received open-label sildenafil.
75
Role of Calcium Channel Blockers (CCBs) in PAH
Acute vasodilator challenge should be performed during right heart catheterization— Use inhaled NO or IV epoprostenol for acute challenge
Favorable responders to vasodilator challenge may be treated with CCBs— Decrease in mPAP of at least 10 mm Hg to <40 mm Hg— Increased or unchanged cardiac output— Amlodipine, diltiazem, nifedipine recommended agents
• Avoid verapamil
Patients who fail acute vasodilator challenge should NOT be treated with CCBs
Patients should NOT be treated empirically with CCBs
Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.Badesch DB, et al. Chest. 2004;126(suppl 1):35S-62S.
76
French Registry:Response to Acute Vasodilator Challenge
0
2
4
6
8
10
12
Res
po
nse
(%
)
Idiopathic
N=649.Challenge with vasodilator at time of right heart catheterization.
10.3%
Humbert M, et al. Am J Respir Crit Care Med. 2006;173(9):1023-1030.
0%
2.6%
0% 0%
3.3%
1.6%
6.8%
Familial ConnectiveTissue
CongenitalHeart
PortalHypertension
Anorexigens HIV >2 Factors
77
Survival in IPAH on Oral Calcium Channel Blocker Therapy
Sitbon O, et al. Circulation. 2005;111(23):3105-3111.
Survival endpoint included those who received transplants or were lost to follow-up.
1.0
0.8
0.6
0.4
0.2
0
0 2 4 6 8 10 12 14 16 18
38 33 30 22 13 8 3 3 2 1
Years
Failures
Cu
mu
lati
ve S
urv
ival Responders
19 12 7 4 0Subjectsat Risk (n)
RespondersFailures
Long-term Calcium Channel Blocker Therapy
78
PAH-specific Therapies Approved for Use in the US
Endothelin Receptor Antagonists
Phosphodiesterase-type 5 Inhibitors
Prostanoids – Prostacyclin Analogs
Ambrisentan (PO) Sildenafil (PO) Epoprostenol (IV)
Bosentan (PO) Tadalafil (PO) Iloprost (inhaled)
Treprostinil (IV, SC, and inhaled)
FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name. Accessed November 1, 2009.
79
Updated Guidelines: PAH-Specific Therapies Available in the US
Adapted from Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.
Strength of Recommendation
WHO Class II WHO Class III WHO Class IV
A Ambrisentan, bosentan, sildenafil
Ambrisentan, bosentan, epoprostenol IV, iloprost inh, sildenafil
Epoprostenol IV
B Tadalafil Tadalafil, treprostinil SC
Iloprost inh
C Treprostinil SC
E/B Treprostinil IV Treprostinil IV, initial combo tx
E/C Ambrisentan, bosentan, sildenafil, tadalafil
Recently approved Treprostinil inh Treprostinil inh
80
Choice of Initial PAH-specific Therapy
Dependent on many factors— Disease severity— Approval status— Route of administration— Side-effect profile— Patient preference— Physician experience and clinical judgment
Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.
81
Updated Guidelines: Inadequate Clinical Response to Initial PAH Therapy
Atrial septostomy and/or
Lung transplantation
Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.
Failure to show improvement or deterioration with monotherapy
Sequential Combination Therapy
Prostanoids
EndothelinReceptor
Antagonists
PDE5Inhibitors