Consensus Updates in PAH
Classification, Screening and Treatment
ROBYN BARST, MD
Professor Emerita of Pediatrics
Columbia University
College of Physicians & Surgeons
New York, New York
Faculty:
Content Development and Training
Robyn J. Barst, MD
Professor Emerita of Pediatrics
Columbia University College of Physicians & Surgeons
New York, New York
Vallerie McLaughlin, MD
Professor of Medicine
Director, Pulmonary Hypertension Program
University of Michigan
Ann Arbor, Michigan
2
Learning Objectives (CME, CE, CPE)

At the completion of this educational activity,
participants should be able to:
̶
̶
̶
̶
3
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 of
Pulmonary Arterial Hypertension
(PAH)
Updated Definition of PAH
Right Heart Catheterization Confirmed
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
* 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.
Adapted from Badesch DB, et al. J Am Coll Cardiol. 2009;54(suppl 1):S55–S66
Adapted from McLaughlin VV, et al. Circulation. 2009;119(16):2250-2294.
5
Updated Hemodynamic Definitions of
Pulmonary Hypertension
Definition
Characteristics
Clinical group
Pre-capillary PH
Mean PAP ≥25 mm Hg
PWP ≤15 mm Hg
CO normal or reduced

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

CO = cardiac output.
TPG = transpulmonary pressure gradient.
Adapted from: Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
6
Pulmonary arterial
hypertension
 PH due to lung disease
 CTEPH
 PH with unclear or
multifactorial mechanisms
PH due to left heart disease
2009 Updated Clinical Classification of
Pulmonary Hypertension: Group 1


Idiopathic (IPAH)
Heritable (PAH)
—
—
—
—


Drugs and Toxins induced
Associated with
—
—
—
—
—
—

BMPR2
ALK1
Endoglin (with or without hereditary hemorrhagic telangiectasia)
Unknown
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.
7
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.
8
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.
9
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.
10
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.
11
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.
12
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, singleentity category (Group 4)
Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.
13
Updated Diagnostic Algorithm for
Pulmonary Arterial Hypertension
(PAH)
Diagnostic Algorithm for PH
History, Symptoms, Signs Suggestive of PH
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
15
Diagnostic Algorithm for Pulmonary
Hypertension: Clinical Presentation

Symptoms
—
—
—
—
—
—

Breathlessness
Fatigue
Syncope
Weakness
Angina
Abdominal distension
Signs
— Accentuated pulmonary
—
—
—
—
—
—
—
—
Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
McGoon M, et al. Chest. 2004;126(suppl 1):14S-34S.
16
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
Other Physical Findings:
Differential Diagnosis/PH Etiology
Finding
Differential Diagnosis/PAH Etiology
Cyanosis
Right-to-left shunt
Clubbing
Rare in IPAH
Congenital 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
McGoon M, et al. Chest. 2004;126(suppl 1):14S-34S.
17
REVEAL Database:
Most Frequent Symptoms at Diagnosis
11%
11%
Dyspnea at rest
IPAH
APAH
13%
13%
Cough
14%
16%
Dizzy/lightheaded
20%
23%
Presyncope/syncope
20%
21%
Edema
20%
23%
Chest pain/discomfort
27%
24%
Other
29%
26%
Fatigue
83%
84%
Dyspnea on exertion
N=1479.
0
25
Elliott EG, et al. Chest. 2007;132(suppl 4):631S.
18
50
Incidence (%)
75
100
Diagnostic Algorithm for PH
History, Symptoms, Signs Suggestive of PH
Consider Common Causes of PH
Group 2: Left Heart Disease
Group 3: Lung Diseases
and/or Hypoxia
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
19
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.
20
ECG Associated With Right Axis Deviation (RAD)
and Right Ventricular Hypertrophy (RVH)
Image courtesy of Vallerie McLaughlin, MD
21
Electrocardiogram Associated With
Right Bundle Branch Block Plus RVH
Image courtesy of Vallerie McLaughlin, MD
22
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.
23
Chest X-Ray Consistent With PH
Image courtesy of Vallerie McLaughlin, MD
24
Echocardiogram:
Parasternal Long Axis
Image courtesy of Vallerie McLaughlin, MD
25
Echocardiogram:
Parasternal Short Axis
Image courtesy of Vallerie McLaughlin, MD
26
Echocardiogram:
Apical Four Chamber
Image courtesy of Vallerie McLaughlin, MD
27
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
28
Accuracy of PH Diagnosis by
Echocardiography in Advanced Lung Disease


Cohort study of lung
transplant patients (n=374)
All patients
Diagnosis of PH
70
— 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
Studies (%)

60
Overestimation
Accurate
Underestimation
50
40
30
20
10
0
Arcasoy SM, et al. Am J Respir Crit Care Med. 2003;167(5):735-740.
29
No
Pulmonary
Hypertension
Pulmonary
Hypertension
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
Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
30

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
Actual Diagnoses of Patients Referred
to PH Specialty Clinic
Interstitial Lung Disease
5.0%
Venous Thromboembolism
5.0%
Other
Structural Heart Disease
Obstructive Sleep Apnea
LV Dysfunction
Obstructive Lung Disease
12.0%
13.0%
19%
22.0%
24.0%
All Alternative Diagnoses
Moghbelli MH, et al. Am J Respir Crit Care Med. 2008;177:A923.
31
85.0%
Algorithm for Diagnosing and Rating
Severity of PH
History – Physical – CXR - ECG
Echocardiography
VQ Scan - ABGs
CTEPH
Overnight Oximetry
OSA
HIV – ANA - LFTs
Underlying Causes
Functional Testing
Functional Severity
Right Heart Catheterization
Adapted from McLaughlin VV, et al. Circulation. 2009;119(16):2250-2294
32
Index of Suspicion –
Evaluate for LH & RH
disease
Confirm Diagnosis
Diagnostic Algorithm for PH
History, Symptoms, Signs Suggestive of PH
Consider Common Causes of PH
Group 3: Lung Diseases
and/or Hypoxia
Group 2: Left Heart Disease
No
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
33
Diagnostic Algorithm for PH
Consider Group 2 or 3 PH
Yes
No
“Out of proportion”
PH
Perform V/Q Scan
CTEPH
Yes
Segmental Perfusion Defects
PVOD/PCH
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
34
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.
35
Diagnostic Algorithm for PH
Consider Group 2 or 3 PH
Yes
No
“Out of proportion”
PH
Perform V/Q Scan
CTEPH
Yes
PVOD/PCH
Segmental Perfusion Defects
No
Perform RHC
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
36
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.
37
Measuring Pulmonary Capillary Wedge
Pressure
Pulmonary Artery Pressure Decay Curve
160
Balloon
Occlusion
Pressure (mm Hg)
140
120
ARDS
IPAH
100
80
60
40
20
0
0
2
4
6
Time (seconds)
8
10
Time Steady State is Longer in IPAH than in ARDS
ARDS: acute respiratory distress syndrome.
Souza R, et al. Crit Care. 2005;9:R132-R138.
38
12
Inaccurate Readings of PCWP
PA and RV Recordings
in Patient with PAH
Oudiz RJ, et al. Advances PAH. 2005;4(3):26-30.
39
RV Pressure Mistakenly
Recorded as PCWP
Misclassification of PAH Through
Reliance on PCWP vs LVEDP
100
90
Percent (%)
80
70
53.5
60
46.5
50
40
30
20
10
0
PCWP ≤15 mm Hg
LVEDP >15 mm Hg
PCWP ≤15 mm Hg
LVEDP ≤15 mm Hg
N = 11,523, all patients undergoing LHC and RHC over 10 years at single center.
Halpern SD, et al. Chest. 2009;136(1):37-43.
40
Diagnostic Algorithm for PAH:
Results of RHC
mPAP ≥25 mmHg
PWP ≤15 mmHg
Perform RHC
Increased PVR
No
Yes
Search for
other causes
Specific diagnostic tests for PAH causes:
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
41
Evaluating Causes of PAH
mPAP ≥25 mmHg
PWP ≤15 mmHg
Increased PVR
Specific diagnostic tests for PAH causes:
CTD
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
42
3-year Incidence of Pulmonary
Hypertension in Systemic Sclerosis
Estimated
incidence (per
100 patient
years)
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.
43
95% CI
Evaluating Causes of PAH
mPAP ≥25 mmHg
PWP ≤15 mmHg
Increased PVR
Specific diagnostic tests for PAH causes:
CTD
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
44
Drugs/Toxins
PAH Due to Drugs and Toxins
Definite Risk
 Aminorex
 Fenfluramine
 Dexfenfluramine
 Toxic rapeseed oil
Possible Risk
 Cocaine
 Phenylpropanolamine
 St. John’s wort
 Chemotherapeutic agents
 SSRI
Likely Risk
 Amphetamines
 L-tryptophan
 Methamphetamines
Unlikely Risk
 Oral contraceptives
 Estrogen
 Cigarette smoking
Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.
45
SSRIs in Late Pregnancy and Risk of Persistent
Pulmonary Hypertension in the Newborn
Maternal use of
SSRIs
PPHN
(N=377)
Matched
Controls
(N=836)
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
Chambers CD, et al. N Engl J Med. 2006;354(6):579–587.
46
Adjusted Odds
Ratio
P
(95% CI)
value
Evaluating Causes of PAH
mPAP ≥25 mmHg
PWP ≤15 mmHg
Increased PVR
Specific diagnostic tests for PAH causes:
CTD
HIV
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
47
Drugs/Toxins
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.
48
Prevalence of Methamphetamine
Use in HIV-PAH
12%
29%
Methamphetamine
18%
Methamphetamine + cocaine
Cocaine
Denied stimulant use
41%
N = 17 patients with HIV-PAH
Lewis JE et al. Am J Respir Crit Care Med. 2008;177:A444.
49
Evaluating Causes of PAH
mPAP ≥25 mmHg
PWP ≤15 mmHg
Increased PVR
Specific diagnostic tests for PAH causes:
CTD
Drugs/Toxins
HIV
Congenital
heart disease
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
50
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.
51
Evaluating Causes of PAH
mPAP ≥25 mmHg
PWP ≤15 mmHg
Increased PVR
Specific diagnostic tests for PAH causes:
CTD
Drugs/Toxins
HIV
Congenital
heart disease
Portopulmonary
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
52
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.
53
Survival in Portopulmonary
Hypertension Related to Cirrhosis
PoPH without cirrhosis
Cumulative Survival
1.0
0.8
p = 0.003
0.6
PoPH with cirrhosis
0.4
0.2
0
0
12
24
36
48
60
72
84
96
Months
N = 154.
Le Pavec J, et al. Am J Respir Crit Care Med. 2008;178(6):637-643.
54
108 120
Evaluating Causes of PAH
mPAP ≥25 mmHg
PWP ≤15 mmHg
Increased PVR
Specific diagnostic tests for PAH causes:
CTD
Drugs/Toxins
HIV
Congenital
heart disease
Portopulmonary
Schistosomiasis
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
55
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.
56
Evaluating Causes of PAH
mPAP ≥25 mmHg
PWP ≤15 mmHg
Increased PVR
Specific diagnostic tests for PAH causes:
CTD
Drugs/Toxins
HIV
Congenital
heart disease
Portopulmonary
Schistosomiasis
PVOD/PCH
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
57
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.
58
Evaluating Causes of PAH
mPAP ≥25 mmHg
PWP ≤15 mmHg
Increased PVR
Specific diagnostic tests for PAH causes:
CTD
Drugs/Toxins
HIV
Congenital
heart disease
Portopulmonary
Schistosomiasis
PVOD/PCH
Chronic
hemolysis
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
59
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 PVR
Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.
60
Evaluating Causes of PAH
mPAP ≥25 mmHg
PWP ≤15 mmHg
Increased PVR
Specific diagnostic tests for PAH causes:
CTD
Drugs/Toxins
HIV
Congenital
heart disease
No known
cause
Portopulmonary
Schistosomiasis
PVOD/PCH
Chronic
hemolysis
Idiopathic or heritable PAH
Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.
61
Assessment of PAH
Prognostic Factors for Risk of PAH
Disease Progression
Lower Risk
Higher Risk
No
Yes
Progression
Gradual
Rapid
WHO Class
II, III
IV
>380 m
<325 m
Brain natriuretic peptide
<180 pg/mL
>180 pg/mL
Echo findings
Minimal RV
dysfunction
Pericardial effusion;
significant RV
dysfunction
Normal/near normal
RAP and CI
High RAP, Low CI
Evidence of RV failure
6-minute walk distance
Hemodynamics
McLaughlin VV, et al. Circulation. 2006;114(13):1417-1431.
63
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 activities
No discomfort at rest
Normal physical activity causes increased dyspnea, fatigue,
chest pain, or presyncope
III
Marked limitation of physical activity
No discomfort at rest
Less than ordinary activity causes increased dyspnea,
fatigue,
chest pain, or presyncope
Patient unable to perform any physical activity at rest and
may have signs of right ventricular failure
Dyspnea and/or fatigue and/or syncope/near-syncope may be
present at rest, and symptoms are increased by almost any
physical activity
IV
Rich S. World Health Organization. 1998.
64
Distance Walked in 6 Minutes (m)
6-Minute Walk Distance Correlates
With IPAH Disease Severity
800
700
600
*
500
*†
400
300
*†‡
200
100
0
Control
NYHA II
NYHA III
*P<0.05 versus control.
†P<0.05 versus NYHA Class II.
‡P<0.05 vs NYHA Class III.
Miyamoto S, et al. Am J Respir Crit Care Med. 2000;161:487-492.
65
NYHA IV
Impact of Baseline 6-Minute Walk
Distance on Survival in IPAH/HPAH
Epoprostenol Versus Placebo
Percent Survival
100
80
Survivors
(n=73)
60
Deaths
(n=8)
195 + 63
40
Epoprostenol (n=41)
Conventional Therapy (n=40)
20
0
0
2
4
6
8
10
Week
Barst RJ, et al. N Engl J Med. 1996;334(5):296-302.
66
6-Minute
Walk Distance
305 + 14
12
6-minute walk distance at baseline was the
only independent predictor of survival
(P<0.003)
NT-proBNP Elevations Correlate With Right
Ventricular Systolic Dysfunction (RVSD) in PH
5000
4127
NT-proBNP (ng/L)
4000
3000
2000
1000
354
0
With RVSD
Threshold value RVD detection: 1,685 ng/L-1.
Sensitivity for RVD 100%; specificity 94%.
Blyth KG, et al. Eur Respir J. 2007;29(4):737-744.
67
Without RVSD
Composite Scoring System Predicts ^
Disease Progression in PAH
Survival (%)
Composite Score 3-year Survival
100
0-6
75
50
6-9
25
9-12
0
0
Walk (m)
FC
NT-proBNP
1
Time (years)
0
1
2
3
340
260-340
190-260
<190
1
2
3
4
<2000
>2000
QOL (CAMPHOR)
<12
>12
Activity
<11
>11
Symptoms
<16
>16
Anderson D, et al. Am J Respir Crit Care Med. 2008;177:A915.
68
3
2
Heritable PAH: Frequency of BMPR2 ^
and ALK1 Mutations
BMPR2
100
ALK1
92.3
Percent (%)
80
60
40
23.8
20
7.7
5.4
1.3
1.3
0
HPAH
IPAH
N = 222.
Nakanishi N, et al. Am J Respir Crit Care Med. 2008;177:A256.
69
APAH
Updated Treatment Algorithm
For PAH
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 rehabilitation
Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.
71
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.
72
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.
73
Mean Change in 6-Minute
Walking Distance (m)
EARLY: 6MWD Results With Bosentan
for NYHA Class II PAH
30
Bosentan (n=86)
25
20
Placebo (n=91)
15
10
5
0
-5
-10
-15
-20
-25
3
Months
Note: 15% of both groups also received open-label sildenafil.
Galie N, et al Lancet. 2008;371(9630):2093–2100.
74
6
Months
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.
75
French Registry:
Response to Acute Vasodilator Challenge
12
10.3%
Response (%)
10
8
6.8%
6
4
3.3%
2.6%
1.6%
2
0
0%
Idiopathic
Portal Anorexigens
Familial Connective Congenital
Tissue
Heart Hypertension
N=649.
Challenge with vasodilator at time of right heart catheterization.
Humbert M, et al. Am J Respir Crit Care Med. 2006;173(9):1023-1030.
76
0%
0%
HIV
>2 Factors
Survival in IPAH on Oral Calcium
Channel Blocker Therapy
Long-term Calcium Channel Blocker Therapy
Cumulative Survival
1.0
Responders
0.8
0.6
Failures
0.4
0.2
0
0
2
4
6
8
10
12
14
16
18
Years
Subjects
at Risk (n)
38
19
33
12
30
7
22
4
13
0
8
3
3
2
Survival endpoint included those who received transplants or were lost to follow-up.
Sitbon O, et al. Circulation. 2005;111(23):3105-3111.
77
1
Responders
Failures
PAH-specific Therapies Approved
for Use in the US
Endothelin Receptor
Antagonists
Phosphodiesterasetype 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.
78
Updated Guidelines: PAH-Specific
Therapies Available in the US
Strength of
Recommendation
A
B
WHO Class II
Ambrisentan,
bosentan, sildenafil
Tadalafil
WHO Class III
Ambrisentan,
bosentan,
epoprostenol IV,
iloprost inh,
sildenafil
Tadalafil,
treprostinil SC
C
E/B
Treprostinil IV
Treprostinil inh
Adapted from Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.
79
Epoprostenol IV
Iloprost inh
Treprostinil SC
E/C
Recently approved
WHO Class IV
Treprostinil IV, initial
combo tx
Ambrisentan,
bosentan, sildenafil,
tadalafil
Treprostinil inh
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.
80
Updated Guidelines: Inadequate Clinical
Response to Initial PAH Therapy
Failure to show improvement or deterioration with monotherapy
Sequential Combination Therapy
Prostanoids
Endothelin
Receptor
Antagonists
PDE5
Inhibitors
Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.
81
Atrial septostomy
and/or
Lung transplantation