Download Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension:
Disease State and Treatment Options
Dr. William Harvey
Director Pulmonary Artery
Hypertension Clinic
IU Health North Hospital
Presentation Outline
 Definition of PAH
 Pathophysiology
 Epidemiology
 Clinical classification
 Natural history
 Signs and symptoms
 Diagnosis
 Treatment of PAH
2
Pulmonary Arterial Hypertension:
Definition and Histological Characteristics
 Mean PA pressure >25 mm Hg or 30 mm Hg with exercise
(PCWP ≤15 mm Hg)
 PVR >3 Wood units
 Increased pressure load on RV
 Eventual right-sided heart failure and death
adventitia
lumen
intima
media
Plexiform lesion
Normal pulmonary arteriole
Pulmonary arteriole in PAH
Barst et al. J Am Coll Cardiol. 2004;43:40S-47S.
4
Pathophysiology
Pulmonary Artery Hypertension
5
Pathogenesis of PAH: Vasoconstriction
Vasodilation
Decreased
NO synthase
Prostacyclin
NO
Vasoconstriction
Increased
Endothelin
Serotonin
Thromboxane
Mechanisms of Pathology for PAH
Endothelin pathway
Prostacyclin pathway
Nitric oxide pathway
Preproendothelin
Endot
helial
cells
Proendothelin
L-arginine
Arachidonic acid
Prostaglandin I2
NOS
Endothelin-1
EndothelinEndothelinreceptor A
receptor B
Nitric oxide
Exogenous
nitric oxide
Endothelinreceptor
antagonists
cGMP
Vasodilatation and
Phosphodiesterase
type 5
antiproliferation
Vasoconstriction and
proliferation
Phosphodiesterase
type 5 inhibitor
Humbert, et al. N Engl J Med.
Prostaglandin I2
cAMP
Prostacyclin
derivates
Vasodilatation and
antiproliferation
Pathophysiology
9
Epidemiology/Classification
Pulmonary Artery Hypertension
10
11
Epidemiology of PAH (WHO Group I)1
 Idiopathic PAH2
– Incidence is approximately 2 to 5 per million per year
– 2 to 3 times more prevalent in women
– Mean age of 37 years at diagnosis3
 Familial PAH
– Observed in about 6% to 10% of PAH cases3
 Associated PAH
– Approximately 27% of patients with CTD (scleroderma or mixed CTD) have PAH4
- Equally high prevalence in limited and diffuse disease5
– Each year, 0.5% of patients with HIV develop PAH6
– Prevalence of portopulmonary hypertension is 4% to 15% among patients
undergoing evaluation for liver transplantation7-8
– 15% to 30% of all patients with congenital heart disease have PAH9
1. Simonneau et al. J Am Coll Cardiol. 2004;43(12 suppl):5S-12S. 2. Gaine and Rubin. Lancet. 1998;352:719-725. 3. Rich et al. Ann Intern
Med. 1987;107:216-223. 4. Wigley et al. Arthritis Rheum. 2005;52:2125-2132. 5. Launay et al. J Rheumatol. 2007;34:1005-1011.
6. Limsukon et al. Mt Sinai J Med. 2006;73:1037-1044. 7. Colle et al. Hepatology. 2003;37:401-409. 8. Kuo et al. Chest. 1997;112:980-986.
9. Landzberg. Clin Chest Med. 2007;28:243-253.
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13
14
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Epidemiology of PAH
 Rare disease (orphan designation) of the pulmonary
microvasculature affecting 50,000 to 100,000 people in the
United States1
– Affects all ages and races
– Most prevalent in 4th and 5th decades of life
– Higher prevalence in females
 True incidence and prevalence may be underestimated
– Due to under diagnosis (e.g., in patients with HIV) and misdiagnosis
(e.g., asthma)2
 Prevalence of PAH may increase because of demographic
trends in associated conditions
1. Rubin. Chest. 1993;104:236-250. 2. Ghamra and Dweik. Cleve Clin J Med. 2003;70:S2-S8.
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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.
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.
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.
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.
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.
NYHA Functional Classification
NYHA
Definition
Class I
 No symptoms with ordinary physical activity
Class II
 Some symptoms with ordinary activity and
slight limitation of physical activity
Class III
 Symptoms with less than ordinary activity
and increased limitation of physical activity
Class IV
 Symptoms with any activity, possibly even
while at rest
Rich, ed. Executive summary from the World Symposium on Primary Pulmonary Hypertension, Evian, France, 1998:6-10.
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WHO Functional Classification
WHO
Definition
Class I
 No limitation of physical activity; no symptoms
with ordinary physical activity
Class II
 Slight limitation of physical activity; ordinary
physical activity causes PAH symptoms
Class III
 Marked limitation of physical activity; less than
ordinary physical activity causes PAH
symptoms
Class IV
 PAH symptoms with any physical activity and
even at rest; discomfort with any physical
activity; signs of right heart failure
Rubin. Chest. 2004;126(suppl 1):7S-10S.
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Natural History
Pulmonary Artery Hypertension
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Natural History of PAH: NIH Registry1,2
Predicted survival*
Percent survival
69%
56%
46%
38%
Predicted survival
Years
NIH = National Institutes of Health.
Predicted survival according to the NIH equation. Predicted survival rates were 69%, 56%, 46%, and 38% at 1, 2, 3,
and 4 years, respectively. The numbers of patients at risk were 231, 149, 82, and 10 at 1, 2, 3, and 4 years,
respectively. *Patients with primary pulmonary hypertension, now referred to as idiopathic pulmonary hypertension.
1. Rich et al. Ann Intern Med. 1987;107:216-223. 2. D’Alonzo et al. Ann Intern Med. 1991;115:343-349.
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Survival by PAH Etiology
Prognosis in Mixed Treated/Untreated Cohorts
100
Percent survival
80
CHD
CVD
HIV
PPH
PoPH
60
40
20
0
0
1
2
3
4
5
6
Years
CHD = congenital heart disease; CVD = collagen vascular disease; HIV = human immunodeficiency
virus; PAH = pulmonary arterial hypertension; PPH = primary pulmonary hypertension; PoPH =
portopulmonary hypertension.
McLaughlin et al. Chest. 2004;126:78S-92S.
26
PAH/SSc Progresses Even More Rapidly
100
Percent Survival
90
80
70
No Lung involvement
60
50
Lung Involvement without PAH
40
30
20
PAH
10
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Years from Diagnosis of Pulmonary Hypertension
Koh, et al. Br J Rheumatol 1996
13
Signs/Symptoms
Pulmonary Artery Hypertension
28
Symptoms of PAH
Dizziness and/or fainting
(syncope)
Shortness of breath (dyspnea)
Chest pain (angina)
Feeling tired or
worn out (fatigue)
Swollen ankles and legs
(edema)
McLaughlin et al. J Am Coll Cardiol. 2009;53:1573-1619.
See slides 33-39 for Important Safety Information about Remodulin
and refer to the Full Prescribing Information provided.
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Abstract
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.
50
Incidence (%)
75
100
Abstract
Implications of Syncope in Patients with PAH
100
Survival, %
80
P<0.01
60
40
Syncopal at diagnosis
Non-syncopal at diagnosis
20
0
0
1
2
3
4
Follow-up, years
5
N=475 adults with Group 1 PAH completing standardized symptom assessment at time of diagnosis.
P<0.01. Hazard ratio 2.56 [95% CI, 1.26, 4.84].
Le RJ, et al. Chest. 2010;138:927A.
Diagnosis of PAH
Diagnosis of PAH*
Diagnostic
Outcomes
History and physical†
 Evaluate signs and symptoms, family history,
associated diseases, ANAs
Chest x-ray†
 Assess for RV enlargement, peripheral hypovascularity
(pruning), and prominent pulmonary arteries
 Assess for RV and RA enlargement, RV
dysfunction, TR velocity to measure RVSP
Echocardiogram
Electrocardiogram
Cardiac
catheterization†
PFTs
VQ scan
 Evaluate for right heart enlargement and strain, cardiac
rhythm
 Evaluate for CHD; measure wedge pressure or LVEDP;
establish severity and prognosis; test vasodilator
therapy
 Assess obstructive and restrictive airway
disease
 Rule out thromboembolic disease
ANA = antinuclear antibody; CHD = congenital heart disease; LVEDP = left ventricular end-diastolic pressure; PFT =
pulmonary function test; RA = right atrial; RV = right ventricular; RVSP = right ventricular systolic pressure; TR =
tricuspid regurgitation; VQ = ventilation-perfusion.
*Additional tests may be ordered to rule out possible causes of PAH (pulmonary arteriography, blood tests [HIV,
hepatic disease, scleroderma], polysomnography [sleep-disordered breathing]). †Required for referral.
35
36
37
Chest X-Ray Consistent With PH
Image courtesy of Vallerie McLaughlin, MD
39
Signs of PAH on Echocardiogram with
Doppler Apical Four Chamber
IVS
Increased sPAP or TR jet
Right atrial and ventricular
hypertrophy
Flattening of intraventricular
septum
Small LV dimension
Dilated PA
McGoon, et al. Chest 2004
RV
LV
RA
LA
Echocardiogram:
Parasternal Short Axis
Image courtesy of Vallerie McLaughlin, MD
Echocardiogram:
Apical Four Chamber
Image courtesy of Vallerie McLaughlin, MD
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
44
45
46
Accuracy of PH Diagnosis by Echocardiography in Advanced
Lung Disease


70
All patients
–

Diagnosis of PH
Cohort study of lung transplant
patients (n=374)
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
60
Studies (%)

Overestimation
Accurate
Underestimation
50
40
30
20
10
0
Arcasoy SM, et al. Am J Respir Crit Care Med. 2003;167(5):735-740.
No
Pulmonary
Hypertension
Pulmonary
Hypertension
48
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
Abstract
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.
85.0%
50
51
52
53
54
55
56
57
Vasodilator Agents
Nitric Oxide:
– Inhaled gas, short half life, prospective studies, 2080ppm for 3- 5 minutes
Flolan:
– 2-10 ng/kg/min
– Increase by 2ng/kg/min q 15 minutes until goal
– SE: headache, flushing nausea
Response: mean PAP <40mmHg, 10 mmHg
average drop , maintain CO
59
60
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Treatment of Pulmonary Arterial
Hypertension
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
Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.

Supervised exercise program rehabilitation
Additional General and Supportive Measures
in PAH
 Avoid excessive exertion
 Avoid pregnancy
 Avoid constipation
 Encourage smoking cessation
 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.
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.
PAH-specific Therapies Approved
for Use in the US
Endothelin Receptor
Antagonists
Phosphodiesterase-type 5 Prostanoids – Prostacyclin
Inhibitors
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.
Updated Guidelines: PAH-Specific Therapies
Available in the US
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
E/B
Treprostinil SC
Treprostinil IV
E/C
Recently approved
Treprostinil IV, initial
combo tx
Ambrisentan, bosentan,
sildenafil, tadalafil
Treprostinil inh
Adapted from Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.
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.
Determinants of Disease Severity
Determinants of risk
Lower risk
Higher risk
Clinical evidence of RV failure No
Yes
Progression
Gradual
Rapid
WHO functional class
II, III
IV
6MWD
Longer (>400 m)
Shorter (<300 m)
BNP
Minimally elevated
Very elevated
Echocardiographic findings
Minimal RV dysfunction
Significant RV
dysfunction,
pericardial effusion
Hemodynamics
Normal/near normal RAP
and CI
High RAP, low CI
From McLaughlin and McGoon. With permission.
BNP = brain natriuretic peptide; CI = cardiac index; RAP = right artery pressure; RV = right
ventricular.
McLaughlin and McGoon. Circulation. 2006;114:1417-1431.
71
Comparison of Agents
Agent
Route of
Administratio
n
Adverse Events
Headache, jaw pain, flushing, nausea, diarrhea, skin
rash, musculoskeletal pain
Epoprostenol
Continuous IV
infusion
Iloprost
Adaptive aerosol Headache, cough, flushing, jaw pain
device
Treprostinil
» Subcutaneous
» IV
» Pain and erythema at injection site, headache,
nausea, diarrhea, rash
» Headache, jaw pain, flushing, nausea, diarrhea, skin
rash, musculoskeletal pain
Ambrisentan
Oral
Hepatotoxicity (LFT elevation ≥ 3x ULN ~ 2%), lower
extremity edema
Bosentan
Oral
Hepatotoxicity (LFT elevation ≥ 3x ULN ~ 10%), lower
extremity edema, anemia
Sildenafil
Oral
Headache, flushing, dyspepsia, epistaxis
Tadalafil
Oral
Headache, dyspepsia, back pain, myalgia, flushing
McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619.
Pulmonary Arterial Hypertension Treatment Options*
Product
Delivery
Frequency
Indicated population
Oral
t.i.d.
WHO group I
Letairis™ (ambrisentan)
Oral
q.d.
WHO class II-III
Tracleer® (bosentan)
Oral
b.i.d.
WHO class III-IV
Flolan® (epoprostenol sodium)
Injection
IV
Continuous
NYHA FC III-IV
Remodulin® IV
(treprostinil sodium) Injection
IV
Continuous
NYHA FC II-IV
Remodulin® SC
(treprostinil sodium) Injection
SC
Continuous
NYHA FC II-IV
Ventavis® (iloprost) Inhalation
Solution
Inhaled
6-9 x daily
NYHA III-IV
PDE-5 inhibitor
Revatio™ (sildenafil citrate)
Endothelin receptor antagonists
Prostacyclins
*It is important to note that peer-reviewed, head-to-head analyses of the effectiveness of these products have
never been conducted. Only a healthcare provider can determine the proper PAH therapy for each patient.
Flolan is a registered trademark of GlaxoSmithKline. Ventavis and Tracleer are registered trademarks of Actelion Pharmaceuticals US, Inc.
Letairis is a trademark of Gilead Sciences, Inc. Revatio is a trademark of Pfizer Inc. Remodulin is a registered trademark of United
Therapeutics Corp.
73
Treatment Guidelines: Algorithm
General care
Oral anticoagulants ± diuretics ± oxygen ± digoxin
Acute vasoreactivity testing
Positive
Negative
Oral CCB
Sustained response
Yes
No
Lower risk
ETRAs or PDE-5 inhibitors (oral)
Epoprostenol or treprostinil (IV)
Iloprost (inhaled)
Treprostinil (SC)
Higher risk
Epoprostenol or treprostinil (IV)
Iloprost (inhaled)
ETRAs or PDE-5 inhibitors (oral)
Treprostinil (SC)
Investigational protocols
Combination regimens
Continue CCB
Atrioseptostomy
Lung transplantation
Clinical reassessment: consider additional
therapy if goals are not met
From McLaughlin and McGoon. With permission.
CCB = calcium channel blocker; ETRA = endothelin receptor antagonist; PDE-5 = phosphodiesterase type-5.
McLaughlin and McGoon. Circulation. 2006;114:1417-1431.
74
Calcium Channel Blocker Therapy
 Indicated for IPAH patients who respond to acute
vasodilator* testing at the time of cardiac catheterization
– Response defined by reduction in mPAP ≥10 mm Hg to a mPAP
≤40 mm Hg, with an unchanged or increased CO1
 Approximately 12.8% of patients respond to acute
vasodilator testing2
– Only 6.8% had a favorable clinical response to chronic CCB
therapy at 1 year
 Other PAH treatments should be evaluated if patient
does not improve to FC I or II
CO = cardiac output; mPAP = mean pulmonary arterial pressure.
*Inhaled nitric oxide, adenosine, or epoprostenol.
1. Badesch et al. Chest. 2007;131:1917-1928. 2. Sitbon et al. Circulation. 2005;111:3105-3111.
75
Key Treatment Goals
 Improve quality of life and survival
 Improve to FC I or II
 Improve 6MWD to ≥380 m
 Improve hemodynamics
 Alleviate symptoms
McLaughlin and McGoon. Circulation. 2006;114:1417-1431.
76
Treatment Algorithm According to Risk
LOWER-RISK PATIENTS*
ORAL MED
ETRAs
PDE-5
inhibitors
PROSTACYCLIN
Intravenous
Inhaled
Subcutaneous
HIGHER-RISK PATIENTS†
PROSTACYCLIN
Intravenous
Inhaled
Subcutaneous
ETRA = endothelin receptor antagonist; PDE-5 = phosphodiesterase type-5.
*Important characteristics of lower risk include WHO FC II and III, 6MWD >400 m, and minimal
RV dysfunction. †Key characteristics of higher risk include WHO FC IV, 6MWD <300 m, and
significant RV dysfunction.
McLaughlin and McGoon. Circulation. 2006;114:1417-1431.
77
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.
Atrial septostomy
and/or
Lung transplantation
Conclusions
Recognize potential
for PH based on signs
and symptoms
Once start therapy
have close clinical f/u
to follow response
Identify etiology of PH Decide on treatment
and treat reversible
goals
causes
Consider referral to
Use right heart cath to
PAH center or clinic
confirm dx, and help
Future may be
risk stratify
combination therapy
79