Sr Mngt Presentation 2005 - Lafayette Medical Education
Download
Report
Transcript Sr Mngt Presentation 2005 - Lafayette Medical Education
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.
12
13
14
15
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.
16
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.
22
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.
23
Natural History
Pulmonary Artery Hypertension
24
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.
25
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.
30
31
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
62
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