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Transcript of Pulmonary Arterial Hypertension: Disease State and Treatment Options Dr. William Harvey Director...
Pulmonary Arterial Hypertension: Disease State and Treatment Options
Dr. William HarveyDirector Pulmonary Artery
Hypertension ClinicIU Health North Hospital
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Presentation Outline
Definition of PAH
Pathophysiology
Epidemiology
Clinical classification
Natural history
Signs and symptoms
Diagnosis
Treatment of PAH
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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
lumen
media
intima
adventitia
Normal pulmonary arteriole
Plexiform lesion
Pulmonary arteriole in PAH
Barst et al. J Am Coll Cardiol. 2004;43:40S-47S.
PathophysiologyPulmonary Artery Hypertension
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Pathogenesis of PAH: Vasoconstriction
Decreased NO synthaseProstacyclinNO Increased
EndothelinSerotoninThromboxane
Vasodilation
Vasoconstriction
Mechanisms of Pathology for PAH
Humbert, et al. N Engl J Med. 2004;351:1425-1436.
Nitric oxide
cGMPVasodilatation and
antiproliferation
Endothelial cells
Nitric oxide pathway
Preproendothelin ProendothelinL-arginine
NOS
Arachidonic acid Prostaglandin I2
Prostaglandin I2
cAMPVasodilatation and
antiproliferationVasoconstriction and
proliferation
Endothelin-receptor A
Endothelin-receptor B
Endothelin pathway Prostacyclin pathway
Endothelin-1
Endothelin-receptor
antagonists
Exogenous nitric oxide
Prostacyclinderivates
Phosphodiesterase type 5 inhibitor
Phosphodiesterase type 5
Pathophysiology
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Epidemiology/ClassificationPulmonary Artery Hypertension
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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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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.
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.
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NYHA Functional Classification
Rich, ed. Executive summary from the World Symposium on Primary Pulmonary Hypertension, Evian, France, 1998:6-10.
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
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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.
Natural HistoryPulmonary Artery Hypertension
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Natural History of PAH: NIH Registry1,2
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.
Predicted survival*
69%
56%
46%
38%
Predicted survivalPer
cent
sur
viva
l
Years
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Survival by PAH Etiology
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.
0
20
40
60
80
100
0 1 2 3 4 5 6
CHD
CVD
HIV
PPH
PoPH
Years
Per
cent
sur
viva
l
Prognosis in Mixed Treated/Untreated Cohorts
PAH/SSc Progresses Even More Rapidly
Koh, et al. Br J Rheumatol 1996
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Years from Diagnosis of Pulmonary Hypertension
Per
cen
t S
urv
ival
PAH
Lung Involvement without PAH
No Lung involvement
Signs/Symptoms Pulmonary Artery Hypertension
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Symptoms of PAH
McLaughlin et al. J Am Coll Cardiol. 2009;53:1573-1619.
Shortness of breath (dyspnea)
Chest pain (angina)
Swollen ankles and legs (edema)
Dizziness and/or fainting (syncope)
Feeling tired or worn out (fatigue)
See slides 33-39 for Important Safety Information about Remodulin and refer to the Full Prescribing Information provided.
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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.
Abstract
Abstract
Implications of Syncope in Patients with PAH
Le RJ, et al. Chest. 2010;138:927A.
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].
100
80
60
40
20
00 1 2 3 4 5
P<0.01
Syncopal at diagnosisNon-syncopal at diagnosis
Su
rviv
al, %
Follow-up, years
Diagnosis of PAH
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Diagnosis of PAH*
Diagnostic OutcomesHistory and physical† Evaluate signs and symptoms, family history,
associated diseases, ANAsChest x-ray† Assess for RV enlargement, peripheral hypovascularity
(pruning), and prominent pulmonary arteriesEchocardiogram Assess for RV and RA enlargement, RV
dysfunction, TR velocity to measure RVSPElectrocardiogram Evaluate for right heart enlargement and strain, cardiac
rhythmCardiac catheterization†
Evaluate for CHD; measure wedge pressure or LVEDP;
establish severity and prognosis; test vasodilator therapy
PFTs Assess obstructive and restrictive airway disease
VQ scan Rule out thromboembolic disease
*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.
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.
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Chest X-Ray Consistent With PH
Image courtesy of Vallerie McLaughlin, MD
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Signs of PAH on Echocardiogram with Doppler Apical Four Chamber
Increased sPAP or TR jet
Right atrial and ventricular hypertrophy
Flattening of intraventricular septum
Small LV dimension
Dilated PA
LVRV
LARA
IVS
McGoon, et al. Chest 2004
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
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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
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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%
Abstract
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Vasodilator Agents
Nitric Oxide:
– Inhaled gas, short half life, prospective studies, 20-80ppm 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
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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
Supervised exercise program rehabilitation
Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.
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 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.
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
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.
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Determinants of Disease Severity
BNP = brain natriuretic peptide; CI = cardiac index; RAP = right artery pressure; RV = right ventricular. McLaughlin and McGoon. Circulation. 2006;114:1417-1431.
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.
Comparison of Agents
AgentRoute of
Administration
Adverse Events
Epoprostenol Continuous IV infusion
Headache, jaw pain, flushing, nausea, diarrhea, skin rash, musculoskeletal pain
Iloprost Adaptive aerosol device
Headache, cough, flushing, jaw pain
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. McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619.
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Pulmonary Arterial Hypertension Treatment Options*
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.
Product Delivery Frequency Indicated population
PDE-5 inhibitor
Revatio™ (sildenafil citrate) Oral t.i.d. WHO group I
Endothelin receptor antagonists
Letairis™ (ambrisentan) Oral q.d. WHO class II-III
Tracleer® (bosentan) Oral b.i.d. WHO class III-IV
Prostacyclins
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
*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.
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Treatment Guidelines: Algorithm
CCB = calcium channel blocker; ETRA = endothelin receptor antagonist; PDE-5 = phosphodiesterase type-5.McLaughlin and McGoon. Circulation. 2006;114:1417-1431.
General careOral anticoagulants ± diuretics ± oxygen ± digoxin
Acute vasoreactivity testing
Oral CCB Lower risk Higher risk
Sustained response
Continue CCB
ETRAs or PDE-5 inhibitors (oral)
Epoprostenol or treprostinil (IV)Iloprost (inhaled)Treprostinil (SC)
Epoprostenol or treprostinil (IV)Iloprost (inhaled)
ETRAs or PDE-5 inhibitors (oral)Treprostinil (SC)
AtrioseptostomyLung transplantation
Clinical reassessment: consider additional therapy if goals are not met
Investigational protocolsCombination regimens
PositiveNegative
YesNo
From McLaughlin and McGoon. With permission.
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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.
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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.
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Treatment Algorithm According to Risk
ETRA = endothelin receptor antagonist; PDE-5 = phosphodiesterase type-5.
McLaughlin and McGoon. Circulation. 2006;114:1417-1431.
LOWER-RISK PATIENTS*
ETRAsPDE-5
inhibitors
ORAL MED
IntravenousInhaled
Subcutaneous
PROSTACYCLIN
HIGHER-RISK PATIENTS†
IntravenousInhaled
Subcutaneous
PROSTACYCLIN
*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.
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
Conclusions
Recognize potential for PH based on signs and symptoms
Identify etiology of PH and treat reversible causes
Use right heart cath to confirm dx, and help risk stratify
Once start therapy have close clinical f/u to follow response
Decide on treatment goals
Consider referral to PAH center or clinic
Future may be combination therapy
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