Pulmonary Hypertension. Pulmonary Arterial Hypertension Diagnosis, Impact and Outcomes
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1 Pulmonary Hypertension Pulmonary Arterial Hypertension Diagnosis, Impact and Outcomes
2 Pulmonary Arterial Hypertension Disease of small pulmonary arteries Characteristic changes Medial hypertrophy Intimal proliferation In situ thrombosis Plexiform lesions Endothelial Proliferation Medial Hypertrophy Plexiform lesion
3 Pathobiology of PAH Collagen Vascular Disease Congenital Heart Disease Portal Hypertension HIV Infection Drugs and Toxins Pregnancy Intima Aventitia Media Abnormal BMPR2 Gene Other Genetic Factors Early Intimal Proliferation Endothelial Dysfunction Nitric Oxide Synthase Prostacyclin Production Thromboxane Production Endothelin 1 Production Vascular Smooth Muscle Dysfunction Impaired Voltage-Gated Potassium Channel (K v1.5 ) Smooth Muscle Hypertrophy Adventitial and Intimal Proliferation In situ Thrombosis Plexiform Lesion Loss of Response to Short- Acting Vasodilator Trial Smooth Muscle Hypertrophy Advanced Vascular Lesion Vasoconstriction IRREVERSIBLE DISEASE Gaine S. J Am Med Assoc 2000;284:
4 Symptoms Fatigue Shortness of breath Chest pain Dizziness Palpitations Syncope/fainting Edema/swelling Increased abdominal girth Hemoptysis Jaundice Abdominal pain Hoarseness
5 Pathophysiology: Disease Progression Pre-symptomatic/ Compensated Symptomatic/ Decompensating Declining/ Decompensated CO Symptom Threshold PAP PVR Time Right Heart Dysfunction
6 Idiopathic Pulmonary Arterial Hypertension (PPH) Survival (%) % Est. Median survival: 2.8 yrs (95% CI, 1.9 to 3.7 years) 48% 34% Years of follow up adapted from D Alonzo GE, et al. Ann Int Med 1991;115:
7 Prognosis of IPAH Advanced lung cancer WHO Class IV IPAH 6 months Advanced colorectal cancer Advanced breast cancer WHO Class III IPAH 2.6 years WHO Class I - II IPAH 4.9 years Ischemic cardiomyopathy Survival (years) 7 D'Alonzo, Barst et al. Ann Intern Med 1991; 115: Kato et al. Cancer 2001; 92: Felker et al. N Engl J Med 2000; 342:
8 Survival in PAH Percent survival Portopulmonary Connective tissue disease Congenital heart disease Years HIV IPAH McLaughlin VV et al. CHEST
9 Treatment Algorithm
10 Updated Definition of PAH Right Heart Catheterization Confirmed Increased mean pulmonary arterial pressure (mpap)* Normal pulmonary capillary wedge pressure (PCWP) Increased pulmonary vascular resistance (PVR) >25 mm Hg at rest <15 mm Hg >3 Wood units * Normal resting mpap = 8 20 mm Hg. In ACCF/AHA expert consensus; in 4th World Symposium on PH, increased given PVR without a value. Significance of mpap from 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):
11 Updated PAH Classification (2008) IPAH HPAH Associated: Connective Tissue Disease Drugs and Toxins Congenital Heart Disease Schistosomiasis HIV Portal Hypertension Chronic Hemolytic Anemia Associated with venous or capillary involvement (PVOD, PCH)
12 PH Not PAH Pulmonary venous hypertension systolic or diastolic dysfunction or valvular disease Pulmonary hypertension associated with hypoxemia/parenchymal parenchymal lung disease (COPD, ILD, sleep disordered breathing, alveolar hypoventilation disorders, altitude) Chronic thromboembolic PH Miscellaneous
13 Diagnostic tests ECG CXR Echocardiogram Ventilation perfusion lung scan Pulmonary angiogram Chest CT scan Pulmonary function testing (oximetry) [sleep study] RIGHT HEART CATHETERIZATON Serological testing HIV Connective tissue diseases Liver function and hepatitis profile
14 Accuracy of PH Diagnosis by Echo in Advanced Lung Disease Diagnosis of PH 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 Studies (%) Overestimation Accurate Underestimation No Pulmonary Hypertension Pulmonary Hypertension Arcasoy SM, et al. Am J Respir Crit Care Med. 2003;167(5):
15 PH Diagnostic Algorithm History, Symptoms, Signs Suggestive of PH Consider Common Causes of PH GLeft Heart Disease Lung Diseases and/or Hypoxia No Adapted from Galie N, et al. Eur Heart J. 2009;30(20):
16 PAH Diagnostic Algorithm Perform RHC mpap 25 mmhg PCWP 15 mmhg 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):
17 Evaluating Causes of PAH mpap 25 mmhg PWP 15 mmhg Increased PVR Specific diagnostic tests for PAH causes CTD HIV Portopulmonary PVOD/PCH No known cause Idiopathic or heritable PAH Drugs/Toxins Congenital heart disease Schistosomiasis Chronic hemolysis Adapted from Galie N, et al. Eur Heart J. 2009;30(20):
18 PH Diagnosing and Disease Severity History Physical CXR - ECG Echocardiography Index of Suspicion Evaluate for LH & RH disease VQ Scan ABGs/Pulse Oximetry CTEPH Overnight Oximetry HIV Serology (ANA) - LFTs Functional Capacity Testing Obstructive Sleep Apnea Underlying Causes Functional Severity Right Heart Catheterization Confirm Diagnosis Adapted from McLaughlin VV, et al. Circulation. 2009;119(16):
19 Goals of PAH Treatment Improve Overall Quality of Life Improve Survival
20 PAH approved therapy Prostacyclin analogues Flolan - IV (epoprostenol( epoprostenol) Remodulin IV, subcutaneous (treprostinil( treprostinil) Tyvaso inhaled (treprostinil( treprostinil) Ventavis inhaled (iloprost( iloprost) Endothelin receptor antagonists Tracleer - oral ( bosentan) Letairis - oral (ambrisentan( ambrisentan) Phosphodiesterase 5 inhibitors Revatio - oral ( sildenafil) Adcirca - oral (tadalafil( tadalafil)
21 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 E/C Treprostinil IV Treprostinil SC Treprostinil IV, initial combo tx Ambrisentan, bosentan, sildenafil, tadalafil Recently approved Treprostinil inh Treprostinil inh Adapted from Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.
22 Evaluation of Response to Therapy Physical exam JVD, murmurs, edema, ascites,, liver enlargement, hypotension (systolic BP<120) Functional history (WHO or NYHA functional classification, 6 minute walk, exercise test Labs - BNP, renal and hepatic function Echocardiography pericardial effusion Right heart catheterization RAP, CI
23 Prognostic Factors for Risk of PAH Disease Progression 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 Hemodynamics Minimal RV dysfunction Normal/near normal RAP and CI Pericardial effusion; significant RV dysfunction High RAP, Low CI McLaughlin VV, et al. Circulation. 2006;114(13):
24 Assessment of PH Severity: WHO Functional Classification (NYHA Modification for PH) WHO Class I II III IV Description No limitation of usual activities Mild limitation of usual activities No discomfort at rest Normal physical activity causes increased dyspnea, fatigue, chest pain, or presyncope 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 Rich S. World Health Organization
25 6-Minute Walk Distance Correlates With IPAH Disease Severity Distance Walked in 6 Minutes (m) Control * NYHA II * NYHA III * NYHA IV *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:
26 Choice of Initial PAH- specific Therapy Dependent on many factors Disease severity Approval status Route of administration Side-effect effect profile Patient preference Physician experience and clinical judgment Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.
27 Administration of Chronic IV Epoprostenol (Flolan ) Rapidly (t 1 / 2 = 3 min) hydrolyzed in circulation to 6-keto-PGF 1α No oral preparation Must be given via continuous intravenous infusion to achieve sustained pharmacologic effect
28
29 IV Epoprostenol: Tolerability and Safety Jaw pain Headache Diarrhea, Nausea Rash Leg and foot pain Impotence Weight loss Infection, Sepsis Thromboemboli events Systemic hypotension Increased ascites Coronary steal Rebound PH (interrupt infusion) Thrombocytopenia
30 Side effects PDE 5 inhibitors: headache, nosebleeds, nasal congestion, conjunctival injection, lightheadedness ETRA-, edema, nasal congestion, headache, acute hepatotoxicity Inhaled prostacyclin analogues: cough, nausea, headache, flushing, lightheadedness, time consuming Intravenous/subcutaneous prostacyclin analogues: nausea, vomiting, diarrhea, anorexia, weight loss, flushing and rash, faintness, time consuming, leg pain, infection, sepsis, thromboembolic events, e.g. stroke, pulmonary emboli
31 Cold Packs 1993 Mixing
32 Disability Treating physicians - examinations and reports Hospital and lab records Observations of the claimant s abilities during exams Estimate of functional classification ( NYHA or WHO) Activities of daily living Work history Treatments and their success/failures and side effects The claimant s own statements about his or her limitations Any PH physician would be willing to expand on their evaluation of the patients limitations if so requested
33 Composite Scoring System Predicts Disease Progression in PAH Survival (%) Composite Score 3-year Survival Time (years) Walk (m) <190 FC NT-proBNP <2000 >2000 QOL (CAMPHOR) <12 >12 Activity <11 >11 Symptoms <16 > Anderson D, et al. Am J Respir Crit Care Med. 2008;177:A915.
34 34
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