Today Nomenclature review - classification No!! Diagnosis Dated - PDF document

Pulmonary Arterial Hypertension: Is it Primary vs Review and Updates Secondary Pulmonary Veronica Franco, MD Hypertension? Section of Pulmonary Hypertension Section of Heart Failure and Transplantation Ohio State University Today… • Nomenclature review - classification No!! • Diagnosis Dated Nomenclature • Prognosis • Treatment 1

The 2003 Venice Classification of Non-PAH Pulmonary Hypertension • Pulmonary hypertension (PH) with left heart Is it Pulmonary Arterial disease – WHO Class 2 Hypertension (PAH) or � Trigger: High LA Pressure • PH with lung disease/hypoxemia - WHO Class 3 Non-PAH? � Trigger: Hypoxemia and Parenchyma Distortion • PH due to chronic thrombotic and/or embolic disease – WHO Class 4 � Trigger: Obstruction The 2003 Venice Classification of PAH - WHO Class 1 Pulmonary Arterial Hypertension • Pulmonary � Familial PAH (FPAH) Trigger: Mutation/Polymorphism � Idiopathic PAH (IPAH) Hypertension Is a � Associated PAH (APAH) • Connective tissue disease (CTD) Disease of Triggers • Human immunodeficiency virus (HIV) Trigger: Permissive • Portal hypertension Phenotype • Anorexigens • Congenital heart disease (CHD) � Persistent pulmonary hypertension of the newborn (PPHN) � PAH with venule/capillary involvement 2

Safety: Can it hurt the Importance of Classification: Why do it? patient? • Efficacy: What’s the trigger? Can you change it? • LV dysfunction: Pulmonary edema • Safety: Can it hurt the patient? • ILD/COPD: Worsen V/Q mismatch • Cost: How much are we spending for • CTEPH: Delay referral for limited efficacy and small changes in thromboendarterectomy QOL? Efficacy: What’s the trigger? Cost: How much are we Can you change it? spending for limited efficacy and small changes in QOL? • Bosentan: ~35-40k per year • Sildenafil: ~12-15k per year • Inhaled Iloprost: ~60k per year • IV Prostacyclins: ~60-120k per year 3

Pulmonary Arterial Hypertension • Classification Diagnosis PAH = RHC • Diagnosis • Prognosis • Treatment Schema for Patient Evaluation Cardiac Catheterization to Assess Severity and ?RVSP, RVE, RAE Echocardiogram Left heart disease (valvular, HF, CAD) Prognosis of PAH Bubble echo - Congenital heart disease Chest x-ray Emphysema • To measure wedge pressure or LVEDP Fibrosis Thoracic abnormality PFTs +/- Chest CT • Scrutinize wedge tracings!!!! Obstructive Sleep apnea Sleep study • Wedge sat; End expiration VQ scan, angiogram Chronic thromboembolic disease • To exclude or evaluate CHD HIV Serologies • To establish severity and prognosis CTD: scleroderma, SLE, RA, MCTD LFTs • To test vasodilator therapy Portopulmonary Hypertension Eval cirrhosis and Portal HTN Catheterization is required for every patient with Required for diagnosis of PAH suspected pulmonary HTN RHC Vasodilator study 4

Natural History of PAH: Pulmonary Arterial NIH Registry 1,2 Hypertension • Mean Pulmonary artery ≥ 25 mmHg Predicted survival* • Wedge pressure ≤ 15 mmHg 69% Percent survival • PVR > 3 Woods units 56% 46% 38% adventitia lumen intima Plexiform lesion media Years NIH = National Institutes of Health. Pulmonary arteriole in PAH Normal pulmonary arteriole 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. Barst et al. J Am Coll Cardiol . 2004;43:40S-47S. 1. Rich et al. Ann Intern Med . 1987;107:216-223. 2. D’Alonzo et al. Ann Intern Med . 1991;115:343-349. Pulmonary Arterial Survival by PAH Etiology Hypertension Prognosis in Mixed Treated/Untreated Cohorts 100 • Classification 80 CHD Percent survival CVD • Diagnosis HIV 60 PPH • Prognosis PoPH 40 20 • Treatment 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. 5

Correlation of Six-minute-walk PAH Determinants of Risk Test and WHO Functional Class Lower Risk Determinants of Risk Higher Risk Clinical evidence of 800 Distance walked in 6 minutes (m) No Yes * p <0.05 vs control subjects RV failure 700 † p <0.05 vs WHO functional class II Gradual Progression Rapid 600 ‡ p <0.05 vs WHO functional class III * II, III NYHA class IV *† 500 400 Longer (>400 m) 6MW distance Shorter (<300 m) 300 *†‡ Minimally elevated BNP Very elevated 200 Pericardial effusion, Echocardiographic Minimal RV dysfunction significant RV 100 findings dysfunction 0 Normal/near normal Control WHO II WHO III WHO IV Hemodynamics High RAP, low CI RAP and CI McLaughlin VV and McGoon M. Circulation . 2006;114:1417-1431. Miyamoto S et al. Am J Respir Crit Care Med. 2000;161:487-492. Plasma BNP as a Prognostic Impact of Functional Class Indicator of Mortality in Patients on Survival With PPH Functional Class Baseline BNP Follow-up BNP Functional Class at Baseline at 17±15 mos 100 100 100 100 Survival rate (%) BNP <180 pg/mL Survival rate (%) 80 BNP <150 pg/mL 80 80 80 60 60 Survival (%) Survival (%) p <0.0001 FC=1 60 BNP ≥ 150 pg/mL 60 40 40 FC=3 FC=2 40 40 20 20 BNP ≥ 180 pg/mL p <0.05 0 0 20 20 FC=3 FC=4 0 12 24 36 48 0 12 24 36 48 p=0.0001 by log-rank test FC=4 0 Time (mo) Time (mo) 0 0 12 24 36 48 60 72 84 0 12 24 36 48 60 72 84 No. at risk 162 33 95 70 48 30 20 10 No. at risk: 115 112 86 63 46 30 20 10 By multivariate analysis, higher BNP at baseline (RR=11.971, p= 0.0348) and at Months Months follow-up (RR=25.880, p= 0.0243) were independent predictors of mortality McLaughlin VV, et al. Circulation. 2002;106:1477-1482. Nagaya N et al. Circulation. 2000;102:865-870. 6

Predicting Survival and Schematic Progression of PAH Following Therapy Pre-symptomatic/ Symptomatic/ • Clinical parameters Compensated Decompensating � functional class CO � exercise capacity Symptom Threshold � neurohormones • Hemodynamics PAP • Imaging PVR � right ventricle: function and size Time CO= TPG / PVR � pulmonary artery remodeling (future) PAP=pulmonary artery pressure; PVR=pulmonary vascular resistance; TPG=transpulmonary gradient. Courtesy of: Vallerie V. McLaughlin, MD. Schematic Progression of PAH Schematic Progression of PAH Pre-symptomatic/ Pre-symptomatic/ Symptomatic/ Compensated Compensated Decompensating CO CO Symptom Threshold Symptom Threshold PAP PAP PVR PVR Time Time CO= TPG / PVR CO= TPG / PVR PAP=pulmonary artery pressure; PVR=pulmonary vascular resistance; TPG=transpulmonary gradient. PAP=pulmonary artery pressure; PVR=pulmonary vascular resistance; TPG=transpulmonary gradient. Courtesy of: Vallerie V. McLaughlin, MD. Courtesy of: Vallerie V. McLaughlin, MD. 7

Schematic Goals of Therapy Progression of PAH Pre-symptomatic/ Symptomatic/ Declining/ Compensated Decompensating Decompensated • Improve symptoms � 6-minute walk (>380 m) CO � functional class (I or II) Symptom Threshold � CPET (VO 2 max >10.4) � quality of life PAP Right Heart • Improve hemodynamics Dysfunction PVR • Improve survival TPG CO= Time PVR PAP=pulmonary artery pressure; PVR=pulmonary vascular resistance; TPG=transpulmonary gradient. Courtesy of: Vallerie V. McLaughlin, MD. Schematic Progression of PAH Pre-symptomatic/ Symptomatic/ Declining/ Compensated Decompensating Decompensated What Drug and CO When Symptom Threshold PAP Right Heart Dysfunction PVR TPG CO= Time PVR PAP=pulmonary artery pressure; PVR=pulmonary vascular resistance; TPG=transpulmonary gradient. Courtesy of: Vallerie V. McLaughlin, MD. 8

Survival in IPAH PAH Treatments - a Historical Overview Long-term CCB Responders 1 Long-term CCB responders Cumulative Survival CCB, IV treprostinil .8 anticoagulation, Sildenafil digitalis, diuretics .6 SC treprostinil p=0.0007 Ambrisentan .4 Epoprostenol Long-term CCB failure Iloprost Bosentan .2 <1995 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 0 0 2 4 6 8 10 12 14 16 18 (Years) Long-term CCB 38 33 30 22 13 8 3 3 2 1 Subjects responders at risk, n 19 12 7 4 0 Long-term CCB failure CCB = calcium channel blocker. O. Sitbon et al. Circulation 2005 ;111:3105-3111 PAH Basic therapy Oral anticoagulants, Diuretics, O 2 , Digoxin ... Vasodilator study When to use a Positive Negative Calcium Antagonist ? Oral CCB No CCB +++ Sustained Fall in mPAP > 10 mmHg Response + mPAP < 40 mmHg + Normal CO Yes Continue Sitbon O, et al. Circulation . 2005;111:3105-3111. CCB 3 rd World PAH Symposium. J Am Coll Cardiol 2004;43:1S-90S. ACCP Guidelines. Chest 2004;126:1S-92S. Galiè N, et al . ESC Guidelines. Eur Heart J 2004;25:2243-78. 9