Pulmonary Arterial Hypertension: Review and Updates. Is it Primary vs Secondary Pulmonary Hypertension? No!! Dated Nomenclature. Veronica Franco, MD

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

2 The 23 Venice Classification of Non-PAH Pulmonary Hypertension Is it Pulmonary Arterial Hypertension (PAH) or Non-PAH? Pulmonary hypertension (PH) with left heart disease WHO Class 2 Trigger: High LA Pressure PH with lung disease/hypoxemia - WHO Class 3 Trigger: Hypoxemia and Parenchyma Distortion PH due to chronic thrombotic and/or embolic disease WHO Class 4 Trigger: Obstruction Pulmonary Hypertension Is a Disease of Triggers The 23 Venice Classification of PAH - WHO Class 1 Pulmonary Arterial Hypertension Familial PAH (FPAH) Trigger: Mutation/Polymorphism Idiopathic PAH (IPAH) Associated PAH (APAH) Connective tissue disease (CTD) Human immunodeficiency virus (HIV) Trigger: Portal hypertension Permissive Phenotype Anorexigens Congenital heart disease (CHD) Persistent pulmonary hypertension of the newborn (PPHN) PAH with venule/capillary involvement 2

3 Importance of Classification: Why do it? Efficacy: What s the trigger? Can you change it? Safety: Can it hurt the patient? Cost: How much are we spending for limited efficacy and small changes in QOL? Safety: Can it hurt the patient? LV dysfunction: Pulmonary edema ILD/COPD: Worsen V/Q mismatch CTEPH: Delay referral for thromboendarterectomy Efficacy: What s the trigger? Can you change it? Cost: How much are we spending for limited efficacy and small changes in QOL? Bosentan: ~35-4k per year Sildenafil: ~12-15k per year Inhaled Iloprost: ~6k per year IV Prostacyclins: ~6-12k per year 3

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

5 adventitia Pulmonary Arterial Hypertension Mean Pulmonary artery 25 mmhg Wedge pressure 15 mmhg > 3 Woods units Natural History of PAH: NIH Registry 1,2 Percent survival 69% Predicted survival* 56% 46% 38% intima lumen Plexiform lesion media Normal pulmonary arteriole Pulmonary arteriole in PAH Barst et al. J Am Coll Cardiol. 24;43:4S-47S. 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 1 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;17: D Alonzo et al. Ann Intern Med. 1991;115: Pulmonary Arterial Hypertension Classification Diagnosis Prognosis Treatment Survival by PAH Etiology Percent survival Prognosis in Mixed Treated/Untreated Cohorts Years CHD CVD HIV PPH PoPH 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. 24;126:78S-92S. 5

6 PAH Determinants of Risk Lower Risk No Gradual II, III Longer (>4 m) Minimally elevated Minimal RV dysfunction Normal/near normal RAP and CI Determinants of Risk Clinical evidence of RV failure Progression NYHA class 6MW distance BNP Echocardiographic findings Hemodynamics McLaughlin VV and McGoon M. Circulation. 26;114: Higher Risk Yes Rapid IV Shorter (<3 m) Very elevated Pericardial effusion, significant RV dysfunction High RAP, low CI Correlation of Six-minute-walk Test and WHO Functional Class Distance walked in 6 minutes (m) Miyamoto S et al. Am J Respir Crit Care Med. 2;161: * *p<.5 vs control subjects p<.5 vs WHO functional class II p<.5 vs WHO functional class III * * Control WHO II WHO III WHO IV Impact of Functional Class on Survival Survival (%) Functional Class at Baseline p=.1 by log-rank test No. at risk Months FC=3 FC=4 Survival (%) 1 No. at risk: Functional Class at 17±15 mos Months FC=1 FC=2 FC=3 FC= Plasma BNP as a Prognostic Indicator of Mortality in Patients With PPH Survival rate (%) Baseline BNP BNP <15 pg/ml BNP 15 pg/ml 2 p< Time (mo) p< By multivariate analysis, higher BNP at baseline (RR=11.971, p=.348) and at follow-up (RR=25.88, p=.243) were independent predictors of mortality Survival rate (%) Follow-up BNP BNP <18 pg/ml BNP 18 pg/ml Time (mo) McLaughlin VV, et al. Circulation. 22;16: Nagaya N et al. Circulation. 2;12:

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

8 Schematic Progression of PAH CO PAP Pre-symptomatic/ Compensated Symptom Threshold Symptomatic/ Decompensating Declining/ Decompensated Right Heart Dysfunction CO= TPG Time PAP=pulmonary artery pressure; =pulmonary vascular resistance; TPG=transpulmonary gradient. Courtesy of: Vallerie V. McLaughlin, MD. Goals of Therapy Improve symptoms 6-minute walk (>38 m) functional class (I or II) CPET (VO 2 max >1.4) quality of life Improve hemodynamics Improve survival Schematic Progression of PAH CO PAP Pre-symptomatic/ Compensated Symptom Threshold Symptomatic/ Decompensating Declining/ Decompensated Right Heart Dysfunction CO= TPG Time PAP=pulmonary artery pressure; =pulmonary vascular resistance; TPG=transpulmonary gradient. Courtesy of: Vallerie V. McLaughlin, MD. What Drug and When 8

9 PAH Treatments - a Historical Overview CCB, anticoagulation, digitalis, diuretics Epoprostenol SC treprostinil Bosentan IV treprostinil Iloprost Sildenafil Ambrisentan Survival in IPAH Long-term CCB Responders Cumulative Survival Long-term CCB failure Long-term CCB responders p=.7 < CCB = calcium channel blocker. Subjects at risk, n (Years) O. Sitbon et al. Circulation 25;111: Long-term CCB responders Long-term CCB failure PAH Basic therapy Oral anticoagulants, Diuretics, O 2, Digoxin... When to use a Calcium Antagonist? Oral CCB Sustained Response Yes Continue CCB Positive Vasodilator study Fall in mpap > 1 mmhg + mpap < 4 mmhg + Normal CO Negative No CCB +++ Sitbon O, et al. Circulation. 25;111: rd World PAH Symposium. J Am Coll Cardiol 24;43:1S-9S. ACCP Guidelines. Chest 24;126:1S-92S. Galiè N, et al. ESC Guidelines. Eur Heart J 24;25:

10 Oral CCB Positive PAH Basic therapy Oral anticoagulants, Diuretics, O 2, Digoxin... Vasodilator study Negative No CCB +++ Vascular Pathology: Balance of Powers Decreased NO Synthase Prostacyclin t-pa activity Increased ET-1 Serotonin Thromboxane A2 PAI-1 TGF-B Angiotensin II Angiopoietin 1/TIE2 Sustained Response Yes Continue CCB Fall in mpap > 1 mmhg + mpap < 4 mmhg + Normal CO Close monitoring of long-term clinical and hemodynamic effects Sitbon O, et al. Circulation. 25;111: rd World PAH Symposium. J Am Coll Cardiol 24;43:1S-9S. ACCP Guidelines. Chest 24;126:1S-92S. Galiè N, et al. ESC Guidelines. Eur Heart J 24;25: Courtesy of: Ronald J. Oudiz, MD. Vasodilators Antiproliferatives Anticoagulants ADVERSE REMODELING of Vascular Tree Vasoconstrictors Growth Factors Procoagulants Other Medications? 1

11 What is the Optimal Treatment Strategy? Anticoagulate ± Diuretics ± Oxygen ± Digoxin Vasodilator Study Oral CCB Positive Lower Risk Negative Higher Risk vasoconstriction proliferation Sustained Response Yes Continue CCB No ERAs or PDE-5 Is (oral) Epoprostenol or Treprostinil (IV) Iloprost (inhaled) Treprostinil (SC) Reassess consider combo-therapy Investigational Protocols McLaughlin VV and McGoon M. Circulation. 26;114: Epoprostenol or Treprostinil (IV) Iloprost (inhaled) ERAs or PDE-5 Is (oral) Treprostinil (SC) Atrial septostomy Lung Transplant What is the Optimal Treatment Strategy? Anticoagulate ± Diuretics ± Oxygen ± Digoxin Vasodilator Study EARLY trial: Bosentan in NYHA class II Positive Negative Oral CCB Lower Risk Determinants of Risk Higher Risk Sustained Response No Gradual Clinical Evidence of RV Failure Progression Yes Rapid II, III NYHA Class IV Yes Longer (>4 m) 6 Minute Walk Distance Shorter (<3 m) Minimally elevated BNP Very elevated Continue CCB Minimal RV Dysfunction Normal/Near normal RAP and CI Echocardiographic Findings Hemodynamics Pericardial Effusion Significant RV Dysfunction High RAP, Low CI McLaughlin VV and McGoon M. Circulation. 26;114: Galie N et al. Lancet 28; 371:

12 Rx of Heart Failure Stage A High risk with no symptoms Stage B Structural heart disease, no symptoms Stage C Structural disease, previous or current symptoms Risk factor reduction, patient and family education ACE inhibitors and beta-blockers in all patients Stage D Refractory symptoms requiring special intervention Consider multidisciplinary team Revascularization, mitral-valve surgery Cardiac resynchronization if bundle-branch block present Dietary sodium restriction, diuretics, and digoxin ACE inhibitors or ARBs in all patients; beta-blockers in selected patients Inotropes Treat hypertension, diabetes, dyslipidemia; ACE inhibitors or ARBs in some patients Hospice VAD, transplantation Aldosterone antagonist, nesinitide Stage A High risk with no symptoms Rx of Pulmonary Hypertension Stage B PAH with + VDC Stage C PAH with - VDC Low Risk Bosentan +/- Sildenafil +/- Ventavis Calcium Channel Blockers Stage C PAH with - VDC High Risk Aldactone and digoxin Dietary sodium restriction, diuretics Risk factor reduction, patient and family education Stage D Refractory symptoms requiring special intervention IV meds (Flolan or Trepostonil) Transplantation Inotropes, atrial septostomy Consider multidisciplinary team Combination therapy Sleep apnea, Obesity, Uncontrolled hypertension and/or depress LVEF, drug abuse Hospice Jessup M, Brozena S. N Engl J Med. 23;348: Early, Risk-based and Combination Therapy: Changing Paradigms for PAH? Goal-Oriented Therapy Diagnosis of PAH Vasoreactivity test negative NYHA II or IV Baseline examination and 3-to-6-month reevaluation to assess treatment goals (6MWD >38 m, peak VO 2 >1.4 ml/min/kg, peak systolic BP >12 mm Hg during exercise) First-line treatment bosentan Treatment continued Treatment goals not met Addition of Treatment continued sildenafil Addition of Treatment continued inhaled iloprost Transition from inhaled to intravenous iloprost Treatment continued Highly urgent lung transplantation Hoeper et al. Eur Respir J. 25;26:

13 Summary: Treatment Traditional therapies; diuretics, oxygen, phlebotomy still used as indicated; anticoagulants recommended Calcium Channel Blockers should be used in Class II or III acute responders but followed closely for safety & efficacy Newer agents are tailored to WHO class ACCP Guidelines Class IV Infused prostacyclins Class III Oral endothelin receptor antagonists (ERAs), phosphodiesterase (PDE) 5 inhibitors, infused or inhaled prostacyclins Class II PDE 5 inhibitors, or ERAs Consider therapy if evidence of Right Ventricular Dysfunction Combination therapies and an array of investigational therapies hold hope for the future Role of transplantation/septostomy now diminished because of new effective pharmacologic therapies Indications for Referral to a Specialized Center for Rx of PAH Unexplained dyspnea on exertion with evidence of PH on Echo Evidence of moderate to sever PH Estimate PAS pressure > 45 mm Hg on Echo Symptoms consistent with NYHA functional class II or worse Near-syncope or syncope Absence of substantial left sided cardiac disease or parenchymal lung disease Clinical or echocardiographic evidence of RV dysfunction Lower-extremity edema Ascites Right ventricular enlargement or systolic dysfunction on echocardiography Rubin, L. J. et. al. Ann Intern Med 25;143: