Pulmonary Heart Disease: Evaluation and Management

Transcription

1 Pulmonary Heart Disease: Evaluation and Management Robert C. Bourge, MD Professor of Medicine, Radiology, and Surgery Drummond Chair of Cardiovascular Medicine Vice Chair of Clinical Affairs, Department of Medicine Director, Pulmonary Vascular Disease Program The University of Alabama at Birmingham < > Potential Conflicts: Research Grant Support, Consultation Fees, Scientific Advisory Board, and/or speakers' bureau for Actelion, Bayer, CardioMEMS, GenNO, Gilead, Lilly, Novartis, Medtronic, Pfizer, St. Jude, United Therapeutics.

2 Pulmonary Hypertension: WHO Classification WHO Group 1 WHO Group 2 WHO Group 3 WHO Group 4 WHO Group 5 PAH Left-Heart Lung/hypoxia CTEPH Other Idiopathic (PAH) Heritable Drug & toxin induced Associated with other conditions (APAH) Persistent pulmonary hypertension of the newborn WHO GROUP 1 Pulmonary venoocclusive disease Pulmonary capillary hemangiomatosis Systolic dysfunction Diastolic Dysfunction (HFpEF) Valvular Heart Disease Congenital / acquired left heart inflow/ outflow tract obstruction and congenital cardiomyopathies COPD ILD Other pulmonary (mixed restrictive/ obstructive disease) Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities Chronic thromboembolic pulmonary hypertension (CTEPH) PH WITH UNCLEAR MULTIFOACTORIAL MECHANISMS Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH WHO GROUP 1 Persistent pulmonary hypertension of the newborn (PPHN) Simonneau et al. J Am Coll Cardiol 2013;62:D34 41)

3 Survival in Patients with Primary Pulmonary Hypertension: A National Prospective Registry n = 192, dx , f/u through 8/1988 Survival: 5yr 34%, Median 2.8yr D Alonzo, et al, Ann Intern Med 1991; 115:

4 Survival in Patients with Primary Pulmonary Hypertension: A National Prospective Registry OLD DATA PRIOR TO ANY APPROVED THERAPY D Alonzo, et al, Ann Intern Med 1991; 115:

5 Plasma bnp as a Prognostic Indicator in Patients With Primary Pulmonary Hypertension N = 60, 49 rx with oral or IV prostacyclin analogue, data obtained at baseline and 3 months p=<0.05 p=< By multivariate analysis, higher bnp at baseline (RR , p ) and at follow-up (RR , p ) were independent predictors of mortality. Nagaya, et al (Osaka) Circulation 2000; 102; )

6 Correlation of Six minute walk test with Survival in PPH Kaplan-Meier survival curves: median value of distance walked during six-minute walk test in patients with PPH. Patient walking < 332 m had a significantly lower survival rate than those walking farther (log-rank test, p < 0.001). Miyamoto Am J Resp Med 161(2):

7 Pulmonary Heart Disease Primary Pulmonary Hypertension Incidence / Prognosis Pathology / Pathophysiology Diagnosis Therapy

8 Pulmonary Arterial Hypertension: Pathologic Types Plexogenic arteriopathy Mild: Medial hypertrophy with concentric intimal proliferation Severe: concentric intimal fibrosis, plexiform lesions, necrotizing intimal fibrosis Pulmonary Veno-occlusive Disease Fibrosis of the small and medium sized veins with secondary pulmonary arterial hypertensive changes Clinically: PVH with normal LV and Mitral Valve Pulmonary capillary hemangiomatosis Extensive growth and proliferation of the pulmonary capillary network (clinically similar to plexogenic PPH)

9 Vascular Pathology: Balance of Powers NO Synthase Prostacyclin t-pa activity ET-1 Serotonin Thromboxane A2 PAI-1 TGF-B Angiotensin II Vasodilators Antiproliferatives Anticoagulants Vasoconstrictors Growth Factors Procoagulants

10 Vascular Compliance The ability a vascular wall to stretch (dilate) in response to increased flow; the most important regulator of blood flow and arterial pressure Normal Pulmonary Artery Increased Cardiac Output Increased blood flow with little increase or reduction in pressure Pulmonary Vascular Disease Medial Hypertrophy Increased Cardiac Output Smooth Muscle Migration Lumen diameter is unable to increase, (may decrease); RV increases contractile force to compensate and maintain flow (output) = increased pressure

11 PAH: Hemodynamics over Time Pre-symptomatic/ Compensating Symptomatic/ Decompensating Declining/ Decompensated CO Symptom Threshold PAP R Heart Failure/Death PVR Time (variable)

12 Pulmonary Heart Disease Primary Pulmonary Hypertension Incidence / Prognosis Pathology / Pathophysiology Diagnosis Therapy

13 Pulmonary Heart Disease Old Classification: Secondary Pulmonary Hypertension Pulmonary hypertension of infants Congenital diseases of lungs, thorax, and diaphragm Congenital or acquired valvular or myocardial disease Pulmonary thromboembolic disease Sickle Cell Disease IV drug abuse Obstructive lung disease Interstitial lung disease Hypercapnia with arterial hypoxemia Collagen vascular disease Antiphospholipid antibody syndrome Pulmonary venous hypertension (primary or secondary) Pulmonary artery or valve stenosis

14 Diagnostic Tools: Echocardiography Screening Tool for unexplained Dyspnea Evaluation of Left Ventricular functionsystolic and diastolic Evaluation of left and right sided valvular pathology (Color Doppler) Contrast (bubbles) and Color Doppler utilized to detect intracardiac and/or intrapulmonary shunts Estimate PA pressure- must have TR Evaluate right ventricular size, wall thickness and function

15 Updated Hemodynamic Definitions of Pulmonary Hypertension Definition Characteristics Clinical group Pre-capillary PH Mean PAP 25 mm Hg PWP 15 mm Hg CO normal or reduced Pulmonary arterial hypertension PH due to lung disease CTEPH PH with unclear or multifactorial mechanisms Post-capillary PH Mean PAP 25 mm Hg PWP >15 mm Hg CO normal or reduced Passive = TPG 12 mm Hg Reactive = TPG >12 mm Hg PH due to left heart disease CO = cardiac output. TPG = transpulmonary pressure gradient. Adapted from: Galie N, et al. Eur Heart J. 2009;30(20):

16 Diagnostic Tools: Right Heart Catheterization Essential tool for the diagnosis and correct classification of pulmonary hypertension Evaluation of Left Ventricular functionsystolic and diastolic, Wedge pressure (in some cases, LVEDP must be measured) Shunt series for congenital defects Accurate measurement of pulmonary pressures Assessment of hemodynamics which correlate with survival

17 Hemodynamic Profiles in Pulmonary Hypertension Precapillary Pulmonary Hypertension: Systolic, diastolic, and mean PA pressure are high, PCWPmean normal, pulmonary vascular resistance (PVR) elevated, PAEDP is sig. higher than PCWPmean PPH; PH asso. with Col Vas Disease, liver disease, HIV, anorexigens; high altitude PH Postcapillary Pulmonary Hypertension: Systolic, diastolic, and mean PA pressures high, PVR normal, PAEDP < 5mmHg of PAmean LV Systolic or Diastolic Failure, aortic stenosis, mitral stenosis, primary mitral regurgitation, mitral valve obstruction, pulmonary venoocclusive disease (congenital or acquired). Mixed: Systolic, diastolic, and mean PA high, PCWP high, PAEDP modestly higher than PCWPmean Chronic postcapillary pulmonary hypertension Selective or Nonselective Increase in Pulmonary Blood Flow: Systolic, diastolic and mean PA may be high; pulmonary blood flow is increased, PVR normal or slightly increased. Pulmonary venous pressure is modestly increased or normal ASD, VSD, PDA, high-output cardiac failure (thyrotoxicosis), liver disease, chronic anemia Adapted from Chatterjee K, et al, Arch Intern Med :

18 Right Heart Catheterization: Pitfalls Misinterpretation of a damped PA pressure tracing as a PAWP tracing Failing to measure the mean PA and PCWP at end- expiration Recoding the PCWP immediately after balloon occlusion, rather than waiting for steady state in PCWP tracing to occur PVR calculation utilizing only cardiac output obtained by thermodilution without confirming/ utilizing the Fick method, especially in the setting of significant tricuspid regurgitation Oudiz RJ, et al. Advances Pulm Hypertens. 2005;4:15-25.

19 Overestimation of pulmonary artery occlusion pressure in pulmonary hypertension due to partial occlusion Figure 1 Leatherman JW, Crit Care Med :93-97

20 Measuring Pulmonary Capillary Wedge Pressure Pulmonary Artery Pressure Decay Curve Balloon Occlusion Pressure (mm Hg) ARDS IPAH Time (seconds) Time Steady State is Longer in IPAH than in ARDS ARDS: acute respiratory distress syndrome. Souza R, et al. Crit Care. 2005;9:R132-R

21 Diagnostic Tools: CT scanning / MRI High resolution CT scanning Quantification of interstitial fibrosis Ground glass appearance (alveolitis) Poorly defined nodular opacities Prominent septal lines Pleural effusion Adenopathy Helical or Spiral CT (2 nd Gen. Scanner) Pulmonary arterial embolic disease MRI RV Size / Function Gold Standard Lung tissue evaluation (experimental) Pulmonary artery morphology Not PAH Pulmonary venoocclusive disease or capillary hemangiomatosis

22 Pulmonary Arterial Hypertension: Evaluation Vasodilator Challenges Role of pharmacologic / hemodynamic testing o responders (decreased mean PA) WHO Definition: 20% decrease in mpap Revised Definition: Drop in mpap to normal o non-responders (none or less than 20% change) o unfavorable (negative) responders MAP down 20% higher RA pressure lower O2 Saturation

23 Pulmonary Heart Disease Primary Pulmonary Hypertension Incidence / Prognosis Pathology / Pathophysiology Diagnosis Therapy

24 Primary Pulmonary Hypertension: Therapy Anticoagulation Diuretics; Na + / Fluid Restriction Digoxin Oxygen Vasodilators Atrial Septostomy Transplantation

25 Pulmonary Arterial Hypertension: Therapy Anticoagulation Diuretics; Na + / Fluid Restriction Digoxin Oxygen Vasodilators Atrial Septostomy Transplantation

26 Pulmonary Arterial Hypertension: Therapy Anticoagulation Diuretics; Na+ / Fluid Restriction Digoxin Oxygen Vasodilators Calcium Channel Blockers Endothelin Receptor Blockers PDE-5 Inhibitors Prostanoids IV, Sub-Cut, Inhaled, Oral Soluble guanylate cyclase (sgc) stimulator Nitric oxide inhaled (acute use) Investigational Atrial Septostomy Transplantation

27 Mechanisms of Action of Vasodilator Therapies for PH Prostanoids PDE5 Inhibitor Adapted from: Ghofrani, Eur Resp Rev 2009

28 Pulmonary Arterial Hypertension: Therapy Anticoagulation Diuretics; Na+ / Fluid Restriction Digoxin Oxygen Vasodilators Calcium Channel Blockers amlodipine o use only after vaso-reactivity testing o not approved by FDA) Endothelin Receptor Blockers PDE-5 Inhibitors Prostanoids IV, Sub-Cut, Inhaled, Oral Soluble guanylate cyclase (sgc) stimulator Nitric oxide inhaled (acute use) Investigational Atrial Septostomy Transplantation

29 Pulmonary Arterial Hypertension: Therapy Anticoagulation Diuretics; Na+ / Fluid Restriction Digoxin Oxygen Vasodilators Calcium Channel Blockers amlodipine Endothelin Receptor Blockers PDE-5 Inhibitors Prostanoids IV, Sub-Cut, Inhaled, Oral o epoprostenol IV (Flolan) o iloprost - inhaled (Ventavis), IV o treprostinil SC, IV (Remodulin) Inhaled (Tyvaso) Oral (Orenitram) Soluble guanylate cyclase (sgc) stimulator Nitric oxide inhaled (acute use) Investigational Atrial Septostomy Transplantation

30 Prostacyclin (epoprostenol) Na + O 2 C O CH 3 CH OH Prostaglandin I-2, epoprostenol, (Flolan) Main product of arachidonic acid Potent vasodilator, mild inotrope Inhibitor of platelet aggregation Produced by vascular endothelium Discovered by Moncada and Vane* in 1976 Nature 263: , 1976

31 I.V. Epoprostenol (Prostacyclin) vs Conventional Therapy for Primary Pulmonary Hypertension Results: 81 patients randomized o 41 pts: IV epoprostenol and conventional therapy o 40 pts: conventional therapy 8 deaths, all in conventional therapy group 3 patients underwent lung transplantation o 1 in IV epoprostenol group at 11 days o 2 in convent. therapy group at 63 and 68 days. IV epoprostenol stopped in 2 patients o one due to side effects (jaw pain, diarrhea) o one due to inability to manage delivery system N Engl J Med, 1996; 334:

32 I.V. Epoprostenol (Prostacyclin) vs Conventional Therapy for Primary Pulmonary Hypertension N Engl J Med, 1996; 334:

33 treprostinil sodium (Remodulin Injection) Generic Name: Treprostinil Sodium Brand Name: Remodulin Other Names: UT-15 Uniprost, treprostinol O C H 2 C O 2 Descriptions N a H H O H O H Characteristics Prostaglandin family Potent vasodilator of pulmonary and systemic arterial vascular beds Inhibits platelet aggregation Clinical Pharmacology Acute hemodynamic effects in PPH similar to those of epoprostenol Apparent Plasma Half-Life IV: 45 minutes SC: 3 hours Chemically Stable at Neutral ph / Room Temp

34 The SWITCH Study - Safely Transitioning from Inhaled Iloprost to Inhaled Treprostinil Sodium Time Spent on Daily Treatment Activities Baseline (n=70, ILO) Week 12 (n=61, itre) Mean Time Spent on Each Activity (min/day) P-value obtained from Wilcoxon signed-rank test on change from baseline data for subjects with both baseline and follow-up values Gather Supplies Prepare System % 30% 80% 77% P=0.004 P= P< P< Inhalation Clean Total Bourge R, et al, C.V. Therapeutics, % 39.1 P<0.001

35 The Importance of Patient Education

36 Pulmonary Arterial Hypertension: Therapy Anticoagulation Diuretics; Na+ / Fluid Restriction Digoxin Oxygen Vasodilators Calcium Channel Blockers amlodipine Endothelin Receptor Blockers o bosentan oral (Tracleer) o ambrisentan oral (Letaris) o macitentan oral (Opsumit) PDE-5 Inhibitors Prostanoids IV, Sub-Cut, Inhaled, Oral Soluble guanylate cyclase (sgc) stimulator Nitric oxide inhaled (acute use) Investigational Atrial Septostomy Transplantation

37 Choice of Endothelin Receptor Antagonist for the Therapy of PAH Drug Interactions Bosentan (Tracleer) Multiple, and Lowers efficacy of PDE-5 Inhibitors Ambrisentan (Letaris) Few, and Does not lower efficacy of PDE-5 Inhibitors Cost Slightly more expensive Slightly less expensive Dosing Twice a day Once a day (improved compliance) Safety Ongoing risk of liver toxicity (requires FDA mandated monthly liver functions tests). *European postmarketing surveillance data; annual rate. No risk of liver toxicity above placebo (monthly liver function tests NOT required). Bosentan full prescribing information Ambrisentan full prescribing information

38 Pulmonary Arterial Hypertension: Therapy Anticoagulation Diuretics; Na+ / Fluid Restriction Digoxin Oxygen Vasodilators Calcium Channel Blockers amlodipine Endothelin Receptor Blockers PDE-5 Inhibitors o sildenafil - oral (Viagra, Revatio) o tadalafil oral (Cialis, Adcirca) Prostanoids IV, Sub-Cut, Inhaled, Oral Soluble guanylate cyclase (sgc) stimulator Nitric oxide inhaled (acute use) Investigational Atrial Septostomy Transplantation

39 Pulmonary Arterial Hypertension: Therapy Anticoagulation Diuretics; Na+ / Fluid Restriction Digoxin Oxygen Vasodilators Calcium Channel Blockers amlodipine Endothelin Receptor Blockers PDE-5 Inhibitors Prostanoids IV, Sub-Cut, Inhaled, Oral Soluble guanylate cyclase (sgc) stimulator o riociguat (Adempas) Nitric oxide inhaled (acute use) Investigational Atrial Septostomy Transplantation

40 Pulmonary Arterial Hypertension: Therapy Anticoagulation Diuretics; Na+ / Fluid Restriction Digoxin Oxygen Vasodilators Calcium Channel Blockers amlodipine Endothelin Receptor Blockers PDE-5 Inhibitors Prostanoids IV, Sub-Cut, Inhaled, Oral Soluble guanylate cyclase (sgc) stimulator Nitric oxide inhaled (acute use) Investigational Atrial Septostomy Transplantation

41 Pulmonary Arterial Hypertension: Therapy Anticoagulation Diuretics; Na+ / Fluid Restriction Digoxin Oxygen Vasodilators Calcium Channel Blockers amlodipine Endothelin Receptor Blockers PDE-5 Inhibitors Prostanoids IV, Sub-Cut, Inhaled, Oral Soluble guanylate cyclase (sgc) stimulator Nitric oxide inhaled (acute use) Investigational Atrial Septostomy Transplantation

42 DelIVery for Pulmonary Arterial Hypertension (PAH)

43 Pulmonary Arterial Hypertension: Therapy Anticoagulation Diuretics; Na + / Fluid Restriction Digoxin Oxygen Vasodilators Atrial Septostomy Transplantation

44 Medical Therapy vs Transplantation: Weighing the Risks High Risk Patient (usually NYHA Class III and IV) Medical Therapy Risk of Death Quality of Life Symptoms from Disease Medication Side Effects Transplantation Risk of Death Quality of Life Medication Side Effects Intense Medical Follow-up

45 ADULT LUNG TRANSPLANTATION Actuarial Survival By Diagnosis (Transplants: January 1990 June 2001) Alpha-1 Antitrypsin (N=1,234) Cystic Fibrosis (N=1,703) Emphysema/COPD (N=4,353) IPF (N=1,855) PPH (N=691) Sarcoidosis (N = 276) Survival (%) HALF-LIFE Alpha-1: 4.9 Years; CF: 4.4 Years; COPD: 5.5 Years; IFP: 3.0 Years; PPH: 4.0 Years; Sarcoidosis: 4.7 Years Years

46 Hemodynamic Profiles in Pulmonary Hypertension Precapillary Pulmonary Hypertension: Systolic, diastolic, and mean PA pressure are high, PCWPmean normal, pulmonary vascular resistance (PVR) elevated, PAEDP is sig. higher than PCWPmean PPH; PH asso. with Col Vas Disease, liver disease, HIV, anorexigens; high altitude PH Postcapillary Pulmonary Hypertension: Systolic, diastolic, and mean PA pressures high, PVR normal, PAEDP < 5mmHg of PAmean LV Systolic or Diastolic Failure, aortic stenosis, mitral stenosis, primary mitral regurgitation, mitral valve obstruction, pulmonary venoocclusive disease (congenital or acquired). Mixed: Systolic, diastolic, and mean PA high, PCWP high, PAEDP modestly higher than PCWPmean Chronic postcapillary pulmonary hypertension Selective or Nonselective Increase in Pulmonary Blood Flow: Systolic, diastolic and mean PA may be high; pulmonary blood flow is increased, PVR normal or slightly increased. Pulmonary venous pressure is modestly increased or normal ASD, VSD, PDA, high-output cardiac failure (thyrotoxicosis), liver disease, chronic anemia Adapted from Chatterjee K, et al, Arch Intern Med :

47 Hemodynamic Profiles in Pulmonary Hypertension Chronic postcapillary pulmonary hypertension Mechanism: o ~ 1/3 of patients with chronic elevation in PCWP o mechanism of vasoconstriction unknown, o Theories narrowing or closure of the airways by direct encroachment from enlarged venous vessels or interstitial edema, leading to worsening V/Q mismatch transpulmonary endothelin I release is increased, subsegmental infusion of ET blocker causes decrease in local PVR pathology, if very chronic, becomes similar in many patients Adapted from Chatterjee K, et al, Arch Intern Med :

48 Treatment Algorithm for PAH Confirm Diagnosis of PAH! Anticoagulate ± Diuretics ± Oxygen ± Digoxin Acute Vasoreactivity Testing Positive - ~6% Negative Oral Calcium Channel Blocker Sustained Response Yes (~3%) No Lower ± Risk PDE-5 ± ERA (oral) or sgcs Epoprostenol or Treprostinil (IV) Iloprost or Treprostinil (inhaled) Treprostinil (SC or oral) Intra-Pulmonary Shunt If Positive. Consider Inhaled Prostanoid Therapy Higher Risk Epoprostenol or Treprostinil (IV) Iloprost/Treprostinil (inh) Treprostinil (SC), then add PDE-5 ± add ERA Continue CCB Reassess Consider combo-therapy Investigational Protocols Atrial septostomy / Lung Transplant ADAPTED FROM: American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association et al.. (J Am Coll Cardiol 2013;62:D60 72)

49 END Robert C Bob Bourge, MD < bbourge@uab.edu > (800-UAB-MIST)