6/27/2019 PULMONARY HYPERTENSION VERSUS PULMONARY ARTERIAL HYPERTENSION WHAT’S THE DIFFERENCE? Angela Hatch, PA-C 1 DISCLOSURES • Consultant for Actelion Pharmaceuticals, providing consultation on patient perspective and barriers to disease recognition. 2 1 6/27/2019 PULMONARY HYPERTENSION A disease of hemodynamics. • Increased blood pressure in the pulmonary circulation • PH is defined as mean pulmonary artery pressure > 20 mmHg • Normal mean arterial pressure at rest is 14.0+3.3 mmHg • New definition as of March 2018 (published January 2019). 3 HISTORY OF THE WORLD SYMPOSIA ON PULMONARY HYPERTENSION (WSPH) 1st WSPH (1973) • Organized by WHO because of an epidemic of PAH cases due to aminorex (an anorexigen drug) • Achievements • Classification system of PH was created: Primary and Secondary Pulmonary Hypertension • Hemodynamic definition of the disease as a mean arterial pressure of > 25 mmHg was set 4 2 6/27/2019 WSPH (CONTINUED) 2nd WSPH (1998) • A decision was made to start an ongoing series of symposia, fueled by the development of 2 effective treatments: • Flolan (epoprostenol) • High dose CCBs in patients who respond to acute vasoreactivity testing • 5 group classification system was created “Primary and Secondary Pulmonary Hypertension” were abandoned 5 WSPH (CONTINUED) 3rd WSPH (2003) • Specific treatment algorithms were proposed because additional medications were available: • ERAs • Prostacyclins and prostanoids • PDE5 inhibitors • Soluble guanylate cyclase stimulators • Gene mutations had begun to be identified for familial PAH (BMPR2 mutation and others). • 5 classifications remained. 6 3 6/27/2019 WSPH (CONTINUED) 4th WSPH (2008) • Randomized control trial parameters were discussed and defined. • New management strategies again discussed, now including recommendations for treatment of mildly symptomatic patients. 5th WSPH (2013) • Findings and recommendations of 12 Worldwide Task Forces were presented 7 WSPH (CONTINUED) 6th WSPH (2018) – Findings published January 2019 • New definition of pulmonary hypertension was established lowering threshold for diagnosis from a mPAP > 25 mmHg to > 20 mmHg • Following patients should undergo more aggressive assessment and screening: • Congential heart disease (CHD) • Connective tissue disease (CTD) • HIV • Portopulmonary hypertension (POPH) 8 4 6/27/2019 WSPH (CONTINUED) 6th WSPH (continued) • Genetic counseling was recommended for all idiopathic, anorexiant and familial PAH patients and first generation asymptomatic family members. • Post-operative congenital heart disease patients throughout long-term cardiology follow up. • A definition of exercise-induced pulmonary hypertension was still not established. 9 13 TASK FORCES 1) Pathology and Pathobiology 8) New trial designs and potential 2) Genetics and genomics therapies for PAH 3) Pathophysiology 9) Chronic Thromboembolic Pulmonary Hypertension 4) Definitions and Diagnosis 10 & 11) PH due to left heart and lung 5) Epidemiology and registries diseases 6) Standard of care 12)Pediatric PH 7) Treatment Goals 13)Patients’ Perspectives • Defined success of therapy based on symptoms, exercise capacity, and RV function 10 5 6/27/2019 MODIFIED CLASSIFICATION OF PH 1. Pulmonary arterial hypertension (PAH) 3. PH due to lung disease and/or hypoxia 1.1 Idiopathic PAH (IPAH) 3.1 COPD 1.2 Heritable PAH (FPAH) 3.2 Interstitial lung disease 1.2.1 BMPR2 3.3 Other pulmonary diseases with mixed restrictive and 1.2.2 ALK1, ENG, SMAD9, CAV1, KCNK3 obstructive pattern 1.2.3 Unknown 3.4 Sleep-disordered breathing 1.3 Drug- and toxin-induced 3.5 Alveolar hypoventilation disorders 1.4 Associated with 3.6 Chronic exposure to high altitude 1.4.1 Connective tissue diseases 3.7 Developmental lung diseases 1.4.2 HIV infection 4. CTEPH 1.4.3 Portal hypertension 5. PH with unclear multifactorial mechanisms 1.4.4 Congenital heart disease 5.1 Hematological disorders: chronic hemolytic anemia, 1.4.5 Schistosomiasis myeloproliferative disorders, splenectomy Group 1’. Pulmonary veno-occlusive disease and/or pulmonary 5.2 Systemic disorders: sarcoidosis, pulmonary capillary hemangiomatosis Langerhans cell histiocytosis, lymphangioleiomyomatosis, Group 1”. Persistent pulmonary hypertension of the newborn neurofibromatosis, vasculitis PAH long-term responders to calcium channel blockers (2018) 5.3 Metabolic disorders: glycogen storage disease, 2. PH due to left heart disease Gaucher disease, thyroid disorders 2.1 LV systolic dysfunction 5.4 Others: tumoral obstruction, fibrosing mediastinitis, 2.2 LV diastolic dysfunction chronic renal failure, segmental PH 2.3 Valvular disease 2.4 Congenital / acquired left heart inflow / outflow obstruction 11 SO, WHERE’S THE PH REALLY AT? 12 6 6/27/2019 WHY IS PAH SO MUCH WORSE THAN PH? • It’s progressive and there is no reversing damage once it has occurred. The goal of treatment is directed at slowing it down. • There is not a cure and it’s considered terminal – the patient will either die from complete RV failure or require a lung transplant. • Average time from diagnosis to death based on registry findings: • 2.8 years without therapy. • 7 years on therapy. • Average time from lung transplant to death is 5.5 years. • Double lung transplant is required (possible heart and lung). 13 PAH VASCULAR DYSFUNCTION AND REMODELING 14 7 6/27/2019 PAH VASCULAR DYSFUNCTION AND REMODELING Plexiform Lesions https://www.youtube.com/watch?v=VCvBh41OyZs 15 The majority of cases are mixed class disease. (i.e., LV dysfunction and OSA) Over time, PH can cause PAH! 16 8 6/27/2019 PATHOGENESIS OF PAH: LESSONS FROM CANCER 17 HOW DOES PAH PRESENT CLINICALLY? • First symptom is dyspnea on exertion • Breathlessness without overt signs of heart and lung disease is concerning. • Are they always the one who is slower than everyone else? • Fatigue, often chronic and tends to worsen over time • Angina • Edema • Weakness • Lightheadedness and syncope • Tips: • PAH is nearly 4 times as prevalent in females than males, even in FPAH. • Look for hypoxia with exertion • 6MWT is part of the formal diagnostic protocol. • Shape-HF submaximal cardiopulmonary exercise testing provides more information. 18 9 6/27/2019 19 DIAGNOSIS OF PH • It starts with you….. • Incidental findings on EKG, Chest Xray, Echocardiogram • EKG: RVH, RAE, or right axis deviation. Normal EKG doesn’t exclude PH. • CXR, CT: Cardiomegaly with RV enlargement, enlarged pulmonary arteries, pulmonary venous congestion. • Echo: Elevated RVSP and RA pressures, RA and/or RV enlargement, tricuspid regurgitation. 20 10 6/27/2019 DEGREE OF PH BASED ON ECHO Jet of TR (RVSP = 4V2) RA pressure is calculated based on IVC diameter and inspiratory collapse. PASP = RVSP + RAP Tip: If you see a patient’s echo has normal LV systolic and diastolic function, but elevated RVSP you should start to be concerned about possible PAH or CTEPH. 21 22 11 6/27/2019 PAH IS A DISEASE OF RESISTANCE Progression of PVR on Catheterization A dilated RV with low pressures on echo is cause for concern. 23 PH TREATMENT • Early identification and treatment of pulmonary hypertension is advised because advanced disease is less responsive to therapy. • “Primary therapies” are directed at the underlying etiologies. • “Advanced therapies” are directed at the PH itself, rather than the underlying disease. • Only used in Group 1 PAH and Group 4 (CTEPH) • All patients with SpO2 of less than 90% should have oxygen therapy This is critical! • Other medications effective in all groups include the following when indicated: • Diuretics, digoxin, and exercise • Anticoagulation guidelines are unclear. It’s theorized that AC should be used in the following patient groups: • IPAH • FPAH • PAH due to anorexigens • CTEPH 24 12 6/27/2019 PH TREATMENT • Group 1 PAH • There are no effective primary therapies for Group 1 PAH • Oxygen therapy is indicated. Keep SpO2 >90% • CCB (less than 10% of patient’s are responders on RHC) and advanced therapies • Group 2 PH (left heart disease) treat the underlying disease • Group 3 (lung diseases) • Oxygen therapy is the only modality with a proven mortality benefit in this group • Again, treat the underlying disease • Group 4 PH (CTEPH) • Very specific recommendations from Task Force on CTEPH • Anticoagulation • Pulmonary endarterectomy (PEA) is the treatment of choice – don’t wait on this • Medical therapy for patients who aren’t surgical candidates or with residual PH s/p surgery • Group 5 PH • The occurrence of PH in this category is rare and treatment should be directed at the underlying disease 25 ADVANCED THERAPIES • Medication categories: • Calcium channel blockers (if patient shows acceptable vasoreactivity on testing) • Amlodipine, nifedipine, diltiazem • Phosphodiesterase 5 inhibitors • Sildenafil, tadalfil, and vardenafil • Endothelin receptor antagonists • Ambrisentan, macitentan, and bosentan • Prostacyclins/prostanoids • Soluble guanylate cyclase stimulants • Adempas (riociguat) • Increase the sensitivity of sGC to NO and directly stimulate the receptor to mimic the action of NO 26 13 6/27/2019 PROSTANOID DETAILS • Prostanoids – The big guns in PH. • Dilate the blood vessels in the lungs • Slow scarring and cell growth in pulmonary vasculature • Flolan (epoprostenol), Ventavis (iloprost), Remodulin (treprostinil) • Various forms of administration: SubQ and IV most common. • IV therapy is continuous infusion through a central line. • Inhaled variants require 4 times a day dosing. • Oral treprostinil (Orenitram) was approved in 2013 after having been declined by the FDA for approval on two previous