Approach to Pulmonary Hypertension in the Hospital

Transcription

1 Approach to Pulmonary Hypertension in the Hospital Todd M Bull MD Professor of Medicine Director Pulmonary Vascular Disease Center Director Center for Lungs and Breathing Division of Pulmonary Sciences and Critical Care Medicine and Cardiology The Pulmonary Vasculature High capacitance low resistance system 4x increase flow with small change in pressure Vasodilatation and recruitment.

2 Hemodynamic Definition of PH/PAH PH Mean PAP 25 mm Hg PAH Mean PAP 25 mm Hg plus PCWP/LVEDP 15 mm Hg ACCF/AHA/Nice PVR >3 Wood Units Clinical Classification of Pulmonary Hypertension (Nice) 1. PAH Idiopathic PAH Heritable Drug- and toxin-induced Persistent PH of newborn Associated with: CTD HIV infection portal hypertension CHD schistosomiasis 3. PH Owing to Lung Diseases and/or Hypoxia COPD ILD Other pulmonary diseases with mixed restrictive and obstructive pattern Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities 4. CTEPH 1. PVOD and/or PCH 2. PH Owing to Left Heart Disease Systolic dysfunction Diastolic dysfunction Valvular disease Simonneau G et al. J Am Coll Cardiol. 2013;;54;;S43-S PH With Unclear Multifactorial Mechanisms Hematologic disorders Systemic disorders Metabolic disorders Others PAH: WHO group 1 Plexiform Lesion

3 Progressive and Life-limiting Disorder Pathological changes in the pulmonary arteries Hemodynamic impairment CO mpap PVR Adapted from Gaine S. JAMA. 2000;;284: Decreasing mean PAP may not reflect improvement The Right Ventricle Thin muscle with limited contractile reserve. Designed to generate a sustained, low-pressure perfusion. Ejects blood quasi-continuously from the RA to the Lungs Very susceptible to changes in afterload RV: pressure, time, volume Pressure Pressur e Pressure Volume Volume Volume

4 Impact of increased afterload French Registry: Kaplan-Meier Survival Estimates in Combined PAH Population vs NIH-predicted Observed Survival (%) Predicted (NIH Registry) No. at risk: Time (mo) All patients Humbert M et al. Circulation. 2010;;122: Clinical Classification of Pulmonary Hypertension (Nice) 1. PAH Idiopathic PAH Heritable Drug- and toxin-induced Persistent PH of newborn Associated with: CTD HIV infection portal hypertension CHD schistosomiasis chronic hemolytic anemia 3. PH Owing to Lung Diseases and/or Hypoxia COPD ILD Other pulmonary diseases with mixed restrictive and obstructive pattern Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities 4. CTEPH 1. PVOD and/or PCH 2. PH Owing to Left Heart Disease Systolic dysfunction Diastolic dysfunction Valvular disease Simonneau G et al. J Am Coll Cardiol. 2009;;54;;S43-S PH With Unclear Multifactorial Mechanisms Hematologic disorders Systemic disorders Metabolic disorders Others

5 ACCF/AHA Diagnostic Algorithm Pivotal Tests Contingent Tests Contribute to Assessment of: History Exam Index of Suspicion of PH CXR ECG Echocardiogram VQ Scan PFT s Overnight Oximetry HIV ANA LFT s TEE Exercise Echo Pulmonary Angiography Chest CT Angiogram Coagulopathy Profile ABG s Polysomnography Other CTD Serologies RVE, RAE, RVSP, RV Function Left Heart Disease VHD, CHD Chronic PE Ventilatory Function Gas Exchange Sleep Disorder HIV Infection Scleroderma, SLE, RA Portopulmonary Htn Functional Test (6MWT, CPET) RH Cath McLaughlin VV et al. J Am Coll Cardiol. 2009;;53: Vasodilator Test Exercise RH Cath Volume Loading Left Heart Cath Establish Baseline Prognosis Confirmation of PH Hemodynamic Profile Vasodilator Response Clinical Classification of Pulmonary Hypertension (Nice) 1. PAH Idiopathic PAH Heritable Drug- and toxin-induced Persistent PH of newborn Associated with: CTD HIV infection portal hypertension CHD schistosomiasis chronic hemolytic anemia 3. PH Owing to Lung Diseases and/or Hypoxia COPD ILD Other pulmonary diseases with mixed restrictive and obstructive pattern Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities 4. CTEPH 1. PVOD and/or PCH 2. PH Owing to Left Heart Disease Systolic dysfunction Diastolic dysfunction Valvular disease Simonneau G et al. J Am Coll Cardiol. 2009;;54;;S43-S PH With Unclear Multifactorial Mechanisms Hematologic disorders Systemic disorders Metabolic disorders Others Lung Disease and PH WHO class III

6 COPD 215 patients 50% Pam > 25 mm Hg 120 patients 91% Pam>20 mm Hg 4930 patients 30% Pam>25 mm Hg PH-COPD Mild PH PA mean mmhg Thabut Chest 2007

7 PH-COPD and Survival Weitzenblum, E Thorax 1981 Kessler CHEST 1995 Pulmonary Embolism RV function and PE

8 Cumulative incidence of CTEPH Incidence of CTEPH After Pulmonary Embolism Years Pengo V et al. N Engl J Med. 2004;;350: CTEPH Clinical Classification of Pulmonary Hypertension (Nice) 1. PAH Idiopathic PAH Heritable Drug- and toxin-induced Persistent PH of newborn Associated with: CTD HIV infection portal hypertension CHD schistosomiasis chronic hemolytic anemia 3. PH Owing to Lung Diseases and/or Hypoxia COPD ILD Other pulmonary diseases with mixed restrictive and obstructive pattern Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities 4. CTEPH 1. PVOD and/or PCH 2. PH Owing to Left Heart Disease Systolic dysfunction Diastolic dysfunction Valvular disease Simonneau G et al. J Am Coll Cardiol. 2009;;54;;S43-S PH With Unclear Multifactorial Mechanisms Hematologic disorders Systemic disorders Metabolic disorders Others

9 Classification of Pulmonary Hypertension Pulmonary Venous Hypertension (PVH) Vs. Pulmonary Arterial Hypertension (PAH)

10 Classification of PH Pulmonary Venous Hypertension (PVH) RV PA Pulmonary Capillary PV LV Classification of PH Pulmonary Arterial Hypertension (PAH) RV PA Pulmonary Capillary PV LV Management of PAH in 2016

11 General Concepts in PH Care Shrink the RV Starling Curve Careful with Preload changes Unload the RV (PA vasodilation) Afterload Reduction Avoid the Reflex Mechanisms of Action of Approved Therapies for PAH Pre-proendothelin Proendothelin Endothelial cells Nitric Oxide Endothelial cells Prostacyclin Arachidonic acid Prostaglandin I2 receptor A receptor antagonists -1 Smooth muscle cells receptor B Vasoconstriction and proliferation L-arginine Nitric Oxide cgmp L-citrulline Phosphodiesterase type 5 Vasodilation Phosphodiesterase type 5 inhibitor Exogenous nitric oxide and antiproliferation Prostacyclin (prostaglandin I2) camp Vasodilation and antiproliferation Smooth muscle cells Prostacyclin derivatives Humbert M et al. N Engl J Med. 2004;;351: Approved Therapeutic Targets Pre-proendothelin Proendothelin Endothelial cells Nitric Oxide Endothelial cells Prostacyclin Arachidonic acid Prostaglandin I2 receptor A receptor antagonists -1 Smooth muscle cells receptor B Vasoconstriction and proliferation L-arginine Nitric Oxide cgmp L-citrulline Phosphodiesterase type 5 Vasodilation Phosphodiesterase type 5 inhibitor Exogenous nitric oxide and antiproliferation Prostacyclin (prostaglandin I2) camp Vasodilation and antiproliferation Smooth muscle cells Prostacyclin derivatives Humbert M et al. N Engl J Med. 2004;;351:

12 Receptor Antagonists: Pivotal Trials Study Name Drug BREATHE-1 Oral bosentan* vs placebo EARLY Oral bosentan vs placebo ARIES-1&2 Oral ambrisentan vs placebo SERAPHIN Oral macitentan vs placebo N Etiology Class 213 PAH III, IV 185 PAH II 394 PAH II, III 742 PAH II,III Design Double-blind 16-week Double-blind 6-month Double-blind 12-week Double-blind Event-driven morbidity/mortality Positive Results 6MWD Delay clinical worsening Symptoms Delay clinical worsening Hemodynamics 6MWD Delay clinical worsening Delay disease progression 6MWD Symptoms *Bosentan = Tracleer. Approved for FC II-IV mg po bid. Ambrisentan = Letairis. Approved for FC II-III mg po qd Macitentan = Opsumit. Approved for FC II-III. 10 mg po qd. Rubin L et al. N Engl J Med. 2002;;346: Channick RN et al. Lancet. 2001;;358: Galiè N et al. Lancet, 2008;;371: Galiè N et al. Circulation. 2008;;117: Pulido T et al. N Engl J Med. 2013;;369: Approved Therapeutic Targets Pre-proendothelin Proendothelin Endothelial cells Nitric Oxide Endothelial cells Prostacyclin Arachidonic acid Prostaglandin I2 receptor A receptor antagonists -1 Smooth muscle cells receptor B Vasoconstriction and proliferation L-arginine Nitric Oxide cgmp L-citrulline Phosphodiesterase type 5 Vasodilation Phosphodiesterase type 5 inhibitor Exogenous nitric oxide and antiproliferation Prostacyclin (prostaglandin I2) camp Vasodilation and antiproliferation Smooth muscle cells Prostacyclin derivatives Humbert M et al. N Engl J Med. 2004;;351: PDE-5 Inhibitor Pivotal Trials Study Name Drug SUPER-1 Oral sildenafil* vs placebo N Etiol Class Design Positive Results 278 PAH I-IV Double-blind 12-week 6MWD Symptoms Hemodynamics PHIRST-1 Oral tadalafil vs placebo 405 PAH I-IV Double-blind 16-week 6MWD Delay clinical worsening Hemodynamics HRQoL *Sildenafil = Revatio. Approved for FC II-III. 20 mg po tid. Tadalafil = Adcirca. Approved for FC I-IV. 40 mg po qd. Galiè N et al. N Engl J Med. 2005:353: Galiè N et al. Circulation. 2009;;119;;

13 SGC Stimulator Pivotal Trials Study Name Drug PATENT-1 Oral riociguat* vs placebo CHEST-1 Oral riociguat vs placebo N Etiol Class Design Positive Results 443 PAH I-IV 261 CTEPH I-IV Double-blind 12-week Double-blind 16-week 6MWD Symptoms Hemodynamics Delay clinical worsening 6MWD Symptoms Hemodynamics *Riociguat = Adempas. Approved for WHO Group 1;; persistent CTEPH (WHO Group 4) after surgical treatment, or inoperable CTEPH;; titrated to maximum 2.5 mg po tid. 63 patients on exploratory 1.5 mg tid were excluded from efficacy analysis. Ghofrani AH et al. N Engl J Med 2013;; 369: Ghofrani AH et al. N Engl J Med 2013;; 369: Approved Therapeutic Targets Pre-proendothelin Proendothelin Endothelial cells Nitric Oxide Endothelial cells Prostacyclin Arachidonic acid Prostaglandin I2 receptor A receptor antagonists -1 Smooth muscle cells receptor B Vasoconstriction and proliferation L-arginine Nitric Oxide cgmp L-citrulline Phosphodiesterase type 5 Vasodilation Phosphodiesterase type 5 inhibitor Exogenous nitric oxide and antiproliferation Prostacyclin (prostaglandin I2) camp Vasodilation and antiproliferation Smooth muscle cells Prostacyclin derivatives Humbert M et al. N Engl J Med. 2004;;351: Prostacyclin Analogues: Intravenous, Subcutaneous, or Inhaled Epoprostenol (Flolan or Veletri ) Treprostinil (Remodulin ) Treprostinil (Remodulin ) Iloprost (Ventavis ) Treprostinil (Tyvaso ) Epoprostenol IV: FC III-IV, 2 ng/kg/min titrated to desired clinical response in 1-2 ng/kg/min increments. Treprostinil IV / SC: FC II-IV, ng/kg/min/wk. IV=diluted. Inhaled: FC III, to 54 mcg, 4 inh/d. Iloprost Inhaled: FC III-IV, mcg, 6-9 inh/d.

14 Combination Therapy sgc Stimulators PATENT-1*? Prostanoids PATENT-1*? TRIUMPH STEP SERAPHIN?? TRIUMPH PACES Receptor Antagonists? PHIRST* SERAPHIN AMBITION Phosphodiesterase Inhibitors *53% on background ERA for PHIRST, 50% on background ERA or prostanoid for PATENT-1 64% on background PDE-5I or prostanoid in SERAPHIN. AMBITION: Effect of Ambrisentan Plus Tadalafil Versus Monotherapy on Clinical Worsening* Participants with No Event (%) No. at risk: Combination therapy Pooled monotherapy Combination therapy Pooled monotherapy 20 Hazard ratio, 0.50 (95% Cl, ) P< Weeks * Death, hospitalization for worsening PAH, disease progression, unsatisfactory long-term clinical response. Galiè N et al. N Engl J Med. 2015;;373: Recently Completed or Ongoing Clinical Trials of Combination Therapy AMBITION Current Therapy Ambrisentan/ tadalafil/ combo Added Therapy Combo vs mono Patients (n) Study Duration 500 Event-driven Primary Endpoint Morbidity/mortality event Pfizer Bosentan Sildenafil weeks 6MWD COMPASS-2 Sildenafil Bosentan 250 Event-driven ATPAHSS Ambrisentan/ tadalafil/ combo Combo vs mono Morbidity/mortality event weeks RV mass/pvr GRIPHON ERA, PDE-5I, or both Selexipag 1156 Event-driven Morbidity/mortality event Ikaria 1 current therapies Inhaled NO weeks PVR FREEDOM-Ev PDE-5I or ERA Oral treprostinil weeks (6MWD)/event driven 6MWD/ 1st clinical worsening event

15 Management of PH Practical matters Volume status 02 and C02 Arrhythmias (a-fib and a-flutter) A bad reflex IV therapy Volume Status Diuresis Volume Status SV RA pressure

16 Arrhythmias B-Blockers Ca++ Blockers Amiodarone Cardioversion

17 Jeresh Beezold reflex Nausea Diaphoresis Bradycardia PEA PAH and Sepsis Aggressive up front therapy for infection IV therapy Don t interrupt IV therapy

18 Collaborative Care With PH Centers: Initial Steps Local Care Diagnostic dilemmas Diagnostic cath/ vasodilator trial Fluid management Acute issues PAH-specific therapies Side effects Hospitalizations Transplant Clinical trials PH Center Pulmonary Vascular Disease Center Director: Todd M. Bull, MD Pulmonary Arterial Hypertension Pulmonary Embolism/VTE High Altitude PH WHO class III PH Hereditary Hemorrhagic Telangiectasia (HHT) Thanks and Questions??