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Presenter Disclosure Information Evaluation and Treatment of Evaluation and Treatment of Pulmonary Arterial Hypertension Pulmonary Arterial Hypertension I will not discuss off label use or investigational Advanced Lung Disease Course, May

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Evaluation and Treatment of Pulmonary Arterial Hypertension

Advanced Lung Disease Course, May 2015 Teresa De Marco, MD, FACC Professor of Medicine & Surgery Director, Heart Failure and Pulmonary Hypertension Medical Director, Heart Transplantation

Presenter Disclosure Information

Evaluation and Treatment of Pulmonary Arterial Hypertension

I will not discuss off label use or investigational use in my presentation. I have financial relationships to disclose:

  • Consultant for: Actelion, Gilead, United Therapeutics,

Bayer

  • Research support from: United Therapeutics, Reata
  • Honoraria from: Actelion, Gilead

Objectives

Review:

  • Definition and classification of pulmonary

hypertension (PH) and pulmonary arterial hypertension (PAH)

  • Diagnostic approach
  • Treatment

Pulmonary Hypertension (PH)

  • Sustained elevation of mean

pulmonary artery pressure: > 25 mmHg

Simonneau G, et al. J Am Coll Cardiol. 2004:43:5S-12 Simonneau G, et al, J Am Coll Cardiol. 2009;54:S43-54.

MPAP= 1/3(PAs-PAd) + PAd

Normal: 8 - 20 mmHg

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SLIDE 2

2 Updated Clinical Classification

  • f PH (5th WSPH Nice, 2013)
  • Group 1: Pulmonary arterial hypertension (PAH)

1’ Pulmonary veno-occlusive disease (PVOD) or pulmonary capillary hemangiomatosis (PCH) 1” Persistent PH of newborn

  • Group 2: PH due to left heart disease
  • Group 3: PH due to lung diseases and/or hypoxia
  • Group 4: Chronic thromboembolic PH (CTEPH)
  • Group 5: PH with unclear multifactorial mechanisms

Simonneau et al, J Am Coll Cardiol. 20013;62:D34-41.

Etiology of PH on Echocardiogram

  • Single Center Study from Australia

– 4579 patients screened 483 patients (10.5%) with PH on echocardiogram (defined as PASP >40 mm Hg)

Gabbay E. Am J Respir Crit Care Med. 2007;175:A713. The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the ESC and ERS, endorsed by ISHLT. Eur Heart J. 2009;30:2493-2537.

78.7%

5th WSPH Clinical Classification of PAH

(WHO Group 1)

Group 1Pulmonary Arterial Hypertension (PAH)

Idiopathic PAH Heritable BMPR2 ALK-1, endoglin, SMAD9,CAAV1,KCNK3 Unknown Drug and toxin-induced PAH associated with: Connective tissue disease HIV infection Portal hypertension Congenital heart disease Schistosomiasis 1’ – Pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis 1’’ – Persistent PH of the newborn

Simonneau et al, J Am Coll Cardiol. 20013;62:D34-41.

Group 1: Pulmonary Arterial Hypertension (PAH)

  • Characterized by progressive and sustained elevation of

pulmonary artery pressure and vascular resistance: – PA mean > 25 mmHg (nl 8-20 mmHg) – PAWP/LVEDP < 15 mmHg (nl 4-12 mmHg) – PVR > 3 Wood units (240 dyn/sec/cm-5)

  • Subset of PH (15 cases/ million)
  • Vasoconstriction, remodeling,

thrombosis in situ

  • Progressive cardiopulmonary

deterioration

  • Leads to RH failure and death

(67% 5-yr survival)

Hoeper MM, et al. J Am Coll Cardiol. 2013;62:D42-50.

Humbert M et al. Am J Respir Crit Care Med. 2006;173:1023-30 Thenappan T, et al. Eur Respir J. 2010;35:1079-1087.

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SLIDE 3

3

Low Risk

Determinants of Risk

High Risk

No Clinical evidence of RV failure Yes Gradual Disease progression Rapid II, III WHO functional class IV Longer (> 400 meters) 6-MWD Shorter (< 300 meters) Peak VO2 > 10.4 mL/kg/min Cardiopulmonary exercise testing Peak VO2 < 10.4 mL/kg/min Minimally elevated and stable BNP/NT-proBNP Significantly elevated PaCO2 > 34 mm Hg Blood gasses PaCO2 < 32 mm Hg Minimal RV dysfunction ECHO findings Pericardial effusion, RV dysfunction, RA enlargement RAP < 10 mm Hg; CI > 2.5 L/min/m2 Hemodynamics RAP > 20 mm Hg; CI < 2 L/min/m2

McLaughlin, et al. J Am Coll Cardiol 2009;53:1573 D’Alonzo, et al. Ann Int Med 1991;115:343 Raymond, et al. J Am Coll Cardiol 2002;39:1214

PAH Determinants of Patient Risk

and Prognosis

ACC/AHA Expert Consensus

Provencher, et al. E Heart J 2006: 27:589 Nagaya, et al. Circ 2000;102:865 Blyth, et al. Eur Respir J. 2007;29:737

Evaluation

REVEAL Database: Most Frequent Symptoms at Diagnosis

Elliott EG, et al. Chest. 2007;132(4 suppl):631S.

Dyspnea at rest Cough Dizzy/lightheaded Presyncope/syncope Edema Chest pain/discomfort Other Fatigue Dyspnea on exertion

  • 0 25 50

75 100 Incidence (%) IPAH APAH

N=1479.

PAH Diagnostic Guidelines: Decision Analysis

McGoon M, et al. Chest. 2004;126:14S-34S.

Unexplained Symptoms of Dyspnea on Exertion, Syncope/Near Syncope, Fatigue Clinical History, Examination, ECG, Chest X-Ray

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SLIDE 4

4 Signs on Physical Examination

  • Loud pulmonic valve closure (P2) (93%)
  • TR murmur (40%)
  • PR murmur (13%)
  • Right-sided fourth heart sound
  • Right ventricular lift
  • Jugular venous distention
  • RV third heart sound (23%)
  • Peripheral edema (32%)
  • Ascites
  • Low BP, low PP, cool extremities (low CO,

peripheral vasoconstriction, hypoperfusion)

  • Stigmata of secondary causes PAH

Signs of RHF

McLaughlin VV et al. J ACC. 2009;53:1573-1619 McGoon M, et al. Chest Rich S, et al. Ann Intern Med. 1987;107:216-223.

Electrocardiogram

Image courtesy of Vallerie McLaughlin, MD

  • Insufficiently sensitive as screening tool for PH
  • Prognosis:
  • p-wave in II, qR V1, RVH
  • risk of death
  • RAD, RAE, RBBB,RVH

Bossone E, et al. Chest 2002;121:513 McGoon M, et al. Chest 2004;126:14S-34S McLaughlin VV et al. JACC 2009;53:1573-1619.

Prominent Central Pulmonary Artery Peripheral Hypovascularity Right Descending Pulmonary Artery RV Enlargement

  • Cardiac enlargement
  • Prominent proximal PA s
  • “Pruning” of distal PA s
  • No evidence of pulmonary edema
  • Lungs appear normal

Chest Radiograph in PAH

PAH Diagnostic Guidelines: Decision Analysis

McGoon M, et al. Chest. 2004;126:14S-34S.

Clinical History, Examination, Chest X-Ray, ECG Is There a Reason to Suspect PH? Yes No Echocardiography Work-Up for Other Conditions

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SLIDE 5

5

LV RV

Apical Four Chamber Normal PAH

LV RV RA LA

Parasternal Short Axis

Signs of PAH with Echo/Doppler

  • Increased sPAP or TR jet
  • Right atrial and ventricular

hypertrophy/enlargement

  • Flattening of intraventricular

septum

  • Tricuspid regurgitation
  • Small LV dimension

LV RV LA RA IVS

ePAsP = 4V2 + eRAP

Traditional ECHO does not accurately measure:

  • Mean PA pressure
  • PAWP
  • Cardiac output (blood flow)
  • Cannot calculate PVR
  • Other limitations-15% no TR jet,

not all congenital lesions obvious, small errors in TRV tracing can alter results

McGoon M, et al. Chest

PAH Diagnostic Guidelines

McGoon M, et al. Chest. 2004;126:14S-34S.

Echocardiography Indicates PH

Evaluate for Associated Causes V/Q scan PFTs Arterial Saturation

HIV Infection, Scleroderma, SLE, Other CTD, Liver Disease, CHD, Drug- Associated Parenchymal Lung Disease, Hypoxemia,

  • r Sleep Disorder

Suspected Chronic PE

PAH Diagnostic Guidelines

McGoon M, et al. Chest. 2004;126:14S-34S.

Echocardiography Indicates PH

Evaluate for Associated Causes V/Q scan PFTs Arterial Saturation

HIV Infection, Scleroderma, SLE, Other CTD, Liver Disease, CHD, Drug- Associated Parenchymal Lung Disease, Hypoxemia,

  • r Sleep Disorder

Suspected Chronic PE

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SLIDE 6

6 Ventilation Perfusion Lung Scan

Idiopathic PAH Chronic PE

Ventilation Perfusion Perfusion Ventilation

3 – 4% of acute PE do not entirely resolve 50% of those with CTEPH do not have hx of acute PE V/Q scan should be performed to exclude CTEPH even when another explanation for PH is present CTEPH: >1 segmental-sized or larger mismatched perfusion defects Normal or very low probability V/Q scan excludes CTEPH

PAH Diagnostic Guidelines

McGoon M, et al. Chest. 2004;126:14S-34S.

Echocardiography Indicates PH

Evaluate for Associated Causes V/Q scan PFTs Arterial Saturation

HIV Infection, Scleroderma, SLE, Other CTD, Liver Disease, CHD, Drug- Associated Parenchymal Lung Disease, Hypoxemia,

  • r Sleep Disorder

Suspected Chronic PE

Pulmonary Function Tests, Arterial Blood Gases, and Oxygen Saturation

  • Findings suggestive
  • f PAH

DLCO 40% - 80% of expected – Mild to moderate

  • f

lung volumes – Peripheral airway

  • bstruction

– Arterial O2 tension normal

  • r slightly at rest

– Arterial CO2 is – SpO2 preserved at rest, may be with exercise/ambulation

  • Findings suggestive of

alternate PH diagnoses – Hypoxic PH due to COPD

  • Irreversible airway
  • bstruction + increased

residual volumes

  • reduced DLCO + normal or

increased CO2 tension

– Interstitial lung disease

  • Decrease in lung volume +
  • Decreased DLCO

Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.

PAH Diagnostic Guidelines: Confirmation of PAH

Adapted from McGoon M, et al. Chest. 2004;126:14S-34S.

Echocardiography Indicates PH Right Heart Catheterization

  • Establish diagnosis
  • Ascertain etiology
  • Establish severity & prognosis
  • Verify presence and severity of shunts
  • Evaluate vasoreactivity
  • Guide treatment
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SLIDE 7

7 Algorithm for Assessment of Vasoreactivity in Patients with PAH

Right Heart Catheterization With Acute Vasoreactivity Testing (iNO, epoprostenol, adenosine) Non - responder Consider: Oral ERAs/PDEI-5/sGCS Inhaled Iloprost SQ/IV/inhaled/PO Treprostinil IV Epoprostenol Responder (<15%) Consider: Hemodynamically- Monitored Trial of Calcium Channel Blocker

mPA 10 mmHg mPA < 40 mmHg No CO

(<10% respond long-term)

PAH Diagnostic Workup

McGoon M, et al. Chest. 2004;126:14S-34S.

Right Heart Catheterization Confirms PAH

6-minute walk, Borg score NYHA/WHO functional class

Establish Baseline, Prognosis, and Document Progression/Response to Treatment With Serial Re-assessment

Treatment Goals of Management of PAH Prevent right heart failure

  • Alleviate symptoms
  • Improve exercise capacity
  • Improve functional class
  • Improve hemodynamics
  • Prevent clinical worsening
  • Reduce morbidity, mortality
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SLIDE 8

8 Overview: 2013 WSPH Treatment

Algorithm

Adapted from Galié N et al JACC. 2013;62 (25,

  • Suppl. D):D60-D72.

Supervised Exercise Training Psychosocial Support Avoidance of Strenuous Activity Pregnancy Avoidance Immunizations (influenza)

General Measures and Supportive Therapy Expert Referral (PH Center) Acute Vasoreactivity Testing

Oral Anticoagulants IPAH, heritable PAH anorexigen-induced PAH APAH Diuretics Oxygen Digoxin (controversial)

Non-Vasoreactive

WHO-FC I-III CCB Sustained Response (WHO FC I-II) Continue CCB YES

Initial Therapy With PAH Approved Drugs

(Recommended Compounds Depend on WHO-FC Status)

Sequential Combination Therapy Referral for Lung Transplantation

Vasoreactive

Inadequate Clinical Response Inadequate Clinical Response

  • n Maximal Therapy

Balloon Atrial Septostomy Consider for Lung Transplantation NO

Therapeutic Targets for PAH

Humbert M, Sitbon O, Simonneau G. N Engl J Med 2004;351:1425-36

Phosphodiesterase type 5 inhibitor Exogenous nitric oxide sGC stimul. Endothelin receptor antagonists Prostacyclin derivatives Endothelin receptor A Endothelin 1 Nitric oxide Prostacyclin (prostaglandin I2) Endothelin receptor B Vasodilation and antiproliferation Vasodilation and antiproliferation Vasoconstriction and proliferation cGMP cAMP Pre-proendothelin

  • Proendothelin

L-arginine

  • L-citrulline

Arachidonic acid

  • Prostaglandin I2

+ +

Phosphodiesterase type 5 Smooth muscle cells Endothelin cells Vessel lumen Nitric oxide pathway Endothelin pathway Prostacyclin pathway

FDA-Approved Specific Therapies for PAH

Endothelin Receptor Antagonists (oral)

  • Bosentan
  • Ambrisentan
  • Macitentan

Phosphodiesterase Type-5 Inhibitors (oral)

  • Sildenafil
  • Tadalafil

Prostacyclin Derivatives

  • Epoprostenol: IV (survival data)
  • Iloprost: inhalational
  • Treprostinil: inhalational, po, SQ or IV

Soluble Guanylate Cyclase Stimulators (oral)

  • Riociguat (also approved for CTEPH)

NO Pathway

Intravenous epoprostenol Subcutaneous treprostinil Inhalational Iloprost

Inhalational Treprostinil

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SLIDE 9

9 5th WSPH Drug Recommendations

INITIAL THERAPY WITH APPROVED PAH DRUGS

RED: Clinical trials supporting approval utilized mortality and morbidity endpoints in randomized controlled studies or reduced all- cause mortality. Level of evidence is based on the WHO-FC and the majority of patients in supportive trials.

Recommenda- tion Eviden- ce WHO-FC II WHO-FC III WHO-FC IV I A or B

Ambrisentan Bosentan Macitentan Riociguat Sildenafil Tadalafil Ambrisentan Bosentan Macitentan Riociguat Sildenafil Tadalafil Treprostinil (s.c. or inhaled) Iloprost (inhaled) Epoprostenol Epoprostenol (i.v.)

IIa C

Iloprost (i.v.) Treprostinil (i.v.) Ambrisentan Bosentan Macitentan Riociguat Sildenafil Tadalafil Treprostinil (s.c., i.v., inhaled)

IIb B

Beraprost

C

Initial Combination Therapy Initial Combination Therapy

Adapted from Galié N, et al. Updated treatment algorithm of pulmonary arterial

  • hypertension. JACC. 2013;62 (25, Suppl. D):D60-D72.

5th WSPH: Prognostic Variables Used in Clinical Practice To Set Treatment Goals

Variable Recommended Goal

NYHA Functional class I or II Echocardiography/CMR Normal/near normal RV size and function Hemodynamics Normalization of RV function

  • RAP < 8 mm Hg and
  • CI > 2.5 to 3.0 L/min/m2

6 Minute walk distance Cardiopulmonary exercise testing >380-440 m (or more in younger pts) Peak VO2 >15 mL/min/kg and EqCO2 <45 L/min/L/min B-type natriuretic peptide Normal

McLaughlin VV, et al. J Am Coll Cardiol. 2013;62:D73-81.

Inadequate Clinical Response to Initial PAH Therapy

Failure to show improvement or deterioration with monotherapy

Consider eligibility for lung transplant

Inadequate Clinical Response on Maximal Therapy? Lung transplant (I-C) BAS (Iia- C)

Adapted from Galié N et al JACC. 2013;62 (25):D60-D72.

New Paradigm- AMBITION: Ambrisentan-Tadalafil Up-front Combination Therapy

Primary Endpoint: Time to First Clinical Failure Event Primary Analysis Set

Event-Free (%)

Time (weeks)

HR: 0.502 95% CI(0.348, 0.724) p=0.0002

0 24 48 72 96 120 144 168 192

1 year 88.9% 1 year 75.5% Combination therapy Pooled monotherapy 2 year 79.7% 2 year 63.2% 3 year 56.1% 3 year 67.6% Combination: 253 229 186 145 106 71 36 4 Pooled monotherapy: 247 209 155 108 77 49 25 5

Number at risk: Abstract

Rubin L, et al. Chest. 2014;146:339A.

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SLIDE 10

10

PAH: Therapy

Transplantation - lung / heart-lung

  • Indicated for patients who continue to deteriorate

with poor QOL despite aggressive therapy

  • 1 year survival – 70-90%
  • 5 year survival – 50-60%
  • Mortality on waiting list remains high

(20% per yr despite LAS)

  • Aggressive pre-transplant management can

mortality

Chen H, et al. Am J Resp Crit Care Med 2009;180:468

PAH: Summary

  • PAH is a progressive disease associated with

significant morbidity and mortality

  • Echocardiography and right heart catheterization

are the primary diagnostic modalities

  • Strides

made thus far in pathogenesis and pathobiology have lead to more effective therapies

  • Current therapies have significant limitations and

are costly

  • New

therapeutic agents and strategies are available and emerging