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Screening Diagnosis and Treatment of PAH:

An OverviewKerri Akaya Smith, MD

Wednesday, April 25

Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension

1

Screening, Diagnosis, and Treatment of

Pulmonary Arterial Hypertension (PAH):

An Overview

New Jersey Association of Osteopathic Physicians & Surgeons

Atlantic City, New Jersey

April 25, 2018

K. Akaya Smith, MDAssistant Professor of Medicine

Perelman School of Medicine at the University of Pennsylvania

Medical Director, Pulmonary Hypertension Program

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania

Faculty Disclosure

• Dr. Smith has received research support/grants from Eiger

BioPharmaceuticals, Inc, Gilead Sciences, Inc., Actelion Pharmaceuticals

US, Inc, and United Therapeutics Corporation.

• Dr. Smith has also served on an advisory committee for United Therapeutics

Corporation.


2

The Pulmonary Hypertension Association (PHA)

is the leading non-profit organization for PH research,

public awareness, and services. The organization

has over 12,000 members, including patients, family

members, and medical professionals.

www.PHAssociation.org

Let’s get started . . .

Vascular Pressure in Systemic and Pulmonary Circulations (mm Hg)

PulmonaryCirculation

Systemic Circulation

SystemicArteries

PulmonaryArteries

SystemicVeins Pulmonary

Veins

120/80, mean 93 25/8, mean 14

LAMean

5

RAMean 2-

5

RV25 / 2-5

LV120 / 5-10

Mean 12Mean 30

LungBody

Kovacs G et al. Eur Respir J. 2009;34:888-894.


3

5th World Symposium on PH:Classification of PH 1. Pulmonary arterial hypertension

1.1 Idiopathic PAH1.2 Heritable PAH

1.2.1 BMPR21.2.2 ALK1, ENG, SMAD9, CAV1, KCNK31.2.3 Unknown

1.3 Drug- and toxin-induced1.4 Associated with

1.4.1 Connective tissue diseases1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart disease1.4.5 Schistosomiasis

1’. Pulmonary veno-occlusive disease and/orpulmonary capillary hemangiomatosis

1’’. PPHN

2. PH due to LHD2.1 LV systolic dysfunction2.2 LV diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart

inflow/outflow obstruction

3. PH due to lung diseases and/or hypoxia3.1 COPD3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive

and obstructive pattern3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung diseases

4. CTEPH

5. PH with unclear multifactorial mechanisms

5.1 Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy

5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis

5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders

5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH

Simonneau G et al. JACC 2013;62:D34-41.

5th World Symposium on PH: Hemodynamic Definition of PH/PAH

PH

PAHMean PAP ≥25 mm Hg plusPAWP ≤15 mm Hg plusPVR >3 Wood units

Mean PAP ≥25 mm Hg at rest during RHC

Hoeper MM et al. J Am Coll Cardiol. 2013;62:D42-D50.







1’’. PPHN





4. CTEPH

5. PH with unclear multifactorial mechanisms

5.1 Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy

5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis





4

Heritable PAH • Autosomal dominant• BMPR2 (bone morphogenetic protein receptor type 2)

is the major predisposing gene• Mutation detection rate for known genes is ≈75% in

familial PAH • Major predisposing gene has a highly variable

penetrance between families• Genetic anticipation

• ALK1 (ACVRL1; activin A receptor type-II-like kinase 1) is major gene when PAH is associated with hereditary hemorrhagic telangiectasia (HHT)

Soubrier F et al. J Am Coll Cardiol. 2013;62:D13-D21.Simonneau G et al. J Am Coll Cardiol. 2013;62:D34-D41.

PAH Related to ConnectiveTissue Disease• Connective tissue diseases

– limited scleroderma (most common)– diffuse scleroderma – mixed connective tissue disease– systemic lupus erythematosus– rheumatoid arthritis– Sjogren’s syndrome

• PH is one of the leading causes of death in scleroderma

• Similar to IPAH pathology• Medical treatment same as for IPAH, but benefits less

than for IPAHHachulla E et al. Rheumatology. 2009;48:304-308.

Prevalence of PAH in Scleroderma

• Prevalence 7.9% in large prospective study (N=599) with confirmatory catheterizations

– excluded severe PFT abnormalities– all underwent Doppler echocardiography – catheterization if VTR >3 m/sec or

2.5–3 m/sec + unexplained dyspnea

• Prevalence of PAH: found in 47 of 599 scleroderma patients

– 29 had known PAH at study entry – 18 patients were newly diagnosed with PAH

Hachulla E et al. Arthritis Rheum. 2005;52:3792-3800.


5

Portopulmonary Hypertension

• Prevalence overall: 2-5% by RHC; liver transplant candidate: 4% to 17%

• Dependent on portal HTN, not hepatocellular dysfunction

• Poor prognosis: higher risk of death than IPAH pts

• Liver transplant

– may improve survival with mild to moderate PAH(28-56%, 5 yr)

– significant PAH (mPAP >35 mm Hg) predicts unacceptably high perioperative mortality

Budhiraja R et al. Chest. 2003. Hadengue A et al. Gastroenterology. 1991. Castro M et al. Mayo Clin Proc. 1996. Kawut SM et al. Liver Transpl. 2005. Ramsay MA et al. Liver Transpl Surg. 1997. Krowka MJ et al. Clin Chest Med. 2005. Krowka MJ et al. Liver Transpl. 2004. Swanson KL et al. Hepatology. 2004.







1’’. PPHN





4. CTEPH

5. PH with unclear multifactorial mechanisms5.1 Hematological disorders: chronic hemolytic anemia,

myeloproliferative disorders, splenectomy5.2 Systemic disorders: sarcoidosis, pulmonary

Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis




Most Common Cause of Elevated PAPs by Echo: Left Heart DiseaseSymptoms

– paroxysmal nocturnal dyspnea

– orthopnea

History– diabetes

– hypertension

– obesity

– coronary artery disease

– metabolic syndrome

ECG– atrial fibrillation

– absence of right axis deviation

Echo– left atrial enlargement

– left ventricular hypertrophy

– normal RA, RV

– abnormal diastolic filling

– mitral or aortic disease


6

Percentage of PAH and PVH Patients With All 4 Metabolic Syndrome Factors

*p≤0.005; **p=0.023.Robbins IM et al. Chest. 2009;136:31-36.

0

20

40

60

80

100

Percentof

patients**

*

*

*

PAHPVH

HTN13.7

(1.6-113.0)

Obesity7.1

(1.9-26.8)

DM5.7

(1.6-20.4)

HL4.2

(1.2-15.7)OR

95% CI







1’’. PPHN





4. CTEPH







Chronic Obstructive Pulmonary Disease (COPD) and PH• Retrospective study of 215 COPD patients• 13.5% had a PA mean >35 mm Hg• Correlated best (inversely) with PaO2• A small number had only moderate obstruction: treatable sub-group?

Thabut G et al. Chest. 2005;127:1531-1536. FEV1 (% pred.)

mPAP (mm Hg)

10

20

30

40

60

50

0 20 40 60 80

4

12

3


7







1’’. PPHN





4. CTEPH







Incidence of CTEPH

• Approximately 3% to 4% 1-2 yr after acute PE

• USA: 600,000 cases ofacute PE each year

• Only 40% to 50% of CTEPH patients have a history ofprevious episodes of acutePE

• VQ scan identifies old PE better than CTA

McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.Pengo V et al. N Engl J Med. 2004;350:2257-2264.Tapson VF, Humbert M. Proc Am Thorac Soc. 2006;3:564-567.

Years

Cum

ulat

ive

inci

denc

e of

CTE

PH

0 1 2 3 4 7 8 9 10 115 60.00

0.01

0.02

0.03

0.04

Pathology of PAH

Gaine S. JAMA. 2000;284:3160-3168.

WHO Group I: Characterized by progressive growth and vasoconstriction of small pulmonary arteries


8

PAH: Hemodynamic and Clinical Course

NORMAL

Time

PAP

PVR

CO

INYHA

Adventitia

Media

Intima

Adapted from Gaine S. JAMA. 2000;284:3160-3168.

NORMAL

Adventitia

Media

Intima

REVERSIBLE DISEASE

Time

PAP

PVR

CO

I II IIINYHA

Smooth Muscle Hypertrophy

Early Intimal Thickening



NORMAL

Adventitia

Media

Intima


Early Intimal Thickening

REVERSIBLE DISEASE

IRREVERSIBLE DISEASE

Plexiform Lesions

Thrombosis

Adventitial, Intimal Proliferation


Time

PAP

PVR

CO

I II III IVNYHA




9

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5

Percent survival

McLaughlin VV et al. Chest. 2004;126:78S-92S.

Congenital heart disease

Portopulmonary

IPAH

CTD

HIV

Years

Survival in PAH

Adapted from: Sitbon O et al. J Am Coll Cardiol. 2002;40:780-788. D’Alonzo GE et al. Ann Intern Med.1991;115:343-349. McLaughlin VV et al. Chest. 2004;126:78S-91S.

Idiopathic PAH: Survival If Untreated

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 50

20

40

60

80

100

Years of follow-up

Perc

enta

ge s

urvi

ving

NIH registrySitbon historical controlACCP estimate

• Incidence: 2-6 cases per million in US

• Poor prognosis in an era lacking therapy

• Therapeutic options and research efforts now offer more hope

French Registry: Kaplan-Meier Survival Estimates in Combined PAH Population vs NIH-predicted

Humbert M et al. Circulation. 2010;122:156-163.

0 12 24 36Time (mo)

Survival (%)

0

40

80

100

60

20

Observed

Predicted (NIH Registry)

No. at risk:All patients 56 98 120 13369 113 127


10

REVEAL: Observed 1-year Survival From Time of Enrollment According to Predicted Risk Strata

Benza RL et al. Circulation. 2010;122:164-172.

Months from enrollment

Survival (%)

0

60

100

80

40

0 3 6 9 122 5 8 111 4 7 10

Risk strataLowAverageModerately highHighVery high

No. at risk:LowAverageMod. highHighVery high

1374665280295102

1368659277293100

136465727429196

135965326928489

135664826427781

135264726327074

135164026026372

134662825925569

134162525524761

133661825424159

131160424923855

130460224423352

130359624322549

Key Pathways Implicated in PAH Pathogenesis

Humbert M et al. N Engl J Med. 2004;351:1425-1436.

cGMP

cAMP

Vasoconstriction

and proliferation

Endothelinreceptor A Endothelin

receptor B

Vasodilation

and antiproliferation

Phosphodiesterase type 5

Vasodilation


Nitric Oxide

Endothelin-1

Pre-proendothelin

L-arginine

Prostaglandin I2

L-citrulline

Nitric OxidePathway

EndothelinPathway

ProstacyclinPathway

Endothelial cells

Proendothelin

Endothelial cells

Arachidonic acid

Smooth muscle cells

Prostacyclin (prostaglandin I2)

Smooth muscle cells

Case: Jane

• 37-yr-old woman, previously healthy

• Delivered second child 14 mo previously

• Limited exercise tolerance since delivery, attributed to weight gain

• Dyspnea while playing with older child; syncope while walking up an incline


11

Jane: Initial Symptoms

• Currently has dyspnea with mild exertion, walks slowly in store

• Exertional light-headedness

• Atypical chest pain

• Occasional palpitations

• Lower extremity edema

Multiple Guidelines, Consistent Message: Comprehensive Diagnostic Evaluation/ Robust PH Specialty Center Collaboration Are Necessary

Follow Basic Steps of American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Consensus Algorithm, With Some Updates• To identify:

– the presence of PH

– which group of PH (WHO I-V)

McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.Developed in Collaboration With the American College of Chest Physicians; American Thoracic Society, Inc; and the Pulmonary Hypertension Association


12

Echocardiogram

PFT’s

Polysomnography

V/Q Scan

• Sleep Disorder

• Chronic PE

Functional Test(6MWT, CPET)

Overnight Oximetry

HistoryExamCXRECG

HIV

ANA

LFT’s

RH Cath

TEEExercise Echo

Pulmonary AngiographyChest CT AngiogramCoagulopathy Profile

Vasodilator TestExercise RH CathVolume Loading

ABG’s

• Index of Suspicion of PH

• RVE, RAE, RVSP, RV Function

• Left Heart Disease• VHD, CHD

• Ventilatory Function• Gas Exchange

Other CTD Serologies

• HIV Infection

• Scleroderma, SLE, RA

• Portopulmonary Htn

• Establish Baseline• Prognosis

• Confirmation of PH• Hemodynamic Profile• Vasodilator Response

Pivotal Tests Contingent Tests Contribute to Assessment of:

Left Heart CathMcLaughlin VV et al. J Am Coll Cardiol.2009;53:1573-1619.

ACC

F/AH

A D

iagn

ostic

Alg

orith

m

History and Physical Exam Findings Are Insensitive Unless Advanced Disease/RV Failure Present

History Exam (PH) Exam (RV Failure)• Dyspnea (86%)• Fatigue (27%)• Chest pain (22%)• Edema (22%)• Syncope (17%)• Dizziness (15%)• Cough (14%)• Palpitations

(13%)

• Loud P2 (listen at apex)• RV lift (left parasternal –

fingertips)• RV S3, S4• Systolic murmur (TR;

inspiratory augmentation)• Early systolic click• Midsystolic ejection

murmur• Diastolic murmur (PR)

• JVD; increased A wave, V wave; hepatojugular reflex

• Pulsatile liver• Hepatomegaly• Edema• Ascites• Low BP, low PP, cool

extremities

REVEAL. Brown LM et al. Chest. 2011;140:19-26. Adapted from McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.

Jane: Physical Exam

• HR 90 bpm; BP 130/68 mm Hg; Wt 190 lb; Ht 5'4"

• JVP ~15 cm, reduced carotid upstrokes

• Clear lungs

• Palpable RV heave, RRR, normal S, loud P2,III/VI, TR m

• 2+ LE edema


13

Jane: Additional History

• PMH: 2 children, 4 yr and 14 mo

– IBS: diet-controlled

• Meds: none

• Allergies: contrast dye

• FH: PPH in a paternal aunt, CAD, DM, Htn

• SH: rare ETOH, o/w unremarkable

Healthy

Peripheral hypo-vascularity (pruning)

Prominent centralpulmonary artery

Adapted from McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.

Chest Radiograph May Show Right Heart and Vascular Abnormalities in Advanced Disease

PH

Healthy

RV enlargement into retrosternal clear space


PH

Chest Radiograph May Show Right Heart and Vascular Abnormalities in Advanced Disease


14

Electrocardiogram May Show Right Heart Abnormalities in Advanced Disease

Right Axis Deviation

Right Atrial Enlargement Right Ventricular Strain

Right Ventricular Hypertrophy

Image courtesy Christopher F. Barnett, MD, MPH

Echocardiogram

PFT’s

Polysomnography

V/Q Scan

• Sleep Disorder

• Chronic Thromboembolic PH


Overnight Oximetry

HistoryExamCXRECG

HIV

ANA

LFT’s

RH Cath

TEEExercise Echo



ABG’s






• HIV Infection







ACC

F/AH

A D

iagn

ostic

Alg

orith

m

Checklist for Echocardiographic Assessments When PH Is Suspected• Estimate pulmonary artery systolic pressure

• Evaluate severity of TR

• Evaluate right heart size and function

• Exclude left heart valvular disease and systolic dysfunction

• Exclude congenital heart disease

• Differentiate PAH from PH due LHD

• Estimate RA pressure

• Evaluate for pericardial effusion



15

Barnett C et al. JAMA. 2008;299:324-331.

Modified Bernoulli EquationRVSP= 4(VTR)2 + RAP

PASP Is Estimated Using Tricuspid Regurgitant Jet Velocity

PASP=RVSP in the absence of pulmonic outflow obstruction

B

TR Jet Signal Quality Affects Reliability of Estimated PASP

Poor signal quality Good signal quality

Images courtesy Christopher F. Barnett, MD, MPH

Structural Echocardiographic Findings in Patients With PH

• RV enlargement• RA enlargement• Septal flattening• Pericardial effusion

McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.


16

Echocardiogram

PFT’s

Polysomnography

V/Q Scan

• Sleep Disorder



Overnight Oximetry

HistoryExamCXRECG

HIV

ANA

LFT’s

RH Cath

TEEExercise Echo



ABG’s






• HIV Infection







ACC

F/AH

A D

iagn

ostic

Alg

orith

m

Ventilation Perfusion Scan (V/Q): Best Screening Test to Exclude CTEPH• Should never be missed

• Is potentially curable with pulmonary endarterectomy (PEA)

• 3% to 4% of acute PE will develop CTEPH

• Half of those with CTEPH do not have an apparent history of thromboembolism

• Normal V/Q scan excludes CTEPH

• CTEPH may be diagnosed on CT pulmonary angiogram, however, reported sensitivity varies from 50-98%

McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619. Fedullo PF et al. N Engl J Med. 2001; 345:1465-72. Reichelt A et al. Eur J Radiol. 2009;71:49-54. Tunariu N et al. J Nucl Med. 2007;48:680-4.

Ventilation Perfusion Scan (V/Q) to Exclude CTEPH

Image courtesy Kelly Chin, MD


17

High-Quality Conventional Pulmonary Angiography: Gold Standard Test for CTEPH Diagnosis

PA LateralReproduced with permission from Barnett, CF, in: Yuan JX-J et al, eds, Textbook of Pulmonary Vascular Disease. Springer, 2011.

CTEPH: A Surgical Disease Survival Without Surgery Is Poor

Image courtesy Christopher F. Barnett, MD, MPH

Echocardiogram

PFT’s

Polysomnography

V/Q Scan

• Sleep Disorder



Overnight Oximetry

HistoryExamCXRECG

HIV

ANA

LFT’s

RH Cath

TEEExercise Echo



ABG’s






• HIV Infection







ACC

F/AH

A D

iagn

ostic

Alg

orith

m


18

Presence and Severity of Lung Disease Must Be Assessed • Abnormalities on PFTs may suggest cause of PAH or

reveal PH from lung disease (Group III)

• CT scanning useful in identifying parenchymal lung disease

• 20% have isolated reduction in DLCO

• DLCO mildly reduced(60%-80% predicted NIH registry)

• PVR correlates with reduction in DLCO

IPAH and CTEPH

• 20% have isolated reduction in DLCO

• Severity predicts future PAH

• DLCO correlates inversely with PASP

Systemic Sclerosis

DLCO=diffusing capacity of the lungs for carbon monoxide

Overnight Pulse Oximetry Is a Useful Screening Test for Sleep Disordered Breathing

• Hypoxia may signal underlying sleep apnea

• In patients with obstructive sleep apnea (OSA), PAPs reported to decrease in response to CPAP therapy

• Untreated—response to other treatment likely to be less effective

Somers VK et al. J Am Coll Cardiol. 2008;52:686-717.

Echocardiogram

PFT’s

Polysomnography

V/Q Scan

• Sleep Disorder



Overnight Oximetry

HistoryExamCXRECG

HIV

ANA

LFT’s

RH Cath

TEEExercise Echo



ABG’s






• HIV Infection







ACC

F/AH

A D

iagn

ostic

Alg

orith

m


19

Class Description

I No limitation of physical activity; ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope

IISlight limitation of physical activity; no discomfort at rest; ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope

IIIMarked limitation of physical activity; no discomfort at rest; less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope

IVUnable to carry out any physical activity without symptoms; signs of right-heart failure; dyspnea and/or fatigue may be present at rest; discomfort is increased by any physical activity

Functional Assessment: WHO Functional Class Modified From NYHA Classification

Rubin LJ. Chest. 2004;126:7S-10S.

Jane: Laboratory Studies

• ANA: negative

• Echo: normal LV function, RAE, RVE, RVSP 60 mm Hg, TEE—no shunt found after agitated saline injection

• VQ: normal

• PFTs: normal volumes and flows, DLCO 81%

• 6MWD: 222 m, 99-96%

Echocardiogram

PFT’s

Polysomnography

V/Q Scan

• Sleep Disorder



Overnight Oximetry

HistoryExamCXRECG

HIV

ANA

LFT’s

RH Cath

TEEExercise Echo



ABG’s






• HIV Infection







ACC

F/AH

A D

iagn

ostic

Alg

orith

m


20

Cardiac Catheterization

• Confirm echo findings

• Survey for left heart disease

– measure wedge pressure or LVEDP

• Measure CO; calculate PVR

• Exclude systemic to pulmonary shunts

• Establish severity and prognosis

• Acute vasodilator challenge

Required when PAH is suspected

Assessment of Pressures as the Catheter Passes Through the Heart

Reproduced with permission from Barnett Cf. In: Murray & Nadel’s Textbook of Respiratory Medicine, 6th ed, Elsevier 2016.

PAVC RA RV PVPC

LA LV Ao

Pulmonary venous hypertensionElevated PCWP, normal PVR

PAHPH with respiratory diseaseCTEPHNormal PCWP, elevated PVR

Other:high CO

PH: The Importance of Hemodynamics


21

Vasodilator Testing Identifies Patients Who Respond Well Long Term to Treatment With Calcium Channel Blockers

• Vasodilator testing

– Nitric Oxide Inh orepoprostenol IV

– Positive testdefined by:

Drop in mPAP ≥10 mm Hg to a mPAP≤40 mmHg

+ normal CO

Years

Long-term CCB responders*

Long-term CCB failure

38 33 30 22 13 8 3 3 2 119 12 7 4 0

Subjectsat risk, n

Cum

ulat

ive

surv

ival

Responders

Failure

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10 12 14 16 18

p=0.0007

*~50% of acute responders or ≤7% of IPAH patients

Sitbon O et al. Circulation. 2005;111:3105-3111.

Jane: Right Heart Cath

1/29/07Baseline

Nitric Oxide20 ppm

RAP (mm Hg) 19 20

PAP (mm Hg) 93/40, mean 63 93/46, mean 64

LVEDP (mm Hg) 10

Oxygen saturation (%)Pulmonary arteryFemoral artery

52.991.4

58.391.7

Cardiac output / Cardiac index(L/min) Fick 2.5/1.3 2.88/1.52

PVR (Wood units) Fick 21.2 15.2

Screening and Diagnosis Summary

• High index of suspicion

• Thorough diagnostic evaluation

• Exclude thromboembolic disease

• Evaluate potential causes/contributing issues

• RHC required prior to initiating PAH therapy

• Baseline functional evaluation


22

PAH Treatment Goals

• Fewer/less severe symptoms

• Improved exercise capacity

• Improved hemodynamics

• Prevention of clinical worsening

• Improved quality of life

• Improved survival

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

5th World Symposium on PH Goals of Therapy: Setting the Bar Higher

Functional Class • I or II

Hemodynamics • Normalization of RV function (RAP <8 mm Hg and CI >2.5-3.0 L/min/m2)

Echocardiography/ MRI • Normal/near normal RV size and function

BNP level • ‘Normal’

6MWD • 380-440 m, may not be aggressive enough

CPET • Peak VO2 >15 mL/kg/min• VE/VCO2 @ AT <45

Anticoagulate ± Diuretics ±Oxygen ± Digoxin

Positive

Sustained Response

Oral CCB

Continue CCB

Yes

Negative

What Is the Optimal Treatment Strategy?

Acute Vasoreactivity Testing

No LOWER RISK DETERMINANTS OF RISK HIGHER RISK

No Clinical evidence ofRV failure Yes

Gradual Progression of symptoms Rapid

II, III WHO class IVLonger (>400 m) 6MWD Shorter (<300 m)

Peak VO2 >10.4 mL/kg/min CPET Peak VO2 <10.4 mL/kg/min

Minimal RV dysfunction Echocardiography

Pericardial effusion,significant RV

enlargement/dysfunction;RA enlargement

RAP <10 mm Hg;CI >2.5 L/min/m2 Hemodynamics RAP >20 mm Hg;

CI <2.0 L/min/m2

Minimally elevated BNP Significantly elevated

McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619..


23

Chronic Adjuvant Therapies in PAHDigoxin• Variable inotropic effect and use• No long-term data; need to balance unproven benefits with known risksOxygen• Use to prevent hypoxic vasoconstriction• Consider exercise, sleep, altitude • Aim for target saturation >90%• May not correct hypoxia with shuntDiuretics• Most need; hypotension not a contraindication (may need BP support)• Renal function and electrolytes must be monitored closelyAnticoagulation• Recommended in IPAH• Observational studies only (2 retrospective, 1 prospective); need to balance

unproven benefits with known risks• INR 1.5 – 2.5Adapted from: Badesch DB et al. Chest. 2004;126:35S-62S. Badesch DB et al. Chest. 2007;131:1917-1928.McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.

Other Management Issues

• Encourage exercise and activity within the limits of disease and ability to maintain O2 levels

• Consider enrollment in a pulmonary rehabilitation program

• Immunizations

• Contraception




Positive

Sustained Response

Oral CCB

Continue CCB

Yes

Negative

Acute Vasoreactivity Testing

No LOWER RISK DETERMINANTS OF RISK HIGHER RISK



II, III WHO class IVLonger (>400 m) 6MWD Shorter (<300 m)






CI <2.0 L/min/m2



24

Sitbon O et al. Circulation. 2005;111:3105-3111.

Survival in IPAH:Long-term CCB Responders

Years

Long-term CCB responders (~50% of acute responders or ≤7% of IPAH patients)

Long-term CCB failure

38 33 30 22 13 8 3 3 2 1

19 12 7 4 0Subjectsat risk, n

Cum

ulat

ive

surv

ival

Long-term CCBresponders

Long-term CCBfailure

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10 12 14 16 18

p=0.0007


Revised Definition of Vasodilator Responder

“Vasodilator Response”• Fall in mPAP ≥10 mm Hg• + mPAP (absolute) ≤40 mm Hg• + Normal CO

• Only acute vasodilator responders should be tried on CCB therapy to treat PAH

PAH Determinants of RiskLOWER RISK DETERMINANTS OF RISK HIGHER RISK



II, III WHO class IV

Longer (>400 m) 6MWD Shorter (<300 m)




enlargement/dysfunction; RA enlargement


CI <2.0 L/min/m2




25




Sustained Response

Continue CCB

Yes

Negative

No LOWER RISK DETERMINANTS OF RISK HIGHER RISKNo Clinical evidence of RV failure Yes

Gradual Progression of symptoms RapidII, III WHO class IV

Longer (>400 m) 6MWD Shorter (<300 m)Peak VO2 >10.4 mL/kg/min CPET Peak VO2 <10.4 mL/kg/min


Pericardial effusion, significant RV



CI <2.0 L/min/m2


Acute Vasoreactivity TestingPositive

Oral CCB

Approved Therapeutic Targets


cGMP

cAMP

Vasoconstriction

and proliferation

Endothelinreceptor A

Endothelin-

receptor

antagonists

Endothelinreceptor B

Phosphodiesterase

type 5 inhibitor

Vasodilation



Vasodilation


Prostacyclin

derivatives

Nitric Oxide

Endothelin-1

Pre-proendothelin

L-arginine

Prostaglandin I2

L-citrulline

Nitric OxidePathway

EndothelinPathway

ProstacyclinPathway

Endothelial cells

Proendothelin

Endothelial cells

Arachidonic acid

Smooth muscle cells


Smooth muscle cells

Exogenous

nitric oxide

sGC

stimulator



cGMP

cAMP

Vasoconstriction

and proliferation


Endothelin-

receptor

antagonists


Phosphodiesterase

type 5 inhibitor

Vasodilation



Vasodilation


Prostacyclin

derivatives

Nitric Oxide

Endothelin-1

Pre-proendothelin

L-arginine

Prostaglandin I2

L-citrulline

Nitric OxidePathway

EndothelinPathway

ProstacyclinPathway

Endothelial cells

Proendothelin

Endothelial cells

Arachidonic acid

Smooth muscle cells


Smooth muscle cells

Exogenous

nitric oxide

sGC

stimulator


26

Iloprost (Ventavis®)Treprostinil (Tyvaso®)

Prostacyclin Analogues: Intravenous, Subcutaneous, Inhaled, or Oral

WG

Treprostinil (Remodulin®)

Treprostinil (Orenitram®)Selexipag (Uptravi®)

Epoprostenol (Flolan®

or Veletri®)Treprostinil (Remodulin®)

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, 1.25-2.5 ng/kg/min/wk. IV=diluted. Inhaled: FC III, to 54 mcg, 4 inh/d. Oral: FC II-III, starting at 0.25 mg bid and titrated in 0.25 mg increments as tolerated. Selexipag: FC II-III, starting at 200 mcg bid, and titrated as tolerated up to 1600 mcg bid . Iloprost Inhaled: FC III-IV, 2.5-5 mcg, 6-9 inh/d.

Prostacyclin Analogues: Pivotal Trials for IV and SC Formulations

Study Name / Drug N / Etiol / Class Design Positive Results

IV epoprostenolvs conventional Rx

81IPAH/FPAH

III,IV

Open-label12-week

• 6MWD• Symptoms• Hemodynamics• Survival

IV epoprostenolvs conventional Rx

111APAH SSc

III,IV

Open-label12-week

• 6MWD• Hemodynamics• Symptoms

TRUSTIV treprostinil vs placebo

44PAH

III

Double-blind, placebo-controlled12-week

• 6MWD• Symptoms

SC treprostinil vs SC placebo

470PAHII-IV

Double-blind12-week

• 6MWD• Symptoms• Hemodynamics

Barst RJ et al. N Engl J Med. 1996;334:296-301.Badesch D et al. Ann Intern Med 2000;132:425-432.Hiremath J et al. J Heart Lung Transplant. 2010;29:137-149. Simonneau G et al. Am J Respir Crit Care Med. 2002;165:800-804.

100

80

60

40

20

0Week

Epoprostenol (n=41)

0 2 4 6 8 1210

Conventional therapy (n=40)

Surv

ival

(%)

p=0.003*

*Two-sided, by log-rank test.Barst RJ et al for the PPH Study Group. N Engl J Med. 1996;334:296-301.

Survival Among Patients With IPAH: Epoprostenol vs Conventional Therapy


27

Prostacyclin Analogues: Pivotal Trials for Inhaled and Oral FormulationsStudy Name / Drug

N / Etiol / Class Design Positive Results

AIRInhaled iloprost vs placebo

203PH

III-IV

Double-blind12-week

• Composite end point• 6MWD • Symptoms• Hemodynamics

TRIUMPH 1Inhaled treprostinil vsplacebo§

235PAHIII-IV*

Double-blind12-week on

background oral Rx

• 6MWD

FREEDOM-MOral treprostinil vs placebo

228PAHII-III

Double-blind, placebo-controlled

12-week

• 6MWD

GRIPHONOral selexipag vs placebo

1156PAHII-III

Double-blind, naïveor on background

ERA and/or PDE5I,event-driven

morbidity/mortality

• Time to first morbid or mortality event

* Approved for class III only. §Included background therapy with ERA or PDE5-I.Olschewski H et al. N Engl J Med. 2002;347:322-329. McLaughlin VV et al. J Am Coll Cardiol. 2010;55:1915-1922Hiremath J et al. J Heart Lung Transplant. 2010;29:137-149. Jing Z-C et al. Circulation. 2013;127:624-633. Sitbon O et al. NEJM. 2015;373:2522-33.

Prostanoid Side Effects

• Flushing

• Headache

• Diarrhea, nausea, vomiting

• Jaw pain

• Leg pain

• Hypotension

• Dizziness

• Syncope

• Rebound PH if interruption of epoprostenol delivery (due to short half-life)

• Delivery site complications (pain, infection, cough, thrombosis, infusion)

Vary according to drug and route of delivery

cGMP

cAMP

Vasoconstriction

and proliferation


Endothelin-

receptor

antagonists


Phosphodiesterase

type 5 inhibitor

Vasodilation



Vasodilation


Prostacyclin

derivatives

Nitric Oxide

Endothelin-1

Pre-proendothelin

L-arginine

Prostaglandin I2

L-citrulline

Nitric OxidePathway

EndothelinPathway

ProstacyclinPathway

Endothelial cells

Proendothelin

Endothelial cells

Arachidonic acid

Smooth muscle cells


Smooth muscle cells

Exogenous

nitric oxide

sGC

stimulator


Adapted from Humbert M et al. N Engl J Med. 2004;351:1425-1436.


28

Endothelin Receptor Antagonists: Pivotal Trials

Study NameDrug

NEtiology

Class Design PositiveResults

BREATHE-1Oral bosentan* vs placebo

213PAHIII, IV

Double-blind16-week

• 6MWD• Delay clinical worsening• Symptoms

EARLYOral bosentanvs placebo

185PAH

II

Double-blind6-month

• Delay clinical worsening• Hemodynamics

ARIES-1&2Oral ambrisentan§vs placebo

394PAHII, III

Double-blind12-week

• 6MWD• Delay clinical worsening

SERAPHINOral macitentan†

vs placebo

742PAHII,III

Double-blindEvent-driven

morbidity/mortality

• Delay disease progression• 6MWD• Symptoms

Rubin L et al. N Engl J Med. 2002;346:896-903. Channick RN et al. Lancet. 2001;358:1119-1123. Galiè N et al. Lancet. 2008;371:2093-2100. Galiè N et al. Circulation. 2008;117:3010-3019. Pulido T et al. N Engl J Med. 2013;369:809-818.

*Bosentan = Tracleer®. Approved for FC II-IV. 62.5-125 mg po bid.§Ambrisentan = Letairis®. Approved for FC II-III. 5-10 mg po qd†Macitentan = Opsumit®. Approved for FC II-III. 10 mg po qd.

Endothelin Receptor Antagonists: Side Effects• Nasal congestion

• Abnormal hepatic function*

– monthly LFTs required for bosentan

• Anemia

– monitor CBC quarterly

• Edema

– lower extremity edema may require diuretic adjustment

• Teratogenic

– use requires dual contraceptive methods (hormonal plus barrier)

*PHA Scientific Leadership Council recommends LFT testing at onset of all treatments for PAH and periodically thereafter, at prescriber’s discretion.

cGMP

cAMP

Vasoconstriction

and proliferation


Endothelin-

receptor

antagonists


Phosphodiesterase

type 5 inhibitor

Vasodilation



Vasodilation


Prostacyclin

derivatives

Nitric Oxide

Endothelin-1

Pre-proendothelin

L-arginine

Prostaglandin I2

L-citrulline

Nitric OxidePathway

EndothelinPathway

ProstacyclinPathway

Endothelial cells

Proendothelin

Endothelial cells

Arachidonic acid

Smooth muscle cells


Smooth muscle cells



Exogenous

nitric oxide

sGC stimulator


29

PDE-5 Inhibitor Pivotal Trials

Study NameDrug

NEtiolClass

Design Positive Results

SUPER-1Oral sildenafil*vs placebo

278PAHI-IV

Double-blind12-week


PHIRST-1Oral tadalafil§vs placebo

405PAHI-IV

Double-blind16-week

• 6MWD• Delay clinical

worsening• Hemodynamics• HRQoL

Galiè N et al. N Engl J Med. 2005:353:2148-2157.Galiè N et al. Circulation. 2009;119;2894-2903.

*Sildenafil = Revatio®. Approved for FC II-III. 20 mg po tid.§Tadalafil = Adcirca®. Approved for FC I-IV. 40 mg po qd.

PDE-5 Side Effects

• Nose bleed

• Headache

• Dyspepsia

• Flushing

• Diarrhea

• Visual changes

Contraindicated with use of nitrate

sGC Stimulator Pivotal Trials

Study NameDrug

NEtiolClass

Design Positive Results

PATENT-1Oral riociguat*vs placebo

443PAHI-IV

Double-blind12-week

• 6MWD• Symptoms• Hemodynamics• Delay clinical worsening

CHEST-1Oral riociguatvs placebo

261CTEPH

I-IV

Double-blind16-week


*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.

Ghofrani HA et al. N Engl J Med. 2013;369:319-329.Ghofrani HA et al. N Engl J Med. 2013;369:330-340.


30

sGC Stimulator Side Effects

• Headache

• Dizziness

• Dyspepsia/gastritis

• Nausea

• Diarrhea

• Hypotension

• Vomiting

• Anemia

• Gastroesophageal reflux

• Constipation

Contraindicated in pregnancy, with use of nitrates or NO donors in any form, or with use of PDE inhibitors

• Supervised exercise training (I-A)• Psycho-social support (I-C)• Avoid strenuous physical activity

(I-C)• Avoid pregnancy (I-C)• Influenza and pneumococcal

immunization (I-C)

• Oral anticoagulants: – IPAH, heritable PAH, and PAH

due to anorexigens (IIa-C)– APAH (Ilb-C)

• Diuretics (I-C)• Oxygen (I-C)• Digoxin (IIb-C)

Continue CCB

WHO FC I-III CCB (I-C)

Sustained response

(WHO FC I-II)

VASOREACTIVE NON-VASOREACTIVE

5th World Symposium on PH:2013 PAH Treatment Algorithm

Galiè N et al. J Am Coll Cardiol. 2013;62:D60-D72.

INITIAL THERAPY WITH PAH-APPROVED DRUGS

YES

NO

Acute vasoreactivity test (I-C for IPAH) (IIb-C for APAH)

Expert Referral (I-C)

General measures and supportive therapy

5th World Symposium on PH:2013 Treatment Algorithm

Galiè N et al. J Am Coll Cardiol. 2013;62:D60-D72.

Sequential CombinationTherapy (I-A)

Referral for LungTransplantation (I-C)

Consider Eligibility for Lung Transplantation

Inadequate ClinicalResponse

on Maximal Therapy

INITIAL THERAPY WITH PAH-APPROVED DRUGS

PDE-5 I orsGCs

ERAs

Prostanoids

++

+

Balloon AtrialSeptostomy (IIa-C)

Inadequate ClinicalResponse


31

INITIAL THERAPY WITH PAH-APPROVED DRUGSYELLOW: Morbidity and mortality as primary end point in randomized controlled study or reduction in all-cause mortality (prospectively defined)Level of evidence based on WHO-FC of majority of patients of studies

Evidence WHO FC II WHO FC III WHO FC IV

Rec

omm

enda

tion

I A or B

•Ambrisentan, Bosentan•Macitentan•Riociguat•Sildenafil •Tadalafil

•Ambrisentan, Bosentan, Epoprostenol IV

• Iloprost inh•Macitentan•Riociguat•Sildenafil •Tadalafil•Treprostinil SC, inh

•Epoprostenol IV

IIa C

• Iloprost IV*, TreprostinilIV

•Ambrisentan, Bosentan, Iloprost inh and IV*

•Macitentan•Riociguat•Sildenafil, Tadalafil•Treprostinil SC, IV, Inh*

IIb

B •Beraprost*

C• Initial Combination Therapy

• Initial Combination Therapy

5th World Symposium on PH:2013 PAH Treatment Algorithm

Galiè N et al. J Am Coll Cardiol. 2013;62:D60-D72. *Not approved in US.

Combination Therapy

sGCStimulators Prostanoids

EndothelinReceptor

Antagonists

Phospho-diesteraseInhibitors

TRIUMPHSTEP

SERAPHIN†

GRIPHONγ

TRIUMPHPACES

GRIPHON

PATENT-1*

PATENT-1*

?

?

???

PHIRST*SERAPHIN†

AMBITION

*53% on background ERA for PHIRST, 50% on background ERA or prostanoid for PATENT-1 †64% on background PDE-5I or prostanoid in SERAPHIN. γ84% on background ERA and/or PDE-5I in GRIPHON

Weeks0 1921444824 72 96 168120

Hazard ratio, 0.50 (95% Cl, 0.35-0.72)P<0.001

0

60

100

80

40

20

Combination therapy

Pooled monotherapy

AMBITION: Effect of Ambrisentan Plus Tadalafil Versus Monotherapy on Clinical Worsening*

* Death, hospitalization for worsening PAH, disease progression, unsatisfactory long-term clinical response.Galiè N et al. N Engl J Med. 2015;373:834-44.

Part

icip

ants

with

no

even

t (%

)

No. at risk:Combination therapyPooled monotherapy

229

209

186

155

145

108

106

77

71

49

36

25

4

5

253

247


32

Sitbon O et al. N Engl J Med. 2015;373:2522-33.

Selexipag vs placebo: RR 40%; HR=0.60; p<0.0001

No. at RiskPlacebo 582 433 347 220 149 88 28Selexipag 574 455 361 246 171 101 40

Pat

ient

s w

ithou

t an

even

t (%

)

00

20

40

80

60

12 18 24 30 366Months

Placebo

Selexipag

80% on background therapy:- 47% on ERA or PDE5I- 33% on ERA+PDE5I

GRIPHON: Effect of Selexipag on Time to First Morbidity or Mortality Event

SERAPHIN: Effect of Macitentan on Disease Progression

* Worsening of PAH, initiation of treatment with IV or SC prostanoids, lung transplantation or atrial septostomyPulido T et al. N Engl J Med. 2013;369:809-818.

0

40

80

100

60

20

Months

Pat

ient

s w

ithou

t an

even

t re

late

d to

PA

H o

r dea

th fr

om

from

any

cau

se*

(%)

0 6 12 363018 24

No. at risk:PlaceboMacitentan 3 mgMacitentan 10 mg

250250242

188213208

160188187

233241

648091

135166171

122147155

Macitentan 10 mg qdMacitentan 3 mg qdPlacebo

64% on background therapy:- 62% PDE5I- 5% Prostanoid

COMPASS-2: Effect of Sildenafil + BosentanVersus Sildenafil + Placebo on Time to First Morbidity/Mortality Event*

* All-cause death, hospitalization for worsening PAH or IV prostanoid, atrial septostomy, lung transplant, or PAH worsening. McLaughlin VV et al. Eur Respir J. 2015;46:405–413 | DOI: 10.1183/13993003.02044-2014

Patients at risk (n)Placebo 175 154 140 123 118 107 90 76 68 61 55 48 43 36 32 26

Bosentan 159 144 128 114 103 97 88 82 69 57 50 42 32 24 21 15

100

90

80

70

60

50

40

30

20

10

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60

Patie

nts

with

out a

n ev

ent (

%)

Months

Sildenafil + BosentanSildenafil + Placebo


33

Combination Therapy Caveats

• Experience evolving

• Most data from ‘add-on’ - ? De novo? Order?

• More drugs available

– more options

– more ways to get it wrong

• More questions than answers

• Costs/expenditures; third-party hurdles

Taichman DB. Ann Intern Med. 2008;149:583-585.

Jane: Initial Management

• Admitted to hospital following cath

• IV diuresis

• IV epoprostenol initiation

On-therapy Prognostic Indicators• Functional class I or II

• 6MWD >380 m

– limiting supporting data; do not use in isolation

• Hemodynamics

– normal cardiac index (>2.2 L/min/m2)

– normal RA pressure

• Positive response to CCB

• BNP <180 pg/mLSitbon O et al. J Am Coll Cardiol. 2002;40:780-788. McLaughlin VV et al. Circulation. 2002;106:1477-1482.Wensel R et al. Circulation. 2002;106:319-324.


34

Important Prognostic Variables

Humbert M et al. Circulation. 2010;122:156-163.Benza RL et al. Circulation. 2010;122:164-172.

• Functional class• 6-minute walk• RAP• CO• Age• Gender• Etiology

French Registry

• Functional class• 6-minute walk• PVR, RAP• Vitals• BNP• Pericardial effusion• DLCO• Age• Gender• Etiology

REVEAL Registry

Jane: Return Visits in May & September

• Significantly improved

• No limitations

• Functional class I

• Meds

– epoprostenol 30 ng/kg/min

– warfarin

– furosemide 20 mg

– KCl 10 mEq qd

Jane: Follow-up Physical Exam

• HR 80 bpm; BP 103/59 mm Hg; Wt 144.8 lb

• JVP 6, carotid upstrokes normal

• Clear lungs

• Palpable RV heave, normal S, loud P2, II/VI TR murmur

• No LE edema


35

Jane: 6MWD

• 222 m: 99-96% in January

• 486 m: 99-97% in May

• 556 m: 99-97% in September

Local Care PH Center

Collaborative Care With PH Centers:

• Diagnostic dilemmas• Diagnostic cath/

vasodilator trial• Fluid management• Acute issues• PAH-specific therapies• Side effects• Hospitalizations • Transplant• Clinical trials

Thank you for your participation!

For more information on upcoming PHA

Medical Education Programs, please visit:

www.PHAssociation.org

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