CPC19 PAH - naceonline.comnaceonline.com/CME-Courses/cpc-slides/CPC19_PAH_Print.pdf · vCharles D. Burger, MD ... Based on the pathophysiology of pulmonary arterial...

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Pulmonary Arterial Hypertension: Importance of Early Diagnosis and Management

Facultyv Charles D. Burger, MD

Director, Pulmonary Vascular CenterMayo ClinicJacksonville, FL

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DisclosuresvCharles D. Burger, MD has received research grants from Actelion and Gilead.

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Learning Objectives1. Describe the fundamentals of the pathophysiology of pulmonary arterial

hypertension (PAH)

2. Recognize the signs and symptoms indicative of PAH and identify at-risk patients using PAH-associated risk factors

3. Describe recommendations for diagnostic strategies to facilitate identification of PAH and referral of patients to pulmonary specialists/centers

4. Identify current therapies and their recommended applications for the treatment of patients with PAH

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Pre-test Questions

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Pre-Test Question 1Pre-P1: Based on the pathophysiology of pulmonary arterialhypertension (PAH), which of the following is a hallmark of endstagedisease?1. Left ventricular hypertrophy

2. Death from coronary heart disease

3. Right ventricular failure

4. Lung failure

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Pre-Test Question 2Pre-P2: All of the following are significant risk factors for pulmonaryarterial hypertension, except:1. Scleroderma

2. Heart failure with preserved ejection fraction (diastolic heart failure)

3. Autoimmune hepatitis with cirrhosis

4. Methamphetamine use

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Pre-Test Question 3Pre-P3: Mary is a 36 year-old school teacher who presents to your officewith dyspnea and family history of PAH. You suspect she has PAH andconsidering starting her on treatment. Which of the following diagnostictests would you order to confirm her diagnosis before starting her ontherapy for PAH?1. Right heart catheterization

2. Echocardiogram3. Ventilation-perfusion (VQ) lung scan

4. Pulmonary function tests

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Pre-Test Question 4

Pre-P4: Which of the following statements regarding the treatment ofPAH is true?1. Calcium-channel blockers can be tried as initial therapy in all patients

with Group 1 PAH2. PAH therapies are available only in oral or intravenous formulations

3. Risk assessment in PAH is unwarranted because empiric treatment isequally effective

4. Epoprostenol is considered the best treatment for PAH patients withNYHA Functional Class IV

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Pathophysiology

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PrevalencevRare disease narrowing the pulmonary microvasculature

v15-50 people/million of all ethnicities in the Western worldvMost prevalent in fourth and fifth decades of lifevHigher prevalence in women than men (>75% women in United States)

vPAH may be underestimatedvNonspecific symptomsvMisdiagnosis (e.g., asthma, left heart disease)vLimited screening of patients at increased risk such as scleroderma, cirrhosis, or

HIV.

Badesch DB, et al. REVEAL. Chest. 2010;137:376-387.11

Pathophysiology

Time

Presymptomatic/ Compensated

Symptomatic/ Decompensating

Right Heart Dysfunction

Declining/ Decompensated

Usual time of diagnosis

Cardiac output

Pulmonary

artery pressure

Right atrial pressure

Pulmonary vascular

resistance

Adapted from: Hill NS. Pulmonary Hypertension Therapy. Summit Communications, LLC; 2006:9.12

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PAH Vascular Remodeling

v‘Vasculopathy’vLeads to reduced blood flow through the lungs

vDecreased cardiac output—‘Fixed Stenosis’

vDecreased oxygen to the tissues

vDecreased ATP production

vFatigue

vRV failure—end-stages of PAH

13ATP = adenosine triphosphate; RV = right ventricle.Thenappan T, et al. BMJ. 2018;360:j5492.

PAH ProgressionvPatients die of right heart failure. vVolume overload does not cause “CHF”vVolume overload does cause RV overload/ischemia

and decreased blood flow (CO) delivered to the lungs (and thus to the LV and to the tissues)

CO = cardiac output; LV = left ventricle; PBF = pulmonary blood flow.Thenappan T, et al. BMJ. 2018;360:j5492.

Consequences of PAH

↑ PVR

↑ RV afterload

↓ RV ejection (CO) & ↓ PBF

RV hypertrophy & dilation

Death

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PAH DefinitionvHemodynamics by right heart catheterization

vMean pulmonary artery pressure ≥ 25 mmHg

vPulmonary artery wedge pressure (PAWP) ≤ 15 mmHg

vPulmonary vascular resistance (PVR) ≥ 3 Wood units

vExclusion of other diagnostic groupsvGroup 2 heart failure, including HFpEF, elevated PAWP

vGroup 3 lung disease and/or OSA

vGroup 4 CTEPH

HFpEF = heart failure with preserved ejection fraction; OSA = obstructive sleep apnea; CTEPH = chronic thromboembolic pulmonary hypertension.15

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Diagnostic Groups for Pulmonary Hypertension (PH)vGroup 1 – Pulmonary Arterial Hypertension (PAH)

vGroup 2 – Pulmonary Venous Hypertension (PVH)

vGroup 3 – PH owing to lung disease/sleep apnea

vGroup 4 – Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

vGroup 5 – Miscellaneous (e.g., Sarcoidosis)

Galiè N, et al. Eur Respir J. 2015;46:903-975.

N O A P P R O V ED

T H ER A P Y

N O A P P R O V ED

T H ER A P Y

N O A P P R O V ED

T H ER A P Y

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REVEAL Registry: Associated Causes of PAH

Connective Tissue Disorders, 50%

Congenital Heart Disease, 20%

Portopulmonary Hypertension, 11%

Drugs/Toxins 10.5%

HIV, 4.0% Other, 5.5%

~50% of PAH is associated with an underlying medical

condition

Badesch DB, et al. Chest. 2010;137:376-387.

N = 1,280 patients with PAH in REVEAL registry

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Risk Evaluation

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Delay in Diagnosis of PAH is Associated with Worsening Functional Class

N = 32 IPAH patients interviewed through Australian national health system. Mean time from symptom onset to diagnostic RHC = 47 months. Strange G. Pulm Circ. 2013;3:89–94.

FC II

FC II I

FCIV

0102030405060708090

At Symptomonset

At Diagnosis

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REVEAL Symptom Spectrum (n = 2,967)

Badesch DB, et al. Chest. 2010;137:376-387.

vSymptomsvDyspnea 83%vFatigue 27%vChest pain or LE edema 20%vExertional Syncope 17%vCough 14%

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Modified NYHA Functional Class

Sx = symptoms such as dyspnea, chest pain, and near-syncope or syncope

vI No limitationvII Mild limitation: Sx with ordinary activity

vIII Moderate limitation: Sx with low-level activity

vIV Severe limitation: Sx at rest, exertional syncope

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Subgroups for Group 1 PAH

Simonneau G, et al. J Am Coll Cardiol. 2013; 62:D34-41.

vIdiopathic PAH

vHeritable

vPAH Related to:

v Drugs and Toxins

v Collagen vascular disease

v HIV

v Portal hypertension

v Congenital heart disease

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Risk GroupsvFamily history PAH

vDrug use such as anorexigens and methamphetamines

vCVD, particularly scleroderma

vHIV/AIDS

vLiver disease with portal hypertension

vCongenital heart disease

CVD = cardiovascular disease.Coghlan JG, et al. Ann Rheum Dis. 2014;73(7):1340-9. Khanna D, et al. Arthritis Rheum. 2013;65(12):3194-201. Gladue H, et al. J Rheumatol. 2013;40:1706–11. 23

Drugs and Toxins

vClassic exposure dietary suppressant e.g. fenfluramine/phentermine

(also known as “fen/phen”)

vMethamphetamines are a rising concern

vCertain TKIs; e.g., dasatinib

TKI = tyrosine kinase inhibitors.Galiè N, et al. Eur Respir J. 2015;46:903-975.24

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Collagen Vascular DiseasevClinical Setting

vPatients with known scleroderma are at risk for PAHvUsually triggered by complaints of dyspnea

vMultiple screening algorithms exist for PAH in patients with scleroderma

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Screening for PAHvPatients with scleroderma are at high risk and should be screened annually for

PAH1,2

vDETECT: Used two-step screening guideline

vStep 1: Telangiectasias, anti-centromere antibodies, right-axis deviation on ECG, low DLCO, and low N-terminal pro-B-type natriuretic peptide

vStep 2: Echocardiography followed by RHC

vDETECT has good sensitivity, low specificity

DLCO, diffusion capacity for carbon monoxide; ECG, electrocardiogram.1. Hoeper MM, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D42-50. 2. Coghlan JG, et al. Ann Rheum Dis. 2014;73(7):1340-9. 26

Risk FactorsvScleroderma 10%

vCHD 5%

vCirrhosis 1%

vHIV 0.5%

CHD = coronary heart disease.Galiè N, et al. Eur Respir J. 2015;46:903-975.27

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Diagnosis

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Examination Findings• No acute distress• HR: 78; RR: 14; BP: 140/95 • RA SpO2: 95%• Heart sounds:

• RRR, loud P2• Pansystolic murmur of tricuspid regurgitation

• Lungs • Clear bilaterally

• ECG:• Right-axis deviation• No evidence of MI

Heart: RRR, Increased P2,

2/6 SM at mid-sternal border

Lung: CTA w/o wheeze/crackle

JVD

Edema

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ECG

RAD = right-axis deviation; RAE = right atrial enlargement; RVH = right ventricular hypertrophy.McGoon M, et al. Chest. 2004;126(1 Suppl):14S-34S.

35-yr old Female

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ECG

RVH

RV Strain

RAD

RAE

RAD = right-axis deviation; RAE = right atrial enlargement; RVH = right ventricular hypertrophy.McGoon M, et al. Chest. 2004;126(1 Suppl):14S-34S.

35-yr old Female

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Pulmonary Hypertension by Echo ≠ PAH

Left heart disease, 78.70%

Congenital heart disease, 1.90%

Lung disease/sleep-related

hypoventilation, 9.70%

CTEPH, 0.60% PAH, 2.30% Unknown, 6.80%

vSingle Australian community of 160,000 vEtiology of pulmonary hypertension noted on echocardiogram

N = 483 of 4579 patients with echo PASP >40 mm Hg; CTEPH = chronic cardioembolic pulmonary hypertension.Gabby E. Am J Respir Crit Care Med. 2007;175:A713. 32

Echocardiogram: Four Chambers

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Echo: Tricuspid Regurgitation

Modified Bernoulli’s Equation:4 x (V)² + RAP = RVSP (PASP)

V=tricuspid jet velocity (m /s); RAP= right atrial pressure; RVSP=right ventricular systolic pressure; PASP=pulm onary artery systolic pressure.

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MPAP by Echo

vMPAP defines the disease (≥25 mmHg)

vCorrelates with the outcome

MPAP = mean pulmonary artery pressure.Aduen JF, Burger CD, et al. J Am Soc Echocardiogr. 2009;22(7):814-9.35

EchocardiogramvPros

vReadily available and noninvasive

vCan detect evidence of left heart disease

vCan estimate right heart pressures and size/function, detecting PH (but not PAH)

vCons

vDoes not measure left heart pressures, so it cannot diagnose PAH

vCannot eliminate left-to-right shunt

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Diagnostic Workup

PH = pulmonary hypertension; PA = pulmonary artery; RA = right atrial; PCWP = pulmonary capillary wedge pressure;

LVEDP = left ventricular end diastolic pressure; CO = cardiac output; PVR = peripheral vascular resistance; SVC = superior vena cava.

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

Echocardiography Suggests PH

Right Heart Catheterization to Confirm PH/PAH

Document PA and RA pressures; PCWP (LVEDP or LA pressure, if

PCWP is unobtainable or uncertain);

CO, PVR, SVC, RA, and PA saturations; response to

acute vasodilator testing

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Cardiac CatheterizationvExclude congenital heart disease

vMeasure wedge pressure or LVEDP

vEstablish severity and prognosis

vTest vasodilator therapy

Catheterization is required when pulmonary hypertension is suspected

McGoon M, et al. Chest. 2004;126:14S-34S. McLaughlin VV, et al. J Am Coll Cardiol. 2009;53:1573-1619. Galiè N, et al. Eur Heart J. 2009; 30:2493-537.38

Diagnosis and Group Classification

Adapted from McLaughlin VV, et al. Circulation. 2009;119(16):2250-229439

History – Physical – CXR: ECG

Echocardiography

VQ Scan: ABGs

Overnight Oximetry

HIV – ANA: LFTs

Functional Testing

Right Heart Catheterization

Index of Suspicion –Evaluate for LH & RH

disease

CTEPH

OSA

Underlying Causes

Functional Severity

Confirm Diagnosis

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Group 4 CTEPHvCTEPH potentially is curable by pulmonary thromboendarterectomyvTherefore, it is very important to not overlook this diagnosisvA VQ scan — not CTA — is the best test to screen for CTEPHvPH Center referral is mandatory for this diagnosis

CTEPH = chronic thromboembolic pulmonary hypertension; VQ = ventilation perfusion; CTA = CT angiography angiography.40

Risk Assessment

Parameter Low to Moderate High

NYHA Functional Class I-II III-IV

BNP (pg/mL) <50 >180

6 MWD (meters) >440 <165

RA Pressure (mmHg) 5 15-20

Cardiac Index (L/m/m2) Normal <2

BNP = brain natruetic peptide.Benza R, et al. Chest. 2012;141(2):354-362. Austin C, et al. Chest. 2015;147(1):198-208.41

ERS 2015: Evidence-based Treatment Algorithm for PAH Patients (Group 1)

Galiè N, Humbert M, Vachiery J-L, et al. Eur Heart J. 2016;37:67-119.

Treatm ent-Naïve Patient

Patient Already on Treatm ent

CCB Therapy

PAH Confirm ed by Expert Center

Acute Vasoreactivity Test(NO, epo, adenosine)

InitialM onotherapy

Initial OralCom bination

Initial Com binationIncluding IV PCA

General M easures

Supportive Therapy

Nonvasoreactive

Low or Interm ediate Risk(W HO FC II-III)

Vasoreactive

Inadequate Clinical ResponseConsider Referral for Lung

Transplantation

High Risk(W HO FC IV)

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Treatment Strategy

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NO = nitric oxide; sGC stimul. = soluble guanylate cyclase stimulator.Humbert M, et al. N Engl J Med. 2004;351:1425-1436.

Big Endothelin

Endothelin-converting Enzym e

EndothelinReceptor A

EndothelinReceptor B

Vasoconstrictionand Proliferation

EndothelinReceptor

Antagonists

Endothelin-1

Endothelin Pathway

Arachidonic Acid

ProstacyclinSynthase

Vasodilatationand Antiproliferation

Prostacyclin

cAM P

ProstacyclinDerivativesProstacyclinDerivatives

Prostacyclin Pathway

Arginine

Nitric OxideSynthase

Vasodilatationand Antiproliferation

Nitric Oxide

cGM P ExogenousNO

Phosphodiesterase Type-5

PhosphodiesteraseType-5 Inhibitors

Nitric Oxide Pathway

sGC stim ul.

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Targets for PAH Therapies

Pharmacotherapy for PAH: Routes of DeliveryvOral therapy

vCalcium-channel blockers (Do not use empirically! They must be vasoreactive with preserved CO)vEndothelin receptor antagonists (ERAs)vPhosphodiesterase 5 (PDE5) inhibitors

vSoluble guanylate stimulatorvProstacyclin analogs and receptor agonists

vInhaled therapyvInhaled treprostinil and prostacyclin

vInfusion therapyvIV epoprostenol

vIV or SQ treprostinil

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FDA-Approved Drugs

NYHA FC II NYHA FC III NYHA FC IV

Ambrisentan (ERA) All 3 ERAs Epoprostenol* IV

Bosentan (ERA) Both PDE5is Treprostinil* IV/SQ

Macitentan (ERA) Riociguat All 3 ERAs

Sildenafil (PDE5i) Treprostinil (po, IV/SQ, inhaled) Both PDE5is

Tadalafil (PDE5i) Selexipag Riociguat

Riociguat (sGC stim.) Iloprost (inhaled) Treprostinil* (po, inhaled)

Selexipag (PRA)

* Prostacyclins.ERA = endothelin receptor antagonist; PDE5i = phosphodiesterase 5 inhibitors; sGC stim. = soluble guanlate cyclase stimulator; PRA = prostacyclin receptor agonist; po = by mouth. Galiè N, et al. Eur Respir J. 2015;46:903-975.46

ERS 2015: Evidence-based Treatment Algorithm for PAH Patients (Group 1)

Galiè N, Humbert M, Vachiery J-L, et al. Eur Heart J. 2016;37:67-119.

Treatm ent-Naïve Patient

Patient Already on Treatm ent

CCB Therapy

PAH Confirm ed by Expert Center

Acute Vasoreactivity Test(NO, epo, adenosine)

InitialM onotherapy

Initial OralCom bination

Initial Com binationIncluding IV PCA

General M easures

Supportive Therapy

Nonvasoreactive

Low or Interm ediate Risk(W HO FC II-III)

Vasoreactive

Inadequate Clinical ResponseConsider Referral oor Lung

Transplantation

High Risk(W HO FC IV)

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GoalsvSingle-center, goal-directed study

vFunctional Class ≤ IIvBNP normalv6 MWD >380 to 440 mvNormalize RV functionvExercise: VO2 >15 mL/kg/min; VE/VCO2 <45

6 MWD = 6-minute walk distance.Hoeper MM, et al. Eur Respir J. 2005;26:858-863.48

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Hospitalization Following PAH DiagnosisREVEAL population

(N = 3515; data download February 4, 2013)

Newly diagnosed(n = 960)

Newly diagnosed;PCWP ≤15 mm Hg (n = 865)

At risk for on-studyhospitalizations (n = 862)

Not newly diagnosed(n = 2555)

Not meeting hemodynamicscriteria (n = 95)

Died in hospitalat enrollment (n = 3)

PAH-related hospitalization(n = 257, 52.4%)

≥1 hospitalization admissionpostenrollment (n = 490, 56.8%)

No hospitalization admissionspostenrollment (n = 372, 43.2%)

PAH-unrelated hospitalization(n = 214, 43.7%)

Indeterminate hospitalization(n = 19, 3.9%)

Burger CD, et al. Chest. 2014;146(5):1263-1273.49

Survival

57%±4%

68%±4%

100

90

80

70

60

50

40

0

0 6 12 18 24 30 36

243211

192178

167154

139134

118113

10190

7961

No. at riskPAH related

PAH unrelated

Perc

ent

(%)

of

pat

ien

ts s

urv

ivin

g

T im e from date of discharge (m onths)

PAH related (n = 257)PAH unrelated (n = 214)

p = 0.037

Burger CD, et al. Chest. 2014;146(5):1263-1273.50

Treatment Goals

vReduce symptom burden

vAvoid hospitalization

vMinimized treatment burden

vImprove survival

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Collaborative Care with PH Centers

Local Care PH Center

• Diagnostic dilemmas

• Diagnostic cath/vasodilator trial

• Complex comorbidities

• Failure to achieve Rx goals

• Considering prostanoids

• Considering combination Rx

• Clinical trials

• Transplant referral

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SummaryvGroup 1 PAH is a rare disease requiring complete diagnostic evaluation, including

right heart catheterization

vGroup 2 PVH and Group 3 PH caused by lung disease are much more common and typically are diagnosed by echocardiography alone

vMust exclude Group 4 CTEPH by a VQ scan

vTreatments are complex and referral to a PH Center is recommended

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Resources

vWeb-based

vPhassociation.org

vMayoclinic.org

vGuidelines

v2015 ESC/ERJ PH Guideline: Galiè N, et al. Eur Respir J. 2015;46:903-975.

v2018 6th WSPH: Galiè N, McLaughlin VV, et al. Eur Respir J. 2018 Dec 14.

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Post-test Questions

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Post-test Question 1Post-P1: Based on the pathophysiology of pulmonary arterialhypertension (PAH), which of the following is a hallmark of endstagedisease?1. Left ventricular hypertrophy

2. Death from coronary heart disease

3. Right ventricular failure

4. Lung failure

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Post-test Question 2Post-P2: All of the following are significant risk factors for pulmonaryarterial hypertension, except:1. Scleroderma

2. Heart failure with preserved ejection fraction (diastolic heart failure)

3. Autoimmune hepatitis with cirrhosis

4. Methamphetamine use

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Post-test Question 3Post-P3: Mary is a 36 year-old school teacher who presents to your officewith dyspnea and family history of PAH. You suspect she has PAH andconsidering starting her on treatment. Which of the following diagnostictests would you order to confirm her diagnosis before starting her ontherapy for PAH?1. Right heart catheterization

2. Echocardiogram3. Ventilation-perfusion (VQ) lung scan

4. Pulmonary function tests

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Post-test Question 4

Post-P4: Which of the following statements regarding the treatment ofPAH is true?1. Calcium-channel blockers can be tried as initial therapy in all patients

with Group 1 PAH

2. PAH therapies are available only in oral or intravenous formulations

3. Risk assessment in PAH is unwarranted because empiric treatment is equally effective

4. Epoprostenol is considered the best treatment for PAH patients with NYHA Functional Class IV

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Q&A

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