suspecting pulmonary hypertension in the dyspneic patient: who, … · 2018-09-25 · osteopathic...

Osteopathic Physicians and Surgeons of Oregon

Annual Primary Care ConferenceSunday, September 16, 2018

Suspecting Pulmonary Hypertension

in the Dyspneic Patient:

Who, When, and How

Catherine J. Markin, MDClinical Vice President, Medical Subspecialties

Legacy Medical Group

Medical Director, Pulmonary Hypertension Program

Legacy Health

Portland, Oregon

Faculty Disclosures

• Has no financial conflicts to disclose.

The Pulmonary Hypertension Association (PHA)

is the leading non-profit organization for PH research,

public awareness, and services. The organization

has over 16,000 members, including patients, family

members, and medical professionals.

www.PHAssociation.org

Let’s get started…

PH Lessons

1. Pulmonary Hypertension Is Common

2. WHO Group I PAH Is Rare but Deadly—

Make the Diagnosis Early

3. Know the PH Clinical Clues in the Dyspneic

Patient

4. Look Beyond the PA Pressure on

Echocardiography

5. Definitive Diagnosis of PAH Requires Invasive

Hemodynamic Testing

PH Lessons (cont’d)

6. Always Look for the Underlying Cause of PH

7. Treatment of PH—Get the Diagnosis Correct

and Determine Functional Status

8. Lack of Response to Acute Vasodilator

Challenge in PAH ≠ Untreatable

9. First Do No Harm—Learn to Differentiate WHO

Group I PAH From Other Forms of PH

10. Appropriate, Timely, and Collaborative Care:

Key to Early and Effective Treatment of PH in

the Dyspneic Patient

Case Presentations

2 Women With Dyspnea


Patient 2Patient 1 Patient 2

Age: 57 years

Patient 1

Comorbidities:

• HTN

• Diabetes

• CKD

• Atrial fibrillation


Patient 2

Age: 48 years

Comorbidities:

• HTN

• CKD

• Systemic sclerosis

Patient 2

NYHA Class III

• BP: 120/84 mm Hg

• JVP elevated

• Regular rate, rhythm

• Loud 2

• 3/6 murmur

(holosystolic,

left sternal border)

• 2+ leg edema

NYHA Class III

Patient 1

• BP: 172/65 mm Hg

• JVP elevated

• Irregularly irregular

• Loud P2

• 2/6 murmur

(holosystolic,

left sternal border)

• 2+ leg edema


What do we do?

Does this patient have pulmonary hypertension (PH)?

If PH, does this patient have pulmonary arterial hypertension, PAH?

PAH versus PH, why should I care?

Pulmonary Arterial Hypertension (PAH): Key Points• Average 14-mo delay from initial presentation to

diagnosis: need to diagnose early

• Evaluation must be methodical and include

echocardiography and right heart catheterization

• To treat effectively and avoid harm, PAH must be

differentiated from pulmonary venous hypertension

• Prognosis improves with therapy, but PAH remains a

progressive fatal disease

• Therapies and management strategies continue to

evolve

RVRA LVLAPA PVVC A

Pulmonary Hypertension = abnormally

high pressure in the pulmonary arteries

Mitral/Aortic valvular

disease

Systolic dysfunction

Diastolic dysfunction

Veno-occlusive disease

Pericarditis

Lung disease

Sleep apnea

Thromboembolic diseasePre-

capillary

disease

Pulmonary Arterial

(PAH)

Cor PulmonalePost-capillary (PVH)

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

PH

PAHMean PAP ≥25 mm Hg plus

PAWP ≤15 mm Hg plus

PVR >3 Wood units

Mean PAP ≥25 mm Hg

at rest during RHC

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

Look for 6th World Symposium Update

End of 2018

5th World Symposium on PH:Classification1. Pulmonary arterial hypertension

1.1 Idiopathic PAH

1.2 Heritable PAH

1.2.1 BMPR2

1.2.2 ALK1, ENG, Smad 9, CAV1, KCNK3

1.2.3 Unknown

1.3 Drug- and toxin-induced

1.4 Associated with

1.4.1 Connective tissue disease

1.4.2 HIV infection

1.4.3 Portal hypertension

1.4.4 Congenital heart diseases

1.4.5 Schistosomiasis

1’. Pulmonary veno-occlusive disease and/or

pulmonary capillary hemangiomatosis

1’’. Persistent PH of the newborn

2. PH due to left heart disease

2.1 LV systolic dysfunction

2.2 LV diastolic dysfunction

2.3 Valvular disease

2.4 Congenital/acquired left heart inflow/outflow tract

obstruction and congenital cardiomyopathies

3. PH due to lung diseases and/or hypoxia

3.1 Chronic obstructive pulmonary disease

3.2 Interstitial lung disease

3.3 Other pulmonary diseases with mixed restrictive

and obstructive pattern

3.4 Sleep-disordered breathing

3.5 Alveolar hypoventilation disorders

3.6 Chronic exposure to high altitude

3.7 Developmental lung diseases

4. Chronic thromboembolic PH

5. PH with unclear multifactorial mechanisms

5.1 Hematological disorders: chronic hemolytic anemia,

myeloproliferative disorders, splenectomy

5.2 Systemic disorders: sarcoidosis, pulmonary

histiocytosis, lymphangioleiomyomatosis,

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. J Am Coll Cardiol. 2013;62:D34-D41. Look for 6th World Symposium Update End of 2018

Lesson 1

Pulmonary Hypertension

Is Common

PH in the Community: PASP and Survival

All Participants

(N=1413)Overall Log Rank p<0.001

No Cardiopulmonary Disease

(N=778)Overall Log Rank p=0.002

*Bonferroni-adjusted p<0.05 in pairwise comparison with lowest tertile.

Lam CSP et al. Circulation. 2009;119:2663-2670.

86420

Time (yr)

Cu

mu

lati

ve

su

rviv

al

1.00

0.95

0.90

0.85

PASP quintile

1: 15-23 mm Hg

2: 24-25 mm Hg

3: 26-29 mm Hg

4: 30-32 mm Hg*

5: 34-66 mm Hg*

86420

Time (yr)C

um

ula

tive

su

rviv

al

PASP tertile

1: 15-24 mm Hg

2: 24-28 mm Hg

3: 28-43 mm Hg*

1.000

0.975

0.950

0.925

0.900

Up to 20% of the US population has echo

evidence of PH

100

75

50

25

0

PH Is Common in Elderly Patients With Heart Failure With Preserved EF

• PH by echo in a community-

based sample:

– heart failure with

preserved EF: 83% with

PH

– HTN but no CHF (control):

8% with PH

• Patients with PH:

– older

– higher systolic BP

– larger LA size

– higher E/e’ ratio

Lam CS. J Am Coll Cardiol. 2009;53:1119.

Cu

mu

lative

(%

)

10 30 50 70 90 110

PASP (mm Hg)

HTN

HFpEF

p<0.001

100

75

50

25

0

PH

pre

va

len

ce

(%

)

HTN

8%

HFpEF

83%

p<0.001

Epidemiology of PH by Echo

• Single echo lab / Australian community of 165,450

• Etiology of PH noted on echocardiogram

N=936 of 10,314 patients with echo PASP >40 mm Hg.

Strange G et al. Heart. 2012;98:1805-1811.

Miscellaneous, 2.7%

Lung disease,

Sleep-related

hypoventilation,

9.3%

CTEPH, 2.0%

PAH, 2.7%

Unknown,

15.4%

Left heart

disease, 67.9%

Lesson 2

WHO Group I PAH Is Rare

but Deadly—

Make the Diagnosis Early

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 5

0

20

40

60

80

100

Years of follow-up

Perc

enta

ge s

urv

ivin

g

NIH registry

Sitbon historical control

ACCP 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

Schematic Progression of PAH

Time

PAP

PVR

Presymptomatic/

Compensated

Symptomatic/

Decompensating

Symptom Threshold

Right Heart

Dysfunction

Declining/

Decompensated

CO=TPG

PVR

TPG=transpulmonary gradient.

Advanced Functional Class at Diagnosis Common and Indicates Delayed Recognition

Perc

ent

of

patients

FC

III/IV

at

dia

gnosis

REVEAL Registry(N=1831)

NIH Registry(N=187)

French Registry(N=674)

100

80

60

40

20

0

• Approximate prevalence: 15 cases/million

• More common in women

• Spans broad age range

• Delay in diagnosis persists

• Most patients diagnosed with late symptoms

• Poor prognosis if untreated (median survival <3 yr)

Badesch DB et al. Circulation. 2010;137:376-387. D’Alonzo GE. Ann Intern Med. 1991;115:343-349.

Humbert M et al. Am J Respir Crit Care Med. 2006;173:1023-1030.

Lesson 3

Know the PH Clinical Clues

in the Dyspneic Patient

Patient Presentation: Nonspecific Symptoms

0 10 20 30 40 50 60 70

Edema

Palpitations

Chest pain

Near syncope/syncope

Fatigue

Dyspnea

Patients (%)

Rich A et al. Ann Intern Med. 1987;107:216-223.

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

NIH Registry (1981 to 1985) 1.3 years

REVEAL Registry (2006 to 2007) 1.1 years

Multiple

educational

efforts

Median Time From Symptom Onset to Diagnosis

Is There a Reason to Suspect PAH?Clinical Presentation

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.

Risk Factors

Is There a Reason to Suspect PAH?

• Family history

• Connective tissue disease

• Congenital heart disease

• Portal hypertension—orthotopic liver transplant

candidate

• Environmental/drug factors

• HIV

Right Axis RVH

Right

Atrial

Enlarge-

ment

RV Strain

Is There a Reason to Suspect PAH?ECG

Normal

Abnormal

RV enlargement

into retrosternal

clear space

Peripheral hypo-

vascularity (pruning)

Prominent central

pulmonary artery

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

Is There a Reason to Suspect PAH?Chest X-ray

Is There a Reason to Suspect PAH? Echo• RV enlargement

• RA enlargement

• Septal straightening

• Loss of IVC inspiratory collapse

• Tricuspid regurgitation

• Pericardial effusion

• Decreased RV systolic dysfunction

– TAPSE (tricuspid annular plane systolic

excursion)

TAPSE 1.5 cmTAPSE 2.3 cm

Relatively preserved

RV function

RV dysfunction

McLaughlin VV et al.

J Am Coll Cardiol.

2009;53:1573-1619.

Is There a Reason to Suspect PAH?VQ Scan

Idiopathic

Pulmonary

Arterial

Hypertension

Chronic

Pulmonary

Embolism

Chronic Thromboembolic PH (CTEPH)

Not a PAH subgroup, but:

• Should never be missed

• Is potentially curable with thromboendarterectomy (PEA)

• 3% to 4% of acute PE do not entirely resolve

• One half of those with CTEPH do not have an apparent

history of acute PE

• Normal VQ scan excludes chronic PE

• CT angiogram can detect chronic clot (experienced

radiologist is required)

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

retraction with

partial obstruction

retraction with

total obstruction

CTEPH: CT Angiogram

Disturbed resolution of thrombus*

*Castañer E et al. Radiographics. 2009;29:31-53.

Less

subtle

thrombus

PEA

web or bands

recanalizationstenosis

fresh

thrombus

Is There a Reason to Suspect PAH?Pulmonary Function

• Underlying lung disease (diagnostic group III)

• Abnormalities consistent with PH

• 20% have an isolated reduction

in DLCO

• DLCO mildly reduced

(60%-80% predicted NIH registry)

• PVR correlates with reduction in

DLCO

IPAH and CTEPH

• 20% have an isolated reduction

in DLCO

• Severity predicts future PAH

• DLCO correlates inversely with

PASP

Systemic Sclerosis

DLCO=diffusing capacity of the lungs for carbon monoxide

Is There a Reason to Suspect PAH? Overnight Oximetry

• Hypoxia may signal underlying sleep apnea

• In patients with obstructive sleep apnea (OSA),

pulmonary artery pressures (PAP) are 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.

Substrate Further Assessment Rationale

Known BMPR2

mutation

Echo yearly; RHC if echo shows

evidence of PAH

Early PAH detection; 20%

chance of developing PAH

Systemic

sclerosis*

Echo yearly; RHC if echo shows

evidence of PAH8% prevalence of PAH

HIVEcho if symptomatic; RHC if echo

shows evidence of PAH0.5% prevalence of PAH

Portal

hypertension

Echo if OLT considered; RHC if

echo shows evidence of PAH

4% prevalence of PAH;

predictive of poor outcome

Congenital

heart disease

Echo and RHC at diagnosis;

consider repair of L-R shunt defect

High PAH probability if

unrepaired (Eisenmenger)

Screening Guidelines: Patients With Known PAH Risk


*Systemic sclerosis: consider echocardiogram if or unexplained declining DLCO.% DLCO

% FVC>1.6

Diagnostic Algorithm for PH

• Identical for local practitioners and PH specialists

• Requirements:

– thorough evaluation

– high quality studies and interpretation

• Establish a suspicion of PAH

• Confirm the diagnosis (right heart catheterization)

• Classify the type of PH (Group I-V)

• Determine the disease severity

• Select the appropriate treatment for patients with PAH


Strengths Limitations

Echocardiography in PH

• Best screening tool for PH

• Inexpensive, portable, readily

available, non-invasive, no

radiation

• Allows for serial assessment

• Provides clues to other

diagnoses (eg, LHD, CHD)

• Experienced techs/MDs

essential

• Imaging quality suboptimal in

patients with poor windows

(eg, lung disease, obesity)

• Right ventricle not imaged

adequately in some labs

• TR jet inadequate to

determine RVSP in

10%–25% of patients


Bossone E et al. Chest. 2005;127:1836-1843.

Brecker SJ. Br Heart J. 1994;72:384-389.

Echocardiogram

PFT’s

Polysomnography

VQ Scan

• Sleep Disorder

• Chronic PE

Functional Test

(6MWT, CPET)

Overnight

Oximetry

History

Exam

CXR

ECG

HIV

ANA

LFT’s

RH Cath

TEE

Exercise Echo

Pulmonary Angiography

Chest CT Angiogram

Coagulopathy Profile

Vasodilator Test

Exercise RH Cath

Volume 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.

AC

CF

/AH

A D

iagnostic A

lgorith

m

Lesson 4

Look Beyond the PA Pressure

on Echocardiography

PAH: RV Changes

Normal PH

RA

LA

RV

LV

TTE apical

4-chamber view

Key Features of PAH on Echo

• Enlarged RV with normal or small LV

• RA, RV, and PA enlargement

• RV dysfunction

• Increased RVSP

• Interventricular septal flattening during systole

± diastole

• Mitral E/A wave ratio <1.0



Essential Components of the Echocardiogram in PH

• Doppler estimate of RVSP

• Assess biventricular size and systolic function

• Look for interventricular septal shift

• Discriminate between pulmonary arterial and pulmonary

venous causes of PH (if possible)

• Assess for congenital heart shunt lesions

• Document pericardial effusion



Estimation of RV Systolic Pressure (RVSP)

RVSP = 4(velocity of TR)2 + RA

pressure

= 4(4)2 + 20

= ~84 mm Hg

Lesson 5

Definitive Diagnosis of PAH

Requires Invasive

Hemodynamic Testing

Catheterization is required when pulmonary

arterial hypertension is suspected

Diagnostic Cardiac Catheterization

• Establish the presence of PH

• Make the diagnosis of PAH

– measure wedge pressure and/or LVEDP

• Determine severity and prognosis of disease

• Exclude congenital heart disease

• Perform acute vasodilator test

Post-capillary PH

Pre-capillary PH

RA RV PA PVPC

LA LV Ao

PCWP >15 mm Hg

PVR <3 Wood units

PCWP <15 mm Hg

PVR ≥3 Wood units

Other:

High COPCWP <15 mm Hg

PVR <3 Wood units

PH: Define the Lesion(mean PAP ≥25 mm Hg)

Mixed PHPCWP >15 mm Hg

PVR ≥3 Wood units

Lesson 6

Always Look for the

Underlying Cause of PH

Echocardiogram

PFT’s

Polysomnography

VQ Scan

• Sleep Disorder

• Chronic PE

Functional Test

(6MWT, CPET)

Overnight

Oximetry

History

Exam

CXR

ECG

HIV

ANA

LFT’s

RH Cath

TEE

Exercise Echo

Pulmonary Angiography

Chest CT Angiogram

Coagulopathy Profile

Vasodilator Test

Exercise RH Cath

Volume 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.

AC

CF

/AH

A D

iagnostic A

lgorith

m

Lesson 7

Treatment of PH—Get the

Diagnosis Correct and

Determine Functional Status

PAH Treatment Goals

• Improve survival

• Improve quality of life

• Improve exercise

capacity

– 6MWD

– WHO functional

classification

• Improve hemodynamics

• Fewer/less severe

symptoms

• Prevent clinical

worsening

– escalation of therapy

– hospitalization

– lung transplantation

– death

Chronic Adjuvant Treatment

Digoxin

• Use to prevent hypoxic vasoconstriction

• Consider exercise, sleep, altitude

• Aim for target saturation >90%

• May not correct hypoxia with shunt

Oxygen


Badesch DB et al. Chest. 2007;131:1917-1928.

• Variable inotropic effect and use

• No long-term data; need to balance unproven benefits

with known risks

0 1 2 3

Chronic Adjuvant Treatment

• Recommended in IPAH and

CTEPH

• Observational data only

• Need to balance unproven

benefits with known risks

• INR goal 1.5 – 2.5

Poor CO

and hypotension

Diuretics

Improved CO

and BP

Observed Survival in IPAH Patients

With and Without Anticoagulation

(60)

(49)

(36)(21)

(14)(7)

Years

Percent

surviving

No Anticoagulation

Anticoagulation

Fuster V et al. Circulation. 1984;70:580-587. Badesch DB et al.

Chest. 2004;126:35S-62S. Olsson KM et al. Circulation. 2014; 29:57–65.

Diuretics

Anticoagulation

• Most patients need

• Hypotension not a contraindication

• Renal function and electrolytes

must be monitored closely

20

40

60

80

100

0

(+) Vasodilator Response—ONLY IF RESPONDER

(−) Vasodilator Response or Non-sustained

Vasodilator Response

PAH Therapy

• Calcium channel blockers

• Endothelin receptor antagonists

• Phosphodiesterase-5 inhibitors

• sGC stimulator

• Prostanoids


Mechanisms of Action of Approved Therapies for PAH

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

cGMP

cAMP

Vasoconstriction

and proliferation

Endothelinreceptor A

Endothelin-

receptor

antagonists

Endothelinreceptor B

Phosphodiesterase

type 5 inhibitor

Vasodilation

and antiproliferation

Phosphodiesterase type 5

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

Prostacyclin (prostaglandin I2)

Smooth muscle cells

Exogenou

s nitric

oxide

sGC

stimulator

Local Practitioners

Choice of Therapy

• Knowledge and management of comorbid illnesses

• Geographically close to patients

• Established therapeutic relationship

PH Centers

• Experience with therapy escalation

• Knowledge of drug-drug interactions; eg, PDE-5 inhibitors

and antiretroviral therapy

• Nursing support for management of parenteral medications

• Relationships with other subspecialists; eg, lung transplant

centers

Initial Therapy: Making the Right Decision

• Make sure the patient truly has PAH and not

another type of PH (especially pulmonary venous

hypertension)

• Severity of disease

• Patient preference

• Trying to weigh the data (evidence-based)

• When “comparing” trials, examine objective

baseline characteristics (6MWD, hemodynamics)

PAH Determinants of Risk


LOWER RISK DETERMINANTS OF RISK HIGHER RISK

NoClinical evidence of

RV failureYes

Gradual Progression of symptoms Rapid

II, 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

Minimal RV dysfunction Echocardiography

Pericardial effusion,

significant RV

enlargement/dysfunction;

RA enlargement

RAP <10 mm Hg;

CI >2.5 L/min/m2 HemodynamicsRAP >20 mm Hg;

CI <2.0 L/min/m2

Minimally elevated BNP Significantly elevated

• 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:PAH Treatment Algorithm

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

INITIAL THERAPY WITH

PAH-APPROVED DRUGSYES

NO

Acute vasoreactivity test

(I-C for IPAH) (IIb-C for APAH)

Expert Referral (I-C)

General measures and supportive therapy

Look for 6th World Symposium Update End of 2018

Approved Therapeutic Targets

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

cGMP

cAMP

Vasoconstriction

and proliferation

Endothelinreceptor A

Endothelin-

receptor

antagonists

Endothelinreceptor B

Phosphodiesterase

type 5 inhibitor

Vasodilation


Phosphodiesterase type 5

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

Prostacyclin (prostaglandin I2)

Smooth muscle cells

Exogenous

nitric oxide

sGC

stimulator

PDE-5 Inhibitor Pivotal Trials

Study Name

Drug

N

Etiol

Class

Design Positive Results

SUPER-1

Oral sildenafil*

vs placebo

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

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 Name

Drug

N

Etiol

Class

Design Positive Results

PATENT-1

Oral riociguat*

vs placebo

443

PAH

I-IV

Double-blind

12-week

• 6MWD

• Symptoms

• Hemodynamics

• Delay clinical worsening

CHEST-1

Oral riociguat

vs placebo

261

CTEPH

I-IV

Double-blind

16-week

• 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.

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

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

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

Endothelin Receptor Antagonists: Pivotal Trials

Study Name

Drug

N

Etiology

Class Design

Positive

Results

BREATHE-1

Oral bosentan*

vs placebo

213

PAH

III, IV

Double-blind

16-week

• 6MWD


• Symptoms

EARLY

Oral bosentan

vs placebo

185

PAH

II

Double-blind

6-month


• Hemodynamics

ARIES-1&2

Oral ambrisentan§

vs placebo

394

PAH

II, III

Double-blind

12-week

• 6MWD


SERAPHIN

Oral macitentan†

vs placebo

742

PAH

II,III

Double-blind

Event-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.

Iloprost (Ventavis®)

Treprostinil (Tyvaso®)

Prostacyclin Analogues: Intravenous, Implanted, 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. Treprostinil Implanted: FC II-IV, same as

patient’s current IV dose

Prostacyclin Analogues: Pivotal Trials for IV and SC Formulations

Study Name / DrugN / Etiol /

ClassDesign Positive Results

IV epoprostenol

vs conventional Rx

81

IPAH/FPAH

III,IV

Open-label

12-week

• 6MWD

• Symptoms

• Hemodynamics

• Survival

IV epoprostenol

vs conventional Rx

111

APAH SSc

III,IV

Open-label

12-week

• 6MWD

• Hemodynamics

• Symptoms

TRUST

IV treprostinil vs

placebo

44

PAH

III

Double-blind,

placebo-

controlled

12-week

• 6MWD

• Symptoms

SC treprostinil

vs SC placebo

470

PAH

II-IV

Double-blind

12-week

• 6MWD

• Symptoms

• Hemodynamics

Prostacyclin Analogues: Pivotal Trials for Inhaled and Oral Formulations

Study Name / Drug

N / Etiol /

Class Design Positive Results

AIR

Inhaled iloprost vs placebo

203

PH

III-IV

Double-blind

12-week

• Composite end point

• 6MWD

• Symptoms

• Hemodynamics

TRIUMPH 1

Inhaled treprostinil vs

placebo§

235

PAH

III-IV*

Double-blind

12-week on

background oral Rx

• 6MWD

FREEDOM-M

Oral treprostinil vs placebo

228

PAH

II-III

Double-blind,

placebo-controlled

12-week

• 6MWD

GRIPHON

Oral selexipag vs placebo

1156

PAH

II-III

Double-blind, naïve

or 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;55:1915-1922

Hiremath 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

5th World Symposium on PH:2013 Treatment Algorithm

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

Sequential Combination

Therapy (I-A)

Referral for LungTransplantation (I-C)

Consider Eligibility for

Lung Transplantation

Inadequate Clinical

Response

on Maximal Therapy

INITIAL THERAPY WITH PAH-APPROVED DRUGS

PDE-5 I orsGCs

ERAs

Prostanoids

++

+

Balloon AtrialSeptostomy (IIa-C)

Inadequate Clinical

Response

Look for 6th World Symposium Update End of 2018

Combination Therapy

sGC

StimulatorsProstanoids

Endothelin

Receptor

Antagonists

Phospho-

diesterase

Inhibitors

TRIUMPH

STEP

SERAPHIN†

GRIPHONγ

TRIUMPH

PACES

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

Lesson 8

Lack of Response to Acute

Vasodilator Challenge in

PAH ≠ Untreatable

Acute Vasodilator Trial

• Purpose:

– identify vasodilator “responders” who are candidates

for CCB therapy

• Short-acting vasodilators

– inhaled nitric oxide is preferred

• Definition of response

– decrease in mPAP by ≥10 mm Hg down to

mPAP of ≤40 mm Hg

– with improvement or maintenance of

cardiac output

Rubin LJ. Chest. 2004;126:4S-6S.

Lesson 9

First Do No Harm—Learn to

Differentiate WHO Group I

PAH From Other Forms

of PH

Is It Left Heart Disease?

Symptoms

– 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

Problems With Incorrect Treatment

• WHO Group 1 PAH: True PAH

– incorrect treatment with systemic vasodilators could lead to

profound hypotension, death

• WHO Group 2 PH: PH due to LHD

– incorrect treatment with pulmonary vasodilators could lead to

pulmonary edema, CHF exacerbation

• WHO Group 3 PH: PH due to hypoxemia/lung disease

– incorrect treatment with pulmonary vasodilators could lead to

increased V/Q mismatch, worsening hypoxemia

• WHO Group 4 PH: CTEPH

– treating with pulmonary vasodilators likely not harmful, but

don’t delay referral for potentially curative surgical

thromboendarterectomy (if indicated)

Lesson 10

Appropriate, Timely, and

Collaborative Care:

Key to Early and Effective

Treatment of PH in the

Dyspneic Patient

Goals of Collaborative Care

Clinical Practice Guidelines

Clinical Trial Evidence

Best PracticeLocal Practitioners

PH Specialists

Local Care PH Center

• Diagnostic dilemmas

• Diagnostic cath/

vasodilator trial

• Fluid management

• Acute issues

• PAH-specific therapies

• Side effects

• Hospitalizations

• Transplant

• Clinical trials

Collaborative Care With PH Centers:Initial Steps

Collaborative Care With PH Centers:Ongoing Care

Local Care

• Symptom evaluation

• Titrate diuretics

• Monitor Rx

• Need to change Rx

• Manage SEs

• ? Transplant

• Evaluate acute issues

• Acute hospital care

• Emotional support

PH Center

Timing of Referral to a PH Center

• Dependent on a local physician’s level of comfort

• Referral can occur at multiple junctures

Abnormal symptoms, exam, and initial screening (echo)

Pivotal tests (without RHC)

Diagnosis (RHC with vasodilator challenge)

Treatment escalation

PH Center

PH Center

PH Center

PH Center

PH Center

Treatment

Case Resolutions


Patient 2

Echo

• LV: EF 58%

• Grade 1 diastolic

dysfunction

• RV: size

• 3+ RV dysfunction

• PASP: 76 mm Hg

• RA: 10 mm Hg

• 2+ TR


Echo

Patient 1

• LV: EF 65%

• Grade 3 diastolic

dysfunction

• RV: size

• Normal RV function

• PASP: 60 mm Hg

• RA: 10 mm Hg

• 1+ TR

Patient 2

Invasive

Hemodynamics

• RA: 12 mm Hg

• mPAP: 41 mm Hg

• PCWP: 10 mm Hg

• CO: 2.6 L/min

• PVR: 11.9 Wood units

• BP: 93/69 mm Hg

• Vasodilator challenge with iNO:

non-responder


Invasive

Hemodynamics

Patient 1

• RA: 15 mm Hg

• mPAP: 42 mm Hg

• PCWP: 29 mm Hg

• CO: 6.7 L/min

• PVR: 1.8 Wood units

• BP: 172/65 mm Hg

• Vasodilator challenge with iNO:

not indicated (high PCWP)

Patient 2

Final Diagnosis

• WHO Group I—

pulmonary arterial

hypertension (PAH)

• PAH due to connective

tissue disease


Final Diagnosis

Patient 1

• WHO Group II—

pulmonary venous

hypertension (PVH)

• Heart failure with

preserved EF (HFpEF)

Patient 2: PAH

Clinical Course

• PDE-5 inhibitor:

no improvement

• ERA added

• symptoms over time

• Now on parenteral

prostanoid with

improved symptoms

• NYHA II


Clinical Course

Patient 1: PVH

• Carvedilol

• Furosemide

• Co-managed with

nephrology

• Improved symptoms

• NYHA II

Summary: PH Lessons

1. PH is common, but most often due to LHD or

chronic lung disease: selective pulmonary

vasodilators are not proven in these patients

2. PAH is rare but deadly: outcomes have

improved but not as much as we would like;

diagnosis must be made earlier

3. Know the PH clinical clues in the dyspneic

patient

4. Know the limitations of echo, and look beyond

PA pressure to the RV to evaluate size/function

5. Definitive diagnosis of PH requires heart cath

Summary: PH Lessons (cont’d)

6. Identify underlying cause of PH: etiology

important = prognostic and Rx implications

7. Treatment of PH is based on correct diagnosis

and functional status

8. Lack of response to acute vasodilator challenge

in PAH does not mean the patient is untreatable

9. Learn to differentiate Group I PAH from other

forms of PH: when in doubt, ask for help

10. Collaborative care: key to early and effective

treatment of PH in the dyspneic patient

Final Housekeeping

• Hand in CME evaluation

form and be sure you

signed in at the

registration desk

• Bring your PHA information

home

• Expect an email from WUSM

with a link to access your

CME certificate

CME Course Evaluation:

Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension: An Overview

Friday, August 7, 2015 – Lincoln, Nebraska

Deborah J. Levine, MD

Your Professional Degree/Certification (check one):

MD/DO NP PA PharmD RPh RN/LPN RRT Other (please specify)

Check&here&also&if&you&are&in&training&as&a: Fellow Resident Medical Student

Your Medical Specialty or Focus of Practice (check one):

☐ Pulmonary/Critical Care/Respiratory/Sleep ☐ Family Practice/General Medicine

☐ Cardiology/Cardiovascular/CCU ☐ Pediatrics

☐ Rheumatology ☐ Pediatric Specialist*

☐ Hospitalist ☐ Emergency/Urgent/Acute Care

☐ Internal Medicine/Primary Care ☐ Surgery*

☐ Other Internal Medicine* ☐ Other* *Please indicate specialty

PRESENTATION

Considering pertinence, presentation, and audiovisual, what is your overall evaluation of the speaker?

(Circle one) Poor Fair Good Very Good Excellent

OVERALL COURSE

Your OVERALL EVALUATION of the course (circle one): Poor Fair Good Very Good Excellent

Target Audience

This activity has been designed for pulmonologists, cardiologists, rheumatologists, internists, and primary care physicians, as well as

nurses, physician assistants, and other allied health professionals who help care for patients with PAH.

Educational Objectives

This CME program is designed to improve competence, performance, and patient care practices by instructing clinicians in the highest

quality of care for patients with PAH. At the conclusion of the program, participants should be able to:

· Accurately diagnose patients through comprehensive screening and early recognition of symptoms

· Evaluate the patient’s condition and prescribe long-term optimal management, including knowing when and how to treat and

when to consult with colleagues at an established PAH center

1. Did the course fulfill the objectives and was the intended result of those objectives achieved? Yes No

If not, please explain:

2. Was the presentation free from commercial bias? Yes No

If not, please explain:

Continued on reverse side

Please complete both sides of this evaluation form and return it to the Registration Desk

before you leave.

Thank you for your participation!

For more information on upcoming PHA

Medical Education Programs, please visit:

www.PHAssociation.org

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