Pulmonary Arterial Hypertension in Rural Communities: Early Diagnosis and Intervention to Improve Outcomes

Pulmonary Arterial Hypertensionin Rural Communities:

Early Diagnosis and Interventionto Improve Outcomes

• Jointly sponsored by Postgraduate Institute for Medicine

and Horizon CME

• Postgraduate Institute for Medicine designates this

activity for

– A maximum of 1 AMA PRA Category 1 Credits™ for

physicians

• This activity was supported by an independent

educational grant from Actelion

• Disclosures and conflicts of interest for content

development faculty, speakers, and independent clinical

reviewers are listed in your handouts

Activity Overview

• Identify the signs, symptoms, and risk factors associated with

PAH to facilitate timely referral of patients to specialized

pulmonary hypertension centers for early diagnosis and

treatment

• Explain the WHO PH Groups and functional status

classifications for PAH and their impact on treatment selection

• Outline the diagnostic tests that may be used to identify

patients with PAH

• Identify the indications and contraindications for currently

available therapies used in the treatment of patients with PAH

• Describe the role of PCPs in managing PAH patients

Objectives

What do you do?

• 54 year old female with fatigue, dizziness and shortness

of breath x 2-3 years, progressed over the last year

• She climbs stairs slowly, trouble walking up grades, pedal

edema more than a year

• Scleroderma diagnosed 7 years ago

• Echo shows normal LV function, RV pressure estimated

at 80 mmHg; RV dilated, hypofunctional

Case Report

mPAP ≥25 mmHg

mPAP = mean pulmonary artery pressure; PAWP = pulmonary artery wedge pressure; PVR = pulmonary vascular resistance.

Hoeper MM, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D42-50.

PAH definition:

• mPAP ≥25 mmHg

• PAWP ≤15 mmHg

• PVR >3 Wood Units

• PAP associated with adverse changes:

– in the pulmonary vasculature (vasculopathy), and

– at the level of the right ventricle (hypertrophy)

• Absence of lung disease, left-sided heart disease

Pulmonary Hypertension

Pulmonary Hypertension (PAH)

Left-sided heart disease

Lung disease/hypoxia

Types of Pulmonary Hypertension


Lung disease/hypoxia


Thromboembolic

disease


Lung disease/hypoxiaThromboembolic

disease

IPAH and APAH


IPAH = idiopathic pulmonary artery hypertension; APAH = associated pulmonary artery hypertension.

5th World Symposium on Pulmonary Hypertension

Nice, France February 27-March 1, 2013

2013 Updated Clinical Classificationof Pulmonary Hypertension (PH)

PH: Diagnostic Classification1. Pulmonary arterial hypertension (PAH)

1.1. Idiopathic PAH (IPAH)

1.2. Heritable

1.2.1. BMPR2

1.2.2. ALK1, ENG, SMAD9, CAV1, KCNK3

1.2.3. Unknown

1.3. Drug- and toxin-induced

1.4. Associated with

1.4.1. Connective tissue diseases (CTD)

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. Left ventricular systolic dysfunction

2.2. Left ventricular 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 hypoxemia

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. Hematologic disorders: chronic hemolytic anemia, myeloproliferativedisorders 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, fibrosingmediastinitis, chronic renal failure, segmental PH

Simonneau G, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D34-41.

• Incidence: 1-2 cases per million per year

(“epidemic” in the 1990’s)

• Female: Male = >3:1 range 2:1 to 9:1)

• Average age: 32 years

• Symptoms: (~2 years from onset to diagnosis)

– dyspnea (60%),

– weakness (19%),

– recurrent syncope (13%).

Idiopathic PAH

McGoon MD, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D51-9. Hoeper MM, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D42-50.

• Family history of PAH

• Congenital heart disease

• Connective tissue diseases (i.e., SSC, SLE)

• Drugs and toxins (i.e., aminorex,

methamphetamines, fenfluramine)

• Human immunodeficiency virus (HIV)

• Portal hypertension

Risk Factors for PAH

SSc = systemic sclerosis; SLE = systemic lupus erythematosus.

Morrell NW. F1000 Biol Rep. 2010;2. pii:22. McLaughlin VV, et al. J Am Coll Cardiol. 2009;53(17):1573-1619. Humbert M, Souza R, Simonneau G (eds): Pulmonary Vascular Disorders. Prog Respir Res. Basel, Karger, 2012, vol 41, pp 76-84. Simonneau G, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D34-41.

*Untreated patients; IPAH = idiopathic pulmonary arterial hypertension; NYHA = New York Heart Association.

D'Alonzo GE, et al. Ann Intern Med. 1991;115(5):343-9.

IPAH Survival According toNYHA Functional Class(NIH Registry – 1980’s Data)

NYHA Class Median Survival*

I and II 58.6 months

III 31.5 months

IV 6 months

RHF = right heart failure.

Galiè N, et al. Eur Heart J. 2009;30(20):2493-537.

WHO Functional Classification of PAH

Class Definition

IPts without limitation of physical activity. Ordinary physical activity does

not cause undue dyspnoea or fatigue, chest pain, or near syncope.

IIPts with slight limitation of physical activity. They are comfortable at rest.

Ordinary physical activity causes undue dyspnoea or fatigue, chest pain,

or near syncope.

IIIPts with marked limitation of physical activity. They are comfortable at

rest. Less than ordinary activity causes undue dyspnoea or fatigue,

chest pain, or near syncope.

IVPts with inability to carry out any physical activity without symptoms.

They manifest signs of RHF. Dyspnoea and/or fatigue may even be

present at rest. Discomfort is increased by any physical activity.

PH: Diagnostic Classification1. Pulmonary arterial hypertension (PAH)

1.1. Idiopathic PAH (IPAH)

1.2. Heritable

1.2.1. BMPR2

1.2.2. ALK1, ENG, SMAD9, CAV1, KCNK3

1.2.3. Unknown

1.3. Drug- and toxin-induced

1.4. Associated with

1.4.1. Connective tissue diseases (CTD)

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. Left ventricular systolic dysfunction

2.2. Left ventricular 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 hypoxemia

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. Hematologic disorders: chronic hemolytic anemia, myeloproliferativedisorders 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, fibrosingmediastinitis, chronic renal failure, segmental PH

Simonneau G, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D34-41.

Largest group of associated

PAH conditions

Survival Curves of Scleroderma PAH Patients Based on Organ

Involvement

Condliffe R, et al. Am J Respir Crit Care Med. 2009;179(2):151-7

ATP = adenosine triphosphate; RV = right ventricle.

Courtesy of Oudiz RJ.

‘Vasculopathy’

• Leads to reduced blood flow through the lungs

• Decreased cardiac output—‘Fixed Stenosis’

• Decreased oxygen to the tissues

• Decreased ATP production

• Fatigue

RV failure—end-stages of PAH

PAH Vascular Remodeling

Pathogenesis of PAH

HIV = human immunodeficency virus; BMPR2 = bone morphogenetic protein receptor II gene.

Gaine S. JAMA. 2000;284(24):3160-8.

1. Risk Factors and

Associated Conditions

Collagen Vascular Disease

Congenital Heart Disease

Portal Hypertension

HIV Infection

Drugs and Toxins

Pregnancy

Susceptibility

Abnormal BMPR2 Gene

Other Genetic Factors

Normal Reversible Disease Irreversible Disease

2. Vascular Injury

Endothelial Dysfunction

↓ Nitric Oxide Synthase

↓ Prostacyclin Production

↑ Thromboxane Production

↑ Endothelin 1 Production

Vascular Smooth Muscle Dysfunction

Impaired Voltage-Gated

Potassium Channel (Kv1.5)

3. Disease Progression

Loss of Response to

Short-Acting Vasodilator Trial

CO = cardiac output; LV = left ventricle; PBF = pulmonary blood flow.


• Patients die of right heart failure.

• Volume overload does not cause “CHF”

• Volume overload does cause

RV overload/ischemia

and decreased blood flow

(CO) delivered to the

lungs (and thus to the

LV and to the tissues)

PAH Progression

Consequences of PAH

↑ PVR

↑ RV afterload

↓ RV ejection (CO) & ↓ PBF

RV hypertrophy & dilation

Death

Is There a Reason to Suspect PAH?

CXR = chest x ray; ECG = electrocardiogram.

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

• Clinical History

– Symptoms, risk factors, family history, exam, CXR, ECG…

• Non-specific Symptoms

– Dyspnea – 60% of IPAH (NIH Registry)

– Fatigue, weakness (reflects impaired O2 transport)

– Chest pain, syncope – 40% of IPAH

• Symptoms of Related Conditions

– CHF, Sleep apnea, arthralgias, arthritis, rash

– Liver disease, Appetite suppressant exposure, Deep venous

thrombosis or pulmonary embolism, HIV risk factors, Underlying

lung disease

• Non-specific nature of complaint can lead to:

– Confusion with other conditions

– Delayed diagnosis


CXR = chest x ray; ECG = electrocardiogram; BMPR-II = bone morphogenetic protein receptor type II.


• Clinical History

– Symptoms, risk factors, family history, exam, CXR, ECG…

• Non-specific Symptoms

– Dyspnea – 60% of IPAH (NIH Registry)

– Fatigue, weakness (reflects impaired O2 transport)

– Chest pain, syncope – 40% of IPAH

• Symptoms of Related Conditions

– CHF, Sleep apnea, arthralgias, arthritis, rash

– Liver disease, Appetite suppressant exposure, Deep venous

thrombosis or pulmonary embolism, HIV risk factors, Underlying

lung disease

• Family History: defective BMPR-II gene – 25% of “IPAH”



Findings on Physical Examination

– Loud pulmonic valve closure (P2)

– Right-sided fourth heart sound

– Graham-Steele murmur

– Jugular venous distention

– Right ventricular heave

– Peripheral edema, ascites

Bogaard HJ, et al. Chest. 2009;135:794-804.

Key Finding in PAH:Right Ventricular Dysfunction

A Normal B IPAH

RV LV

RV LV

Increased Index of Suspicion is a Must

• Unexplained dyspnea

• Autoimmune disease

• History of drug exposure (diet pills, amphetamines)

• Family history of PH or PH-like illness

Diagnostic Algorithm

How Is PAH Diagnosed?


DLco = diffusing capacity for carbon monoxide. Hoeper MM, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D42-50.

NICE PAH Diagnostic Algorithm

Echocardiography compatible with PH?

Consider most common causes of PH

(i.e., left heart disease, lung disease)PH unlikely

History, signs, risk factors, ECG, X-ray,

PFT incl. DLCO, consider BGA, HR-CT

Consider other causes

or recheck

Diagnosis or heart disease or

lung disease confirmed?

No signs of severe PH/RV

dysfunction

Signs of severe PH/RV

dysfunction

V/Q scintigraphy

Unmatched perfusion defects?

Treat

underlying disease

Refer to

PH expert center

NO

YESYES

NOYES

Symptoms, signs, history suggestive of PAH

Dilated,

hypofunctional

RV

Small,

flattened

LV


Echocardiography in Evaluation of PH

LHD = left-sided heart disease; CHD = coronary heart disease.

• Echocardiography is often the 1st window into the

discovery of PH

• Echo can help diagnose LHD and CHD, and can

characterize PH severity

• Echo has several limitations:

– PH by ECHO does not necessarily = PAH, it is much

more likely to be Group 2 or 3 PH

– Even with PAH confirmed, beware of the accuracy of

your measurements

Echocardiography:Points to Remember

DLco = diffusing capacity for carbon monoxide.



REFER!

Consider referral to card/pulm specialists




PFT incl. DLCO, consider BGA, HR-CT,

Polysomnogram


or recheck




dysfunction


dysfunction

V/Q scintigraphy


Treat

underlying disease

Refer to

PH expert center

NO

YESYES

NOYES


Deano RC, et al. JAMA Intern Med. 2013;173(10):887-93.

N=141 patients referred over a 10-month period for PH evaluation.

39% of patients initiated on PAH-specific meds prior to referral did not have Group I PAH.

Post Referral Diagnosis

Group 1 Group 2 Group 3 No PH Unk.

Pre-

Referral

Diagnosis

Group 1 41 (73%) 3 (5%) 4 (7%) 7 (12%) 1 (18%)

Group 2 0 8 (61%) 1 (8%) 4 (31%) 0

Group 3 4 (17%) 4 (17%) 13 (56%) 2 (9%) 0

Unk. 12 (29%) 13 (31%) 1 (2%) 14 (33%) 2 (5%)

The Multicenter RePHerral Study: Referral of Patients with PH Diagnoses to

Tertiary PH Centers

Incorrect Pre-Referral DiagnosisCorrect Pre-Referral Diagnosis

• “Of the 98 patients who received a definitive

diagnosis before referral, 32 (33%) received a

misdiagnosis”

• “Patients referred to PH centers for diagnosis

and treatment are often referred late (with

functional class III or IV disease), receive

misdiagnoses, and are inappropriately prescribed

medications.”

RePHerral Study: Findings

Deano RC, et al. JAMA Intern Med. 2013;173(10):887-93.

• “High-volume specialized centers have

recurrently shown to obtain the best outcomes for

patients in different areas of medicine while

maintaining greatest patient satisfaction, lowest

complication rates, shortest length of hospital

stay and best value for healthcare payers.”

• It is recommended that PAH patients be

referred to expert centers after diagnosis

Updated Treatment Algorithm of PAHReferral Centers

Galiè N, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D60-72.

Select Criteria for Accredited PH Care Centers

http://www.phassociation.org/PHCareCenters/MedicalProfessionals/CenterCriteria. Accessed Oct. 10, 2014.

The purpose of the PHA-Accredited

Pulmonary Hypertension Care Centers (PHCC)

initiative is to establish a program of accredited centers

with expertise in PH that aspires to improve

overall quality of care and ultimately improve outcomes

of patients with PH, particularly PAH, a rare and

life-threatening group of disease.

REFER!DLco = diffusing capacity for carbon monoxide.







PFT incl. DLCO, consider BGA, HR-CT


or recheck




dysfunction


dysfunction

V/Q scintigraphy


Treat

underlying disease

Refer to

PH expert center

NO

YESYES

NOYES



V/Q scintigraphy


CTEPH likely

CT angiography, RHC plus PA

(PEA expert center)

RHC

PAPm ≥25 mmHg,

PAWP ≤15 mmHg, PVR >3 WU

PAH likely

Specific diagnostic testsConsider other causes

PVOD

PCH

Other

(group 57)

Idiopathic or Heritable

PAH

Family history; consider

genetic studies

(expert centers only)

CTD CHD

Drugs

Toxins

Porto-

Pulmonary

HIVSchisto-

somiasis

Group 1

PAH

YES NO

YES NO

V/Q Scan in PH – A Required Screen for CTEPH

• CT angiography

– Good for acute PE; insensitive for CTEPH

• V/Q Scan

– Sensitive, less specific follow-up abnormal test with

pulmonary angiography

– Consider referral to specialty PH/CTEPH center

– In PAH, perfusion images can show mottling; no

segmental mismatches should be seen

PE = pulmonary embolism; V/Q = ventilation perfusion.

McLaughlin VV, et al. J. Am. Coll. Cardiol. 2009;53(17):1573-1619

PFTs in PH- A Required Screen for ILD

• Use in combination with history/physical,

radiography

• % predicted FVC/ % predicted DLco ratio >1.6 or

an unexplained decrease in DLco suggests PAH

PFTs = pulmonary function test; ILD = interstitial lung disease; FVC = forced vital capacity; DLco =

diffusing capacity for carbon monoxide.

McLaughlin VV, et al. J Am Coll Cardiol. 20098;53(17):1573-1619.

Cardiac Catheterization

The Gold-Standard for PAH Diagnosis


• Mean RAP (normal < 6 mmHg)

• PAP (normal < 28/12 mmHg)

• Mean PAP (normal < 20 mmHg)

– PH definition > 25 mmHg

• PCWP (normal < 12 mmHg)

– PAH allows PCWP < 15 mmHg

• Cardiac Output (normal 2.5 - 4.0 l/min/m2)

Key Measurements of RHC

RHC = right heart catheterization.


PH Clinical Follow-up:Routine Measures

a. Intervals should to be adjusted to individual patients needs; b. Usually one of the two exercise tests is performed; c. Is recommended; d. Should be performed. RHC = right heart catheterization.

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

At Baseline

(prior to

Therapy)

Every

3-6 Monthsa

3-4 Months

after Initiation

or Changes

in Therapy

In Case of

Clinical

Worsening

Clinical Assessment

WHO-FC

ECG

✔ ✔ ✔ ✔

6MWTb ✔ ✔ ✔ ✔

Cardio-Pulmonary

Exercise Testingb ✔ ✔ ✔

BNP/NT-proBNP ✔ ✔ ✔ ✔

Echocardiography ✔ ✔ ✔

RHC ✔c ✔d ✔d

Humbert M, et al. Eur Respir Rev Off J Eur Respir Soc. 2012;21(126):306–312. Holliman K. Amercian CollPhysicians ACP Internist. 2013.

• An initial suspicion for PH is important for early

recognition and intervention.

• A thorough workup for common causes of PH is

required.

• Right heart catheterization is mandatory for

making the correct diagnosis.

• The management of PH depends on the etiology

(Group I, II, III, IV, V).

Diagnostic Algorithm for PH Key Points

• Treatment failure is based on a set of goals, rather than a

change in one or more measures:

– No decrease in 6MW (>380?)

– Get to NYHA/WHO FC I or II

– Keep the patient out of the hospital

– Etc…

• “...studies focusing on outcomes have shown that no

single test can reliably serve as a long-term prognostic

marker and that composite treatment goals are more

predictive of long-term outcome.”

Treatment Goals in PAH

McLaughlin VV, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D73-81.

• Diuretics

• Oxygen

• Warfarin*

• Exercise training

PAH Treatment:General Measures and Supportive Therapy

*Idiopathic pulmonary artery hypertension only.

• Vasoreactivity is defined as a

• Decrease in mPAP of >10 mmHg

• To a mPAP of <40 mmHg

• With a normal CO

in response to IV epoprostenol, IV adenosine or inhaled NO

• Calcium Channel Blockers (CCBs) should only be used in

“vasoreactive” PAH patients

• Clinical response to CCB response must be carefully

followed

of patients

PAH Treatment: Acute Vasoreactivity Testing

CCB = calcium channel blocker; CO = cardiac output; RAP = right atrial pressure.

McLaughlin VV, et al. J Am Coll Cardiol. 20098;53(17):1573-619. Galiè N, et al. J Am Coll Cardiol. 2013;62(25

Suppl):D60-72. ESC/ERS/ISHLT, Galiè N, et al. Eur Respir J. 2009;34(6):1219-63.

DO NOT USE CCBs unless patient is proven to have

an acute vasodilator response in at catheterization

AND the CO is preserved, with normal RAP. Risks for

inappropriate use include syncope, shock, and

possibly death

Endothelin pathway

Nitric oxide pathway

Prostacyclin pathway

Humbert M, et al. N Engl J Med. 2004;351:1425-36.

3 Key Signaling Pathways in PAH

2000 2002 2004 2006 2008 2010

Oral tadalafil and

inhaled treprostinil

• Epoprostenol approved for APAH

• SQ treprostinil and oral bosentan

for IPAH & APAH

Approval Date

2012 2014

IPAH = idiopathic pulmonary artery hypertension; APAH = associated pulmonary artery hypertension.

http://emedicine.medscape.com/article/301450-treatment#aw2aab6b6b4. Accessed October 22, 2014.

FDA-Approved Therapies

The Evolution of PAH Therapies

IV treprostinil &

inhaled iloprost

Oral sildenafil

Oral ambrisentan

Oral riociguat and

macitentan

Oral treprostinil

PAH Specific Agents: Prostacyclin Analogues

HA = headache; D = diarrhea; N = nausea; V = vomiting; ER = extended release; PE = pulmonary

embolism; Sx = symptoms. AC = anticoagulant. http://emedicine.medscape.com/article/301450-medication#3.

Accessed December 21, 2014. http://www.pdr.net/browse-by-drug-name. Accessed December 21, 1014.

Epoprostenol Iloprost Treprostinil

Route IV Inhalation IV, SQ, inhalation, PO

Indication WHO Group I PAH WHO Group I PAH WHO Group I PAH

Contraindications

CHF or pulmonary

edema during initial

dose titration

None

Severe hepatic

impairment for ER

tablets

Side effects

Flushing, HA, jaw pain,

D, N, V, rash,

thrombocytopenia

Flushing, cough,

hypotension, N, HA,

bronchospasm

Flushing, headache,

nausea, diarrhea, jaw

pain, rash

Comments

AC should be initiated

to decrease PE or

systemic embolism risk

(not guideline based)

Hemoptysis has been

reported with iloprost

use

Abrupt withdrawal may

worsen PAH Sx, can

occur with other

agents in this class as

well

PAH Specific Agents: Endothelin Antagonists

IPF = idopathic pulmonary fibrosis; ALT = alanine transaminase; AST = aspartate transaminase; Hgb =

hemoglobin.

http://emedicine.medscape.com/article/301450-medication#3. Accessed December 21, 2014.

http://www.pdr.net/browse-by-drug-name. Accessed December 21, 1014.

Bosentan Ambrisentan Macitentan

Route PO PO PO

Indication WHO Group I PAH WHO Group I PAH WHO Group I PAH

Contraindications Pregnancy Category X

Pregnancy Category

X, WHO Group 3 PH,

IPF

Pregnancy Category X

Side effects

Increased ALT/AST,

HA, Nasal congestion,

edema, decreased Hgb

Increased ALT/AST,

edema, HA, nasal

congestion, dyspnea,

decreased Hgb

Increased ALT/AST,

nasal congestion, HA,

anemia, bronchitis

Comments

Serum liver enzymes at

baseline & then

monthly, monthly

pregnancy tests

Pregnancy test at

baseline & then

monthly

Pregnancy test at

baseline & then

monthly

PAH Specific Agents: PDE-5 Inhibitors and sGC Stimulators

PDE-5 = phosphodiesterase type 5; sGC = soluble guanylate cyclase; NO = nitric oxide.

http://emedicine.medscape.com/article/301450-medication#3. Accessed December 21, 2014.

http://www.pdr.net/browse-by-drug-name. Accessed December 21, 1014.

Sildenafil Tadalafil Riociguat

Route PO PO PO

Indication WHO Group I PAH WHO Group I PAHWHO Group I PAH,

WHO Group 4 PH

ContraindicationsOrganic nitrates in

any form

Organic nitrates in any

formPregnancy Category X

Side effects

HA, flushing,

epistaxis, dyspepsia,

insomnia, erythema,

diarrhea

HA, myalgia, flushing,

respiratory tract

infection, dyspepsia,

nasal congestion

HA, dyspepsia and

gastritis, dizziness, N, D,

V, hypotension

Comments

Vaso-occlusive crisis

(PAH secondary to

sickle-cell anemia)

CYP3A4 inhibitors

may increase drug

levels

Monthly pregnancy tests

and 1 month after

discontinuation

Clinical Value of PAH Specific Agents

• Prostacyclin analogues, endothelin antagonists, PDE-5

inhibitors, and sGC stimulators

– Improve symptoms and exercise capacity

– Delay clinical worsening of PAH

sGC = soluble guanylate cyclase.

McLaughlin VV, et al. J Am Coll Cardiol. 2009;53:1573-1619. Khaybullina D, et al. P T. 2014;39(11):749-58.

Galiè N, et al. Eur Heart J. 2009;30:394-403.

Survival with PAH Drugs: Meta AnalysisStudy ID RR (95% CI) % Weight

Rubin et al 0.36 (0.04, 3.00) 5.21

Barst et al 0.06 (0.00, 0.96) 2.92

Badesh et al 0.79 (0.22, 2.77) 17.59

Langleben et al 1.66 (0.07, 39.30) 2.32

Simmoneau et al 2002 0.92 (0.38, 2.21) 29.81

Galiè et al 1.00 (0.06, 15.65) 3.07

Olschewski et al 0.25 (0.03, 2.22) 4.91

Rubin et al 0.24 (0.02, 2.60) 4.08

Barst et al 0.47 (0.04, 5.01) 4.12

Sastry et al 0.39 (0.02, 8.73) 2.42

Barst et al 1.54 (0.06, 37.19) 2.29

Galiè et al 1.01 (0.11, 9.55) 4.60

Galiè et al 0.41 (0.11, 1.49) 13.77

Galiè et al 0.99 (0.06, 15.58) 3.05

Simonneau et al 2008 0.07 (0.00, 1.15) 2.85

Channick et al (Excluded) 0.00

Singh et al (Excluded) 0.00

Galiè et al (Excluded) 0.00

Barst et al (Excluded) 0.00

McLaughlin et al (Excluded) 0.00

Hooper et al (Excluded) 0.00

Overall 0.57 (0.35, 0.93) 100.00

0.01 0.1 0 10 100Favors Controls

FavorsTreatments

• Treatment choice may be based on:

– Disease severity

– Patient preference

– Patient feasibility

– Clinical trial availability

– PAH type?

Treatment Approach to PAH

6-MWD = 6 minute walk distance; PaCO2 = partial pressure of carbon dioxide.

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

PAH Determinants of Patient RiskACCF/AHA Expert Consensus

Low Risk Determinants of Risk High Risk

NoClinical evidence of RV

failureYes

Gradual Disease progression Rapid

II, III WHO functional class IV

Longer (>400 meters) 6-MWD Shorter (<300 meters)

Peak VO2 >10.4

mL/kg/min

Cardiopulmonary exercise

testing

Peak VO2 <10.4

mL/kg/min

Minimally ↑ and stable BNP/NT-proBNP Significantly ↑

PaCO2 >34 mm Hg Blood gasses PaCO2 <30 mm Hg

Minimal RV dysfunctionECHO findings

MRI

Pericardial effusion, RV

dysfunction, RA

enlargement

RAP <10 mm Hg; Cl >2.5

L/min/m2 HemodynamicsRAP >20 mm Hg; Cl <2

L/min/m2

• The relative efficacy of prostacyclins vs ERAs vs

PDE-5 inhibitors is poorly described (no head-to-

head studies)

• Cost considerations have usually taken a back seat

in PAH treatment (already changing with generics)

• The optimal strategy for initial use is not clear, ie,

which drug(s) to use first, when and how to combine,

up-front therapy, etc.

• There is limited evidence for the use of PAH drugs in

patients with multifactorial causes of PH

PAH Drugs: Unresolved Issues

• Atrial septostomy

• Lung transplantation

• Exercise training

PAH Non-Medical Treatments:

Christie JD, et al. J Heart Lung Transplant. 2012;31(10):1073-86.

29th Adult Lung Transplant Report – 2012

Half-Life

Alpha-1 6.2 Years

CF 7.5 Years

COPD 5.3 Years

IPF 4.4 Years

PAH 5.0 Years

Sarcoidosis 5.3 Years

Alpha-1 (N=2,490)

CF (N=5,608)

PAH (N=1,308)

Sarcoidosis (N=849)

IPF (N=7,540)

COPD (N=11,948)

High

Initial

Mortality

Overall Survival

0

20

80

Su

rviv

al

(%)

100

0 2 4

40

10

60

Years

8 11 14

70

90

30

50

61 3 7 9 135 1210

Christie JD, et al. J Heart Lung Transplant. 2012;31(10):1073-86.

29th Adult Lung Transplant Report – 2012

0

20

80

Su

rviv

al

(%)

100

0 2 4

40

10

60

Years

8 11 14

70

90

30

50

6

Alpha-1 (N=1,860)

CF (N=4,217)

1 3 7 9 135 1210

PAH (N=831)

Sarcoidosis (N=573)

IPF (N=5,079)

COPD (N=8,969)

Half-Life

Alpha-1 8.6 Years

CF 10.4 Years

COPD 6.8 Years

IPF 6.8 Years

PAH 10.0 Years

Sarcoidosis 8.4 Years

All comparisons are

statistically significant

at 0.05 except

Alpha-1 vs Sarcoidosis,

CF vs PAH and

COPD vs IPF

“1-Year” Survivors

All made it

to 1 year f/u

PAH

Mereles D, et al. Circulation. 2006;114(14):1482-9.

PAH Rehab in Europe:Exercise and Respiratory Training on 6MW

-80

20

170

Ch

an

ge i

n 6

-Min

ute

Walk

ing

Dis

tan

ce (

m)

220

0 3 15

70

-30

120

Weeks

0 3 15

Secondary Training Group (N=10)Primary Training Group (N=15)

Control Group (N=15)

• Low level graded aerobic exercise, such as

walking, as tolerated is recommended

• Intensive exercise training in one study of 30 stable

patients on disease-targeted medical therapy

showed improvements in 6MW test, quality of life,

functional class, and peak oxygen consumption over

15 weeks

• Patients should avoid heavy physical exertion or

isometric exercise (straining against a fixed

resistance) as this may evoke exertional syncope

2009 ACCF/AHA PH GuidelinesGeneral Measures


• Exercise within symptom limits is recommended

• Mild breathlessness is acceptable but exertion that leads

to severe breathlessness, exertional dizziness, or chest

pain should be avoided

• But when physically deconditioned, patients may

undertake supervised exercise rehabilitation

• More data are required before appropriate

recommendations can be made regarding exercise

rehabilitation

ESC/ERS PH GuidelinesPhysical Activity and Supervised Rehabilitation

ESC/ERS/ISHLT, Galiè N, et al. Eur Respir J. 2009;34(6):1219-63.

PAH Treatment GoalsSummary

• Traditional surrogate endpoints used in PAH trials

have been informative for PAH drug development

and approval

• Short-term surrogate endpoints may be less

informative than longer-term, harder endpoints in

predicting outcome

• A therapeutic approach using a composite of clinical,

laboratory, and functional measures for monitoring

progress/worsening of PAH patients is recommended

Role of PCPs in Screening and Diagnosis of PAH Patients

Recognize possible PAH in the patient presenting with

unexplained dyspnea on exertion

Initiate appropriate screening evaluation

• Chest X-ray, PFT, ECG, VQ scan, oximetry

Facilitate appropriate referral to specialty center

• Contact a specialist in pulmonary hypertension

• Obtain appropriate referrals and approvals from the patient’s insurer

• Provide the patient’s records to the specialty center

PCPs = primary care providers.

Rubin LJ, Badesch DB. Ann Intern Med. 2005;143:282-292.

Unexplained dyspnea on exertion with evidence of PH on

echocardiography

Evidence of moderate to severe PAH

• Estimated pulmonary arterial systolic pressure 45 mm Hg on

echocardiogram

• Symptoms consistent with NYHA functional class II

• Near-syncope or syncope

Absence of substantial left-sided cardiac disease or parenchymal lung

disease

Clinical or echocardiographic evidence of right ventricular dysfunction

• Lower-extremity edema

• Ascites

• Right ventricular enlargement or systolic dysfunction on echocardiogram

Consider Referral to PH Specialty Center…

NYHA = New York Heart Association.


• High-risk patients

• Patients with NYHA/WHO class IV symptoms

• NYHA/WHO class III patients with worsening or not

responding to initial treatment

• Patients with concomitant/comorbid conditions that

complicate treatment

• Patients with pulmonary hypertension of unclear etiology

• Lack of clinical experience in providing initial or long-term

management of patients with pulmonary hypertension

Consider Referral to PH Specialty

Center…

Role of PCPs in the Co-Management of PAH Patients

Provide regular follow-up in the patient’s local community

• Assess volume status, vital signs, and oxygenation

• Monitor laboratory test results, including serum electrolyte levels, renal

function, and results of liver function tests

• Manage low-dose anticoagulation with warfarin, if indicated

• Maintain close communication with PH referral center

• Manage co-morbidities such as renal dysfunction, sleep issues,

endocrinopathies, and anemia

• Survey for catheter-related blood stream infections

Provide emergency care in the patient’s local community


• Timely referral and diagnosis of PAH is essential for optimal

outcomes

• Proper classification of PH is essential before considering

treatment; the management is dependent on the etiology

• >10 treatments for PAH targeting 3 molecular pathways are

available in oral, inhaled, and parenteral form

• The evidence base is limited for informing us on the optimal

treatment strategy of PAH; combining PAH drugs / knowing

what to use first is only recently better understood; how to

handle co-morbidities and the importance of modulating

pulmonary hemodynamics is still challenging

• PCPs play an important role in early identification, referral, and

co-management of PAH patients

Conclusions

Health & Medicine

Pulmonary Arterial Hypertension in Rural Communities: Early Diagnosis and Intervention to Improve Outcomes