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

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

Thromboembolic
disease

Thromboembolic
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 Classification
of Pulmonary Hypertension (PH)

PH: Diagnostic Classification
1. 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, 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(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 to
NYHA 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
I
Pts without limitation of physical activity. Ordinary physical activity does
not cause undue dyspnoea or fatigue, chest pain, or near syncope.
II
Pts with slight limitation of physical activity. They are comfortable at rest.
Ordinary physical activity causes undue dyspnoea or fatigue, chest pain,
or near syncope.
III
Pts 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.
IV
Pts 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 Classification
1. 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, 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(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.
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

REFER!
Consider referral to card/pulm specialists
PH unlikely
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 PAH
Referral 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!
PH unlikely
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 tests
PVOD
PCH
Other
(group 57)
Idiopathic or Heritable
PAH
Family history; consider
genetic studies
(expert centers only)
CTD CHD
Drugs
Toxins
Porto-
Pulmonary
HIV
Schisto-
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 Coll
Physicians 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 PAH
WHO Group I PAH,
WHO Group 4 PH
Contraindications
Organic nitrates in
any form
Organic nitrates in any
form
Pregnancy 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 Analysis
Study 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 10 100
Favors
Controls
Favors
Treatments

• 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 Risk
ACCF/AHA Expert Consensus
Low Risk Determinants of Risk High Risk
No
Clinical evidence of RV
failure
Yes
Gradual Disease progression Rapid
II, III WHO functional class IV
Longer (>400 meters) 6-MWD Shorter (<300 meters)
Peak VO2 >10.4
mL/kg/min
Cardiopulmonary exercise
testing
Peak VO2 <10.4
mL/kg/min
Minimally ↑ and stable BNP/NT-proBNP Significantly ↑
PaCO2 >34 mm Hg Blood gasses PaCO2 <30 mm Hg
Minimal RV dysfunction
ECHO findings
MRI
Pericardial effusion, RV
dysfunction, RA
enlargement
RAP <10 mm Hg; Cl >2.5
L/min/m2 Hemodynamics
RAP >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
Survival(%)
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
Survival(%)
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
Changein6-MinuteWalking
Distance(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 Guidelines
General 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 Guidelines
Physical Activity and Supervised Rehabilitation
ESC/ERS/ISHLT, Galiè N, et al. Eur Respir J. 2009;34(6):1219-63.

PAH Treatment Goals
Summary
• 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

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

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