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

2. Activity Overview
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

3. Objectives
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

4. Case Report 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
What do you do?

5. Pulmonary Hypertension
mPAP ≥25 mmHg
Arterial
Pulmonary Hypertension (PAH)
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
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.

6. Types of Pulmonary Hypertension
Lung disease/hypoxia
Left-sided heart disease

7. Types of Pulmonary Hypertension
Lung disease/hypoxia
Thromboembolic
disease
Left-sided heart disease

8. Types of Pulmonary Hypertension
Lung disease/hypoxia
Thromboembolic
disease
Left-sided heart disease
IPAH and APAH
IPAH = idiopathic pulmonary artery hypertension; APAH = associated pulmonary artery hypertension.

9. 2013 Updated Clinical Classification of Pulmonary Hypertension (PH)
5th World Symposium on Pulmonary Hypertension
Nice, France February 27-March 1, 2013

10. PH: Diagnostic Classification
1. Pulmonary arterial hypertension (PAH) 1.1. Idiopathic PAH (IPAH) 1.2. Heritable BMPR ALK1, ENG, SMAD9, CAV1, KCNK Unknown 1.3. Drug- and toxin-induced 1.4. Associated with Connective tissue diseases (CTD) HIV infection Portal hypertension Congenital heart diseases 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
NO APPROVED THERAPY
NO APPROVED THERAPY
NO APPROVED THERAPY
Simonneau G, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D34-41.

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

12. Risk Factors for PAH 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
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): Humbert M, Souza R, Simonneau G (eds): Pulmonary Vascular Disorders. Prog Respir Res. Basel, Karger, 2012, vol 41, pp Simonneau G, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D34-41.

13. 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
*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.

14. WHO Functional Classification of PAH
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.
RHF = right heart failure.
Galiè N, et al. Eur Heart J. 2009;30(20):

15. PH: Diagnostic Classification
1. Pulmonary arterial hypertension (PAH) 1.1. Idiopathic PAH (IPAH) 1.2. Heritable BMPR ALK1, ENG, SMAD9, CAV1, KCNK Unknown 1.3. Drug- and toxin-induced 1.4. Associated with Connective tissue diseases (CTD) HIV infection Portal hypertension Congenital heart diseases 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
NO APPROVED THERAPY
Largest group of associated
PAH conditions
NO APPROVED THERAPY
NO APPROVED THERAPY
Simonneau G, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D34-41.

16. 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

17. PAH Vascular Remodeling
‘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
ATP = adenosine triphosphate; RV = right ventricle.
Courtesy of Oudiz RJ.

18. Pathogenesis of PAH Normal Reversible Disease Irreversible Disease
1. Risk Factors and
Associated Conditions
Collagen Vascular Disease
Congenital Heart Disease
Portal Hypertension
HIV Infection
Drugs and Toxins
Pregnancy
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
Susceptibility
Abnormal BMPR2 Gene
Other Genetic Factors
Normal Reversible Disease Irreversible Disease
HIV = human immunodeficency virus; BMPR2 = bone morphogenetic protein receptor II gene.
Gaine S. JAMA. 2000;284(24):

19. PAH Progression 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)
Consequences of PAH
↑ PVR
↑ RV afterload
↓ RV ejection (CO) & ↓ PBF
RV hypertrophy & dilation
Death
CO = cardiac output; LV = left ventricle; PBF = pulmonary blood flow.
Courtesy of Oudiz RJ.

20. Is There a Reason to Suspect PAH?
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.
McGoon M, et al. Chest. 2004;126:14S-34S.

21. Is There a Reason to Suspect PAH?
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”
CXR = chest x ray; ECG = electrocardiogram; BMPR-II = bone morphogenetic protein receptor type II.
McGoon M, et al. Chest. 2004;126:14S-34S.

22. Is There a Reason to Suspect PAH?
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
McGoon M, et al. Chest. 2004;126:14S-34S.

23. Key Finding in PAH: Right Ventricular DysfunctionRV LV RV LV
A Normal
B IPAH
Bogaard HJ, et al. Chest. 2009;135:

24. Increased Index of Suspicion is a Must
How Is PAH Diagnosed?
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
McGoon M, et al. Chest. 2004;126:14S-34S.

25. NICE PAH Diagnostic Algorithm
Symptoms, signs, history suggestive of PAH
Echocardiography compatible with PH?
YES NO
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?
YES
YES
No signs of severe PH/RV dysfunction
Signs of severe PH/RV dysfunction NO
Treat underlying disease
V/Q scintigraphy Unmatched perfusion defects?
Refer to PH expert center
DLco = diffusing capacity for carbon monoxide.
Hoeper MM, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D42-50.

26. Echocardiography in Evaluation of PH
Dilated, hypofunctional RV
Small,
flattened LV
Courtesy of Oudiz RJ.

27. Echocardiography: Points to Remember
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
LHD = left-sided heart disease; CHD = coronary heart disease.

28. NICE PAH Diagnostic Algorithm
Echocardiography compatible with PH?
Consider referral to card/pulm specialists
YES NO
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,
Polysomnogram
Consider other causes or recheck
Diagnosis or heart disease or lung disease confirmed?
YES
YES
No signs of severe PH/RV dysfunction
Signs of severe PH/RV dysfunction NO
Treat underlying disease
V/Q scintigraphy Unmatched perfusion defects?
Refer to PH expert center
REFER!
DLco = diffusing capacity for carbon monoxide.
Hoeper MM, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D42-50.

29. The Multicenter RePHerral Study: Referral of Patients with PH Diagnoses to Tertiary PH Centers
Post Referral Diagnosis
Group 1
Group 2
Group 3
No PH
Unk.
Pre-
Referral Diagnosis
41 (73%)
3 (5%)
4 (7%)
7 (12%)
1 (18%)
8 (61%)
1 (8%)
4 (31%)
4 (17%)
13 (56%)
2 (9%)
12 (29%)
13 (31%)
1 (2%)
14 (33%)
2 (5%)
Incorrect Pre-Referral Diagnosis
Correct Pre-Referral Diagnosis
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.
Deano RC, et al. JAMA Intern Med. 2013;173(10):

30. RePHerral Study: Findings
“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.”
Deano RC, et al. JAMA Intern Med. 2013;173(10):

31. Updated Treatment Algorithm of PAH Referral Centers
“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
Galiè N, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D60-72.

32. Select Criteria for Accredited PH Care Centers
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.
Accessed Oct. 10, 2014.

33. NICE PAH Diagnostic Algorithm
Echocardiography compatible with PH?
YES NO
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?
YES
YES
No signs of severe PH/RV dysfunction
Signs of severe PH/RV dysfunction NO
Treat underlying disease
V/Q scintigraphy Unmatched perfusion defects?
Refer to PH expert center
REFER!
DLco = diffusing capacity for carbon monoxide.
Hoeper MM, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D42-50.

34. NICE PAH Diagnostic Algorithm
V/Q scintigraphy Unmatched perfusion defects?
YES NO
CTEPH likely CT angiography, RHC plus PA (PEA expert center)
RHC PAPm ≥25 mmHg, PAWP ≤15 mmHg, PVR >3 WU
YES NO
PAH likely
Specific diagnostic tests
Consider other causes
CTD
CHD
Drugs Toxins
Porto- Pulmonary
Group 1 PAH
HIV
Schisto-somiasis
PVOD
PCH
Other (group 57)
Family history; consider genetic studies (expert centers only)
Idiopathic or Heritable PAH
Hoeper MM, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D42-50.

35. 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):  

36. 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 ;53(17):

37. Cardiac Catheterization
The Gold-Standard for PAH Diagnosis
McLaughlin VV, et al. J Am Coll Cardiol ;53(17):

38. Key Measurements of RHC
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 l/min/m2)
RHC = right heart catheterization.
McLaughlin VV, et al. J Am Coll Cardiol ;53(17):

39. PH Clinical Follow-up: Routine Measures
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
In the day-to-day clinical management of patients with PAH, a variety of clinical assessments are recommended. Patients initiating or changing therapy should be more carefully monitored because of the risk of treatment ineffectiveness and the need to rapidly move to alternatives.
Reference:
Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30:
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:

40. Diagnostic Algorithm for PH Key Points
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).
Humbert M, et al. Eur Respir Rev Off J Eur Respir Soc. 2012;21(126):306–312. Holliman K. Amercian Coll Physicians ACP Internist

41. Treatment Goals in PAH
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.”
McLaughlin VV, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D73-81.

42. PAH Treatment: General Measures and Supportive Therapy
Diuretics
Oxygen
Warfarin*
Exercise training
*Idiopathic pulmonary artery hypertension only.

43. PAH Treatment: Acute Vasoreactivity Testing
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
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
CCB = calcium channel blocker; CO = cardiac output; RAP = right atrial pressure.
McLaughlin VV, et al. J Am Coll Cardiol ;53(17): Galiè N, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D ESC/ERS/ISHLT, Galiè N, et al. Eur Respir J. 2009;34(6):

44. 3 Key Signaling Pathways in PAH
Endothelin pathway
Prostacyclin pathway
Nitric oxide pathway
Humbert M, et al. N Engl J Med. 2004;351:

45. The Evolution of PAH Therapies
Epoprostenol approved for APAH
SQ treprostinil and oral bosentan
for IPAH & APAH
Oral ambrisentan
Oral treprostinil
IV treprostinil &
inhaled iloprost
Oral tadalafil and
inhaled treprostinil
Oral sildenafil
Oral riociguat and
macitentan
2000
2002
2004
2006
2008
2010
2012
2014
Approval Date
FDA-Approved Therapies
IPAH = idiopathic pulmonary artery hypertension; APAH = associated pulmonary artery hypertension.
Accessed October 22, 2014.

46. PAH Specific Agents: Prostacyclin Analogues
Epoprostenol
Iloprost
Treprostinil
Route IV
Inhalation
IV, SQ, inhalation, PO
Indication
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
HA = headache; D = diarrhea; N = nausea; V = vomiting; ER = extended release; PE = pulmonary embolism; Sx = symptoms. AC = anticoagulant. Accessed December 21, Accessed December 21, 1014.

47. PAH Specific Agents: Endothelin Antagonists
Bosentan
Ambrisentan
Macitentan
Route PO
Indication
WHO Group I PAH
Contraindications
Pregnancy Category X
Pregnancy Category X, WHO Group 3 PH, IPF
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
IPF = idopathic pulmonary fibrosis; ALT = alanine transaminase; AST = aspartate transaminase; Hgb = hemoglobin.
Accessed December 21, Accessed December 21, 1014.

48. PAH Specific Agents: PDE-5 Inhibitors and sGC Stimulators
Sildenafil
Tadalafil
Riociguat
Route PO
Indication
WHO Group I PAH
WHO Group I PAH, WHO Group 4 PH
Contraindications
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
PDE-5 = phosphodiesterase type 5; sGC = soluble guanylate cyclase; NO = nitric oxide. Accessed December 21, Accessed December 21, 1014.

49. 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: Khaybullina D, et al. P T. 2014;39(11):

50. 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
0.24 (0.02, 2.60)
4.08
0.47 (0.04, 5.01)
4.12
Sastry et al
0.39 (0.02, 8.73)
2.42
1.54 (0.06, 37.19)
2.29
1.01 (0.11, 9.55)
4.60
0.41 (0.11, 1.49)
13.77
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
McLaughlin et al
Hooper et al
Overall
0.57 (0.35, 0.93)
100.00
Favors Treatments
Favors Controls
0.01
0.1 10
100
Galiè N, et al. Eur Heart J. 2009;30:

51. Treatment Approach to PAH
Treatment choice may be based on:
Disease severity
Patient preference
Patient feasibility
Clinical trial availability
PAH type?

52. 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
6-MWD = 6 minute walk distance; PaCO2 = partial pressure of carbon dioxide.
McLaughlin VV, et al. J Am Coll Cardiol. 2009;53:

53. PAH Drugs: Unresolved Issues
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

54. PAH Non-Medical Treatments:
Atrial septostomy
Lung transplantation
Exercise training

55. 29th Adult Lung Transplant Report – 2012
Overall Survival
100
Half-Life
Alpha-1
6.2 Years CF
7.5 Years
COPD
5.3 Years
IPF
4.4 Years
PAH
5.0 Years
Sarcoidosis 90 80 70 60
High Initial Mortality
Survival (%) 50 40
Alpha-1 (N=2,490)
CF (N=5,608) 30
COPD (N=11,948) 20
IPF (N=7,540)
PAH (N=1,308) 10
Sarcoidosis (N=849) 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Years
Christie JD, et al. J Heart Lung Transplant. 2012;31(10):

56. 29th Adult Lung Transplant Report – 2012
“1-Year” Survivors
100
Half-Life
Alpha-1
8.6 Years CF
10.4 Years
COPD
6.8 Years
IPF
PAH
10.0 Years
Sarcoidosis
8.4 Years 90 80
All made it to 1 year f/u 70 60
PAH
Survival (%) 50
All comparisons are statistically significant at 0.05 except Alpha-1 vs Sarcoidosis, CF vs PAH and COPD vs IPF 40
Alpha-1 (N=1,860)
CF (N=4,217) 30
COPD (N=8,969) 20
IPF (N=5,079)
PAH (N=831) 10
Sarcoidosis (N=573) 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Years
Christie JD, et al. J Heart Lung Transplant. 2012;31(10):

57. PAH Rehab in Europe: Exercise and Respiratory Training on 6MW
Secondary Training Group (N=10)
Primary Training Group (N=15)
Control Group (N=15)
220
170
120
Change in 6-Minute Walking Distance (m) 70 20
-30
-80 3 15 3 15
Weeks
Mereles D, et al. Circulation. 2006;114(14):

58. 2009 ACCF/AHA PH Guidelines General Measures
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
McLaughlin VV, et al. J Am Coll Cardiol. 2009;53(17):

59. ESC/ERS PH Guidelines Physical Activity and Supervised Rehabilitation
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/ISHLT, Galiè N, et al. Eur Respir J. 2009;34(6):

60. 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

61. 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:

62. Consider Referral to PH Specialty Center…
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
NYHA = New York Heart Association.
Rubin LJ, Badesch DB. Ann Intern Med. 2005;143:

63. Consider Referral to PH Specialty Center…
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

64. 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
Rubin LJ, Badesch DB. Ann Intern Med. 2005;143:

65. Conclusions
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