A case based presentation on diagnosis and management of pulmonary hypertension

1. Pulmonary Hypertension
A case based presentation for general physicians
Sarfraz Saleemi MD
PH program of Excellence
King Faisal Specialist Hospital & Research Center
Riyadh, Saudi Arabia

2. A 30-year-old pediatric nurse who is non-smoker, married with one healthy child,
presents to the family health clinic with progressive shortness of breath on exertion for
two years. She has been diagnosed to have bronchial asthma in her local hospital for
which she takes inhaled steroids. She denies cough, chest pain, fever and weight loss.
There is no family history of heart and lung disease. Her only medication in addition to
inhaler steroid is oral contraceptives.
Her vital signs shows normal temperature, regular pulse, blood pressure 105/50 and
oxygen saturation 95% breathing room air. Her BMI is 23 .
Her clinical examination is unremarkable. Routine laboratory investigations including
CBC, renal and hepatic panels are within normal range.
You order a chest X-ray and pulmonary function test which are reported as normal.
You request a Ventilation/perfusion lung scan as you are worried she may have
pulmonary embolism. The V/Q scan is reported as negative.

3. How will you manage this patient?
A. Prescribe a course of oral steroids and add an inhaled beta-agonist
B. Order CT pulmonary angiogram as you are not satisfied with result
of V/Q scan.
C. Refer the patient to pulmonologist as you feel you have done all the
investigations with no clear diagnosis.
D. Prescribe anxiolytic medications as you feel her symptoms are
anxiety related.
E. Arrange an urgent transthoracic echocardiogram

4. When to suspect PH
Clinical &
Lab finding
suggestive
of PH
Raised
JVP
ECG
RBBB RVH
tall P wave
Exertional
dyspnea
Elevated
pro-BNP
Enlarged
PA on
X-ray
Para-sternal
heave
Reduced
DLCO

5. Symptoms (%)
Dyspnea 98
Fatigue 73
Chest pain 47
Near Syncope 41
Syncope 36
Leg Edema 37
Palpitations 33
SYMPTOMS OF PULMONARY HYPERTENSION
IJ Clin Pract Suppl. 2007 Sep;(156):5-14. Review.

6. Physical exam findings
• Loud pulmonary second heart sound
• Tricuspid regurgitant murmur
• Parasternal heave indicating right ventricular enlargement
• Jugular venous distension
• Peripheral edema
• Hepatomegaly
• Ascites – in advance right heart failure

7. ECG- abnormal in ~ 80% of patients at diagnosis
.

8. - abnormal in ~ 90% of patients at diagnosisChest X-ray

9. Chest CT - PA/Ao Diameter >1 to identify PH
Ao/PA
Ng CS et al. J Thorac Imaging.1999 Oct;14(4):270-8.
• Sensitivity 0.70
• Specificity 0.92

10. Badesch D et al. J Am Coll Cardiol. 2009;54:S55-S66.
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Hemodynamic Definition of PH/PAH
PH
PAH
Mean PAP ≥25 mmHg
PCWP/LVEDP ≤15 mmHg
PVR >3 Wood Units (>240 dynes)
Mean PAP ≥25 mm Hg

11. Pulmonary Circulations – Low pressure, Low resistance, High capacitance
Pulmonary
Circulation
Systemic
Circulation Arteries Arteries
Veins Veins
120/80, mean 93 25/8, mean 14
Right
Ventricle
25/2-5
Left
Ventricle
120/5-10
LungBody
SVR= 17.6 PVR= 1.8
High
capacitance
3.8 billion capillaries

12. Ibn al-Nafis
• Discovered Pulmonary circulation nearly 350
years before Sir William Harvey(1616) of
England
• Described the purification of blood in the
lungs where it was refined in contact with the
air inhaled from the outer atmosphere
Historical Perspective

13. PH is not one disease!
The spectrum of diseases with high pulmonary pressure

14. LV
LA
RA
RV
PT
Pre-capillary vs. Post-capillary pulmonary hypertension
(PAH) (PVH)
Pre-capillary PH
PCWP<15 mmHg
Post -capillary PH
PCWP >15 mmHg

15. PH
Venous
Group 2
Hypoxemic
Group 3
Miscellaneous
/unclear
mechanism
Group 5
Thrombo-
embolic
Group 4
Arterial
Group I
Classification of Pulmonary Hypertension
J Am Coll Cardiol. 2013 Dec 24

16. Epidemiology
 PAH - 10 to 52 cases per million (70–80% Females)
 Average age of PAH patients at diagnosis - 53 ± 14 years
 Idiopathic PAH - 1-2 cases per million
 HIV- infected patients - 0.5%
 Systemic sclerosis - 7-12%
 Sickle cell disease - 2-3.7.5%
 CTEPH -1-4% of patients following acute PE.
British Journal of General Practice, November 2012

17. REVEAL Registry – PAH (group 1)
2967 patients.
Adapted from Badesch DB et al. Chest. 2010;137:376-387.
Overall PAH Associated PH
Associated
(50.7%)
Idiopathic
(46.2%)
Heritable
(2.7%)
Pulmonary
veno-occlusive
(0.4%)
Connective tissue/
collagen vascular
(49.9%)
Congenital
heart disease
(19.5%)
HIV
(4.0%)
Other
(5.5%)
Portopulmonary (10.6%)

18. Vasoconstrictors
Vasodilators
Imbalance of vasoconstrictors and vasodilators
Endothelin-1
Thromboxane A2
Leukotrienes
Serotonin
Angiotensin II
Platelet activating factor
NO
PGI2
Vasodilators
Antiproliferatives
Anticoagulants
Vasoconstrictors
Proliferative
Procoagulants
Pathophysiology of PH
Normal PAH

19. Right Ventricular Changes in PH
Increased
pulmonary
arterial
pressure
RV pressure
overload
Myocardial
remodeling
with RV
hypertrophy
RV dilatation,
increased
wall stress
and
dysfunction
RV failure
and Cor
Pulmonale
Peña, Elena, et al. Radiographics 32.1 (2011): 9‐32.

20. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension
DIAGNOSIS

21. Echocardiographic probability of
pulmonary hypertension in symptomatic patients with
a suspicion of pulmonary hypertension

22. Back to the case ……
Echocardiogram was done and reported as:
Normal LVEF
Normal aortic and mitral valves
Normal Left atrium
Tricuspid valve – mild regurgitation
TRV 2.9 m/s Right atrium and right ventricle mildly dilated
RVSP = 55 mm Hg
No pericardial effusion
Bubble study did not show evidence of shunt

23. Back to the case ……
Echo – High probability for PH
What should we do next?
Left heart disease and intra-cardiac shunt ruled out
Lung disease unlikely – Chest X-ray and PFT – normal
What is the next step in the management?

24. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension
DIAGNOSIS

25. Natural History of PAH: NIH Registry
Predicted survival according to the NIH equation. Predicted survival rates were 69%, 56%, 46%, and 38% at 1, 2, 3,
and 4 years, respectively. The numbers of patients at risk were 231, 149, 82, and 10 at 1, 2, 3, and 4 years,
respectively. *Patients with primary pulmonary hypertension, now referred to as idiopathic pulmonary hypertension.
1. Rich et al. Ann Intern Med. 1987;107:216-223. 2. D’Alonzo et al. Ann Intern Med. 1991;115:343-349.
Predicted survival
69%
56%
46%
38%
Percentsurvival
Years
Median survival = 2.6 years

26. PAH is a Fatal Disease Comparable to Cancer
D’Alonzo et al; Ann Internal Med (1991), Kato et al; Cancer (2001), Soerjomataram et al; Breast Cancer Res.
Treatment (2008)
Advanced lung cancer
Survival (years)
WHO class IV PAH
Advanced colon cancer
Advanced breast cancer
Advanced prostate
cancer
WHO class III PAH
WHO class I-II PAH
Early breast cancer
2.6 years
4.9 years
6 months
0 1 2 3 4 5 6
>10years

27. Sitbon et al. Slides presented at European Respiratory Society; September 16-18, 2007; Stockholm, Sweden.
Survival With Modern Therapies

28. McLaughlin VV, et al. Circulation. 2002;106:1477-1482.
0
20
40
60
80
100
Survival(%)
0 12 24 36 48 60 72 84
No. at risk 162 33 95 70 48 30 20 10
Months
FC=3
FC=4
p=0.0001 by log-rank
test
847260483624120
100
80
60
40
20
0
FC=1
No. at risk:
FC=2
FC=3
FC=4
Survival(%)
Months
Impact of Functional Class on Survival
Functional Class
at Baseline
Functional Class
at 17 ± 15 months
102030466386112115

29. WHO functional class for PH patients
Class I: Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or
near syncope
Class II: Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity
causes undue dyspnea or
fatigue, chest pain, or near syncope
Class III: Marked limitation of physical activity. Comfortable at rest. Less than ordinary
physical activity causes symptoms
Class IV: Inability to carry out physical activity without symptoms. Manifest signs of right
heart failure. Symptoms may be present at rest.

30. 1%
24%
n=674
12%
(%) 63%
100
80
60
40
20
0 FC I FC II FC III FC IV
WHO FC
FC at the time of diagnosis of PAH
Humbert et al; Am J Respir Crit Care Med (2006)
French National Registry (2002-2003)

31. Pulmonary Circulation | January-March 2013 | Vol 3 | No 1
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A
Y
S
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D
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32. Pulmonary Circulation | January-March 2013 | Vol 3 | No 1
95%
5%
96%
5%
0%
0%

33. WHO SHOULD BE SCREENED
Annual screening recommended in patients with…
• Systemic sclerosis
• Family history of a heritable form of PAH
• Portal hypertension considered for organ transplant

34. Back to the case ……
Right heart catheterization result
• Mean PAP
PCWP
• PVR
• CO
• RAP
• Vaso-reactivity (using NO)
(A decrease in mean PAP >10 mmHg to ≤ 40 mmHg
Normal or ↑ Cardiac output)
66 mmHg
11 mmHg
15 WU
4.2/2.1
Negative
11 mmHg

35. Back to the case ……
What is the diagnosis?
Pulmonary arteria hypertension
What is the next step in managing this patient?

36. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension

37. Back to the case ……
CTD antibody profile normal
Liver US with Doppler – negative
HIV serology – Negative
Schistosoma antibodies – Negative
No significant drug history
No family history of pulmonary hypertension
Echo with bubble study has ruled out CHD

38. Back to the case ……
What is the final diagnosis?
Pulmonary arteria hypertension
What is the next step in managing this patient?

39. Treatment
Treatment
naive patient
PAH confirmed by
expert center
General measures
Supportive therapy
Acute vasoreactivity test
(I-PAH, H-PAH, D-PAH only)
Vasoreactive
CCB Therapy
Non-vasoreactive
(or not IPAH/HPAH/DPAH)
Low/int Risk High Risk
Oral
Monotherapy
Oral Combo
Therapy
Parenteral
Therapy
Inadequate response
Double/triple sequential therapy OR lung transplant
.
Galie N, ESC/ERS 2015 Guidelines

40. Risk Assessment
.
Galie N, ESC/ERS 2015 Guidelines
Estimated 1-year
mortality
Low Risk
(<5%)
Intermediate
(5-10%)
High Risk
(>10%)
Right heart failure No No Yes
Progression No Slow Rapid
Syncope No Occasional Repeated
WHO FC I or II III IV
6MWD >440 m 165–440 m <165
CPET VO2 max >15
Ve/VCO2 <36
VO2 max 11-15
Ve/VCO2 36-45
VO2 max <11
Ve/VCO2 >45
NT-pro BNP <50 50-300 >300
Hemodynamics RA <8 mmHg
CI >2.5
SvO2 >65%
RA 8-14 mmHg
CI 2.0-2.4
SvO2 60-65%
RA >14 mmHg
CI <2
SvO2 <60%

41. Back to the case ……
Intermediate
Right heart failure No
Progression Slow
Syncope No
WHO FC III
6MWD 350 m
NT-pro BNP 290
Hemodynamics RA 11 mmHg
CI 2.1

42. <1995 1995 2001 2002 2004 2005 2007 2009 2013 2015
CCB
Anticoagulation
Digitalis
Diuretics
IV Epoprostenol
Bosentan
SC Treprostenol
IV Treprostenol
Inhaled
Iloprost
Sildenafil
Ambrisartan
Tadalafil
Inhaled
Treprostinil
Macitentan
Riociguat
Pulmonary Hypertension Treatment Timeline
IV Sildenafil
Oral
Treprostinil
Selexipag
BREATHE
SUPER
ARIES
PHIRST
AIR
SERAPHIN
PATENT
CHEST
GRIPHON
FREEDOM

43. Route
Indication
(WHO)
Drawback Cost / year
Bosentan,
Ambrisentan
Macitentan
PO II-IV
Hepatotoxicity
(mainly with Bosentan)
$35,000
Sildenafil PO I-IV Headache $10,000
Iloprost INH III-IV Fluctuating levels $75,000
Treprostinil
SQ
IV
II-IV
Site pain
Catheter-related
$50,000-
150,000
Epoprostenol IV III-IV Catheter-related
$50,000-
100,000
SimplicityEfficacy

44. Back to the case ……
Patient was started on double vasodilator therapy including
Sildenafil 20 mg TID and Macitentan 10 mg daily
She was seen 3 months later ….
FC II (previous III)
6 MWD = 410 ( previous 350)
NT-pro BNP = 200 ( previous 290)
Clinical examination did not show evidence of right heart failure
No history of syncope during this period

45. Back to the case ……
What should we advise her at this stage?
Continue same medication.
Discontinue Macitentan and continue Sildenafil
Add inhaled prostacyclin to maximize the therapy
Patient profile has improved to low risk group – continue the same
treatment

46. Back to the case ……
Patient comes to family health for a routine follow up after her visit
to PH clinic.
What will you advise her?

47. Role of primary care physician in management of PH patient
 Advise on healthy lifestyle
 Sodium restriction
 Abstinence from smoking
 Avoid high altitude
 <4,000 feet above sea level
 Physical activity improve exercise capacity and quality of life
 Avoid heavy physical exertion in the setting syncopal symptoms
 Avoid pregnancy – advise contraceptive measures
Pregnancy is absolute contraindication – peripartum mortality upto 30%
 Update vaccination status – Influenza and Pneumococcal vaccine
 Check the oxygen status and provide oxygen if needed.
 Advise on compliance of PH patients – interruption of scheduled doses can have devastating
effect because of rebound increase in PAP

48. Treatment for non-PAH group pulmonary hypertension
 Group 2 (Left heart disease) – treat the under lying heart condition
 Group 3 ( Hypoxemic) – Oxygen therapy and treat underlying lung disease
 Group 4 ( Thromboembolic – CTEPH)) – Surgery – pulmonary endarterectomy
non-operable cases should receive vasodilator treatment
CTEPH is the only type of PH which is curable
Group 5 (Miscellaneous group) – no clear guidelines how to treat these patient. Assess
individual cases for treatment decisions.
Patients with no response to maximum medical treatment should be referred for lung
transplant

49. Conclusion
 PAH is a rare but fatal disease if not recognized and treated early.
 Think of pulmonary hypertension in any patient with unexplained dyspnea.
 Screen by Transthoracic Doppler Echocardiogram. Echo request should mention PH as
and indication.
 Patient with intermediate to high probability of PH on echocardiogram should be
referred to PH physician after doing initial screening for heart and lung conditions as a
possible cause for PH
 Definitive diagnosis of PAH is made by right heart catheterization.
 PAH treatment depends on risk profile and individual patient assessment.
 Calcium channel blockers is treatment of choice in vaso-reactive PH on cardiac cath.
 Pregnancy may cause significant challenges and is contraindicated
 Patient with PH need a comprehensive general health and life style evaluation and
advice.

50. Thank you
Saudi guidelines on the diagnosis and treatment of pulmonary hypertension: 2014 updates.
Ann Thorac Med 2014;9, Suppl S1:1-15