Pulmonary Hypertension dr deepak yaduvanshi

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• PULMONARY HYPERTENSION

• Dr Deepak Yaduvanshi

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Learning objectives

• Background
• Pathogenesis overview
• Orphan disease child
• Review classification
• Diagnostic dilemma approach
• Evidence
• Treatment Modalities
• Way ahead

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Orphan Disease
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Pulmonary HypertensionDiagnosis
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PAH Why can it be difficult to diagnose?

• Typically non-specific symptoms
• Venous jugular distension
• Hepato-jugular reflux
• Hepatomegaly
• Hepatalgia
• Difficult to distinguish from other
  cardio-pulmonary disorders1
• Clinical examination often unremarkable1
• Because of the uncommon nature of the disorder,
  PAH may not be considered early amongst the
  differential diagnoses1

The diagnosis of PAH is often delayed for two or
more years2
1. N Engl J Med 1997 336 111-7 2. BMJ 2003
326 835-836
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PAH How is it diagnosed?

• Diagnosis four-stage approach

Eur Heart J 2004 25 2243-2278
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Chest X-ray
A normal Chest X-ray does NOT exclude PH

• Following features in chest X-ray may help to
  diagnose
• Central pulmonary artery dilation with transverse
  diameter of gt16 mm
• Pruning of peripheral pulmonary vessels
• Prominent pulmonary outflow tract
• Elevated cardiac apex due to right ventricular
  hypertrophy ( severe PH)
• Enlarged right atrium (severe PH)
• Hamptons hump area of infarct seen as a
  wedge-shaped opacity adjacent to the visceral
  pleural space with its apex directed towards
  hilum may be rare
• Enlarged heart due to left ventricular
  hypertrophy and dilatation with pulmonary venous
  hypertension (PVH) and pulmonary oedema
• Pleural effusion (severe PH with heart failure)
• Hyperinflation, lung fibrosis (in case of PH
  associated with lung disease)

1. Handler C., Coghlan G. Pulmonary Hypertension.
Oxford 2012 1 2. J. Am. Coll. Cardiol.
2009531573-1619
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Chest X-ray
Normal Right Heart
enlarged
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ECHO .RHC
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ECHO

• Echocardiography can prove to be the most useful
  non-invasive method for screening of pulmonary
  arterial hypertension (PAH)
• Arbitrary criteria for estimating the likely
  presence of pulmonary hypertension (PH) include
• Tricuspid regurgitation velocity gt 3.4 m/s,
• Doppler-calculated pulmonary arterial (PA)
  systolic pressure gt 50 mmHg,
• with/without additional echocardiographic
  variables suggestive of PH

• Additional echocardiographic variables
• Increased velocity of pulmonary regurgitation
• Short acceleration time of right ventricular (RV)
  ejection into the PA
• Increased dimension of the right heart chamber,
  abnormal shape and function of interventional
  septum, increased RV wall thickness and dilated
  main PA

1. Eur Respir J 2009 34 1219-1263 2. J Am Coll
Cardiol. 2009531573-1619
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Echocardiography

• Different parameters on echocardiography indicate
  the progression of the disease.
• Early-stage PAH
• RV size and function is normal elevated PAP
• Progressive PAH
• RV and RA enlargement
• RV ejection fraction may decrease
• Interventricular septal flattening
• RV volume overload
• Underfilled left heart chambers
• Late-stage PAH
• Severe RV dilatation and dysfunction

1. Eur Respir J 2009 34 1219-1263 2. J Am Coll
Cardiol. 2009531573-1619
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Old Classification of PH
Pulmonary Hypertension
PRIMARY No known cause
SECONDARY Due to some other cause
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New classification of PH (Venice 2003) WHO
clinical classification system

• Group I Pulmonary arterial hypertension
• Group II Pulmonary venous hypertension
• Group III PH associated with hypoxemia
• Group IV PH from chronic thrombotic disease,
  embolic disease or both
• Group V Miscellaneous

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Why does the pressure increase?

• Impaired production of
• vasodilator substances
• Nitric oxide
• Prostacylin

• Increased production of
• vasoconstrictor substances
• Endothelin
• Thromboxane A2

NO, PGI2 ET, TXA2
Vasoconstriction resistance
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Re modelling
Normal pulmonary artery
Remodelled artery in PAH
Intima(endothelial cells)
Media(smooth muscle cells)
Adventitia(fibroblasts)
ET receptors
Fibroblast
Smooth muscle cell
European Heart Journal 2008 29 1936-1948
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WHO Functional Class
WHO Symptomatic profile
Class I Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause dyspnoea or fatigue, chest pain or near syncope
Class II Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnoea or fatigue, chest pain or near syncope
Class III Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnoea or fatigue, chest pain or near syncope
Class IV Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnoea and/or fatigue may even be present at rest
Chest 200412614S-34S
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Treatment of Pulmonary Hypertension
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What is the Aim!
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Am Heart J 2011 162 201 - 13
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The Indian Scenario
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Clinical trials with Bosentan

• BREATHE 1 Class III and IV of PAH
• BREATHE 2 Combination with epoprostenol
• BREATHE 3 PK in children gt 10 kg
• BREATHE 4 HIV infection
• BREATHE 5 In Eisenmenger syndrome
  (Congenital heart disease)
• EARLY NYHA class II
• BUILD IPF
• RAPIDS I and II Digital ulcers
• COMPASS Combination with sildenafil
• FUTURE Pediatric

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Study 351 (Efficacy of bosentan in PAH)
100

50
0
-50
Baseline
Week 4
Week 8
Week 12
Week 20
Change in 6-min walking distance from baseline to
week 20
N32, t12wks, bosentan 62.5 bd X 4 wks 125bd X
4 wks
Lancet 2001 358 119-23
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Selective inhibition of ETA
Endothelin
Activation of ETB receptors mediates
Activation of ETA receptors
Mediates clearance of circulating ET1 from the
lungs
Vasoconstriction
Release of NO prostacyclin vasodilation
Fibrosis
Proliferation
Hypertrophy
Cell migration
ETA
ETB
Exhibits anti-proliferative properties
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BNP concentrations reduced
each Plt0.003
A statistically significant improvement in time
to clinical worsening was observed for patients
receiving Ambrisentan compared with placebo
(Plt0.001)
BNP Plasma Brain natriuretic peptide
Circulation 2008 117 3010-3019
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Hemodynamic parameters improved over 2 years
Post hoc analysis of 58 pts with moderate PAH
Am J Cardiovasc Drugs 2011 11 215-226 ACCP
2009 P107, San Diego
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Assessments and follow-up
Eur Heart J 2009 30 24932537
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Response to Therapy
J Am Coll Cardiol 201362D7381
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Combination therapy

• Existing PAH therapies act by 3 different
  mechanisms , yet potentially complementary
  mechanisms, using combination therapy may provide
  additive benefit by simultaneously addressing
  multiple disease pathways
• synergistic action
• ATHENA-1 A Randomized, Multicenter Study of
  Ambrisentan and Sildenafil Combination Therapy in
  Subjects With Pulmonary Arterial Hypertension Who
  Have Demonstrated a Suboptimal Response to
  Sildenafil
• COMPASS-1 Effects of Combination of Bosentan and
  Sildenafil vs Sildenafil Monotherapy on Morbidity
  and Mortality in Symptomatic Patients With
  Pulmonary Arterial Hypertension

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Combining Bosentan and Sildenafil is safe
effective in IPAH
6-MWD (m)
500
400
300
200
100
n 9
115mnths
Baseline 2
Baseline 1
3 Months
3 Months
6-12 Months
N9 NYHA III/IV Bosentan 62.524
wk1252 Sildenafil 253/254---4-12 wk503
Eur Respir J 2004 241007-1010
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Tadalafil reduced the incidence of clinical
worsening in patients already receiving Bosentan
The PHIRST trial N 405 (IPAH ? 60, CTD ?
25) 53 recd concomitant bosentan
Am J Respir Crit Care Med 1792009A3373
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Surgical
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Treatment Algorithm
Pulmonary arterial hypertension (WHO functional
class II, III, or IV)
Conventional therapy (oral anticoagulant
diuretics oxygen)
Acute vasodilator response
Yes
No
Oral calcium-channel blockers
Class II
Class IV
Class III
PDE5 Inhibitor or Prostacyclin analogue
Sustained Response
Intravenous prostacyclin or Endothelin-receptor
antagonist or Prostacyclin analogues or PDE5
Inhibitor
Endothelin-receptor antagonist or PDE5
Inhibitor or Prostacyclin analogues or Intravenous
prostacyclin
Yes
No
No improvement or deterioration
For III IV Combination therapy
Continue calcium-channel blockers
Atrial septostomy or Lung transplantation
Adapted from Humbert M et al. N Engl J Med.
20043511425-1436.
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Changing Paradigm.
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Questions