Concise PPT on PHTN management

1. Advances in management of pulmonary hypertension
Speaker – Dr. Rajeev sharma
Preceptor – Dr. Sandeep singh
Dr. S ramakrishnan

2. Points of Discussion
 Introduction
 Approach to patient
 Management of PAH
 Recent advances
 Summary

3. Pulmonary circulation
 Distensible, low pressure
 Normal PAP: 24/9 mmHg
 MPAP: 15 mmHg
 PVR: 50-150 dyn.s/cm5
 PCWP : <15 mm Hg
PAH is defined as MPAP > 25 mm Hg at rest

4. Natural History
 NIH registry of IPAH patients from 1981-1985 showed a
median survival of 2.8 years
 Recently report suggest 3-year survival < 60% despite current
therapy - need for more option
Circulation. 2010;122:156-163
Chest. 2004;126:78S–92S.

5. Classification
2.4 Congenital/acquired left heart
inflow/outflow tract obstruction and
congenital cardiomyopathies

6. Approach to patient

7. Diagnostic algorithm
Suspicion of PAH
History, clinical examination,
chest X- ray, electrocardiogram

8. Diagnostic algorithm
TTE (with bubble contrast)
PAH : diagnosis,
severity, clue to the
cause

9. Diagnostic algorithm
RHC - Confirmation of diagnosis
Vasodilator response

10. Diagnostic algorithm
V/Q Scan
Pulmonary angiography
Multi-detector CT
Coagulation profile
Chronic pulmonary
embolism

11. Diagnostic algorithm
Pulmonary function tests
Arterial blood gas analysis
Overnight polysomnography
Gas exchange
Ventilatory function

12. Diagnostic algorithm
CTD work up : ANA/RF/ANCA/ anti
DNA Topoisomerase antibody,
HIV ELISA
LFT,TFT ,serum ACE level
Scleroderma, SLE
HIV
PP Hypertension

13. Approach to treatment
1. General measures
2. Primary therapy
3. Supportive therapy
4. Advanced therapy

14. Treatment Considerations
 No Cure with drugs
Goals are
 To decrease PVR & Pressure
 Reduce symptoms
 Increase patient activity & longevity

15. General measures

16. Physical activity
 Encouraged to be active within symptom limits
 Study has shown the value of a training programme in
improving exercise performance
Mereles D et al Circulation 2006;114:1482–1489.

17. Pregnany & contraception
 30–50% mortality in patients with PAH
 Barrier contraceptive methods are safe but unpredictable effect
 Progesterone-only preparations are effective approaches to
contraception
 Bosentan may reduce the efficacy of OCP
 IUCD- vasovagal reaction - poorly tolerated

18. Primary therapy
Anticoagulation
Thromboendarterectomy
Oxygen therapy
Treat underlying
Heart disease
No effective therapy
Advanced therapy used
1
4
2
3

19. Supportive therapy

20. Oxygen
 Main therapy for Group 3 PAH
 Maintain SPo2 > 90 %
 NOTT trial compared continuous (19 hours/ day) to nocturnal
(12 hours/ day) oxygen administration
 Three-year mortality rate was lower with continuous oxygen
than nocturnal oxygen (22 versus 42 percent)
Ann Intern Med 1980 ;93;391

21. NOTT Trial

22. Diuretics
 Symptom benefit
 Decrease RV filling pressure & wall stress
 Arrhythmia risk & may decrease CO

23. Digoxin
 No long term studies
 Used in patients with Rt Heart failure & low CO state
 PAH with atrial arrhythmias

24. Anticoagulation
Rationale
 High prevalence of thrombotic lesions in IPAH
 Thrombin leads to disease progression
 Survival advantage with warfarin
Chest. 1997;112:714 –21
Circulation. 1984;70:580 –7.

25. Anticoagulation
COMPERA Registry
 Prospective registry
 To assess role of OAC in various forms of PAH
 1283 patients ( n=738 (58%) received OAC )
 800 patients are of IPAH ( including 34 patients with heritable
& drug-associated PAH )
 Target INR was 2-3
Circulation 2014

26. Anticoagulation
COMPERA registry
 Anticoagulation used in 66% of IPAH and in 43% of other
forms of PAH
 OAC in IPAH was associated with significantly better 3-year-
survival (p=0.006)
 The survival difference at 3 years remained statistically
significant(p=0.017)
 OAC not associated with a survival benefit in other forms of
PAH

27. Anticoagulation
Recommended in
 IPAH
 Heritable PAH
 Anorexigen associated PAH
 CTEPH

28. Advanced therapy
CCB Prostanoid
ERB PDE 5 I

29. CCB
 Oldest class of drugs
 Only in patients with definite vasoreactivity
 A retrospective analysis of 557 patients with IPAH showed that only
13% of patients had vasoreactivity, of these only 50% benefitted
from CCB
Circulation. 2005 Jun 14;111(23):3105-3111. Epub 2005 Jun 6.
Drug Starting Dose Usual Dose Maximum
Daily Dose
Amlodipine 2.5mg OD 20 mg OD 20-30 mg
Nifedipine 30 mg BD(SR) 120-240 mg per
day
240 mg
Diltiazem 60 mg TDS 240-720 mg per
day
920 mg

30. PDE-5 Inhibitor
Sildenafil
Tadalafil
Verdanafil
Vasodilation
Antiproliferative action
Headache,flushing,epistaxis
impaired colour vision

31. PDE-5 Inhibitor
PHIRST- Tadalafil
 RCT on 405 patients of PAH showed favorable effects on
hemodynamics & exercise capacity at largest doses(40 mg OD)
 Significantly improved 6 MWD at 16 week both in treatment
naïve and on baseline bosentan therapy group
Circulation 2009;119:2894–2903.

32. ERA
Drug Route Dose Advantage Disadvant
Bosentan oral
62.5-125
mg BD
•6MWT
•NYHA
•Heamod Elevation
OT/PT
Ambrisentan oral
5-10 mg
OD
-DO-
Sitaxentan Withdrawn due to fatal hepatic failure

33. Prostanoids
Drug Route Dose Advantage
Disadvanta
ge
Epoprostenol
IV
(infusion)
•25-40
ng/kg/min
•6 MWT
•NYHA
class
• Survival
•Long term
IV access
•Rebound
•Jaw pain
Iloprost Inhaled • 9-10
doses/day
-Do-
•Frequent
dosing

34. Riociguat
 Soluble GC stimulator
 Dual action
 In RCT( n-443 ) – PATENT 1 Trial - Riociguat significantly
improved exercise capacity (Both in naïve and baseline B or E)
 FDAApproved for Class II-IV
 Dose – 2.5 mg TDS

36. Riociguat

38. Vardenafil
 More potent PDE 5 Inhibitor
Evaluation study
RCT – 70 patient
Dose - 5 mg Bid for 12 week
Improved 6MWD , hemodyanamics
Improved clinical outcomes
Not Approved

39. Macitentan
 Sustained receptor binding and enhanced tissue penetration
 In RCT ( SERAPHIN)- 742 pt ( 1:1:1 - P : M3: M10 )
64 % on baseline PDE-5 I or prostanoid
Reduced morbidity and mortality
Well tolerated
 FDAApproved for Class II-IV with
 Dose – 10 mg

42. Oral Treprostinil
Freedom –M trial
 RCT - 349 patient (Treprostinil - 233 , placebo - 116) not on ERA or
PDE -5 I
 At 12 week 6MWD improved significantly (P=0.0125)
 Improves exercise capacity in patient not receiving other treatment
 Based on this trial oral Treprostinil was approved in dec 2013
Circulation 2013;127:624-633.

43. Selexipag
 Selective prostacyclin receptor agonist
 Chemically distinct from prostacyclin
 Oral
 Long acting - Twice daily dosing & less fluctua

44. Selexipag
GRIPHON trial
 RCT to assess safety and efficacy of selexipag
 N – 1156 ( placebo (n=582) or selexipag (n=574)
 Selexipag reduced risk of M/M event vs placebo (p<0.0001)by 40%
 Effect was observed irrespective of background treatment
 The most frequent adverse events were headache, diarrhea, nausea,
jaw pain
JACC 2015

45. Imatinib mesylate
 Rationale : PAH
Vasoconstriction + Remodeling
PDGF and c-KIT Proliferation of VSMC
Imatinib

46. Impres study
 24-week RCT ( n – 202 )
 PVR > 800 and on ≥ 2 drugs
 Primary outcome - change in 6MWD
 Dose – 200 - 400 mg / day

47. Impres study

48. Impres study
 Placebo-corrected effect on 6MWD - 32m (P=0.002)
 PVR decreased by 379 dynes·sec ( P<0.001)
 Functional class, TTCW and mortality did not differ
 Effect maintained in the extension study
 Adverse events and discontinuation more
 Subdural hematoma more ( 2+6 ) - imatinib and
anticoagulation

49. Impres study
 Study suggest imatinib improves exercise capacity and
hemodynamics in patients with
Advanced PAH who remain symptomatic on at least
2 drugs of the currently available 3 drug classes

50. Combination Therapy
 Use of more than 1 class of drugs
 Now recommended
 Multiple combinations effective and well tolerated
 Patient should be reassessed every 3–6 months and addition of
new therapy considered when goals have not met

51. Sequential Combination Therapy
Well studied
Class 1 A recommendation
 SERAPHIN
 PATENT
 GRIPHON
 PHIRST

52. COMPASS 1 COMPASS 2 COMPASS 3
Pt on B > 12 week
Single oral S dose of
25mg
Sig decrease in PVR &
MPAP
Pt on S for > 12 week
Placebo / B
No effect on mortality
Improved 6MWD
and NT-pro BNP
More LFT abnor ( B >P)
Naïve pt
B till 16 week / B 0r B +
S ( based on
achievement of 6 MWD
of 380 m at 16 week )
Showed that B+S result
in more achievement of
predefined 6MWD ( 31 %
at 28 week c/f B alone
16 % at 16 week )
Well tolerated
J Am Coll Cardiol. 2013 Chest. 2010J Clin Pharma 2009

53. Upfront Combination Therapy
 Commencing > 1 therapies in treatment naive patients
 Less data
 WHO functional class III/IV -- IIb-C

54. BREATHE-2 AMBITION
• 33 patient
• B + E / E + P in 2:1 manner
• Trend toward improvement but
no sig difference in Hemody or
clinical
• Less s/e of Epo in combination
group
• RCT – 500 patients
• 253 A+ T , 247 A or T
• Combination therapy superior
to monotherapy
• Less hospitalization
• improved 6 MWD
•
Eur Respir J 2004 Euro Resp J 2014

55. Triple Upfront Combination
• E + B + S in severe PAH ( class III/IV)
• A prospective analysis of 19 patients of idiopathic or heritable
PAH
• Significant improvements in haemodynamics, func class and
6MWD
• 3-year survival rate of 100%( Expected- 49% )
• Achievement of WHO functional class I or II in all
Eur Respir J 2014; 43: 1691–1697

56. Balloon atrial septostomy

57. Indications
 Patients with persistent RHF or recurrent syncope despite
medical therapy
 Bridge to transplant
 Palliation

58. Rationale
 Improved CO
 RV decompression
 Reduced sympathetic activity
 Improved o2 transport ( despite fall in spo2)
Most favorable results  patient with RAP 10-20mmHg

59. BAS
2.Mean RAP
3. Size of BAS
4.LA
pressur
e
5.LV
Functio
n

60. BAS
Graded dilatation
End-points
 LV EDP reaches 18mmHg
 SpO2 80% or 10% from baseline
 16mm dilatation is achieved

62. Stent fenestration technique
 Control degree of shunt & Maintain patency
 Free of thrombotic complications ( c/f Fenestrated ASO )
 Mounted on balloon catheter that is constricted by loop
 Full balloon inflation result in diabolo-shaped stent

63. Diabolo Fenestrated Stent Technique

64. Stent Across the Atrial Septum

65. ASO With Self-Made Fenestration

66. BAS
 BAS at early stage of disease (mean RAP of 9 ± 5 mm Hg and syncope
rather than overt RHF ) may offer a survival advantage
 Timing of BAS should be before
RAP ≥20 mm Hg
LV EDP >18 mm Hg
PVRI >55 U/m2
Baseline SPO2 <90%
Eur Respir J 2011;38:1343–8

67. Pott shunt
Rationale
 Decompression
 Blood is shunted into the dAo, which avoids exposing the
brain and myocardium to desaturated blood
 Reliable shunting than ASD

68. Pott shunt
 In a series of 8 children of IPAH
 NYHA IV with repeated syncope or signs RHF
 Six of 8 patients survived and remained well ( func class 1 /2 )
at a mean follow-up of 63 months
 Improved 6MWD & BNP levels
Ann Thorac Surg 2012;94:817–24

69. TPS
 Percutaneous Pott shunt in a series of 4 adults ( total 7
critically ill )
 Brockenbrough needle and the "stiff" end of a 0.014-inch wire
used to puncture the dAo and LPA.
 After balloon dilation, an iCAST 7 × 22-mm covered stent
 Two patient died
 Remaining 2 did well over 4 month follow up
J Heart Lung Transplant 2013;32:381–7

70. TPS

71. TPS
 In 3 patients with IPAH and severe PH having small PDA
 PDA allowed easy insertion of covered stent
 After a mean follow-up of 14 ± 9 months, all 3 patients
showed improved functional capacity and improved RV
function
 No major complications or deaths
Circ Cardiovasc Interv 2013

72. TPS
 The optimal timing – Not clear
 Should be reserved for patients in whom BAS or lung
transplantation is contraindicated

73. Balloon pulmonary angioplasty
 PEA in CTEPH is contraindicated in the presence of
Severe underlying lung disease
Lesions located in distally
 BPA improves pulmonary blood flow distribution and increases
pulmonary vascular capacitance, decreasing RV afterload

74. Balloon pulmonary angioplasty
 Feinstein et al. - BPA in 18 patients with CTEPH
 Gradually dilated using balloons - sized to be 75% to 100% of
vessel diameter
 Improved in NYHA class, 6MWD and mean PAP
 Repeat angiography demonstrated that all previously treated
vessels remained patent at 1 to 40 months after initial BPA
Circulation 2001;103:10–3.

75. Balloon pulmonary angioplasty
 Kataoka et al. BPA in 29 patients with CTEPH
 Significant improvements in hemodynamic parameters,
functional capacity and BNP levels at 6 months
Circ Cardiovasc Interv 2012;5:756–62

76. Balloon pulmonary angioplasty
 Mizoguchi et al. performed BPA in 68 inoperable CTEPH.
 All patients showed significant improvements in PAP, BNP
levels, and functional exercise capacity
 66 patients were alive at 2.2 ± 1.4 years
 Follow-up at 1 year confirmed improved angiographic
appearance of the pulmonary arteries
Circ Cardiovasc Interv 2012;5:748–55

77. Balloon pulmonary angioplasty

78. Balloon pulmonary angioplasty
 Reperfusion pulmonary injury can be a fatal complication
 Limit dilation to no more than 2 vessels per sitting
 IVUS & OCT to ensure that the maximal size is not >90% of
the original size of the vessel diameter
 In candidates found to be unsuitable for PEA, BPA can be
considered an alternative

79. Pulmonary artery denervation
Rationale
 Increased β1-adrenoreceptor RNA expression on pulmonary
blood vessels
 Increased sympathetic activity demonstrated by higher MSNA
 Post-BAS, MSNA levels decrease compared with controls
 Baroreceptors near bifurcation of the MPA and are involved in
facilitating a neural reflex

80. PADN-1 Study

81. PADN-1 Study
 Patient -21 ( 13 - PADN )
 PADN at bifurcation of MPA and at ostial RPA & LPA
 Significant improvement of
Mean PAP (p<0.01)
6 MWT ( p < 0.006)
Tei index (p < 0.001)

82. PADN

83. PADN

84. EPC
 BM derived
 Involved in endothelial homeostasis & angiogenesis
 Junhui et al. Found decreased EPCs in IPAH
 Act through paracrine mechanism

85. EPC

86. EPC
 RCT comparing effects of early EPC transplantation plus
conventional therapy with those of conventional therapy alone
in 31 patients with IPAH
 EPC significantly improved exercise tolerance and pulmonary
haemodynamics
J Am Coll Cardiol 2007; 49:1566–1571

87. EPC
 A pilot study showed that EPC transplantation was associated
with significant improvements in exercise capacity, NYHA
class and pulmonary haemodynamics in children with IPAH
Pediatr Transplant 2008; 12: 650–655

88.  Hemoptysis remains a major cause of morbidity in
patients of PAH ( sp. ES )
 AIIMS data – 41 patients of ES studied
 24 had no hemoptysis and 17 patients had hemoptysis
 Mean age of the patients was 23.7 ± 7.9 years with a range
from 13 – 50 years
Bronchial artery embolization

89. Bronchial artery embolization
 Highly successful in acute termination of hemoptysis
 Polyvinyl alcohol particles of 250–500 microns size
 Complications- rare and include
Non-target embolization
Subintimal dissection
Arterial perforation

90. Bronchial artery embolization
 In study of 21 patient BAE procedure was successful in 96%
patients
 14 in BAE therapy group and 7 in the conservative group
 28-day mortality was 14% in the BAE group and 28.5% in the
conservatively managed group (p= 0.57)
 Recurrence rate 43%
Int J Clin Pract Suppl. 2012

91. PAH mangement

92. PAH mangement

93. PAH mangement

94. Older
• Sildenafil
• Tadalafil
• Bosentan
• Ambrisentan
• Epoprostenol
Newer
• Riociguat
• Vardenafil
• Macitentan
• Oral
Treprostinil
• Selexipag
• Imatinib
Intervention
• BAS with
stenting
• BPA
• TPS
• PADN
• EPC
Combination therapy – sequential/ upfront

95. Thank you