1. EVALUATION & MANAGEMENT OF PULMONARY ARTERIAL HYPERTENSION
Dr Sandeep Mohanan
Senior Resident
Department of Cardiology, CGMC

2. OUTLINE EVALUATION MANAGEMENT Clinical diagnosis of PAH
Diagnostic work up : 1) Initial , 2) Elaborate
Prognostic work up
Strategic work up - AVT
MANAGEMENT
Current pharmacological armamentarium - AT
Surgical measures
Follow up
AT for specific aetiologies of PAH

3. INTRODUCTION Prevalence of PAH ~ 15/million - IPAH ~ 6/ million
Important to classify PH by etiological causes
– the natural history, prognosis & management varies widely.
Non-PAH PH vs PAH

4. Case scenario.... PAH A 36 year old female
No significant past medical history
c/o progressive DOE from NYHA I to II over previous 6 months.
Tiredness, fatigue
O/E : Tachypnoeic, Tachycardia,
, Mild pedal edema, Loud P2, Pulmonary ESM, Pulmonary phasic EC
BA, Pneumonia, ILD, RHD, CHD, Anaemia, Thyroid disorders, HTN, CAD, Psychogenic.....PAH
PAH

5. Delay in diagnosis of IPAH
32 patients with IPAH were studied from 4 tertiary centres in Australia
>85 % patients are diagnosed when they reach WHO III / IV symptoms
Strange G et al. Time from symptoms to definitive diagnosis of idiopathic pulmonary arterial hypertension: The DELAY study. Pulm Circ 2013;3:89-94.

6. Natural history of PAH
Median survival for PAH is 2 to 3 years (NIH registry (1984) ) –PPH(IPAH)
However, the more recent REVEAL registry shows improved survival
McLaughlin VV et al. Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:78S–92S
M.D. McGoon* and D.P. Miller.REVEAL: a contemporary US pulmonary arterial hypertension registry Eur Respir Rev 2012; 21: 123, 8–18.

7. ESTABLISHING THE CLINICAL DIAGNOSIS
History:
- Dyspnoea (>90%), angina, syncope
Underlying cardiac/lung disease/sleep (snoring)/systemic disorders
History s/o PVH
Haemoptysis
c.f/s/o RVF
Family history

8. Physical Examination:
Cyanosis: Usually late in the natural history for non-respiratory causes.
Clubbing – suggests Eisenmengers / Respiratory causes
Respiratory system examination
BMI, Neck height/width, Thyroid examination

10. INITIAL DIAGNOSTIC WORK UP
ECG
CXray
2D Doppler Echo +/- contrast
PFT
CT chest
Lung perfusion scan
CPET/ 6MWT/TMT – To assess baseline functional status & CP-metabolic function before initiating treatment.
Establishing the diagnosis
of PAH
Grading the severity
Assessing RV function
Ruling out left heart/structural
cardiac causes
Ruling out respiratory causes
Detect additional respiratory
pathology
Ruling out CTEPH

11. ECG:
CXR:

12. ECHOCARDIOGRAPHY IN PAH
Diagnosis of PAH: RVH, RAE, hypertensive TR, PA size, M mode findings
Alternate causes: Structural acquired/congenital heart disease
Additional information: LV systolic and diastolic function
Severity of PAH: Doppler assessment of PR, TR and PAH
Prognosis: RA, RV structural and functional abnormalities

13. Specific diagnostic capability of Echo in PAH
(Contrast echo may be required)

14. Assessment of PAH PASP = 4 V2(TR gradient) + RAP
TR in 80% of patients with PASP > 35 mmHg
~ 96% of those > 50 mmHg1.
Variable correlation between TTE and RHC measurements of PASP depending co-morbidities-- ranging from in patients with cardiac disease to 0.69 in patients with advanced lung disease2
TR may not always be analyzable ( ~20% -- contrast echo may help)
Only ~ 50 % of PAH due to respiratory disease are gradable
Erroneous estimations also result from poor RAP assumptions
1. Quantitative assessment of pulmonary hypertension in patients with tricuspid regurgitation using continuous wave Doppler ultrasound. J Am Coll Cardiol. 1985 Aug;6(2):
2. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung Disease. Am J Respir Crit Care Med. 2003 Mar 1;167(5):

15. RAP estimation
IVC diameters at end-expiration and during “sniff” manoeuvre
However recent data suggest a change in these estimations1.
- RAP cut off of 10 mmHg ~ 20 mm IVC size
- Optimal collapsibility index = 40 %
- Inaccurate to classify RAP into 5mmHg fractions
1. Brennan JM. Reappraisal of the use of inferior vena cava for estimating right atrial pressure. J Am Soc Echocardiogr Jul;20(7):

16. mPAP = 4 V2 (peak PR gradient) + RAP
Mild PAH -- (PASP >35 mmHg)
(3rd World Symposium on PAH, Venice)
Age >50 yrs, obesity, athletes and males may have mild PAH without actual disease ---PAH diagnosis must be complimented by clinical scenario and RV function assessment.
Recent studies have pointed out a good correlation between Echo-PASP and mean PAP by RHC1,2 :
mPAP(Syyed formula) = 0.65 PASP mmHg
mPAP (Chemla formula)= 0.61 PASP +2 mmHg
mPAP = 4 V2 (peak PR gradient) + RAP
PADP = 4 V2 (end-diastolic pressure) + RAP
Syyed R et al. The relationship between the components of pulmonary artery pressure remains constant under all conditions in both health and disease. Chest. 2008;133:
2. Steckelberg. Derivation of mean pulmonary artery pressure from noninvasive parameters. J Am Soc Echocardiogr.2013 May;26(5):464-8.

17. ESC 2009 recommendations on diagnosis of PH based on TRV & PASP
Mild PAH is not
reliably assessed
by Echo parameters

18. RV outflow acceleration time
Normally >110ms
- Supposed to be even more accurate than TR velocity gradient for the assessment of PH
IVRT
N<75ms
IVRT increases with PAH

19. RV assessment RV - MORPHOLOGICAL ASSESSMENT:
LVs index (LV eccentricity index D2/D1)
LVd index – correlates with clinical profile
Provides information of the degree of pressure and volume overload
Correlates with clinical improvement after advanced treatment
3) RA area index - higher values had worse prognosis
4) Pericardial effusion – most strong indicator of mortality
(directly correlates with RAP and inversely with cardiac index)
5) RV-LV interdependency :
D shaped septum and rarely paradoxical septal motion
Altered LV shape in end-systole and early diastole – Abnormal LV diastolic function parameters
6) RVH : RV free wall > 5mm
Normal LA are < 20 cm2 , Raarea = /- 2cm sq
RA area index = RA area/ height in m
1.Hinderliter AL, et al. Frequency and prognostic significance of pericardial effusion in primary pulmonary hypertension. Am J Cardiol 1999; 84:
2. Raymond RJ, et al. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol. 2002;39:

20. RV – FUNCTIONAL ASSESSMENT
- Loss of peristaltic movements from sinus to infundibulum in the presence of high afterload and RV dilation1 – Decreased RV output
RVEF : not practical/ reliable by 2D TTE
RV fractional area change– poor clinical utility
TAPSE : Based on the principle of preferentially longitudinal shortening effecting RV SV ejection
Correlates with RVEF (by radionuclide angiography) and mPAP2
< 20mm considered abnormal
TAPSE </= 14mm ~ severe RV dysfunction3
However doubts on reliability exist, in the presence of severe TR
(J Am Soc Echocardiogr. 2006;19: )
Mebazaa A,.Acute right ventricular failure- from pathophysiology to new treatments. Intensive Care Med. 2004;30:
Ueti Om et al. Assessment of right ventricular function with Doppler echocardiographic indices derived from tricuspid annular motion: comparison with radionuclide angiography. Heart 2002; 88: 244-8
Ghio S, et al. Prognostic usefulnes of the tricuspid annular plane systolic excursion in patients with congestive heart failure secondary to idiopathic or ischemic dilated cardiomyopathy. Am J Cardiol 2000; 85:837-42

21. Tricuspid annular peak systolic velocity (TASV) :
- >12 cm/s considered normal
TASV < 11.5cm/s correlates with RVEF <45%1
Doppler RV index (Tei index/MPI) :
= IVCT+ IVRT /ET ( Normally < 0.28)
- With chronic PAH, RV P-V relationships resembles the LV with an increase in IVCT and IVRT and a decrease in ETs
- Strong predictor of outcome in PAH
1. Meluzin J, Spinarova L, Bakala J, et al. Pulsed Doppler tissue imaging of the velocity of tricuspid annular systolic motion.
A new, rapid, non-invasive method of evaluating rightventricular systolic function. Eur Heart J 2001; 22:

22. Important Echo measures in PAH
Echocardiographic assesment of PAH. European Respiratory Review 2012.

23. Algorithm for PH evaluation by echocardiography
ACC/AHA 2009
consensus on PAH

24. PULMONARY FUNCTION TEST
– to r/o restrictive/ obstructive airway diseases
- DLco may be decreased to 40-80% in PAH

25. CT CHEST – HRCT +/- CECT PAH assessment Respiratory causes (ILD, COPD)
CTEPH : Especially,
for those whose lung
perfusion scans cannot
be reliably interpreted

26. PVOD : Characteristic changes of interstitial oedema with diffuse central ground-glass opacification and thickening of interlobular septa; additional findings may include lymphadenopathy and pleural effusion.
PCH : suggested by diffuse bilateral thickening of the interlobular septa and the presence of small, centrilobular, poorly circumscribed nodular opacities; and sometimes angiomatous lesions

27. LUNG PERFUSION SCAN -- Tc99m MAA
Sensitivity and Specificity approaches 100% .

28. FUNCTIONAL WORK UP Median survival: WHO I : 6 years WHO II : 6 yrs
WHO III : 2.5 yrs
WHO IV : 6months

29. 6 MINUTE WALK TEST Most important baseline functional assessment.
Prognostification as well as patient follow up
< 200m -- worse prognosis and mortality
HR chronotopic responses are to be assessed.
Advance therapy trials for PAH show improvements varying from 30 to 50m correlating with a clinically significant benefit.

30. CARDIO-PULMONARY EXERCISE TESTING
Simultaneous measurement of respiratory gas exchange parameters along with upright bicycle ergometry stress testing
VO2 , PkVO2, Anaerobic threshold, Ve/VCO2, SpO2
Valuable predictor of prognosis and improvement with Rx
PkVO2>10.4ml/kg/min – better 1 yr survival
However methodological inconsistencies in various centres make it unattractive for clinical trials.
TMT using Naughton-Balke protocol also compares well with 6MWT and CPET in assessing the functional capacity.
Wensel R, Opitz CF, Anker SD, et al. Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonaryexercise testing. Circulation. 2002;106:319 –24

31. ADVANCED DIAGNOSTIC WORK UP
Elaborate diagnostic work up
Cardiac MRI
Cardiac catheterization

32. Elaborate diagnostic work up
CBC, Sickling test, LDH
ABG
CTD work up – ANA, ds DNA Scl70, anti-centromere Abs, U3RNP, RA
LFT, USG abdomen
HIV, HBsAg, HCV
BNP
S. Uric acid
Thrombophilia work up
TFT
Overnight oximetry --- Polysomnography
BMPR2 mutation

33. cMRI Pulmonary artery stiffness : Assess RV morphology and function
RV systolic & diastolic dysfunction--- poor prognostic indicator
- RV SV </= 25ml/m2
- RV-EDV >/= 84ml/m2
- LV-EDV</= 40ml/m2 ,predictors of mortality and Rx failure1
- RV:LV mass index > 0.6 – PH
- Delayed contrast enhancement – function of PH severity3
Pulmonary artery stiffness :
Relative cross-sectional area change <16% -- Inc mortality in PAH patients2
Compliments evaluation for sarcoidosis etc
1 . van Wolferen SA, et al. Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension. Eur Heart J. 2007;28:1250–7 .
2. Gan CT et al. Noninvasively assessed pulmonary artery stiffness predicts mortality in pulmonary arterial hypertension. Chest. 2007;132:1906 –12.
3. Shehata M et al. Myocardial delayedenhancement in pulmonary hypertension: pulmonary hemodynamics, right ventricular function, and remodeling. AJR Am J Roentgenol.2011;196:87-94

34. RIGHT HEART CATHETERIZATION
Not routinely recommended.
However ACC 2009 advises RHC to confirm diagnosis and define accurate hemodynamic profile in PAH patients– gold standard
IC recommendation by ECS 2009 for all PAH patients
Important for vasodilator testing and also suggested before CHD correction
Complications – 1.1% , Mortality – 0.05%
mPAP, mRAP and CI significantly correlate with survival
D’Alonzo GE et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115:343-9

35. RHC- procedure pearls and pitalls
Staff experience, sedation, procedure related complications, temporal variations in hemodynamics.
Measurements must be at end-expiration
Limiting factors : Accuracy and errors in PCWP, method of COP estimation, complex structural heart disease

36. BASIC DATA FROM A RHC

37. Basic calculations from a RHC in PAH
mPAP = PAPdiastolic+ (PAPsystolic- PAPdiastolic) / 3
COFICK = Oxygen consumption(ml/min)/ (CaO2 –CvO2)
(Ca O2 = 1.36 * Hb * 10 * Sa O2 )
PVR = 80 * (mPAP – PCWP) / CO dyne.sec.cm-5
SVR = 80 * (mBP-RAP) / CO dyne.sec.cm-5 (TPR = mBP/CO)
PVRI = PVR * BSA

38. STRATEGIC WORK UP -Acute vasodilator testing
~ 10% of IPAH patients have predominant vasoconstriction1 – CCB responsiveness
Responders have an excellent prognosis – 95% at 5 yrs
Vasodilator testing in PAH patients improves overall survival by selective CCB treatment2.
ESC 2009 – IC for IPAH & IIB for other forms of PAH
(Not recommended for Group 2-5)
1. Rich S. The effect of high doses of CCBs on survival in primary pulmonary hypertension.N Engl J Med. 1992;327:76 – 81.
2. Malhotra R et al. Vasoreactivity to inhaled nitric oxide with oxygen predicts long-term survival in pulmonary arterial hypertension. Pulm Circ 2011;1:250-8

39. (ESC, ACCP & AHA guidelines)
Response to AVT – Decrease in mPAP by at least 10mmHg to a value </= 40mmHg, with an unchanged or increase in COP
(ESC, ACCP & AHA guidelines)
( Decrease of >20% in mPAP & >30% in PVR – favourable response)
~ 10-20% (12.6%) 1 of IPAH patients are “ AVT responders” -- However only less than half of these are long term CCB responders.
Positive AVT criteria should be met before long term CCBs are considered for PAH Rx
AVT is less useful for 1) other Group 1 subtypes of PAH
2) for NYHA 3 & 4 patients
The AVT criteria for response is primarily based on a series by Sitbon et al...
Sitbon O, Humbert M, Jais X,et al.Long-term response tocalcium channel blockers in idiopathic pulmonary arterial hypertension.Circulation2005; 111: 3105–3111
1. Sitbon O et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005;111:3105–11.

40. AVT technique
NO is most commonly used and best available agent– however is costly and requires costly equipment.
Epoprostenol is next most commonly used agent
Started at low doses with gradual uptitration
Careful BP monitoring & discontinuation if SBP < 85mmHg
Measurements repeated every 10-15mins till:
1) SBP drop by 30% or < 85 mm Hg
2) HR increase by 40% or greater than 100/min or HR drop to less than 65/min + symptomatic hypotension
3) Intolerable side effects--headache, lightheadedness, nausea.
4) Target response achieved
5) Maximum dose of vasodilator agent given

41. Diagnostic approach in PAH – ACC/AHA 2009

42. PROGNOSTICATION OF PAH
BNP >150pg/ml
NT-proBNP >1400pg/ml
McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114:1417–31

43. Echo determinants of Prognosis in PAH
TAPSE also has prognostic value
PASP determined by TRV is not prognostic !!
*Pulmonary hypertension: echocardiographic assessment . Italian Heart Journal 2005.
*Raymond RJ et al. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension.J Am Coll Cardiol 2002;39:1214 –1219.

44. TREATMENT OF PAH Improvement of symptoms - Dyspnoea, QOL
Improving functional capacity - 6MWT
Improving objective parameters – mPAP, PVR, COP
Reverse/ Prevent disease progression
Counselling ---Diet, exercise, vaccinations, pregnancy
 Medications

45. General Measures Low level graded aerobic exercises as tolerated
Avoid heavy exertion & isometric exercises
Caution at high altitudes (> m)
In-flight oxygen for those with SpO2<92%
Influenza and pneumococcal vaccinations (Class IC – ESC 2009)
Na restriction < 2.4g/d
Avoid pregnancy/ early termination if conceived – 30-50% maternal mortality. ( Class IC – ESC 2009)
Contraceptive advise
Weiss BM et al. Outcome of pulmonary vascular disease in pregnancy: a systematic overview from 1978 through J Am Coll Cardiol. 1998;31:1650 –7

46. Drugs for PAH CCBs Advanced vasodilator therapies: Prostacyclins
PDE-5 inhibitors
ET receptor antagonists
Supportive therapy – Warfarin, Diuretics, O2
IV. RHF specific therapy

47. CCBs for PAH
Only for those with a positive AVT / other indications for CCBs ( ~10-20%) % 1
95% five year survival (if AVT+ve) ~ 5-10% -- ~7% 1
Long acting nifedipine, diltiazem, amlodipine
(Verapamil should not be used)
Choice based on HR of patient (>/< 80/min)
- Nifedipine SR- 30mg bd to mg/d
- Diltiazem - 60mg tds to mg/d
- Amlodipine – 2.5mg od to 20mg/d
1. Sitbon et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005;111:3105–11.

48. w/f hypotension, pulmonary edema, peripheral edema
Reassessment after 3-4 months
- Responder : Improvement in WHO class (to NYHAI/II) along with improvement in hemodynamics
Non-responder – consider advanced PAH therapy
In 2 large series of patients who were acute responders, the characteristics of those who had near perfect survival on CCBs for up to 18 years --- acute fall in mean PAP of 39% & PVR of 50%.
CCBs usually not useful outside the cohort of IPAH/FPAH !!
(Long-term response to calcium-channel blockers in non-idiopathic pulmonary arterial
hypertension. European Heart Journal (2010) 31, 1898–1907)

49. ADVANCED THERAPY (AT) FOR PAH

50. PROSTANOIDS 1.EPOPROSTENOL:
- Improves WHO class, hemodynamics, exercise tolerance & survival in PAH
Mean improvement in 6MWT ~ m & PAP by 20-30%
CV catheter implanted surgically – continuous infusion
Huge learning curve and self-care responsibility for patient
Has to be prepared daily
Typical dose – ng/kg/min by slow uptitration
Interruption by pump malfunction/catheter blockage may be catastrophic (T1/2 – 3-6 mins) -- REBOUND PH
CRBSIs ( / patient-yr)
S/E – Flushing, headache, diarrhoea, foot pain, rash, myalgias, jaw claudication, high output cardiac failure& pulm edema in PVOD/PCH
relaxation of vascular smooth muscle cell,
inhibition of platelet aggregation,
healing of endothelial injury,
inhibition of smooth cell proliferation,
-facilitating reverse remodelling

51. Experience of > 15 years with epoprostenol (FDA Approved- 1995)
Only PAH-drug to show a survival improvement in a RCT1
Also been studied with beneficial results in APAH (CHD, Porto-pulm HTN & HIV-associated) and inoperable CTEPH
Bridge to lung transplantation
Should be administered at experienced centres.
Not the ideal drug --- non-curative, expensive
Not available in India
1. Barst RJ et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The PPH Study Group.N Engl J Med1996;334:296–302.
* Sitbon O et al: Long-term intravenous epoprostenol infusion in primary pulmonary
hypertension. J Am Coll Cardiol 40:780, 2002.

52. 2. TREPROSTINIL:
More convenient usage than Epoprostenol (longer T1/2 -4hrs and stability)
75-150ng/kg/min
Injection site pain, headache, diarhoea, flushing
Gram negative sepsis ! (low threshold for empiric antibiotics)
- S/c approved in 2002, I/V approved in 2004
3. ILOPROST:
Inhalation -- ~ 6-12 nebulizations/day (T1/2 – 20-30min) , also oral/i.v
Approved in 2004
However no proven benefit in the long term as monotherapy.
Similar S/E profile as epoprostenol
4. BERAPROST:
Oral , rapid action
Doubtful long-term efficacy ( Benefits lasting only 3-6months)
Approved in Japan

53. PDE-5 inhibitors SILDENAFIL :
By decreasing cGMP degradation – decreased proliferation & increased apoptosis of PASMCs
Increases RV inotropy ( NEJM 2009;361: )
20 mg tds is the recommended starting dose – titrated to 80mg tds as tolerated
Onset ~ 45-60mins
Approved for PAH in 2005
Even though used off-label for paediatric PAH, FDA in 2012 recommended against their use1.
Long term beneficial effects have recently been reported in the SUPER-2 study2
Barst RJ et al. A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naïve children with pulmonary arterial hypertension. Circulation 2012;125:
2. Rubin LJ et al. SUPER-2 Study Group. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: the SUPER-2 study. Chest.2011 Nov;140(5):

54. - Caution while usage with ART
S/E of Sildenafil –
Headache, flushing, visual blurring, cyanopsia, hypotension, MI, optic neuropathy, hearing loss, priapism, increased IOP, nasal congestion.
- Caution while usage with ART
C/I in CLD, CKD, nitrate usage, retinal degenerative disorders, recent CVA/MI
Has been studied and validated for combination therapy with Bosentan and epoprostenol .
In India – 25/50/100 mg tablets ~ Rs/25mg
Preferable 1st drug to start for WHO I &II in Indian patients.

55. PHIRST study in IPAH – similar to Sildenafil
2. TADALAFIL :
PHIRST study in IPAH – similar to Sildenafil
Recent PHIRST-2 shows good long term results1
40mg od dose
FDA approved in 2009
3. VARDENAFIL:
5mg bd
Has additional antioxidant effects
1. Oudiz RJ et al. Tadalafil for the treatment of pulmonary arterial hypertension: a double-blind 52-week uncontrolled extension study. J Am Coll Cardio 2012 Aug 21;60(8):

56. Endothelin antagonists
1. BOSENTAN:
Nonselective(ETA+ETB )ET1-R blocker:62.5mg to 125mg bd
Mean improvement of 6MWT by ~50- 75m1
Improvements in mPAP and PVR
FDA approved in 2001
Beneficial in APAH(HIV, CTD), inoperable CTEPH (BENEFIT trial) and congenital heart disease (BREATHE-5 trial)2
Also found beneficial in early symptomatic PAH (WHO –II)
( EARLY study) 3 - FDA approval in 2009
1.Rubin LJ, et al. Bosentan therapy for pulmonaryarterial hypertension. N Engl J Med. 2002;346:896 –903.
2. Galie N et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind,
randomized,placebo-controlled study. Circulation. 2006;114:48 –54.
3. Galie N et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan
(EARLYstudy): a double-blind, randomised controlled trial. Lancet. 2008;371:2093–100

57. Survival benefit not proved by placebo controlled studies yet
But improved survival rates when compared with the NIH registry1
1. McLaughlin et al.Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J Feb; 25(2):244-9.

58. S/E :
Significant transaminitis – 10-15% (monthly LFT)
Anaemia (?dilutional) – 10% ( 3monthly CBC)
Bosentan withdrawal –death
Headache, hypotension, flushing, peripheral edema
? Male infertility
CYP 450 inducer of 2C9 and 3A4
C/I in pregnancy and lactation (teratogenic)
In India – Cipla (Bosetan) and Lupin (Lupibose)
~ Rs 115 for 62.5mg

59. 2. SITAXSENTAN : 3. AMBRISENTAN :
Selective ETA antagonist
STRIDE-1 & -2
100mg od
FDA(Europe)
Increases INR with warfarin (CYP2C9 inhibitor)
3. AMBRISENTAN :
Less hepatotoxicity
ARIES-1 & -2
5mg - 10mg od
FDA(USA) – 2007
4. MACITENTAN :
Dual ETA/B receptor with high lipophilicity
SERAPHIN study (ongoing)
742 patients years-- Decreased mortality by 45% (2012 update)
Recent metaanalysis of all PAH therapy types (21 trials, 3140 patients) – mortality reduction~ 43% (Eur Heart J 2009;30: )

60. COMBINATION THERAPY for PAH
ADVANCED PAH THERAPY USE IN THE ‘REVEAL’ REGISTRY
Maximum efficacy with minimum toxicity
Multiple observational studies with overall possible benefit
Bosentan +Epoprostenol: BREATHE-1 trial (+/--)
Sildenafil +Epoprostenol: PACES trial (+) (Ilo /Trep also tested +)
Bosentan + Iloprost: STEP trial ( +), COMBI trial (+/-)
Sildenafil + Bosentan : 2 obs trials ( + )
Bosentan + Sildenafil + Iloprost – Beneficial
-- Overall may be considered in unsuccessful monotherapy and the optimal combination should be individualized1
-- ”Goal oriented therapeutic strategy”
1. Buckely et al. Combination in management of PAH. : Pulmonary Hypertension Reviews. International Journal of Clinical Practice; Volume 67, Issue Supplement s179, pages 13–23, May 2013

61. SUPPORTIVE THERAPIES -Warfarin in PAH
Recommended for IPAH – INR (ESC IIa for IPAH,FPAH and anorexigen-PAH ; IIb for APAH)
(based primarily on observational studies in IPAH and anorexigen-PAH)
Suppresses the development of new thrombotic lesions
Particularly beneficial along with long term epoprostenol infusion
Possible interaction (inconsistent) with Bosentan to be kept in mind --- more frequent monitoring
( Bosentan is a CYP inducer)
Risks of bleeding to be weighed appropriately
No evidence in other PAH subgroups
Lack of RCTs for Class I recommendations
* Johnson SR et al. Anticoagulation in pulmonary arterial hypertension: a qualitative systematic review. Eur Respir J 2006 Nov;28(5):
* Bartlett, M. The Role of Warfarin Anticoagulation in Pulmonary Hypertension. Advances in Pulmonary Hypertension. 2012; 11,1:

62. Other supportive therapies for PAH
Diuretics
Oxygen therapy when there is PO2 <60mmHg
LTOT may be considered when necessary.
Digoxin may be considered for RVF/ atrial tachyarrhythmias.
Management of arrhythmias

63. NEWER DRUGS FOR PAH
Despite progress in medical therapies – overall survival and functional status is still poor
cGMP stimulators -- Riociguat
Inhaled VIP
Prostacyclin receptor agonists - Selexipag
TKIs – Imatinib (PAR-2 inhibitor)
Sertonin antagonist - Terguride
VEGF inhibitors
Rho kinase inhibitors - Fasudil
Angiopoietin inhibitors
Elastase inhibitors - Elafin
Gene therapy
Stem cell therapy

64. SURGICAL MEASURES
Failure to respond – inevitable result of RV failure – rapid deterioration
Atrial septostomy
Heart-lung transplantation
Thrombo-endarterectomy for CTEPH
RV mechanical assist ( under research)

65. ATRIAL SEPTOSTOMY
1) In severe intractable RHF with syncopal symptoms on maximal advanced PAH therapy and inotropes.
(avoided when RAP>20mmHg, PVR>55WU & SpO2<80%-- end-stage)
2) When advanced medical therapy is not available.
3) Bridge to transplantation
Mainly improves COP (~ 1 l/min) & systemic O2 transport--improves symptoms and functional status
~ 5-15% procedural mortality
Kothari et al (AIIMS) , 11 patients, IPAH
---improvement in symptoms/hemodynamics % mortality --- recommended early in the course.

66. HEART-LUNG TRANSPLANTATION
Poor response to advanced therapies ~ 25%
PVOD, PCH
SLTx/DLTx/HLTx
The International Society for Heart and Lung Transplant registry reports 1-, 3-, 5-,and 10-year survivals of 66%, 57%, 47%, and 27%, respectively in post-transplant PAH patients.

67. ESC 2009 guidelines

68. Patient follow up
ACC/AHA 2009 on PAH

69. Scope of ATs for other conditions than IPAH
Heart failure – Sildenafil beneficial at 12 weeks. No long term studies
COPD – Sildenafil – no significant benefit (COPD 2012 Jun;9(3):268-75)
-- Bosentan – no definite benefit (Eur Respir J. 2008 Sep;32(3):619-28)
ILD -- Sildenafil – may be beneficial (Respirology. 2010 Nov;15(8): )
-- Bosentan –no definite benefit
[ 1. J Rheumatol.2011 Oct;38(10): ; 2. BUILD-3 ]
CHD -- Sildenafil – beneficial in short term studies ASD> VSD
(1.Cardiology in the Young,2011, 21, pp ; 2.Heart 2011;97: )
-Bosentan -- BREATHE-5 trial : Symptomatic benefit at 40 months
[ IB (ESC 2009) for WHO III Eisenmenger’s ]
**PAH-AT for Eisenmenger’s has significant benefits in terms of symptoms, QOL, hemodynamics as well as survival.1,2
(1. Management of ES in the modern treatment era. Eur Resp Rev 2011;20:122,
2. Improved survival among ES patients receiving advanced PAH therapy. Circulation.2010;121:1-4 )
VSD – both laminar as well as circumferential strain of slow ASD—only laminar strain of flow...Therefore PAH is more severe in posttricuspid

70. CONCLUSION
PAH is commonly a secondary manifestation of an underlying disease process which needs to be corrected.
Failure to correct the underlying pathophysiology may lead to progression of PAH severity and ultimately RV dysfunction----mortality.
Diagnosis should be approached in a structured manner with careful exclusion of treatable causes
IPAH is a diagnosis of exclusion.
A careful estimation and prognostication of PAH is mandatory by functional testing, 2D-Echo and RHC

71. AVT should be done for all PAH patients where CCB therapy may improve survival.
Several advanced therapies are now available for PAH which may improve symptoms and survival.
Detailed patient counselling, lifestyle measures and individualization of therapeutic protocols, are necessary i/v/o of the overall progressive nature of the disease.

72. References Braunwald’s Textbook of Heart Diseases (9th edition)
Hurst’s THE HEART
Moss and Adams Textbook of Paediatric Cardiology
Guidelines for the diagnosis and treatment of PAH. ESC 2009 guidelines
Expert consensus document on PAH. ACCF/AHA 2009
Chemla et al. Hemodynamic evaluation of PH. Eur Resp J 2002;20:
Echocardiographic assessment of pulmonary hypertension: standard operating procedure. Eur Respir Rev 2012; 21: 125, 239–248.
Assessment of Right Ventricular Structure and Function in Pulmonary Hypertension. J Cardiovasc Ultrasound 2011;19(3):
The Effects of Vasodilators in Pulmonary Hypertension Pulmonary Vascular or Peripheral Vascular? Circ Heart Fail. 2009;2;
Bartlett, M. The Role of Warfarin Anticoagulation in Pulmonary Hypertension. Advances in Pulmonary Hypertension. 2012; 11,1:
Combination in management of PAH. : Pulmonary Hypertension Reviews. International Journal of Clinical Practice; Volume 67, Issue Supplement s179, pages 13–23, May 2013.
Computed tomography and cardiac magnetic resonance imaging in pulmonary hypertension. Progress in Cardiovascular Diseases 55 (2012) 161–171.
M.D. McGoon* and D.P. Miller.REVEAL: a contemporary US pulmonary arterial hypertension registry Eur Respir Rev 2012; 21: 123, 8–18
Anita Saxena, Pulmonary hypertension—“state of the art” management in 2012; IHJ Jan-Feb 2012.
Multiple references as mentioned in footnote of slides.

73. SURVIVAL IN PAH
Sunil Pauwaa et al. Survival in pulmonary arterial hypertension: A brief review of registry data Pulm Circ. 2011 Jul-Sep; 1(3): 430–431.

74. Dyspnoea in PAH
1) Complex interactions of peripheral chemo/mechano receptors and central receptors
2) C fibres in pulmonary vasculature and vagal innervations of RA are activated causing rapid shallow breathing
3) Pulmonary mechanics are normal; however PA O2 is affected ----Decreased oxygen consumption, decreased VeCO2-----Premature lactic acidemia
4) There is a fixed physiological dead space due to reduced perfusion
5) Decreased LV compliance

75. Proposed RAP estimation from IVC collapsibility data
JBrennan JM. Reappraisal of the use of inferior vena cava for estimating right atrial pressure. J Am Soc Echocardiogr Jul;20(7):

76. Follow up strategy for specific aetiology