Transcript evaluation & management of pulmonary arterial

EVALUATION & MANAGEMENT OF
PULMONARY ARTERIAL
HYPERTENSION
Dr Sandeep Mohanan
Senior Resident
Department of Cardiology, CGMC
OUTLINE
EVALUATION
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Clinical diagnosis of PAH
Diagnostic work up : 1) Initial , 2) Elaborate
Prognostic work up
Strategic work up - AVT
MANAGEMENT
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Current pharmacological armamentarium - AT
Surgical measures
Follow up
AT for specific aetiologies of PAH
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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
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Case scenario....
• 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
PAH
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disorders, HTN, CAD, Psychogenic.....PAH
Delay in diagnosis of IPAH
>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
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hypertension: The DELAY study. Pulm Circ 2013;3:89-94.
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
etD.P.
al. Miller.REVEAL:
Prognosis of pulmonary
arterial
hypertension:
evidence-based
practice
M.D. McGoon*VV
and
a contemporary
US pulmonary
arterialACCP
hypertension
registry Eurclinical
Respir Rev
62012;
guidelines.
21: 123, 8–18.Chest. 2004;126:78S–92S
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
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• Physical Examination:
- Cyanosis: Usually late in the natural history for nonrespiratory causes.
- Clubbing – suggests Eisenmengers / Respiratory causes
• Respiratory system examination
• BMI, Neck height/width, Thyroid examination
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INITIAL DIAGNOSTIC WORK UP
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ECG
-Establishing the diagnosis
of PAH
CXray
-Grading the severity
-Assessing RV function
-Ruling out left heart/structural
2D Doppler Echo +/- contrast
cardiac causes
PFT
- Ruling out respiratory causes
-Detect additional respiratory
CT chest
pathology
- Ruling out CTEPH
Lung perfusion scan
CPET/ 6MWT/TMT – To assess baseline functional
status & CP-metabolic function before initiating
treatment.
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• ECG:
• CXR:
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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
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Specific diagnostic capability of Echo in PAH
(Contrast echo may be required)
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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 0.96-0.98 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):359-65.
2. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung Disease. Am J
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Respir Crit Care Med. 2003 Mar 1;167(5):735-40.
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.
15 2007
Jul;20(7):857-61.
• 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 + 0.55 mmHg
mPAP (Chemla formula)= 0.61 PASP +2 mmHg
• mPAP = 4 V2 (peak PR gradient) + RAP
• PADP = 4 V2 (end-diastolic pressure) + RAP
1.
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: 633-639
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2. Steckelberg. Derivation of mean pulmonary artery pressure from noninvasive parameters. J Am Soc Echocardiogr.2013
May;26(5):464-8.
ESC 2009 recommendations on diagnosis of PH
based on TRV & PASP
Mild PAH is not
reliably assessed
by Echo parameters
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• 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
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RV assessment
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RV - MORPHOLOGICAL ASSESSMENT:
1) LVs index (LV eccentricity index D2/D1)
2) 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
1.Hinderliter AL, et al. Frequency and prognostic significance of pericardial effusion in primary pulmonary hypertension. Am J
Cardiol 1999; 84: 481-4.
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2. Raymond RJ, et al. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol.
2002;39:1214-1219.
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;19:902-910.)
1.
Mebazaa A,.Acute right ventricular failure- from pathophysiology to new treatments. Intensive Care Med. 2004;30: 185-196.
2.
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
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secondary to idiopathic or ischemic dilated cardiomyopathy. Am J Cardiol 2000; 85:837-42
3.
• 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: 340-8.
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Important Echo measures in PAH
Echocardiographic assesment of PAH. European Respiratory Review 2012.
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Algorithm for PH evaluation by echocardiography
ACC/AHA 2009
consensus on PAH
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• PULMONARY FUNCTION TEST
– to r/o restrictive/ obstructive airway diseases
- DLco may be decreased to 40-80% in PAH
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• CT CHEST – HRCT +/- CECT
- PAH assessment
- Respiratory causes
(ILD, COPD)
- CTEPH : Especially,
for those whose lung
perfusion scans cannot
be reliably interpreted
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• 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
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• LUNG PERFUSION SCAN -- Tc99m MAA
Sensitivity and Specificity approaches 100% .
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FUNCTIONAL WORK UP
Median survival:
WHO I : 6 years
WHO II : 6 yrs
WHO III : 2.5 yrs
WHO IV : 6months
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6 MINUTE WALK TEST
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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.
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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
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ADVANCED DIAGNOSTIC WORK UP
• Elaborate diagnostic work up
• Cardiac MRI
• Cardiac catheterization
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Elaborate diagnostic work up
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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
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cMRI
• 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 :
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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
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function, and remodeling. AJR Am J Roentgenol.2011;196:87-94
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
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national prospective registry. Ann Intern Med. 1991;115:343-9
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
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BASIC DATA FROM A RHC
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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
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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
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hypertension. Pulm Circ 2011;1:250-8
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
1. Sitbon O et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. 39
Circulation 2005;111:3105–11.
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
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Diagnostic approach in PAH – ACC/AHA 2009
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PROGNOSTICATION OF PAH
BNP >150pg/ml
NT-proBNP >1400pg/ml
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McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114:1417–31
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
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Cardiol 2002;39:1214 –1219.
TREATMENT OF PAH
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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
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General Measures
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Low level graded aerobic exercises as tolerated
Avoid heavy exertion & isometric exercises
Caution at high altitudes (>1500-2000m)
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
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from 1978 through 1996. J Am Coll Cardiol. 1998;31:1650 –7
Drugs for PAH
I. CCBs
II.
a)
b)
c)
Advanced vasodilator therapies:
Prostacyclins
PDE-5 inhibitors
ET receptor antagonists
III. Supportive therapy – Warfarin, Diuretics, O2
IV. RHF specific therapy
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CCBs for PAH
• Only for those with a positive AVT / other indications for
CCBs ( ~10-20%) -- 12.6% 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 120-240mg/d
- Diltiazem - 60mg tds to 240- 720mg/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.
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• 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)
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ADVANCED THERAPY (AT) FOR PAH
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PROSTANOIDS
1.EPOPROSTENOL:
- -relaxation
Improves WHO
class, hemodynamics,
of vascular
smooth muscleexercise
cell, tolerance & survival in
PAH
-inhibition
of platelet aggregation,
- -healing
Mean improvement
in 6MWT
of endothelial
injury, ~ 30 -40m & PAP by 20-30%
-inhibition of smooth cell proliferation,
- -facilitating
CV catheterreverse
implanted
surgically – continuous infusion
remodelling
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Huge learning curve and self-care responsibility for patient
Has to be prepared daily
Typical dose – 25-40 ng/kg/min by slow uptitration
Interruption by pump malfunction/catheter blockage may be
catastrophic (T1/2 – 3-6 mins) -- REBOUND PH
- CRBSIs ( 0.1-0.4 / patient-yr)
- S/E – Flushing, headache, diarrhoea, foot pain, rash, myalgias, jaw
claudication, high output cardiac failure& pulm edema in PVOD/PCH
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• 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
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hypertension. J Am Coll Cardiol 40:780, 2002.
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
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PDE-5 inhibitors
1. SILDENAFIL :
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1.
By decreasing cGMP degradation – decreased proliferation &
increased apoptosis of PASMCs
Increases RV inotropy ( NEJM 2009;361:1864-1871)
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;125:324-334.
2. Rubin LJ et al. SUPER-2 Study Group. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension:
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the SUPER-2 study. Chest.2011 Nov;140(5):1274-83.
• 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 ~ 12-15 Rs/25mg
• Preferable 1st drug to start for WHO I &II in Indian patients.
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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 double55
blind 52-week uncontrolled extension study. J Am Coll Cardio 2012 Aug 21;60(8):768-74.
Endothelin antagonists
1. BOSENTAN:
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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
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- 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
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hypertension. Eur Respir J. 2005 Feb; 25(2):244-9.
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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
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2. SITAXSENTAN :
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Selective ETA antagonist
STRIDE-1 & -2
100mg od
FDA(Europe) - 2006
Increases INR with warfarin (CYP2C9 inhibitor)
3. AMBRISENTAN :
- Selective ETA antagonist
- 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 --3.5 years-- Decreased mortality by 45% (2012 update)
Recent metaanalysis of all PAH therapy types (21 trials, 3140 patients)
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– mortality reduction~ 43% (Eur Heart J 2009;30:394-403)
COMBINATION THERAPY for PAH
ADVANCED
THERAPY
IN THEtoxicity
‘REVEAL’ REGISTRY
• MaximumPAH
efficacy
with USE
minimum
• 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 of60
Clinical
Practice; Volume 67, Issue Supplement s179, pages 13–23, May 2013
SUPPORTIVE THERAPIES
-Warfarin in PAH
• Recommended for IPAH – INR 1.5 - 2.5 (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):999-1004.
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* Bartlett, M. The Role of Warfarin Anticoagulation in Pulmonary Hypertension. Advances in Pulmonary Hypertension.
2012; 11,1: 15-16.
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
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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
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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)
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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-- 18.6% mortality --recommended early in the course.
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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.
66
ESC 2009
guidelines
67
Patient follow up
ACC/AHA 2009 on PAH
68
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):1226-32.)
-- Bosentan –no definite benefit
[ 1. J Rheumatol.2011 Oct;38(10):2186-92; 2. BUILD-3 ]
• CHD -- Sildenafil – beneficial in short term studies ASD> VSD
(1.Cardiology in the Young,2011, 21, pp 631-638; 2.Heart 2011;97:1876-1881)
-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;20:122,293-301
2. Improved survival among ES patients receiving advanced PAH therapy. Circulation.2010;121:1-469
)
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
70
• 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.
71
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;20:1314-1331.
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):115-125.
The Effects of Vasodilators in Pulmonary Hypertension Pulmonary Vascular or Peripheral Vascular?
Circ Heart Fail. 2009;2;145-150.
Bartlett, M. The Role of Warfarin Anticoagulation in Pulmonary Hypertension. Advances in
Pulmonary Hypertension. 2012; 11,1: 15-16.
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.
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Multiple references as mentioned in footnote of slides.
SURVIVAL IN PAH
Sunil Pauwaa et al. Survival in pulmonary arterial hypertension: A brief review of registry data Pulm Circ. 2011 Jul73
Sep; 1(3): 430–431.
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
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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
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Echocardiogr. 2007 Jul;20(7):857-61.
Follow up strategy for specific aetiology
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