Post on 12-Aug-2019
CONUNDRUMS IN PULMONARY ARTERIAL HYPERTENSION
MOHAMMED RAFIQUE ESSOP
MILPARK HOSPITAL
and
UNIVERSITY OF THE WITWATERSRAND
POINTS FOR DISCUSSION
• What is the pathogenetic mechanism of PAH?
• Importance of RV function
• New therapies in the near future
• Monotherapy versus combination therapy
• Role of Warfarin anticoagulation
• Therapeutic targets in PAH
• Does PAH therapy reduce mortality?
• Management of the critically ill patient
• Role of ECLS and lung transplantation
• How do we make PAH treatment more widely available?
VASODILATOR IMBALANCE IN PAH
BosentanMacitentanAmbrisentan
IV, inhaled or subcutaneous prostacyclin analoguesSelexipag (oral)
VASODILATOR IMBALANCE IN PAH
BosentanMacitentanAmbrisentan
IV, inhaled or subcutaneous prostacyclin analoguesSelexipag (oral)
Inhaled NOPDE5 inhibitors
SildenafilVardenafil
Riociguat
Anticoagulate ± Diuretics ± Oxygen ± Digoxin
Positive
Sustained Response
Oral CCB
Continue CCB
Yes
Negative
APPROACH TO TREATMENT IN PAH
No LOWER RISK DETERMINANTS OF RISK HIGHER RISK
No Clinical evidence of RV failure Yes
Gradual Progression of symptoms Rapid
II, III WHO class IV
Longer (>400 m) 6MWD Shorter (<300 m)
Peak VO2 >10.4 mL/kg/min CPET Peak VO2 <10.4 mL/kg/min
Minimal RV dysfunction Echocardiography
Pericardial effusion,
significant RV
enlargement/dysfunction;
RA enlargement
RAP <10 mm Hg;
CI >2.5 L/min/m2 HemodynamicsRAP >20 mm Hg;
CI <2.0 L/min/m2
Minimally elevated BNP Significantly elevated
Acute Vasoreactivity Testing
ACC/AHA CONSENSUS PAH TREATMENT ALGORITHM
Atrial septostomyLung transplant
Reassess: considercombo-therapy
ERAs or PDE-5 Is (oral)
Epoprostenol or Treprostinil (IV)
Iloprost (inhaled)
Treprostinil (SC, inhaled)
No
Anticoagulate ± Diuretics ± Oxygen ± Digoxin
Sustained Response
Positive
Oral CCB
Continue CCB
Yes
Negative
Investigational Protocols
Lower Risk
Epoprostenol or Treprostinil (IV)
Iloprost (inhaled)
ERAs or PDE-5 Is (oral)
Treprostinil (SC)
Higher Risk
Acute Vasoreactivity Testing
COMBINATION THERAPY
• Combination therapy is the cornerstone of therapy of many other serious illnesses including cancer, HIV, hypertension and heart failure
• Combination therapy• Upfront?
• Rapid sequential?
INITIAL USE OF AMBRISENTAN AND TADANAFIL IN PAH -AMBITION TRIAL
Galie et al; NEJM;2015:834-44
• 500 patients with PAH
• Randomised to Ambrisentan + Tadanafil vs monotherapy with Ambrisentan or Tadanafil
• Primary endpoint defined as a composite of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long term clinical response
SELEXIPAG FOR THE TREATMENT OF PAH-GRIPHON TRIALSitbon et al, NEJM;2015;373:2522-33
• Double blind placebo controlled trial
• 1156 patients randomised to Selexipag or placebo
• 3 year follow up
• Primary endpoint also clinical failure ie composite of death and hospital admission for worsening symptoms
• 47% on background monotherapy with either ERB or PDE5 inhibitor and 33% on dual therapy
MACITENTAN AND MORBIDITY AND MORTALITY IN PAHSERAPHIN TRIAL
Pulido et al,NEJM 2013;369:889-18
• 742 patients with FC 2-3 symptoms randomised to Macitentan or placebo
• 66% on background therapy with PDE5 inhibitor
• Primary endpoint clinical failure
MACITENTAN AND MORBIDITY AND MORTALITY IN PAHSERAPHIN TRIAL
Pulido et al,NEJM 2013;369:889-18
HR 0.55P<0.001
CHD = congenital heart disease; CTD = connective tissue disease; ET-1 = endothelin-1; HIV = human immunodeficiency disease;
NO = nitric oxide; PAH = pulmonary arterial hypertension; PGI2 = prostacyclin
Adapted from Gaine S. JAMA 2000;284:3160–8.
Pathogenesis of PAH
Normal Reversible diseaseIrreversibledisease
VASCULAR INJURY DISEASE PROGRESSION
Endothelial dysfunction
↓NO synthase
↓PGI2 production
↑Thromboxane production
↑ET-1 production
Vascular smooth muscle dysfunction
Smooth muscle
hypertrophy
Vasoconstriction
Smooth muscle
hypertrophy
Adventitial and intimal
proliferation
In situ
thrombosis
Plexiform
lesion
Advanced vascular lesion
Early intimal
proliferation
RISK FACTORS AND ASSOCIATED
CONDITIONS
Adventitia
Media
Intima
CTD
CHD
Portal hypertension
HIV
Drugs and toxins
Pregnancy
SUSCEPTIBILITYBMPR2 mutation
Other genetic factors
Pulmonary hypertensiondiagnostic approach
I. PH suspicion
II. PH detection
III. PH class identification
IV. PH evaluation: Type
V. Severity Assessment
RHC + vasoreactivity, biomarkers
6-minute walk test, peak VO2
Blood tests & immunologyHIV testAbdominal ultrasound scan
Pulmonary function tests & ABGVentilation / perfusion lung scanHigh resolution CTSpiral CTPulmonary angiography
ECGChest radiographyTT echocardiography
Symptoms & physical examinationScreening proceduresIncidental findings
ESC and ACCP Guidelines
Suspected Pulmonary
Hypertension
Echocardiogram Chest X-Ray PFT’sSleepStudy
Ventilation-Perfusion scan,angiography
Autoantibodytests
HIV testLFTs and clinical
evidence of cirrhosisand portal htn
•Left heart disease•Valvular/Congenital
Heart Disease
•Emphysema• Fibrosis•Thoracic abnl
Sleepdisorder
ChronicThrombo-embolism
•Scleroderma•SLE•RA•Vasculitis
HIV infectionPortopulmonaryHypertension
Diagnosis of Pulmonary Hypertension
Required When Clinically Indicated
Prevalence of PAH in Associated Conditions4th World Symposium on PH (2008)
Associated Condition Prevalence of PAH
Systemic sclerosis 7-12 %
HIV infection 0.46-0.5 %
Portal hypertension 2-6 %
Congenital heart disease 1.6-12.5 per million in those with congenital systemic-
to-pulmonary shunts → 25-50 % affected by
Eisenmenger syndrome
Schistosomiasis 4.6 % in those with hepatosplenic disease
Chronic hemolytic anemia Highly variable; currently being studied
Simonneau, et al. J Am Coll Cardiol. 2009;54(1):S43-54.
FBK – 22 year old female
• Progressive fatigue and dyspnea
• Several episodes of syncope
• ITP on treatment several years – Platelets 20
• One pregnancy 2 years earlier - ? Uncomplicated
• Negative ANF and normal CTPA
• Severe PHT – PASP 9040/60mmHg
• PDE 5 inhibitor + steroids
2 months later...
Chest pain
+ D-Dimer
CTPA +
APLA ++
ENA ++
SLE + APAH
Improvement with Clexane + Azothiaprine
UTILITY OF ECHOCARDIOGRAPHY FOR PULMONARY HYPERTENSION
• Quantification of pulmonary artery pressure
• Defining the etiology for PH
• Evaluation of impact on RV size and function
• Monitoring response to pharmacologic or interventional procedure
ESTIMATION OF RIGHT ATRIAL PRESSURE
RAP (mmHg) IVC DIAMETER (mm)
IVC COLLAPSE (%)
HEPATIC VEIN DILATATION
< 5 < 10 + -
5-10 10-15 > 50 -
10-15 15-20 < 50 -
15-20 > 20 < 50 -
> 20 > 20 < 50 (or sniff neg)
+
RIGHT VENTRICULAR FUNCTION
• Systolic apical displacement of the tricuspid annulus• Normal RV function > 20mm
• Mild RV dysfunction 10-20mm
• Severe RV dysfunction < 10mm
OTHER WAYS TO ASSESS PULMONARY HYPERTENSION
• Time to peak PA velocity: <80msec = PH, > 110msec = normal PA pressure
• Mid-systolic closure of PV on M-Mode
• Mid-systolic notch in PA velocity
• In the presence of a VSD, PA systolic pressure can be estimated as: SBP – Doppler pressure gradient across VSD
Echocardiography in PAH
• Sensitivity and Specificity for PAH greatest when cut-off value for RVSP estimate used is >45 mm Hg
• Modest changes in RVSP may not accurately reflect true hemodynamic changes over time
• Survival does not correlate with PA pressure2
• Other echo parameters correlate with survival3
3 Raymond et al: JACC 2002;39:1214
1 Arcasoy et al: AJRCCM 2003; 167: 7352 McLaughlin et al: Circulation 2002;106:1477
Raymond, et al. J Am Coll Cardiol. 2002;39:1214-19.
Right Atrial Size Pericardial Effusion LV-Eccentricity Index
RA size < median
RA size > median
No effusion
Effusion
EI < median
EI > median
EI < median
EI > median
No effusion
Effusion
RA size < median
RA size > median
Years
Su
rviv
al (
%)
Fre
edo
m f
rom
Co
mp
osi
te
En
dp
oin
t (%
)
0
20
40
60
80
100
0
20
40
60
80
100
0
20
40
60
80
100
0
20
40
60
80
100
0
20
40
60
80
100
0
20
40
60
80
100
0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4
0 1 2 3 40 1 2 3 4 50 1 2 3 4 5
5
5
ECHO Predictors of Outcome
Years
TAPSE and Mortality in the PAH PatientP
roba
bilit
y of
sur
viva
l
A. Overall cohort B. PAH only
Months
Pro
babi
lity
of s
urvi
val
Months
TAPSE ≥ 1.8 cmTAPSE ≥ 1.8 cm
TAPSE < 1.8 cm TAPSE < 1.8 cm
Log rank χ2 10.0
P-value=0.002
Log rank χ2 6.8
P-value=0.009
Forfia et al. 2006.
Right heart catheterization (RHC)
Definite confirmation of PAH diagnosis
Assessment of the severity of haemodynamic impairment
Testing of the vasoreactivity of the pulmonary circulation
Hemodynamics – NIH Registry
4
Fre
qu
en
cy
Right Atrial Pressure (mm Hg)
30
20
10
08 12 16 20 24 28
Normal Range
1
Fre
qu
en
cy
Cardiac Index (L/Min/M2)
50
30
10
0
40
20
2 3 4 5 6 7 8
Normal Range
20 60 80
50
Fre
qu
en
cy
Mean Pulmonary Artery Pressure(mm Hg)
40
30
20
10
040 100 120
Normal Range
10 40 50
30
Fre
qu
en
cy
Pulmonary Vascular Resistance Index(L/Min/M2)
25
20
15
10
030 70 80
5
20 60 90
Normal Range
Reduction of mean PAP ≥ 10 mmHg
To reach mean PAP ≤ 40 mmHg
With an increased or unchanged cardiac output
Acute vasodilator testingDefinition of "true responder"
Low Risk Determinants of Risk High Risk
No Clinical evidence of RV failure Yes
Gradual Disease progression Rapid
II, III WHO functional class IV
Longer (> 400 meters) 6-MWD Shorter (< 300 meters)
Peak VO2 > 10.4 mL/kg/min Cardiopulmonary exercise testing Peak VO2 < 10.4 mL/kg/min
Minimally elevated and stable BNP/NT-proBNP Significantly elevated
PaCO2 > 34 mm Hg Blood gasses PaCO2 < 32 mm Hg
Minimal RV dysfunction ECHO findingsPericardial effusion, RV dysfunction,
RA enlargement
RAP < 10 mm Hg;
CI > 2.5 L/min/m2Hemodynamics
RAP > 20 mm Hg;
CI < 2 L/min/m2
McLaughlin, et al. Circulation. 2006;114:1417-31.
McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619.
PAH Determinants of Patient RiskACC/AHA Expert Consensus