Aristotle University of Thessaloniki Cardiology Clinic, AHEPA Hospital

Σύνδροµο Eisenmenger Νέα δεδοµένα στη σταδιοποίηση

κινδύνου και στη θεραπεία

George Giannakoulas, MD Assistant Professor of Cardiology Aristotle University of Thessaloniki

Declaration of interest

Honoraria for lectures or Advisory boards: MSD, Glaxo, Actelion, Bayer, United Therapeutics, ELPEN Pharmaceuticals

Clinical classification of PAH in CHD

1. Eisenmenger’s syndrome – Shunt reversal (R-L or bidirectional) resulting in cyanosis

2. PAH with prevalent L-R shunts – L-R shunt through moderate to large defects, with mild to moderate

increase in PVR, with no cyanosis 3. PAH with small/coincidental defects

– (usually VSD <1 cm or ASD <2 cm) with a clinical picture very similar to IPAH

4. PAH after defect closureGalie N et al. Eur Heart J 2015

I

Shear stress & stretch Vascular Remodeling

Bidirectional or RL shunt

PAH associated with L-R shunt

Eisenmenger syndrome

Endothelial dysfunction

L-RR-L

IV-VII III

Shunt

Histology

PVR PVRSlide Courtesy: K. Dimopoulos

Eisenmenger syndrome: Prevalence in the spectrum of ACHD

• Patients at risk of developing ES – ~50% of patients with large unrepaired VSDs2 – ~10% of patients with large unrepaired ASDs2 – ~90% of patients with unrepaired AVSDs3 – Almost 100% of patients with unrepaired truncus arteriosus2

• Estimated prevalence of ES = 11 per million inhabitants4

• Estimated prevalence of ES = 1.8% in the Greek ACHD registry (CHALLENGE registry)

1. Mulder BJ. Eur Respir Rev 2010; 19:308-13. 2. Beghetti M and Galiè N. J Am Coll Cardiol 2009; 53:733-40.

3. Collins-Nakai RL and Rabinovitch M. Cardiol Clin 1993; 11:675-87. 4. Van de Bruaene, et al. Acta Cardiol 2009; 64:447-53.

Survival (%)

ES is thought to have better long-term outcomes than iPAH

Follow-up (years)

(37) (30)(17)

(22)(11)

(3)(57)

(26) (17) (5)(2)

(1)

0

20

40

60

80

100

1 2 3

PAH-CHD (ES)IPAH

Hopkins W, et al. J Heart Lung Transplant 1996;15:100-15

The remarkable RV of Eisenmenger syndrome

• Eisenmenger • iPAH

Dimopoulos K, Giannakoulas G et al. Curr Opin Cardiol 2008

However, not all ES have preserved RV function

• Pretricuspid defects • Complex defect

Difference in outcome between pre and post-tricuspid Eisenmenger patients

Moceri et al, Int J Cardiol 2015

Outcomes of Patients With CHD-Associated PAH(from the REVEAL Registry)

Barst et al. Am J Cardiol 2014

p=0.25

Prognostication

PULMONARY HYPERTENSION CYANOSIS

CARDIAC DEFECT

Scoliosis

↑ ↑ Perioperative risk

Exercise intolerance Arrhythmias

Thrombosis

Heart failureBleeding

Organ failureHyperviscosity

↑ ↑ Pregnancy risk

Disability

↓ QoL Sudden death

Hepatic dysfunction

Renal failure

HyponatremiaTIA/CVA

Syncope

GoutCholelithiasis

Endocarditis

Increased morbidity

Biochemical FunctionalImaging

Functional predictors of outcome:

6-minute walk distance

Imaging predictors of outcome:

Example of echo composite score

S SD

Systole/Diastole duration

RA area RA/LA area

TAPSE

S SDComposite score • TAPSE<15mm • Systole/diastole time on TR ≥1.5 • RA area ≥25cm2 • RA area/LA area ratio ≥1.5

Echocardiographic Composite score

Composite score • TAPSE<15mm • Systole/diastole time on TR ≥1.5 • RA area ≥25cm2 • RA area/LA area ratio ≥1.5

Impaired Biventricular Function is Associated With Mortality in Eisenmenger Syndrome – a CMR study

Jensen A et al. Circ Cardiovasc Imaging 2015

Broberg G et al. J Cardiovasc Magn Reson 2014

• n=30 ES patients • LGE was present in 22/30 (73%)

patients, in small amounts (mean 1.4% of total ventricular mass)

Biochemical predictors of outcome

Brain Natriuretic Peptide

Eisenmenger syndrome (n=181, age 36.9±12.1 years, 31% with Down syndrome)

Schuuring MJ et al. Int J Cardiol 2015

WHO class and clinical events were not predictors of worse outcome

Implication of initiation of combo depending on NTproBNP and TAPSE and NOT on symptoms

How to improve outcome?

1. Avoid pitfalls

Background

• 16 year-old female cyanotic patient with Down syndrome is referred from a private cardiologist for evaluation

• 2 weeks ago she was prescribed macitentan from a periphery General Hospital with the diagnosis of VSD-Eisenmenger

How many pitfalls can you see here?

Pitfalls

1. No Right Heart Catheterisation !!

2. Macitentan is not indicated for Eisenmenger syndrome !

3. Give me some Cardiac Imaging please?

Right heart catheterisation (under GA)

• mPAP 17mmHg • RV 80/10 mmHg • Systemic pressures (Ao) 71/41 mmHg

Message

• Not all elevated right ventricular pressures are Eisenmengers!

AVOID PREGNANCY

Bedard et al EHJ 2009

30

17

3628

56

33

0

10

20

30

40

50

60

1997-2007 1978-1996

%

iPAHCHD-PAHoPH

p=0.047▪ Maternal mortality risk 30%

▪ Baby growth retardation risk 80%: premature

▪ Risk of spontaneous abortions

▪ Also interruption of pregnancy carries significant risks

Manes A, et al. Eur Heart J 2013

Survival rates of clinical subgroups of PAH-CHD

Survival rates in a predominantly adult population (n = 192) over a 20-year period

ES: Eisenmenger syndrome; SP: Systemic-to-pulmonary shunts; SD: Small defects; CD: Cardiac defect correction

0.00

Follow-up (years)

Sur

viva

l

5 10 15 20

0.2

0.4

1.0

0.8

0.6

ESPAH-SPPAH-SDPAH-CD

Log-rank p < 0.0001

ES 90 71 59 52 48 PAH-SP 48 22 18 11 10 PH-SD 10 4 4 2 0 PAH-CD 44 22 12 4 3

Patients at risk:

ESPAH-SP

PAH-SD

PAH-CD

Endocarditis Prophylaxis

Causes of CVA in cyanotic ACHD: iron deficiency and venesections

Risk of CVA is increased in the presence of:

• arterial hypertension,

• atrial fibrillation,

• history of phlebotomy and microcytosis (p = 0.005).

Ammash, Warnes, JACC 1996

Iron supplementation in cyanotic ACHD: Exercise capacity and QoL

Tay E, et al. IJC 2010

How to improve outcome?

BREATHE-5: Reduced PVR and increased 6-MWD

-400

-300

-200

-100

0

100

200

300

Placebo (n = 17)

Bosentan (n = 36)

PVR

(dyn·s·c

m-5

) C

hang

e fr

om b

asel

ine

-40-30-20-10

0102030405060

Placebo (n = 17)

Bosentan (n = 37)

6-M

WD

(m)

Cha

nge

from

bas

elin

e Galiè N, et al. Circulation 2006; 114:48-54.

TE = -472 dyn·s·cm-5, p = 0.038 TE = 53.1 m, p = 0.008

Long-term effect of PAH-advanced therapies in Eisenmenger patients

Diller GP, et al. Int J Cardiol 2012

PAH advanced therapies are associated with an improved outcome

A retrospective, single-centre study in 229 patients with ES

Dimopoulos K, et al. Circulation 2010; 121:20-5.

No advanced therapies

Advanced therapies

p=0.015

HR 0.16, 95% CI: 0.04-0.71

retrospective, single-centre study in 229 ES

patients

• Phase 3, multicenter, double blind, randomized, parallel-group, placebo-controlled study

• Treatment period: 16 weeks • Results expected in 2017 • Primary objective

– To evaluate the effects of Macitentan on Exercise Capacity in Subjects With Eisenmenger Syndrome

39

Design and Objectives

Acknowledgements Aristotle University of Thessaloniki

Pulmonary Hypertension Unit, AHEPA Hospital

Back up slides

6 months ago…

• 32 year-old female with 22q11.2 deletion syndrome and known Eisenmenger VSD followed by general cardiologists with a history of syncopal and presyncopal episodes for the last 8 months. She insists that she had been mildly symptomatic although she has limited her exercise capacity

• Under supplemental oxygen and dual oral PAH therapy (bosentan and sildenafil)

RHC (Fick)

Pressures Systolic Diastolic Mean

RA 6

RV 93 5

PAWP 11

PA 89 42 59

LV 120 0

SVO2: 40% CO: 1,87 (l/min) CI: 1,45 (l/min/m2)

PVR: 25.7 W PVRi: 33.0 (W/m2) Qp/Qs: 0,34

Thomas IC et al. Int J Cardiol 2013

Diller G et al. Circulation 2014

Diller G et al. Circulation 2014

1098 patients (median age 34·4years, range 16·1-84·4years, 65·1% female, 31·9% with Down syndrome)

Kempny et al, Submitted JAMA

The MUSES collaborationParameter Unit HR P-valueAge 10years 1·35 1·14 - 1·61 <0·001Pre-tricuspid shunt - 1·97 1·12 - 3·46 0·019Oxygen saturation at rest 10% 0·61 0·46 - 0·82 <0·001Six minute walking distance 100m 0·67 0·54 - 0·82 <0·001Presence of pericardial effusion - 2·35 1·33 - 4·13 0·003

95% CI

Kempny et al, Submitted JAMA

The MUSES collaboration

• Action 1: identify patients with PAH-CHD lost to follow-up and those followed in non-specialist centres

• Action 2: screen all congenital heart disease patients thoroughly for the presence of pulmonary arterial hypertension

• Action 3: educate cardiologists and pulmonary hypertension physicians on the distinct features of Eisenmenger syndrome

• Action 4: standardize treatment, avoid pitfalls, and challenge old myths in Eisenmenger syndrome

• Action 5: do not close defects in Eisenmenger syndrome or other PAH-CHD with established pulmonary vascular disease

• Action 6: use PAH therapies to improve exercise capacity, quality of life, and prognosis in Eisenmenger syndrome

• Action 7: be inclusive of other types of PAH-CHD, beyond Eisenmenger syndrome • Action 8: explore the concept of a ‘permissive’ trait genotype in patients with

large ASDs who develop out-of-proportion pulmonary arterial hypertension and Eisenmenger syndrome

• Action 9: promote clinical research and collaboration between specialist centres on areas of controversy and lack of evidence

• Action 10: support care of pulmonary arterial hypertension related to congenital heart disease patients in the developing world

Diller et al. Eur Heart J 2016

Thomas IC et al. Int J Cardiol 2013

C-reactive protein in adults with PAH-CHD

Allow patients to become more active

– Do housework – Garden – When watching TV, sit up instead of lying on the sofa. Or stretch. – Spend a few minutes pedaling on your stationary bicycle while watching TV. – Throw away your video remote control. – Get up off the couch and get your drink yourself. – Stand up while talking on the telephone. – Park farther away at the shopping centre/ work – Keep exercise equipment repaired and use it!

Dimopoulos et al Eur Heart J 2014

Death according to GFR

Cum

ulat

ive

Mor

talit

y(%

)

0 1 2 3 4 5 60

10

20

30

40

50

GFR<60ml/min/1.73m2

GFR=60-90ml/min/1.73m2

GFR>90ml/min/1.73m2

Time(years)

p<0.0001

p=0.03

p<0.0001

Dimopoulos et al. Circulation 2008

Renal dysfunction predicts adverse outcome in ACHD

Results Unadjusted mortality curves according to hyponatremia

Median follow-up of 4.1 years 96 deaths

Eisenmenger n=16 “Complex diagnoses” n=15 “Valvar” disease n=12 Mustard groups n=12,…

Patients at risk

825 730 592 515 321848Na>135mmol/l 142 125 113 92 72156Na ≤ 135mmol/l

0 1 2 3 4 5

Cum

ulat

ive

Mor

talit

y (%

)

10

20

30

Na>135mmol/l

Na ≤ 135mmol/l

Time(years)

Logrank p<0.0001

0

HR 3.26 (2.15-4.95)

Dimopoulos et al. Circulation 2010

Conclusions

• Never trust an Eisenmenger patient regarding WHO class • Prostanoids should be considered as a potential treatment modality

in ES patients who fail conventional therapy.

Take home messages• Prevalence • Immortal time bias • Prognosis vs iPAH • Prognosis inside ES differs (pre vs post capillary) • Treatment

Symptoms – worse exercise capacity

Kempny et al. Eur Heart J 2012