ipertensione polmonare postembolica-cteph

UNIVERSITY OF PAVIA SCHOOL OF MEDICINE - SAN MATTEO HOSPITAL - PAVIA - ITALY

Andrea M D’Armini, MD, FCCP

CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSIONFROM TRANSPLANT TO CONSERVATIVE SURGERY

Cardiac SurgeryUniversity of Pavia School of Medicine

Foundation I.R.C.C.S. “San Matteo” HospitalPavia, Italy


SURGICAL TREATMENT OF CTEPH: FROM TRANSPLANT TO CONSERVATIVE SURGERY

BACKGROUND

Chronic Thromboembolic Pulmonary Hypertension

Acute Pulmonary Embolism


• Chronic thromboembolic pulmonary hypertension (CTEPH) represents a sequel of non-resolved venous thromboembolism with fatal natural history due to chronic right ventricular failure

• Progress in surgical treatment over the past decade has considerably improved the outcome of CTEPH patients


BACKGROUND



INTRODUCTION

• CTEPH represents the only type of pulmonary hypertension surgically treatable, in the majority of cases, without transplant

• This life-saving conservative surgery is called pulmonary endarterectomy (PEA)


Vascular lung diseases suitable for transplantation are:

• Idiopathic Pulmonary Hypertension

• Eisenmenger’s Syndrome

• CTEPH


VASCULAR LUNG DISEASES


• Eisenmenger’s Syndrome

• Idiophatic Pulmonary Hypertension

1990 2011

Optimal Medical Therapy

BEFORE

HL/L Transplantation


VASCULAR LUNG DISEASES


• 1007 HEART TRANSPLANTS

• 309 LUNG TRANSPLANTS

• 39 HEART-LUNG TRANSPLANTS


THORACIC TRANSPLANTATION1355 TRANSPLANTS (17/11/1985 – 19/05/2011)

1355 INTRATHORACIC TRANSPLANTS


348 LUNG AND HEART-LUNG TRANSPLANTS• 79 VASCULAR LUNG DISEASES

• 269 PARENCHYMAL LUNG DISEASES




U. G. PRE DLTx U. G. 1° POST DLTx

DLTx for FAMILIAL PULMONARY HYPERTENSION




DLTx for FAMILIAL PULMONARY HYPERTENSION

RIGHT HEART CATHETERIZATION

PRE-DLTx 1° POST-DLTx

Right Atrium 13 9

Right Ventricle 118/0 25/0

Pulmonary Arterial Pressure 118/82/60 38/25/16 (-70%)

Systemic Arterial Pressure 96/76/61 113/73/53

Pulmonary Capillary Wedge Pressure 5 10

Cardiac Output 2.9 6.2 (+114%)

Cardiac index 1.6 4.0

Pulmonary Vascular Resistance 2134 155 (-91%)




HLTx for EISENMENGER’S SYNDROME

M. P. PRE HLTx M. P. 1° POST HLTx




HLTx for EISENMENGER’S SYNDROME

Systolic Pulmonary Arterial Pressure 105 mmHg

Right Ventricular End-Diastolic Diameter 110 mm

Inferior Vena Cava 34 mm

PRE-OPERATIVE ECHOCARDIOGRAPHY

Right Atrium 6 mmHg

Right Ventricle 23/0 mmHg

Pulmonary Arterial Pressure 23/11/6 mmHg

Pulmonary Capillary Wedge Pressure 6 mmHg

Cardiac Output 7.1 L/min

Cardiac Index 4.3 L/min/m2

Pulmonary Vascular Resistance 45 dyne*sec*cm-5

POST-OPERATIVE RIGHT HEART CATHETERIZATION




1990 2011

From Transplant

to Conservative Surgery (PEA)


SURGICAL TREATMENT OF CTEPHPAVIA EXPERIENCE - 356 PEAs

• CTEPH(NO SPECIFIC DRUGS ARE CURRENTLY APPROVED FOR CTEPH)



EPIDEMIOLOGY

• Epidemiologic data: in Italy ≈ 65.000 cases / year of acute symptomatic pulmonary embolism (PE)

• Prevalence of CTEPH in pts surviving an acute PE (≈ 80 %) is calculated between 0.5% – 3.8%

→ up to 2.000 new cases / year

• Considering asymptomatic pulmonary embolism and misdiagnosed pulmonary embolism, the true incidence of CTEPH may be even greater

• Jamieson SW, Kapelanski DP. Pulmonary endarterectomy. Curr Probl Surg 2000; 37:165-252

• Fedullo PF, Auger WR, Kerr KM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. N Engl J Med 2001; 345:1465-72

• Pengo V, Lensing AV, Prins MH, Marchiori A, Davidson BL, Tiozzo F et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004; 350:2257-64



CURRENT SITUATION

• CTEPH is still under-diagnosed and nowadays only few physicians are aware of the surgical procedure called PEA

• For all these reasons about 9000 PEA have been performed worldwide so far with ≈ 30 % of all cases carried out by the San Diego Group



NATURAL HISTORY

• Pulmonary embolism (symptomatic / asymptomatic)

• “Honeymoon” period: months / years

• Hypertensive remodeling of the patent pulmonary vascular bed (Eisenmenger-like)

• Right ventricle hypertrophy with progressive right heart deterioration right failure

• Left ventricle compression with left heart functional impairment



GENERAL CONDITIONS

• Low cardiac output with dyspnea, cough, cyanosis, hepatomegaly, ascites, lower limb edema, syncope, hemoptysis and interscapular olosystolic murmur

• Hypoxemia with exercise, sometimes at rest also

• Frequent positive anamnesis for deep venous thrombosis and / or coagulative and immunologic disorders



COAGULATIVE DISORDERS

DISORDER % PTS MEAN ± SD RANGE

HYPERHOMOCYSTEINEMIA (μmol/L) 72.6 % 21.7 ± 8.3 14.1 – 63.2

EXCESS FACTOR VIII ANTIGEN (%) 78.2 % 206.7 ± 33.9 161.1 – 392.9

EXCESS FACTOR VIII RISTOCETIN (%) 47.6 % 182.1 ± 46.6 150.0 – 334.0

EXCESS FACTOR VIII (%) 27.4 % 179.3 ± 25.8 153.4 – 220.0

PAI EXCESS (U/ml) 53.2 % 5.1 ± 1.2 3.6 – 7.9

FACTOR V LEIDEN 15.3 % 1.34 ± 0.55 0.50 – 1.99



IMMUNOLOGIC DISORDERS

DISORDER % PTS MEAN ± SD RANGE

Anti-Nuclear Antibodies (ANA) 23.4 % – –

Lupus Anticoagulant (LAC) 19.4 % – –

Anti-Cardiolipin Antibodies (ACA) IgG 20.2 % 56.3 ± 40.3 10.3 – 121.0

Anti-Cardiolipin Antibodies (ACA) IgM 13.7 % 30.8 ± 30.5 7.3 – 101.0

Anti-Phospholipid Antibodies (APA) IgG 14.5 % 63.2 ± 36.5 8.4 – 121.0

Anti-Phospholipid Antibodies (APA) IgM 12.9 % 28.0 ± 23.5 10.1 – 91.3

Positive Direct Coombs’ Test 8.9 % – –


• A PERMANENT INFERIOR VENA CAVA FILTER was placed before PEA in the majority (333/356) of patients

• Lifelong oral anticoagulation was prescribed after PEA


MARKED THROMBOPHILIA


• The indications for the surgical treatment of these patients are based on

CLINIC

HEMODYNAMIC

• The indications for the type of surgery are based on

ANATOMY


INDICATIONS FOR SURGERY



CLINIC

The clinical indication changes substantially

according to the different surgical treatment of CTEPH


• Age < 60 yrs

• WHO III or IV

• Contraindications

• Tx “window”

• Age is not a contraindication

• Symptomatic PH (WHO II-III-IV)

• Absence of severe pulmonary parenchymal disease

• Elective surgery

Tx PEA

TRANSPLANT WINDOW

TOO LATETOO EARLY


CLINIC


• Pulmonary hypertension (mPAP 25 mmHg)

• Pulmonary wedge pressure < 15 mmHg

• Causing low cardiac output

• Resulting in calculated pulmonary vascular resistances (PVR) > 300 dyne*sec*cm-5


HEMODYNAMIC

PRECAPILLARY PULMONARY HYPERTENSION


• The surgical treatment depends on the localization of the lesions in the pulmonary arterial branches

• Lesions can be classified asPROXIMAL

DISTAL


ANATOMY



ANATOMYPROXIMAL LESIONS



M.B. – 62 yrs M – Jul 2001 – PEA #64

Perfusion and ventilation scan

Pulmonary angiogram

Hemodynamic

mPAP 67CI 1.6PVR 1766



ANATOMYDISTAL LESIONS



S.S. – 31 yrs M – Sep 2002

Perfusion and ventilation scan

Pulmonary angiogram

Hemodynamic



• Growing single surgeon’s experience due to learning curve

Which lesions have to be considered as inoperable?

• Different operability assessments from different Centers

(operability ranges from 60 – 90 % from unpublished data)


OPERABILITY ASSESSMENT


Concomitant severe parenchymal lung disease is the real absolute contraindication to PEA

Such patients are not suitable for PEA and must be listed for DLTx (if indicated)


CONTRAINDICATION TO PEA



P.B. – 60 yrs M – Jun 2002

Perfusion and ventilation scintigraphy

Pulmonary angiography

CT scan

Hemodynamic




REFERENCE


• National referral program

• Begin: April 1994

• To date: 356 PEAs performed


OUR PROGRAM


55101

124

15

1916

28

7

47

205

18 153

6

14

Pts coming from outside Italy- Greece 1- Kosovo 1- Uganda 1

2

2

Pavia

≤ 10 pts

11 – 20 pts

≥ 21 pts


PATIENTS’ REFERRALOF 356 PEAs


0

10

20

30

40

50

60

70

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

Pat

ien

ts

65 PEAs in almost 8 yrs

65 PEAs in 1 yr


SURGICAL TREATMENT OF CTEPHPAVIA EXPERIENCE - 356 PEAs



MAIN WORLD PEA CENTERS

Paris, France≈100 PEAs / year

NATIONAL REFERRAL PROGRAM FOR EXCELLENCE

Cambridge, UK≈80 PEAs / year

NATIONAL REFERRAL PROGRAM BY LAW

Pavia, Italy≈60 PEAs / year

MORE THAN ONE PROGRAM

Bad Nauheim, Germany≈50 PEAs / year

MORE THAN ONE PROGRAM

San Diego, California, USA≈130 PEAs / year

NATIONAL REFERRAL PROGRAM FOR EXCELLENCE


08-MAR-1991

First HLTx for CTEPH

11-APR-1994

First PEA

28-JUL-2003

First PEA in patient listed for DLTx


SURGICAL TREATMENT OF CTEPH

25-DEC-1995

First DLTx for CTEPH


Tx for CTEPH

0

1

2

3

4

5

6

7

8

1991-1995 1996-2000 2001-2005 2006-2010

MO

RE DIA

GN

OSI

SM

ORE DISTAL PEAs


TRANSPLANT FOR CTEPH 18 / 79

PATIENTS DIAGNOSED WITH CTEPH

0

10

20

30

40

50

60

70

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

PEAs PERFORMED

0

10

20

30

40

50

60

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010



AMOUNT OF PATIENTSNEW EVALUATIONS

54

108

0

20

40

60

80

100

120

2004 2010

Pat

ien

ts

+ 100%



AMOUNT OF PATIENTSDIAGNOSTIC ACCURACY

34

82

20 260

10

20

30

40

50

60

70

80

90

2004 2010

Pat

ien

ts

IPCTE

Other

63%

76%

+ 13%



AMOUNT OF PATIENTSOPERABILITY RATE

25

73

9 90

10

20

30

40

50

60

70

80

2004 2010

Pat

ien

ts

Operable

Inoperable

74%

89%

+ 15%



AMOUNT OF PATIENTSPEAs PERFORMED

22

65

0

10

20

30

40

50

60

70

2004 2010

PE

As

+ 195 %



PAVIA CTEPH PROGRAMJanuary, 1st - December, 31st 2004 130 pts

EVALUATION (54 pts) FOLLOW-UP (72 pts) DLTx (4 pts)

CONFIRMED (34 pts - 63%) OTHER DIAGNOSIS (20 pts - 37%)

• RECENT EMBOLIZATION (3 pts) - 2 medical therapy - 1 surgical embolectomy

• TUMORS (5 pts) - 3 pulmonary angiosarcoma - 1 adenocarcinoma with pulmonary artery thrombosis - 1 intestinal tumor with liver metastases

• MISCELLANEOUS (12 pts)

OPERABILITY RATE 74 %

• PROXIMAL LESIONS (25 pts) - 22 PEAs - 2 pts refused - 1 pt died on evaluation

• DISTAL LESIONS (7 pts) - 5 DLTx waiting-list - 2 medical therapy (too old for DLTx)

• ASSOCIATION WITH SEVERE EMPHYSEMA (2 pts) - 2 DLTx waiting-list



PAVIA CTEPH PROGRAMJanuary, 1st – December, 31st 2010 231 pts

New Evaluations (108 pts) PEAs FUP (99 pts) Clinical Trials (23 pts) HLTx (1 pt)



• PROXIMAL LESIONS (73 pts) - 65 PEAs - 4 pts waiting for PEA - 3 pts refused PEA - 1 pt with severe co-morbidities

• DISTAL LESIONS (8 pts) - 8 medical therapy: 5 too old for DLTx 3 too early for DLTx


• MINIMAL CTE LESIONS WITHOUT PH (2 pts) - 2 medical therapy


• TUMOR (3 pts) - 3 pulmonary angiosarcoma

• ASSOCIATION WITH SEVERE EMPHYSEMA (1 pt) - 1 DLTx waiting-list



PAVIA CTEPH PROGRAMJanuary, 1st – May, 19th 2011 122 pts

New Evaluations (50 pts) PEAs FUP (56 pts) Clinical Trials (15 pts) DL/HLTx (1 pt)



• PROXIMAL LESIONS (26 pts) - 28 PEAs (4 pts evaluated in 2010) - 2 pts waiting for PEA

• DISTAL LESIONS (2 pts) - 2 medical therapy: 1 too old for DLTx 1 too early for DLTx


• TUMOR (1 pt) - 1 pulmonary angiosarcoma



PEA POPULATIONOF 356 PEAs

Age 56 16 (11 84) years

Gender 170 M – 182 F

NYHA class 31 II – 165 III – 156 IV

Length III / IV 19 23 months

Urgent / Emergent 74 / 352

Oxygen therapy 171 / 352



ECHOCARDIOGRAPHY



CARDIAC MAGNETIC RESONANCE



ARTERIAL BLOOD GASESOF 356 PEAs

Mean SD Range

Pa O2 65 10 43 97 mmHg

Pa CO2 31 7 24 43 mmHg

O2-sat 93 3 84 98 %



MODIFIED BRUCE TESTOF 356 PEAs

Steps Walking distance

No (Pa O2 < 60) 36.9% 103 ± 160 (0 – 852) meters

Step 0 - ½ 56.8%

Step 1 - 2 4.5%

Step 3 - 4 1.8%


Peak exercise

No (ECG, advanced NYHA IV, other) 16.3%

Watts 25 12.0%

Watts >25 / 50 50.0%

Watts >50 / 75 15.2%

Watts >75 6.5%


CARDIOPULMONARY EXERCISE TESTINGOF 200 PEAs



CARDIOPULMONARY EXERCISE TESTINGOF 200 PEAs

Mean SD Range

Peak-DP 16037 4822 5600 30600 mmHg*FC

Peak-VO2 9.9 3.6 3.0 29.4 ml/min/kg

Peak-Exe 50 22 15 160 watt



PULMONARY ENDARTERECTOMY


E.L. – 38 yrs M – Dec 1999 – PEA #42mPAP 43 20 (-53%)CO 3.3 6.9 (+109%)PVR 994 220 (-78%)


TYPICAL SURGICAL SPECIMENS

P.A. – 66 yrs M – Jun 2001 – PEA #60mPAP 50 25 (-50%)CO 2.6 4.4 (+69%)PVR 1385 364 (-74%)



DISTAL LESIONSJAMIESON TYPE IIILEARNING CURVE



JAMIESON TYPE I vs. TYPE II vs. TYPE III

L.M.E.L. - 65 yrs M - Oct 2004 - PEA #119mPAP 39 19 (-51%)CO 4.4 5.4 (+23%)PVR 665 222 (-66%)

G.A.C. - 52 yrs F - Jul 2003 - PEA #96mPAP 48 27 (-44%)CO 2.1 4.2 (+100%)PVR 1638 381 (-77%)

B.A. - 43 yrs F - May 2009 - PEA #233mPAP 49 19 (-61%)CO 3.3 5.0 (+52%)PVR 1067 224 (-79%)



JAMIESON TYPE III

B.A. - 43 yrs F - May 2009 - PEA #233mPAP 49 19 (-61%)CO 3.3 5.0 (+52%)RVEF 16 35 (+119%)PVR 1067 224 (-79%)


Pre-operative Pulmonary Angiogram

Pre-operative 64-HRCT

F.C. - 33 yrs F - Apr 2009 - PEA #225mPAP 52 20 (-62%)CO 4.6 4.7 (+2%)RVEF 32 41 (+28%)PVR 870 255 (-71%)


JAMIESON TYPE III




B.R.A. - 72 yrs FmPAP 44CO 2.9RVEF 28PVR 1159


INOPERABILE CTEPH?




B.R.A. - 72 yrs F - Mar 2009 - PEA #222mPAP 44 33 (-25%)CO 2.9 4.9 (+69%)RVEF 28 34 (+21%)PVR 1159 457 (-61%)

B.R.A. - 72 yrs FmPAP 44CO 2.9RVEF 28PVR 1159


JAMIESON’S TYPE III DISEASE




G.G. - 62 yrs FmPAP 51CO 2.6RVEF 19PVR 1415


INOPERABILE CTEPH?




G.G. - 62 yrs F - Sep 2009 - PEA #240mPAP 51 27 (-47%)CO 2.6 4.0 (+54%)RVEF 19 24 (+26%)PVR 1415 460 (-68%)

G.G. - 62 yrs FmPAP 51CO 2.6RVEF 19PVR 1415


JAMIESON’S TYPE III DISEASE



JAMIESON TYPE III

From July 2003 to date, 27 PEAs were performed in patients with

– age < 60 years

– severe dyspnea (WHO III – IV)

– distal CTEPH (Jamieson type III)

…otherwise they would have been listed for transplantation


A peculiar case: a “seasoned veteran” in CTEPH

XX-XX-1949

ITALIANVARESE

HOUSE PAINTER

150 cm

48 KgSystemic arterial hypertension

Gastroesophageal reflux disease

P. F. #255


JAMIESON TYPE III


JULY 2005Admission to the Cardiology ward of a local hospital

• ECG: right ventricle overload

• Echocardiogram: dilation and hypokinesia of the right chambers

severe tricuspid regurgitation

severe pulmonary hypertension (sPAP 85 mmHg)

• Lung V/Q scan: bilateral mismatches with multiple perfusion defects

• HRCT scan: multiple bilateral segmental perfusion defects

• Venous echocolordoppler of lower limbs : negative

JUNE 2004Onset of mild dyspnea (WHO II)

JUNE 2005Worsening of dyspnea (WHO III)

CTEPH


JAMIESON TYPE III



SEPTEMBER 2005Admission to our Division for operability assessment

• COMPLETE DIAGNOSTIC WORKUP: CTEPH CONFIRMED

• Right Heart Catheterization: RA 1 mmHg

RV 82 / 0 mmHg

PA 82 / 39 / 13 mmHg

PCWP 3 mmHg

CO 3.3 L/min

CI 2.2 L/min

RVEF 25 %

PVRP 873 dyn*s*cm-5

• OPERABILITY: INOPERABLE FOR EXCLUSIVELY DISTAL DISEASE

DOUBLE LUNG TRANSPLANT WAITING LIST


JAMIESON TYPE III



LUNG V/Q SCAN

VENTILATION PERFUSION


JAMIESON TYPE III



PULMONARY ANGIOGRAM


JAMIESON TYPE III



HRCT SCAN


JAMIESON TYPE III



DECEMBER 2005Enrollment in the BENEFIT study

(bosentan vs. placebo in inoperable forms of CTEPH)

Enrollment

27-DEC-2005

End of study (16 weeks)

28-APR-2006

Open label extension

26-OCT-2006

RA 4 4 6 mmHg

RV 82/2 82/0 85/3 mmHg

PA 82/46/24 82/45/22 85/49/28 mmHg

PCWP 5 5 5 mmHg

CO 3.1 2.4 3.0 L/min

CI 2.1 1.6 2.0 L/min/m2

RVEF 34 11 12 %

PVR 1057 1343 1164 dyn*s*cm-5

Serum-BNP 360 324 151 pg/ml

WHO III III II

INOPERABILITY CONFIRMED BY THE INTERNATIONAL COMMITTEE


JAMIESON TYPE III



BENEFIT and BENEFIT-OPEN LABEL EXTENSIONClinical course

6mWT

270290

480456 462

442418

0

100

200

300

400

500

600

Dec-05 Apr-06 Oct-06 May-07 Oct-07 May-08 J an-09

Follow-up

me

ters

15-FEB-2008 Withdrawal from DLTx waiting list

WHO III WHO II

BENEFIT-Open LabelBENEFIT


JAMIESON TYPE III



BILATERAL PULMONARY ENDARTERECTOMY

Right: upper, middle and lower lobeLeft: upper lobe, lingula and lower lobe

Moderate hypothermia (23° C)

Intermittent circulatory arrests right side: 91 minleft side: 47 mintotal time: 138 min

OCTOBER 2009Worsening of dyspnea (back to WHO III)

NOVEMBER 2009Admission to our Division for therapy update

NEW OPERABILITY ASSESSMENT → NOW TECHNICALLY OPERABLE

(JUST ALIKE THE PREVIOUS FINDINGS)


JAMIESON TYPE III



BILATERAL PEA – SURGICAL SPECIMEN


JAMIESON TYPE III



Preoperative

27-NOV-2009

At discharge

15-DEC-2009

3 months FUP

26-FEB-2010

RA 7 3 3 mmHg

RV 120/0 53/0 35/0 mmHg

PA 120/65/36 53/22/8 35/19/12 mmHg

PCWP 5 5 5 mmHg

CO 3.5 3.9 4.2 L/min

CI 2.4 2.7 2.9 L/min/m2

RVEF 6 18 21 %

PVR 1371 308 267 dyn*s*cm-5

Serum-BNP 996 742 106 pg/ml

WHO III I I

– 81 %

BILATERAL PEAHemodynamic results


JAMIESON TYPE III



The “seasoned veteran”

DIAGNOSIS

TRANSPLANT WAITING LIST

SPECIFIC MEDICAL THERAPY PULMONARY

ENDARTERECTOMY(Gold Standard)


JAMIESON TYPE III

SPECIFIC PAH-DRUG DISCONTINUATION


0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180

Months after PEA

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%P

erc

ent

age


CUMULATIVE PROPORTION SURVIVINGOF 356 PEAs

Operative mortality Global 32/356 (9.0%) NYHA II 0/32 (0.0%) NYHA III 8/165 (4.8%) NYHA IV 24/159 (15.1%)

Jan 08 – May 11 13/182 (7.1%)

187 144 125 108 91 71 54 42 33 30 22 14 7 3 2

89.21.9 87.12.

2 86.52.2

85.62.4 84.52.

6 83.12.9 81.63.

2 79.23.9

79.23.9



CUMULATIVE PROPORTION SURVIVING45 PTS ON WAITING LIST FOR TRANSPLANT IN CTEPH

SURVIVALWAITING LIST FOR TRANSPLANT IN CTEPH

0 365 730 1095 1460 1825 2190 2555 2920 3285 3650 4015 4380

Time (days)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Cum

ulat

ive

Prop

ortio

n Su

rviv

al



CUMULATIVE PROPORTION SURVIVING18 TRANSPLANTS IN CTEPH

SURVIVALTRANSPLANT IN CTEPH

0 365 730 1095 1460 1825 2190 2555 2920 3285 3650 4015 4380 4745 5110 5475

Time (days)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Cum

ulat

ive

Prop

ortio

n Su

rviv

al



FOLLOW-UP

In literature few data are reported on mid- and long- term cardiopulmonary function, particularly on exertion, and on clinical outcomes after PEA



FOLLOW-UP TIMING

• All pts underwent follow-up evaluation at:– discharge (at this interval NYHA class, lung function, and exercise

tolerance are excluded because pts are to close to the surgical procedure)

– 3th month

– yearly for 5 years

– 7th, 10th and 15th year (10 controls)



NYHA FUNCTIONAL CLASS

NYHA Functional Class

0

10

20

30

40

50

60

70

80

90

100

Pre-op 3 mesi 1 anno 3 anni 5 anni 7 anni 10 anni

Follow-up

% p

ati

ents

I -I I

I I I -IV

Pre-op 3m 1y 3y 5y 7y 10y

pp < 0.01 < 0.01



mean PULMONARY ARTERY PRESSURE

mean Pulmonary Arterial Pressure

0

10

20

30

40

50

60

Pre-op Dimiss 3 mesi 1 anno 3 anni 5 anni 7 anni 10 anni

Follow-up

mm

Hg

pp < 0.01 < 0.01

Pre-op disch 3m 1y 3y 5y 7y 10y



PULMONARY VASCULAR RESISTANCES

Pulmonary Vascular Resistances

0

200

400

600

800

1000

1200

Pre-op Dimiss 3 mesi 1 anno 3 anni 5 anni 7 anni 10 anni

Follow-up

dyne*se

c*cm

-5

pp < 0.01 < 0.01

Pre-op disch 3m 1y 3y 5y 7y 10y



ECHOCARDIOGRAPHYBefore PEA



ECHOCARDOGRAPHYFirst echo after PEA – POD #9



ECHOCARDIOGRAPHY3-months FUP after PEA



CARDIAC MAGNETIC RESONANCEBefore PEA First CMR after PEA – POD #6



CARDIAC MAGNETIC RESONANCE4-years FUP after PEAFirst CMR after PEA – POD #6



ARTERIAL OXYGEN PARTIAL PRESSURE

Arterial Oxygen Partial Pressure

0

10

20

30

40

50

60

70

80

90

100


Follow-up

mm

Hg

pp < 0.01 < 0.01




MODIFIED BRUCE TEST

Modified Bruce Test

0

100

200

300

400

500

600

700

800

900

1000


Follow-up

met

ers

pp < 0.01 < 0.01




RESULTS• The majority of pts experienced dramatic improvement in

pulmonary hemodynamics after PEA

• After PEA the decrease in pulmonary artery pressure is immediate (in O.R.) and associated with complete recovery of RV morphology (at discharge)

• The functional results also show a progressive good recovery over a longer time (about years)



RESULTS

• About 10-15% of our pts showed no statistically significant differences compared to pre-op or a persistent PH after PEA

• About 5-10% of our pts showed a new increase in pulmonary pressure after PEA over time

• The reason could be a secondary small vessel arteriopathy (Eisenmenger-type syndrome) in the non-obstructed segments of the lungs already present at the time of PEA


PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE

MEDICAL THERAPYINOPERABLE CTEPH OR

RECURRENT PH AFTER PEA



OPERABILITY ASSESSMENT

Some patients can not undergo PEA, due to:

• Significant comorbilities (i.e.: severe parenchymal lung disease, malignacy)

• Pulmonary arteries retraction following long lasting total obstruction

• Exclusively distal lesions

CLINICAL TRIAL TARGET


Pre-operative V/Q scan

Pre-operative right pulmonary angiogram

Pre-operative RHCmPAP 50CI 1.4PVR 1241RVEF 9

Extensive obstruction of the right proximal PA branches; only sub-segmental lesions on the left PA


PRE-OPERATIVE LONG LASTING DISEASE


• A right monolateral PEA was performed

• Impossible to wean off the patient from cardio-pulmonary by-pass due to right ventricle failure

• On ECMO for two days; the sternum was left open for two more days

• Mechanical ventilation 9 days ICU stay 14 days Hospital stay

21 days

First PO RHC controlmPAP 26 (-48%)CI 2.0 (+43%)PVR 410 (-67%)RVEF 25 (+178%)




Pre-operative

• “Steel” phenomenon in the non dissected branches (left lung) present at first control (before discharge)

• Usually reversible since the third month FUP

• In this case only partially reversibleBefore discharge

3-month FUP 1-year FUP 2-year FUP




Riedel M. Chest 1982;81(2):151-8.

• No CT-scan evidence of new thromboembolic material

• Very long pre-operative NYHA III-IV class period (65 months): probably severe and non-reversible small vessels disease

RHC data FUP: 2 years

mean Pulmonary Artery Pressure

0

10

20

30

40

50

60

Before PEA Discharge 3 months 1 year 2 years

Cardiac Index

0.0

0.5

1.0

1.5

2.0

2.5


Pulmonary Vascular Resistances

0

200

400

600

800

1000

1200

1400


Right Ventricle Ejection Fraction

0

5

10

15

20

25

30

35




TYPICAL PATIENT WITH

RECURRENT PH AFTER PEA



PAVIA CTEPH PROGRAMJanuary, 1st - December, 31st 2009 142 pts

NEW EVALUATIONS (99 pts) PEAs FOLLOW-UP (43 pts)



• PROXIMAL LESIONS (62 pts) - 54 PEAs - 1 pt waiting for PEA - 4 pts refused PEA - 2 pts with “too old” lesions (pulmonary artery retraction) - 1 pt general condition too compromised

• DISTAL LESIONS (8 pts)

- 8 medical therapy: 5 too old for DLTx 3 too early for DLTx


• MINIMAL CTE LESIONS WITHOUT PH (4 pts) - 4 medical therapy

9 CHEST SCREENING

- 6 INOPERABLE CTEPH

- 3 PH AFTER PEA




HIGHER ENROLLING CENTERS FEATURES

National referral program

Higher patients amount

Higher operability rate

ANYWAY

number of inoperable patients

won’t be affectedCLINICAL TRIAL TARGETS


Higher operability rate


HIGHER ENROLLING CENTERS FEATURES

More Jamieson type III PEAs

CLINICAL TRIAL TARGETS

Higher PH recurrence after PEA



PH – MEDICAL THERAPHY


No drugs are currently approved for CTEPH


CTEPH – MEDICAL THERAPHY

Further clinical trials are needed



BENEFiT STUDY



BENEFiT STUDY

STUDY DESIGN

• Phase III, randomized vs. placebo (1:1)

• International multicentre (26 sites in 13 Countries)

• 157 pts (18 – 80 yrs)

• CTEPH - inoperable (exclusively distal lesions)- persistent or recurrent PH after PEA

• WHO functional class II – IV

• 6mWT distance < 450 m

Jaïs X, D’Armini AM, Jansa P et al. J Am Coll Cardiol 2008 Dec 16;52(25):2127-34



BENEFiT STUDY



*Analysis excluded patients judged operable by the Operability Evaluation Committee (n=11)

†Analysis excluded patients with missing baseline or post-baseline assessment(s) (n=9 for pulmonary vascular resistance [PVR] analysis; n=6 for 6-min walk distance [6MWD] analysis)

mPAP = mean pulmonary artery pressure mRAP = mean right atrial pressure

NT-proBNP = N-terminal pro-brain natriuretic peptide; PEA = pulmonary endarterectomy; TPR = total pulmonary resistance; WHO = World Health Organization.


BENEFiT STUDY




BENEFiT STUDY




CHEST STUDY

RATIONALERATIONALERIOCIGUAT Soluble guanylate-cyclase stimulatorRIOCIGUAT Soluble guanylate-cyclase stimulator

Chronic Thromboembolic Pulmonary Hypertension sGC-Stimulator Trial

riociguat



CHEST STUDYChronic Thromboembolic Pulmonary Hypertension

sGC-Stimulator Trial

• Phase III, double-blind, randomized vs. Placebo (2:1)• International, multicenter (28 Countries)• N = 270 pts (18 – 75 yrs)• Inoperable CTEPH (peripheral localization) or recurrent

PH after PEA• PH pts WHO II-IV• 6 MWD > 150 m and < 450 m• PVR > 480 dyne*sec*cm-5

• mPAP > 25 mmHg riociguat



CHEST STUDYHIGHER ENROLLING CENTERS FEATURES

• Lower screening failures rate in Centers where an expert surgeon is actively involved in the operability assessment

• National referral program with high patients amount

• Good quality of imaging and expertise of radiologists

• Active PEA Program with scheduled follow-up visits


• Slow recruitment

– each Center should NOT participate in more than one clinical trial for CTEPH (rare disease)

• High screening failure rate

– careful evaluation before screening

• Furthermore, it’s becoming more and more difficult to see untreated CTEPH patients (eligible for clinical trials)


CHEST STUDYOPEN QUESTIONS


CHEST STUDIES: THE PAVIA EXPERIENCE

CHESTTOP 5 ENROLLING CENTERS



CONCLUSION

• Poor survival rate of untreated pts (10% 5-yrs survival if mPAP 50 mmHg), low mortality rate after PEA and good mid- and long- term results confirm PEA as the procedure of choice for operable CTEPH pts

• The improvement of functional capacity strictly depends on the hemodynamic changes after PEA

• When CTEPH is diagnosed, given the natural history of the disease, patients should be referred for surgery even when in NYHA functional class II


• CTEPH pts should be referred early to Centres experienced in both PEA and Tx, to offer the best treatment and to achieve the best results

• This strategy maximizes the use of scarce donor organs by offering, when feasible, a non-transplant option


CONCLUSION



PAVIA PULMONARY ENDARTERECTOMY GROUP

• Cardiac Surgery M Viganò, AM D’Armini, G Silvaggio, S Nicolardi, M Morsolini, G Mattiucci

• Anestesiology M Maurelli, T Bianchi, R Veronesi, M Toscani, C Dezza,

E Milanesi, B Lusona, B Rossini• Critical Care A Braschi, V Emmi, G Rodi, G Sala Gallini

F Capra Marzani, M Zanierato, F Mojoli• Cardiology L Oltrona Visconti, S Ghio, A Raisaro, L Scelsi, C

Raineri• Respiratory Disease M Luisetti, I Cerveri, A Corsico• Radiology I R Dore• Radiology II F Zappoli Thyrion, P Quaretti, A Azzaretti, G

Rodolico• Nuclear Medicine C Aprile• Reumatology C Montecucco, R Caporali• Thromboembolism F Piovella, M Barone, C Beltrametti• Pathology E Arbustini, M Grasso• General Rehabilitation E Dalla Toffola, L Petrucci• Pulmonary Rehabilitation C Fracchia, G Callegari• Biostatistics C Klersy

ipertensione polmonare postembolica-cteph

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