La gestione delle complicanze

e approcci personalizzati: dalla

letteratura all’esperienza clinica

C. Maiello, C. Amarelli

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

% o

f T

ran

spla

nts

0

5

10

15

20

25

30

35

0-10 11-17 18-34 35-49 50-59 60+ Mean Age

Mea

n d

on

or

age

(yea

rs)

HEART TRANSPLANTS: Donor Age by Year of Transplant

ISHLT

2009

Older donors: increased risk for the development of CAV

Hearts from older donors exhibit worse long-term renal function

Arterialhypertension

Loss of functional coronary reserve

(smokers, Diabetics)

Increased riskof EGF

Higher incidenceof LOS

Coronary Passenger

Atherosclerosis

CAV inHearts fromolder donors

ADULT HEART TRANSPLANT RECIPIENTS: Cause of Death (Deaths: January 1992 - June 2006)

CAUSE OF DEATH 0-30 Days

(N = 3,006)

31 Days –

1 Year

(N = 2,722)

>1 Year –

3 Years

(N = 2,135)

>3 Years –

5 Years

(N = 1,857)

>5 Years –

10 Years

(N = 4,054)

>10 Years

(N = 2,107)

CARDIAC ALLOGRAFT VASCULOPATHY

52 (1.7%) 127 (4.7%) 298 (14.0%) 299 (16.1%) 581 (14.3%) 309 (14.7%)

ACUTE REJECTION 193 (6.4%)338

(12.4%)220 (10.3%) 82 (4.4%) 69 (1.7%) 26 (1.2%)

LYMPHOMA 2 (0.1%) 54 (2.0%) 85 (4.0%) 96 (5.2%) 195 (4.8%) 73 (3.5%)

MALIGNANCY, OTHER 1 (0.0%) 57 (2.1%) 218 (10.2%) 340 (18.3%) 749 (18.5%) 392 (18.6%)

CMV 4 (0.1%) 34 (1.2%) 16 (0.7%) 3 (0.2%) 5 (0.1%) 1 (0.0%)

INFECTION, NON-CMV 393 (13.1%)896

(32.9%)276 (12.9%) 180 (9.7%) 442 (10.9%) 213 (10.1%)

GRAFT FAILURE 1,257 (41.8%) 500 (18.4%)

499 (23.4%) 379 (20.4%) 765 (18.9%) 353 (16.8%)

TECHNICAL 233 (7.8%) 28 (1.0%) 17 (0.8%) 17 (0.9%) 36 (0.9%) 20 (0.9%)

OTHER 162 (5.4%) 175 (6.4%) 187 (8.8%) 147 (7.9%) 339 (8.4%) 175 (8.3%)

MULTIPLE ORGAN FAILURE

356 (11.8%) 268 (9.8%) 117 (5.5%) 102 (5.5%) 309 (7.6%) 190 (9.0%)

RENAL FAILURE 20 (0.7%) 25 (0.9%) 36 (1.7%) 65 (3.5%) 225 (5.6%) 173 (8.2%)

PULMONARY 133 (4.4%) 108 (4.0%) 96 (4.5%) 85 (4.6%) 172 (4.2%) 99 (4.7%)

CEREBROVASCULAR 200 (6.7%) 112 (4.1%) 70 (3.3%) 62 (3.3%) 167 (4.1%) 83 (3.9%)

ISHLTLast updated based on data as of December 2006

2009J Heart Lung Transplant 2008;27: 937-983

AGE DISTRIBUTION OF HEART TRANSPLANT RECIPIENTS BY ERA

0

5

10

15

20

25

30

35

40

0-9 10-19 20-29 30-39 40-49 50-59 60-69 70+

Recipient Age

% o

f tr

an

sp

lan

ts

1982-1991 (N = 21,126)

1992-2001 (N = 40,356)

2002-6/2008 (N = 21,609)

P < 0.0001

ISHLT

2009

Impact of recipient age

Moresusceptible

to adverse events

More prone to developing

Metabolic Syndrome

Higher incidence of

post-transplantinfections

Higher IncidenceOf

Renal Dysfunction

Older recipients

Increased risk of tumour

Everolimus

Synergistic with CNIs (low rates of acute rejection)

Non-nephrotoxic

May be CNI and steroid-sparing

Possibly anti-atherogenic

Possibly anti-neoplastic

Synergistic with CNIs (enhanced nephrotoxicity)

Side effects:

– Hyperlipidemia

– Bone marrow suppression

– Impaired wound healing?

Why? Why not?

8

PSIs in KTx & HTx: chronic graft vascular disease & atherosclerosis

Favourable effects Unfavourable effects

CNIs minimization/ withdrawal Hyperlipidemia

– Hypertension– Hyperlipidemia– Diabetes– creatinine

creatinine (with full-dose CNI)

Acute rejections

CMV infection

Effect on (injured) vascular wall

Atherosclerotic Paradox (???)

Reduces acute rejection1

Is associated with a lower incidence of CMV infection2

Inhibits vascular remodeling2

Is not nephrotoxic3

Everolimus – targets the primary causes of progressive allograft dysfunction

1. Nashan B. Transplantation Proc 2001;33:3215–20.2. Eisen HJ et al. N Engl J Med 2003;349(9):847-858.3. Schuler W. et al Transplantation 1997;64:36-42

Esposizione alla CSA nei pazienti in everolimus

Efficacy improves with trough levels >3 ng/mL (Study 253)

Fre

edo

m f

rom

acu

te r

ejec

tio

n (

%)

100

90

80

70

60

50

40

30

20

10

0

0 25 50 75 100 125 150 175 200 225

Everolimus 3–8 ng/mL

Everolimus <3 ng/mL

AZA

Everolimus>8 ng/mL

Post-transplantation (Days)

Fre

edo

m f

rom

acu

te r

ejec

tio

n (

%)

100

90

80

70

60

50

40

30

20

10

0

0 25 50 75 100 125 150 175 200 225

Everolimus 3–8 ng/mL

Everolimus <3 ng/mL

AZA

Everolimus>8 ng/mL

Post-transplantation (Days)

100

90

80

70

60

50

40

30

20

10

0

100

90

80

70

60

50

40

30

20

10

0

0 25 50 75 100 125 150 175 200 225

Everolimus 3–8 ng/mL

Everolimus <3 ng/mL

AZA

Everolimus>8 ng/mL

Post-transplantation (Days)

RAD B253: Study Design

Randomization at first dose of

Certican

SAMPLE SIZE: *Study unblinded at 12 months

Primary efficacy failure: AZA 45%, Everolimus 30% 210 per treatment arm (two-sided alpha at 2.5%, power 80%)

HeartHeartTransplantationTransplantation

CerticanCertican 1.5 mg/day + full dose 1.5 mg/day + full dose NeoralNeoral,,AZA placebo + corticosteroidsAZA placebo + corticosteroids

AZA 1AZA 1--3mg/kg/day + full dose 3mg/kg/day + full dose NeoralNeoral,,Everolimus placebo + corticosteroidsEverolimus placebo + corticosteroids

CerticanCertican 3 mg/day + full dose 3 mg/day + full dose NeoralNeoral,,AZA placebo + corticosteroidsAZA placebo + corticosteroids

6 monthefficacy

4 yearextension

72 hrs

12 &24 month *safety/efficacy

IVUS

Baseline IVUS

634 Patients52 Centers

Randomization at first dose of

Certican

SAMPLE SIZE: *Study unblinded at 12 months

Primary efficacy failure: AZA 45%, Everolimus 30% 210 per treatment arm (two-sided alpha at 2.5%, power 80%)

HeartHeartTransplantationTransplantation

CerticanCertican 1.5 mg/day + full dose 1.5 mg/day + full dose NeoralNeoral,,AZA placebo + corticosteroidsAZA placebo + corticosteroids

AZA 1AZA 1--3mg/kg/day + full dose 3mg/kg/day + full dose NeoralNeoral,,Everolimus placebo + corticosteroidsEverolimus placebo + corticosteroids

CerticanCertican 3 mg/day + full dose 3 mg/day + full dose NeoralNeoral,,AZA placebo + corticosteroidsAZA placebo + corticosteroids

6 monthefficacy

4 yearextension

72 hrs

12 &24 month *safety/efficacy

IVUS

Baseline IVUS

634 Patients52 Centers

Everolimus adverse events profile

Body system Adverse reaction

Infections and infestations Viral, bacterial and fungal infections, sepsis

Blood and lymphatic system disorders

Leucopenia, thrombocytopenia, anaemia, coagulopathy

Metabolic and nutrition disorders

Hypercholesterolemia, hyperlipidemia,hypertriglyceridemia

Gastrointestinal disorders Abdominal pain, diarrhea, nausea, vomiting

Skin and subcutaneous tissue disorders

Acne, surgical wound complication

Selected Laboratory Abnormalities: Lipids on Study Drug Treatment (Study B253)

1.5 mg RAD 3.0 mg RAD AZA At month 12 (mmol/L)

Mean Cholesterol 5.7* 5.8* 5.2

Mean Triglycerides 3.1* 3.0* 2.1

Mean LDL-Cholesterol 3.1 3.0 2.9

Mean HDL-Cholesterol 1.3 1.3 1.3

*p<0.05, RAD vs AZA

Use of Statins (Study B253)

1.5 mg RAD 3.0 mg RAD AZA

Any HMG CoA 90.0% 90.5% 89.7%reductase inhibitor

Pravastatin 136 (65%) 136 (64%) 134 (63%)

Atorvastatin 69 (33%) 66 (31%) 57 (27%)

Simvastatin 36 (17%) 36 (17%) 33 (15%)

Fluvastatin 30 (14%) 32 (15%) 31 (14%)

Hyperlipidemia Esperienza del Centro di Napoli

MMF

RAD

Aza Mico RAD

Colesterolo 1 anno Trigliceridi 1 anno

Variables

0,0000

50,0000

100,0000

150,0000

200,0000V

alu

es

Report

Statistics : Mean

19218

2179

154

Wound Healing Complications

22

Adverse Events: Wound-Healing (Study B253)

1.5 mg Certican AZA

Lymphocele 4.8% 0.9%

Surgical wound compl. 5.7% 6.1%

Wound dehiscence 1.9% 0.5%

Pericardial effusion 23% 16.8%

Starting dose: 1–3 mg/day, no loading dose target level: 5–10 ng/mL

Kuppahally et al. Am J Transplant 2006

Complication Sirolimus(n=48)

MMF(n=46)

p value

All wound complications

25 (52.0%) 13 (28.2%) 0.019

Deep wound complication

0.012

– Sterile dehiscence 3 (6.3%) 0

– Sternal osteomyelitis

1 (2.1%) 0

– Mediastinitis/deep organ infection

13 (27.0%) 6 (13.0%)

Wound healing complications with de novo sirolimus versus MMF-based regimen in

cardiac transplant recipients

Wound healing complications (B253)

Event

RAD 1.5mg RAD 3.0mg AZA

P-valueN=209 N=211 N=214

Pat with sternal wound infection 18(8.6%) 18 (8.5%) 11(5.1%) n.s.

Wound complication (not LVAD site) 4 (1.9%) 4 (1.9%) 3 (1.4%) n.s.

Oozing/serous drainge (sternal site) 6 (2.9%) 14 (6.6%) 11 (5.1%)

n.s.

Wound dehiscence

-at sternal site

-- with infection

--wthout infection

-other

3 (1.45)

1 (0.55)

2 (1.0%)

1 (0.5%)

5 (2.4%)

1 (0.5%)

4 (1.9%)

0

2 (0.9%)

1 (0.55)

1 (0.5%)

0

n.s.

n.s.

n.s.

n.s

Lymphocele

-groin

-other

10 (4.8%)

5 (2.4%)

5 (2.4%)

9 (4.3%)

7 (3.3%)

2 (1.0%)

2 (0.9%)

1 (0.5%)

1 (0.5%)

0.065

n.s.

n.s.

Infezioni della ferita Esperienza del centro di Napoli

3% 3% 7% 7%0%

10%20%30%40%50%60%70%80%90%

100%

CSA/EVE CSA/MMF

No

InfezioneSuperficiale

Deiscenza

3135

Linfocele nei pazienti Redo con isolamento dei vasi femorali

Esperienza del Centro di Napoli

12%

0%

40%

0%

20%

40%

60%

80%

100%

CSA/EVE CSA/MMF CSA/EVERedo

No

Linfocele

3135 12

Edema Caso clinico

F 31 post-valvolare in pz già sottoposta (3° redo) a sostituzione valvolare aortica 01/03 e duplice intervento di SPA 04/03 per endocardite recidivante destruente dell’annulus e della giunzione M-Ao.(terzo intervento complicato da Mediastinite recidivante 05/03).

Ingresso in lista Luglio 2003 GFR 100ml/m2

Novembre 2006 scompenso di circolo con necessità di CVVH ed inotropi

Trapianto il 29.11.2006 in anticipo con organo in eccedenza (Rovigo 41 anni Trauma, ipotensione prolungata 4 h e ipossia di 20 min, Dopa 20 γ/Kg/min , ischemia 4.30)

CERTICAN DE NOVO Alla dimissione (01/07) GFR 19.3 ml/m2

Dopo 6 mesi GFR 20 ml/m2

Al 7° mese switch a MMF per Angioedema Dopo 1 mese GFR 36.2 ml/m2

Oggi GFR 56.3ml/m2

Event Everolimus1.5 mg/day(n = 209)

Everolimus 3.0 mg/day(n = 211)

Aza

(n = 214)

Significance

Pericardial/pleural effusion

Pleural effusion 32 (15.3%) 32 (15.1%) 31 (14.5%) n.s.

Mild pericardial effusion(no non drug therapy/no hospitalization)

12 (5.7%) 10 (4.7%) 12 (5.6%)

Moderate pericardial effusion (non drug therapy)

17 (8.1%) 14 (6.6%) 17 (7.9%) n.s.

Severe pericardial effusion (non drug therapy/hospitalization)

21 (10.0%) 25 (11.8%) 7 (3.3%) p < 0.01

Cardiac tamponade 5 (2.4%) 9 (4.3%) 3 (1.4%) p < 0.07 vs everolimus 3.0 mg/day

Patients with pericardial effusion and/or pleural effusion (B253)

Proteinuria

Diekmann et al, American Journal of Transplantation 2004; 4:1869-1875

20-30 -20 -10 0 10 20

Time after conversion (months)

0,2

0,3

0,4

0,5

0,6

0,7

0,8

-30 -20 -10 0 10

Time after conversion (months)

0,2

0,3

0,4

0,5

0,6

0,7

0,8

1/C

reati

nin

e

(dL/

mg)

Pre-conversion proteinuria below 0.8 g/day was the only predictor for positive outcome of conversion in a multivariate analysis

Predictors of success in conversion from CNI to

sirolimus in CAD

Responders

Non-responders

Corretto Timing dello switch

Proteinuria Esperienza del centro di Napoli

Su circa 50 Switch ad everolimus in mantenimento 5 pazienti attualmente sono in dialisi (in 2 pazienti switch per insufficienza renale)

Lo switch era stato in tutti i casi tardivo (creatinina >2,5mg/dl)

Il dosaggio della proteinuria delle 24 ore è entrato nella pratica clinica da circa 1 anno.

Infections

ADULT HEART TRANSPLANT RECIPIENTS: Cause of Death (1982-2001)

ISHLT Registry

0%

20%

40%

60%

80%

100%

0-30 Days (N = 3,144)

31 Days - 1 Year (N = 2,934)

>1 Year - 3 Years (N = 1,925)

>3 Years - 5 Years (N = 1,363)

>5 Years (N = 2,831)

Per

cen

tag

e o

f d

eath

s

Other

Technical

Graft Failure - Other

Primary Graft Failure

Infection, Non-CMV

Acute Rejection

CMV

Malignancy, Other

Lymphoma

CAV

0.25% 2.3% 1.1% 0.22% 0.11% CMV

Safety B253 Study

Viral Infections

CMV (%) 8.6* 8.1* 22.2

Herpes simplex (%) 8.1 5.7 10.7

Herpes zoster (%) 3.8 6.6 5.6

*p < 0.05 vs. AZA

Everolimus Everolimus AZA1.5mg 3.0mg

SirolimusViral Infections

CMV (%) 11.7 8.1 20.4

Herpes simplex (%) 17.7 29.3 15.9

Herpes zoster (%) 8.8 1.7 9.1

Keogh et al, Circulation 2004

Sirolimus Sirolimus AZA3mg 5mg

Fewer CMV infections with everolimus

*p<0.05 vs MMF or AZA

19

22

*8

*5

*8

*8

0

5

10

15

20

25

Pat

ien

ts (

%)

Everolimus

1.5 mg/day(n=194)

Everolimus

3.0 mg/day(n=198)

MMF2 mg/day(n=196)

AZA1–3 mg/kg/day

(n=214)

Renal transplants (Study 201)

Heart transplants (Study 253)

Everolimus

1.5 mg/day(n=209)

Everolimus

3.0 mg/day(n=211)

CMV infection in heart transplant recipients:association with impaired endothelial function

Petrakopoulou et al., Circulation 2004

D+/R-Recipient at risk

for survival

D+/R-Recipient at risk

for survival

737% versus 863%at 60 months

43

Infections (Study B253)

INFECTIONS 1.5 mg RAD 3.0 mg RAD AZA(N=209) (N=211) (N=214)

Viral 14.8%a 17.1%b 31.3%CMV 8.1%a 8.1%a 22.0%Herpes simplex 8.1% 5.7% 10.3%Herpes zoster 2.9% 5.7% 4.7%

Bacterial 33.0%a 37.9%b 24.8%

Fungal 7.7% 11.4% 8.9%Aspergillus 1.9% 2.4% 0.5%Candida 4.7% 8.5% 7.4%

a) RAD 1.5 mg vs AZA; b) RAD 3mg vs AZA; (p<0.05)

Infezioni da CMV Esperienza del centro di Napoli

20%

5%0%

64%

35%

3%

35%

21%

0%0%

20%

40%

60%

80%

CSA/EVE CSA/MMF TAC/MMF

Riattivazione

Trattamento

Malattia

35 31 15

ADULT HEART TRANSPLANT RECIPIENTS: Cumulative incidence of leading causes of death

(Transplants: January 1992 - June 2003)

0,0%

1,0%

2,0%

3,0%

4,0%

5,0%

6,0%

0 1 2 3 4 5 6 7 8

Time (years)

% c

au

se

-sp

ec

ific

de

ath

s

CAV Acute Rejection Malignancy (non-Lymph/PTLD)Primary Failure Graft Failure CMVInfection (non-CMV)

ISHLT 2005J Heart Lung Transplant 2005;24: 945-982

Pneumonia

Pneumonia post solid organ transplant

CAP ...

Months post-transplantation

1 65432Tx

S. aureus (MRSA)EnterobacteriaceaeNon-FermenterLegionella

Mycobacteria, NocardiaPneumocystis, Aspergillus, Cryptococcus

CMVRSV(Para)InfluenzaEBV

Opportunistic pneumonia

PneumococcusMycoplasmaLegionellaH. influencaS. aureusEnterobacteriaceae

HAP/VAP

Candida

Phase I Phase II Phase III

Infections leading to discontinuation of study medication – B253 study

Anemia (%) 0 5 (2.4) 1 (0.5)Leukopenia (%) 4 (1.9) 5 (2.4) 6 (2.8)Thrombopenia (%) 0 4 (1.9) 1 (0.5)

Infections (%) 4 (1.9) 10 (4.7) 4 (1.9)

Creatinine (%) 4 (1.9) 1 (0.5) 1 (0.5)Respiratory (%) 7 (3.3) 2 (0.9) 1 (0.5)

Adverse event Everolimus Everolimus AZA1.5 mg/day 3.0 mg/day

Bacterial and fungal infections in study B253

Bacterial (%) 33* 38* 25

Fungal (%) 7.7 11.4 8.9

Aspergillus (%) 2 2.4 0.5

Candida (%) 4.7 8.5 7.4

*p < 0.05 vs AZA

Everolimus Everolimus AZA1.5 mg/day 3.0 mg/day

Pneumocystis carinii and PSI (StudyB253)

Everolimus (B253) 0.47 1.4 0.45

PSI low PSI high AZA1.5 mg/day 3.0 mg/day

Infections Reported as AE’s /Study 2411

Everolimus (N=91)

MMF

(N=83)

n (%) n (%)Any infection 59 (64.8) 56 (67.5)Bacterial 29 (31.9) 30 (36.1)Fungal 9 (9.9) 2 (2.4)Viral 15 (16.5) 21 (25.3) Cytomegalovirus 3 (3.3) 14 (16.9)Other 10 (11.0) 13 (15.7)

Infezioni di ferita e PolmonitiEsperienza del centro di Napoli

14%

2%

28%

4%0%

6%0%

20%

40%

60%

80%

100%

CSA/EVE CSA/MMF TAC/MMF

Polmoniti

Ferita

No

1535 31

53

New Era in ImmunsuppressionNew Era in ImmunsuppressionIS scheme for all patientsIS scheme for all patients

Individualised ImmunsuppressionIndividualised Immunsuppression

Combination of drugs depending on risk factorsCombination of drugs depending on risk factors

highhigh lowlowpreTX rejection markers high (PRA‘s, posXM)preTX rejection markers high (PRA‘s, posXM)

Early rejectionEarly rejection

Late RetransplantationLate Retransplantation

InfectionsInfections

old Patientsold Patients

DiabeticsDiabetics

Skin-tumorsSkin-tumors

Side effectsSide effectscancercancer

recurrent rejectionrecurrent rejectionEarly development of graft vasculopathy or BOSEarly development of graft vasculopathy or BOS

54

55

0

20

40

60

80

100

Cyclosporine Tacrolimus Rapamycin MMF Azathioprine Prednisone

% o

f P

ati

en

ts

Year 1 (N = 4,072)

Year 5 (N = 2,928)

ADULT HEART RECIPIENTS Maintenance Immunosuppression at Any Time During Follow-up Period

For follow-ups between October 1999 and December 2001

ISHLT DATA 2002

0

20

40

60

80

100

CalcineurinInhibitor

CellCycle Prednisone CalcineurinInhibitor

CellCycle Prednisone

% o

f P

ati

en

ts

CyA

TacTac

CyA

AZA

AZA

MMF

MMF

ADULT HEART RECIPIENTS Maintenance Immunosuppression at Time of Follow-up

For follow-ups between October 1999 and December 2001

ISHLT DATA 2002

1 Year Follow-up (N = 3,165) 5 Year Follow-up (N = 2,588)

0%

20%

40%

60%

80%

100%

Year 1 (N = 3,165) Year 5 (N = 2,588)

% o

f P

ati

en

ts

None Given

Other

Tacrolimus + MMF

Tacrolimus + AZA

Cyclosporine + MMF

Cyclosporine + AZA

ADULT HEART RECIPIENTS Maintenance Immunosuppression at Time of Follow-up

For follow-ups between October 1999 and December 2001

ISHLT DATA 2002

POST-HEART TRANSPLANT MORBIDITY FOR ADULTS Cumulative Incidence for Survivors (April 1994-December 2000)

ISHLT DATA 2002

Outcome By 1 Year By 5 Years

Hypertension 72.4% (N=12,496)

95.1% (N=3,465)

Renal Function (N=12,511) (N=3,776)

Normal 74.8% 69.1% Renal Dysfunction 14.9% 17.6% Creatinine>2.5 mg/dl 9.0% 10.4% Chronic Dialysis 1.2% 2.5% Renal Transplant 0.2% 0.4%

Hyperlipidemia

48.7% (N=13,183)

81.3% (N=3,899)

Diabetes 24.1% (N=12,487)

32.0% (N=3,444)

CAV 8.2% (N=11,260) 33.2% (N=2,376)

HEART TRANSPLANTATION Actuarial Survival (1982-2001)

ISHLT DATA 2002

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Years Post-Transplantation

Su

rviv

al

(%)

N=60,936

Half-life = 9.3 yearsConditional Half-life = 11.8 years

0

20

40

60

80

100

Cyclosporine Tacrolimus Rapamycin MMF Azathioprine Prednisone

% o

f P

ati

en

ts

Year 1 (N = 5,068) Year 5 (N = 5,068)

ADULT HEART RECIPIENTS Maintenance Immunosuppression at Time of Follow-up

For the Same Patients(Follow-ups: January 2000 - June 2008)

ISHLT

Analysis is limited to patients who were alive at the time of the follow-up2009

0

20

40

60

80

100

Cyclosporine Tacrolimus Rapamycin MMF Azathioprine Prednisone

% o

f P

atie

nts

2000 (N = 1,503) 2003 (N = 1,610) July 2007 - June 2008 (N = 1,705)

ADULT HEART RECIPIENTS Maintenance Immunosuppression at Time of 1 Year Follow-up

NOTE: Different patients are analyzed in each time frame.

ISHLT

Analysis is limited to patients who were alive at the time of the follow-up2009

0%

20%

40%

60%

80%

100%

Year 1 (N = 5,068) Year 5 (N = 5,068)

% o

f P

ati

en

ts

None

Other

Tacrolimus

Cyclosporine

Rapa + cellcycle

Rapa + calcineurin

Tacrolimus + MMF

Tacrolimus + AZA

Cyclosporine + MMF

Cyclosporine + AZA

ADULT HEART RECIPIENTS Maintenance Immunosuppression Drug Combinations at Time of Follow-up

For the Same Patients(Follow-ups: January 2000 - June 2008)

ISHLT

Analysis is limited to patients who were alive at the time of the follow-up2009

POST-HEART TRANSPLANT MORBIDITY FOR ADULTS

Cumulative Prevalence in Survivors at 1, 5 and 10 Years Post-Transplant (Follow-ups: April 1994 - June 2008)

Outcome Within 1

Year

Total N with known

response

Within 5 Years

Total N with known

response

Within 10 Years

Total N with

known response

Hypertension 73.3% (N = 22,977) 93.3% (N = 9,853) 97.4% (N = 2,229)

Renal Dysfunction 27.2% (N = 23,581) 31.9% (N = 11,110) 38.3% (N = 3,077)

Abnormal Creatinine < 2.5 mg/dl 18.5% 21.6% 24.8% Creatinine > 2.5 mg/dl 7.0% 7.5% 7.4% Chronic Dialysis 1.4% 2.4% 4.7% Renal Transplant 0.3% 0.4% 1.5%

Hyperlipidemia 57.6% (N = 24,319) 87.7% (N = 11,093) 93.3% (N = 2,650)

Diabetes 27.8% (N = 23,623) 36.1% (N = 10,235) 38.6% (N = 2,392)

Cardiac Allograft Vasculopathy 7.8% (N = 21,357) 30.8% (N = 7,495) 51.9% (N = 1,542)

ISHLT

2009

POST-HEART TRANSPLANT MORBIDITY FOR ADULTS Cumulative Prevalence in Survivors within 1 and 5 Years

Post-Transplant (Transplants: 2000 - June 2003)For the Same Patients

Outcome Within 1

Year

Total number

with known response

Within 5 Years

Total number

with known response

Hypertension 76.3% (N = 2,324) 89.8% (N = 2,324)

Renal Dysfunction 26.9% (N = 2,324) 30.9% (N = 2,324)

Abnormal Creatinine < 2.5 mg/dl 20.4% 24.2%

Creatinine > 2.5 mg/dl 5.6% 4.6%

Chronic Dialysis 0.6% 1.7%

Renal Transplant 0.2% 0.3%

Hyperlipidemia 74.1% (N = 2,324) 91.3% (N = 2,324)

Diabetes 26.6% (N = 2,324) 38.7% (N = 2,324)

Cardiac Allograft Vasculopathy 5.2% (N = 2,324) 27.5% (N = 2,324)

ISHLT

2009

Renal Outcome in Selected young patients

Effetto in diverse categorie di GFR preoperatorio (MDRD)

7 Pazienti con GFR > 90:– 102,2 pre 100,1 1a

26 Pazienti con GFR 60-90:– 73,3 pre 53,4 1a

22 Pazienti con GFR < 60:– 50,7 pre 57,4 1a

1 Paziente con GFR < 30:– 26,1 pre 46,9 1a

Caso Clinico M 64 CMD post-ischemica in pz operato per endocardite

aortica post coronarografia (SVA+ Duplice BPAC) Ipertensione polmonare irreversibile con O2 e Flolan Dopo 3 mesi di Sildenafil3,6UW All’ingresso in lista per TC GFR 70,4 ml/m2 Dialisi

per scompenso di circolo Trapianto il 12.03.2007 in anticipo con organo marginale

(Torino 22 anni Trauma, arresto cardiaco di 5 min, Nora 0,14 γ/Kg/min, Adr 0,11 γ/Kg/min, ischemia 4.30)

CERTICAN DE NOVO Alla dimissione GFR 34,8 ml/m2 A 3 anni GFR 48,1 ml/m2 Attualmente GFR 58,52 ml/m2

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Years

Su

rviv

al

(%)

Half-life = 10.0 yearsConditional Half-life = 13.0 years

N=78,050

ISHLT

N at risk at 22 years: 145

HEART TRANSPLANTATION Kaplan-Meier Survival (1/1982-6/2007)

2009

ADULT HEART TRANSPLANTATION Kaplan-Meier Survival by Era (Transplants: 1/1982 – 6/2007)

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Years

1982-1991 (N=18,846)

1992-2001 (N=35,238)

2002-6/2007 (N=15,620)

All comparisons significant at p < 0.0001

HALF-LIFE 1982-1991: 8.8 years; 1992-2001: 10.5 years; 2002-6/2007: NA

Su

rviv

al (

%)

ISHLT

2009

71

Nell’ultimo anno 3 pazienti in Everolimus/MMF per Renal Dysfunction

Lessons learnt

Start PSI after delay post-transplantation (3–5 days) Induction therapy helps to delay therapy without increase Rejection

Rate Start with low dose (even 0,25 mg x 2 /die) Mantain chest tube until Dry If Necessary Open pleural cavity during transplantation to allow

drainage (redo) Routine use of ECHO (1 x week) to detect potential pericardial

effusion Sequential Therapy in redo requiring femoral vessels cannulation

There seem to be differences between sirolimus & everolimus with regard to wound healing in clinical trials

Lessons learnt

In Selected Patients Sequential Therapy Could Allow Reduction of the incidence of Adverse Events

– Patients with Perioperative Renal Disfunction– Patients requiring long Intubation– Obese Patients– Redo Patients– UNOS 1 patients (higher risk of long intubation)

Often these patients are also the best candidate to Everolimus

Lessons learnt

Switch to MMF may be valuable when severe proteinuria or Angioedema.

Renal Outcome depends from CSA trough level, Everolimus must always be used in a policy of CNI minimization.

In heart transplantation Hyperlipidemia and Skin Disorders are not a burden.

Older recipients CSA/Eve (Start with low dose)

Preoperative Renal Dysfunction

Always use EVE + low CNI dose

CMV mismatch Everolimus +/- Prophylaxis (VAL-G)

Paediatrics Everolimus +/- Tacrolimus

Patients with previousHBV HCV HIV or EBV Everolimus + Antiviral Therapy

Everolimus in special populations

Young Patients TAC/MMF

Older Donors CSA/EVE

Perioperative Renal Dysfunction

Exclude Proteinuria before start Everolimus

Proteinuria Avoid Everolimus or associate ACE-Inhibitors

All Patients in Eve Associate Statins If Tolerate

Everolimus in special populations