Università Magna Græcia di Catanzaro

Dipartimento di Medicina Sperimentale e Clinica

Cattedra di Medicina Interna ed U.O. Malattie Cardiovascolari

Prof. Francesco Perticone

Update Scompenso Cardiaco:

Trattamento Chirurgico o Farmacologico?

Ischemia

Ricanalizzazione

& riperfusione

“ No reflow “

“R E A L T Á”

Activation of RAS and SNS

Growth andfibrosis

Ischemia andEnergy depletion

Apoptosis

CAD progression

Necrosis

RemodelingRemodeling

Altered geneexpression

Myocardial DisfunctionMyocardial Disfunction Reinfarction

Cell DeathCell Death

Control Acute Compensated Decompensated

Heart Failure, clinical status

AC

E a

cti

vity

Tissue

Plasma

ACE Activity in

Heart Failure

Metanalisi degli studi SAVE, AIRE e TRACE del trattamento con ACE-inibitori in pazienti con scompenso cardiaco o disfunzione ventricolare sinistra nel corso di infarto miocardico

(ACE Inhibitor Myocardial

Infarction Collaborative Group,

Lancet, 2000)

mortalità

controlli

trattati

23.4%

29.1%

OR (95% IC)

0.74 (0.66-0.83)

ACE inibitori nel post-infarto

CONSENSUS I

V-HeFT II

SOLVD

SOLVD-P

Ve

ntr

icu

lar

dysfu

ncti

on

an

d/o

r C

HF

se

veri

ty

Time since AMI

24 h 16 days

ISIS-4GISSI-3CCS-1CONSENSUS IICAPTINCAST

• HOPE• QUIET• PEACE• ALLHAT• EUROPA

• HOPE• QUIET• PEACE• ALLHAT• EUROPA

SMILESMILE

AIRE

SAVE

AIRE

SAVE

VALIANTVALIANT

Rimodellamento Ventricolare dopo IMA

Fase acuta Rimodellamentoprecoce tardivo

0

5

10

15

20

25

30

35

0 1 2 3 6 9 12

An

gio

ten

sin

a I

I (p

g/m

l)

0

40

80

120

160

Ald

oste

ron

e (p

g/m

l)

Il Fenomeno dell’Escape del Sistema RAAin Corso di ACE-inibizione

mesi

SPIRONOLATTONE

PLACEBO

Pro

ba

bilit

à d

i S

op

ravvi

ven

za

0 3 6 9 12 15 18 21 24 27 30 33 36 mesi

P < .001

0.00

0.45

0.50

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Placebo

Spironolattone

N° a rischio

841 775 723 678 628 592 565 483 379 280 179 92 36

822 766 739 698 669 639 608 526 419 316 193 122 43

B Pitt et al. N Engl J Med 1999;709-717

RALES

Pharmacologic Effects

vs

Biologic Effects

Le “sorprese” dei grandi trial

Ace-inibitori, sartani e ....

• prevenzione primaria della disfunzione

ventricolare e dello scompenso

•prevenzione degli eventi coronarici

• prevenzione degli eventi cerebrovascolari

• prevenzione della fibrillazione atriale

• prevenzione del diabete mellito

The Concept of ADLG (Average Duration of Life Gained)

Time

Pro

po

rtio

n o

f p

ati

en

ts a

live

TreatedTreated

UntreatedUntreated

1.0

0.0

Qual’ è la reale capacità degli ACE-I di prolungare la sopravvivenza ?

ADLG

9 mesi

3 mesi

1 mese

15 mesi

rischio relativo

27 %

16 %

7 %

18 %

Modello clinico

CONSENSUS I

SOLVD

GISSI / ISIS / CCS

TRACE

Randomised Clinical Trials in CHF

Trial

CONSENSUSRALESCOPERNICUSBESTCIBIS IIV-HeFT IISOLVD-TUS CARVEDILOLMERIT-HFSAVEELITE IIVal-HeFTELITE I

Annualized placebomortality rate

58.0 %24.0 % 18.5 %16.6 %13.2 %12.5 %11.8 %11.1 %11.0 %10.5 %10.4 %10.0 %8.7 %

HEART FAILURE

Pathophysiological Abnormalities

structural remodeling and dilation of LV

reduced myocytes shortening and wall motion

Na retention and circulatory congestion

vasoconstriction and vascular remodeling

neurohormonal activation

ATTIVAZIONE SIMPATICACONSEGUENZE SFAVOREVOLI

• Aumento del lavoro cardiaco

• Riduzione della perfusione coronarica

• Aumento del pre e post-carico

• Ritenzione idrica e congestione del circolo

• Ischemia e necrosi miocardica

• Ipokaliemia e aritmie

Terapia Ottimizzata per lo Scompenso: Importanza della Normalizzazione del BNP

Troughton et al. Lancet. 2000;355:1125-30.

NT-BNP tritrated group (n=33)

Usual care group (n=36)

Time after randomisation (weeks)

0 30 60 90 120 150 180

Heart failure or death

Pa

tie

nts

re

ma

inin

g e

ve

nt-

fre

e (

%)

0

50

60

70

80

90

100

P = .49

Tempo (mesi)

* BNP

Plasmatico

(pg/mL)

n = 844 PlaceboBasale = 177.6

ValsartanBasale = 183.5

n = 1890

n = 1710

n = 1850n = 1633

n = 823

P < 0.001 P < 0.001P < 0.001

0 4 12 24-40

-30

-20

-10

0

10

20

Latini R et al. J Card Fail. 2001;7(Suppl 2):Abstract 198.

Variazione dei Livelli Plasmatici di BNP

*Media ± SEM

Trial n Reduction in p value

relative risk

CIBIS-I 641 -20% ns

CIBIS-II 2647 -34% p<0.0001

ANZ 415 -23% ns

US Carvedilol 1094 -65% p<0.001

MERIT-HF 3991 -34% p=0.0062*

*Adjusted for two interim analyses

-Blockade in Mild-to-Moderate Heart FailureMortality Reduction

Normale

1 11

11

11

1

2 2

11 1

Scompenso cardiaco

1

2

2

2

2

1

1 1

1

1

11 2

2a1

a1

Lo Scompenso Cardiaco Modifica la Densità

dei Recettori Adrenergici nel Miocardio

CHARM-Added and Val-HeFT (CV death or hospitalization for HF)

Placebo Candesartan Placebo Valsartan

Events/treated 538/1272 483/1276 737/2499 650/2511

% 42.3 37.9 29.5 25.9

HR 0.85 0.86

95% CI 0.75-0.96 0.77-0.95

P value 0.011 0.004

%

42.3%

29.5%

37.9%

25.9%

0

10

20

30

40

50

CHARM Val-HeFT

Placebo Candesartan Valsartan

Granger CB et al. Lancet. 2003;362:772-776.

Cohn JN et al. N Engl J Med. 2001;345:1667-1675.

CHARM-Added: Prespecified subgroups, CV death or CHF hosp.

Beta- Yes 223/702 274/711

blocker No 260/574 264/561

Recom. Yes 232/643 275/648

dose of No 251/633 263/624

ACE inhib.

All patients 483/1276 538/1272

Candesartan Placebo

candesartan better

Hazard ratio

placebo better

0.6 0.8 1.0 1.2 1.4

p-value fortreatment interaction

0.14

0.26

Komajda M et al. Eur Heart J 2003

Utilisation of Blockade for CHFin Clinical Practice

32.721.2 20.5 17.2

61.8

36.9 35.7

86.9

0

50

100

Perceptions

Regarding Tolerability of Blockade in CHF

• Complexity in initiation and up-titration

• Risk of intolerance and / or worsening of CHF symptom status esp. with initiation

• Delay in beneficial effects on outcomes

• All of the above esp. true in patients with advanced disease

Cardiologo

Internista Geriatra

Medico di MG

Esistono differenze di trattamento

a seconda dei medici?

Cardiologi Internisti P

NYHA I-II <15% 50% 0.01

Età media 68±19 72±6 0.01

Ecocardiogramma 49% 34% 0.01

Uso diuretici 87% 76% 0.02

Inotropi ev 9% 1,3% 0.02

Reospedalizzazione 30% 44% 0.04

Reis SE et al. J Am Coll Cardiol 1997;30:733-8

CHF Hospitalization: Specialty Related

Disparities in Practice Patterns and Outcome

Cardiologi GP P

Maschi 78% 42% <0.001

Età Media 64,2 78,2 <0.001

Eco 97% 12% <0.001

Rx Torace 84% 51% <0.001

Coronarografia 26% 3% <0.001

C. Ischemica 56% 31% <0.001

ACE-I 76% 40% <0.001

Betabloccanti 30% 8,7% <0.001

Spironolattone 32% 11% <0.001

Dicumarolici 29% 6,8% <0.001

Rutten FH et al. Eur J Heart Failure 2003;5:337-44

Differences Between Practioners and Cardiologists in

Diagnosis and Management of Heart Failure: A Survey in

Every-day Practice

37%

92%

3%

25%

0,30%

12%

0,50%

20%

0%

20%

40%

60%

80%

100%

Echo Holter Angio TE

Medicina Cardiologia

Procedure eseguite durante il ricovero

Eur Heart J 2001;22:506

75%

16%

9%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Medicina Cardiologia Altri Reparti

DRG 127 in Lombardia, Liguria e Toscana

1997

TERAPIA FARMACOLOGICA DURANTE LA DEGENZA

TEMISTOCLE

(hearT failurE epideMIological STudy FADOI-ANMCO in itaLian pEople)

Medicine(n. 1338)

Cardiologie(n. 789)

p

Inotropi 14.3% 25.6% <.0001ACE-inibitori 73.0% 70.5% NSDigitale 70.2% 64.4% 0.0056Furosemide 95.5% 95.7% NSSpironolattone 34.4% 52.1% <.0001Betabloccanti 7.3% 15.7% <.0001ARBs 5.2% 9.2% 0.0003Amiodarone 10.7% 25.9% <.0001

TERAPIA FARMACOLOGICA ALLA DIMISSIONE

TEMISTOCLE

(hearT failurE epideMIological STudy FADOI-ANMCO in itaLian pEople)

Medicine(n. 1259)

Cardiologie(n. 748)

p

Inotropi 5.9% 5.2% NSACE-inibitori 75.8% 71.0% 0.02Digitale 61.5% 59.9% NSFurosemide 85.5% 89.6% 0.0082Spironolattone 31.3% 49.1% <.0001Betabloccanti 8.7% 17.8% <.0001ARBs 6.2% 9.2% 0.012Amiodarone 8.1% 22.9% <.0001

Chi Deve Fare Che Cosa?

The explosion in HF devices, part 1: Culture,

economics, and unresolved issues

This represents a real ethical dilemma that in this country we tend not to be very good at facing directly

I think there is an ethical imperative to consider implanting these devices into all these patients

In Sweden there is not the money for this, so we don't screen

Some cardiologists are leaping onto devices as cure-alls when patients aren't even on maximal medical therapy

The trial experience is in a relatively select group

We may be changing their mode of death from a sudden arrhythmic death to drowning by heart failure

Reduction in all-cause and cardiac mortality in

the overall study group (n=713)

0.03 0.15 to 0.68

0.36 All-cause mortality

0.04 0.16 to 0.78

0.39 Cardiac mortality

Adjusted p 95% CI Relative risk reduction

End point

Mitchell LB et al. J Am Coll Cardiol 2003; 42:81-87.

Changes in Plasma Ang II Levels During Ang I Infusion

Ueda S et al. Hypertension 1998

0 5 10 15 20 0 5 10 15 20

0 5 10 15 20

0

50

100

150

200

250

300

0 5 10 15 20

Ch

an

ge

in

Pla

sm

a A

ng

II (p

mo

l/l)

Ang I (ng/Kg/ml)

II

II

DD

DD

enalaprilat

placebo1 hour

10 hours

0

50

100

150

200

250

300

0

50

100

150

200

250

300

0

50

100

150

200

250

300

0 6 1 18 24 30

1.00

0.80

0.60

0.40

0.20

0.00

Months follow up

Tra

nsp

lan

t-fr

ee

su

rviv

al

ACE II

ACE ID

ACE DD

p = 0.005

ACE Polymorphism and -Blocker Therapy

McNamara DM et al. Circulation 2001;103:1644

0 6 1 18 24 30

1.00

0.80

0.60

0.40

0.20

0.00

Months follow up

Tra

nsp

lan

t-fr

ee

su

rviv

al

p = 0.007

No b-blocker

b-blocker

DD genotype

ACE Polymorphism and -Blocker Therapy

McNamara DM et al. Circulation 2001;103:1644