La cardioprotezione farmacologica in fase acuta

1
La cardioprotezione farmacologica in fase acuta
Minimaster Cuore e Diabete

• Antonio Mafrici
• UCIC Dipartimento cardiologico A. De Gasperis
• A.O. Ospedale Niguarda-Cà Granda Milano

Azienda Ospedaliera Ospedale Niguarda Ca' Granda
2
Diabetes and Mortality Following Acute Coronary
Syndromes JAMA. 2007298(7)765-775
3
Diabetes and Mortality Following Acute Coronary
Syndromes JAMA. 2007298(7)765-775
4
Diabetes and Mortality Following JAMA
2007298765-775
5
Diabetes and Mortality Following Acute Coronary
Syndromes JAMA. 2007298(7)765-775
30dSTEMI OR 1,40
1y STEMI HR 1,22
1y UA/NSTEMI HR 1,65
30d UA/NSTEMI OR 1,78
6
Guidelines for the diagnosis and treatment of
non-ST-segment elevation ACS
Eur Heart J 20072815981660
7
Current Use of GP IIb/IIIa Antagonists in
Non-ST-Elevation Myocardial Infarction NRMI
JACC 2003424553
Diabetes mellitus OR 0.89 (0.85 0.94)
8
CRUSADE Registry
Bhatt DL et al. JAMA 20042922096-2104
Diabetes mellitus OR 0.93 P 0.04
9
Strategia Invasiva
senza cath-lab con cath-lab

Diabete non D Diabete no D

Di Chiara A. et al. Eur Heart J 2006 27
10
Guidelines on diabetes, pre-diabetes, and
cardiovascular diseases executive summary.
(Management of CVD CAD)
Eur Heart J 20072888136
11
Guidelines on diabetes, pre-diabetes, and
cardiovascular diseases executive summary.
Eur Heart J 20072888136
12
Guidelines on diabetes, pre-diabetes, and
cardiovascular diseases executive summary. Eur
Heart J 20072888136
13
Guidelines on diabetes, pre-diabetes, and
cardiovascular diseases executive summary. Eur
Heart J 20072888136
14
?
Roffi, Eur Heart J 200425190-8
15
Diabetes Atherosclerosis - ACS

• High-risk patient
• Comorbidities
• Atherosclerotic
• burden?

High-risk plaque
High-risk blood
Prothrombotic state
16
Diabetes Increased Pleatelet Adhesion and
Aggregation
Aggregates
NIDDM N82 Controls N71
Shear-induced platelet adhesion and
aggregation on extracellular matrix
Knobler H et al. Thromb Res 199890181-90
17
CAPRIE Aspirin vs Clopidogrel in DM
3866 diabetic pts
Bhatt DL et al. AJC 200290625-8
18
Diabetes - Prothrombosis
Lim HS et al. Diabetes Medicine 200522249-55
19
Diabetes - Impaired Fibrinolysis
N871
Adjustment for TG, insulin sensitivity, age, BP,
BMI, WHR, BP medications
Byberg, L. et al. ATVB199818258-264
20
Diabetes Mellitus High-Risk Plaque
Coronary atherectomy specimes of diabetic (N
47) and nondiabetic patients (N48)

• Diabetic plaque
• Lipid rich atheroma?
• Thrombus?
• Inflammatory component?

Moreno PR et al. Circulation 20001022180-4
21
Antiplatelet Trialists Collaboration
Ngt140000 Overal risk reduction 22
Collaboration, A. T. BMJ 200232471-86
22
Diabetes Aspirin Resistance
N172
62

• PFA-100 Analyzer Closure Time (CT)
• Responders CT gt300 sec
• Semi-responsers CT 166-300 sec
• Non-responders CT lt165 sec

21
17
Fateh-Moghadam S. et al. Acta Diabetol
20054299-103
23
ACS Setting CURE
Risk Ratio 95 CI
Placebo
Clop
N
Population
CV death, MI, stroke
Diabetes
16.7
14.2
2840
No diabetes
9.9
7.9
9722
1.0
0.2
0.4
0.8
1.2
1.4
0.6
Clopidogrel Better
Placebo Better
Yusuf S et al. NEJM 2001345494-502
24
PCI CURE
CV Death or MI
Risk Ratio 95 CI
Placebo
Clopid.
N
0.77
16.5
Diabetes
12.9
504
0.66
No Diabetes
11.7
7.9
2154
1.0
0.2
0.4
0.8
1.2
1.4
0.6
Placebo Better
Clopidogrel Better
SR Mehta, et al. Lancet 2001358527-33
25
PCI Setting CREDO
N2116
Clopidogrel 300 mg loading 3 hours prior to PCI
and continued for 1 y vs 1 month post PCI only
Steinhubl SR et al. JAMA 20022882411-2420
26
Platelet Aggregation on Sustained Antiplatelet
Therapy
Sustained (gt 1 month) dual antiplatelet treatment
in stented patients
aspirin 100 mg/d and clopidogrel 75 mg/d
Non-diabetic patients n60
Angiolillo DJ et al. Diabetes 2005 542430-5
27
Platelet Activation on Sustained Antiplatelet
Therapy
Sustained (gt1 month) dual antiplatelet therapy
aspirin 100 mg/d and clopidogrel 75 mg/d
100
Diabetic patients n60
80
Non-diabetic patients n60
60
Positive platelets
40
20
0
PAC-1
P-selectin
(activated IIb/IIIa receptor)
Angiolillo DJ et al. Diabetes 2005 542430-5
28
Diabetic Patients 30-Day Mortality
Odds Ratio 95 CI
Trial
Placebo
IIb/IIIa
N
6.1
PURSUIT
5.1
2163
p 0.33
4.2
1.8
PRISM
687
p 0.07
PRISM-PLUS
6.7
3.6
p 0.17
362
p 0.022
7.8
5.0
GUSTO IV
1677
p 0.51
6.2
PARAGON A
4.6
412
p 0.93
PARAGON B
4.8
4.9
1157
Pooled
6.2
4.6
OR 0.74
6458
p 0.007
0
0.5
1
1.5
2
NNT 63
Placebo Better
IIb/IIIa Better
Diabetes-treatment interaction P0.036
Roffi et al.,Circulation 2001104 2767-71
29
SCA e DiabeteTrattamento della fase acuta

• Beta-bloccanti
• Studi di epoca pre-trombolitica hanno
  evidenziato riduzioni di mortalità fino al 37
• Sub-analisi di studi più recenti hanno confermato
  una riduzione di mortalità sempre attorno al 40

30
Effect of acute and long-term treatment with ß
blockers on mortality and reinfarction in
diabetic and nondiabetic patients
McGuire and Granger, Am Heart J 1999
100
90
Nondiabetic Patients Diabetic Patients

80
70
60

Reduction with Beta-blocker Compared with placebo

50

40

30
20
10
reinfarction
reinfarction
mortality
mortality
Acute Intervention
Long-term Intervention
31
20479 patients with STEMI treated with
fibrinolysis and randomized to a strategy of
enoxaparin (up to 8 days) or unfractionated
heparin (UFH) (48 hours) in ExTRACT-TIMI
25. Patients with DM 3060
Am Heart J 20071541078-84.
32
ExTRACTTIMI 25 trial
Am Heart J 20071541078-84.
33
ExTRACTTIMI 25 trial
Am Heart J 20071541078-84.
34
SCA e DiabeteTrattamento della fase acuta

• ACE-Inibitori
• GISSI 3 Riduzione di mortalità del 44 nei
  diabetici tipo 1 e del 24.5 in quelli di tipo 2
• Metanalisi 17,3 vite salvate ogni 1000 pazienti
  trattati

35
GISSI 3 Circulation 1997964239
36
GISSI 3. Circulation 1997964239
37
SCA e DiabeteTrattamento della fase acuta

• STATINE
• Come ipocolesterolemizzanti
• Per i possibili effetti pleiotropici

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SCA e DiabeteTrattamento della fase acuta

• STATINE
• Studio HPS 20536 pazienti con Diabete e/o
  Malattie vascolari
• Simvastatina 40 mg
• Follow-up 5 anni

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SCA e DiabeteTrattamento della fase acuta

• Studio HPS
• Riduzione mortalità coronarica 18
• Riduzione IMA 38
• Riduzione di eventi maggiori coronarici 11.8
  vs 8.7
• INDIPENDENTE DAI LIVELLI DI LDLc

40
SCA e DiabeteTrattamento della fase acuta

• Studio HPS- Diabetici
• Riduzione di eventi maggiori coronarici
  - con precedenti CV 33.4 vs 37.8
  - senza precedenti CV 13.8 vs 18.6 -
  cumulativa 20.2 vs 25.1

13.8 vs 18.6 33.4 vs 37.8
41
Acute coronary syndromes and diabetes is
intensivelipid lowering beneficial? Results of
the PROVE IT-TIMI 22 trial Eur Heart J 200627
23232329

• The rate of acute cardiac events (death,
  myocardial infarction, and
• unstable angina requiring rehospitalization) was
  much higher in
• patients with DM, but Was reduced with intensive
  vs. standard
• therapy similarly in diabetic (21.1 vs.26.6, HR
  0.75, P 0.03) and
• non-diabetic patients (14.0 vs 18.0, HR 0.76,
  P 0.002)
• P-interaction 0.97.

42
Early Statin Treatment Following AcuteMyocardial
Infarction and 1-Year Survival
JAMA. 2001285430-436
43
The effect of early, intensive statin therapy on
acute coronary syndrome a meta-analysis of
randomized controlled trials. Hulten Arch
Intern Med 200616618141821.

• Meta-analysis including 13 trials and 17 963
  patients
• Early statin therapy safe and had a positive
  impact
• on outcome.
• Beneficial effects on the rate of death and
• cardiovascular events over 2 years of follow-up
• (HR 0.81, 95 CI, 0.770.87, P , 0.001).
• Survival benefit was apparent only after 4
  months,
• achieving statistical significance by 12 months.

44
JAMA. 20062952046-2056
45
JAMA. 20062952046-2056
46
JAMA. 20062952046-2056
47
The efficacy and safety of intensive statin
therapya meta-analysis of randomized trials
Josan, CMAJ 2008178(5)576-84
48
Josan, CMAJ 2008178(5)576-84

• Our analysis supports the use of more intensive
• statin regimens in patients with established
  coronary
• artery disease.
• There is insufficient evidence to advocate
  treating to
• particular LDL targets, using combination lipid-
• Lowering therapy to achieve these targets or for
• using more intensive regimens in patients without
• established coronary artery disease

49
Cardioprotezione

• Diabetes 57696-705, 2008 Acute Metformin
  Therapy Confers Cardioprotection Against
  Myocardial Infarction Via AMPK-eNOSMediated
  Signaling
• Effect of Modified Glucose-Insulin-Potassium on
  Free Fatty
• Acids, Matrix Metalloproteinase, and
  Myoglobin in ST-Elevation
• Myocardial Infarction Am J Cardiol
  20071001614 1618

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Cardioprotezione
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Diabete e sistema emocoagulativo
52

• Patogenesi multifattoriale
• Autonomic dysfunction, metabolic derangements,
  abnormalities in ion homeostasis, alteration in
  structural proteins, and interstitial fibrosis.
  Sustained hyperglycemia also may increase
  glycation of interstitial proteins such as
  collagen, which results in myocardial stiffness
  and impaired contractility.

Circulation 20071153213-3223
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Cardioprotezione
Ital Heart J Suppl 2004 5 605-615
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Cardiomiopatia metabolica

• Il diabete mellito è caratterizzato da un ridotto
  metabolismo del glucosio e del lattato e da un
  accentuato (rispetto al normale) metabolismo
  degli acidi grassi da parte dei miocardiociti
• Laumentato uptake supera le capacità di
  ossidazione del cuore, causando un accumulo di
  lipidi che determinano un effetto tossico
  (lipotossicità)

Circulation 20071153213-3223
56
Cardiomiopatia metabolica

• I prodotti intermedi del metabolismo lipidico
  (ceramidi) possono provocare apoptosi dei
  cardiomiociti, contribuendo alla disfunzione
  miocardica
• Molti sono i meccanismi implicati nella
  variazione metabolica laumentato rilascio dei
  FAs, lalterato signaling dellinsulina, e
  lattivazione di pathway trascrizionali che
  coinvolgono i PPARa, responsabili del metabolismo
  dei lipidi intracellulari (ciò è stato osservato
  nelle condizioni di obesità o di sovraccarico
  calorico)

Circulation 20071153213-3223
57

• I meccanismi ipotizzati per spiegare gli effetti
  cardiotossici dei
• lipidi sono numerosi
• Tossicità diretta di gocciole lipidiche o di FAs
  sulla funzione miofbrillare
• Apoptosi indotta da FAs
• Produzione di ROS dallossidazione dei lipidi
• Attivazione della PKC
• Effetto delle ceramidi
• Quando il rapporto ossidazione/ captazione dei
  lipidi è alterato leccesso di FAs segue la via
  del metabolismo non ossidativo che si ritiene
  associato a cardiotossicità

Curr Opin Lipidol 18277282. 2007
58
Cardiomiopatia metabolica

• La produzione di energia è meno favorevole con
  lossidazione dei lipidi (ridotta efficienza
  energetica) e questo potrebbe rendere il cuore
  più vulnerabile allo stress emodinamico o
  ischemico
• Lefficienza energetica è inversamente correlata
  con lobesità, lintolleranza glicidica, la
  resistenza allinsulina (studi con PET)

59
Considerazioni

• Antiossidanti
• la magniferina, che aumenta le attivià endogene
  antiossidanti
• Metallotionine ad elevato contenuto di cisteina
  ed affinità per gli ioni di metalli pesanti
• Viatmine C-E
• Agonisti dei PPAR
• Farmaci metabolici (trimetazidina, ranolazina)
• Statine

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Considerazioni

• Terapie mirate alla manipolazione dei pathway
  metabolici e dellespressione genica
  costituiscono un affascinante obiettivo, e non
  solo per la cura della cardiomiopatia diabetica
  (Trimetazidina, Ranolazina)

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De hoc satis

• Claudite iam rivos, pueri,
• prata sat biberunt

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SCA e DiabeteAltri problemi

• Insufficienza renale conclamata o meno
  nefrotossicità del mdc
• Stenosi delle arterie renali ACE-Inibitori
• Vasculopatia carotidea rischio di stroke durante
  coronarografia o BPAC
• Vasculopatia periferica problemi per luso
  sicuro della contropulsazione aortica
• Ateromasia dellalbero arterioso embolie
  colesteriniche dopo coronarografia o fibrinolisi,
  dissecazioni arteriose

66
Primary Percutaneous Coronary Intervention
Compared With Fibrinolysis for MyocardialInfarctio
n in Diabetes Mellitus Results From the Primary
Coronary Angioplasty vs Thrombolysis2 Trial
Arch Intern Med. 2007167(13)1353-1359
67
Primary Percutaneous Coronary Intervention
Compared With Fibrinolysis for MyocardialInfarctio
n in Diabetes Mellitus Results From the Primary
Coronary Angioplasty vs Thrombolysis2 Trial
Arch Intern Med. 2007167(13)1353-1359
68
SCA e DiabeteEventi a 5 anni STEMI

• Re-IMA 42 vs 25
• Morte 55 vs 30

69
SCA e DiabeteMortalità 42 gg STEMI

• IMA e fibrinolisi 8
• IMA no fibrinolisi 17
• IMA diabete e fibrinolisi 17
• IMA diabete no fibrinolisi 30

70
SCA e DiabeteScompenso STEMI

• IMA e fibrinolisi 8
• IMA no fibrinolisi 22
• IMA diabete e fibrinolisi 22
• IMA diabete no fibrinolisi 39

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Diabetes-ACS30-Day Mortality
Diabetes ? Independent Predictor of Mortality HR
1.7
5.5
3.0
p lt 0.001
PARAGON A PARAGON B PURSUIT GUSTO IV
72
SCA e DiabeteAngina instabile e NSTEMI

• Mortalità
• 3 mesi 8,6 vs 2,5 plt0,014
• 12 mesi 16,7 vs 8,6 plt0,029

73
SCA e DiabeteAngina instabile e NSTEMI (OASIS
Registry)

Malmberg Circulation 2000 1021014
74
SCA e DiabeteAngina instabile e AMI GUSTO IIb
Diabete e shift ST
Necessità di insulina
No Diabete, shift ST
McGuire Eur Heart J 2000211750
75
SCA e DiabeteAngina instabile e AMI GUSTO IIb

• Diabete No Diabete OR
• Morte 6,9 4.1
  1.75
• (Re)infarto 8.2 5.3
  1.59
• Entrambi 13.1 8.5
  1.63

McGuire Eur Heart J 2000211750
76
SCA e DiabeteTrattamento della fase acuta

• Inibitori della GP 2b/3a, 6458 pz
• Placebo
  Trattati OR
  
• Morte 30 gg 6.2 4.6
  0.76
• (Nessun effetto nei non
  diabetici)
• Morte 30gg PCI 4.0 1.2 0.30
• Endpoint 15.8 9.9
  0.58
• cumulativo

Roffi Circulation 2001 1042767
77
Diabetes Mellitus The Major Risk Factor in
Unstable Coronary Artery Disease Even After
Consideration of the Extent of Coronary Artery
Disease and Benefits of Revascularization (FRISC
substudy)
NO INVAS
INVAS
J Am Coll Cardiol 20044358591
78
Diabetes Mellitus The Major Risk Factor in
Unstable..
Total
J Am Coll Cardiol 20044358591
Invasive
79
1-Year Mortality by Diabetic Status
1462 Diabetics 5072 Nondiabetics
4.5
P0.031
Death ()
2.6
2.5
1.9
P0.10
EPIC EPILOG EPISTENT
Bhatt DL et al. JACC 200035922-8.
80
Roffi ,Circulation 2001104 2767-71