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Antiaggregazione nel diabetico:Credenze ed evidenze
Department of Clinical Pharmacology and EpidemiologyConsorzio Mario Negri SudS. Maria Imbaro (CH)Italy
Antonio Nicolucci
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L’aspirina è efficace nei pazienti ad alto rischio cardiovascolare
L’aspirina è efficace nei pazienti con DM
I pazienti con DM presentano un alto rischio cardiovascolare
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EVIDENCE BASED MEDICINE
o
EMINENCE BASED MEDICINE?
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Studio attivato agli inizi degli anni ‘80
Pazienti con diabete: 2,4%
Number of myocardial infarctions
Aspirin Group Placebo group
11/275 (4.0%) 26/258 (10.1%)
p=0.22
N Engl J Med 1989
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Dato presente solo nella discussione dell’articolo!
Studio condotto fra il 1980 e il 1985
3711 pazienti con diabete, di cui quasi la metà con storia pregressa di CVD
CV death, MI, RR=0.90 (0.74-1.09)Stroke
Fatal and non-fatal MI RR=0.82 (0.65-1.03)
JAMA 1992
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Pazienti con diabete: 8% (previous MI? Previous stroke?)
“The relative benefit of ASA on major cardiovascular events and all myocardial infarction was about the same in the group of patients with diabetes mellitus as in the whole HOT population”.
Lancet. 1998;351(9118):1755-62
I risultati non si riferiscono ai pazienti con diabete
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LO STUDIO PPP
0.90
0.91
0.92
0.93
0.94
0.95
0.96
0.97
0.98
0.99
1.00
Time0 1 2 3 4 5
Aspirin No Diabetes
Log-Rank Test No Diabetes 2=4.98 p-value=0.03
No Aspirin No Diabetes
Aspirin Diabetes
No Aspirin DiabetesLog-Rank Test Diabetes 2=0.13 p-value=0.71
Pro
babi
lityMain end point (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) according to aspirin and diabetes status
Diabetes Care 2003; 26:3264-3272.
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Diabetes yes ( )
ASA Ctr.
Diabetes no ( )
ASA Ctr.
20 (3.9%) 22 (4.3%) 30 (1.6%) 51 (2.7%)
53 (10.2%) 59 (11.5%) 98 (5.3%) 142 (7.5%)
25 (4.8%) 20 (3.9%) 42 (2.3%) 61 (3.2%)
10 (1.9%) 8 (1.6%) 8 (0.4%) 25 (1.3%)
Non-cardiovascular 15 (2.9%) 12 (2.3%) 34 (1.9%) 36 (1.9%)
5 (1.0%) 10 (2.0%) 15 (0.8%) 22 (1.2%)
9 (1.7%) 10 (2.0%) 11 (0.6%) 19 (0.1%)
Angina pectoris 13 (3.1%) 16 (3.9%) 42 (2.7%) 51 (3.1%)
TIA 7 (1.7%) 10 (2.4%) 22 (1.4%) 32 (2.0%)
Peripheral artery disease 11 (2.6%) 13 (3.2%) 6 (0.4%) 16 (1.0%)
Revasculatisation proced. 8 (1.9%) 10 (2.4%) 15 (1.0%) 22 (1.4%)
RR (95%CI)
1.00
. .
.
Aspirin worseAspirin better1.00
Main combined end-point
Total CV events
All deaths
Cardiovascular
All myocardial infarction
All stroke
0.10 10.00
0.59 (0.37-0.94)0.90 (0.50-1.62)
0.69 (0.53-0.90)0.89 (0.62-1.26)
0.70 (0.47-1.04)1.23 (0.69-2.19)
0.32 (0.14-0.72)1.23 (0.49-3.10)
0.97 (0.60-1.56)1.23 (0.58-2.61)
0.69 (0.36-1.35)0.49 (0.17-1.40)
0.59 (0.28-1.25)0.89 (0.36-2.17)
0.85 (0.56-1.28)0.80 (0.39-1.64)
0.71 (0.41-1.22)0.69 (0.27-1.79)
0.38 (0.15-0.99)0.83 (0.38-1.84)
0.70 (0.36-1.36)0.79 (0.31-1.97)
Diabetes Care 2003; 26:3264-3272.
LO STUDIO PPP
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Sanderson, S. et. al. Ann Intern Med 2005;142:370-380
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Presenza di un ambiente pro-infiammatorio e pro-
trombotico con attivazione piastrinica attraverso vie
alternative che non richiedono il coinvolgimento del TXA2
Sintesi di TXA2 non sensibile all’azione dell’ASA
Cause genetiche: polimorfismi del gene del COX-1, del
recettore della Glicoproteina IIb/IIIa (PIA2) o di altri geni.
RIDOTTA EFFICACIA DELL’ASPIRINA: POSSIBILI MECCANISMI
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Evangelista V. Thromb Haemost. 2005;93:8-16
cytokines
CD40L
Inflammatory reaction
MMP
TF
COX-1TxA2
Thrombin
ASA-insensitiveplatelet activation
ASA-sensitive TxA2 synthesis
ASA-insensitiveTxA2 synthesis Platelets
AGEs
ROS
Hyperglycemia
Hyperinsulinemia Insulin Resistance
Dyslipidemia
Hypertension
DIA
BE
TE
S
Platelet reactivity Leukocyte adhesion TF expression TF expressing microparticles ROS production
Endothelial dysfunctions Adhesive molecules Chemokines COX-2 TxA2
PgI2
NO PAI-1
Circulating cells dysfunctions
Atheroscleroticplaque
Plaque instability
COX-2
REAZIONE INFIAMMATORIA NELLA PLACCA E EFFICACIA ANTI-TROMBOTICA DELL’ASPIRINA
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Curves of the inhibition by ASA of the collagen (a) or arachidonic acid-induced aggregation in platelet-rich plasma from diabetic patients ( ) and control healthy subjects ( ).
Reduced sensitivity of platelets from type 2 diabetic patients to acetylsalicylic acid (aspirin) – its relation to metabolic control
Watala C. Thrombosis Research 2004; 113: 101-113
The reduced response of platelets from diabetic subjects to aspirin was associated with a higher level of HbA1c, lower concentration of HDL-cholesterol and a higher total cholesterol concentration.
ASPIRINO RESISTENZA: ASPETTI CLINICI
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AGEs
ROS
Hyperglycemia
HyperinsulinemiaInsulin Resistance
Dyslipidemia
Hypertension
DIA
BE
TE
S
INFLAMMATION
THROMBOSIS
Asp
irin
Re
sis
tan
ce
ACE-I
TZDs
STATINS
x
x
x
Endothelium Adhesive molecules
Chemokines
COX-2 TxA2
PgI2
NO
PAI-1
Circulating cellsLeukocyte adhesion TF expression
TF expressing microparticles
Atheroscleroticplaque TF
MMPs TxA2
Evangelista V. Thromb Haemost. 2005;93:8-16
RIDUZIONE DEL POTENZIALE INFIAMMATORIO NELLA PLACCA E MIGLIORAMENTO DELLA EFFICACIA ANTI-
TROMBOTICA DELL’ASPIRINA
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La terapia antiaggregante con ASA potrebbe essere meno efficace nei soggetti con DM per la presenza di un contesto trombogenico poco influenzabile dall’inibizione della COX-1 piastrinica
Non è chiaro se il DM possa rappresentare un caso particolare di “aspirino-resistenza”
A tutt’oggi esistono controversie riguardo il fenomeno dell’aspirino resistenza:
Mancanza di una definizione standard
Prevalenza del fenomeno non chiara
Assenza di un meccanismo biologico chiaramente definito
Incertezza riguardo la sua rilevanza per la prevenzione CV
Assenza di provate strategie terapeutiche per le persone affette
Gli studi in corso, che coinvolgono numeri importanti di pazienti con DM, potranno contribuire a chiarire il ruolo dell’ASA nella prevenzione degli eventi CV
CONCLUSIONI