Introduzione all’importanza della doppia
antiaggregazione
e del raggiungimento dei target
Cesare Greco
Le modificazioni dell’epidemiologia
e le difficoltà dalla prevenzione secondaria
Mortality composition at 5 years follow up
100%
97%
86%
In-H
68%
Post-H
STEMI
NSTEMI
UA
Fox Eur Heart J 2010
Fox Eur Heart J 2010
Registro IN-ACS Outcome
Mortalità intraospedaliera e ad 1 anno:
SCA-NSTE e STEMI
15%
STEMI
SCA NSTE
10%
9.8%
8.6%
X4
X2
5%
4.4%
2%
In-H
Dimissione
1 anno
Rizzello Acute Card Care 2012
Registro IN-ACS Outcome
Reinfarto dalla dimissione ad 1 anno:
SCA-NSTE e STEMI
10%
STEMI
5.4 %
5%
4.3%
SCA NSTE
Rizzello Acute Card Care 2012
Registro IN-ACS Outcome
Sottoutilizzo dei trattamenti raccomandati alla
dimissione negli STEMI ad alto rischio (non riperfusi)
STEMI Non riperfusi
STEMI PCI
STEMI Trombolisi
Antiaggreganti
93%
99%
96%
Doppia
antiaggregazione
58%
94%
63%
Betabloccanti
71%
83%
75%
Statine
68%
78%
77%
P<0.0001 per tutti
Pedone Acute Card Care 2009
Total mortality at 6 months follow up
STEMI x 2
NSTEMI x4
Discharge-30 days
30 days-6 months
BLITZ4 Performance of CCU
Adherence to pharmacological therapy
Discharge
6 months
11.706 AMI patients from 163 Coronary Units
BLITZ4 Performance of Centers
Process of care
In-Hospital indicators
LV function assessment
LDL measurement
Risk stratification
Post-discharge indicators
Anti smoke counseling
Cardiac rehabilitation referral
30 day and 31–365 day mortality after first time hospitalisation
for myocardial infarction between 1984 and 2008
in a Danish nationwide cohort study
Schmidt et al. BMJ 2012
Kostis Circ Cardiovasc Qual Outcomes 2010
Therapeutic Control of Blood Pressure*
100%
90%
80%
70%
P=0.57
60%
50%
40%
30%
20%
10%
0%
Survey 1
Survey 2
Survey 3
Czech Rep.
Finland
France
Germany
Hungary
Italy
Netherland
s
Slovenia
ALL
34,4%
47,2%
30,1%
39,1%
43,4%
29,1%
47,9%
36,7%
44,1%
39,7%
29,1%
45,2%
44,0%
55,0%
44,1%
41,0%
45,7%
34,8%
43,3%
43,5%
35,3%
37,7%
31,1%
41,4%
41,0%
41,2%
38,7%
* SBP/DBP < 140/90 mmHg for non-diabetics or < 130/80 mmHg for diabetics
S2 vs. S1 : P=0.98
S3 vs. S2 : P=0.36
S3 vs. S1 : P=0.37
The EUROASPIRE Surveys
Prevalence of Diabetes*
100%
90%
80%
70%
60%
50%
P=0.004
40%
30%
20%
10%
0%
Czech
Rep.
Finland
France
Germany
Hungary
Italy
Netherlands
Slovenia
ALL
Survey 1
21,8%
15,4%
16,7%
13,5%
26,6%
17,2%
10,3%
17,4%
17,4%
Survey 2
Survey 3
21,5%
30,8%
18,7%
19,1%
27,5%
34,2%
13,5%
22,6%
21,1%
44,8%
21,8%
21,7%
13,2%
20,6%
23,8%
18,8%
20,1%
28,0%
* Self-reported history of diagnosed diabetes
S2 vs. S1 : P=0.21
S3 vs. S2 : P=0.02
S3 vs. S1 : P=0.001
The EUROASPIRE Surveys
Prevalence of Smoking*
100%
90%
80%
70%
60%
50%
40%
P=0.64
30%
20%
10%
0%
Czech
Rep.
Finland
France
Italy
Netherlands
Slovenia
ALL
Survey 1
22,0%
12,8%
25,0%
16,8%
23,3%
18,6%
31,8%
13,3%
20,3%
Survey 2
19,3%
21,6%
24,2%
16,8%
30,1%
15,1%
28,3%
14,6%
21,2%
Survey 3
22,2%
16,8%
24,8%
18,4%
18,3%
14,0%
15,1%
12,0%
18,2%
Germany Hungary
* Self-reported smoking or CO in breath > 10 ppm
S2 vs. S1 : P=0.83
S3 vs. S2 : P=0.37
S3 vs. S1 : P=0.48
The EUROASPIRE Surveys
DAT administered prior to acute coronary syndrome (ACS)
event, at hospital discharge, and at 6- and 12-months
Zeymer Eur J Prev Cardiol 2012
Aderenza, tollerabilità ed efficacia
Interruzione dei trattamenti raccomandati durante
il follow-up in pazienti con Pregresso IMA
100%
Dati del registro SIMG - Health Search - JCVM 2009
80%
60%
40%
20%
0%
1 anno
2 anni
ASA
Beta-B
3 anni
Statine
4 anni
ACE/ARB
5 anni
L’Interruzione precoce delle terapie farmacologiche
basate sull’evidenza dopo una SCA è molto frequente
I dati del Registro PREMIER
100
Predittori indipendenti di
interruzione della terapia
Pazienti (%)
75
 Età avanzata (≥70 anni)
 Basso livello socio-economico
 Sesso femminile
50
1521 pazienti dimessi dopo IMA
25
Aspirina
 Mancata effettuazione di PTCA
durante il ricovero
 Presenza di patologie maggiori
concomitanti
Statine
Beta-bloccanti
0
0
3
6
9
Mesi di Follow-up
12
Ho PM,et al Arch. Int. Med. 2006
Ho et al. Arch Intern Med. 2006;166:1842-1847
Eur Heart J 2008
Spertus Circulation 2006
14,007 patients admitted for MI in the first hal f of 2006
Tuppin Arch Cardiovasc Dis 2010
Osservatorio ARNO Cardiovascolare
La prevenzione secondaria dopo un evento di
Sindrome Coronarica Acuta
http://osservatorioarno.cineca.org
Osservatorio ARNO Cardiovascolare
La prevenzione secondaria dopo un evento di
Sindrome Coronarica Acuta
http://osservatorioarno.cineca.org
Osservatorio ARNO Cardiovascolare
La prevenzione secondaria dopo un evento di
Sindrome Coronarica Acuta
http://osservatorioarno.cineca.org
Osservatorio ARNO Cardiovascolare
La prevenzione secondaria dopo un evento di
Sindrome Coronarica Acuta
http://osservatorioarno.cineca.org
Osservatorio ARNO Cardiovascolare
La prevenzione secondaria dopo un evento di
Sindrome Coronarica Acuta
http://osservatorioarno.cineca.org
Osservatorio ARNO Cardiovascolare
La prevenzione secondaria dopo un evento di
Sindrome Coronarica Acuta
http://osservatorioarno.cineca.org
Aderenza, tollerabilità ed efficacia
Patrono et al. for ESC Task Force Eur Heart J 2004
Patrono N Engl J Med 2011
The risk for serious GI bleeding with low-dose ASA is
continuous (VALIANT trial)
Dotted lines: 95% CIs of the estimated rate
ASA = acetylsalicylic acid; CI = confidence interval; GI = gastrointestinal
Moukarbel Eur Heart J 2009
Aspirin leads to suppression of mucosal prostaglandin synthesis
and subsequent formation of mucosal erosions
Whereas the inhibition of thromboxane-A2-mediated platelet
function is dose independent (at least for daily doses N30 mg),
the impairment of PGE2-mediated cytoprotection in the GI mucosa
is dose dependent
Patrono et al. for ESC Task Force Eur Heart J 2004
ASA therapy increases the odds of upper
GI bleeding
Low-dose ASA
ASA = acetylsalicylic acid; GI = gastrointestinal; NSAIDs = non-steroidal anti-inflammatory drugs.
*non-ASA NSAID; **any dose, for less than 1 month
Weil et al. BMJ 1995
Alternative ASA formulations do not reduce the
relative risk of upper GI bleeding
ASA dose ≤ 325 mg/day
Kelly et al. Lancet 1996
(75 or 81)
Primary efficacy end point (CV death, myocardial infarction, or stroke)
Steinhubl for CHARISMA Ann Int Med 2009
Effects of Aspirin Dose When Used Alone or in Combination
With Clopidogrel in Patients With Acute Coronary Syndromes:
the CURE Study
Aspirin dose and the incidence of major bleeding
*Adjusted for gender, weight, hypertension, components of the TIMI risk
score, rates of angiography, PCI and CABG, and the use of NSAIDs,
heparin, GP2B3A inhibitors, oral anticoagulants, open-label ticlopidine, or
clopidogrel at any time during the study period
Peters Circulation 2003
Risk of upper GI bleed among low-dose ASA users is
reduced by proton pump inhibitor (PPI) use
•
2049 cases of upper GI bleed; 20 000 controls (The Health
Improvement Network UK primary care database)
•
Current use of PPI for >30 days reduced the risk of upper GI bleed in
low-dose ASA users and other at-risk groups
Population
Risk ratio (95% CI)
All patients
0.80 (0.68, 0.95)
Low-dose ASA users
0.58 (0.42, 0.80)
Dual antiplatelet therapy
0.21 (0.05, 0.87)
NSAID users
0.48 (0.30, 0.77)
Coxib users
0.50 (0.19, 1.33)
Corticosteroid users
0.67 (0.33, 1.36)
Warfarin users
0.48 (0.22, 1.04)
Lin Gastroenterology 2011
GI problems reported by patients taking lowdose ASA for CV risk management
Moberg C et al. The Patient 2011
ASTERIX randomized study: ulcer incidence
Patients (%) with gastric
or duodenal ulcer
7
26 weeks
6,2
6
5
4
71% reduction in
ulcer occurrence
p=0.0007
3
2
1,8
1
0
Esomeprazole 2020
mgmg
od
Esomeprazole
Placebo
Placebo
Yeomans Am J Gastroenterol 2008
ASTERIX study: resolution of upper GI
symptoms from aspirin*
Esomeprazole
20 mg od
Placebo
P value
Epigastric pain
47/56 (83.9)
28/42 (66.7)
0.05
Epigastric burning
32/44 (72.7)
18/31 (58.1)
0.19
Epigastric
discomfort
43/63 (68.3)
29/57 (50.9)
0.05
Heartburn
35/39 (89.7)
28/42 (66.7)
0.01
Acid regurgitation
19/22 (86.4)
13/23 (56.5)
0.03
Nausea
25/27 (92.6)
11/14 (78.6)
0.20
Bloating
67/86 (77.9)
41/62 (66.1)
0.11
Symptom, n/N (%)
*Analysis concerns patients with resolution of investigator-assessed upper GI
symptoms at 26 weeks, among patients with the symptom at baseline
Yeomans Am J Gastroenterol 2008
Lack of pharmacokinetic interaction between
esomeprazole and low-dose ASA
Arithmetic mean plasma concentration–time profiles of ASA (325 mg) and esomeprazole
(40 mg) following 5 days’ repeated oral administration, alone and in combination
4.0
Low-dose ASA alone
Low-dose ASA +
esomeprazole
20
15
10
Esomeprazole alone
Esomeprazole +
low-dose ASA
3.5
Concentration (mmol/L)
Concentration (mmol/L)
25
3.0
2.5
2.0
1.5
1.0
5
0.5
0
0
0
1
ASA = acetylsalicylic acid
2
3
4
Time (hours)
5
6
0
2
4
6
8
Time (hours)
10
12
Niazi Int J Clin Pharmacol Ther 2009
Aderenza, tollerabilità ed efficacia
Perk Eur Heart J 2012
Incidenza di eventi in funzione dei livelli di CLDL raggiunti nei trial con statine
30
4S - Placebo
25
Rx - Statin therapy
PRA – pravastatin
ATV - atorvastatin
Prevenzione Secondaria
4S - Rx
20
LIPID - Placebo
15
CARE - Placebo
LIPID - Rx
CARE - Rx
Prevenzione Primaria
TNT – ATV10 HPS - Placebo
HPS - Rx
PROVE-IT - PRA
WOSCOPS – Placebo
TNT – ATV80
AFCAPS - Placebo
10
5
6
AFCAPS - Rx
JUPITER - Rx
0
40
(1.0)
60
(1.6)
80
(2.1)
WOSCOPS - Rx
ASCOT - Placebo
ASCOT - Rx JUPITER - Placebo
100
(2.6)
120
(3.1)
140
(3.6)
160
(4.1)
LDL-C, livelli raggiunti, mg/dL (mmol/L)
180
(4.7)
200
(5.2)
Riduzione percentuale del C-LDL in funzione
della dose delle statine (mg)
Studio STELLAR
10
Variazione del colesterolo LDL (%)
vs. basale
0
-30
-40
-50
-60
40
80
Riduzione media della colesterolemia
LDL ottenuta con rosuvastatina
rispetto alle altre statine
-10
-20
20
+26%
+17%
Pravastatina
(n=485)
+8%
Simvastatina
(n=648)
*
†
Rosuvastatina
‡ (n=473)
Atorvastatina
(634)
*p<0,002 vs Atorvastatina 10 mg; Simvastatina 10, 20, 40 mg; Pravastatina10, 20, 40 mg
†p<0,002 vs Atorvastatina 20, 40 mg; Simvastatina 20, 40, 80 mg; Pravastatina 20, 40 mg
‡p<0,002 vs Atorvastatina 40 mg; Simvastatina 40, 80 mg; Pravastatina 40 mg
Jones PH et al. Am J Cardiol 2003;92:152-160
LUNAR (Limiting UNder-treatment of lipids
in ACS with Rosuvastatin)
Primary Endpoint
0
Rosuvastatin
20 mg
Rosuvastatin
40 mg
Atorvastatin
80 mg
-10
Average
change in
LDL-C from
baseline (%)
-20
-30
-40
-42.0
-50
*p< 0.05 versus atorvastatin 80 mg
-46,8
-42,7
*
Similar results were achieved in all subcategories of ACS
Pitt B et al. Am J Cardiol 2012
LUNAR
15
Secondary Endpoint
***
**
Mean
change in
HDL-C from
baseline (%)
10
11,9
9,7
5,6
5
0
Rosuvastatin
Rosuvastatin
40 mg
20 mg
**p< 0.01, *** p<0.001 versus atorvastatin 80 mg
Atorvastatin
80 mg
Pitt B et al. Am J Cardiol 2012
LUNAR
Safety & Tolerability
Rosuvastatin
20 mg/day
(n=267)
Rosuvastatin
40 mg/day
(n=263)
Atorvastatin
80 mg/day
(n=269)
28 (10.5%)
23 (8.7%)
38 (14.1%)
Serious Cardiovascular
AE*
9 (3.4%)
5 (1.9%)
6 (2.2%)
Unstable angina
Myocardial infarction
Cerebrovascular accident
4 (1.5%)
5 (1.9%)
0
3 (1.1%)
2 (0.8%)
0
3 (1.1%)
2 (0.7%)
1 (0.4%)
10 (3.7%)
5 (1.9%)
16 (6.1%)
6 (2.3%)
25 (9.3%)
17 (6.3%)
0
2 (0.8%)
1 (0.4%)
Variable
Any Serious AE*
Withdrawal due to AE
Musculoskeletal and
connective tissue disorders
Death*
*None of the serious adverse effects (AEs), serious cardiovascular AEs or deaths were
considered by the investigators to be related to study treatment
Pitt B et al. Am J Cardiol 2012
Antiplatelet Therapy in ACS
ASA
ASA + Clopidogrel
ASA +
Prasugrel
Reduction
in
Ischemic
Events
- 22%
- 20%
- 19%
+ 60%
Placebo
Placebo
APTC
APTC
Single
Antiplatelet Rx
+ 38%
CURE
CURE
Dual
Antiplatelet Rx
+ 32%
TRITON -TIMI 38
TRITON-TIMI 38
Higher
IPA
Increase
in
Major
Bleeds
20%
Events in PLATO stratified by renal function
(A) Primary composite of
cardiovascular death, myocardial
infarction, and stroke
(B) total mortality
James Circulation 2010
Composite end point CV death, MI, stroke
Kohli Circulation 2013
Composite end point CVD/MI/Stroke/SRI/RI/TIA/ATE
Kohli Circulation 2013
Composite end points of CVD/MI/Stroke/UR
Kohli Circulation 2013
Kohli Circulation 2013
PLATO major bleeding events.
Kohli Circulation 2013
Valutazione economica: ticagrelor vs. clopidogrel nelle SCA
per un'attesa di vita di 15.3 anni:
morte CV
 ICER/QALY € 10.621
mortalità totale 
8.345
Lucioni C, Pharmacoeconomics 2011
Conclusioni
Le modificazioni dell’epidemiologia clinica della fase post acuta delle SCA
rendono indispensabile rifondare la prevenzione secondaria
Per migliorare i risultati della prevenzione secondaria è necessario
promuovere l’aderenza alla terapia farmacologica e raggiungere i target
terapeutici indicati dalle Linee Guida
La tollerabilità e l’efficacia dei farmaci, in particolare di statine ed
antiaggreganti, sono strumenti essenziali per il raggiungimento
degli obiettivi terapeutici e per la riduzione degli eventi