Introduzione all’importanza della doppia antiaggregazione
e del raggiungimento dei target
Cesare Greco
Le modificazioni dell’epidemiologiae le difficoltà dalla prevenzione secondaria
Fox Eur Heart J 2010
68%
86%
97%
STEMI NSTEMI UA
In-H
Post-H
Mortality composition at 5 years follow up
100%
Fox Eur Heart J 2010
Registro IN-ACS OutcomeMortalità intraospedaliera e ad 1 anno:
SCA-NSTE e STEMI
5%
10% 8.6%
2 %
4.4%
STEMI
SCA NSTE
In-H Dimissione 1 anno
15%
9.8%
Rizzello Acute Card Care 2012
X 4X 2
Registro IN-ACS OutcomeReinfarto dalla dimissione ad 1 anno:
SCA-NSTE e STEMI
5%
10%
5.4 %4.3%
STEMI
SCA NSTE
Rizzello Acute Card Care 2012
Registro IN-ACS OutcomeSottoutilizzo dei trattamenti raccomandati alla
dimissione negli STEMI ad alto rischio (non riperfusi)
Pedone Acute Card Care 2009
STEMI Non riperfusi STEMI PCI STEMI Trombolisi
Antiaggreganti 93% 99% 96%
Doppia 58% 94% 63%antiaggregazione
Betabloccanti 71% 83% 75%
Statine 68% 78% 77%
P<0.0001 per tutti
STEMI x 2NSTEMI x4
Total mortality at 6 months follow up
Discharge-30 days 30 days-6 months
BLITZ4 Performance of CCU Adherence to pharmacological therapy
11.706 AMI patients from 163 Coronary Units
Discharge 6 months
BLITZ4 Performance of Centers Process of care
LV function assessment
LDL measurement
Risk stratification
Anti smoke counseling
Cardiac rehabilitation referral
In-Hospital indicators
Post-discharge indicators
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*
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Survey 1 34,4% 39,1% 47,9% 39,7% 44,0% 41,0% 43,3% 37,7% 41,0%Survey 2 47,2% 43,4% 36,7% 29,1% 55,0% 45,7% 43,5% 31,1% 41,2%Survey 3 30,1% 29,1% 44,1% 45,2% 44,1% 34,8% 35,3% 41,4% 38,7%
Czech Rep. Finland France Germany Hungary Italy Netherlands Slovenia ALL
P=0.57
S2 vs. S1 : P=0.98S3 vs. S2 : P=0.36S3 vs. S1 : P=0.37
* SBP/DBP < 140/90 mmHg for non-diabetics or < 130/80 mmHg for diabetics
The EUROASPIRE Surveys
Prevalence of Diabetes*
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Survey 1 21,8% 15,4% 16,7% 13,5% 26,6% 17,2% 10,3% 17,4% 17,4%Survey 2 21,5% 18,7% 27,5% 13,5% 21,1% 21,8% 13,2% 23,8% 20,1%Survey 3 30,8% 19,1% 34,2% 22,6% 44,8% 21,7% 20,6% 18,8% 28,0%
Czech Rep. Finland France Germany Hungary Italy Nether-
lands Slovenia ALL
P=0.004
S2 vs. S1 : P=0.21S3 vs. S2 : P=0.02S3 vs. S1 : P=0.001
* Self-reported history of diagnosed diabetes
The EUROASPIRE Surveys
Prevalence of Smoking*
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
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%
Czech Rep. Finland France Germany Hungary Italy Nether-
lands Slovenia ALL
P=0.64
S2 vs. S1 : P=0.83S3 vs. S2 : P=0.37S3 vs. S1 : P=0.48
* Self-reported smoking or CO in breath > 10 ppm
The EUROASPIRE Surveys
Zeymer Eur J Prev Cardiol 2012
DAT administered prior to acute coronary syndrome (ACS) event, at hospital discharge, and at 6- and 12-months
Aderenza, tollerabilità ed efficacia
Interruzione dei trattamenti raccomandati durante il follow-up in pazienti con Pregresso IMA
Dati del registro SIMG - Health Search - JCVM 2009
0%
20%
40%
60%
80%
100%
1 anno 2 anni 3 anni 4 anni 5 anni
ASA Beta-B Statine ACE/ARB
Ho PM,et al Arch. Int. Med. 2006
L’Interruzione precoce delle terapie farmacologiche basate sull’evidenza dopo una SCA è molto frequente
I dati del Registro PREMIER
0
25
50
75
100
0 3 6 9 12Mesi di Follow-up
Pazi
enti
(%)
Aspirina Statine
Beta-bloccanti
Predittori indipendenti di interruzione della terapia
Età avanzata (≥70 anni) Basso livello socio-economico Sesso femminile Mancata effettuazione di PTCA
durante il ricovero Presenza di patologie maggiori
concomitanti
1521 pazienti dimessi dopo IMA
Ho et al. Arch Intern Med. 2006;166:1842-1847
Eur Heart J 2008
Spertus Circulation 2006
Tuppin Arch Cardiovasc Dis 201014,007 patients admitted for MI in the first hal f of 2006
http://osservatorioarno.cineca.org
Osservatorio ARNO CardiovascolareLa prevenzione secondaria dopo un evento di Sindrome Coronarica Acuta
http://osservatorioarno.cineca.org
Osservatorio ARNO CardiovascolareLa prevenzione secondaria dopo un evento di Sindrome Coronarica Acuta
http://osservatorioarno.cineca.org
Osservatorio ARNO CardiovascolareLa prevenzione secondaria dopo un evento di Sindrome Coronarica Acuta
http://osservatorioarno.cineca.org
Osservatorio ARNO CardiovascolareLa prevenzione secondaria dopo un evento di Sindrome Coronarica Acuta
http://osservatorioarno.cineca.org
Osservatorio ARNO CardiovascolareLa prevenzione secondaria dopo un evento di Sindrome Coronarica Acuta
http://osservatorioarno.cineca.org
Osservatorio ARNO CardiovascolareLa prevenzione secondaria dopo un evento di Sindrome Coronarica Acuta
Aderenza, tollerabilità ed efficacia
Patrono N Engl J Med 2011Patrono et al. for ESC Task Force Eur Heart J 2004
The risk for serious GI bleeding with low-dose ASA is continuous (VALIANT trial)
Dotted lines: 95% CIs of the estimated rateMoukarbel Eur Heart J 2009ASA = acetylsalicylic acid; CI = confidence interval; GI = gastrointestinal
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 upperGI bleeding
Weil et al. BMJ 1995
Low-dose ASAASA = acetylsalicylic acid; GI = gastrointestinal; NSAIDs = non-steroidal anti-inflammatory drugs.*non-ASA NSAID; **any dose, for less than 1 month
Alternative ASA formulations do not reduce the relative risk of upper GI bleeding
Kelly et al. Lancet 1996
ASA dose ≤ 325 mg/day
Steinhubl for CHARISMA Ann Int Med 2009
(75 or 81)
Primary efficacy end point (CV death, myocardial infarction, or stroke)
Peters Circulation 2003
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
Effects of Aspirin Dose When Used Alone or in Combination With Clopidogrel in Patients With Acute Coronary Syndromes:
the CURE Study
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
Lin Gastroenterology 2011
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)
GI problems reported by patients taking low-dose ASA for CV risk management
Moberg C et al. The Patient 2011
ASTERIX randomized study: ulcer incidence
71% reduction inulcer occurrencep=0.0007
1,8
6,2
0
1
2
3
4
5
6
7
Esomeprazole 20 mg od Placebo
Patie
nts
(%) w
ith g
astr
ic
or d
uode
nal u
lcer
Yeomans Am J Gastroenterol 2008
26 weeks
Esomeprazole 20 mg Placebo
ASTERIX study: resolution of upper GI symptoms from aspirin*
Symptom, n/N (%) Esomeprazole20 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) 0.19Epigastric 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
*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
ASA = acetylsalicylic acid
Arithmetic mean plasma concentration–time profiles of ASA (325 mg) and esomeprazole (40 mg) following 5 days’ repeated oral administration, alone and in combination
Niazi Int J Clin Pharmacol Ther 2009
Con
cent
ratio
n (m
mol
/L)
0 2 4 6 8 10 12
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
Time (hours)
Esomeprazole aloneEsomeprazole + low-dose ASA
Con
cent
ratio
n (m
mol
/L)
0 1 2 3 4 5 6
25
20
15
10
5
0
Time (hours)
Low-dose ASA aloneLow-dose ASA + esomeprazole
Aderenza, tollerabilità ed efficacia
Perk Eur Heart J 2012
JUPITER - Rx JUPITER - Placebo
LDL-C, livelli raggiunti, mg/dL (mmol/L)
WOSCOPS – PlaceboAFCAPS - Placebo
ASCOT - PlaceboAFCAPS - Rx WOSCOPS - Rx
ASCOT - Rx
4S - Rx
HPS - Placebo
LIPID - Rx
4S - Placebo
CARE - Rx
LIPID - PlaceboCARE - Placebo
HPS - Rx
0
5
10
15
20
25
30
40(1.0)
60(1.6)
80(2.1)
100(2.6)
120(3.1)
140(3.6)
160(4.1)
180(4.7)
Inci
d en z
a d i
ev e
nti
(%)
6
Prevenzione Secondaria
Prevenzione Primaria
Rx - Statin therapyPRA – pravastatinATV - atorvastatin
200(5.2)
PROVE-IT - PRATNT – ATV10
TNT – ATV80
Incidenza di eventi in funzione dei livelli di C-LDL raggiunti nei trial con statine
Jones PH et al. Am J Cardiol 2003;92:152-160
Vari
azio
ne d
el c
oles
tero
lo L
DL
(%)
vs.
bas
ale
10 4020 80
Simvastatina(n=648)
Pravastatina(n=485)
Rosuvastatina(n=473)
Atorvastatina(634)
0
-10
-20
-30
-40
-60
-50
‡†
*
*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
+8%
+17%
+26%
Riduzione media della colesterolemia LDL ottenuta con rosuvastatina rispetto alle altre statine
Riduzione percentuale del C-LDL in funzionedella dose delle statine (mg)
Studio STELLAR
-46,8-42,7-42.0
-50
-40
-30
-20
-10
0
*
Average change in LDL-C from baseline (%)
Rosuvastatin20 mg
Rosuvastatin40 mg
Atorvastatin80 mg
Primary Endpoint
*p< 0.05 versus atorvastatin 80 mg
Similar results were achieved in all subcategories of ACS Pitt B et al. Am J Cardiol 2012
LUNAR (Limiting UNder-treatment of lipids in ACS with Rosuvastatin)
9,7
11,9
5,6
0
5
10
15
**
Mean change in HDL-C from baseline (%)
Rosuvastatin20 mg
Rosuvastatin40 mg
Atorvastatin80 mg
***
LUNARSecondary Endpoint
**p< 0.01, *** p<0.001 versus atorvastatin 80 mg Pitt B et al. Am J Cardiol 2012
LUNARSafety & Tolerability
VariableRosuvastatin
20 mg/day(n=267)
Rosuvastatin40 mg/day
(n=263)
Atorvastatin80 mg/day
(n=269)
Any Serious AE* 28 (10.5%) 23 (8.7%) 38 (14.1%)
Serious Cardiovascular AE*
9 (3.4%) 5 (1.9%) 6 (2.2%)
Unstable angina 4 (1.5%) 3 (1.1%) 3 (1.1%)Myocardial infarction 5 (1.9%) 2 (0.8%) 2 (0.7%)Cerebrovascular accident 0 0 1 (0.4%)
Withdrawal due to AE 10 (3.7%) 16 (6.1%) 25 (9.3%)Musculoskeletal and connective tissue disorders
5 (1.9%) 6 (2.3%) 17 (6.3%)
Death* 0 2 (0.8%) 1 (0.4%)
*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
0
1 08
Placebo APTC CURE TRITON-TIMI 38Single
Antiplatelet RxDual
Antiplatelet RxHigher
IPA
ASA ASA + Clopidogrel ASA +
Prasugrel- 22%
- 20%
- 19%
+ 60% + 38% + 32%
Reduction in
IschemicEvents
Increase in
Major Bleeds
Placebo APTC CURE TRITON -TIMI 38
8,688
8,763
0 10 20 30
8
6
4
2
0
Cum
ulat
ive
inci
denc
e (%
)
Clopidogrel
Ticagrelor
4.775.43
HR 0.88 (95% CI 0.77–1.00), p=0.045
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,875
8,942
8,763
8,827
Days after randomisation
31 90 150 210 270 330
8
6
4
2
0
Clopidogrel
Ticagrelor
5.28
6.60
8,688
8,673
8,286
8,397
6,379
6,480
Days after randomisation*
HR 0.80 (95% CI 0.70–0.91), p<0.001
8,437
8,543
6,945
7,028
4,751
4,822
Cum
ulat
ive
inci
denc
e (%
)
K-M estimate of primary efficacy endpoint over time (Composite of CV death, MI or stroke)
*Excludes patients with any primary event during the first 30 days
Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57
20%
Events in PLATO stratified by renal function(A) Primary composite of cardiovascular death, myocardial infarction, and stroke
(B) total mortality
James Circulation 2010
Kohli Circulation 2013
Composite end point CV death, MI, stroke
Composite end point CVD/MI/Stroke/SRI/RI/TIA/ATEKohli Circulation 2013
Composite end points of CVD/MI/Stroke/URKohli Circulation 2013
Kohli Circulation 2013
Kohli Circulation 2013 PLATO major bleeding events.
Valutazione economica: ticagrelor vs. clopidogrel nelle SCA
per un'attesa di vita di 15.3 anni:
morte CV ICER/QALY € 10.621mortalità totale 8.345
Lucioni C, Pharmacoeconomics 2011
Conclusioni
Le modificazioni dell’epidemiologia clinica della fase post acuta delle SCArendono indispensabile rifondare la prevenzione secondaria
Per migliorare i risultati della prevenzione secondaria è necessariopromuovere l’aderenza alla terapia farmacologica e raggiungere i targetterapeutici indicati dalle Linee Guida
La tollerabilità e l’efficacia dei farmaci, in particolare di statine ed antiaggreganti, sono strumenti essenziali per il raggiungimentodegli obiettivi terapeutici e per la riduzione degli eventi
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