Giuseppe Micieli

1
Dal mondo statistico al mondo reale come
utilizzare i dati derivanti dai trial
XVI Congresso Nazionale SINV Vibo Valentia 7-9
Dicembre 2007 La medicina dellictus e.. la
prevenzione

• Giuseppe Micieli
• UO Neurologia I e Stroke Unit
• IRCCS Istituto Clinico Humanitas
• Rozzano (MI)

2
Established modifiable Stroke Risk Factors

• Prior TIA or stroke
• Hypertension
• Cardiac disease
• Atrial fibrillation
• Hyperlipemia
• Carotid stenosis
• Diabetes
• Cigarette smoking
• Physical inactivity
• Heavy alcohol use

3
Number needed to treat for various
stroke-prevention measures
4
Major trials of Angiotensin-modifying
antihypertensive agents
Sanossian N and Ovbiagele B. The Neurologist
200612(1)14-31
5
MOSES StudyEnd Point Analysis and Cumulative
Event Rate
Schrader J et al. Stroke 2005361218-1226
6
Stroke and Cholesterol
7
Stroke mortality (11663 death) versus usual total
cholesterol
Prospective Study Collaboration. Lancet
20073701829-1839
8
SPARCL Primary Endpoint
Amarenco P et al. N Engl J Med 2006355549-59
9
SPARCL Time to Stroke/TIA
Amarenco P et al. N Engl J Med 2006355549-59
10
SPARCL Post-hoc Analysis by Type of Stroke
Amarenco P et al. N Engl J Med 2006355549-59
11
Risk for 12-month all-cause mortality associated
with discontinuation of statin therapy
Caltagirone C et al, Stroke 2007
12
Main amplification pathways of platelet
activation and action of antiplatelet agents
Fontana P and Reny JL. Eur J Vasc Endovasc Surg
2007341-17
13
ICTUS ISCHEMICO
Origine non-cardioembolica (aterotrombotica,
lacunare, criptogenetica)
Origine cardioembolica (attraverso la
fibrillazione atriale)
Dicumarolici o ASA (se la TAO è controindicata)
Terapia antipiastrinica Classe I Livello A
Sì
Allergia allAspirina?
No
Clopidogrel Monoterapia (Classe IIa-Level B)

• ASA Dip o CLO opzioni sicure Classe II liv. A
• ASA DIP suggerito piuttosto che ASA Classe IIa
  liv. A

Scelta su parametri individuali
Algoritmo di trattamento per la prevenzione
secondaria dellictus ischemico (ASA, Sacco et
al. 2006)
ASA a 50-325 mg ASA Dip Clopidogrel (Evitare
la combinazione di CLOASA)
14
Antiplatelet treatments and their indication
Fontana P and Reny JL. Eur J Vasc Endovasc Surg
2007341-17
15
MATCH Adding ASA to Clopidogrel Shows a
Non-Significant Trend for the Reduction of Major
Vascular Events in High-Risk Cerebrovascular
Patients1
Primary Endpoint (ITT)
IS, MI, VD, rehospitalization for acute ischaemic
event
0.20
Placebo
ASA
0.16
RRR 6.4 (p0.244)
0.12
Cumulative event rate
0.08
0.04
0.00
0
3
6
9
12
15
18
Months of follow-up
All patients received clopidogrel and other
standard therapies
Diener HC et al. Lancet 2004364331-337
16
MATCH Life-threatening and Major Bleeding
Life threatening any fatal bleeding event, or a
drop in haemoglobin of gt5 g/d, or significant
hypotension with the need of inotropes
(hemorrhagic shock) or, symptomatic intracranial
hemorrhage, or requiring transfusion of gt4 units
of RBC or equivalent amount of whole blood Major
bleeding significantly disabling (with
persistent sequelae), or intraocular bleeding
leading to significant loss of vision or,
requiring transfusion of lt3 units of RBC or
equivalent amount of whole blood
Diener HC et al. Lancet 2004364331-337
17
CHARISMA Primary Efficacy Results (MI/Stroke/CV
Death) by Category of Inclusion Criteria
1.4
1.2
1.6
0.6
0.8
0.4
Clopidogrel ASA Better
Placebo ASA Better
RFRisk Factors ATAtherothrombosis
Bhatt DL. Oral presentation at ACC 2006
(http//acc06online.acc.org/)
18
CHARISMA Hemorrhagic StrokesThe combination of
Clopidogrel and ASA does not increase the risk of
intracranial hemorrhage as compared to ASA alone
All hemorrhagic stroke (overall
population)Primary Intracranial Hemorrhage
19
ESPRIT Time-to-event curves for primary outcome
event
Primary outcome event
25
Aspirin alone Aspirin dipyridamole
20
15
Cumulative event rate ()
10
5
HR 0.82 (95 CI 0.66-1-02) (on treatment)
0
0
1
2
3
4
5
20
ESPRIT Occurrence of bleeding according to
treatment
Aspirin Dypiridamole
Aspirin
21
ESPRIT

• - Open trial
• - ASA doses
• Interval index event randomization
• TIA/minor stroke
• Lower than expected rate of events
• Composite outcome
• 30 reduction in major bleeding (plausibility)
• Benefit after 2 years since inclusion
• 17 discontinuation of ASADIP (headache)
• ITT vs PP analysis

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CARESS Clopidogrel Significantly Reduces the
Incidence of MES in Patients with Recent
Symptomatic Carotid Stenosis
RRR 25.2 p0.078
RRR 37.3 p0.011
100
100
Primary Endpoint Results Number of MES
Patients at D7
100
76.0
80
72.5
Placebo
56.8
60
of Patients
Clopidogrel
45.5
40
20
0
On a background of ASA 75 mg qd Offline
analysis
Baseline
Day 1
Day 7
Markus HS t al Circulation 20051112233-2240
23
Lo studio FASTER
Clopidogrel carico con 300 mg quindi 75 mg
die Simvastatina 40 mg die
ASA 82 mg die
162 mg il primo giorno se non già in terapia con
ASA
Kennedy J, Lancet Neurol 2007
24
Lo studio FASTER Outcome primario Stroke
ischemico o emorragico a 90 giorni
3.8
Kennedy J, Lancet Neurol 2007
25
Lo studio FASTER Outcome secondari Combinazione
di qualsiasi stroke, infarto miocardico, morte
vascolare
3.3
Kennedy J, Lancet Neurol 2007
26
Lo studio FASTER Outcome terziari Combinazione
di qualsiasi stroke, TIA, sindrome coronarica
acuta, tutte le cause di morte
7.0
Kennedy J, Lancet Neurol 2007
27
FASTER Site and severity of bleeding outcome
Kennedy J, Lancet Neurol 2007
28
Prasugrel vs Clopidogrel in Acute Coronary
Syndromes
Wiviott SD et al. New Eng J Med 20073572001-2015
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La terapia antiaggregante problemi non risolti

• Epoca di inizio del trattamento
• Stenosi carotidea sintomatica
• Recidiva di ictus durante prevenzione primaria
  con ASA
• Trattamento specifico nei sottotipi
  anatomo-clinici di ictus a genesi non
  cardioembolico
• Possibili effetti non ottimali dal trattamento
  con dosi fisse di farmaco
• Rischio di sanguinamento con laumento della
  intensità della antiaggragazione

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