ANTIPLATELET TREATMENT IN HIGH-RISK PATIENTS

1
ANTIPLATELET TREATMENT IN HIGH-RISK PATIENTS
Stefano SavonittoDipartimento Cardiologico A.
De GasperisOspedale Niguarda Ca Granda
Milano, Italy
Treatment oh high-risk cardiac patients
Turin, 16 november 2007
2
The relationships among baseline risk, benefit
and NNT for an effective treatment
100- 80- 60- 40- 20- 0-
-1000 -800 -600 -400 -200 -100 -50 -1
Absolute Benefit
NNT (cost)
0 25 50
75 100
Absolute Risk
3
(No Transcript)
4
Procedural benefit vs baseline risk vs
iathrogenic risk with PCI
20- 16- 12- 8- 4- 0-
-50 -40 -30 -20 -10 -0
Extent of ischemic risk
Extent of benefit from PCI
DeathMI/year
?
RRR
2- 4- 6- 8- 10-
Maj bleed ARF MI
Extent of iathrogenic risk
Stable CAD
NSTEACS
STEMI
Source 2006 ESC PCI guidelines Mehta SR, JAMA
2005 Keeley EJ, Lancet 2003 Savonitto S, IHJ
2005
5
The relationships among baseline risk, bleeding
risk and net clinical benefit for an effective
treatment
100- 80- 60- 40- 20- 0-
Anti-ischemic effect
Treatment effect
Net clinical benefit
Bleeding risk
0 25 50
75 100
Ischemic Risk
6
Balance of Efficacy and Safety
Wiviott SD, NEJM 20073572001

15
138 events
Clopidogrel
HR 0.81(0.73-0.90)P0.0004
12.1
CV Death / MI / Stroke
9.9
10
NNT 46
Prasugrel
Endpoint ()
5
35 events
TIMI Major NonCABG Bleeds
Prasugrel
2.4
HR 1.32(1.03-1.68)P0.03
1.8
Clopidogrel
0
NNH 167
0
30
60
90
180
270
360
450
Days
7
Defining the high-risk coronary patients

• Chronic CAD
• prior cardiac events
• 3-vessel disease
• LV dysfunction
• recent DES
• PAD
• diabetes
• CKD

• NSTEACS
• ST depression
• Tn elevation
• refractory ischemia
• LV dysfunction
• diabetes
• elderly
• CKD

• STEMI
• elderly
• high Killip
• prior MI
• large MI
• failed lysis
• diabetes
• CKD

8
Antiplatelet therapy in high-risk patients

• Chronic CAD
• prior cardiac events
• 3-vessel disease
• LV dysfunction
• recent DES
• PAD
• diabetes
• CKD

• NSTEACS
• ST depression
• Tn elevation
• refractory ischemia
• LV dysfunction
• diabetes
• elderly
• CKD

• STEMI
• elderly
• high Killip
• prior MI
• large MI
• failed lysis
• diabetes
• CKD

9
Additive effect of streptokinase and aspirin
ISIS-2 Lancet 19882349-60
10
COMMIT Effect of CLOPIDOGREL on Death in
hospital
Placebo ASA 1846 deaths (8.1)
Clopidogrel ASA 1728 deaths (7.7)
7 (SE3) relative risk reduction (2P0.03)
Dead ()
Lancet 2005
Days since randomisation (up to 28 days)
11
COMMIT Effects of CLOPIDOGREL on Death, Re-MI
or Stroke
Placebo ASA 2311 events (10.1)
Clopidogrel ASA 2125 events (9.3)
9 (SE3) relative risk reduction (2P0.002)
Event ()
Lancet 2005
Days since randomisation (up to 28 days)
12
COMMIT Major bleed in hospital

• 
  Clopidogrel Placebo
• Type
  (n22,958) (n22,891)
• Cerebral
• Fatal 39 40
• Non-fatal 16 15
• Non-cerebral
• Fatal 36 37
• Non-fatal 46 36
• Any major bleed 134 124
• 
  (0.58) (0.54)

Lancet 2005
13
Primary Angiographic Outcomes (median 3.5 days)
Placebo
OddsRatio
P value
Clopidogrel
Outcome
21.7
0.64
lt0.001
15.0
Primary End Point ()
lt0.001
0.59
18.4
11.7
TIMI Flow Grade 0/1
0.08
0.70
3.6
2.5
MI
2.2
1.17
0.49
2.6
Death
Angiographic ()
60.8
1.36
lt0.001
67.8
TIMI Flow Grade 3
51.2
1.21
0.008
55.8
TIMI Myocardial Perfusion 3
50.8
0.73
lt0.001
43.0
Thrombus
14
No excess bleeding
Outcome Clopidogrel () Placebo () P value
Through angiography
TIMI major (Hgb ? gt5 g/dL or ICH) 1.3 1.1 NS
TIMI minor (Hgb ? 3-5 g/dL) 1.0 0.5 NS
Intracranial hemorrhage 0.5 0.7 NS
Through 30 days
TIMI major 1.9 1.7 NS
In those undergoing CABG 7.5 7.2 NS
CABG w/in 5 d of study med 9.1 7.9 NS
TIMI minor 1.6 0.9 NS
15
TIMI Grade 3 Flow at 60 Minutes
100
Standard Lytic
Combo Rx
3
TIMI 14
2
SPEED
80
70
1
Meta-analysis
61
51
60
46
of Patients
40
20
n 1317
n 323
n 90
n 30
0
Accelerated
Reteplase
Abciximab Reteplase
t-PA
(10 U 10 U)
(5 U 5 U)
1 Circulation 199898I-784
2 Circulation 20001012788-94
3 EHJ 2000 211944-53
16
GUSTO VComposite Endpoints
30
p lt 0.0001
20.6
20
16.2
of Patients
p 0.0011
8.8
10
7.4
p lt 0.0001
3.5
2.3
0
Death / Re-MI
Re-MI
Death / Re-MI / Urgent PCI
through 30 days through 7 days / discharge
Lancet 2001 3571905-14
17
GUSTO VPrimary Endpoint 30 Day Mortality
5.9
5.6
p 0.43 for superiority
Mortality
Days
Lancet 2001 3571905-14
18
GUSTO V30 Day Mortality in higher risk subgroups
20
Std. Dose Reteplase (n 8260)
Abciximab ? Dose Reteplase (n 8328)
15
p 0.17
p 0.58
p 0.37
p 0.83
Mortality
10
8.8
8.5
8.2
7.6
5.3
5.0
4.4
4.4
5
n 13782
n 2633
n 10387
n 6197
0
Non-Anterior
Non-Diabetics
Diabetics
Anterior
Infarct Location
Lancet 2001 3571905-14
19
GUSTO V Baseline risk and effect of
Abciximabxreteplase vs reteplase on 30-day
mortality
P 0.24 for interaction
Brener SJ, AHJ 200515089
20
GUSTO V Non-Intracranial Bleeding
50
40
p lt 0.0001
30
p lt 0.0001
24.6
20.0
of Patients
20
13.7
11.4
p lt 0.0001
p lt 0.0001
p lt 0.0001
5.7
10
4.0
3.5
1.8
1.1
0.5
0
Mild Bleeding
Moderate Bleeding
Severe Bleeding
Any Bleeding
Receiving Transfusions
Lancet 2001 3571905-14
21
GUSTO V age and effect of abciximabxreteplase
vs reteplase on the risk of intracranial
haemorrhage
Or (95CI) of combo therapy on risk of ICH based
on logistic regression model
6- 5- 4- 3- 2- 1- 0-
Higher risk with combo
Lower risk with combo
30 40 50 60
70 80 90 yrs
Savonitto S , EHJ 2003 241807-14
22
IRA patency, major bleeding and heparin dose
TIMI-14
Major bleeding
60-minute IRA TIMI 3
10- 8- 6- 4- 2- 0-
100- 80- 60- 40- 20- 0-
72
7.0
68
1.0
Standard-dose Heparin
Very low dose Heparin
Standard-dose Heparin
Very low dose Heparin
Very-low-dose Heparin
30 U/kg bolus 4 U/kg/h infusion
60 U/kg bolus 7 U/kg/h infusion
Standard-dose Heparin
Antman EM, et al. Circulation 1999992720-32
23
Abciximab for primary PCI in STEMIsignificant
mortality reduction
-29
De Luca G, et al. JAMA 20052931759
24
Abciximab vs placebo or control for STEMI
N1101
RR 0.695 (0.482 1.003)
RR 0.633 (0.452 0.887)
10.8
12.9
19.0
14.3
25
Primary endpoint
Ellis S, NEJM in press
p0.55
26
ASSENT IV Mortality at 30 Days
Mortality ()
P0.04
50/828 32/835
Van de Werf F, Lancet 2005
27
Nonintracranial bleeding
Ellis S, NEJM in press
plt0.001
plt0.001
p0.025
p0.008
p0.006
p0.547
p0.025
p0.141
p0.127
28
30 Day Bleeding
UFH GP IIb/IIIa (N1802) Bivalirudin (N1800) P Value
Protocol Major, non CABG 8.3 4.9 lt0.0001
Protocol Major, All 10.8 6.8 lt0.0001
Blood transfusion 3.5 2.1 0.01
TIMI Major 5.0 3.1 0.003
TIMI Minor 4.6 2.8 0.008
TIMI Major or Minor 9.6 5.9 lt0.0001
GUSTO LT or Severe 0.6 0.4 0.65
GUSTO Moderate 5.0 3.1 0.003
GUSTO LT or Sev or Mod 5.6 3.5 0.003
Primary endpoint Life threatening
Stone GW, TCT 2007
29
30 Day Mortality
3.1
Death ()
2.1
HR 95CI 0.66 0.44, 1.00 P0.048
Time in Days
Stone GW, TCT 2007
30
Antiplatelet therapy in high-risk patients

• Chronic CAD
• prior cardiac events
• 3-vessel disease
• LV dysfunction
• recent DES
• PAD
• diabetes
• CKD

• NSTEACS
• ST depression
• Tn elevation
• refractory ischemia
• LV dysfunction
• diabetes
• elderly
• CKD

• STEMI
• elderly
• high Killip
• prior MI
• large MI
• failed lysis
• diabetes
• CKD

31
PCI-CURE Long-term Efficacy of Clopidogrel
Composite of CV-death or MI from randomization to
end of follow-up
12.6
0.15
Placebo Clopidogrel
31 RRR p0.002 n2658
Cumulative hazard rates
8.8
0.10
0.05
0.0
0
100
200
300
400
10
40
Days of follow-up
median time from randomization to PCI (10 days)
Mehta S. Lancet. 2001358527-533
32
Effects of Clopidogrel Stratified by TIMI Risk
Score at 12 Months1,2
ARR 1.6 1.6 4.8 RRR 29 15 27
25
n 1,989
20.7
20
15.9
15
n 7,297
Placebo
p 0.003
11.4
MI, stroke or vascular death ()
Clopidogrel
9.8
10
n 3,276
p 0.02
5.7
4.1
5
p 0.03
0
Low risk
Moderate risk
High risk
Absolute risk reductionRelative risk reduction
The CURE Trial Investigators. N Engl J Med 2001
345 494502. Budaj AJ et al J Am Coll Cardiol
2002 39, (suppl B) 441B.
33
Clinical suspicion of ACS
Physical examination, (Echocardiogram) ECG
monitoring, Blood samples
2002 ESC guidelines
No persistent ST-Segment elevation
Persistent ST-Segment elevation
Undetermined diagnosis
Heparin (LMWH or UFH), ASA, Clopidogrel,
Betablockers, Nitrates
Thrombolysis PCI
ASA
High risk
Low risk
Start immediately
Second troponin measurement
Gp2b/3a Cor. Angiography
Positive
Twice negative
PCI, CABG or medical management Depending upon
clinical and angiographic features
Stress testCor. angiography
omit clopidogel if the patient is likely to go
to CABG within 5 days
34
Anti-thrombotic medications for PCI in UA/NSTEMI
2005 ESC PCI guidelines
Recommen- dation
Studies for Level A or B
Procedure
Indication
All procedures
ASA
I C
-
Clopidogrel
I B
CURE
Immediately (if clinically justifiable) and
prolonged for 9-12 months
GP IIb/IIIa inhibitor Abciximab
Immediately before PCI in high-risk ACS
I A
CAPTURE, EPIC
ISAR REACT-2
GP IIb/IIIa inhibitor Eptifibatide
Immediately before PCI in high-risk ACS
I C
-
GP IIb/IIIa inhibitor Tirofiban, Eptifibatide
Upstream in high-risk ACS pretreatment (48-72
hrs) before angiography and PCI
I C
-
Enoxaparin
Replacement for UFH in high-risk NSTE-ACS, if
invasive strategy is not applicable
I C
-
Bivalirudin
Replacement for UFH ( GP IIb/IIIa inhibitors) to
reduce bleeding complications
II a C
-
Silber S, et al. Eur Heart J 2005
35
Clopidogrel treatment and off-pump CABG related
bleeding
Reexploration as a Result of Bleeding Rate ()

• The unadjusted reexploration as a result of
  bleeding rate in the group that was administered
  clopidogrel was 6.4 compared with 1.4 for the
  unexposed group (plt0.01)

p lt 0.01
N1281 gt7 days
N281 lt7 days
Kapetanakis EI, Circulation 20061331667
36
1636 consecutive pts between 2000 and 2002 at the
Mayo Clinic in-H outcome compared between pts
with or without ASAgt5 days prior to CABG
N1316
N320
37
Variables independently associated with CABG
TACTICS TIMI 18
Sadanandan ACC 2003
38
Association of CABG with Increasing Risk Score
Overall TACTICS TIMI 18 Population
N1433
Plt0.0001 C-statistic 0.72
CABG ()
Risk score
Sadanandan ACC 2003
39
Would you start clopidogrel before angiography
in this patient?
40
Probability of 30-D death by sum of ST
depression on the admission ECG the GUSTO IIb
ECG corelab
50- 40- 30- 20- 10- 0-
0,35
Incidence of 3VD and LMCA disease by quartiles
of S ST depression
3-vessel disease
LM disease
0,3
0,25
0,2
Probability of 30-day death
3 Q (n1366)
12 Q (n2493)
4 Q (n1333)
0,15
0,1
Probability of death
95 confidence limits
0,05
0
0
5
10
15
20
25
30
35
40
45
sum of ST depression (mm)
Savonitto S et al Eur Heart J 200526 2106
41
ISAR-COOL 30-day outcome
All pts with clopidogrel 60075 mg
Delay 86h Delay 2.4h
p0.04
of patients
Death / MI
Death
Non-fatal MI
Non-fatal Q-wave MI
Neumann FJ et al. JAMA 20032901593-9
42
(No Transcript)
43
Lack of Efficacy of Clopidogrel Pre-Treatment in
the Prevention of Myocardial Damage After
Elective Stenting
N 203
van der Heijden et al. JACC 2004 4420.
44
Impact of abciximab on top of ASA and clopidogrel
depends on patients baseline risk
Death or MI at 30 days
20- 18- 16- 14- 12- 10- 8- 6- 4- 2- 0-
18.3
P0.02
13.1
P0.98
P0.91
4.6
4.6
4.0
4.0
Placebo Abciximab
Placebo Abciximab
Placebo Abciximab
ISAR REACT 1 Stable patients
ISAR REACT 2 NSTEACS TnT -
ISAR REACT 2 NSTEACS TnT
Kastrati A, NEJM 2004, JAMA 2006
45
ISAR-REACT 2 Trial Secondary Endpoint

• There was no difference between the abciximab and
  placebo groups in in-hospital major and minor
  bleeding (pNS for both).
• There was one intracranial bleed in each group.
• 2.5 of patients received transfusions in the
  abciximab group compared with 2.0 in the placebo
  group (RR 1.25)

In-hospital Major and Minor Bleeding () pNS
Kastrati A, JAMA 2006
46
ACUITY TIMING Upstream vs cathlab GPIIb/IIIa RB
in NSTEACS
47
Tissue Level Perfusion by TMPG pre and post-PCI
p0.015
P 0.0009
TMPG 0/1 ()
TMPG 0/1 ()
HBD Tirofiban
Abciximab
Upstream Tirofiban
Upstream Tirofiban
HBD Tirofiban
Abciximab
Pre-PCI
Post-PCI
Bolognese L et al. JACC 200647522
48
Event rates for patient undergoing CABG (lt 72 h
of GP IIb/IIIa discontinuation)
33.6
35
23.8
cumulative incidence ()
25
RRR 30 p 0.002
placebo eptifibatide
15
0
30
60
90
120
150
180
days from randomization
Marso SP et al Circulation 20001022952-8
49
Clopidogrel on top of aspirine in non-ST
elevation ACS
12156 pts gt3 months, lt12 months
RR
placebo
clopidogrel
I Endpoint (CV deathMIstrokerefractory
ischemia) CV death MI Stroke Non CV death
9.28
11.5
5.06
5.4
5.19
5.4
1.2
1.4
0.67
0.7
0
1
1.5
0.5
Clopidogrel better
The CURE Trial Investigators. N Engl J Med 2001
345 494
50
Bleedings

P0.0001
P0.003
P0.03
PNS
PNS
PNS
(2 units)
51
Healthy Volunteer Crossover Study
100
N66
80
InterpatientVariability
60
IPA at 24 hours ()
40
InterpatientVariability
20
Clopidogrel Responder
0
Clopidogrel Non-responder
-20
Response to Prasugrel 60 mg
Response to Clopidogrel 300 mg
From Brandt JT AHJ 2007153 66-9
52
Balance of Efficacy and Safety

15
138 events
Clopidogrel
HR 0.81(0.73-0.90)P0.0004
12.1
CV Death / MI / Stroke
9.9
10
NNT 46
Prasugrel
Endpoint ()
5
35 events
TIMI Major NonCABG Bleeds
Prasugrel
2.4
HR 1.32(1.03-1.68)P0.03
1.8
Clopidogrel
0
NNH 167
0
30
60
90
180
270
360
450
Days
53
Net Clinical BenefitBleeding Risk Subgroups
Risk ()

37
Yes
Prior Stroke / TIA
-16
No
Pint 0.006
-1
gt75
Age
-16
Pint 0.18
lt 75
3
lt 60 kg
Wgt
Pint 0.36
-14
gt60 kg
-13
OVERALL
0.5
1
2
Prasugrel Better
Clopidogrel Better
HR
54
Antiplatelet therapy in high-risk patients

• Chronic CAD
• prior cardiac events
• 3-vessel disease
• LV dysfunction
• recent DES
• PAD
• diabetes
• CKD

• NSTEACS
• ST depression
• Tn elevation
• refractory ischemia
• LV dysfunction
• diabetes
• elderly
• CKD

• STEMI
• elderly
• high Killip
• prior MI
• large MI
• failed lysis
• diabetes
• CKD

55
Long-term outcome of stable CAD in late 80ies
CNR-OD 1 Multicenter study (late eighties) 1083
patients with stable CAD followed for 6611
months
10- 8- 6- 4- 2- 0-
Cardiac death
Myocardial infarction
total
8
total
5.3
per year
per year
1.5
1.0
56
20-year survival after CABG in 3939 patients
operated on between 1973 and 1979 Emory
University
100- 90- 80- 70- 60- 50- 40- 30- 20- 10- 0-
37
29
Men
Women
0 5
10
15 20

years
Weintraub W et al, Circulation 20031071271-7
57
Long-term outcome after PTCA
856 PATIENTS PTCA year 1980-85
van Domburg RT, Eur Heart J 200122934-41
58
Primary end-point
CV death, nonfatal MI, revasc, stroke
30
25
Placebo
20
Event rate ()
15
Simvastatin
10
5
0
0
1
2
3
4
5
6
Years of follow-up
60(18)
Absolute benefit/1000 (SE)
THE LANCET, Vol. 360, July 6, 2002
59
Primary end-point
CV death, nonfatal MI, cardiac arrest
Placebo
RRR 20
p 0,0003
Perindopril
Yearly rate placebo group 2,4
Lancet. 2003362782-788.
60
Major adverse CV event rates at 1 year Results
from the REACH registry
Total (n63129)
Symptomatic (n51685)
Multiple RF only (n11444)
Event
CV death Non-fatal MI Non-fatal stroke CV
death/MI/stroke
1.5 1.1 1.6 3.5
1.7 1.2 1.8 3.9
0.6 0.8 0.8 1.7
RF, risk factors CV, cardiovascular MI,
myocardial infarction
From Van de Werf F, EHJ 2007
61
The ILLUMINATE Study
0.8
1.2

• 15,067 patients
• mean age 61
• 74 hypertension
• 69 prior CABG or PCI
• 45 prior MI
• 60 history of angina
• LDL 80 mg/dL

5.0
6.2
Barter P. N Engl J Med 20073572109-22
62
Absolute Effects of Aspirin on the Risk of
Vascular Events (Nonfatal MI, Nonfatal Stroke, or
CV Death in Five Groups of High-Risk Patients.
(ATT Collaboration BMJ 2002)
63
Vascular events avoided using low-dose
aspirin, Baseline risk and bleeding events
Patrono C,NEJM 2005
64
Excess of upper GI bleeding with low-dose
aspirin Depending on previous clinical history
Patrono C,NEJM 2005
65
MI/Stroke/CV Death at 30 months by Category of
Inclusion Criteria
Population N RR (95 CI) p value Qualifying CV
Disease 12,153 0.88 (0.77, 0.998) 0.046
Coronary 5,835 0.86 (0.71, 1.05) 0.13
Cerebrovascular 4,320 0.84 (0.69, 1.03) 0.09
PAD 2,838 0.87 (0.67, 1.13) 0.29 Multiple Risk
Factors 3,284 1.20 (0.91, 1.59) 0.20 Overall
Population 15,603 0.93 (0.83, 1.05) 0.22
1.4
1.2
1.6
0.6
0.8
0.4
Clopidogrel ASA Better
Placebo ASA Better
Bhatt DL. NEJM 2006
66
Cardiovascular mortality
Wang TH, Eur Heart J 2007282200
67
Occurrence of early and late angiographically- doc
umented stent thrombosis in the Rotterdam
and Bern registries
0.6 per year
30D
3y
Independent predictors
HR
95CI ACS at presentation 2.3
1.3-4.0 Diabetes 2.0
1.1-3.8
Daemen J, Lancet 2007369667
68
Dark chocolate improves coronary vasomotion and
reduces platelect reactivity
22 heart transplant recipients Double-blind,
random. study
Coronary artery diameter by QCO at baseline and
change after cold pressor test
control
chocolate
Shear stress dependent platelet adhesion at high
shear rate
Flammer AJ, Circulation 2007, in press
69
An old concept confirmed in acute and high-risk
patients
I would especially commend the physician who, in
acute diseases, by which the bulk of mankind are
cutoff, conducts the treatment better than
others
HIPPOCRATES (c.a. 460- ca. 377 B.C.)
70
An old concept confirmed in low-risk patients
Primum non nocere
HIPPOCRATES (c.a. 460- ca. 377 B.C.)
71
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