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Should we use bivalirudin ?
FibrinFibrin
2
1
ThrombinThrombin2
1
ThrombinThrombin
2
1
TrombinaTrombina
2
1
TrombinaTrombina
BivalirudinBivalirudin
ADVANTAGES
- No requirement for anti-thrombin III- Effective on clot-bound thrombin- Plasma half-life 25 minutes- No anticoagulation monitoring
Primary Endpoint in the ACUITY trial
11,7%
7,3%5,7%
3,0%
10,1%
7,8%
Net clinicaloutcome
Ischemiccomposite
Major bleeding
30
da
y e
ve
nts
(%
)
UFH/Enoxaparin+GPI (N=4603) Bivalirudin alone (N=4612)
UFH/Enoxaparin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin Alone
PNI <0.0001PSup = 0.015
PNI = 0.011PSup = 0.32
PNI <0.0001PSup <0.0001
0 1 2
Net Clinical Outcome CompositeUFH/Enoxaparin + IIb/IIIa vs. Bivalirudin AloneUFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone
Yes (n=3197)No (n=6008)
Low (0-2) (n=1291)Intermed (3-4) (n=4407)
High (5-7) (n=2449)
Elevated (n=5368)Normal (n=3841)
Risk ratio±95% CI
Risk ratio±95% CI
BivalAlone
UFH/Enox+ IIb/IIIa
9.2%11.3%
12.2%11.1%
P Pint
0.76 (0.65-0.89)1.02 (0.86-1.21)
12.2%7.1%
13.3%9.4%
0.92 (0.80-1.06)0.75 (0.61-0.93)
0.230.01
<0.0010.83
0.35
0.02
0.18
13.0%8.6%
13.7%10.6%
0.96 (0.80-1.14)0.81 (0.69-0.95)
0.610.01 0.42
Biomarkers (CK/Trop)
ST Deviation
TIMI Risk Score
Pre Thienopyridine
6.4% 10.2% 0.63 (0.43-0.91) 0.019.4% 10.2% 0.92 (0.77-1.10) 0.34
13.9% 15.2% 0.92 (0.76-1.11) 0.36
Yes (n=5192)No (n=4023)
RR (95% CI)
Bivalirudin alone betterBivalirudin alone better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa better
Effetto della bivalirudina sui sanguinamenti non legati al sito di accesso arterioso all’analisi cumulativa degli studi REPLACE-2,
ACUITY e HORIZONS.
Landmark Analysis: 30-Day Stent Thrombosis (N=3,124)
Bivalirudin: 1749 1714 1711 1673 1663 1591
UFH + GP IIb/IIIa: 1818 1805 1804 1746 1724 1625
Patients at Risk
Bivalirudin UFH + GP IIb/IIIa
Est
ima
ted
Ev
ent
Rat
e (%
)
Days from Randomisation
0
1
2
3
4
5
5 10 15 20 25 300 0.5 1
23
4
30
19
Data on file: The Medicines Company Analysis of safety population in all patients receiving stents
Platelet Activation Mechanisms
ThrombinThrombin
ThromboxaneThromboxaneAA 22
5HT5HT
P2Y12
ADPADP ADPADPADPADP
5HT5HT
PLATELETPLATELETACTIVATIONACTIVATION
P2Y15HT2A
PAR1
PAR4
Densegranule
ThrombinThrombingenerationgeneration
ShapeShapechangechange
IIb3
IIb3
FibrinogenFibrinogenIIb3
AggregationAggregation
AmplificationAmplificationAlpha
granule
Coagulation factorsCoagulation factorsInflammatory mediatorsInflammatory mediators
TPa
CoagulationCoagulation
GPVI
CollagenCollagen
ATPATPATPATP
P2X1
ASPIRINASPIRIN
x TICLOPIDINETICLOPIDINECLOPIDOGRELCLOPIDOGRELPRASUGRELPRASUGREL
ACTIVE ACTIVE METABOLITEMETABOLITE
x TICAGRELORTICAGRELOR CANGRELORCANGRELOR
GP IIb/IIIa ANTAGONISTSGP IIb/IIIa ANTAGONISTS
xx
Storey RF. Curr Pharm Des. 2006;12:1255-59.
PRIMARY COMPOSITE ENDPOINT* IN TRITON AND PLATO TRIALS
9,9
12,1
9,8
11,7
0,00
5,00
10,00
15,00
20,00
TRITON PLATO
CLOPIDOGREL
NEW DRUG
P<.001 P<.001
*Death,MI,Stroke
CLINICAL CHARACTERISTICS OF TRITON AND PLATO POPULATION
TRITON (N=13608 pts )
PLATO ( N= 18624 pts )
% PCI 99 64
% CABG 1 10
% NON-INVASIVE 0 29
% STEMI 26 38
Prasugrel (studio TRITON) e’ stato confrontato con clopidogrel 300 mg LD + 75 mg MD.
Ticagrelor (studio PLATO) e’ stato confrontato con clopidogrel 300-600 mg LD + 75mg MD.
Study Design, Flow and Compliance
25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)Planned Early (<24 h) Invasive Management with intended PCIIschemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)
25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)Planned Early (<24 h) Invasive Management with intended PCIIschemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)
PCI 17,232(70%)
Angio 24,769(99%)
Angio 24,769(99%) No PCI 7,855
(30%)
No Sig. CAD 3,616 CABG 1,809 CAD 2,430
Randomized to receive (2 X 2 factorial):
CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d)
ASA: High Dose (300-325 mg/d) vs Low dose (75-100 mg/d)
Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30
Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCI
Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30
Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCI
Days
Cu
mu
lati
ve H
azar
d
0.0
0.01
0.02
0.03
0.04
0 3 6 9 12 15 18 21 24 27 30
Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients
Clopidogrel Standard
Clopidogrel Double
HR 0.8595% CI 0.74-0.99
P=0.036
15% RRR15% RRR
CV Death, MI or StrokeCV Death, MI or Stroke
CLOPIDOGREL
TICAGRELOR
8,688
8,763
0 10 20 30
8
6
4
2
0
Cu
mu
lati
ve i
nci
de
nce
(%
)
Clopidogrel
Ticagrelor
4.77
5.43
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
Cu
mu
lati
ve i
nci
de
nce
(%
)
Primary efficacy endpoint over time (composite of CV death, MI or stroke)
*Excludes patients with any primary event during the first 30 days
CARDIOVASCULAR DEATH IN TRITON AND PLATO TRIALS
2,12,4
4
5,1
0
5
10
TRITON PLATO
NEW DRUG
CLOPIDOGREL
P<.001
Diabetic SubgroupDiabetic Subgroup
0
2
4
6
8
10
12
14
16
18
0 30 60 90 180 270 360 450
HR 0.70P<0.001
Days
En
dp
oin
t (%
)
CV Death / MI / Stroke
TIMI Major NonCABG Bleeds
NNT = 20 (46)
N=3146N=3146
17.0
12.2
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel 2.6
2.5
ARC Definite or Probable Late Stent Thrombosis* in Patients Receiving DES
HR 0.46 (0.22-0.97); P=0.04
ARC = Academic Research Consortium; DES = drug-eluting stent
Days
30 90 150 210 270 330 390 450
% o
f S
ub
jec
ts
0.0
0.5
1.0
1.5
2.0
2.5
Prasugrel
Clopidogrel0.91
0.42
P=.04P=.04
NON-CABG RELATED TIMI MAJOR BLEEDING IN TRITON AND PLATO TRIALS
2,41,8
2,82,2
0
5
TRITON PLATO
CLOPIDOGREL
NEW DRUG
P=.03P=.03
FATAL BLEEDING IN TRITON AND PLATO TRIALS
0,4
0,1
0,30,3
0
1
TRITON PLATO
CLOPIDOGREL
NEW DRUG
P=.002
INTRACRANIAL HEMORRAGES IN TRITON AND PLATO TRIALS
0,30,3
0,20,1
0,3
0,1
0
1
TRITON PLATO PLATO (+Unknown origin)
CLOPIDOGREL
NEW DRUG
P=.06 P<.05
Balance of Efficacy and Safety in Patients Balance of Efficacy and Safety in Patients <75 Yrs, ≥60 kg, and Without TIA/Stroke<75 Yrs, ≥60 kg, and Without TIA/Stroke
En
dp
oin
t (%
)
0
2
4
6
8
1 0
1 2
1 4
1 6
0 30 90 180 270 360 450
Hazard Ratio, 1.240(95% CI, 0.91-1.69)
P=0.17
Hazard Ratio, 0.75(95% CI, 0.66-0.84)
P<0.001
Clopidogrel
Prasugrel
Clopidogrel
Prasugrel 1.95%
1.50%
11%
8.4%
CV Death / NF MI / NF Stroke
Non-CABG TIMI Major Bleeding
Days
NNT37
NNH222
Adapted from Wiviott SD et al NEJM 357: 2001, 2007Presented at TCT 2009, San Francisco, CA
CLINICAL CHARACTERISTICS OF TRITON AND PLATO POPULATION
Variable\\\\ TRITON PLATO
AGE (years) 61 62
% FEMALE SEX 26 28
% Cl Creat <60 ml/min 11 4
% DIABETES 23 25
% PRIOR MI 18 20
% PRIOR CABG 8 6
For High Risk,RR=0.58
[ 0.34, 0.98]P= 0.037
Parodi G. TCT 2009
COMPOSITE ENPOINT IN CURRENT-OASIS 7
4,4 4,24,2
4,9
4,53,9
0
2
4
6
ALL PATIENTS NO PCI PCI
DOUBLE
STANDARD
P=NS
P=NSP=0.036
CARDIOVASCULAR DEATH IN STEMI PATIENTS INCLUDED IN TRITON
2,4
3,43,3
4,3
0
5
10
CV DEATH ALL DEATHS
PRASUGREL
CLOPIDOGREL
STENT THROMBOSIS IN TRITON AND PLATO TRIALS
1,1
2,42,2
2,9
0
2
4
TRITON PLATO
CLOPIDOGREL
NEW DRUG
P<.001P=.02
COMPOSITE ENPOINT IN DIABETIC PATIENTS
12,2
17
14,1
16,2
0
5
10
15
20
25
TRITON PLATO
CLOPIDOGREL
NEW DRUG
P<.001NS
CARDIOVASCULAR DEATH IN TRITON AND PLATO TRIALS
2,12,4
4
5,1
0
5
10
TRITON PLATO
NEW DRUG
CLOPIDOGREL
P<.001
MYOCARDIAL INFARCTION IN TRITON AND PLATO TRIALS
7,3
9,5
5,8
6,9
0
5
10
15
TRITON PLATO
CLOPIDOGREL
NEW DRUG
P<.001
P=.005
CABG RELATED TIMI MAJOR BLEEDING IN TRITON AND PLATO TRIALS
13,4
3,25,3
5,8
0
5
10
15
20
TRITON PLATO
CLOPIDOGREL
NEW DRUG
P<.001
STROKE IN TRITON AND PLATO TRIALS
11
1,5 1,31,2 1,1
0
5
TRITON PLATO PLATO INVASIVE
CLOPIDOGREL
NEW DRUG
FATAL HEMORRAGES IN PLATO
0,10,01
0,1
0,3
0
1
INTRACRANIAL NON-INTRACRANIAL
CLOPIDOGREL
NEW DRUG
P=.03
P=.02
NON-ADHERENCE TO STUDY DRUG
( MEDIAN TREATMENT TIME FOR PLATO 9 MONTHS , FOR TRITON 14.5 MONTHS )
16,3 15,7
23,4 21,5
0
5
10
15
20
25
30
TRITON PLATO
CLOPIDOGREL
NEW DRUG
COMPOSITE ENPOINT IN CURRENT-OASIS 7
4,53,9 4,2
4,9
0
2
4
6
PCI NO PCI
DOUBLE
STANDARD
P=.036
P=NS
Days
Cu
mu
lati
ve H
azar
d
0.0
0.00
40.
008
0.01
2
0 3 6 9 12 15 18 21 24 27 30
Clopidogrel Standard Dose
Clopidogrel Double Dose
42% RRR
HR 0.5895% CI 0.42-0.79
P=0.001
Clopidogrel: Double vs Standard DoseDefinite Stent Thrombosis (Angio confirmed)
Ticagrelor better Clopidogrel better
Ti. Cl.Total
Patients
KM % atMonth 12
HR (95% CI)Hazard Ratio
(95% CI)
Yes
Yes
Revascularization History of CABG
Sex
Weight Group
≥65 Years
Characteristic
0.5 1.0 2.0
17256 9.5 11.2 0.86 (0.78, 0.94)<80 kg
1312 13.1 17.3 0.75 (0.60, 0.99)≥60 kg
5288 11.2 13.2 0.83 (0.71, 0.97)
<60 kg
13336 9.2 11.1 0.85 (0.76, 0.95)Female
2878 16.8 18.3 0.94 (0.78, 1.12)
Male
15744 8.6 10.4 0.82 (0.74, 0.91)≥75 Years
7979 13.2 16.0 0.83 (0.74, 0.94)<75 Years
10643 7.2 8.5 0.85 (0.74, 0.97)<65 Years
1152 19.0 20.8 0.87 (0.66, 1.13)Age Group
17462 9.2 11.1 0.84 (0.76, 0.93)No
1106 19.5 21.7 0.88 (0.67, 1.15)Previous TIA/Non-hemorrhagic Stroke
17518 9.2 11.0 0.84 (0.77, 0.93)No
Yes
Central/South America
≥80 kg
North America
1237 15.2 17.9 0.86 (0.65, 1.13)Europe/Middle East/Africa
1714 11.4 14.8 0.80 (0.61, 1.04)Asia/Australia
4662 14.1 16.2 0.88 (0.76, 1.03)Region
13962 8.4 10.2 0.83 (0.74, 0.92)No
9513 8.3 10.5 0.79 (0.69, 0.90)Medical History of DM
9055 11.4 12.8 0.90 (0.79, 1.01)
0.2
p- value(Interaction)
0.76
0.84
0.86
0.22
0.82
0.36
0.17
0.05
1814 11.9 9.6 1.25 (0.93, 1.67)13859 8.8 11.0 0.80 (0.72, 0.90)
0.49
Primary endpoint in pre-defined subgroups (cont’d)
Ticagrelor better Clopidogrel better
Ti. Cl.Total
Patients
KM % atMonth 12
HR (95% CI)Hazard Ratio
(95% CI)
Yes
Yes
Revascularization History of CABG
Sex
Weight Group
≥65 Years
Characteristic
0.5 1.0 2.0
17086 11.5 10.9 1.06 (0.96, 1.16)<80 kg
1296 12.6 15.2 0.82 (0.60, 1.12)≥60 kg
5237 10.7 10.5 1.01 (0.85, 1.21)
<60 kg
13184 11.9 11.4 1.05 (0.94, 1.16)Female
2846 14.2 13.3 1.04 (0.84, 1.29)
Male
15574 11.1 10.8 1.04 (0.94, 1.15)≥75 Years
7892 14.4 13.6 1.07 (0.95, 1.22)<75 Years
10528 9.5 9.5 1.00 (0.87, 1.13)<65 Years
1136 14.6 14.9 0.99 (0.71, 1.37)Age Group
17284 11.4 11.0 1.04 (0.95, 1.14)No
1092 7.3 7.8 0.94 (0.60, 1.49)Previous TIA/Non-hemorrhagic Stroke
17329 11.8 11.4 1.04 (0.95, 1.14)No
Yes
Central/South America
≥80 kg
North America
1230 15.6 13.2 1.22 (0.89, 1.66)Europe/Middle East/Africa
1692 10.6 10.8 1.03 (0.76, 1.40)Asia/Australia
4621 14.1 14.8 0.95 (0.81, 1.12)Region
13800 10.8 10.0 1.08 (0.97, 1.20)No
9423 11.4 10.5 1.08 (0.95, 1.23)Medical History of DM
8959 11.7 11.9 0.99 (0.88, 1.13)
0.2
P value(Interaction)
0.68
0.77
0.42
1.00
0.76
0.12
0.35
0.75
1752 12.9 12.2 1.06 (0.80, 1.40)13747 11.1 11.0 1.01 (0.91, 1.13)
0.21
HRs and cumulative incidence of major bleeding in pre-defined subgroups (cont’d)
FATAL BLEEDING IN TRITON AND PLATO TRIALS
0,4
0,1
0,30,3
0,2
0,3
0
1
TRITON PLATO PLATO INVASIVE
CLOPIDOGREL
NEW DRUG
P=.002
MAJOR BLEEDING
Preliminary Results
Safety outcomes at 1 monthSafety outcomes at 1 month Safety outcomes at 1 monthSafety outcomes at 1 month
NSTE-ACS NSTE-ACS 2 of 3 Criteria: Ischemic symptom, ST-T change, troponin rise2 of 3 Criteria: Ischemic symptom, ST-T change, troponin rise
with TIMI score with TIMI score >> 3 3
Immediate cathImmediate cath Next day cathNext day cath
All PCIs on abciximabAll PCIs on abciximab
1-month Follow-up1-month Follow-up
IVRS RANDOMIZATIONIVRS RANDOMIZATION
85% of radial access
Preliminary Results
Safety outcomes at 1 monthSafety outcomes at 1 monthSafety outcomes at 1 monthSafety outcomes at 1 month
Immediate Delayed PP
Major bleeding at 1 month, (%)Major bleeding at 1 month, (%) 4.0 6.8 0.250.25
Non-CABG major bleedingNon-CABG major bleeding 2.3 5.1 0.260.26
CABG-related major bleedingCABG-related major bleeding 1.7 1.7 1.001.00
Transfusion Transfusion >> 2 units 2 units 3.4 5.6 0.320.32
Transfusion Transfusion >> 5 units 5 units 1.1 1.1 1.001.00
Thrombocytopenia at 1 month, (%)Thrombocytopenia at 1 month, (%) 2.9 4.5 0.410.41
Non-CABG Non-CABG thrombocytopenia,thrombocytopenia, (%) (%) 2.3 4.0 0.540.54
Post-CABG Post-CABG thrombocytopenia,thrombocytopenia, (%) (%) 0.6 0.6 1.001.00
Preliminary Results
Sites of Major BleedingsSites of Major BleedingsSites of Major BleedingsSites of Major Bleedings
1- Gastro-Intestinal1- Gastro-Intestinal 44
2- Puncture-related2- Puncture-related 44
3- Hemopericardium3- Hemopericardium 22
4- Intracranial4- Intracranial 11
5- Epistaxis5- Epistaxis 11
6- Hematoma (not puncture-related)6- Hematoma (not puncture-related) 11
unknownunknown 77
One patient had 2 bleeding events
n
Other findings
All patientsTicagrelor(n=9,235)
Clopidogrel(n=9,186) p value*
Dyspnoea, %
Any
With discontinuation of study treatment
13.8
0.9
7.8
0.1<0.001
<0.001
Holter monitoring at first week , %
Ventricular pauses =>3 sec ,%
Ventricular pauses =>5 sec ,%
(n=1451)
5.8
2.0
(N=1415)
3.6
1.2
0.01
0.10
*p values were calculated using Fischer’s exact test
TCT 2009
3.0% 3.0%
3.8% 3.8%
HR [95%CI] = HR [95%CI] = 1.30 [0.86-1.95]1.30 [0.86-1.95]
P = 0.10P = 0.10
1-Year Stent Thrombosis1-Year Stent Thrombosis: Impact of : Impact of Clopidogrel Loading Dose (all pts)Clopidogrel Loading Dose (all pts)
19831983 19061906 18811881 18581858 18321832 1653165310341034 983983 974974 965965 952952 871871
Number at riskNumber at risk600 mg600 mg300 mg300 mg
600mg Clopidogrel600mg Clopidogrel
300mg Clopidogrel300mg Clopidogrel
Def
/Pro
b S
ten
t T
hro
mb
osi
s (%
)D
ef/P
rob
Ste
nt
Th
rom
bo
sis
(%)
00
11
22
33
44
55
Time in daysTime in days
00 3030 6060 9090 120120 150150 180180 210210 240240 270270 300300 330330 365365
TCT 2009
0.8%0.8%
2.2% 2.2%
3.2% 3.2%
0.8%0.8%
HR [95%CI] = HR [95%CI] = 0.96 [0.41-2.23]0.96 [0.41-2.23]
P = 0.92P = 0.92
HR [95%CI] = HR [95%CI] = 1.47 [0.93,2.33]1.47 [0.93,2.33]
P = 0.18P = 0.18
19831983
1034103419781978 19201920 18811881 18581858 18321832 16531653
10271027 990990 974974 965965 952952 871871
Number at riskNumber at risk
600 mg600 mg
300 mg300 mg
Def
/Pro
b S
ten
t T
hro
mb
osi
s (%
)D
ef/P
rob
Ste
nt
Th
rom
bo
sis
(%)
00
11
22
33
44
55
Time in DaysTime in Days
00 11 3030 9090 180180 270270 365365
Stent Thrombosis 1-Day Landmark Stent Thrombosis 1-Day Landmark Analysis:Analysis: Impact of Clopidogrel Loading Impact of Clopidogrel Loading
600mg Clopidogrel600mg Clopidogrel
300mg Clopidogrel300mg Clopidogrel
TCT 2009
2.8% 2.8%
3.6% 3.6%
HR [95%CI] =HR [95%CI] =0.78 [0.44-1.37]0.78 [0.44-1.37]
P = 0.38P = 0.38
727727 693693 685685 678678 668668 592592829829 793793 778778 768768 759759 698698
Number at riskNumber at riskEptifibatideEptifibatideAbciximabAbciximab
Def
/Pro
b S
ten
t T
hro
mb
osi
s (%
)D
ef/P
rob
Ste
nt
Th
rom
bo
sis
(%)
00
11
22
33
44
Time in daysTime in days
00 3030 6060 9090 120120 150150 180180 210210 240240 270270 300300 330330 365365
EptifibatideEptifibatide
AbciximabAbciximab
1-Year Stent Thrombosis: 1-Year Stent Thrombosis: Impact of Impact of GPI in the UFH Group GPI in the UFH Group
November 15, 2007
August 30, 2009
Conclusioni (1)
• La bivalirudina riduce i sanguinamenti locali e d’organo nei pazienti con SCA sottoposti a PCI , soprattutto in quelli a maggior rischio emorragico ( anziani ).
• Per una efficace copertura antiischemica deve essere associata ad un regime di doppia anti-aggregazione piastrinica (aspirina + bloccante recettore P2Y12).
Conclusioni (2)
- I nuovi farmaci che bloccano il recettore P2Y12 ( prasugrel, ticagrelor ) sono risultati piu’ efficaci del clopidogrel grazie alla loro migliore farmacocinetica e farmacodinamica. Ad essi si associa tuttavia un maggior rischio emorragico .
- L’analisi di efficacia e di rischio in particolari sottogruppi di pazienti con SCA potra’ permettere di utilizzare il farmaco piu’ vantaggioso per la condizione clinica del singolo paziente .
TCT 2009
Independent Predictors of Subacute ST Independent Predictors of Subacute ST (Cox Model)(Cox Model)
Variable HR [95% CI] P-value
Insulin-treated diabetes 4.43 [2.03, 9.65] 0.0002
History of CHF 4.16 [1.61, 10.76] 0.003
Pre-PCI TIMI flow 0/1 2.21 [1.05, 4.63] 0.04
Final TIMI flow 0/1 3.72 [1.10, 12.55] 0.03
Stent to lesion length ratio 1.44 [1.20, 1.71] <0.0001
Clopidogrel loading dose 600 mg (vs. 300 mg)
0.49 [0.27, 0.89] 0.01
Montalescot et al. ESC 2008
Stent thrombosis (ARC Definite/probable )
HR=0.58 (0.36–0.93) NNT=83
p=0.02 RRR=42%
0 100 200 300 4000
1
2
3
Pro
po
rtio
n o
f p
atie
nts
(%
)
Time (Days)
2.4
1.2
2.8
1.6p=0.008RRR=51%
Clopidogrel
Prasugrel
Age-adjusted HR=0.59 (0.37-0.96)
ARC Definite or Probable Stent Thrombosis (day 0 to day 450)
2.35
1.13
HR 0.48 (0.36-0.64); P<0.0001
Prasugrel
Clopidogrel
1 year: 1.06 vs. 2.15%HR 0.48 (0.36-0.65); P<0.0001
ARC = Academic Research Consortium
Days
0 50 100 150 200 250 300 350 400 450
% o
f S
ub
jec
ts
0.0
0.5
1.0
1.5
2.0
2.5
52% RRR
3
9.5
8.1
4.2
0
2
4
6
8
10
30-day 1 year
BIVALIRUDIN
UFH + GPIIbIIIa INH.
DEATH RATE IN ELDERLY PATIENTS IN THE ACUITY TRIAL
Net Clinical BenefitNet Clinical BenefitBleeding Risk SubgroupsBleeding Risk Subgroups
OVERALL
>=60 kg
< 60 kg
< 75
>=75
No
Yes
0.5 1 2
Prior Stroke / TIA
Age
Wgt
Risk (%)
+ 37
-16
-1
-16
+3
-14
-13
Prasugrel Better Clopidogrel BetterHR
Pint = 0.006
Pint = 0.18
Pint = 0.36
Post-hoc analysisPost-hoc analysis
TCT 2009
2.8% 2.8%
3.6% 3.6%
HR [95%CI] =HR [95%CI] =0.78 [0.44-1.37]0.78 [0.44-1.37]
P = 0.38P = 0.38
727727 693693 685685 678678 668668 592592829829 793793 778778 768768 759759 698698
Number at riskNumber at riskEptifibatideEptifibatideAbciximabAbciximab
Def
/Pro
b S
ten
t T
hro
mb
osi
s (%
)D
ef/P
rob
Ste
nt
Th
rom
bo
sis
(%)
00
11
22
33
44
Time in daysTime in days
00 3030 6060 9090 120120 150150 180180 210210 240240 270270 300300 330330 365365
EptifibatideEptifibatide
AbciximabAbciximab
1-Year Stent Thrombosis: 1-Year Stent Thrombosis: Impact of Impact of GPI in the UFH Group GPI in the UFH Group
TCT 2009
3.0% 3.0%
3.8% 3.8%
HR [95%CI] = HR [95%CI] = 1.30 [0.86-1.95]1.30 [0.86-1.95]
P = 0.10P = 0.10
1-Year Stent Thrombosis1-Year Stent Thrombosis: Impact of : Impact of Clopidogrel Loading Dose (all pts)Clopidogrel Loading Dose (all pts)
19831983 19061906 18811881 18581858 18321832 1653165310341034 983983 974974 965965 952952 871871
Number at riskNumber at risk600 mg600 mg300 mg300 mg
600mg Clopidogrel600mg Clopidogrel
300mg Clopidogrel300mg Clopidogrel
Def
/Pro
b S
ten
t T
hro
mb
osi
s (%
)D
ef/P
rob
Ste
nt
Th
rom
bo
sis
(%)
00
11
22
33
44
55
Time in daysTime in days
00 3030 6060 9090 120120 150150 180180 210210 240240 270270 300300 330330 365365
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,560
8,678
8,405
8,520
8,177
Days after randomisation
6,703
6,796
5,136
5,210
4,109
4,191
0 60 120 180 240 300 360
6
5
4
3
2
1
0
7
Cu
mu
lati
ve i
nci
de
nce
(%
)
Clopidogrel
Ticagrelor
5.8
6.9
8,279
HR 0.84 (95% CI 0.75–0.95), p=0.005
0 60 120 180 240 300 360
6
4
3
2
1
0
Clopidogrel
Ticagrelor
4.0
5.1
HR 0.79 (95% CI 0.69–0.91), p=0.001
7
5
9,291
9,333
8,865
8,294
8,780
8,822
8,589
Days after randomisation
7079
7119
5,441
5,482
4,364
4,4198,626
Myocardial infarction Cardiovascular death
Cu
mu
lati
ve i
nci
de
nce
(%
)
Secondary efficacy endpoints over time
TICAGRELOR (AZD6140)
A non-thienopyridine, in the chemical class CPTP (CycloPentylTriazoloPyrimidine)
1) First oral reversible ADP P2Y12 receptor antagonist
2) Direct acting via the P2Y12 receptor - metabolism not
required for activity ( not a pro-drug ) 3) More potent platelet inhibitor than clopidogrel
HO
HN
HO OH
O S
F
F
NN
N
NN
2.6
7.76.8
3.2
0123456789
30-day 1 year
BIVALIRUDIN
UFH + GPIIbIIIa INH.
DEATH RATE IN ELDERLY PATIENTS UNDERGOING PCI
Messaggi finali (1)
- La doppia terapia antiaggregante e’ un cardine fondamentale del trattamento delle sindromi coronariche acute.
- Lo studio CURRENT ha mostrato che nei pazienti con sindrome coronarica acuta il doppio dosaggio di clopidogrel ( 600 mg seguito da 150 mg per una settimana ) migliora i risultati clinici ad 1 mese solo nei pazienti sottoposti a PCI.
Messaggi finali (2)
- I nuovi farmaci che bloccano il recettore P2Y12 ( prasugrel, ticagrelor ) sono risultati piu’ efficaci del clopidogrel negli studi di confronto a lungo termine grazie alla loro migliore farmacocinetica e farmacodinamica. Da non sottovalutare tuttavia il maggior rischio emorragico ad essi associato.
- L’analisi di efficacia e di rischio di questi nuovi farmaci antipiastrinici in particolari sottogruppi di pazienti con SCA potra’ permettere di utilizzare il farmaco piu’ vantaggioso per la condizione clinica del singolo paziente .
TRITON TIMI-38 STEMI cohort
Efficacy endpoints at 30 days
Montalescot et al. ESC 2008
* ARC def/probable
0
2
4
6
8
10
All Death MI UTVR StentThrombosis*
CV Death/MI
CV Death/MI/UTVR
CV Death/MI/Stroke
Pro
po
rtio
n o
f p
op
ula
tio
n (
%)
p= 0.04
p= 0.01
p= 0.13p= 0.008
p= 0.004 p= 0.02p= 0.002
Clopidogrel
Prasugrel
Other findings – laboratory parameters
All patientsTicagrelor(n=9,235)
Clopidogrel(n=9,186) p value*
% increase in creatinine from baseline
At 1 month
At 12 months
Follow-up visit
10 22
11 22
10 22
8 21
9 22
10 22
<0.001
<0.001
0.59
% increase in uric acid from baseline
At 1 month
At 12 months
Follow-up visit
14 46
15 52
7 43
7 44
7 31
8 48
<0.001
<0.001
0.56
Values are mean % SD; *p values were calculated using Fisher’s exact test
CREDO: Benefits of Clopidogrel Plus Aspirin CREDO: Benefits of Clopidogrel Plus Aspirin to 1 Year Following PCI to 1 Year Following PCI
CV Death, MI or Stroke
* Plus ASA and other standard therapies .Steinhubl S, et al. JAMA. 2002;288:2411-2420
Co
mb
ined
En
dp
oin
t O
ccu
rren
ce (
%)
Months From Randomization
27% RRR
P=.02
Placebo*Clopidogrel*
0
5
10
15
8.5%
11.5%
0 3 6 9 12
2485 PATIENTS WITH STENT PLACEMENTPRETREATED WITH CLOPIDOGREL 600 mg
August 30, 2009 at 08.00 CET
Diabetic SubgroupDiabetic Subgroup
0
2
4
6
8
10
12
14
16
18
0 30 60 90 180 270 360 450
HR 0.70P<0.001
Days
En
dp
oin
t (%
)
CV Death / MI / Stroke
TIMI Major NonCABG Bleeds
NNT = 20 (46)
N=3146N=3146
17.0
12.2
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel 2.6
2.5
990 patients with ACS990 patients with ACS
Patients with age <75 , weight >60 Kg Patients with age <75 , weight >60 Kg
and no prior CVA/TIAand no prior CVA/TIA
CLOPIDOGRELCLOPIDOGREL
(n=5383)(n=5383)PRASUGREL PRASUGREL
(n=5421)(n=5421)
CV EVENTS CV EVENTS 11% 11% (12,1%)(12,1%) 8,3% 8,3% (9,9%)(9,9%)
(DEATH ,MI,STROKE)(DEATH ,MI,STROKE)P<.001
NNT=37 (46)
Other findings
All patientsTicagrelor(n=9,235)
Clopidogrel(n=9,186) p value*
Dyspnoea, %
Any
With discontinuation of study treatment
13.8
0.9
7.8
0.1<0.001
<0.001
Neoplasms arising during treatment, %
Any
Malignant
Benign
1.4
1.2
0.2
3.6
1.2
0.4
0.17
0.69
0.02
*p values were calculated using Fischer’s exact test
Holter monitoring & Bradycardia related events
Holter monitoring at first weekTicagrelor(n=1,451)
Clopidogrel(n=1,415) p value
Ventricular pauses ≥3 seconds, %
Ventricular pauses ≥5 seconds, %
5.8
2.0
3.6
1.2
0.01
0.10
Holter monitoring at 30 daysTicagrelor(n= 985)
Clopidogrel(n=1,006) p value
Ventricular pauses ≥3 seconds, %
Ventricular pauses ≥5 seconds, %
2.1
0.8
1.7
0.6
0.52
0.60
Bradycardia-related event, %Ticagrelor(n=9,235)
Clopidogrel(n=9,186) p value
Pacemaker Insertion
Syncope
Bradycardia
Heart block
0.9
1.1
4.4
0.7
0.9
0.8
4.0
0.7
0.87
0.08
0.21
1.00
Kaplan Meier estimates of non-CABG-related TIMI Major bleeding
Non-ideal population Ideal population
TIMI major non-CABG bleeding
Montalescot et al. ESC 2008
0.5
1.0
2.0
2.5
1.5
2.1
2.4
HR=1.11 (0.70–1.77) NNH=333Pro
po
rtio
n o
f p
atie
nts
(%
)
Time (Days)
p=0.65
0 100 200 300 4000
ClopidogrelPrasugrel
Age-adjusted HR=1.19 (0.75-1.89)
Montalescot et al. ESC 2008
Stent thrombosis
ARC Definite/probable
HR=0.58 (0.36–0.93) NNT=83
p=0.02 RRR=42%
0 100 200 300 4000
1
2
3
Pro
po
rtio
n o
f p
atie
nts
(%
)
Time (Days)
2.4
1.2
2.8
1.6p=0.008RRR=51%
Clopidogrel
Prasugrel
Age-adjusted HR=0.59 (0.37-0.96)
Diabetic SubgroupDiabetic Subgroup
0
2
4
6
8
10
12
14
16
18
0 30 60 90 180 270 360 450
HR 0.70P<0.001
Days
En
dp
oin
t (%
)
CV Death / MI / Stroke
TIMI Major NonCABG Bleeds
NNT = 20 (46)
N=3146N=3146
17.0
12.2
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel 2.6
2.5
ARC Definite or Probable Early Stent Thrombosis (0–30 days)
Prasugrel
Clopidogrel
1.56
0.64
HR 0.41 (0.29-0.59); P<0.0001
Days
0 5 10 15 20 25 30
% o
f S
ub
ject
s
0.0
0.5
1.0
1.5
2.0
2.5
ARC = Academic Research Consortium
ARC Definite or Probable Late Stent Thrombosis* in Patients Receiving DES
HR 0.46 (0.22-0.97); P=0.04
ARC = Academic Research Consortium; DES = drug-eluting stent
Days
30 90 150 210 270 330 390 450
% o
f S
ub
jec
ts
0.0
0.5
1.0
1.5
2.0
2.5
Prasugrel
Clopidogrel0.91
0.42
P=.04P=.04
COMPOSITE ENPOINT IN CURRENT-OASIS 7
4,53,9 4,2
4,9
0
2
4
6
PCI NO PCI
DOUBLE
STANDARD
P=.036
P=NS
Clopidogrel: Double vs Standard DosePrimary Outcome and Components
Standard Double HR 95% CI P Intn P
CV Death/MI/Stroke
PCI (2N=17,232) 4.5 3.9 0.85 0.74-0.99 0.0360.016
No PCI (2N=7855) 4.2 4.9 1.17 0.95-1.44 0.14
Overall (2N=25,087) 4.4 4.2 0.95 0.84-1.07 0.370
MI
PCI (2N=17,232) 2.6 2.0 0.78 0.64-0.95 0.0120.025
No PCI (2N=7855) 1.4 1.7 1.25 0.87-1.79 0.23
Overall (2N=25,087) 2.2 1.9 0.86 0.73-1.03 0.097
CV Death
PCI (2N=17,232) 1.9 1.9 0.96 0.77-1.19 0.681.0
No PCI (2N=7855) 2.8 2.7 0.96 0.74-1.26 0.77
Overall (2N=25,087) 2.2 2.1 0.96 0.81-1.14 0.628
Stroke
PCI (2N=17,232) 0.4 0.4 0.88 0.55-1.41 0.590.50
No PCI (2N=7855) 0.8 0.9 1.11 0.68-1.82 0.67
Overall (2N=25,087) 0.5 0.5 0.99 0.70-1.39 0.950
Death, MI , urgent revascularization
Clopidogrel in ACSClopidogrel in ACS
0,00
0,02
0,04
0,06
0,08
0,10
0,12
0,14
Cum
ulat
ive
Haz
ard
Rat
e
Clopidogrel Clopidogrel + ASA*+ ASA*
33 66 99
Placebo Placebo + ASA*+ ASA*
Months of Follow-UpMonths of Follow-Up
pp = 0.00009 = 0.00009N = 12,562N = 12,562
00 1212
* In addition to other standard therapies.* In addition to other standard therapies.The CURE Trial InvestigatorsThe CURE Trial Investigators. . N Engl J Med.N Engl J Med. 2001;345:494 2001;345:494
20%20%Relative RiskRelative Risk
ReductionReduction
Primary End Point – MI/Stroke/CV DeathPrimary End Point – MI/Stroke/CV Death
TIMI major and minor bleeding TIMI major and minor bleeding
Should we use bivalirudin ?
FibrinFibrin
2
1
ThrombinThrombin2
1
ThrombinThrombin
2
1
TrombinaTrombina
2
1
TrombinaTrombina
BivalirudinBivalirudin
Bivalirudin as an Alternative to UFH/LMWHBivalirudin as an Alternative to UFH/LMWH
• Advantages of the direct thrombin inhibitor bivalirudin
– No requirement for anti-thrombin III– Effective on clot-bound thrombin– Inhibits thrombin-mediated platelet activation– Plasma half-life 25 minutes– No requirement for anticoagulant monitoring
• Advantages of the direct thrombin inhibitor bivalirudin
– No requirement for anti-thrombin III– Effective on clot-bound thrombin– Inhibits thrombin-mediated platelet activation– Plasma half-life 25 minutes– No requirement for anticoagulant monitoring
3.4
4.7
1.4
5.9
4.8
10.6
0,0
5,0
10,0
15,0
Inability to cross Crossover Failure
RADIAL ACCESS
FEMORAL ACCESS