HEARTLINE 2014
IRCCS S. Martino
Genoa Cardiology Meeting
SCA-NSTEMI
Trattamento antipiastrinico
ed eccesso di sanguinamento :
dove portano i risultati dell’ ACCOAST ?
Luigi Oltrona Visconti
Divisione di Cardiologia
IRCCS Fondazione Policlinico S. Matteo
Pavia
2011
PCI-CURE
Principali risultati
PCI-CURE - Disegno dello studio (2)
Giorno 30
Mesi 12
Clopidogrel 75 mg/die
+ terapia tradizionale §
(n=1313)
PCI
Placebo 1 cpr/die +
terapia tradizionale
Mesi 12 (n=1345)
Tienopiridina
Giorno 30
+ASA in aperto*
per 2-4 settimane
PCI = Intervento coronarico percutaneo
§
* La terapia in aperto comprendeva un antagonista del recettore dell'ADP in
associazione a ASA
§ La terapia tradizionale comprendeva sempre ASA, e poteva anche includere
eparina, LMWH, inibitori della GP IIa/IIIb post randomizzazione, beta-bloccanti,
ACE inibitori, ipolipidemizzanti e/o altre terapie o interventi (ad es. PTCA,
CABG), a discrezione del medico
LMWH, eparina a basso peso molecolare; GP, glicoproteina; PTCA, angioplastica
coronarica transluminale percutanea; CABG, bypass coronarico
The CURE Investigators. N Eng J Med August 2001
PCI-CURE: 31% Riduzione del Rischio
Relativo a Lungo Termine1
Tasso di rischio cumulativo
Endpoint: Infarto Miocardico o Morte Cardiovascolare
Placebo*
(n = 1,345)
0.15
31%
Riduzione
del rischio relativo
Tempo mediano
dalla PCI
0.10
Clopidogrel*
(n = 1,313)
p < 0.002
0.05
0.00
0 10
100
200
Giorni di follow-up
*On top of standard therapy (including ASA)
1. Mehtra SR et al. Lancet 2001; 358: 527–33.
300
400
The CREDO Trial
Clopidogrel for the Reduction of Events
During Observation
Disegno dello studio
PCI
28 Giorni
12 Mesi
Braccio
Clopidogrel
Pre-trattaento
LD
Clopidogrel#
Clopidogrel#
Clopidogrel*
Braccio
Placebo
R
Clopidogrel#
LD Placebo#
LD=dose di carco, PT= Pre-trattamento, R= Randomizzatzione
# in aggiunta alla terapia standard comprendente ASA (325 mg)
•in aggiunta alla terapia standard comprendente ASA (81-325 mg)
Steinhubl S, et al. JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420
Placebo*
Precoce effetto del pretrattamento con
Clopidogrel: risultati “ Per – Protocollo »
COMPARSA DELL’ ENDPOINT COMPOSITO (%)
Risultati a 28 giorni
(Morte, IM e TVR urgente)
8.3%
18.5 % RRR
p = 0.23
6.8%
PT con Clopidogrel*
Senza PT con Clopidogrel*
0
7
14
21
GIORNI DALLA RANDOMIZZAZIONE
*Dal PCI sino al 28 giorno, In aggiunta alla terapia standard comprendente ASA (325mg dalla
randomizzazione al 28° giorno)
PT= Pre-trattamento
UTVR: Target Vessel Revascularization Urgente
Steinhubl S, et al. JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420
28
Momento della dose di carico
risultato a 28 giorni
Eventi (%)
PT-Clopidogrel* Senza-PT
Clopidogrel*
Senza-PT Clopidogrel
migliore
PT-Clopidogrel
migliore
n
< 6 hrs
7.9
7.0
893
6 to 24 hr
5.8
9.4
851
RRR -13.4
p=NS
RRR 38.6
p=0.05
RRR 18.5
p=0.23
Risultati globali dello studio CREDO
0.6
0.8
1.0
1.2
Hazard ratio (95% CI)
* In aggiunta alla terapia standard comprendente ASA, PT= Pre-trattamento
Steinhubl S, et al. JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420
Nuovi antiaggreganti orali : prasugrel – evidenze cliniche di efficacia
Study Design
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
CV death, MI, Stroke
2o endpoints:
CV death, MI, Stroke, Rehosp-Rec Isch
death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
CV
Nuovi antiaggreganti orali : prasugrel – evidenze cliniche di efficacia
Primary Endpoint CV Death,MI,Stroke
15
Primary Endpoint (%)
Clopidogrel
12.1
(781)
9.9
(643)
10
Prasugrel
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
HR 0.80
P=0.0003
5
HR 0.77
P=0.0001
ITT= 13,608
0
0 30 60 90
Days
180
270
LTFU = 14 (0.1%)
360
450
A Comparison of Prasugrel at the Time of
Percutaneous Coronary Intervention Or as
Pre-treatment At the Time of Diagnosis in
Patients with Non-ST-Elevation Myocardial
Infarction (NSTEMI)
ACCOAST Trial design
NSTEMI + Troponin ≥ 1.5 times ULN local lab value
Clopidogrel naive or on long term clopidogrel 75 mg
Randomize 1:1
n~4100 (event driven)
Double-blind
CABG
or
Medical
Management
(no more prasugrel)
Prasugrel 30 mg
Placebo
Coronary
Angiography
Coronary
Angiography
Prasugrel 30 mg
Prasugrel 60 mg
PCI
PCI
CABG
or
Medical
Management
(no prasugrel)
Prasugrel 10 mg or 5 mg (based on weight and age) for 30 days
1° Endpoint: CV Death, MI, Stroke, Urg Revascularization, GP IIb/IIIa bailout at 7 days
Montalescot G et al. Am Heart J 2011;161:650-656
NEJM 2013;369:999-1010
Clinical questions and
rationale of the study
To answer the question:
IN NSTEMI patients, does having good inhibition of P2Y12 mediated
platelet activation and aggregation prior to the start of PCI reduce
the incidence of ischemic events compared to administration of a
fast acting inhibitor (prasugrel) on the table?”
Potential benefits of pretreatment:
Prevention of ischemic events in NSTEMI patients while waiting for
the PCI, during and after PCI.
Potential risks of pretreatment:
Bleeding risks need to be considered when starting platelet
inhibition in NSTEMI patients before the coronary anatomy is known
(eg, the patient will not be a candidate for PCI- medical
management or CABG).
Enrollment:
>4,000 patients in 19 Countries
Poland: 847
Sweden: 4
Canada: 146
Netherlands: 142
Belgium: 81
Portugal: 17
Germany: 529
France: 586
Czech Rep: 292
Austria: 172
Italy: 628
Montalescot et al. NEJM 2013; epub Sept 1
Finland: 42
Latvia: 5
Lithuania: 73
Slovakia: 47
Hungary: 134
Romania: 85
Turkey: 112
Israel: 131
Toni Badia,
Ospedale Misericordia e Dolce, Prato;
Sergio Berti,
Fondazione Toscana G. Monasterio -Ospedale del Cuore G. Pasquinucci, Massa;
Leonardo Bolognese, Cardiovascular and Neurological Department Azienda Ospedaliera Arezzo;
Francesco Maria Bovenzi,
Ospedale Campo di Marte, Lucca;
Paola Camisasca,
Nuovo Ospedale San Gerardo, Monza, Milano;
Claudio Cavallini,
Ospedale Santa Maria della Misericordia,Perugia;
Raffaele De Caterina, Ospedale SS. Annunziata, Chieti;
Stefano De Servi,
Ospedale di Legnano, Legnano,Milano;
Giuseppe Fantini,
Policlinico Universitario Modena, Modena;
Claudio Fresco,
Azienda Ospedaliero Universitaria Santa Maria della Misericordia, Udine;
Antonio Manari,
Azienda Ospedaliera-IRCCS S. Maria Nuova, Reggio Emilia;
Sebastiano Marra,
Azienda Ospedaliera S.Giovanni Battista, Torino;
Ciro Mauro,
AziendaOspedaliera Antonio Cardarelli, Napoli;
Luca Olivotti,
Ospedale Santa Corona, Pietra Ligure;
Anna Sonia Petronio, Stabilimento Ospedaliero di Cisanello, Pisa;
Francesco Prati,
S. Giovanni Hospital, Rome;
Bernhard Reimers, Ospedale Civile di Mirano, Venezia;
Massimo Santini,
Ospedale S. Filippo Neri, Roma;
Silva Severi,
Ospedale Misericordia, Grosseto;
Luigi Oltrona Visconti,
Division of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia;
Corrado Tamburino, Ospedale Ferrarotto, Catania;
Roberto Zanini,
Ospedale Civile Carlo Poma, Mantova.
Main Inclusion/Exclusion Criteria
Inclusion
NSTEMI symptoms within 48 hours prior to study entry
Elevated troponin (≥1.5 times ULN) per local lab(s)
Patient to be scheduled for coronary angiography and PCI within 2
hours to 24 hours of randomization and no later than 48 hours after
randomization
Exclusion
STEMI patients
Medical history contraindicating therapy with prasugrel
History of stroke or transient ischemic attack (TIA)
LD of any P2Y12 antagonist ≤ 7 days of study entry
Montalescot G et al. Am Heart J 2011;161:650-656.e1
Patient Disposition
Total Randomized
N=4038
5 Subjects Revoked Consent
ITT and All Treated
N= 4033
Pre-treatment
N=2037
No Pre-treatment
N=1996
Day 7
N=2009 (98.63%)
Day 7
N=1964 (98.40%)
Day 30 Visit
N=1958 (96.12%)
Day 30 Visit
N=1924 (96.39%)
Lost to Follow-up 1 (0.05)
Lost to Follow-up 2 (0.10)
Montalescot et al. NEJM 2013; epub Sept 1
Baseline Characteristics
Characteristics
Age (mean, yrs)
Female sex (%)
Weight (mean, kg)
BMI ≥ 30 (%)
CV risk factors (%)
Diabetes mellitus
Dyslipidemia
Hypertension
Current smoker
Region of enrolment (%)
Eastern Europe/Israel
Western Europe/Canada
Montalescot et al. NEJM 2013; epub Sept 1
Pre-treatment
No Pre-treatment
(N =2037)
63.8
27.1
81.7
29.0
(N =1996)
63.6
28.0
81.5
28.2
20.3
44.9
62.8
34.1
20.4
45.1
61.4
32.5
42.4
57.6
41.5
58.5
Baseline Characteristics
Pre-treatment
No Pre-treatment
(N =2037)
(N =1996)
75.8
24.2
1899 (34.0)
78.4
21.6
1941 (34.0)
Symptom onset to 1st LD, median
2036 (14.6)
1996 (15.2)
 1st LD to coronary angiogram, median
2017 (4.4)
1985 (4.2)
Femoral
1140 (56.6)
1136 (57.3)
Radial
869 (43.2)
842 (42.5)
Characteristics
GRACE score (%)
<140
≥140
CRUSADE score n, (median)
Timing (hr)
Access (%)‖
Montalescot et al. NEJM 2013; epub Sept 1
Baseline Characteristics
Pre-treatment No Pre-treatment
Concomitant medications through 7 days (%)
Aspirin, (%)
Antithrombin Use, (%)*
UFH
LMWH
Bivalirudin
Fondaparinux
Proton pump inhibitor
Beta blockers
Statins
ARBs
ACE inhibitors
Calcium channel blockers
On a MD of clopidogrel at randomization**
(N =2037)
98.2
(N =1996)
98.0
65.4
29.1
0.8
4.7
54.8
84.4
89.5
13.7
69.0
29.9
2.2
65.5
30.6
0.6
3.3
55.8
84.3
89.5
12.0
71.8
27.3
2.2
*Monotherapy is reported; N=1323 for pre-treatment and N=1275 for no pre-treatment
**75-mg dose allowed per the protocol
Montalescot et al. NEJM 2013; epub Sept 1
Efficacy Results
1° Efficacy End Point @ 7 + 30 days
(All Patients)
Montalescot et al. NEJM 2013; epub Sept 1
Secondary Efficacy Endpoint of CV Death,
MI, Stroke (All Patients)
15
Endpoint (%)
CV Death, MI, Stroke
HR, 0.98
(95% 0.78, 1.23)
P=0.86
HR, 1.00
(95% 0.79, 1.28)
P=0.98
10
No Pre-treatment
7.2
No Pre-treatment
6.4
5
Pre-treatment
7.1
Pre-treatment
6.4
0
0
5
10
15
20
25
30
1823
1867
1691
1687
Days From First Dose
No. at Risk
No pre-treatment
Pre-treatment
1996
2037
Montalescot et al. NEJM 2013; epub Sept 1
1854
1892
1843
1881
1838
1874
1832
1872
1° Efficacy Endpoint
(PCI Patients)
20
CV Death, MI, Stroke,
UR, GPIIb/IIIa Bailout
PCI Cohort
Endpoint (%)
15
Pre-treatment
13.1
No Pre-treatment
13.8
No Pre-treatment
13.1
10
Pre-treatment
14.1
HR, 1.03
(95% 0.84, 1.26)
P=0.77
HR, 1.01
(95% 0.82, 1.24)
P=0.93
5
0
0
No. at Risk, Efficacy
End Point:
No pre-treatment
Pre-treatment
5
10
15
20
25
30
1177
1186
1177
1172
Days From First Dose
1372
1389
Montalescot et al. NEJM 2013; epub Sept 1
1191
1206
1187
1202
1183
1194
1179
1189
Major Efficacy Endpoints Through
7 Days (All Patients)
Endpoint
CVD, MI, stroke, UR or
GPIIb/IIIa bailout
(primary endpoint)
Pre-treatment No pre-treatment
(n = 2037)
(n = 1996)
HR*
(95% CI)
P-Value†
203 (10.0)
195 (9.8)
1.02 (0.84, 1.25)
0.81
All cause
8 (0.4)
10 (0.5)
0.78 (0.31, 1.98)
0.61
CV
7 (0.3)
10 (0.5)
0.69 (0.26, 1.80)
0.44
119 (5.8)
109 (5.5)
1.07 (0.83, 1.39)
0.60
Stroke
8 (0.4)
10 (0.5)
0.78 (0.31, 1.98)
0.60
UR
22 (1.1)
26 (1.3)
0.83 (0.47, 1.46)
0.52
GPIIb/IIIa bailout
76 (3.7)
78 (3.9)
0.96 (0.70, 1.31)
0.79
Death
MI
*Hazard ratio and two-sided 95% CI are from a Cox proportional hazards model with treatment as a fixed effect.
†Two-sided P-value based on the log rank test.
Montalescot et al. NEJM 2013; epub Sept 1
1° Efficacy Endpoint Through 7 Days for
Prespecified Subgroups (All Patients)
Total
Patients
Overall (pre-treatment vs. no pre-treatment)
Pre-tx
n (%)
No Pre-tx
n (%)
Hazard Ratio
(95% CI)
Interaction
P-value†
4033
203 (9.97)
195 (9.77)
1.02 (0.84, 1.25)
PCI
CABG
Medical Management
2781
238
1014
185 (13.21)
9 (7.44)
9 (1.74)
181 (13.11)
8 (6.84)
6 (1.20)
1.01 (0.83, 1.25)
1.08 (0.42, 2.79)
1.45 (0.52, 4.09)
0.54
<75 years
>75 years
3318
715
160 (9.62)
43 (11.53)
162 (9.79)
33 (9.65)
0.99 (0.79, 1.23)
1.20 (0.76, 1.88)
0.45
Male
Female
Weight
<60 kg
>60 kg
Diabetes
Yes
No
Tobacco Use
Yes
No
History of Hypertension
Yes
No
History of Hypercholesterolemia
Yes
2923
1110
152 (10.24)
51 (9.24)
149 (10.36)
46 (8.24)
0.99 (0.79, 1.24)
1.14 (0.76, 1.70)
0.54
205
3824
7 (6.80)
195 (10.09)
12 (11.76)
183 (9.68)
0.56 (0.22, 1.43)
1.05 (0.86, 1.28)
0.20
820
3213
46 (11.14)
157 (9.67)
37 (9.09)
158 (9.94)
1.25 (0.81, 1.93)
0.97 (0.78, 1.21)
0.30
1340
2683
71 (10.25)
132 (9.87)
68 (10.51)
126 (9.37)
0.98 (0.70, 1.36)
1.06 (0.83, 1.35)
0.71
2504
1529
131 (10.24)
72 (9.50)
119 (9.71)
76 (9.86)
1.06 (0.83, 1.36)
0.97 (0.70, 1.33)
0.66
1814
96 (10.50)
87 (9.67)
1.10 (0.82, 1.47)
0.53
No
Prior clopidogrel treatment
Yes
No
Time from Sx to LD
<median
>median
Time from first LD to angio/PCI
<median
>median
GRACE score
<140
>140
Access
Femoral
Radial
Brachial*
Prasugrel MD
5 mg
10 mg
Region
Eastern Europe/Israel
Western Europe/Canada
2219
107 (9.53)
108 (9.85)
0.97 (0.74, 1.26)
232
3801
11 (9.82)
192 (9.97)
13 (10.83)
182 (9.70)
0.91 (0.41, 2.03)
1.03 (0.84, 1.26)
0.76
1990
2008
84 (8.24)
119 (11.91)
105 (10.82)
90 (8.92)
0.76 (0.57, 1.01)
1.36 (1.03, 1.78)
0.004
1998
2003
120 (12.07)
82 (8.02)
109 (10.86)
86 (8.77)
1.13 (0.87, 1.46)
0.91 (0.67, 1.23)
0.30
3079
852
154 (10.05)
44 (9.73)
143 (9.24)
47 (11.75)
1.09 (0.87, 1.37)
0.82 (0.55, 1.24)
0.24
2276
1711
7
125 (10.96)
76 (8.75)
1 (25.00)
111 (9.77)
83 (9.86)
1 (33.33)
1.14 (0.88, 1.47)
0.88 (0.64, 1.20)
NE
0.21
470
2198
40 (16.46)
131 (11.86)
30 (13.22)
133 (12.17)
1.28 (0.80, 2.05)
0.98 (0.77, 1.25)
0.33
1692
2341
66 (7.65)
137 (11.67)
63 (7.60)
132 (11.31)
Age
Sex
0.1
0.2
0.5
Pre-treatment better
1
2
5
No pre-treatment better
*Hazard ratio not evaluated for <10 events. †Interaction P-value is from a Cox proportional hazards model with treatment,
subgroup, and the treatment-by-subgroup interaction as fixed effects; PCI includes 11 patients with PCI + CABG.
Montalescot et al. NEJM 2013; epub Sept 1
1.02 (0.72, 1.43) 0.93
1.03 (0.81, 1.31)
Safety Results
All TIMI (CABG or non-CABG) Major Bleeding
(All Treated patients)
5
Hazard Ratio, 1.90
(95% 1.19, 3.02)
P=0.006
Endpoint (%)
4
Hazard Ratio, 1.97
(95% 1.26, 3.08)
P=0.002
Pre-treatment
2.9
3
Pre-treatment
2.6
2
All TIMI Major Bleeding
1
No Pre-treatment
1.5
0
No Pre-treatment
1.4
0
No. at Risk, All TIMI
Major Bleeding:
No pre-treatment
Pre-treatment
5
10
15
20
25
30
1284
1297
1263
1280
Days From First Dose
1996
2037
Montalescot et al. NEJM 2013; epub Sept 1
1947
1972
1328
1339
1297
1310
1288
1299
All TIMI Major Bleeding (PCI Patients)
5
Endpoint (%)
4
3
HR, 2.69
(95% 1.13, 6.40)
P=0.02
All TIMI Major Bleeding
PCI Cohort
HR, 2.65
(95% 1.23, 5.70)
P=0.010
2
Pre-treatment
1.4
Pre-treatment
1.7
1
No Pre-treatment
0.5
No Pre-treatment
0.7
0
0
No. at Risk, All TIMI
Major Bleeding:
No pre-treatment
Pre-treatment
5
10
15
20
25
30
1268
1280
1249
1269
Days From First Dose
1372
1389
Montalescot et al. NEJM 2013; epub Sept 1
1356
1364
1302
1314
1280
1293
1272
1282
Non-CABG TIMI Major Bleeding Endpoints
Through 7 Days (All Treated Patients)
3.0
Pre-treatment (N=2037)
Most Frequent Locations of Major Bleed
No Pre-treatment (N=1996)
Event Rate (%)
2.5
2.0
P=0.003
1.5
1.3
P=0.002
1.0
0.8
NE*
0.5
0.5
0.0
N=
27
9
Non-CABG TIMI Major Bleeding
*not evaluable
Montalescot et al. NEJM 2013; epub Sept 1
<0.1 0
1
0
Fatal Bleeding
0.2
17
3
Life Threatening Bleeding
All TIMI Major Bleeding for Prespecified
Subgroups Through 7 days (All Treated Patients)
Total
Patients
Pre-tx
(%)
No Pre-tx
(%)
4033
52 (2.55)
27 (1.35)
1.90 (1.19, 3.02)
PCI
CABG
Medical Management*
2781
238
1014
22 (1.57) 11 (0.80)
25 (20.66) 16 (13.68)
5 (0.97)
0 (0.00)
1.98 (0.96, 4.09)
1.59 (0.85, 2.98)
NE
0.74
<75 years
>75 years
3318
715
36 (2.16)
16 (4.29)
22 (1.33)
5 (1.46)
1.64 (0.96, 2.78)
2.95 (1.08, 8.05)
0.31
2923
1110
31 (2.09)
21 (3.80)
21 (1.46)
6 (1.08)
1.43 (0.82, 2.49)
3.61 (1.46, 8.95)
0.09
205
3824
5 (4.85)
47 (2.43)
1 (0.98)
26 (1.37)
NE
1.78 (1.10, 2.87)
0.35
820
3213
6 (1.45)
46 (2.83)
6 (1.47)
21 (1.32)
0.98 (0.32, 3.05)
2.16 (1.29, 3.62)
0.22
1990
2008
28 (2.75)
24 (2.40)
18 (1.86)
9 (0.89)
1.50 (0.83, 2.71)
2.70 (1.25, 5.80)
0.23
1998
2003
27 (2.72)
24 (2.35)
12 (1.20)
15 (1.53)
2.28 (1.16, 4.51)
1.54 (0.81, 2.93)
0.41
2051
1789
23 (2.23)
27 (2.97)
10 (0.98) 2.29 (1.09, 4.81)
15 (1.71) 1.75 (0.93, 3.28)
0.59
3079
852
34 (2.22)
16 (3.54)
18 (1.16)
8 (2.00)
1.92 (1.09, 3.41)
1.76 (0.75, 4.12)
0.87
2276
1711
29 (2.54)
22 (2.53)
18 (1.58)
8 (0.95)
1.62 (0.90, 2.91)
2.67 (1.19, 6.00)
0.66
1692
2341
14 (1.62)
38 (3.24)
5 (0.60)
22 (1.89)
2.69 (0.97, 7.47)
1.74 (1.03, 2.94)
0.46
Overall (pre-treatment vs. no pre-treatment)
Age
Hazard Ratio Interaction
(95% CI)
P-value†
Sex
Male
Female
Weight
<60 kg*
>60 kg
Diabetes
Yes
No
Time from Sx to LD
<median
>median
Time from first LD to angio/PCI
<median
>median
CRUSADE score‡
<median
>median
GRACE score
<140
>140
Access
Femoral
Radial
Region
Eastern Europe/Israel
Western Europe/Canada
0.2
0.5
Pre-treatment better
1
2
5
10
15
No pre-treatment better
*Hazard ratio not evaluated for <10 events. †Interaction P-value is from a Cox proportional hazards model with treatment, subgroup, and
the treatment-by-subgroup interaction as fixed effects; ‡CRUSADE score is a post-hoc analysis; PCI includes 11 patients with PCI +
CABG.2013; epub Sept 1
Montalescot et al. NEJM
GUSTO, STEEPLE Bleeding Endpoints/
TIMI Transfusion Through 7 Days (All Treated Patients)
Pretreatment
(n = 2037)
No pretreatment
(n = 1996)
HR*
(95% CI)
P-Value†
GUSTO moderate or severe,
CABG or non-CABG
70 (3.4)
35 (1.8)
1.98 (1.32, 2.97)
<0.001
STEEPLE major (non-CABG)
46 (2.3)
18 (0.9)
2.52 (1.46, 4.35)
<0.001
STEEPLE minor (non-CABG)
58 (2.8)
38 (1.9)
1.50 (1.00, 2.26)
0.05
Total Transfusion ‖
41 (2.0)
22 (1.1)
1.84 (1.09, 3.08)
0.02
20 (1.0)
7 (0.4)
2.81 (1.19, 6.63)
0.01
Endpoint
Non-CABG TIMI major‖
*Hazard ratio and two-sided 95% CI are from a Cox proportional hazards model with treatment as a fixed effect. †Two-sided
P-value based on the log rank test. ‖Transfusion includes: any transfusion, fresh frozen plasma, packed red blood cells, platelets,
whole blood cells. Event rates are raw percents.
Montalescot et al. NEJM 2013; epub Sept 1
Overall Conclusions
 In NSTEMI patients managed invasively within
48 hours of randomization, pre-treatment with
prasugrel does not reduce major ischemic
events up to 30 days and increases major
bleeding complications.
 The efficacy and safety results are consistent
among patients undergoing PCI
 No subgroup appears to have a favorable
risk/benefit ratio with pre-treatment.
Considerations
Overall Conclusions (L. Oltrona)
 in intermediate risk NSTEMI patients
 early invasively managed (median 4.3 hrs post randomisation)
 pre-treatment with 30 mg of prasugrel (+ 30 mg at the time
of PCI) does not reduce major ischemic events up to 30
days but increases major bleeding complications.
 ( The efficacy and safety results are consistent among patients
undergoing PCI. No subgroup appears to have a favorable risk/benefit
ratio with pre-treatment)
Drug failure or strategy failure ?
The most frequent questions
1. Risk-level of population
2. Timing of PCI
3. Drug dosage (pharmacodynamic considerations)
4. Clopidogrel pretreated
5. Medically managed pts
6. Femoral vs radial approach
The most frequent questions
1. Risk-level of population
2. Timing of PCI
3. Drug dosage (pharmacodynamic considerations)
4. Clopidogrel pretreated
5. Medically managed pts
6. Femoral vs radial approach
Baseline Characteristics
Age < 75 Years (N = 7243)
Overall Population (N = 9326)
Prasugrel
(N = 3620)
Clopidogrel
(N = 3623)
Prasugrel
(N = 4663)
Clopidogrel
(N = 4663)
62 (56–68)
62 (56–68)
66 (58–74)
66 (59–73)
Female sex—%
36.2
35.6
39.2
39.1
Body weight < 60 kg—%
13.1
12.8
15.2
14.9
NSTEMI
67.8
67.2
70.4
69.4
Unstable angina
32.2
32.8
29.6
30.6
Diabetes mellitus
38.5
39.3
37.7
38.3
Current/recent smoking
23.3
23.6
19.7
20.2
Prior myocardial infarction
43.3
44.8
42.9
43.3
Prior PCI
27.0
29.1
25.6
26.7
Prior CABG
14.6
16.3
15.2
16.1
GRACE risk score
114 (101–128)
115 (102–128)
122 (105–140)
121 (106–138)
Creatinine clearance—mL/min
81 (63–104)
81 (63–102)
73 (54–97)
73 (54–96)
42.1
43.1
41.2
41.4
Age—yr
Disease classification—%
Medical History—%
Baseline risk assessment
Angiography performed pre-randomization—%
Post-randomization revascularization performed in 7.5% of patients
Baseline Characteristics by CrCl and Dose of Study Drug
CrCl <50 ml/min
(n=1730)
CrCl ≥50 ml/min
(n=7257)
Excess dose
(n=594)
Adjusted dose
(n=1136)
Standard dose
(n=7257)
77.5
(72.0, 81.7)
78.0
(72.0, 82.5)
65.1
(58.4, 71.9)
Female sex
56.4
46.3
27.1
Region of enrollment
North America
Western Europe
Eastern Europe
Middle East, Africa, Asia
21.0
53.2
9.4
16.3
35.6
30.5
9.2
24.6
29.9
41.0
11.5
17.5
Diabetes
32.7
40.8
28.4
Dyslipidemia
58.8
59.1
57.2
Hypertension
79.6
82.7
68.6
Prior CABG
14.0
19.6
12.5
Prior MI
30.0
35.7
26.0
Prior PCI
28.3
28.2
23.6
43.9
(37.3, 47.3)
38.8
(31.7, 44.9)
81.4
(66.3, 101.7)
8.6
48.1
43.3
7.9
42.8
49.3
18.4
48.2
32.4
Baseline characteristics (%)
Median age, yrs*
Baseline CrCl (ml/min)*
TIMI risk categories
0-2
3-4
>4
ECG Abnormalities: Ischemia/ ST
Depression at Baseline
Pre-treatment
(N=2037)
n (%)
No Pre-treatment
(N=1996)
n (%)
Total
(N=4033)
n (%)
1118 (55)
1061 (54)
2179 (54)
ST depression 0.5 to <1 mm
420 (38)
353 (33)
773 (35)
ST depression ≥ 1 mm
289 (26)
240 (23)
529 (24)
ECG abnormality at baseline; n (%)
Ischemic abnormalities
Montalescot et al. NEJM 2013; epub Sept 1
Montalescot et al. Am Heart J 2011; 161 : 650-656
The most frequent questions
1. Risk-level of population
2. Timing of PCI
3. Drug dosage (pharmacodynamic considerations)
4. Clopidogrel pretreated
5. Medically managed pts
6. Femoral vs radial approach
Time to Angiography/PCI
Time (hrs) to Angiography/PCI
5
4.5
4.4
4.3
4
3.5
3.2
3
2.4
2
1
0
ACCOAST
CURRENTOASIS 7
CHAMPIONPHOENIX
TRACER
PLATO NSTEMIACS
Montalescot et al. NEJM 2013; epub Sept 1
Tricoci P, et al. N Engl J Med. 2012;366(1):20-33.
Mehta SR, et al. N Engl J Med. 2010;363(10):930-942.
Cannon CP, et al. Lancet. 2010;375(9711):283-293.
Bhatt DL, et al. N Engl J Med. 2013;368(14):1303-1013.
Stone GW, et al. N Engl J Med. 2006;355(21):2203-2016.
ACUITY
No differences between quartiles of time to PCI
(highest quartile > 15 hours)
Time intervals to angio/PCI
Hospital admission
Real world ??
Hours
0 2 4 6 8 10 12 14 16 18 20 22 24
mean
CREDO
48
72
96
120
10 days
IR median
PCICURE
median
ACCOAST
LOV 13
The most frequent questions
1. Risk-level of population
2. Timing of PCI
3. Drug dosage (pharmacodynamic considerations)
4. Clopidogrel pretreated
5. Medically managed pts
6. Femoral vs radial approach
ACCOAST PFS: Results
• VerifyNow P2Y12 PRU
350
60 mg
LD2
Placebo
LD1
Pre-treatment (30/30)
No Pre-treatment (0/60)
*P<0.05
P<0.05
P2Y12 Reaction Units
300
250
Approximate
time of PCI
200
150
30 mg
LD1
*
100
*
50
30 mg
LD2
0
Pre LD1 Pre LD2
(baseline)
0.5
1
2
3
Hours (post LD2)
Montalescot et al. NEJM 2013; epub Sept 1
4
24
Inhibition of Platelet Aggregation
After a Single Prasugrel 30 mg Dose
Inhibition of Platelet Aggregation (%)
14 healthy Caucasian subjects, IPA (LTA 20 µM ADP), mean ± SD
100
Prasugrel 30 mg
80
60
40
±2 SD (representing 95% of the data)
20
Non-responders: IPA <20%
0
Mean ± SD
0.5 1 2
Small DS, et al. Clin Ther 2010;32:365-379
4
Time Post-dose (Hours)
24
The most frequent questions
1. Risk-level of population
2. Timing of PCI
3. Drug dosage (pharmacodynamic considerations)
4. Clopidogrel pretreated
5. Medically managed pts
6. Femoral vs radial approach
Montalescot et al. Am Heart J 2011; 161 : 650-656
Backups
Treatment Emergent Adverse Event Through 30 Days
From First LD Reported in >1% of Total Population
Treatment Emergent Adverse Event
(System organ class and preferred term)
Pretreatment
N=2037
No Pretreatment
N=1996
Total
N=4033
n
%
n
%
n
(1.88)
30
(1.50)
68 (1.69)
0.371
60
(3.01)
162 (4.02)
0.001
Pvalue
%
Respiratory, thoracic and mediastinal disorders
Epistaxis
38
Vascular disorders
Hematoma
Montalescot et al. NEJM 2013; epub Sept 1
102 (5.01)
Primary and Secondary Efficacy
Endpoints Prior to Angiography
Pretreatment
N=2014
No Pretreatment
N=1981
Total
N=3995
16 (0.79)
18 (0.91)
34 (0.85)
CVD
0 (0.00)
0 (0.00)
0 (0.00)
MI
6 (0.30)
8 (0.40)
14 (0.35)
Stroke
0 (0.00)
0 (0.00)
0 (0.00)
UR
5 (0.25)
7 (0.35)
12 (0.30)
0.832
GPIIb/IIIa Bailout
5 (0.25)
5 (0.25)
10 (0.25)
1.000
Primary Composite
Components
CVD/MI/Stroke/UR/GPIIb/IIIa
Bailout
*P-value based on two-sided Pearson Chi-square test.
Montalescot et al. NEJM 2013; epub Sept 1
Pvalue*
0.926
0.852
TIMI Bleeding Criteria
Non-CABG Related Bleeding:
1. Major
•Any intracranial bleeding (excluding microhemorrhages <10 mm evident only on gradient-echo MRI)
•Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL or a ≥15% absolute
decrease in haematocrit
•Fatal bleeding (bleeding that directly results in death within 7 d)
2. Minor
•Clinically overt (including imaging), resulting in hemoglobin drop of 3 to <5 g/dL or ≥10% decrease in
haematocrit
•No observed blood loss: ≥4 g/dL decrease in the haemoglobin concentration or ≥12% decrease in
haematocrit
•Any overt sign of hemorrhage that meets one of the following criteria and does not meet criteria for a major
or minor bleeding event, as defined above
•Requiring intervention (medical practitioner-guided medical or surgical treatment to stop or treat bleeding,
including temporarily or permanently discontinuing or changing the dose of a medication or study drug)
•Leading to or prolonging hospitalization
•Prompting evaluation (leading to an unscheduled visit to a healthcare professional and diagnostic testing,
either laboratory or imaging)
3. Minimal
•Any overt bleeding event that does not meet the criteria above
•Any clinically overt sign of haemorrhage (including imaging) associated with a <3 g/dL decrease in
haemoglobin concentration or <9% decrease in haematocrit
•TIMI Bleeding Criteria
•Bleeding in the Setting of CABG:
•Fatal bleeding (bleeding that directly results in death)
•Perioperative intracranial bleeding
•Reoperation after closure of the sternotomy incision for the purpose of controlling
bleeding
•Transfusion of ≥5 U PRBCs or whole blood within a 48-h period; cell saver transfusion
will not be counted in calculations of blood products.
•Chest tube output >2 L within a 24-h period
Steeple Bleeding Criteria
Major Bleeding
•Fatal bleeding
•Retroperitoneal, intracranial, or intraocular bleeding
•Bleeding that causes hemodynamic compromise requiring specific treatment
•Bleeding that requires intervention (surgical or endoscopic) or decompression of a closed
space to stop or control the event
•Clinically overt bleeding, requiring any transfusion of ≥1 U PRBC or whole blood
•Clinically overt bleeding, causing a decrease in hemoglobin of ≥3 g/dL (or, if hemoglobin
level is not available, a decrease in hematocrit of ≥10%)
Minor
•Gross hematuria not associated with trauma (eg, from instrumentation)
•Epistaxis that is prolonged, is repeated, or requires plugging or intervention
•Gastrointestinal hemorrhage
•Hemoptysis
•Subconjunctival hemorrhage
•Hematoma >5 cm or leading to prolonged or new hospitalization
•Clinically overt bleeding, causing a decrease in hemoglobin of 2 to 3 g/dL
Uncontrolled bleeding requiring protamine sulfate administration
MI Summary through 7 Days ITT Population
CEC adjudicated
Pre-treatment
(N=2037)
No Pre-treatment
(N=1996)
119
109
n (%)
n (%)
Type 1
4 (3.36)
7 (6.42)
Type 2
1 (0.84)
2 (1.83)
Type 3
1 (0.84)
1 (0.92)
Type 4a
110 (92.44)
98 (89.91)
Type 4b
0 (0.0)
1 (0.92)
Type 5
3 (2.52)
0 (0.0)
Other
0 (0.00)
0 (0.00)
Total subjects with
MI
Type of MI
Data on File, Daiichi Sankyo, Inc. and Eli Lilly and Company
Primary Efficacy Composite Endpoint
(CVD, MI, Stroke, UR, GPIIb/IIIa Bailout through 7 Days from 1st LD)
Overall and by Subcohort
Cohort or
Subcohort
Pre-treatment
N=2037
No Pre-treatment
N=1996
Total
N=4033
N
n/%
HRa (95% CI)
P
valueb
N
n/%
N
n/%
Overall
2037
203 (9.97)
1996
195 (9.77)
4033
398 (9.87)
1.02 (0.84, 1.25)
0.812
PCI Only
1394
183 (13.13)
1376
180 (13.08)
2770
363 (13.10)
1.01 (0.82, 1.24)
0.927
PCI+CABG
6
2 (33.33)
5
1 (20.00)
11
3 (27.27)
NE
NE
CABG Only
121
9 (7.44)
117
8 (6.84)
238
17 (7.14)
1.08 (0.42, 2.79)
0.879
MM
516
9 (1.74)
498
6 (1.20)
1014
15 (1.48)
1.45 (0.528, 4.09)
0.475
Abbreviations: CVD = cardiovascular death; GP = glycoprotein; HR = hazard ratio based on Cox proportional hazard model
with no pre-treatment in denominator and pre-treatment in numerator; LD = loading dose; MI = myocardial infarction; NE =
not estimable; UR = urgent revascularization.
a HR (pre-treatment/no pre-treatment) and two-sided 95% CI are from a Cox proportional hazards model with treatment as a
fixed effect. b Two-sided P-value based on the log rank test.
Data on File, Daiichi Sankyo, Inc. and Eli Lilly and Company
Major and Other Efficacy Endpoints Through 30
days (All Patients)
Pre-treatment
(n = 2037)
No pre-treatment
(n = 1996)
HR*
(95% CI)
P-Value†
CVD, MI, stroke, UR,
or GPIIb/IIIa bailout
219 (10.8)
216 (10.8)
1.00 (0.83, 1.20)
0.98
CVD, MI, or stroke
144 (7.1)
144 (7.2)
0.98 (0.78, 1.23)
0.86
CVD or MI
135 (6.6)
130 (6.5)
1.02 (0.80, 1.30)
0.88
CVD, MI, or UR
157 (7.7)
146 (7.3)
1.06 (0.85, 1.33)
0.62
CVD
14 (0.7)
22 (1.1)
0.62 (0.32, 1.22)
0.16
MI
126 (6.2)
116 (5.8)
1.07 (0.83, 1.37)
0.62
Endpoint
30 Days
*Hazard ratio and two-sided 95% CI are from a Cox proportional hazards model with treatment as a fixed effect.
†Two-sided P-value based on the log rank test.
Montalescot et al. NEJM 2013; epub Sept 1
Major Efficacy Endpoints Through 30 Days
(All Patients)
Pre-tx
Total
Patients n (%)
No Pre-tx
n (%)
Hazard Ratio
(95% CI)*
P-value†
CVD, MI, stroke, UR, or GPIIb/IIIa bailout
4033
219 (10.8)
216 (10.8)
1.00 (0.83, 1.20)
0.98
CVD, MI, or stroke
4033
144 (7.1)
144 (7.2)
0.98 (0.78, 1.23)
0.86
4033
135 (6.6)
130 (6.5)
1.02 (0.80, 1.30)
0.88
4033
157 (7.7)
146 (7.3)
1.06 (0.85, 1.33)
0.62
4033
14 (0.69)
22 (1.1)
0.62 (0.32, 1.22)
0.16
4033
126 (6.2)
116 (5.8)
1.07 (0.83, 1.37)
0.62
CVD, or MI
CVD, MI, or UR
CVD
MI
0.5
0.2
Pre-treatment better
1
2
No pre-treatment better
*Hazard ratio and two-sided 95% CI are from a Cox proportional hazards model with treatment as a fixed effect.
†Two-sided P-value based on the log rank test.
Montalescot et al. NEJM 2013; epub Sept 1
Primary and Secondary Efficacy
Endpoints Prior to Angiography
4
No Pre-treatment
3.2
3
Endpoint (%)
P=0.926
Pre-treatment
2.5
2
CV Death, MI, Stroke,
UR, GPIIb/IIIa Bailout
Preangiography
1
0
0
No. at Risk:
No pre-treatment
Pre-treatment
1
Days From First Dose
134
113
1981
2014
Primary Composite Components
CVD/MI/Stroke/UR/GPIIb/IIIa Bailout
CVD
MI
Stroke
UR
GPIIb/IIIa Bailout
Pre-treatment
N=2014
*P-value based on two-sided Pearson Chi-square test.
Montalescot et al. NEJM 2013; epub Sept 1
2
16 (0.79)
0 (0.00)
6 (0.30)
0 (0.00)
5 (0.25)
5 (0.25)
134
113
No Pretreatment
N=1981
18 (0.91)
0 (0.00)
8 (0.40)
0 (0.00)
7 (0.35)
5 (0.25)
Total
N=3995
34 (0.85)
0 (0.00)
14 (0.35)
0 (0.00)
12 (0.30)
10 (0.25)
P-value*
0.926
0.852
0.832
1.000
All TIMI (CABG or non-CABG) Major or
Minor Bleeding (All Treated Patients)
10
All TIMI Major or
Minor Bleeding
HR, 2.29
(95% 1.62, 3.22)
P<0.001
Endpoint (%)
8
HR, 2.15
(95% 1.50, 3.07)
P<0.001
6
Pre-treatment
5.5
Pre-treatment
4.7
4
2
No Pre-treatment
2.5
No Pre-treatment
2.2
0
0
5
10
15
20
25
30
1276
1264
1254
1247
Days From First Dose
No. at Risk
No pre-treatment
Pre-treatment
1996
2037
Montalescot et al. NEJM 2013; epub Sept 1
1934
1934
1320
1308
1289
1277
1280
1267
TIMI Bleeding Endpoints Through 7 Days
(All Treated Patients)
Endpoint
No prePre-treatment treatment
(n = 2037)
(n = 1996)
HR*
(95% CI)
PValue†
All CABG or non-CABG TIMI major
bleeding (key safety endpoint)
52 (2.6)
27 (1.4)
1.90 (1.19, 3.02)
0.006
Non-CABG TIMI major bleeding
27 (1.3)
9 (0.5)
2.95 (1.39, 6.28)
0.003
Fatal bleeding
1 (<0.1)
0 (0.00)
NE
NE
Life threatening bleeding
17 (0.8)
3 (0.2)
5.56 (1.63,19.0)
0.002
Non-CABG TIMI major/minor bleeding
61 (3.0)
20 (1.0)
3.02 (1.82, 5.01) <0.001
CABG Only TIMI major bleeding
(n=121)
25 (20.7)
(n=117)
16 (13.7)
1.59 (0.85, 2.98)
0.14
*Hazard ratio and two-sided 95% CI are from a Cox proportional hazards model with treatment as a fixed effect. †Two-sided
P-value based on the log rank test. Event rates are raw percents.
Montalescot et al. NEJM 2013; epub Sept 1
Number of Patients with Life Threatening
Bleeding Through 7 Days (PCI Cohort)
14
Pre-treatment
No Pre-treatment
12
Number of Patients
12
10
8
6
5
4
3
2
2
2
1
2
1
0
0
0
Life Threatening
Bleeding
Access Site
Pericardial
Retroperitoneal
Location of Life Threatening Bleed
Montalescot et al. NEJM 2013; epub Sept 1
Other
TIMI Non-CABG Major Bleeding for Prespecified
Subgroups Through 7 days (All Treated Patients)
Total
Pre-tx
Patients n (%)
Overall (pre-treatment vs. no pre-treatment)
No Pre-tx
n (%)
Hazard Ratio
(95% CI)
Interaction
P-value†
4033
27 (1.33)
9 (0.45)
2.95 (1.39, 6.28)
PCI
CABG*
Medical Management*
2781
238
1014
20 (1.43)
2 (1.65)
5 (0.97)
8 (0.58)
1 (0.85)
0 (0.00)
2.48 (1.09, 5.62)
NE
NE
0.29
<75 years
3318
15 (0.90)
8 (0.48)
1.87 (0.79, 4.42)
0.12
>75 years
715
12 (3.22)
1 (0.29)
11.01 (1.43, 84.70)
2923
1110
12 (0.81)
15 (2.72)
5 (0.35)
4 (0.72)
2.32 (0.82, 6.58)
3.85 (1.28, 11.61)
0.51
205
3824
3 (2.91)
24 (1.24)
1 (0.98)
8 (0.42)
NE
2.94 (1.32, 6.55)
0.99
820
3213
5 (1.21)
22 (1.35)
2 (0.49)
7 (0.44)
NE
3.09 (1.32, 7.23)
0.81
232
3801
1 (0.89)
26 (1.35)
0 (0.00)
9 (0.48)
NE
2.83 (1.32, 6.03)
0.99
1990
2008
14 (1.37)
13 (1.30)
4 (0.41)
5 (0.50)
3.36 (1.11,10.22)
2.62 (0.93, 7.34)
0.75
1998
2003
13 (1.31)
13 (1.27)
4 (0.40)
5 (0.51)
3.29 (1.07,10.09)
2.49 (0.89, 7.00)
0.72
GRACE score
<140
>140
3079
852
14 (0.91)
13 (2.88)
6 (0.39)
3 (0.75)
2.37 (0.91, 6.15)
3.83 (1.09, 13.45)
0.55
Access
Femoral
Radial*
2276
1711
20 (1.75)
6 (0.69)
7 (0.62)
2 (0.24)
2.87 (1.21, 6.78)
NE
0.99
Region
Eastern Europe/Israel
1692
10 (1.16)
3 (0.36)
3.20 (0.88, 11.62)
0.88
2341
17 (1.45)
6 (0.51)
2.84 (1.12, 7.19)
Age
Sex
Male
Female
Weight
<60 kg*
>60 kg
Diabetes
Yes*
No
Prior clopidogrel treatment
Yes*
No
Time from Sx to LD
<median
>median
Time from first LD to angio/PCI
<median
>median
Western Europe/Canada
0.2
0.5
1
Pre-treatment better
2
5
10
20
30
40
50
60
70
80
90
No pre-treatment better
*Hazard ratio not evaluated for <10 events. †Interaction P-value is from a Cox proportional hazards model with treatment, subgroup, and
the treatment-by-subgroup interaction as fixed effects; PCI includes 11 patients with PCI + CABG.
Montalescot et al. NEJM 2013; epub Sept 1
TIMI, GUSTO, STEEPLE Bleeding Endpoints
Through 7 Days (All Treated Patients)
6
Event Rate (%)
Pre-treatment (N=2037)
No Pre-treatment (N=1996)
4
P<0.001
2.3
2
P=0.003
1.3
P=0.001
1.0
0.9
0.5
0.2
0
N=
27
9
Non-CABG TIMI Major Bleeding
Montalescot et al. NEJM 2013; epub Sept 1
20
4
GUSTO Severe or Life
Threatening Non-CABG Bleeding
46
18
STEEPLE Non-CABG Major
Non-CABG TIMI Major Bleeding Endpoints
Through 30 Days (All Treated Patients)
5.0
Pre- treatment (N=2037)
No Pre-treatment (N=1996)
4.5
Most Frequent Locations of Major Bleed
4.0
Event Rate (%)
3.5
3.0
2.5
P=0.002
2.0
P<0.001
1.6
1.5
NE*
1.0
0.6
0.5
0.0
N=
32
11
Non-CABG TIMI Major Bleeding
*not evaluable
Montalescot et al. NEJM 2013; epub Sept 1
0.1
3
1.1
0
0.2
0
22
Fatal Bleeding
4
Life Threatening Bleeding
TIMI Bleeding Endpoints Through 30 Days
(All Treated Patients)
Pretreatment
(n = 2037)
No pretreatment
(n = 1996)
All CABG or non-CABG TIMI major
bleeding (key safety endpoint)
58 (2.8)
29 (1.5)
1.97 ( 1.26, 3.08) 0.002
Non-CABG TIMI major bleeding
32 (1.6)
11 (0.6)
2.86 (1.44, 5.68)
0.002
Fatal bleeding
3 (0.1)
0 (0)
NE
NE
Life threatening bleeding
22 (1.1)
4 (0.2)
5.40 (1.86,15.68) <0.001
73 (3.6)
(n=157)
27 (17.2)
23 (1.2)
(n=157)
16 (10.2)
3.15 (1.97, 5.03) <0.001
Endpoint
Non-CABG TIMI major/minor bleeding
CABG Only TIMI major bleeding
HR*
(95% CI)
1.77 (0.95, 3.28)
PValue†
0.07
*Hazard ratio and two-sided 95% CI are from a Cox proportional hazards model with treatment as a fixed effect. †Two-sided Pvalue based on the log rank test. Event rates are raw percents.
Montalescot et al. NEJM 2013; epub Sept 1