Luigi Oltrona Visconti Divisione di Cardiologia IRCCS Fondazione Policlinico S. Matteo Pavia
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Transcript of Luigi Oltrona Visconti Divisione di Cardiologia IRCCS Fondazione Policlinico S. Matteo Pavia
Luigi Oltrona ViscontiDivisione di CardiologiaIRCCS Fondazione Policlinico S. MatteoPavia
HEARTLINE 2014
IRCCS S. Martino
Genoa Cardiology Meeting
SCA-NSTEMISCA-NSTEMITrattamento antipiastrinico Trattamento antipiastrinico
ed eccesso di sanguinamento : ed eccesso di sanguinamento : dove portano i risultati dell’ ACCOAST ?dove portano i risultati dell’ ACCOAST ?
SCA-NSTEMISCA-NSTEMITrattamento antipiastrinico Trattamento antipiastrinico
ed eccesso di sanguinamento : ed eccesso di sanguinamento : dove portano i risultati dell’ ACCOAST ?dove portano i risultati dell’ ACCOAST ?
2011
PCI-CURE Principali risultati
PCI-CURE - Disegno dello studio (2)
* 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
Mesi 12Clopidogrel 75 mg/die + terapia tradizionale §
(n=1313)
Placebo 1 cpr/die +terapia tradizionale §
(n=1345)
PCI = Intervento coronarico percutaneo
Giorno 30
Tienopiridina +ASA in aperto*
per 2-4 settimane
Mesi 12Giorno 30
*On top of standard therapy (including ASA)
PCI-CURE: 31% Riduzione del Rischio Relativo a Lungo Termine1
1. Mehtra SR et al. Lancet 2001; 358: 527–33.
Endpoint: Infarto Miocardico o Morte Cardiovascolare
0.00
0.05
0.10
0.15
0 100 200 300 400
Giorni di follow-up
Tas
so d
i ris
chio
cu
mu
lati
vo
Placebo*
(n = 1,345)
Riduzionedel rischio relativo
p < 0.002Clopidogrel*
(n = 1,313)
Tempo mediano dalla PCI
10
31%
The CREDO TrialClopidogrel for the Reduction of Events
During Observation
Disegno dello studio B
racc
io
Clo
pido
grel
Bra
ccio
P
lace
bo
PCI 28 Giorni
LD Placebo#
Pre-trattaento
LD Clopidogrel#
Clopidogrel#
Clopidogrel#
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)
RR
Clopidogrel*
Placebo*
12 Mesi
Steinhubl S, et al. JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420
Precoce effetto del pretrattamento con Clopidogrel: risultati “ Per – Protocollo »
18.5 % RRR
p = 0.23
*Dal PCI sino al 28 giorno, In aggiunta alla terapia standard comprendente ASA (325mg dalla randomizzazione al 28° giorno) PT= Pre-trattamentoUTVR: Target Vessel Revascularization Urgente
GIORNI DALLA RANDOMIZZAZIONE0 7 14 21 28
PT con Clopidogrel*
Senza PT con Clopidogrel*
6.8%
8.3%
(Morte, IM e TVR urgente)Risultati a 28 giorni
Steinhubl S, et al. JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420
CO
MP
AR
SA
DE
LL
’ EN
DP
OIN
T C
OM
PO
SIT
O (
%)
Momento della dose di carico risultato a 28 giorni
0.6 0.8 1.0 1.2
Hazard ratio (95% CI)
< 6 hrs 7.9 7.0 893
6 to 24 hr 5.8 9.4 851
RRR -13.4p=NS
RRR 38.6 p=0.05
RRR 18.5p=0.23
Risultati globali dello studio CREDO
n PT-Clopidogrel* Senza-PT Clopidogrel*
Eventi (%)Senza-PT Clopidogrel
migliorePT-Clopidogrel
migliore
* In aggiunta alla terapia standard comprendente ASA, PT= Pre-trattamento
Steinhubl S, et al. JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420
Study Design
Double-blind
ACS (STEMI or UA/NSTEMI) & Planned PCI
ASA
PRASUGREL60 mg LD/ 10 mg MD
CLOPIDOGREL300 mg LD/ 75 mg MD
1o endpoint: CV death, MI, Stroke2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch
CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleedsKey Substudies: Pharmacokinetic, Genomic
Median duration of therapy - 12 months
N= 13,600
Nuovi antiaggreganti orali : prasugrel – evidenze cliniche di efficacia
0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81(0.73-0.90)P=0.0004
Prasugrel
Clopidogrel
HR 0.80P=0.0003
HR 0.77P=0.0001
Days
Pri
ma
ry E
nd
po
int
(%) 12.1
(781)
9.9 (643)
Primary Endpoint CV Death,MI,StrokePrimary Endpoint CV Death,MI,Stroke
NNT= 46
ITT= 13,608ITT= 13,608 LTFU = 14 (0.1%)LTFU = 14 (0.1%)
Nuovi antiaggreganti orali : prasugrel – evidenze cliniche di efficacia
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 designACCOAST Trial design
Prasugrel 30 mg
Prasugrel 60 mg Prasugrel 30 mg
Prasugrel 10 mg or 5 mg (based on weight and age) for 30 days
PCI
1° Endpoint: CV Death, MI, Stroke, Urg Revascularization, GP IIb/IIIa bailout at 7 days
Placebo
CoronaryAngiography
n~4100 (event driven)
CoronaryAngiography
PCI
CABG or
MedicalManagement
(no prasugrel)
CABG or
MedicalManagement
(no more prasugrel)
Montalescot G et al. Am Heart J 2011;161:650-656
Randomize 1:1Double-blind
NSTEMI + Troponin ≥ 1.5 times ULN local lab valueClopidogrel naive or on long term clopidogrel 75 mg
NEJM 2013;369:999-1010
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).
Clinical questions and rationale of the study
Enrollment:Enrollment: >4,000>4,000 patients in 19 Countriespatients in 19 Countries
Canada: 146
Finland: 42
Hungary: 134Netherlands: 142
Sweden: 4
Belgium: 81
France: 586
Austria: 172
Italy: 628
Israel: 131
Poland: 847
Czech Rep: 292
Germany: 529
Romania: 85Turkey: 112
Lithuania: 73
Portugal: 17
Slovakia: 47
Latvia: 5
Montalescot et al. NEJM 2013; epub Sept 1
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 CriteriaMain Inclusion/Exclusion Criteria
InclusionNSTEMI 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
ExclusionSTEMI patientsMedical 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 DispositionPatient Disposition
Pre-treatmentN=2037
Lost to Follow-up 1 (0.05)
ITT and All TreatedN= 4033
Total RandomizedN=4038
5 Subjects Revoked Consent
Day 30 Visit N=1958 (96.12%)
Day 7N=2009 (98.63%)
No Pre-treatmentN=1996
Lost to Follow-up 2 (0.10)
Day 30 VisitN=1924 (96.39%)
Day 7N=1964 (98.40%)
Montalescot et al. NEJM 2013; epub Sept 1
Baseline CharacteristicsBaseline Characteristics
CharacteristicsPre-treatment
(N =2037)
No Pre-treatment
(N =1996)Age (mean, yrs) 63.8 63.6
Female sex (%) 27.1 28.0
Weight (mean, kg) 81.7 81.5
BMI ≥ 30 (%) 29.0 28.2
CV risk factors (%)
Diabetes mellitus 20.3 20.4
Dyslipidemia 44.9 45.1
Hypertension 62.8 61.4
Current smoker 34.1 32.5
Region of enrolment (%)
Eastern Europe/Israel 42.4 41.5
Western Europe/Canada 57.6 58.5
Montalescot et al. NEJM 2013; epub Sept 1
CharacteristicsPre-treatment
(N =2037)
No Pre-treatment
(N =1996)GRACE score (%) <140 75.8 78.4 ≥140 24.2 21.6
CRUSADE score n, (median) 1899 (34.0) 1941 (34.0)
Timing (hr)
Symptom onset to 1st LD, median 2036 (14.6) 1996 (15.2)
1st LD to coronary angiogram, median 2017 (4.4) 1985 (4.2)
Access (%)‖
Femoral 1140 (56.6) 1136 (57.3)
Radial 869 (43.2) 842 (42.5)
Baseline CharacteristicsBaseline Characteristics
Montalescot et al. NEJM 2013; epub Sept 1
Concomitant medications through 7 days (%)
Pre-treatment
(N =2037)
No Pre-treatment
(N =1996)Aspirin, (%) 98.2 98.0Antithrombin Use, (%)*
UFH 65.4 65.5LMWH 29.1 30.6Bivalirudin 0.8 0.6Fondaparinux 4.7 3.3
Proton pump inhibitor 54.8 55.8Beta blockers 84.4 84.3Statins 89.5 89.5ARBs 13.7 12.0ACE inhibitors 69.0 71.8Calcium channel blockers 29.9 27.3On a MD of clopidogrel at randomization** 2.2 2.2
Baseline CharacteristicsBaseline Characteristics
*Monotherapy is reported; N=1323 for pre-treatment and N=1275 for no pre-treatment **75-mg dose allowed per the protocolMontalescot et al. NEJM 2013; epub Sept 1
Efficacy ResultsEfficacy Results
1° Efficacy End Point @ 7 + 30 days1° Efficacy End Point @ 7 + 30 days (All Patients) (All Patients)
Montalescot et al. NEJM 2013; epub Sept 1
Secondary Efficacy Endpoint of CV Death, Secondary Efficacy Endpoint of CV Death, MI, Stroke (All Patients)MI, Stroke (All Patients)
Days From First Dose
0 5 10 15 20 25 30
En
dp
oin
t (%
)
0
5
10
15
Pre-treatment7.1
CV Death, MI, Stroke
No Pre-treatment7.2
HR, 0.98 (95% 0.78, 1.23)P=0.86
HR, 1.00 (95% 0.79, 1.28)P=0.98
Pre-treatment6.4
19962037
18541892
18431881
18381874
18321872
18231867
16911687
No. at RiskNo pre-treatmentPre-treatment
No Pre-treatment6.4
Montalescot et al. NEJM 2013; epub Sept 1
1° Efficacy Endpoint1° Efficacy Endpoint (PCI Patients) (PCI Patients)
Days From First Dose
0 5 10 15 20 25 30
En
dp
oin
t (%
)
0
5
10
15
20
Pre-treatment14.1
CV Death, MI, Stroke, UR, GPIIb/IIIa Bailout
PCI Cohort
No Pre-treatment13.8
HR, 1.03(95% 0.84, 1.26)P=0.77
HR, 1.01(95% 0.82, 1.24)P=0.93
Pre-treatment13.1
No Pre-treatment13.1
13721389
11911206
11871202
11831194
11791189
11771186
11771172
No. at Risk, EfficacyEnd Point:No pre-treatmentPre-treatment
Montalescot et al. NEJM 2013; epub Sept 1
Major Efficacy Endpoints Through Major Efficacy Endpoints Through 7 Days (All Patients)7 Days (All Patients)
*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.
EndpointPre-treatment
(n = 2037)No pre-treatment
(n = 1996)HR*
(95% CI) P-Value†
CVD, MI, stroke, UR or GPIIb/IIIa bailout (primary endpoint)
203 (10.0) 195 (9.8) 1.02 (0.84, 1.25) 0.81
Death
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
MI 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
Montalescot et al. NEJM 2013; epub Sept 1
1° Efficacy Endpoint Through 7 Days for 1° Efficacy Endpoint Through 7 Days for Prespecified Subgroups (All Patients)Prespecified Subgroups (All Patients)
*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.
0.1 0.2 0.5 1 2 5
Overall (pre-treatment vs. no pre-treatment)
PCI
CABG
SexMale
Female
Age<75 years>75 years
Prasugrel MD5 mg10 mg
RegionEastern Europe/Israel
Western Europe/Canada
DiabetesYesNo
203 (9.97)
Hazard Ratio(95% CI)
1.02 (0.84, 1.25)
TotalPatients
4033
2781
Medical Management
Prior clopidogrel treatment
GRACE score<140>140
Weight<60 kg>60 kg
Pre-treatment better No pre-treatment better
185 (13.21) 1.01 (0.83, 1.25)
238 9 (7.44) 1.08 (0.42, 2.79)1014 9 (1.74) 1.45 (0.52, 4.09)
Pre-txn (%)
232 11 (9.82) 0.91 (0.41, 2.03)
1990 84 (8.24) 0.76 (0.57, 1.01)2008 119 (11.91) 1.36 (1.03, 1.78)
1998 120 (12.07) 1.13 (0.87, 1.46)2003 82 (8.02) 0.91 (0.67, 1.23)
3079 154 (10.05) 1.09 (0.87, 1.37)852 44 (9.73) 0.82 (0.55, 1.24)
2923 152 (10.24) 0.99 (0.79, 1.24)
1110 51 (9.24) 1.14 (0.76, 1.70)
3318 160 (9.62) 0.99 (0.79, 1.23)715 43 (11.53) 1.20 (0.76, 1.88)
205 7 (6.80) 0.56 (0.22, 1.43)3824 195 (10.09) 1.05 (0.86, 1.28)
2198 131 (11.86) 0.98 (0.77, 1.25)470 40 (16.46) 1.28 (0.80, 2.05)
820 46 (11.14) 1.25 (0.81, 1.93)3213 157 (9.67) 0.97 (0.78, 1.21)
AccessFemoral
Brachial*Radial
Tobacco UseYesNo
History of HypertensionYes
NoHistory of Hypercholesterolemia
Yes
No
1692
2341
2504
1529
1814
2219
131 (10.24) 1.06 (0.83, 1.36)
72 (9.50) 0.97 (0.70, 1.33)
96 (10.50) 1.10 (0.82, 1.47)
107 (9.53) 0.97 (0.74, 1.26)
1340 71 (10.25) 0.98 (0.70, 1.36)2683 132 (9.87) 1.06 (0.83, 1.35)
2276 125 (10.96) 1.14 (0.88, 1.47)1711 76 (8.75) 0.88 (0.64, 1.20)
7 1 (25.00)
InteractionP-value†
0.54
0.76
0.30
0.24
0.45
0.54
0.20
0.30
0.71
0.66
0.53
0.21
0.33
195 (9.77)
No Pre-txn (%)
181 (13.11)
8 (6.84)6 (1.20)
13 (10.83)
105 (10.82)90 (8.92)
109 (10.86)86 (8.77)
143 (9.24)47 (11.75)
149 (10.36)
46 (8.24)
162 (9.79)33 (9.65)
12 (11.76)183 (9.68)
133 (12.17)30 (13.22)
37 (9.09)158 (9.94)
119 (9.71)
76 (9.86)
87 (9.67)
108 (9.85)
68 (10.51)126 (9.37)
111 (9.77)83 (9.86)1 (33.33)
66 (7.65) 1.02 (0.72, 1.43)63 (7.60)
137 (11.67) 1.03 (0.81, 1.31)132 (11.31)
0.93
YesNo 3801 192 (9.97) 1.03 (0.84, 1.26)182 (9.70)
0.004Time from Sx to LD
<median>median
Time from first LD to angio/PCI <median>median
NE
Montalescot et al. NEJM 2013; epub Sept 1
Safety ResultsSafety Results
All TIMI (CABG or non-CABG) Major Bleeding All TIMI (CABG or non-CABG) Major Bleeding
(All Treated patients) (All Treated patients)
Days From First Dose
0 5 10 15 20 25 30
En
dp
oin
t (%
)
0
1
2
3
4
5
Pre-treatment2.9
No Pre-treatment1.5
Hazard Ratio, 1.97 (95% 1.26, 3.08)P=0.002
All TIMI Major Bleeding
Hazard Ratio, 1.90(95% 1.19, 3.02) P=0.006
Pre-treatment2.6
No Pre-treatment1.4
19962037
19471972
13281339
12971310
12881299
12841297
12631280
No. at Risk, All TIMI Major Bleeding:No pre-treatmentPre-treatment
Montalescot et al. NEJM 2013; epub Sept 1
All TIMI Major Bleeding (PCI Patients)All TIMI Major Bleeding (PCI Patients)
Days From First Dose
0 5 10 15 20 25 30
En
dp
oin
t (%
)
0
1
2
3
4
5
Pre-treatment1.7
No Pre-treatment0.7
HR, 2.65 (95% 1.23, 5.70) P=0.010All TIMI Major Bleeding
PCI Cohort
HR, 2.69(95% 1.13, 6.40)P=0.02
Pre-treatment1.4
No Pre-treatment0.5
13721389
13561364
13021314
12801293
12721282
12681280
12491269
No. at Risk, All TIMI Major Bleeding:No pre-treatmentPre-treatment
Montalescot et al. NEJM 2013; epub Sept 1
Non-CABG TIMI Major Bleeding Endpoints Non-CABG TIMI Major Bleeding Endpoints Through 7 Days (All Treated Patients)Through 7 Days (All Treated Patients)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Non-CABG TIMI Major Bleeding Fatal Bleeding Life Threatening Bleeding
Eve
nt
Rat
e (%
)
Pre-treatment (N=2037)
No Pre-treatment (N=1996)
Most Frequent Locations of Major Bleed
P=0.003
NE*
P=0.002
*not evaluable
N= 27 9 1 0 17 3
0<0.10.5
1.3
0.8
0.2
Montalescot et al. NEJM 2013; epub Sept 1
*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.
All TIMI Major Bleeding for Prespecified All TIMI Major Bleeding for Prespecified Subgroups Through 7 days (All Treated Patients)Subgroups Through 7 days (All Treated Patients)
Overall (pre-treatment vs. no pre-treatment)
PCICABG
SexMaleFemale
Age<75 years>75 years
RegionEastern Europe/IsraelWestern Europe/Canada
DiabetesYesNo
52 (2.55)
Hazard Ratio(95% CI)
1.90 (1.19, 3.02)
TotalPatients
4033
2781
Medical Management*
GRACE score<140>140
Weight<60 kg*>60 kg
22 (1.57) 1.98 (0.96, 4.09)238 25 (20.66) 1.59 (0.85, 2.98)
1014 5 (0.97)
Pre-tx(%)
1990 28 (2.75) 1.50 (0.83, 2.71)2008 24 (2.40) 2.70 (1.25, 5.80)
1998 27 (2.72) 2.28 (1.16, 4.51)2003 24 (2.35) 1.54 (0.81, 2.93)
3079 34 (2.22) 1.92 (1.09, 3.41)852 16 (3.54) 1.76 (0.75, 4.12)
2923 31 (2.09) 1.43 (0.82, 2.49)1110 21 (3.80) 3.61 (1.46, 8.95)
3318 36 (2.16) 1.64 (0.96, 2.78)715 16 (4.29) 2.95 (1.08, 8.05)
205 5 (4.85)3824 47 (2.43) 1.78 (1.10, 2.87)
16922341
820 6 (1.45) 0.98 (0.32, 3.05)3213 46 (2.83) 2.16 (1.29, 3.62)
InteractionP-value†
0.74
0.23
0.41
0.31
0.09
0.35
0.22
0.87
27 (1.35)
No Pre-tx(%)
11 (0.80)16 (13.68)0 (0.00)
18 (1.86)9 (0.89)
12 (1.20)15 (1.53)
18 (1.16)8 (2.00)
21 (1.46)6 (1.08)
22 (1.33)5 (1.46)
1 (0.98)26 (1.37)
6 (1.47)21 (1.32)
AccessFemoralRadial
2276 29 (2.54) 1.62 (0.90, 2.91)1711 22 (2.53) 2.67 (1.19, 6.00)
0.6618 (1.58)8 (0.95)
14 (1.62) 2.69 (0.97, 7.47)5 (0.60)38 (3.24) 1.74 (1.03, 2.94)22 (1.89)
0.46
Pre-treatment better No pre-treatment better
Time from Sx to LD <median>median
Time from first LD to angio/PCI <median>median
NE
NE
CRUSADE score‡<median>median
2051 23 (2.23) 2.29 (1.09, 4.81)1789 27 (2.97) 1.75 (0.93, 3.28)
0.5910 (0.98)15 (1.71)
0.2 0.5 1 2 5 10 15
Montalescot et al. NEJM 2013; epub Sept 1
GUSTO, STEEPLE Bleeding Endpoints/GUSTO, STEEPLE Bleeding Endpoints/TIMI Transfusion Through 7 Days (All Treated Patients)TIMI Transfusion Through 7 Days (All Treated Patients)
Endpoint
Pre-treatment(n = 2037)
No pre-treatment(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
Non-CABG TIMI major‖ 20 (1.0) 7 (0.4) 2.81 (1.19, 6.63) 0.01*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 ConclusionsOverall 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.
ConsiderationsConsiderations
Overall Conclusions (L. Oltrona)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 PCI3. 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 PCI3. Drug dosage (pharmacodynamic considerations)4. Clopidogrel pretreated 5. Medically managed pts 6. Femoral vs radial approach
Baseline CharacteristicsBaseline Characteristics
Age < 75 Years (N = 7243) Overall Population (N = 9326)
Prasugrel (N = 3620)
Clopidogrel (N = 3623)
Prasugrel (N = 4663)
Clopidogrel (N = 4663)
Age—yr 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
Disease classification—%
NSTEMI 67.8 67.2 70.4 69.4
Unstable angina 32.2 32.8 29.6 30.6
Medical History—%
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
Baseline risk assessment
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)
Angiography performed pre-randomization—% 42.1 43.1 41.2 41.4
Post-randomization revascularization performed in 7.5% of patients
CrCl <50 ml/min (n=1730)
CrCl ≥50 ml/min(n=7257)
Excess dose
(n=594)
Adjusted dose
(n=1136)
Standard dose
(n=7257)
Baseline characteristics (%)
Median age, yrs* 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
21.053.29.4
16.3
35.630.59.2
24.6
29.941.011.517.5
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
Baseline CrCl (ml/min)* 43.9(37.3, 47.3)
38.8(31.7, 44.9)
81.4(66.3, 101.7)
TIMI risk categories 0-2 3-4 >4
8.648.143.3
7.942.849.3
18.448.232.4
Baseline Characteristics by CrCl and Dose of Study Drug
ECG Abnormalities: Ischemia/ ST ECG Abnormalities: Ischemia/ ST Depression at Baseline Depression at Baseline
ECG abnormality at baseline; n (%)
Pre-treatment(N=2037)
n (%)
No Pre-treatment(N=1996)
n (%)
Total(N=4033)
n (%)
Ischemic abnormalities 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)
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 PCI3. Drug dosage (pharmacodynamic considerations)4. Clopidogrel pretreated 5. Medically managed pts 6. Femoral vs radial approach
Time to Angiography/PCITime to Angiography/PCI
4.3
3.2
4.4
3.5
2.4
4.5
0
1
2
3
4
5
ACCOAST CURRENT-OASIS 7
CHAMPION-PHOENIX
TRACER PLATO NSTEMI-ACS
ACUITY
Tim
e (h
rs)
to A
ng
iog
rap
hy/
PC
I
Montalescot et al. NEJM 2013; epub Sept 1
Mehta SR, et al. N Engl J Med. 2010;363(10):930-942.
Bhatt DL, et al. N Engl J Med. 2013;368(14):1303-1013.
Tricoci P, et al. N Engl J Med. 2012;366(1):20-33.
Cannon CP, et al. Lancet. 2010;375(9711):283-293.
Stone GW, et al. N Engl J Med. 2006;355(21):2203-2016.
No differences between quartiles of time to PCI (highest quartile > 15 hours)
LOV 13
Time intervals to angio/PCI
Hospital admission
Hours 0 2 4 6 8 10 12 14 16 18 20 22 24 48 72 96 120 10 days
ACCOAST
PCI-CURE
CREDO
Real world ??
IR
median
medianmean
The most frequent questions
1. Risk-level of population 2. Timing of PCI3. Drug dosage (pharmacodynamic considerations)4. Clopidogrel pretreated 5. Medically managed pts 6. Femoral vs radial approach
ACCOAST PFS: ResultsACCOAST PFS: Results
• VerifyNow P2Y12 PRU
Montalescot et al. NEJM 2013; epub Sept 1
Hours (post LD2)
P2
Y1
2 R
ea
cti
on
Un
its
0
50
100
150
200
250
300
350 Pre-treatment (30/30)No Pre-treatment (0/60)
Pre LD1(baseline)
Pre LD2 0.5 2 3 41 24
*
*
P<0.05*P<0.05
PlaceboLD1
30 mgLD1
Approximatetime of PCI
60 mgLD2
30 mgLD2
Inhibition of Platelet Aggregation Inhibition of Platelet Aggregation After a Single Prasugrel 30 mg DoseAfter a Single Prasugrel 30 mg Dose
Time Post-dose (Hours)
Inh
ibit
ion
of
Pla
tele
t A
gg
reg
atio
n (
%)
0
20
40
60
80
100
Prasugrel 30 mg
Mean ± SD
0.5 1 2 4 24
Non-responders: IPA <20%
±2 SD (representing 95% of the data)
14 healthy Caucasian subjects, IPA (LTA 20 µM ADP), mean ± SD
Small DS, et al. Clin Ther 2010;32:365-379
The most frequent questions
1. Risk-level of population 2. Timing of PCI3. 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
BackupsBackups
Treatment Emergent Adverse Event Through 30 Days Treatment Emergent Adverse Event Through 30 Days From First LD Reported in >1% of Total PopulationFrom First LD Reported in >1% of Total Population
Pre-treatmentN=2037
No Pre-treatmentN=1996
TotalN=4033
P-value
Treatment Emergent Adverse Event(System organ class and preferred term)
n % n % n %
Respiratory, thoracic and mediastinal disorders
Epistaxis 38 (1.88) 30 (1.50) 68 (1.69) 0.371
Vascular disorders
Hematoma 102 (5.01) 60 (3.01) 162 (4.02) 0.001
Montalescot et al. NEJM 2013; epub Sept 1
Primary and Secondary Efficacy Primary and Secondary Efficacy Endpoints Prior to AngiographyEndpoints Prior to Angiography
Primary Composite Components
Pre-treatmentN=2014
No Pre-treatmentN=1981
TotalN=3995
P-
value*
CVD/MI/Stroke/UR/GPIIb/IIIa Bailout 16 (0.79) 18 (0.91) 34 (0.85) 0.926
CVD 0 (0.00) 0 (0.00) 0 (0.00)
MI 6 (0.30) 8 (0.40) 14 (0.35) 0.852
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
*P-value based on two-sided Pearson Chi-square test.
Montalescot et al. NEJM 2013; epub Sept 1
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
•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
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
Steeple Bleeding Criteria
MI Summary through 7 Days ITT Population MI Summary through 7 Days ITT Population CEC adjudicatedCEC adjudicated
Pre-treatment(N=2037)
No Pre-treatment(N=1996)
Total subjects with MI
119 109
Type of MI 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)
Data on File, Daiichi Sankyo, Inc. and Eli Lilly and Company
Cohort or Subcohort
Pre-treatmentN=2037
No Pre-treatment N=1996
TotalN=4033
HRa (95% CI)P
valueb
N n / % 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) 0.475Abbreviations: 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.
Primary Efficacy Composite Endpoint(CVD, MI, Stroke, UR, GPIIb/IIIa Bailout through 7 Days from 1st LD) Overall and by Subcohort
Data on File, Daiichi Sankyo, Inc. and Eli Lilly and Company
Major and Other Efficacy Endpoints Through 30 Major and Other Efficacy Endpoints Through 30 days days (All Patients) (All Patients)
*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.
EndpointPre-treatment
(n = 2037)No pre-treatment
(n = 1996)HR*
(95% CI) P-Value†
30 Days
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
Montalescot et al. NEJM 2013; epub Sept 1
Major Efficacy Endpoints Through 30 Days Major Efficacy Endpoints Through 30 Days (All Patients) (All Patients)
*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.
0.2 0.5 1 2
CVD, MI, stroke, UR, or GPIIb/IIIa bailout
CVD, or MI
CVD, MI, or stroke
CVD
Hazard Ratio(95% CI)*
TotalPatients
CVD, MI, or UR
Pre-treatment better No pre-treatment better
Pre-txn (%)
4033 135 (6.6) 1.02 (0.80, 1.30)
4033 219 (10.8) 1.00 (0.83, 1.20)
4033 144 (7.1) 0.98 (0.78, 1.23)
4033 157 (7.7) 1.06 (0.85, 1.33)
4033 14 (0.69)
MI4033 126 (6.2)
P-value†
0.98
0.88
0.62
0.16
0.62
No Pre-txn (%)
130 (6.5)
216 (10.8)
144 (7.2)
146 (7.3)
22 (1.1)
116 (5.8)
0.62 (0.32, 1.22)
1.07 (0.83, 1.37)
0.86
Montalescot et al. NEJM 2013; epub Sept 1
Days From First Dose
0 1 2
En
dp
oin
t (%
)
0
1
2
3
4
Pre-treatment2.5
No Pre-treatment3.2
P=0.926
19812014
134113
134113
No. at Risk:No pre-treatmentPre-treatment
CV Death, MI, Stroke, UR, GPIIb/IIIa Bailout
Preangiography
Primary and Secondary Efficacy Primary and Secondary Efficacy Endpoints Prior to AngiographyEndpoints Prior to Angiography
Primary Composite Components
Pre-treatmentN=2014
No Pre-treatmentN=1981
TotalN=3995
P-value*
CVD/MI/Stroke/UR/GPIIb/IIIa Bailout 16 (0.79) 18 (0.91) 34 (0.85) 0.926CVD 0 (0.00) 0 (0.00) 0 (0.00) MI 6 (0.30) 8 (0.40) 14 (0.35) 0.852Stroke 0 (0.00) 0 (0.00) 0 (0.00) UR 5 (0.25) 7 (0.35) 12 (0.30) 0.832GPIIb/IIIa Bailout 5 (0.25) 5 (0.25) 10 (0.25) 1.000*P-value based on two-sided Pearson Chi-square test.
Montalescot et al. NEJM 2013; epub Sept 1
All TIMI (CABG or non-CABG) Major or All TIMI (CABG or non-CABG) Major or Minor Bleeding (All Treated Patients)Minor Bleeding (All Treated Patients)
Days From First Dose
0 5 10 15 20 25 30
En
dp
oin
t (%
)
0
2
4
6
8
10
Pre-treatment5.5
No Pre-treatment2.5
HR, 2.29(95% 1.62, 3.22)P<0.001
All TIMI Major orMinor Bleeding
No Pre-treatment2.2
19962037
19341934
13201308
12891277
12801267
12761264
12541247
No. at RiskNo pre-treatmentPre-treatment
Pre-treatment4.7
HR, 2.15(95% 1.50, 3.07) P<0.001
Montalescot et al. NEJM 2013; epub Sept 1
TIMI Bleeding Endpoints Through 7 DaysTIMI Bleeding Endpoints Through 7 Days(All Treated Patients)(All Treated Patients)
EndpointPre-treatment
(n = 2037)
No pre-treatment(n = 1996)
HR*(95% CI)
P-Value†
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
12
5
32 22
01 1
00
2
4
6
8
10
12
14
Life ThreateningBleeding
Access Site Pericardial Retroperitoneal Other
Nu
mb
er o
f P
atie
nts
Pre-treatment
No Pre-treatment
Number of Patients with Life Threatening Bleeding Through 7 Days (PCI Cohort)
Location of Life Threatening Bleed
Montalescot et al. NEJM 2013; epub Sept 1
TIMI Non-CABG Major Bleeding for Prespecified TIMI Non-CABG Major Bleeding for Prespecified Subgroups Through 7 days (All Treated Patients)Subgroups Through 7 days (All Treated Patients)
*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.
0.2 0.5 1 2 5 10 20 30 40 50 60 70 80 90
Overall (pre-treatment vs. no pre-treatment)
PCI CABG*
SexMaleFemale
Age<75 years
>75 years
RegionEastern Europe/Israel
Western Europe/Canada
DiabetesYes*No
27 (1.33)
Hazard Ratio(95% CI)
2.95 (1.39, 6.28)
TotalPatients
4033
2781
Medical Management*
Prior clopidogrel treatment
GRACE score<140>140
Weight<60 kg*>60 kg
Pre-treatment better No pre-treatment better
20 (1.43) 2.48 (1.09, 5.62)238 2 (1.65) NE1014 5 (0.97) NE
Pre-txn (%)
232 1 (0.89) NE
1990 14 (1.37) 3.36 (1.11,10.22)2008 13 (1.30) 2.62 (0.93, 7.34)
1998 13 (1.31) 3.29 (1.07,10.09)2003 13 (1.27) 2.49 (0.89, 7.00)
3079 14 (0.91) 2.37 (0.91, 6.15)852 13 (2.88) 3.83 (1.09, 13.45)
2923 12 (0.81) 2.32 (0.82, 6.58)1110 15 (2.72) 3.85 (1.28, 11.61)
3318 15 (0.90) 1.87 (0.79, 4.42)
715 12 (3.22) 11.01 (1.43, 84.70)
205 3 (2.91) NE3824 24 (1.24) 2.94 (1.32, 6.55)
820 5 (1.21)3213 22 (1.35) 3.09 (1.32, 7.23)
AccessFemoralRadial*
1692
2341
2276 20 (1.75) 2.87 (1.21, 6.78)1711 6 (0.69)
InteractionP-value†
0.29
0.99
0.72
0.55
0.12
0.51
0.99
0.81
0.99
9 (0.45)
No Pre-txn (%)
8 (0.58)1 (0.85)0 (0.00)
0 (0.00)
4 (0.41)5 (0.50)
4 (0.40)5 (0.51)
6 (0.39)3 (0.75)
5 (0.35)4 (0.72)
8 (0.48)
1 (0.29)
1 (0.98)8 (0.42)
2 (0.49)7 (0.44)
7 (0.62)2 (0.24)
10 (1.16) 3.20 (0.88, 11.62)3 (0.36)
17 (1.45) 2.84 (1.12, 7.19)6 (0.51)
0.88
Yes*No 3801 26 (1.35) 2.83 (1.32, 6.03)9 (0.48)
0.75Time from Sx to LD
<median>median
Time from first LD to angio/PCI <median>median
NE
NE
Montalescot et al. NEJM 2013; epub Sept 1
TIMI, GUSTO, STEEPLE Bleeding Endpoints TIMI, GUSTO, STEEPLE Bleeding Endpoints Through 7 Days (All Treated Patients)Through 7 Days (All Treated Patients)
1.31.0
2.3
0.50.2
0.9
0
2
4
6
Non-CABG TIMI Major Bleeding GUSTO Severe or LifeThreatening Non-CABG Bleeding
STEEPLE Non-CABG Major
Eve
nt
Rat
e (%
)
Pre-treatment (N=2037)
No Pre-treatment (N=1996)
P=0.003P=0.001
P<0.001
N= 27 9 20 4 46 18
Montalescot et al. NEJM 2013; epub Sept 1
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
Non-CABG TIMI Major Bleeding Fatal Bleeding Life Threatening Bleeding
Eve
nt
Rat
e (%
)
Pre- treatment (N=2037)
No Pre-treatment (N=1996)
P=0.002
NE*
P<0.001
*not evaluable
Non-CABG TIMI Major Bleeding Endpoints Non-CABG TIMI Major Bleeding Endpoints Through 30 Days (All Treated Patients)Through 30 Days (All Treated Patients)
Most Frequent Locations of Major Bleed
N= 32 113 0
22 4
00.10.6
1.6
1.1
0.2
Montalescot et al. NEJM 2013; epub Sept 1
TIMI Bleeding Endpoints Through 30 DaysTIMI Bleeding Endpoints Through 30 Days (All Treated Patients) (All Treated Patients)
Endpoint
Pre-treatment(n = 2037)
No pre-treatment(n = 1996)
HR*(95% CI)
P-Value†
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
Non-CABG TIMI major/minor bleeding 73 (3.6) 23 (1.2) 3.15 (1.97, 5.03) <0.001
CABG Only TIMI major bleeding(n=157)27 (17.2)
(n=157)16 (10.2)
1.77 (0.95, 3.28) 0.07
*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