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 ?

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


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


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%)


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


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)



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


*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)


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


1° Efficacy Endpoint1° Efficacy Endpoint (PCI Patients) (PCI Patients)


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


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


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


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)


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


All TIMI Major Bleeding (PCI Patients)All TIMI Major Bleeding (PCI Patients)


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


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


*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)


PCICABG

SexMaleFemale

Age<75 years>75 years

RegionEastern Europe/IsraelWestern Europe/Canada

DiabetesYesNo

52 (2.55)


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)


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


Time from Sx to LD <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


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.


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


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. Am Heart J 2011; 161 : 650-656

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


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

ACCOAST PFS: ResultsACCOAST PFS: Results

• VerifyNow P2Y12 PRU


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

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


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


Primary and Secondary Efficacy Primary and Secondary Efficacy Endpoints Prior to AngiographyEndpoints Prior to Angiography

Primary Composite Components

Pre-treatmentN=2014


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.


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)



(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


Major Efficacy Endpoints Through 30 Days Major Efficacy Endpoints Through 30 Days (All Patients) (All Patients)


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-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



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


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.


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)


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


TIMI Bleeding Endpoints Through 7 DaysTIMI Bleeding Endpoints Through 7 Days(All Treated Patients)(All Treated Patients)


(n = 2037)


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.


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


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


PCI CABG*

SexMaleFemale

Age<75 years

>75 years

RegionEastern Europe/Israel

Western Europe/Canada

DiabetesYes*No

27 (1.33)


2.95 (1.39, 6.28)

TotalPatients

4033

2781

Medical Management*

Prior clopidogrel treatment

GRACE score<140>140

Weight<60 kg*>60 kg


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)


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


NE

NE


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)


P=0.003P=0.001

P<0.001

N= 27 9 20 4 46 18


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)


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


TIMI Bleeding Endpoints Through 30 DaysTIMI Bleeding Endpoints Through 30 Days (All Treated Patients) (All Treated Patients)

Endpoint

Pre-treatment(n = 2037)


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.


Luigi Oltrona Visconti Divisione di Cardiologia IRCCS Fondazione Policlinico S. Matteo Pavia

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