M. Valgimigli University of Ferrara Italy MultiStrategy Study design MultiStrategy Study design

M. ValgimigliM. ValgimigliUniversity of FerraraUniversity of Ferrara

ItalyItaly

MultiStrategyStudy design

MultiStrategyStudy design

BackgroundBackground

Primary angioplasty is the current Primary angioplasty is the current preferred therapeutic option for patients preferred therapeutic option for patients with ST-segment elevation myocardial with ST-segment elevation myocardial infarction (STEMI).infarction (STEMI).

Routine coronary stent implantation in Routine coronary stent implantation in patients with STEMI decreases the need patients with STEMI decreases the need for target vessel revascularization (TVR).for target vessel revascularization (TVR).

Grines CL, et al. N Engl J Med 1999; 341: 1949Grines CL, et al. N Engl J Med 1999; 341: 1949Stone G, et al. Stone G, et al. N Engl J Med 2002; 346: 957N Engl J Med 2002; 346: 957

STEMI: STEMI: Stent and MortalityStent and Mortality

STEMI: STEMI: Stent and MortalityStent and Mortality

STEMI: STEMI: Stent and ReinterventionStent and Reintervention

STEMI: STEMI: Stent and ReinterventionStent and Reintervention

30 days30 days6 months6 months

What about external What about external validity?validity?

What about external What about external validity?validity?

In some of these trials In some of these trials randomization occurred after randomization occurred after angiography before PCI angiography before PCI In some of these studies In some of these studies randomization occurred after randomization occurred after balloon angioplastyballoon angioplastyIn none of these studies patients In none of these studies patients were recruited without prior were recruited without prior knowledge of coronary anatomyknowledge of coronary anatomy

Mostly excluded patients: Mostly excluded patients:

ShockShock

Diffusely diseased or small Diffusely diseased or small coronary coronary vesselvessel

Large thrombus burden Large thrombus burden

Severe coronary calcification or Severe coronary calcification or tortuosity tortuosity

Bifurcated lesionsBifurcated lesionsIdeal o

r good st

ent candid

ates

Ideal o

r good st

ent candid

ates

Participants:Participants: All Patients with STEMI randomly All Patients with STEMI randomly

assigned to stenting or balloon Angioplasty. assigned to stenting or balloon Angioplasty.

No exclusion criteria were appliedNo exclusion criteria were applied. .

Death or ReinfarctionDeath or Reinfarction

TV

R (

%)

TV

R (

%)

RR 0.98 (95%CI: 0.78-1.22)RR 0.98 (95%CI: 0.78-1.22)

N=1683N=1683

Heart 2005;91:641–645.

0

5

10

15

20

25

Stent

Balloon

LessonsLessons from the BMS from the BMS EraEra

BMS in the setting of STEMI is far BMS in the setting of STEMI is far from being the perfect solution for from being the perfect solution for restenosis and TVR may remain highrestenosis and TVR may remain high

New devices are needed which have New devices are needed which have to be tested in unselected (no to be tested in unselected (no angiographic selection bias) patient angiographic selection bias) patient populationpopulation

GP IIb/IIIa inhibitorsGP IIb/IIIa inhibitorsThe word to the …The word to the …GuidelinesGuidelines

Primary PCI: Primary PCI: Class IIA indicationClass IIA indication

Class IIA indication with StentClass IIA indication with Stent

Class I indication without StentClass I indication without Stent

Class IIB for tirofiban and eptifibatideClass IIB for tirofiban and eptifibatide

Ab

cix

ima

Ab

cix

ima

bbAb

cix

ima

Ab

cix

ima

bb

STEMI UFH - ASAClopidogrel

Tirofiban SHDB

Abciximab stand. regimen

Cypher

BMS

CCU Cath-Lab

Valgimigli et al. Cardiovasc Drugs Ther 04; 18: 225-30

Study designStudy design

Inclusion Criteria: STEMI all comers: shock, elderly included

Exclusion Criteria: Contraindications to Gp IIb/IIIa

Inclusion Criteria: STEMI all comers: shock, elderly included

Exclusion Criteria: Contraindications to Gp IIb/IIIa

175 Randomized

SHDB Tirofiban(n=87)

Abciximab(n=88)

3 No PCI

1:1

219 Assessed for Eligibility 44 Excluded• 34 Not Meeting Inclusion Criteria

• 10 Refused to Participate

3 POBA 74 SES 7 BMS

84 PTCA

Clinical Follow-up

Angiographic Follow-up

Pts not eligible Refused to participate

4 POBA 77 BMS2 SES

83 PTCA 5 No PCI

3 3 74 7 4 77 2 5

0 1 62 4 1 64 1 0

3 2 6 0 3 4 0 50 0 6 3 0 9 1 0

Study ProfileStudy Profile

Valgimigli et al. JAMA 2005; 293: 2109-2117

85% 88%

77% 75%

30-Day Outcome30-Day Outcome n=175n=175

0

2

4

6

8

10

12

14

MACE Death Re-AMI TVR CVA

P=0.33

P>0.99 P=0.62 P=0.62

P=>0.99

%

Abciximab+BMS Tirofiban+SES


Death/MI at 8 MonthsDeath/MI at 8 MonthsDeath/MI at 8 MonthsDeath/MI at 8 Months

0 50 100 150 200 250

Tim e after I n itial Procedure (days)

40

30

20

10

0

Pro

bability o

f Eve

nts

(%)

A bc + BMS (DEA TH / M I )SHDB Tir + SES (DEA TH / M I )

17%

13%

JAMA 2005; 293: 2109-2117

p=0.4

HR 0.71 [95% CI: 0.34-1.5]

0 50 100 150 200 250

Tim e after I n itial Procedure (days)

40

30

20

10

0

Pro

bability o

f Eve

nts

(%)

A bc + BMS (M A CE) SHDB Tir + SES (M A CE)

18%

32%

Death/MI/TVR at 8 MonthsDeath/MI/TVR at 8 Months

HR 0.53 [95% CI: 0.28-0.92]

p=0.043

JAMA 2005; 293: 2109-2117

8-Month Outcome8-Month Outcome n=175n=175

0

5

10

15

20

25

30

35

40

45

50

P=0.043

P=0.8 P=0.6

P=0.01

P>0.99

P=0.004

P=0.005

MACE Death MI TVR CVA 1° EndPointBR

%

Abciximab+BMS

Tirofiban+SES

50%

19%


STEMI All Comers PatientsSTEMI All Comers PatientsSTEMI All Comers PatientsSTEMI All Comers Patients

Aspirin + Clopidogrel Aspirin + Clopidogrel ++ UFHUFHIntent-to-stentIntent-to-stent


N ~ 730N ~ 730N ~ 730N ~ 730

TirofibanTirofibanTirofibanTirofiban AbciximabAbciximabAbciximabAbciximab

SESSESSESSES BMSBMSBMSBMS

MULTI-STRATEGYTrial Design


Università degli Studi di Ferrara - Cattedra di Cardiologia

1:1

1:11:1

Valgimigli M. et al Am Heart J. 2007 Jul;154(1):39-45.

MULTI-STRATEGY

1.1. Whether Whether tirofiban administered at high bolus tirofiban administered at high bolus dose is non inferior to abciximab on the degree of dose is non inferior to abciximab on the degree of cumulative ST-segment resolution, expressed as cumulative ST-segment resolution, expressed as the proportion of patients reaching ≥ 50% the proportion of patients reaching ≥ 50% recovery, at 90’ after the mechanical recovery, at 90’ after the mechanical intervention.intervention.

2.2. Whether SES implantation –based on the Whether SES implantation –based on the intention-to-treat principle– is superior to BMS on intention-to-treat principle– is superior to BMS on the incidence of major adverse cardiovascular the incidence of major adverse cardiovascular events (MACE) within 8 months, defined as the events (MACE) within 8 months, defined as the composite of death, nonfatal myocardial composite of death, nonfatal myocardial infarction and clinically-driven target vessel infarction and clinically-driven target vessel revascularization (TVR). revascularization (TVR).

Primary objectivesPrimary objectives



The effect of tirofiban infusion or SES implantation on The effect of tirofiban infusion or SES implantation on the MACE either singularly considered or as a the MACE either singularly considered or as a composite and on the incidence of stent thrombosis. composite and on the incidence of stent thrombosis.

The effect of tirofiban on the rate of TIMI 3 flow before The effect of tirofiban on the rate of TIMI 3 flow before and after intervention and on partial (and after intervention and on partial (≥≥50%) or 50%) or complete (complete (≥≥70%) cumulative ST segment resolution 70%) cumulative ST segment resolution or in the single lead with greatest ST changes.or in the single lead with greatest ST changes.

The effect of SES implantation on the rate of major The effect of SES implantation on the rate of major cardiovascular events either singularly considered or cardiovascular events either singularly considered or as a composite after thienopyridines discontinuationas a composite after thienopyridines discontinuation

TThe cost-effectiveness profile in STEMI of SES he cost-effectiveness profile in STEMI of SES implantation or tirofiban infusionimplantation or tirofiban infusion

The effect of tirofiban on the rate of bleeding and The effect of tirofiban on the rate of bleeding and thrombocytopeniathrombocytopenia

MULTI-STRATEGYMajor Secondary objectivesMajor Secondary objectives

MULTI-STRATEGY16 Participating centers

MULTI-STRATEGY16 Participating centers


Ferrara, M.ValgimigliFerrara, M.Valgimigli

Valle Oppio, GF PercocoValle Oppio, GF Percoco

Arezzo. L. Bolognese Arezzo. L. Bolognese

Verona, M. Anselmi Verona, M. Anselmi

Bergamo, N. De CesareBergamo, N. De Cesare

Mirano, GP PasquettoMirano, GP Pasquetto

Pavia, E. BramucciPavia, E. Bramucci

Ancona, R. PivaAncona, R. Piva

Torino, I. SheibanTorino, I. Sheiban

Torino, S. ColangeloTorino, S. Colangelo

Roma, F. PratiRoma, F. Prati

Roma, R. VioliniRoma, R. Violini

ItalyItaly ArgentinaArgentina SpainSpain

Buenos Aires, A. RodriguezBuenos Aires, A. Rodriguez

Otamendi HospitalOtamendi HospitalMadrid, R. MorenoMadrid, R. Moreno

Huelva, José DíazHuelva, José Díaz


STEMI All Comers PatientsSTEMI All Comers PatientsSTEMI All Comers PatientsSTEMI All Comers Patients



N ~ 730N ~ 730N ~ 730N ~ 730

TirofibanTirofibanTirofibanTirofiban AbciximabAbciximabAbciximabAbciximab


MULTI-STRATEGYTrial Design



1:1

1:11:1ACC 2008

ACC 2008


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M. Valgimigli University of Ferrara Italy MultiStrategy Study design MultiStrategy Study design