on on-time-timeisala klinieken zwolle randomized trial symptom-to-balloon and one-year mortality (%)...

Isala kliniekenIsala klinieken

ON-TIMEONON--TIMETIME

Harry SuryapranataHarry SuryapranataIsala Isala Klinieken, Zwolle, The Klinieken, Zwolle, The NetherlandsNetherlands

On behalf On behalf of the of the ONON--TIMETIME Study GroupStudy Group

Ongoing Tirofiban In Myocardial Infarction Evaluation


PrimaryPrimary PCIPCI vs Thrombolysis forvs Thrombolysis for AMIAMI

Pooled Analysis Pooled Analysis -- OROR (95% C.I)(95% C.I)23 Randomized Trials 23 Randomized Trials (n=7739)(n=7739)Pooled Analysis Pooled Analysis -- Outcome at 30Outcome at 30--dd

Transferred for Primary PCITransferred for Primary PCI

ZijlstraZijlstra Eur Heart Eur Heart J 2003J 2003Keeley Keeley et al. Lancet 2003et al. Lancet 2003

PCI BetterPCI Better Lysis BetterLysis Bettern=3872 n=3867

7% 9%

3% 7%

DEATH

1% 2%

8% 14%

00 1.01.0 1.51.5 2.02.00.50.5

Re-MI

STROKE

COMBINED

OR (95% C.I)OR (95% C.I)

P < 0.0005P < 0.0005

PCI PCI betterbetter Lysis betterLysis better

1100 0.50.5 1.51.5 22

MortalityMortality

MACEMACE

MortalityMortality

MACEMACE

All Patients All Patients (n=6478)(n=6478)

TransferredTransferred(n=2466)(n=2466)

P < 0.001P < 0.001

Isala kliniekenIsala kliniekenA A simplesimple pair of ECG and pair of ECG and initial angiograminitial angiogram are are effectiveeffective in in assessmentassessment

of of reperfusion successreperfusion success, and in , and in predicting longpredicting long--term clinical outcometerm clinical outcome

MyocardialMyocardial BlushBlush GradeGrade and STand ST--Segment Segment ResolutionResolutionZwolle Zwolle RandomizedRandomized TrialTrial

9090 360360 900900 14401440 252025200.50.5

0.60.6

0.70.7

0.80.8

0.90.9

1.01.0

BlushBlush 00--II

BlushBlush IIII

BlushBlush IIIIII

All patientsAll patients(n=777)(n=777) Trend p<0.0001Trend p<0.0001

DaysDays

MBG & Survival at 7 MBG & Survival at 7 yrsyrs ST Resolution & Survival at 7 ST Resolution & Survival at 7 yrsyrs

5050

6060

7070

8080

9090

100100

00 100100 200200 300300

weeksweeks

Complete Complete (96%)(96%)

Partial Partial (86%)(86%)

No No (71%)(71%)

P < 0.0001P < 0.0001

TIMITIMI--3 3 flowflow (n=403)(n=403)

%%


CumulativeCumulative Survival (%)Survival (%)EmboliEmboli No No EmboliEmboliIncidenceIncidence: : 1616%% (n=102)(n=102) (n=529)(n=529)

TIMITIMI--3 3 flowflow (%)(%) 7373 9292MBG IIMBG II--III III (%)(%) 3232 8383ST ST resolutionresolution (%)(%) 99 6060LVEF LVEF (%)(%) 4242 5151LDHQ72 LDHQ72 (U/L)(U/L) 16121612 847847IIbIIb//IIIa InhIIIa Inh (%)(%) 4848 2626StentStent (%)(%) ** 6363 5858* * nsns

Zwolle Zwolle Randomized Randomized TrialTrialDistal Distal EmbolizationEmbolization

P < 0.001P < 0.00191%

56%

22 44 66

100100

8080

6060

4040

Distal Distal Embolization Embolization No Distal No Distal Embolization Embolization

YearsYears

Treatment strategyTreatment strategy:: •• Mechanical approachMechanical approach ((Embolic Protection DevicesEmbolic Protection Devices))•• Pharmacological approachPharmacological approach (GP(GP--IIbIIb//IIIa inhIIIa inh, , lyticslytics))

00


Multivariate AnalysisMultivariate Analysis (n=1527)(n=1527) Odds Ratio Odds Ratio [95% CI][95% CI] PP

PrePre--procedural procedural TIMITIMI 00--11 2.652.65 [1.89[1.89--3.70]3.70] <0.0001<0.0001

Anterior MIAnterior MI 2.152.15 [1.64[1.64--2.80]2.80] <0.0001<0.0001

Ischemic Ischemic Time Time (min)(min) 1.061.06 [1.03[1.03--1.10]1.10] <0.0001<0.0001

KillipKillip class > 1class > 1 1.781.78 [1.15[1.15--2.74]2.74] 0.0090.009

Age Age ((yrsyrs)) 1.011.01 [1.00[1.00--1.02]1.02] 0.0470.047

Zwolle Zwolle Randomized Randomized TrialTrialPredictors Predictors ofof Impaired Myocardial Perfusion after PrimaryImpaired Myocardial Perfusion after Primary PCIPCI

De Luca, De Luca, SuryapranataSuryapranata et. al. submittedet. al. submitted


Zwolle Zwolle RandomizedRandomized TrialTrialSymptomSymptom--ToTo--Balloon and Balloon and OneOne--year Mortalityyear Mortality (%)(%)

De Luca, De Luca, SuryapranataSuryapranata et. al. JACC 2003et. al. JACC 2003

0

2

4

6

8

10

12

14

4.44.7

8.59.7

1.5 1.2 0.80

5.76.3

11.913

P = 0.02

P = NSP = NS

P = 0.006

All PatientsAll Patients LowLow--RiskRisk HighHigh--RiskRisk(n=1246)(n=1246)(n=1791)(n=1791) (n=545)(n=545)

<< 2 h2 h 22--4 h4 h > 6 h> 6 h44--6 h6 h Adjusted RR [95% CI]:Adjusted RR [95% CI]:1.081.08 [1.01[1.01--1.16]1.16]

De Luca, De Luca, SuryapranataSuryapranata et. al. Circulation 2004et. al. Circulation 2004

Every minute delay counts: not only for Every minute delay counts: not only for thrombolysisthrombolysis, but also for primary PCI, but also for primary PCI

8% increased risk of death for each 30-min delay


Zwolle Zwolle Randomized Randomized TrialTrialPrePre--ProceduralProcedural TIMI TIMI Flow Flow and and Mortality Mortality at at OneOne--YearYear

The The need for need for EARLYEARLY TIMITIMI--3 3 flow flow BEFOREBEFORE PCI procedurePCI procedureDe Luca, De Luca, SuryapranataSuryapranata et. al. JACC 2004et. al. JACC 2004

0

5

10

15

20

25

TIMI 0TIMI 0--11TIMI 2TIMI 2TIMI 3TIMI 3

PrePre--ProceduralProcedural TIMI TIMI FlowFlow

TotalTotal(n=1791)(n=1791)

LowLow--RiskRisk(n=1398)(n=1398)

HighHigh--RiskRisk(n=393)(n=393)

One

One

-- yea

r M

orta

lity

(%)

year

Mor

talit

y (%

)

6.36.35.35.3

3.63.61.91.9 1.81.8

3.53.5

21.421.4

18.218.2

3.83.8

P < 0.05P < 0.05 P = 0.012P = 0.012

P = NSP = NS

0

2

4

6

8

10

12

14

5.3

2.7

5.9

0

4.1

5.5

9.2

12.7

P = NSP = NS P = 0.013P = 0.013

PrePre--ProceduralProceduralTIMI 2TIMI 2--33 (n=470)(n=470)

PrePre--ProceduralProceduralTIMI 0TIMI 0--11 (n=1321)(n=1321)

<< 2 h2 h22--4 h4 h

> 6 h> 6 h44--6 h6 h


MetaMeta--analysisanalysis:: Adjunctive IIbAdjunctive IIb//IIIa Inhibitor on IIIa Inhibitor on 11--year Mortalityyear MortalityABCIXIMABABCIXIMAB CONTROL CONTROL

(n=12835)(n=12835) (n=14720)(n=14720) RR %RR % NNTNNTPPnn

ODDS RATIO [95% ODDS RATIO [95% C.IC.I]] 00 1.01.0 1.51.5 3.03.00.50.5

ADMIRALADMIRAL 3.93.90.20.20.40.4

8.88.8

0.30.3

25.625.6500500250250

15.115.1

CADILLACCADILLACRAPPORTRAPPORT

nsnsnsnsnsns

nsns

nsns

nsns

Petronio et alPetronio et al

GUSTO VGUSTO V

OVERALLOVERALL

20822082483483

8989

1658816588

2755527555

300300

0.40.4 250250

333.3333.3

2.52.5 400400ISARISAR--22 nsns4014015.55.5 18.218.2ACEACE 0.040.04400400

1.61.6 62.562.50.0340.034All PCIAll PCI 37553755

nsnsASSENT IIIASSENT III 60956095 --

nsnsAll LysisAll Lysis 2380023800 --

--

--

ENTIRE 483483 -- --nsns

1.81.8 55.555.5SPEEDSPEED 300300 nsnsTIMI 14TIMI 14 334334 -- --nsns

RandomizedRandomizedTrials (n=27555)Trials (n=27555)

De Luca, De Luca, SuryapranataSuryapranata; in press; in press


A A prospective multicenter randomized prospective multicenter randomized trial trial to compareto compare prepre--hospitalhospital vs vs cathlabcathlab initiationinitiationof of TirofibanTirofiban onon the the initialinitial IRV IRV patencypatency in in ptsptswithwith AMI AMI whowho are are candidates for primary candidates for primary PCIPCI


ONON--TIME TIME Study GroupStudy Group



EarlyEarly LateLate5000 IU heparin 5000 IU heparin

500 mg aspirin i.v500 mg aspirin i.v

Acute Myocardial InfarctionAcute Myocardial Infarctionidentified in ambulance or referral centeridentified in ambulance or referral center

AngiogramAngiogram

PlaceboPlaceboTirofibanTirofiban

TransportationTransportation

PCI centerPCI centerAngiogramAngiogram

PlaceboPlacebo TirofibanTirofibanPCIPCI

1010µµgrgr/kg bolus/kg bolus0.150.15 µµgrgr/kg/min/kg/min

Open label Open label TirofibanTirofiban infusion (24h)infusion (24h)

LMWH (48h), LMWH (48h), Clopidogrel Clopidogrel (300mg loading + 75mg 30(300mg loading + 75mg 30--d), aspirin, Bd), aspirin, B--blocker, blocker, statinstatin, ACE, ACE--inh inh

Second Second bolusbolus


39

76

45

Winschoten

64

27

4142

37

Heerenveen Assen

HoogenveenMeppel

Apeldoorn

Harderwijk

Amersfoort

Groningen

ZwolleAmsterdam

Nieuwegein

Pisa (Italy)Distance Range: 0 - 76 km

5 PCI Centers (8%)8 Referral Centers (51%)2 Ambulance services (41%)

June 2001 June 2001 -- Nov 2003: n=507Nov 2003: n=507

Ambulance

CathlabPCI center

Non PCI clinic

Ambulance

ER

By Ambulance-nurse only

Coordinating center and corelab (Diagram, Zwolle, NL)



EarlyEarly LateLateBaseline DataBaseline Data (n=251)(n=251) (n=256)(n=256)AgeAge ((meanmean, , yryr)) 6363 6161Male Male gendergender (%)(%) 7979 8080Prev Prev MIMI (%)(%) 66 1010DiabetesDiabetes (%)(%) 1010 1111HypertensionHypertension (%)(%) 2727 3030SmokingSmoking (%)(%) 6262 6868Anterior Anterior MIMI (%)(%) 4444 4747Killip > 1Killip > 1 (%)(%) 1616 1515

507507

493493

487487

No AMI (n=14)No AMI (n=14)

2 died before 2 died before angio angio 4 inadequate TIMI4 inadequate TIMI

Primary EndpointPrimary Endpoint

June 2001 June 2001 -- Nov 2003Nov 2003

Misinterpretation computer Misinterpretation computer algorithm in the ambulancealgorithm in the ambulance

(99(99%%))

AMI confirmedAMI confirmed


PresentationPresentation InIn--Out doorOut door TransportationTransportation DoorDoor--toto--AngioAngio AngioAngio--toto--BalloonBalloon

TimeTime--delaysdelays (min)(min)


94 25 33 25 15

00 6060 120120 180180

5959 minmin(11 (11 -- 178)178)EarlyEarly LateLate

minmin

No difference in total timeNo difference in total time--delay between the groups (delay between the groups (196196 vsvs 199199 min)min)



EarlyEarly LateLatePrePre--PCIPCI (n=243)(n=243) (n=244)(n=244) PP

TIMI 3 TIMI 3 (%)(%) 1919 1515 0.220.22

TIMI 2 or 3 TIMI 2 or 3 (%)(%) 4343 3434 0.040.04

TIMI 0 TIMI 0 (%)(%) 4444 5959 0.00130.0013

Thrombus Thrombus (%)(%) 2525 3232 0.060.06

Fresh Fresh OcclOccl (%)(%) 3535 4141 0.200.20

CombinedCombined (%)(%) 6060 7373 0.0020.002

EarlyEarly LateLatePostPost--PCIPCI (n=243)(n=243) (n=244)(n=244)

TIMITIMI--33 (%)(%)8989 9191MBGMBG (%)(%) 00--II 1313 1212

IIII 3737 3535IIIIII 5151 5353

CTFCCTFC (%)(%) 2727 2626

Angiographic ResultsAngiographic Results



0-I II III Yes No(n=301) (n=104) (n=82) p (n=323) (n=164) p

TIMI-3 (%) 89 92 97 0.109 89 94 0.07

MBG-3 (%) 47 52 70 0.003 49 58 0.06

CTFC 28 26 22 0.035 28 24 0.07

Initial TIMI FlowInitial TIMI Flow ThrombusThrombus

PostPost--PCIPCI

Angiographic ResultsAngiographic Results



00 0.50.5 11 1.51.5 22

Initial TIMI 2/3Initial TIMI 2/3Early BetterEarly Better

< 62< 62AgeAge (yrs)(yrs)>> 6262

DiabetesDiabetes

Infarct locationInfarct location

All patientsAll patients

YesYesNoNoAnteriorAnteriorNonNon--anterioranterior

PresentationPresentation (min)(min) < 94< 94>> 9494

GenderGender MaleMaleFemaleFemale

SmokingSmoking YesYesNoNo

PrePre--treatmenttreatment (min)(min)>> 5959< 59< 59

Randomization siteRandomization site ReferralReferralAmbulanceAmbulancePCI centerPCI center

Late BetterLate BetterOR [95% C.I]OR [95% C.I]


EarlyLate

Ongoing Tirofiban In Myocardial Infaction Evaluation

SubgroupSubgroup analysisanalysis:: HighHigh--riskrisk vs Lowvs Low--riskrisk

High-risk(43%)

Low-risk(57%)

47

31

4035

0

10

20

30

40

50

P = 0.025P = 0.025

Initial TIMI 2/3Initial TIMI 2/3

30

19

2924

0

10

20

30

P = 0.04P = 0.04

MBG 2/3MBG 2/3

High-risk(43%)

Low-risk(57%)

%% %%



cTnT+ cTnT-Baseline Data (n=208) (n=236) PAge (mean, yr) 64 60 0.006Female (%) 24 16 0.04Diabetes (%) 13 8 0.09Time-delay (min) 106 80 <0.001Anterior MI (%) 57 34 <0.001Killip > 1 (%) 22 11 0.003Outcome DataTIMI-3 flow 87 93 0.04Death 4.9 1.3 0.03

I.C. ThrombusI.C. Thrombus

23

39

2529

0

10

20

30

40

cTnT pos cTnT neg

P = 0.01P = 0.01

%%EarlyLate


PrePre--ProceduralProcedural TIMITIMI--3 3 FlowFlow


24

1215

12

0

5

10

15

20

25

CRP > 2.6 CRP < 2.6(50%) (50%)

P = 0.02P = 0.02

%%High High vs vs Low CRPLow CRP AmbulanceAmbulance--ER EnrollmentER Enrollment

31

18

25

13

0

5

10

15

20

25

30

35

ADMIRAL On-TIME(n=78) (n=249)

P=0.03P=0.03

IIb/IIIaPlacebo

%%EarlyLate


Clinical OutcomeClinical Outcome at 30 at 30 daysdays

MortalityMortality 1111 (2.2%)(2.2%)

Recurrent Recurrent MIMI 55 (1.0%)(1.0%)

Stroke Stroke (non(non--hemorrhagichemorrhagic)) 11 (0.2%)(0.2%)

Major Major BleedingBleeding 1919 (3.7%)(3.7%)(non CABG (non CABG relatedrelated))

Combined death, reCombined death, re--MI, or stroke only in 15 pts (MI, or stroke only in 15 pts (3.13.1%%))



ConclusionConclusionEarly initiationEarly initiation of of Tirofiban Tirofiban duringduring transport transport for for PCIPCI

Improvement Improvement in IRV in IRV patencypatency (TIMI 2/3)(TIMI 2/3) and and myocardial myocardial perfusionperfusion (MBG 2/3)(MBG 2/3)Significant Significant reductionreduction in i.c. in i.c. thrombusthrombus

Particularly Particularly in in highhigh--riskrisk pts enrolled pts enrolled in the in the ambulanceambulance

FacilitationFacilitation ofof primaryprimary PCIPCI by Tirofiban resultsby Tirofiban results in ain a very low very low raterate ofof mortalitymortality (2%)(2%) and reand re--MI MI (1%)(1%) at 30dat 30dSafe andSafe and attractive for early facilitationattractive for early facilitation of PCI in of PCI in ptsptswithwith AMI,AMI, whowho areare transferred totransferred to a PCI centera PCI center


on on-time-timeisala klinieken zwolle randomized trial symptom-to-balloon and one-year mortality (%)...

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