Transcript Ongoing-Tirofiban In Myocardial Infarction Evaluation

ON-TIME-2
Ongoing-Tirofiban In Myocardial
Infarction Evaluation
Presenter Disclosure Information
Christian W. Hamm, MD, FESC, FACC
The following relationships exist related to this presentation:
Consulting Fees
& speakers honoraria
Merck, GSK, Lilly,
The Med.Comp., Sanofi,
Medtronic, Cordis, Braun,
CVT, Abbott, Roche
Modest Level
ON-TIME-Studies
Prehospital GPIIb/IIIa in AMI
History
ON-TIME 1:
No significant benefit for low bolus dose Tirofiban in AMI
ON-TIME 2 Registry
Open label Tirofiban, high bolus dose
( N=416, Zwolle + Nieuwegein)
ON-TIME 2 Randomized Study
Tirofiban high bolus dose double-blind
+ 600 mg clopidogrel
Ongoing Tirofiban In Myocardial Infaction Evaluation
Trial Design
(Registration: ISRCTN 06195297)
Multicenter, prospective, randomized,
double-blind, placebo-controlled
Analysis: ITT
End-points adjudicated (CEC)
Investigator initiated and driven
Unrestricted grant from Merck & Co Inc.
Ongoing Tirofiban In Myocardial Infaction Evaluation
Trial Leadership
Co-Principle Investigators
Arnoud van ´Hof
Christian W. Hamm
Jurriën M. ten Berg
Steering Committee
P. Stella
L. van den Merckhoff
M. Scheper
T. Dill (Germany, MRI)
G. Giannitsis (biomarker)
J. Brachmann
S. Guptha
CRO
Diagram B.V., J. Klijn
Ongoing Tirofiban In Myocardial Infaction Evaluation
Participating Centers
The Netherlands:
1.
2.
3.
4.
Isala klinieken Zwolle
Antonius Ziekenhuis Nieuwegein
UMC Utrecht
Medisch Spectrum Twente
Dr. A.W.J. van ’t Hof
Dr. J. ten Berg
Drs. P.R. Stella
Dr. K. van Houwelingen
Germany:
1. Kerckhoff-Klinik
2. Universitätsklinikum Heidelberg
3. St. Johannes Hospital Dortmund
4. Klinikum Coburg
5. Klinikum Lüdenscheid
6. Segeberger Kliniken
7. Philipps Universität Marburg
8. Allgemeines Krankenhaus Celle
9. Uni-klinik Giessen
10. Imtalklinik Pfaffenhofen
11. Med. Hochschule Hannover
12. Uniklinik Mannheim
13. Uniklinik Lübeck
14. Stätisches Klinikum Lüneburg
15. Zentralklinikum Suhl
16. Uni-Klinik Rostock
17. Kreiskrankenhaus Bergstrasse
18. Asklepios Klinik St. Georg
19. Klinikum Darmstadt
20. Evangelisches Krankenhaus Holzminden
Prof. Dr. C. Hamm
Prof. Dr. H Katus
Prof. Dr. Heuer
Prof. Dr. J. Brachmann
Dr. Lemke
Prof. Dr. G. Richardt
Prof. Maisch
Prof. Dr. W. Terres
Prof. Dr. H. Tillmanns
Prof. C. Firschke
Prof. Dr. Schieffer
Dr. T. Süselbeck
Prof. Dr. H. Schunkert
Prof. Dr. W. Kupper
Prof. W. Haberbosch
Prof. Dr. C.Nienaber
Dr. W. Auch-Schwelk
Prof. Dr. K.H. Kuck
Prof Dr. G. Werner
Dr. C. Beythien
Belgium:
1. AZ Sint-Jan AV Brugge
Dr. P. Coussement
ON-TIME -2
Acute myocardial infarction
diagnosed in ambulance or referral center
ASA+600 mg Clopidogrel
Placebo
N=984
6/2006-11/2007
Tirofiban *
Transportation
Angiogram
Tirofiban
provisional
PCI centre
PCI
Angiogram
Tirofiban
cont’d
*Bolus: 25 µg/kg & 0.15 µg/kg/min infusion
Ongoing Tirofiban In Myocardial Infaction Evaluation
Endpoints
Primary
• Residual ST segment deviation (>3mm) 1 hour after PCI
Key Secondary
• Combined occurrence of death, recurrent MI, urgent TVR or
thrombotic bailout at 30 days follow-up
• Safety ( major bleeding)
Ongoing Tirofiban In Myocardial Infaction Evaluation
Baseline Data
Placebo
Tirofiban
493
491
62.0 ± 12.0
61.6 ± 11.8
0.599
TIMI - risk> 3
32.2%
27.7%
0.124
Pre - hospital
Randomisation
95.7%
94.5%
0.367
No AMI
5.9%
6.3%
0.777
Patients (n)
Age (yrs)
p- value
Ongoing Tirofiban In Myocardial Infaction Evaluation
Inclusion Site
Ambulance
95%
Referral Center
3%
PCI center (ER)
2%
Ongoing Tirofiban In Myocardial Infaction Evaluation
Ischemic Time
60 min
76
20
25
19
16
d-t-b 35 min
0
60
120
Ischemic Time (min)
SO-1st Contact
Door-Angio
Preparation
Angio-Balloon
Transportation
[ Mean transport distance: 25 km/ 17 miles ]
180
Ongoing Tirofiban In Myocardial Infaction Evaluation
Angiography and Reperfusion
Placebo
n=493
Tirofiban
n=491
p- value
Angio performed
99.0%
98.2%
0.278
PCI
90.0%
87.6%
0.235
CABG
2.7%
2.9%
0.225
Conservative
7.4%
9.5%
0.82
Ongoing Tirofiban In Myocardial Infaction Evaluation
Results: Primary Endpoint
Residual ST deviation at 60 min.
mean ± SD
Placebo
Tirofiban
p- value
94.1%
95.5%
0.358
4.8 ±6.3
3.3 ± 4.3
0.002
normal ECG
30.2%
37.3%
0.031
> 3 mm ST-deviation
44.3%
36.6%
0.026
Readable ECG
Residual
ST - deviation (mm)
Ongoing Tirofiban In Myocardial Infaction Evaluation
Cumulative ST- Deviation over Time
[mm]
16
14.5±9.1
14.3±9.1
Placebo
Tirofiban
12.1±9.4
10.9±9.2
12
8
5.9±8.1
4.4±5.3
4.8±6.3
3.3±4.3
4
p=0.84
0
Diagnosis
0.028
pre Angio
0.022
0.002
60min
90 min
Ongoing Tirofiban In Myocardial Infaction Evaluation
Residual ST-Deviation
and Mortality
30 day Mortality (%)
5
4
P<0.001
4,1
3
2
1
0,6
0
ST dev <3mm
ST dev >3mm
Residual ST > 3 mm (combined)
Tirofiban better
Placebo better
All patients (PCI)
Primary
Endpoint
Subgroups
Male gender
Female gender
Diabetes
No diabetes
TIMI risk > 3
TIMI risk ≤ 3
Age < median value
Age > median value
0.1
1
10
Residual ST > 3 mm (combined)
Tirofiban better
Primary
Endpoint
Subgroups
Placebo better
TIMI pre 0,1
TIMI pre 2,3
Angio < 55 min
Angio > 55 min
Onset of Pain ≤ 76 min
Onset of pain > 76 min
Bail out tirofiban
No bail out tirofiban
0,1
1
10
Ongoing Tirofiban In Myocardial Infaction Evaluation
Clinical Secondary Endpoints: 30 days
Placebo
n=477
Tirofiban
n=473
p-value
Death
19 (4.0%)
11(2.3%)
0.144
Reccurent
RecurrentMIMI
14 (2.9%)
13 (2.7%)
0.863
Stroke
7 (1.5%)
1 (0.2%)
0.069
Urgent TVR
23 (4.8%)
19 (4.0%)
0.546
Death/MI/TVR/Stroke
47 (9.9%)
34 (7.2%)
0.141
Thromb. Bail out
140 (28.5%)
97(19.9%)
0.002
Combined
159 (33.3%)
123 (26.0%)
0.013
0.013
Ongoing Tirofiban In Myocardial Infaction Evaluation
Event-free Survival
90%
Event free survival
80%
Tirofiban
Placebo
70%
60%
50%
P = 0.012
P value 0,012
40%
0
5
10
15
Time (days)
20
25
30
Ongoing Tirofiban In Myocardial Infaction Evaluation
Thrombotic Bail-out and Angiography
Placebo
(n = 493)
Tirofiban
(n = 491)
p-value
Bail- out
28.5%
19.9%
0.002
TIMI-Flow 0-2
9.1%
5.9%
0.058
Abrupt closure
2.2%
0.2%
0.004
Distal embolisation
11.8%
9,0%
0.155
Ongoing Tirofiban In Myocardial Infaction Evaluation
Safety Endpoint: Bleeding
Placebo
n=477
Tirofiban
n=473
p-value
Major
2.9%
4,00%
0.363
Non-CABG
1.5%
1.9%
0.41
Minor
4.4%
6.1%
0.233
Non- CABG
2.7%
4.6%
0.807
Ongoing Tirofiban In Myocardial Infaction Evaluation
Exploratory Endpoints: Biomarkers
Median [Q1 -Q3]
Troponin T
(72-96 hrs)
(n=590)
NT- proBNP
(72-96/ 18-24 hrs)
(n=785)
NT- proBNP
>median
Placebo
Tirofiban
p-value
1.8 µg/L
[0.0009 -11.31]
1.87 µg/L
[0.009-17.73]
0.916
1066 µg/L
[485 - 2664]
891 µg/L
[424 - 1671]
0.026
225/404 (55.7%)
177/386 (45.9%)
0.006
Ongoing Tirofiban In Myocardial Infaction Evaluation
Summary
• Pre-Hospital initiation of tirofiban (HDB) improves
ST resolution before and after primary PCI
• Combined secondary clinical endpoint reduced
• No increase in bleeding risk
Ongoing Tirofiban In Myocardial Infaction Evaluation
Conclusions
• High dose tirofiban on top of clopidogrel (600mg)
in the prehospital setting is safe
• Improves outcome of primary PCI for AMI
• Long term mortality benefit ?
Thank you !
Ongoing Tirofiban In Myocardial Infaction Evaluation
Ongoing Tirofiban In Myocardial Infaction Evaluation
Baseline Data 2
Time lines + Transportation
Placebo
(n=493)
Tirofiban
(n=496)
p- value
79 [45 - 155.8]
72 [44 - 141]
0.377
Study medicationto- angio (min)
55 [43-70]
55 [43-70]
0.844
Transport
Distance (km)
25 [12-41]
25 [12-41]
0.931
mean ± Q1-Q3
Symptom- to Diagnosis (min)
Ongoing Tirofiban In Myocardial Infaction Evaluation
Statistics
Placebo Controlled study (N=958)
Primary End Point
• Relative 20% reduction: 50 to 40%
• N=814 (Alpha 0.05, power 80%), 20% loss, N=958
Key Secondary End Point
•
68% power to detect a Relative 40% difference (13 to 8%)
Open label + Plac controlled (N=1.400)
•
55% power to detect a relative 40% difference in combined death/reMI/urg TVR (7.5 to 4.5%)
Ongoing Tirofiban In Myocardial Infaction Evaluation
Statistics
Placebo Controlled study (N=958)
Primary End Point
• Relative 20% reduction: 50 to 40%
• N=814 (Alpha 0.05, power 80%), 20% loss, N=958
Key Secondary End Point
•
90 % power to detect a relative 30% difference (35 to 25%)
• 80% power to detect a relative 40% difference in
combined death/re-MI/urg TVR (11.5 to 7.5%)
Ongoing Tirofiban In Myocardial Infaction Evaluation
Endpoints - 2
Secondary Other
•
Incidence of TIMI 3 flow of the IRV at initial angiography
•
Incidence of normal MBG
Exploratory
•
Enzymatic Infarct size ( single cTnT 48-72 hours after PCI)
•
Distal Embolisation
•
MRI infarct Size
•
Spect Salvage index
•
Platelet Aggregation