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ON-TIME-2 Ongoing-Tirofiban In Myocardial Infarction Evaluation

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Presentation on theme: "ON-TIME-2 Ongoing-Tirofiban In Myocardial Infarction Evaluation"— Presentation transcript:

1 ON-TIME-2 Ongoing-Tirofiban In Myocardial Infarction Evaluation
Ladies and gentlemen, it's a great pleasure to present to you the ON-TIME-2 study results on behalf of the ON-TIME-2 study group.

2 Presenter Disclosure Information
Christian W. Hamm, MD, FESC, FACC The following relationships exist related to this presentation: Consulting Fees Merck, GSK, Lilly, Modest Level & speakers honoraria The Med.Comp., Sanofi, Medtronic, Cordis, Braun, CVT, Abbott, Roche

3 Prehospital Tirofiban in AMI History
ON-TIME-Studies Prehospital Tirofiban 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 What is the ON-TIME-2 study? The ON-TIME study family investigates the use of tirofiban in patients with ST elevation myocardial infarction. The ON-TIME-1 study showed no significant benefit for low dose of tirofiban in acute myocardial infarction. That is, however, the labeled dose. Other studies found that this dose may be too low. Therefore, we investigated a higher dose, about 2.5 times higher, in the ON-TIME-2 registry. And this was followed by the ON-TIME-2 randomized study which I'd like to present to you in the following. Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.

4 Trial Design (Registration: ISRCTN 06195297)
Ongoing Tirofiban In Myocardial Infarction Evaluation Trial Design (Registration: ISRCTN ) Multicenter, prospective, randomized, double-blind, placebo-controlled Analysis: ITT End-points adjudicated (CEC) Investigator initiated and driven Unrestricted grant from Merck & Co Inc. The ON-TIME-2 study is a multicenter, prospective, randomized, double-blind, placebo-controlled trial. The analysis is intention to treat and all endpoints were adjudicated. The trial is investigator initiated and driven. We had an unrestricted grant from Merck Co. Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.

5 Ongoing Tirofiban In Myocardial Infarction Evaluation
Trial Leadership Co-Principle Investigators Arnoud van t´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 Here you see the trial leadership with Arnoud van t'Hof and Jurrien ten Berg as my co-principle investigators. Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.

6 Participating Centers
Ongoing Tirofiban In Myocardial Infarction Evaluation The Netherlands: 1. Isala klinieken Zwolle Dr. A.W.J. van ’t Hof 2. Antonius Ziekenhuis Nieuwegein Dr. J. ten Berg 3. UMC Utrecht Drs. P.R. Stella 4. Medisch Spectrum Twente Dr. K. van Houwelingen Germany: 1. Kerckhoff-Klinik Prof. Dr. C. Hamm 2. Universitätsklinikum Heidelberg Prof. Dr. H Katus 3. St. Johannes Hospital Dortmund Prof. Dr. Heuer 4. Klinikum Coburg Prof. Dr. J. Brachmann 5. Klinikum Lüdenscheid Dr. Lemke 6. Segeberger Kliniken Prof. Dr. G. Richardt 7. Philipps Universität Marburg Prof. Maisch 8. Allgemeines Krankenhaus Celle Prof. Dr. W. Terres 9. Uni-klinik Giessen Prof. Dr. H. Tillmanns 10. Imtalklinik Pfaffenhofen Prof. C. Firschke 11. Med. Hochschule Hannover Prof. Dr. Schieffer 12. Uniklinik Mannheim Dr. T. Süselbeck 13. Uniklinik Lübeck Prof. Dr. H. Schunkert 14. Stätisches Klinikum Lüneburg Prof. Dr. W. Kupper 15. Zentralklinikum Suhl Prof. W. Haberbosch 16. Uni-Klinik Rostock Prof. Dr. C.Nienaber 17. Kreiskrankenhaus Bergstrasse Dr. W. Auch-Schwelk 18. Asklepios Klinik St. Georg Prof. Dr. K.H. Kuck 19. Klinikum Darmstadt Prof Dr. G. Werner 20. Evangelisches Krankenhaus Holzminden Dr. C. Beythien Belgium: 1. AZ Sint-Jan AV Brugge Dr. P. Coussement In this trial, four centers from the Netherlands, twenty centers from Germany, and one Belgium center participated. Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.

7 ON-TIME -2 N=984 Transportation PCI center PCI
Acute myocardial infarction diagnosed in ambulance or referral center ASA mg Clopidogrel + UFH N=984 6/ /2007 Placebo Tirofiban * Transportation Angiogram PCI center Angiogram Here is the basic layout of the study. Patients with ST-elevation myocardial infarction were diagnosed in the ambulance or referral centers and received aspirin, 600mg loading dose of clopidogrel and unfractionated Heparin. Then they were randomized double-blind to placebo or high-dose tirofiban. After that they were transported by ambulance to the PCI center. Tirofiban was then in the placebo arm, allowed provisional also, given to the patient, also blinded. Tirofiban provisional PCI Tirofiban cont’d *Bolus: 25 µg/kg & 0.15 µg/kg/min infusion Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.

8 Ongoing Tirofiban In Myocardial Infarction 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) The primary endpoints of the study, the surrogate endpoint is residual ST segment deviation, more than 3mm one hour after PCI, because this was shown to be a very good surrogate market of long-term mortality. In addition, we evaluated a number of key secondary endpoints as they are listed here: combined occurrence of death, recurrent myocardial infarction, urgent TVR, or thrombotic bail-out at thirty days follow-up. Important of course is also the safety endpoint, which is bleeding. Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.

9 Ongoing Tirofiban In Myocardial Infarction Evaluation
Baseline Data Now, here you see the baseline data of our patients – 984 patients were included in the study, mean age was around 62. There was no difference between the groups with respect to the TIMI risk and there was also no difference with respect to whether the patient was randomized. Almost all patients were randomized pre-hospital. And about 6% of the patients did not have myocardial infarction. Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.

10 Ongoing Tirofiban In Myocardial Infarction Evaluation
Inclusion Site Ambulance 95% Referral Center 3% PCI center (ER) 2% Here you see the inclusion site, which is important. 95% were included in the study in the ambulance, 3% at the referral center, and only 2% of the patients in the PCI center in the emergency rooms. Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.

11 Ongoing Tirofiban In Myocardial Infarction Evaluation
Ischemic Time 60 min d-t-b 35 min These are the time lines of the study. You see that patients had rather early myocardial infarction. Duration of pain until first contact with the ambulance was a mean 76 minutes. Then it took 20 minutes for establishing the diagnosis and preparing the infusion. We had 25 minutes of transportation time. The mean distance was 17 miles. We had 19 minutes door-to-angio time and 16 minutes angio-to-balloon time, which amounts to 35 minutes door-to-balloon time. [ Mean transport distance: 25 km/ 17 miles ] Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.

12 Angiography and Reperfusion
Ongoing Tirofiban In Myocardial Infarction 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 Here you see the basic angiography and reperfusion management in these patients. Almost all patients had an angio performed. PCI was done in about 90% of the patients. Close to 3% of the patients underwent surgery and 7 or respectively 9% of the patients were treated conservatively. Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.

13 Ongoing Tirofiban In Myocardial Infarction Evaluation
Results: Primary Endpoint Residual ST deviation at 60 min. mean ± SD Placebo Tirofiban p- value Readable ECG 94.1% 95.5% 0.358 Residual 4.8 ±6.3 3.3 ± 4.3 0.002 ST - deviation (mm) Here you see now the primary endpoint of the study, which is residual ST deviation at 60 minutes. We had 95% of readable ECGs in our patients and the amount of residual ST segment deviation was significantly different in favor of the tirofiban group. Also, in the tirofiban group significantly more patients had normal ECG 60 minutes after the PCI. The primary endpoint was more than 3mm deviation and this was highly significantly different with 36% versus 44% in favor of the tirofiban group. normal ECG 30.2% 37.3% 0.031 > 3 mm ST-deviation 44.3% 36.6% 0.026 Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.

14 Cumulative ST- Deviation over Time
Ongoing Tirofiban In Myocardial Infarction Evaluation Cumulative ST- Deviation over Time [mm] 14.5±9.1 14.3±9.1 12.1±9.4 10.9±9.2 5.9±8.1 4.8±6.3 4.4±5.3 Here you see the cumulative ST deviation over time. At the time of diagnosis there was no difference than already pre-angiogram before the balloon was in the vessel. You see an advantage for the tirofiban group. There was less ST deviation and this was further amplified and highly significantly significant 60 minutes and 90 minutes after the procedure. 3.3±4.3 p=0.84 0.028 0.022 0.002 Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.

15 Residual ST-Deviation and Mortality
Ongoing Tirofiban In Myocardial Infarction Evaluation Residual ST-Deviation and Mortality P<0.001 This slide shows you the amount of ST segment depression and mortality, ST segment depression below and above 3mm, just to illustrate to you that this is a parameter that indicates mortality. Patients that had less than 3mm ST segment deviation, had mortality of only 0.06%, versus patients with more than 3mm residual segment deviation, had a mortality of 4.1%. Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.

16 Primary Endpoint Subgroups 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 Now we look at a few subgroups. You see here that, interestingly, the female gender seemed to have major benefit. Also, diabetic patients seemed to have more benefit than non-diabetics. There was no difference with the TIMI risk group and it appeared also that patients that had higher age had more benefit than patients at lower age. Age < median value Age > median value 0.1 1 10 Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.

17 Primary Endpoint Subgroups 10 0,1 1 Residual ST > 3 mm (combined)
Tirofiban better Placebo better Primary Endpoint Subgroups TIMI pre 0,1 TIMI pre 2,3 Angio < 55 min Angio > 55 min Onset of Pain ≤ 76 min Onset of pain > 76 min There was of course no difference or there was of course the trend that patients at higher TIMI rates did better at the end and patients that had the angiogram postponed for more than 55 minutes duration from first contact to the angiogram, they had higher benefits. The longer transport time duration was, the higher the benefit. And it also seemed that patients that had fresher infarctions less than 76 minutes had a higher benefit than patients with older infarctions. There was no difference in patients that received bailout tirofiban and patients that did not. Bail out tirofiban No bail out tirofiban 10 0,1 1 Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.

18 Clinical Secondary Endpoints: 30 days
Ongoing Tirofiban In Myocardial Infarction Evaluation Clinical Secondary Endpoints: 30 days Recurrent MI Now let's look at some secondary endpoints. I must mention that the study size was not calculated to this endpoint. There was already a strong trend to lower mortality. It did not reach significance, but we had 2.3% mortality in the tirofiban group and 4% mortality in the placebo group. There was no difference with respect to recurrent myocardial infarction. There was a strong trend to lower stroke rate in the tirofiban group and there was no major difference with respect to urgent TVR and the combined endpoint – death, myocardial infarction, target vessel revascularization, and stroke – did show a strong trend in favor of tirofiban. However, also, this did not reach statistical significance. However, thrombotic bail-out used was significantly less in tirofiban group as compared to placebo, and this was highly statistically significant. Therefore, the combined clinical endpoint, which includes thrombotic bail-out, the combined clinical endpoint was significantly reduced in our trial. 0.013 Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.

19 Ongoing Tirofiban In Myocardial Infarction Evaluation
Event-free Survival This shows you the event-free survival rate of the secondary clinical endpoint over time, indicating that the tirofiban group had less events than the placebo group. P = 0.013 Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.

20 Thrombotic Bail-out and Angiography
Ongoing Tirofiban In Myocardial Infarction Evaluation Thrombotic Bail-out and Angiography Let's go back to the thrombotic bail-out, which was much more frequently used in the placebo group as compared to tirofiban group. What were the indications for that? Patients had more frequent and lower TIMI flow grades, as you see here with 9.1% versus 5.9%. Abrupt closure was significantly more frequent, the indication in the placebo as compared to tirofiban group and there was also a trend that distal embolization was more frequent in placebo as compared to tirofiban. Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.

21 Safety Endpoint: Bleeding
Ongoing Tirofiban In Myocardial Infarction Evaluation Safety Endpoint: Bleeding 4.0% Now given the fact that GPIIb/IIIa inhibitors can result in bleedings, this was a major endpoint as our safety endpoint in bleeding. And fortunately, we did not see a difference with respect to major bleeding. Particularly, non-CABG major bleedings were very similar. Minor bleedings – there was a trend to more frequent occurrence in the tirofiban. However, also this did not reach statistical significance. 0.115 Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.

22 Exploratory Endpoints: Biomarkers
Ongoing Tirofiban In Myocardial Infarction Evaluation Exploratory Endpoints: Biomarkers We looked at some exploratory endpoints and I'd like to show here the biomarker endpoints. We looked at the troponin T levels at time period hours after the intervention, however there was no difference. On the other hand, NT-proBNP – which is also a strong marker with predictive value – was significantly lower in the tirofiban group as compared to placebo. And if you look at the NT-proBNP levels more above the median you see that this also was significantly different in favor of tirofiban, indicating that this in the long-term follow-up may result in reduced mortality. Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.

23 Ongoing Tirofiban In Myocardial Infarction 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 So in summary, our trial shows that pre-hospital initiation of tirofiban in high dose improves ST resolution before and after primary PCI. Combined secondary clinical endpoint was reduced and we did not see this at an increased rate of bleeding. Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.

24 Ongoing Tirofiban In Myocardial Infarction 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 ? So we conclude that high-dose tirofiban on top of clopidogrel 600mg in the pre-hospital setting is safe. It improves the outcome of primary PCI in patients with myocardial infarction. And we have to wait to see whether there is a long-term benefit. Thank you for the attention. Hamm CW et al. Abstract Presented April 1, 2008, at the American College of Cardiology 57th Annual Meeting in Chicago, IL.


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