Gerhard Steinbeck , D. Andresen, K. Seidl, J. Brachmann,

1. A Randomized Study of the Effects of Defibrillator Implantation Early after Myocardial Infarction in High-Risk Patients on Optimal Medical Therapy Gerhard Steinbeck, D. Andresen, K. Seidl, J. Brachmann, E. Hoffmann, D. Wojciechowski, Z. Kornacewicz-Jach, M. Zembala, G. Lupkovics, F. Hofgärtner, A. Lubinski, K. Wegscheider, M. Rosenqvist, F. Habets, J. Senges on behalf of the IRIS investigators

2. Presenter Disclosure Information Gerhard Steinbeck, MD The following relationships exist related to this presentation: Lecture Fees: AstraZeneca, Medtronic Advisory Board: Medtronic

3. Committees and Investigators Committees: • Data and Safety Monitoring Board: A. Hjalmarson (chair), L. Kappenberger, N. Victor • Steering Committee: Principal investigators: D. Andresen, J. Senges, G. Steinbeck Members: E. Hoffmann, K. Seidl, J. Brachmann, A. Lubinski • Adverse Event Committee: M. Rosenqvist (chair), M. Block, W. Schöls, B. Sredniawa • Data Verification Committee: U. Dorwarth, F. Gindele, B. Mark Statistics: K. Wegscheider Data Coordination Center: OSE Oncology Services Europe S.a.r.l. München Investigators: AUSTRIA: F. Hintringer, Innsbruck. CZECH REPUBLIC: M. Herold, Prague; J. Kauzner, Prague; M. Pleskot, Kralove. GERMANY: E. Altmann, Dresden; D. Andresen, Berlin; J. Aring, Leverkusen; G. Baumann, Chemnitz; R. Becker, Heidelberg; S. Behrens, Berlin; H. Blanke, Gelsenkirchen; C. Bossaller, Gehrden; J. Brachmann, Coburg; B. Cabell, Herrsching; G. Dannberg, Jena; W. Doering (†), München Schwabing; Th. Dorsel, Warendorf; E. Dünninger, Lichtenfels; H. Duwald, Gronau/Leine; R. Fenzl, Berlin; W. Feth, Rockenhausen; S. Fredersdorf, Regensburg; H. Friedl, Amberg; H. Glunz, Kaiserslautern; O. Göing, Berlin; L. Griesbach, Kirchberg; B. Hailer, Essen; A. Hartmann, Leipzig; H. Heuer, Dortmund; F. Hofgärtner, Göppingen; E. Hoffmann, München-Bogenhausen; H. Jenss, Waldshut; W. Jung, Villingen-Schwenningen; J. Isbary, Biberach; Th. Ittel, Stralsund; B. Kaufmann, Wolfach; C. Kirsch, Salzkotten; G. Liebau, Ludwigsburg; J. Manthey, Bad Friedrichshall; M. Manz, Koblenz; H. Mudra, München Neuperlach; A. Mügge, Bochum; H. Nebelsieck, Sindelfingen; J. Neuzner, Kassel; H. Odenthal, Rheine; C. Perings, Lünen; G. Richardt, Bad Segeberg; K. Schmailzl, Neuruppin; B. Schneider, Lübeck; F. Seidel, Kempten-Oberallgäu; J. Senges, Ludwigshafen; G. Steinbeck, München; C. Stellbrink, Bielefeld Mitte; G. Strupp, Fulda; U. Tebbe, Lippe-Detmold; M. Weber, Dachau; K. Weber, Unna; M. Sigg, Ravensburg; C. Wolpert, Mannheim; R. Zotz, Herford; R. Zotz, Schwalmstadt. HUNGARY: I. Édes, Debrecen; T. Forster, Szeged; G. Lupkovics, Zalaegerszeg; B. Merkely, Budapest. P0LAND: A. Cieslinski, Poznan; R. Gil, Warsawa; J. Goch, Lodz; J. Gorny, Olsztyn; W. Kargul, Katowice; K. Kawecka-Jaszcz, Krakow; A. Kleinrok, Zamosc; C. Kornacewicz-Jach, Szczecin; J. Kubica, Bydgoszcz; M. Kurowski, Szczecin; J. Kuzniar, Rzeszow; J. Lelakowsky, Krakow; A. Lubinski, Lodz; P. Miekus, Gdynia; W. Musial, Bialystok; G. Opolski, Warsawa; W. Pluta, Opole; P. Ponikowski, Wroclaw; A. Rynkiewicz, Gdansku; H. Szwed, Warsaw; M. Trusz-Gluza, Katowice; D. Wojciechowski, Warsawa; T. Widomska-Czekajska, Lublin; M. Zembala, Zabrze. RUSSIA: E. Chazov, Moscow; D. Sponsors: Medtronic Bakken Research Center, AstraZeneca

4. Background • All cause mortality and sudden death are highest early after myocardial infarction • Guidelines based on randomized trials recommend not to implant a cardioverter-defibrillator (ICD) within 40 days after acute myocardial infarction (MI) for primary prevention of sudden cardiac death

5. Study Hypothesis Immediate Risk-Stratification Improves Survival (IRIS) study High-risk patients after acute MI will show a better survival when treated early with an ICD compared to patients receiving optimal medical therapy (OMT) alone

6. Methods Used for Risk-Stratification Criterion I Left ventricular ejection fraction (EF) ≤40% on day 5–31, together with heart rate ≥ 90 beats per minute (bpm) on the first available electrocardiogram and/or Criterion II Non-sustained ventricular tachycardia at a rate ≥ 150 bpm during Holter-ECG on day 5-31

7. Study Organization • 1:1 randomized, open-label, investigator-initiated European multicenter trial • ICD implantation early after MI • Optimal acute and long-term medical therapy in both groups • Follow up ≥ 2 years • Intention-to-treat analysis • Primary endpoint: all cause mortality • Secondary endpoints: sudden cardiac death non-sudden cardiac death non-cardiac death

8. Acute Myocardial Infarction Registry of 62,944 patients • Exclusion criteria n=26,445Inclusion criteria not met n=35,188 Eligible day 5-31: n=1,311 • No consent: n=409 Criterion I+ + - Criterion II+ - + 88 604 210 3 Strata: Randomization: n= 902 Consent not valid n=2 Consent not valid n=2 OMT n=453 ICD + OMT n=445 Enrollment: June ’99 – October 2007Follow-up: mean 37 months, range 0-106 months OMT: Optimal Medical Treatment Study Flow Diagram

9. Baseline Demographic Characteristics I

10. Baseline Demographic Characteristics II

11. All Cause Mortality 117 deaths

12. All Cause Mortality 117 deaths 116 deaths

13. EF ≤ 40%, Heart Rate ≥ 90 bpm

14. Rapid Non-sustained Ventricular Tachycardia

15. Hazard Ratios for Death From any Causein Sselected Subgroups of Interest I

16. Hazard Ratios for Death From any Causein Selected Subgroups of Interest II

17. Definition of Sudden Cardiac Death Cardiac death occurring within minutes after the onset of acute symptoms, resulted from a documented cardiac arrhythmia, or was unwitnessed and occurred unexpectedly and without recognizable causes (e.g. during sleep)

18. Sudden Cardiac Death Non-Sudden Cardiac Death Cumulative Risk of Sudden Cardiac Death Cumulative Risk of Sudden Cardiac Death p=0.049 p=0.001 Month after Randomisation Month after Randomisation

19. ICD-related Adverse Events Death within 30 days after randomization: 9 patients in the ICD group 11 patients in the control group Clinically significant complications (requiring surgical correction, hospitalization, or intravenous drug administration) occurred in 65/415 ICD patients (15.7%) - up to 30 days after implant in 19 patients (4.6%) - during later follow-up in 48 patients (11.6%)

20. Summary In a carefully selected post MI study group with moderately reduced EF (mean 35%), all cause mortality and sudden cardiac death were substantial (22.9% and 11.6% at three years, respectively) Early initiation of ICD therapy did not reduce all cause mortality, independent of the way of risk-stratification Sudden cardiac death was reduced by the ICD, which was, however, counterbalanced by an increase of non-sudden cardiac death, an observation that deserves further study

21. Conclusions During the first month after myocardial infarction, in an optimally treated high-risk patient population, ICD implantation does not offer a survival benefit

22. Therapy Compliance 415/445 patients in the ICD arm actually received the device (withdrawal of consent n=14, refusing ICD implant n=11, death prior to implant n=5) ICD implantation was performed 8.8 ± 14.5 days (mean ± SD) after randomization During follow-up, according data provided by investigators, 21.4 % of patients received appropriate shocks 8.0 % of patients received inappropriate shocks ICD explanted or permanently deactivated in 15 patients In summary: 45 patients in the ICD group did not receive (or did not continue on) the ICD 39 patients in the control group received an ICD