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

Presenter Disclosure Information

Gerhard Steinbeck, MD

The following relationships exist related to this presentation:

Lecture Fees: AstraZeneca, Medtronic

Advisory Board: Medtronic

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. WegscheiderData 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

Committees and Investigators

• 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

Background

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

Study Hypothesis

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

Methods Used for Risk-Stratification

• 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

Study Organization

Registry of 62,944 patientsExclusion criteria n=26,445Inclusion criteria not met n=35,188

Acute Myocardial Infarction

Criterion I + + -Criterion II + - +

88 604 210

3 Strata:

Randomization: n= 902

ICD + OMT n=445 OMT n=453

Consent not valid n=2 Consent not valid n=2

Enrollment: June ’99 – October 2007Follow-up: mean 37 months, range 0-106 monthsOMT: Optimal Medical Treatment

Eligible day 5-31: n=1,311No consent: n=409

Study Flow Diagram

Baseline Demographic Characteristics I

Baseline Demographic Characteristics II

All Cause Mortality

117 deaths

All Cause Mortality

117 deaths116 deaths

EF ≤ 40%, Heart Rate ≥ 90 bpm

Rapid Non-sustained Ventricular Tachycardia

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

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

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)

Definition of Sudden Cardiac Death

Sudden Cardiac Death Non-Sudden Cardiac Death

Month after Randomisation

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Month after Randomisation

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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%)

ICD-related Adverse Events

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

Summary

During the first month after myocardial infarction, in an optimally treated high-risk patient population, ICD implantation does

not offer a survival benefit

Conclusions

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 shocks8.0 % 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 ICD39 patients in the control group received an ICD

Therapy Compliance