1. Sudden death as co-morbidity in patients following vascular intervention Sudden death as co-morbidity in patients following vascular intervention Impact of ICD therapy Advanced Angioplasty Meeting (BCIS) London, 16 Jan, 2003 Seah Nisam Director, Medical Science, Guidant Corporation

2. What am I doing here ??

3. Epidemiology of sudden cardiac death Sudden cardiac death (SCD) due to coronary artery disease (CAD) is the single most important cause of death in the adult population of the industrialized world 1 Incidence in Western Europe (similar to US): 300 000 SCD/Y 75-80% due to VT/VF 5-10% due to bradyarrhythmias Out-of-hospital SCD: 8 per 1000 for males between 60-69 years old and a prior history of heart disease 2-5 1 Priori S. European Heart Journal 2001. 2 Carveth. Surg 1974. 3 Vertesi L. Can Med Assoc J 1978. 4 Bachman JW. JAMA 1986. 5 Becker. Ann Emerg Med 1993.

4. SCD in Myocardial infarction 1 Pre-thrombolytic era: Expected mortality after MI ~ 15% at 2.5 years, with ~75% of all deaths being arrhythmic 2 Thrombolytic era: Incidence of cardiac deaths after MI ~ 5% at 2.5 years, with 50% being arrhythmic; VT/VF without preceding ischemia can be expected in 0.5% to 2.5 of patients 3,4 In post MI at high risk (EMIAT, CAMIAT, TRACE, DIAMOND-MI, SWORD), cumulative arrhythmic mortality ~ 5% at 1 Y and 9% at 2y 1 Priori S. European Heart Journal 2001. 2 Marcus. AM J Cardiol 1988. 3 Statters. Am J Cardiol 1996; 4 Hohnloser S. JACC 1999.

5. Great majority of patients in the large ICD trials have CAD and previous CABG/PTCA MADIT (n = 196) MUSTT (n = 704) MADIT II (n = 1232) AVID (n = 1016) Age636865 % Males9285 80 LVEF0.260.300.230.32 NYHA II/III (%)6564656545 Coronary Artery disease (%) 100 81 Previous CABG/PTCA (%) 716757/44~ 50/? (of CAD pts) Mean time post-MI to enrolment (mos) 2739> 36N/A

6. MADIT & MUSTT: ICD reduces mortality by > 50% ICD Control Probability of Survival MUSTT MADIT MUSTT no Tx MUSTT drug Tx MADIT “Conventional” Tx Prystowsky /Nisam (AJC 2000) Hazard ratio: MADIT 0.46 (p =0.009); MUSTT: 0.49 (p = 0.001)

7. 73% Secondary Prevention Studies Primary Prevention Studies 39% 20% 38% 0 54% 51% ICDs reduce mortality by ~ 40% 31%31% in primary prevention as well as in secondary

8. CABG-Patch trial (n = 900) Patients requiring CABG, with LVEF < 0.35, were randomized at time of CABG to ICD or no ICD Patients had no previous history of sustained ventricular arrhythmias (VT/VF) Only arrhythmia “risk stratifier” was signal averaged ECG (SAECG)

9. Why no ICD benefit in CABG-Patch? CABG - for patients requiring and amenable to surgery - is highly effective against mortality and arrhythmias –Mortality 30 days post CABG was only 11% in following 2 years –SAECG (only arrhythmia risk stratifier in CABG-Patch) not a strong one –Risk stratification (SAECG and LVEF) measured before CABG Of all the ICD studies, the only one enrolling patients without sustained VT/VF (either spontaneous or inducible) was CABG-Patch Main lesson from CABG-Patch study: patients without sufficient arrhythmia risk do not benefit from ICD therapy

10. MADIT II – Inclusion/Exclusion Criteria Exclusion criteria Previous cardiac arrest Sustained VT NYHA Class IV CABG or PTCA < 3 months CABG or PTCA planned Life-threatening diseases < 21 years Inclusion criteria MI > 4 weeks LVEF < 30% > 21 years

11. Geelen & BrugadaPACE 1999;22:1132-39 CABG ICD pts.(n = 18) Other ICD pts. (n = 232)

12. Daoud et al American Heart Journal 1995;130:277-80 Appropriate ICD discharges in patients post CABG (n = 412)

13. ACC/AHA/NASPE 1 and ESC 2 Guidelines new recommendations for ICD indications Class IIa Patients with LV ejection fraction of less than or equal to 30%, at least one month post myocardial infarction and three months post coronary artery revascularization surgery 1.Gregaratorios, CIRC Oct 15, 2002 2.Priori, Eur H J, Jan 2003

14. Conclusions Over 80% of patients receiving ICDs have previous M.I. Nearly all CAD patients undergo CABG or PTCA before ICD implantation High percentage of patients receive ICD shocks despite revascularization ICDs reduce all-cause mortality by ~ 40% compared to controls in randomized clinical trials Risk for Sudden death and arrhythmias remains high despite revascularization, and these patients receive significant benefits from ICDs

15. MADIT II medications at last follow-up: optimal and well-matched for both groups CONV ICD (n=490) (n=742) percent Beta-blockers 70 70 ACE inhibitors 72 68 Diuretics 81 76 Digitalis 57 57 Statins 65 71 Amiodarone* 10 13 Antiarrhythmics 2 3 * Principally for control of supraventricular arrhythmias (AF)

16. MADIT II study overview 1232 patients enrolled from 76 centers (75 in U.S., 5 in Europe), from 7/97 to 11/2001 MADIT-II eligibility: Prior MI, ejection fraction < 30% No previous cardiac arrest or sustained VT Randomization 3:2 ICD:control (for analysis of secondary endpoints) Sponsor: Guidant corporation (unrestricted grant and ICDs used in study) R*R* ICD (742) No-ICD (490) Follow-up (average ~ 2 y.) Optimal medical therapy 1232 pts. *Randomization 3:2 (ICD:Control)

17. ICD benefit over and above optimal drug therapy ICD benefit similar in all important sub- groups: age, LVEF, NYHA Class, time from MI, etc. MADIT II showed 31% reduction of total mortality in post-MI patient with depressed LV function A Moss. NEJM 2002

18. 0% 5% 10% 15% 20% 25% 30% β-blockersACE inhibitorsCABG ICDs All-cause Mortality 27 % 20 % 11 % 31 % Trial:BHATSAVE CASS MADIT II N:380022007801232 N:380022007801232 P-value: 0.010.019 n.s.0.016 P-value: 0.010.019 n.s.0.016 Mortality reduction with ICD in MADIT II is higher than major trials that have changed medical practice Courtesy A. Moss, 2002

19. CABG Patch Survival Curves Main study Pilot study Hypothesis (Control Group) 40

20. Indications for implantable cardioverter defibrillator (ICD) therapy Study Group on Guidelines on ICDs of the Working Group on Arrhythmias and the Working Group on Cardiac Pacing of the European Society of Cardiology R.N.W. Hauer (chair), E. Aliot, M. Block, A. Capucci, B. Lüderitz, M. Santini and P.E. Vardas Working Group Report « Prophylactic indication: Non-sustained VT 4 days or more after myocardial infarction with a left ventricular ejection fraction < 40% and inducible VF or sustained VT at electrophysiological study » European Heart Journal (2001) 22, 1074-1081