1. ICDs for Heart Failure Derek T. Connelly President - Heart Rhythm UK Consultant Cardiologist - Glasgow Royal Infirmary September 2005

2. ICD Technology

4. ICD Trials: “Secondary prevention”

5. Randomised Trials of ICD Therapy “Secondary prevention” - patients who have had sustained VT or VF Antiarrhythmics versus Implantable Defibrillator (AVID) - 1997 Antiarrhythmics versus Implantable Defibrillator (AVID) - 1997 Cardiac Arrest Study Hamburg (CASH) - 2000 Cardiac Arrest Study Hamburg (CASH) - 2000 Canadian Implantable Defibrillator Study (CIDS) - 2000 Canadian Implantable Defibrillator Study (CIDS) - 2000

6. Antiarrhythmics Versus Implantable Defibrillator (AVID) 6000 patients screened, 1016 randomised 6000 patients screened, 1016 randomised Mean age 65, 79% male, mean LVEF 31% Mean age 65, 79% male, mean LVEF 31% Inclusion arrhythmia: Inclusion arrhythmia: Ventricular fibrillation45%Ventricular fibrillation45% Ventricular tachycardia with syncope 21%Ventricular tachycardia with syncope 21% Symptomatic VT with LVEF <40%34%Symptomatic VT with LVEF <40%34% ICD in 507, Antiarrhythmic drugs in 509 ICD in 507, Antiarrhythmic drugs in 509 N Engl J Med 1997; 337: 1576-83

8. AVID subgroups

9. S J Connolly, Eur Heart J 2000; 21:2071-8 Meta-analysis - ICD v Amiodarone

10. S J Connolly, Eur Heart J 2000; 21:2071-8 Meta-analysis - ICD v Amiodarone

11. ICD Trials: “Primary prevention”

12. Randomised Trials of ICD Therapy “Primary prevention” - patients who have not yet had VT or VF, but are thought to be at high risk Multicenter Automatic Defibrillator Implantation Trial (MADIT) -1996 Multicenter Automatic Defibrillator Implantation Trial (MADIT) -1996 Multicenter UnSustained Tachycardia Trial (MUSTT) - 1999 Multicenter UnSustained Tachycardia Trial (MUSTT) - 1999 MADIT 2 – 2002 MADIT 2 – 2002 COMPANION – 2004 COMPANION – 2004 SCD-HeFT - 2004 SCD-HeFT - 2004

13. Studies of Non-Sustained VT in pts with CAD, poor LV, inducible sustained VT Multicenter Automatic Defibrillator Implantation Trial (MADIT) Multicenter Automatic Defibrillator Implantation Trial (MADIT) Hypothesis that survival with ICD is better than with antiarrhythmic drugs when VT cannot be suppressed by IV procainamideHypothesis that survival with ICD is better than with antiarrhythmic drugs when VT cannot be suppressed by IV procainamide Multicenter UnSustained Tachycardia Trial (MUSTT) Multicenter UnSustained Tachycardia Trial (MUSTT) Hypothesis that survival with EP guided Rx (with ICD for drug failures) is better than controlsHypothesis that survival with EP guided Rx (with ICD for drug failures) is better than controls

14. Multicenter Automatic Defibrillator Implantation Trial (MADIT) Post - MI patients with asymptomatic non-sustained VT and LVEF < 35%; age 25 - 80 Post - MI patients with asymptomatic non-sustained VT and LVEF < 35%; age 25 - 80 Sustained VT reproducibly inducible at EPS and not suppressible with IV procainamide Sustained VT reproducibly inducible at EPS and not suppressible with IV procainamide Randomised to antiarrhythmic drugs or ICD Randomised to antiarrhythmic drugs or ICD Moss et al N Engl J Med 1996; 335: 2933-40

15. MADIT - Results Moss et al N Engl J Med 1996; 335: 2933-40

16. MUSTT Protocol

17. MUSTT Results 2202 pts with NSVT studied, 767 inducible, 704 pts randomised 2202 pts with NSVT studied, 767 inducible, 704 pts randomised 351 EP guided Rx, 353 no antiarrhythmic Rx351 EP guided Rx, 353 no antiarrhythmic Rx 40% on -blockers, 75% on ACE inhibitors40% on -blockers, 75% on ACE inhibitors 158 pts (45%) on antiarrhythmic drugs 158 pts (45%) on antiarrhythmic drugs Class I 26%, amio 10%, sotlol 9%Class I 26%, amio 10%, sotlol 9% 161 pts (46%) had ICD 161 pts (46%) had ICD Buxton et al N Engl J Med 1999; 341: 1882-90

18. MUSTT Results 5 year mortality 24% in pts with ICD, 55% in those without (p<0.001) 5 year mortality 24% in pts with ICD, 55% in those without (p<0.001) antiarrhythmic drugs had no effect on mortalityantiarrhythmic drugs had no effect on mortality Relative risk of total mortality in ICD treated patients was 0.40 (95% CI 0.27-0.59) Relative risk of total mortality in ICD treated patients was 0.40 (95% CI 0.27-0.59) Buxton et al N Engl J Med 1999; 341: 1882-90

19. MUSTT - Results Buxton et al. N Engl J Med 1999 ;341:1882-90

20. UK ICD Guidelines ‘Secondary Prevention’: ‘Secondary Prevention’: Cardiac arrest due to VT or VFCardiac arrest due to VT or VF Spontaneous sustained VT with syncope or significant haemodynamic compromiseSpontaneous sustained VT with syncope or significant haemodynamic compromise Sustained VT with poor ejection fraction ( 3Sustained VT with poor ejection fraction ( 3 www.nice.org.uk September 2000

21. UK ICD Guidelines ‘Primary Prevention’: ‘Primary Prevention’: Previous MI and all of the following:Previous MI and all of the following: Non-sustained VT on 24 hour ECG monitoring Non-sustained VT on 24 hour ECG monitoring Inducible VT on electrophysiological testing Inducible VT on electrophysiological testing LV ejection fraction 3 LV ejection fraction 3 A familial condition with a high risk of sudden death, e.g. Long QT, HOCM, Brugada syndrome, ARVD, repaired tetralogy of FallotA familial condition with a high risk of sudden death, e.g. Long QT, HOCM, Brugada syndrome, ARVD, repaired tetralogy of Fallot www.nice.org.uk September 2000

22. NICE ICD Guidelines Additional Recommendations Protocols for the implantation of ICDs should be developed, to include: Protocols for the implantation of ICDs should be developed, to include: early referral of appropriate patientsearly referral of appropriate patients rapid decision making and implantationrapid decision making and implantation conscious sedation rather than GAconscious sedation rather than GA rehabilitative approach to after-care, including psychological preparation for living with ICDrehabilitative approach to after-care, including psychological preparation for living with ICD early dischargeearly discharge efficient and comprehensive follow-upefficient and comprehensive follow-up

23. ICD Trials: Why is the benefit greater in “Primary Prevention” studies? In AVID, CASH and CIDS, the main entry criterion was ventricular arrhythmia In AVID, CASH and CIDS, the main entry criterion was ventricular arrhythmia Some patients had preserved LV functionSome patients had preserved LV function Mortality reduction with ICD 28% overallMortality reduction with ICD 28% overall Mortality reduction 34% in patients with LVEF < 35%Mortality reduction 34% in patients with LVEF < 35% In MADIT and MUSTT, the main entry criterion was poor LV function In MADIT and MUSTT, the main entry criterion was poor LV function LVEF <35% in MADIT, <40% in MUSTTLVEF <35% in MADIT, <40% in MUSTT Mortality reduction with ICD 54 - 60%Mortality reduction with ICD 54 - 60% Heterogeneity in antiarrhythmic drug useHeterogeneity in antiarrhythmic drug use

24. Who benefits most from ICDs? 1990’s Patients at highest risk of sudden death are those with ventricular arrhythmias (spontaneous or induced) Patients at highest risk of sudden death are those with ventricular arrhythmias (spontaneous or induced) The ICD is a treatment for ventricular arrhythmias The ICD is a treatment for ventricular arrhythmias2000’s Patients at highest risk of sudden death are those with heart failure due to poor LV systolic function Patients at highest risk of sudden death are those with heart failure due to poor LV systolic function The ICD is a treatment for heart failure The ICD is a treatment for heart failure

25. MADIT-2 Post MI, LVEF < 30% Post MI, LVEF < 30% ICD or control ICD or control Post - randomisation: non-invasive markers, EP study Post - randomisation: non-invasive markers, EP study Primary end-point total mortality; secondary: QOL, cost Primary end-point total mortality; secondary: QOL, cost Target enrolment 1200 patients Target enrolment 1200 patients Klein et al Am J Cardiol 1999; 83: 91D-97D

26. MADIT-2 Study terminated November 20, 2001 Study terminated November 20, 2001 1232 patients randomised 1232 patients randomised 742 defibrillator, 490 conventional742 defibrillator, 490 conventional Mean follow-up 20 months (range 6 days - 53 months Mean follow-up 20 months (range 6 days - 53 months 105 deaths in ICD group (14.2%) 105 deaths in ICD group (14.2%) 97 deaths in conventional group (19.8%) 97 deaths in conventional group (19.8%) 31% reduction in risk of death with ICD 31% reduction in risk of death with ICD Moss et al New Engl J Med 2002; 346: 877-883

27. MADIT-2 Concomitant therapies ACE inhibitors used in 70% ACE inhibitors used in 70%  blockers used in 70%  blockers used in 70% Statins used in 68% Statins used in 68% 57% had previously had CABG 57% had previously had CABG 44% had previously had PTCA 44% had previously had PTCA MADIT-2 targeted patients who were considered suitable for CABG / PTCAMADIT-2 targeted patients who were considered suitable for CABG / PTCA Benefit of ICD is over & above benefit from revascularisationBenefit of ICD is over & above benefit from revascularisation

28. MADIT II Results Moss et al New Engl J Med 2002; 346: 877-883

29. MADIT-2 Subgroup analyses and additional tests Heart rate variability (several parameters), signal averaged ECG - not useful Heart rate variability (several parameters), signal averaged ECG - not useful EP study performed in those with ICD EP study performed in those with ICD If EP +ve, more likely to get VTIf EP +ve, more likely to get VT If EP -ve, more likely to get VF !If EP -ve, more likely to get VF ! Overall limited usefulnessOverall limited usefulness QRS width - powerful predictor of benefit from ICD QRS width - powerful predictor of benefit from ICD

30. Moss et al New Engl J Med 2002; 346: 877-883 MADIT II - Subgroup analysis

32. Bristow et al New Engl J Med 2004; 350: 2140 COMPANION Results

33. Bristow et al New Engl J Med 2004; 350: 2140

34. COMPANION Subgroups

35. Companion Study Biventricular pacing (+ ICD) Biventricular pacing (+ ICD) Improves quality of lifeImproves quality of life Improves 6-minute walk timeImproves 6-minute walk time Reduces need for hospitalisation for heart failureReduces need for hospitalisation for heart failure Improves NYHA functional classImproves NYHA functional class

36. MIRACLE ICD Study Efficacy of antitachycardia pacing 88% from RV (336 episodes)88% from RV (336 episodes) 95% from LV (658 episodes)95% from LV (658 episodes)

37. Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) 2500 patients with symptomatic heart failure (NYHA 2-3) and LV ejection fraction < 35% 2500 patients with symptomatic heart failure (NYHA 2-3) and LV ejection fraction < 35% 50% ischaemic, 50% idiopathic DCM 50% ischaemic, 50% idiopathic DCM Randomised to Randomised to No antiarrhythmic therapyNo antiarrhythmic therapy AmiodaroneAmiodarone ICDICD 5 year follow-up 5 year follow-up Results presented March 2004 Results presented March 2004

38. * Double-blind for drug therapy Hypothesis and Primary Endpoint To determine, by intention-to-treat analysis, if amiodarone or a conservatively programmed shock- only ICD reduces all-cause mortality compared to placebo* in patients with either ischemic or non-ischemic NYHA Class II and III CHF and EF < 35%. To determine, by intention-to-treat analysis, if amiodarone or a conservatively programmed shock- only ICD reduces all-cause mortality compared to placebo* in patients with either ischemic or non-ischemic NYHA Class II and III CHF and EF < 35%.

39. Enrollment Scheme DCM + CAD and CHF  EF < 35%  NYHA Class II or III  6 minute walk, Holter Amiodarone R Placebo ICD

40. Study Drug Dosing Outpatient administration Outpatient administration < 800 mg qd for week 1 < 800 mg qd for week 1 < 400 mg qd for weeks 2-4 < 400 mg qd for weeks 2-4 Chronic dose is weight dependent Chronic dose is weight dependent 200mg/d if <150 lbs200mg/d if <150 lbs 300mg/d if 150-200 lbs300mg/d if 150-200 lbs 400mg/d if > 200 lbs400mg/d if > 200 lbs

41. ICD Guidelines VVI-ICD (Medtronic 7223) VVI-ICD (Medtronic 7223) VF therapy only VF therapy only FDI = 320 ms, NID = 18/12 FDI = 320 ms, NID = 18/12 Hysteresis of 34 bpm (VVI = 50 bpm) Hysteresis of 34 bpm (VVI = 50 bpm) Pre-VT/VF memory activation Pre-VT/VF memory activation

42. Baseline Enrollment Characteristics Age60.1 yrs (51.7, 68.5) median (25 th, 75 th percentiles) Age60.1 yrs (51.7, 68.5) median (25 th, 75 th percentiles) Female23% Female23% Minorities23% Minorities23% Heart rate73 bpm (63, 84) Heart rate73 bpm (63, 84) Blood pressure Blood pressure Systolic118 mmHg (106, 130)Systolic118 mmHg (106, 130) Diastolic 70 mmHg (62, 80)Diastolic 70 mmHg (62, 80) Weight190 lbs (164, 219) Weight190 lbs (164, 219)

43. Baseline Enrollment Characteristics CHF duration24.5 mo (8.1, 59.4) CHF duration24.5 mo (8.1, 59.4) LV EF25.0 (20.0, 30.0 LV EF25.0 (20.0, 30.0 NYHA II, III70%, 30% NYHA II, III70%, 30% Ischemic, non-ischemic52%, 48% Ischemic, non-ischemic52%, 48% 6 minute walk1130 ft (840, 1360) 6 minute walk1130 ft (840, 1360) Diabetes30% Diabetes30% CABG and/or Perc. Revasc.37% CABG and/or Perc. Revasc.37% H/O Hypertension56% H/O Hypertension56% H/O Hyperlipidemia53% H/O Hyperlipidemia53% H/O AF15% H/O AF15% H/O NSVT23% H/O NSVT23% ECG QRS duration ms112 ms (96, 140), 41% > 120 ECG QRS duration ms112 ms (96, 140), 41% > 120

44. Background Medications BaselineLast follow-up ACE Inhibitor85%72% ACE Inhibitor or ARB96%87% Beta-blocker69%78% Spironolactone19%31% Loop diuretics82%80% Aspirin56%55% Statin38%47% Median follow-up 45.5 months

45. Mortality by Intention-to-Treat 0.4 0.3 0.2 0.1 0 Mortality 06121824303642485460 Months of follow-up Amiodarone ICD Therapy Placebo Median follow-up: 45.5 mo (34.8, 55.2) Vital status known on 100% of 2,521 patients 36.1% 7.2%/year

46. Mortality by Intention-to-Treat 0.4 0.3 0.2 0.1 0 Mortality 06121824303642485460 Months of follow-up Amiodarone ICD Therapy Placebo HR97.5% ClP-Value Amiodarone vs. Placebo1.060.86, 1.300.529

47. Amiodarone vs. Placebo Hazard Ratios Patient GroupNHR97.5% Cl All Patients16921.060.86, 1.30 NYHA ClassClass II11950.850.65, 1.11 Class III4971.441.05, 1.97 CHF EtiologyIschemic8791.050.81, 1.36 Non-Ischemic8131.070.76, 1.51 0.5124

48. Additional Subgroups: Amiodarone vs. Placebo Patient GroupNHR97.5% Cl GenderFemale3981.170.72, 1.90 Male12941.040.83, 1.30 LVEF 30%2851.240.66, 2.31 Age 655731.130.83, 1.52 QRS Duration 120 ms6921.050.78, 1.41 RaceWhite12921.060.84, 1.34 Non-White4001.080.71, 1.62 Enrolling CountryU.S.15341.070.86, 1.32 Non-U.S.1580.980.52, 1.84 Beta BlockerYes11621.100.85, 1.42 No5300.980.69, 1.38 DiabetesYes5141.200.87, 1.65 No11781.000.77, 1.30 0.5124

49. Mortality by Intention-to-Treat 0.4 0.3 0.2 0.1 0 Mortality 06121824303642485460 Months of follow-up Amiodarone ICD Therapy Placebo HR97.5% ClP-Value Amiodarone vs. Placebo1.060.86, 1.300.529 ICD Therapy vs. Placebo0.770.62, 0.960.007

50. ICD vs. Placebo Hazard Ratios Patient GroupNHR97.5% Cl All Patients16760.770.62, 0.96 NYHA ClassClass II11600.540.40, 0.74 Class III5161.160.84, 1.61 CHF EtiologyIschemic8840.790.60, 1.04 Non-Ischemic7920.730.50, 1.04 0.250.512

51. Additional Subgroups: ICD vs. Placebo Patient GroupNHR97.5% Cl GenderFemale3820.960.58, 1.61 Male12940.730.57, 0.93 LVEF 30%2851.080.57, 2.07 Age 655780.860.62, 1.18 QRS Duration 120 ms6990.670.49, 0.93 RaceWhite12830.780.61, 1.00 Non-White3930.750.48, 1.17 Enrolling CountryU.S.15120.820.65, 1.04 Non-U.S.1640.370.17, 0.82 Beta BlockerYes11570.680.51, 0.91 No5190.920.65, 1.30 DiabetesYes5240.950.68, 1.33 No11520.670.50, 0.90 0.1251240.250.5

52. SCD-HeFT: Conclusions In class II or III CHF patients with EF < 35% on good background drug therapy, the mortality rate for placebo-controlled patients is 7.2% per year over 5 years In class II or III CHF patients with EF < 35% on good background drug therapy, the mortality rate for placebo-controlled patients is 7.2% per year over 5 years Simple, shock-only ICDs decrease mortality by 23% Simple, shock-only ICDs decrease mortality by 23% Amiodarone, when used as a primary preventive agent, does not improve survival Amiodarone, when used as a primary preventive agent, does not improve survival

53. SCD-HeFT – Cost-benefit analysis Cost per life-year saved (US$) Cost per life-year saved (US$) LVEF < 30%$33,509 LVEF < 30%$33,509 LVEF > 30% $29,275 LVEF > 30% $29,275 Age > 65$39,469 Age > 65$39,469 Age < 65$29,164 Age < 65$29,164 QRS > 120 ms$31,244 QRS > 120 ms$31,244 QRS < 120 ms$34,821 QRS < 120 ms$34,821 Ischaemic$33,603 Ischaemic$33,603 Non-ischaemic$32,170 Non-ischaemic$32,170 DB Mark, AHA November 2004

54. CARE-HF: Background Cardiac dyssynchrony is common in patients with HF due to LVSD Cardiac dyssynchrony is common in patients with HF due to LVSD CRT has been shown to be haemodynamically effective in such patients and to improve CRT has been shown to be haemodynamically effective in such patients and to improve SymptomsSymptoms Quality of lifeQuality of life Exercise capacityExercise capacity Effects of CRT on hospitalisation and mortality remain uncertain Effects of CRT on hospitalisation and mortality remain uncertain

55. Aims To assess the effect on morbidity and mortality of adding CRT to optimised pharmacological therapy in patients with moderate and severe HF due to LVSD complicated by cardiac dyssynchrony To assess the effect on morbidity and mortality of adding CRT to optimised pharmacological therapy in patients with moderate and severe HF due to LVSD complicated by cardiac dyssynchrony To investigate the mechanisms underlying the observed effect to identify markers predicting success or failure of CRT To investigate the mechanisms underlying the observed effect to identify markers predicting success or failure of CRT

56. Main Inclusion & Exclusion Criteria Heart failure for at least 6 weeks requiring loop diuretics Heart failure for at least 6 weeks requiring loop diuretics Currently in NYHA class III/IV Currently in NYHA class III/IV A high standard of pharmacological therapy A high standard of pharmacological therapy LV systolic dysfunction and dilation LV systolic dysfunction and dilation EF 35%; EDD 30mm/height in metresEF 35%; EDD 30mm/height in metres QRS 120 ms QRS 120 ms Dyssynchrony confirmed by echo if QRS 120- 149 msDyssynchrony confirmed by echo if QRS 120- 149 ms Aortic pre-ejection delay >140ms Aortic pre-ejection delay >140ms Interventricular mechanical delay >40 ms Interventricular mechanical delay >40 ms Delayed activation of postero-lateral LV wall Delayed activation of postero-lateral LV wall Patients with AF or requiring pacing excluded Patients with AF or requiring pacing excluded

57. CARE-HF: All-Cause Mortality 571192321365404 Medical Therapy 889213351376409 CRT Number at risk 050010001500 0.00 0.25 0.50 0.75 1.00 Event-free Survival Days Medical Therapy HR 0.64 (95% CI 0.48 to 0.85) P =.0019 CRT

58. Symptoms & Quality of Life at 90 days Outcome Medical Therapy Mean (SD) CRT Group Mean (SD) Difference in means (95% CI; P value) NYHA class 2.7 (0.9) 2.1 (1.0) 0.6 (0.4 to 0.7; P < 0.0001) MLWHF score 40 (22) 31 (22) -10 (-8 to -12; P < 0.0001)

59. Mechanistic Outcomes At 18 months, compared to the control group, patients randomized to CRT had Shorter Interventricular Mechanical delay P < 0.0001 Higher LVEF (by about 7%) P < 0.0001 Less mitral regurgitationP = 0.003 Lower ventricular volumesP < 0.0001 Higher systolic blood pressure P < 0.0001 Lower NT-pro-BNPP < 0.0016

60. Conclusions CRT should be considered as part of routine therapy for patients with moderate to severe HF due to LVSD with evidence (ECG supported by Echo) of cardiac dyssynchrony to*: CRT should be considered as part of routine therapy for patients with moderate to severe HF due to LVSD with evidence (ECG supported by Echo) of cardiac dyssynchrony to*: Improve cardiac function and efficiencyImprove cardiac function and efficiency Improve symptoms and QoLImprove symptoms and QoL Reduce morbidityReduce morbidity Prolong survivalProlong survival These benefits are in addition to those of pharmacological therapy These benefits are in addition to those of pharmacological therapy *http://content.nejm.org/

61. How do we improve quality of life in patients with ICDs? Patient preparation for life with ICD Patient preparation for life with ICD Meticulous implant technique Meticulous implant technique Judicious programming Judicious programming Tachycardia detection- discrimination between VT and SVT / AFTachycardia detection- discrimination between VT and SVT / AF Antitachycardia pacingAntitachycardia pacing Optimal pharmacological therapy Optimal pharmacological therapy Biventricular pacing if needed Biventricular pacing if needed For resynchronisation and ATPFor resynchronisation and ATP Which patients need CRT with defibrillator, which need CRT alone?Which patients need CRT with defibrillator, which need CRT alone? Rehabilitation Rehabilitation Physical and psychologicalPhysical and psychological