ICD FOR PRIMARY PREVENTION

EVIDENCE REVIEW

1

DR SANDEEP.R SR CARDIO

INTRODUCTION

The implantable cardioverter defibrillator (ICD) is a battery-powered implantable device that can detect and terminate potentially life-threatening tachyarrhythmias via defibrillation or antitachycardia pacing to prevent SCD

Sudden cardiac death (SCD) remains the leading cause of death

ICD has been recommended for secondary prevention of sudden cardiac death based on several RCT

2

But only a small percentage of patients who

suffer cardiac arrest survive to benefit from the

ICD therapy as secondary prevention

Thus prophylactic use of ICD for primary

prevention of SCD becomes an attractive option

for high-risk patients

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ICD IN ISCHAEMIC CARDIOMYOPATHY

4

MADIT I(The Multicenter Automatic DefibrillatorImplantation Trial)

32 hospital centers (30 in the United States and 2 in Europe)

Study period 1990-1995

5 (N Engl J Med1996;335:1933-40.)

MADIT I(The Multicenter Automatic DefibrillatorImplantation Trial) INCLUSION CRITERIA EXCLUSION CRITERIA

NYHA I, II, or III with prior M.I Previous cardiac arrest or VT causing syncope that was not associated with AMI

LVEF < 0.35 Acute Myocardial infarction < 3 weeks

Documented episode of asymptomatic unsustained VT

Patients who underwent CABG within the past two months or PTCA within the past three months

Inducible, nonsuppressible VT on EP study

Symptomatic hypotension while in a stable rhythm

Had no CABG /PTCA in last 3 mths

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MADIT I(The Multicenter Automatic DefibrillatorImplantation Trial)

•N=196

•Two patient groups (1:1) randomization 1. Conventional Medical Therapy (CMT) 2.ICD

•Mean follow up 27 months

•Primary endpoint: All cause Mortality

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RESULTS

•CONCLUSION

•54% reduction in all cause mortality in ICD group

•No evidence for of mortality benefit with amiodarone ,betablockers

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CABG Patch trialThe Coronary Artery Bypass Graft (CABG) Patch trial

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•The trial was conducted at 37 clinical centers, 35 in the US & 2 in Germany

INCLUSION CRITERIA

< 80 yrs age

LVEF< 0.36

Abnormalities on a signal-averaged electrocardiogram

•Study period – 1992-98

•The primary endpoint was all-cause mortality

•900 patients who came for elective CABG were randomized into ICD ( 446) VS no ICD group ( 454)

RESULTS

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CONCLUSION•No evidence of improved survival among patients with coronary heart disease, a depressed LVEF , and an abnormal signal-averaged ECG in whom a defibrillator was implanted prophylactically at the time of elective CABG

MUSTT Buxton AE. N Engl J Med

1999;341:1882-90 (Multicentre UnSustained Tachycardia Trial)

The trial was designed to study the concept of guiding the management of high risk patients with the results of EPS

Not primarily designed as a randomized ICD clinical trial

AIM: To evaluate the efficacy of antiarrhythmic therapy guided by EP

testing in reducing the risk of SCD and cardiac arrest among

patients with CAD, LV dysfunction, and asymptomatic, unsustained

VT

STUDY PERIOD-1991-1997 & median follow-up of 39 months

Buxton AE. N Engl J Med 1999;341:1882-90 13

METHODOLOGY

INCLUSION CRITERIA EXCLUSION CRITERIA

Patients with CADH/O syncope/sustained VT/VF > 48hrs of MI

LVEF<40% NSVT due to metabolic causes

Asymptomatic, unsustained VT Symptomatic, unsustained VT

Patients in whom sustained VT were induced by programmed stimulation

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STUDY PROTOCOL

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Primary EndpointArrhythmic death or cardiac arrest

Secondary EndpointsTotal mortalityCardiac mortalitySpontaneous, sustained VT

MUSTT EP-Guided Rx Patients Treatment at Discharge

Buxton AE. N Engl J Med 1999;341:1882-90.

Antiarrhythmic Drugs: 45%

No Rx

7%

ICD

46%

IA

26%

Sotalol

9%

Amiodarone

10%

Results -Arrhythmic Death or Cardiac Arrest

Buxton AE. N Engl J Med 1999;341:1882-90.

No EP-Guided AA Rx EP-Guided Rx, (No ICD and ICD)

p = 0.04

Time after Enrollment (Years)

0 1 2 3 4 50

0.1

0.2

0.3

0.4

0.5

Even

t R

ate

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Results The two-year (12 versus 18 percent) and five-year (25 versus 32

percent) rates for the primary endpoint were significantly lower for EPS

guided therapy compared to no therapy

There was a nearly significant reduction in the secondary endpoint of

total mortality at five years in the group receiving EPS guided therapy

(42 versus 48 percent, p = 0.06).

The reduction in the primary and secondary endpoints in the EPS guided

group was largely attributable to ICD therapy

At five years the primary endpoint occurred in 9 percent of those

receiving an ICD compared with 37 percent of those receiving an

antiarrhythmic drug, and the secondary endpoint occurred in 24 and 55

percent respectively.

There was no difference in outcome between patients receiving no

therapy and those treated with an antiarrhythmic drug 20

CONCLUSION

Electrophysiologically guided antiarrhythmic therapy with

implantable defibrillators but not with antiarrhythmic drugs

reduces the risk of sudden death in high-risk patients with

coronary disease

At 5 years, there were absolute reductions in total

mortality of 31% in the patients receiving ICD therapy when

compared with those receiving pharmacological therapy and

of 24% when compared with those receiving no therapy

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MADIT II

22N Engl J Med, Vol. 346, No. 12

AIM: To evaluate the potential survival benefit of a prophylactically implanted defibrillator (in the absence of electrophysiological testing to induce arrhythmias) in patients with a prior M.I and LVEF< 0.30

Enrolled patients from 76 hospital centers (71 US and 5 in Europe)

INCLUSION EXCLUSION

M.I >4 WEEKS Revascularization within the preceding three months

LVEF <30% M.I < 3 weeks

New York Heart Associationfunctional class IV at enrollment

STUDY PERIOD 1997-2001

PRIMARY OUTCOME ALL CAUSE

MORTALITY

1232 Patients with prior MI more than 30 days and LVEF < 30% randomized in a 3:2 ratio

1232 Patients with prior MI more than 30 days and LVEF < 30% randomized in a 3:2 ratio

Conventional medical therapy

(n=490)

Conventional medical therapy

(n=490)

Implantable defibrillator

(n=742)

Implantable defibrillator

(n=742)

All Cause Mortality - Average follow-up of 20 monthsAll Cause Mortality - Average follow-up of 20 months

Stopped early Stopped early

MADIT II: Study Design

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RESULTS

25

19.8%

14.2%

0%

5%

10%

15%

20%

25%

ConventionalTherapy

ConventionalTherapy

ICDICD

P=0.016P=0.016

DeathAvg. follow-up=20 months

DeathAvg. follow-up=20 months

MADIT II: All-Cause Mortality

Hazard

Ratio = 0.65

Hazard

Ratio = 0.65

MADIT II: Mortality Events

4.1% 3.5%

13.7%

10.0%9.4%

3.6% 3.7%

5.5%

0%

5%

10%

15%

Non CardiacNon Cardiac

ConvTherapy

ConvTherapy

ICDICD

CardiacCardiac

ConvTherapy

ConvTherapy

ICDICD

ArrhythmicArrhythmic Non ArrhythmicNon Arrhythmic

ConvTherapy

ConvTherapy

ICDICD ConvTherapy

ConvTherapy

ICDICD

14.9%

19.9%

0%

5%

10%

15%

20%

ConventionalTherapy

ConventionalTherapy

ICDICD

P=0.09P=0.09

New or Worsening Heart FailureNew or Worsening Heart Failure

MADIT II: CHF

RESULTS

In the current study the survival benefit began approximately nine months after the device was implanted

No ep study used Increased incidence of heart failure in ICD group

REASONS FOR HEART FAILURE 1. INCREASED SURVIVAL 2.SHOCK INDUCED MYOCARDIAL INJURY 3.LONG TERM PACING INDUCED DYSFUNCTION

CONCLUSION

› In patients with a prior myocardial infarction and advanced left ventricular dysfunction, prophylactic implantation of a defibrillator improves survival and should be considered as a recommended therapy

INTERESTING FACTS:

SCD HeFT

Study period 1997-2001

The primary end point of the trial was death from any cause

N=2521

The etiology of cardiomyopathy was ischemic in 52 percent and nonischemic in 48 percent

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INCLUSION CRITERIA

Patients >18 years of age

NYHA class II or III

Stable CHF due to ischemic or non ischemic causes & LVEF < 35 percent

Inclusion criteria

Placebo n=847 ICD implant n=829

40 months average follow- up

• Optimize: B, ACE-I, Diuretics

1 Bardy GH. Chapter Excerpt from Arrhythmia Treatment and Therapy. Woosley RL, Singh SN, editors. Marcel Dekker, 1st edition. 2000;323-42.

Amiodarone n=845

SCD-HeFT - Protocol

RESULTS

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RESULTS

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RESULTS

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SCD-HeFT -Results

In NYHA Class II or III HF patients with EF < 35% on good background therapy, the mortality rate for placebo-controlled patients is 7.2% per year over 5 years

Simple, shock-only ICDs decrease mortality by 23% (p=0.007) & the benefit did not vary according to the cause of CHF

Amiodarone, when used as a primary preventative agent, does not improve survival

EARLY POST MI TRIALS

DINAMIT IRIS

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DINAMITThe Defibrillator in Acute Myocardial Infarction Trial

Evaluated the role of prophylactic ICD implantation compared to no ICDInclusion criteria 674 patients with MI in the preceding 6 to 40 days (mean

18 days) LVEF ≤35 percent Reduced heart rate variability or elevated resting heart rate

(≥80beats/min).

Exclusion criteria Patients with sustained VT >48 hours post-MI, NYHA class

IV HF, or coronary artery bypass grafting (CABG) or three-vessel percutaneous coronary intervention post-MI

Mean follow-up was 30 months.37NEJM 2004:351:2481-8

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RESULTS

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RESULTS

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IRIS trial Immediate Risk Stratification Improves Survival

Enrolled 898 patients

Inclusion criteria: MI within the preceding 5 to 31 days and one or both

of the following two criteria: LVEF ≤40 percent and a resting HR ≥90 beats/min Nonsustained VT at a rate ≥150 beats/min

Mean follow-up - 37 months

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•RESULTS:

•No difference in all-cause mortality

between patients randomly assigned to

ICD therapy VS medical therapy.

•The rate of SCD higher in the control

group

•The number of non sudden cardiac

deaths higher in the ICD arm

Significant recovery of ventricular function may have occurred in some of the patients which would dilute the long-term benefit of the ICD in such patients.

Some SCD events in the early postinfarction period may have been due to recurrent ischemia which would not be definitively treated by ICD discharge

ICD implantation might impose additional risk in these patients immediately post-MI.

The enrollment requirements of reduced heart rate variability in DINAMIT and resting heart rate ≥90 beats/min in IRIS could have selected a group of patients with a high mortality from nonarrhythmic causes .

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COMPARISON OF TRIALS

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ICD IN NONISCHAEMIC CMPY

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DEFINITEDefibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation

N Engl J Med 2004;350:2151-8. 46

•LVEF < 36%•Nonischemic DCMPY•PVCs or NSVT

INCLUSION CRITERIA

N=229 standard

medical therapy

N=229 standard medical

therapy + ICD

N=458

RANDOMIZATION

•The primary end point of the study was death from any cause

•Sudden death from arrhythmia was a pre-specified secondary end point

STUDY PERIOD – 1998-2002

EXCLUSION CRITERIA• NYHA CLASS IV• THOSE WITH PPI

• HEART TRANSPLANT ELIGIBLE

RESULTS

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HR for death from any cause was 0.65 (95% C.I 0.40 to 1.06)

HR for sudden death from arrhythmia was 0.20 (95 % C.I 0.06 to 0.71)

RESULTS

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RESULTS

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COMPARISON OF TRIALS

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ICD COMBINED WITH CRT

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COMPANION trial — The Comparison Of Medical Therapy, Pacing, And Defibrillation In Heart Failure (COMPANION) trial

1520 patients

NYHA class III-IV HF LVEF ≤35 percent Lbbb > 120 msec Nearly half of all patients enrolled had a nonischemic etiology of HF.

Randomly assigned to optimal medical therapy, CRT alone, or CRT+ICD

The primary end point was a composite of death from any cause or hospitalization for any cause

Secondary end point - death from any cause

52NEJM 350:21 MAY 2004

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Results

CRT+ICD , as compared with optimal pharmacologic

therapy, was associated with a 27% reduction in the risk of

death from any cause in the subgroup with ischemic CMPY

(HR for death, 0.73; 95% C.I, 0.52 to 1.04) & a 50 %reduction in nonischemic CMPY

CONCLUSION Patients with advanced heart failure and a prolonged QRS

interval, CRT decreases the combined risk of death from any cause or first hospitalization and, when combined with an ICD, significantly reduces mortality

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MADIT

EPS

MUSTTMADIT IILVEF

SCD-HeFT

COMPANION QRS≥120

DEFINITE

PVCNSVT

SCD-HeFT

COMPANION

LVEF

QRS≥120

THANK YOU

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