Sudden Cardiac Death Prevention: Clinical Trials

Alena Goldman, MD

September 9, 2004

Introduction

SCD: common problem in patient with:

-CAD-LV dysfunction-asymptomatic ventricular arrhythmias

Introduction

- Most sudden deaths and cardiac arrests are due to reentrant VT or VF

- ICD (implantable cardioverter defibrillator) has become primary therapeutic modality for secondary prevention of SCD, and in some patients groups, for primary prevention

Secondary Prevention

• CASH trial (Cardiac Arrest Survival in Hamburg): 23% reduction in mortality in survivors of cardiac arrest receiving ICD vs amiodarone/metoprolol

• CIDS trial (Canadian Implantable Defibrillator Study): ICD vs amiodarone; no mortality difference

• AVID trial (Antiarrhythmic Drug vs Defibrillator): 1016 pts; trial stopped when survival benefit noted in patients treated with ICD vs amiodarone and d,l sotalol

Risk Stratification Strategies

Subgroup analysis of AVID trial:

1. LVEF>35%: no difference in survival between ICD and antiarrhythmic drugs

2. Etiology of Heart Disease (most evidence for coronary heart disease and dilated cardiomyopathy)

3. Effects of shock: recurrence of shocks is independent predictor of poor outcome

Risk Stratification Strategies, cont’d

• Effects of Electrical Storm: >3 episodes of VT/VF in 24 hours; increased risk for cardiac nonsudden death (MI)

• Mode of Death: ? Due to electromechanical dissociation rather than recurrent ventricular tachyarrhythmias

Primary Prevention: Who is at High Risk?

ACC/AHA/NASPE task force recommendations:

1. Patients with CHD; prior MI; LV dysfunction; h/o NSVT; with inducible sustained VT/VF at EPS (without suppression by class I antiarrhythmic)

2. Patients with syncope with inducible sustained VT/VF at EPS when antiarrhythmic therapy not effective, not tolerated, not preferred

Ischemic Cardiomyopathy Primary Prevention Trials

• MADIT I

• MUSTT

• MADIT II

• CABG Patch

• CAT

MADIT I (NEJM, December 1996)

Why care?

30% 2 year mortality in patients with unsustained VT and h/o previous MI and LV dysfunction

Aim of trial:

To show that prophylactic implantation of ICD, as compared to conventional medical therapy, would improve survival in high risk patients

MADIT I, Cont’d

Methods/Inclusion Criteria:-25-80 yo-h/o MI 3 weeks prior to study-NYHA class I,II,or III-LVEF <0.35-documented asymptomatic unsustained VT

(3-30 beats)-no indications for CABG

MADIT I; Cont’d

Exclusion criteria:-previous cardiac arrest or VT/syncope not

associated with MI-symptomatic hypoT while in stable rhythm’-recent MI (within 3 weeks)-CABG within past 2 months-coronary angioplasty within past 3 months-pts with cerebrovascular disease

MADIT I

Eligible Patients

EPS

Induced VT yes no Suppression with Procainamide conventional therapy (n=101)yes no (n=196) ICD (n=95)

MADIT I

Statistical Analysis:

-designed to have 85% power to detect 46% reduction in mortality rate

-Triangular sequential design modified for two sided alternatives in order to terminate trial once one of boundaries is reached

-transthoracic and transvenous ICDs used; analysis stratified based on device type

MADIT I: Results

-efficacy boundary of sequential design crossed when 51 deaths were reported study stopped

-superiority of ICD vs conventional therapy, i. e. survival difference (p 0.009); 95% CI 0.26-0.82

-Kaplan-Meier curves separate early and remain separated for 5 years

Conventional ICDCardiac death 27 11Noncardiac 6 4Unknown 6 0Total 39 15

MADIT I: Discussion

-significant reductions in incidence of overall mortality, cardiac mortality and arrhythmic deaths in patients with ICD group

-subset analysis:

Survival benefit only in patients with more severe heart disease (LVEF<26%; CHF requiring therapy; QRS duration >12 sec)

MADIT I: Limitations

-Selected patients are less likely to respond to antiarrhythmic drug (since selected only non-reponders to procainamide)

-More patients in ICD group were receiving beta-blocker

-antiarrhythmics may increase mortality via proarrhythmic effect

-no “treatment free group”

MADIT II; NEJM Mar 2002

Why care?Criticism of MADIT I: prognostic value of

negative EPS is uncertain

Aim:To show potential survival benefit of a

prophylactically implanted ICD (in the absence of EPS) in patients with prior MI and LVEFof 0.30 or less

MADIT II: Inclusion Criteria

-age >21

-h/o prior MI (one month or more before trial)

-LVF of .30 or less

Random assignment in 3:2 ratio to get either ICD or conventional medical therapy

MADIT II: Exclusion Criteria

-FDA approval for ICD

-NYHA class IV at enrollment

-CABG within 3 months

-MI within past month

-Cerebrovascular disease

MADIT II: Analysis

-death from any cause as primary end point-intention-to-treat analysis-95% power to detect 38% reduction in 2

year mortality rate among patients in defibrillator group

-triangular sequential design-trial stopped in 2001 after the upper

boundary (ICD superiority) was reached (p=0.027)

MADIT II: Results

-1232 patients enrolled: 742 patients in ICD group; 490 patients in conventional medical therapy group

-mean follow up 20 months# deaths ICD group Conventional group 105(14.2%) 97(19.8%)-Superiority of ICD therapy (p 0.016)-Kaplan-Meier survival curves diverge at 9 months -no difference in effects on survival in subgroups based on

age, sex, ef, NYHA class or QRS interval (with exception of less benefit with EF>25%)

MADIT II

Adverse effects:

-Higher incidence of new or worsened heart failure in ICD group (p 0.09)

MADIT II: Discussion

-31% risk reduction in risk of death with prophylactic ICD implantation in patients wit h/o MI and LVEF of 0.30 or less

-benefits begin 9 months after device implantation (? Due to absence of stratification for arrhythmia vs better medical management vs lower EF cut-off as compared to MADIT I)

-more CHF in ICD group (? Higher inidence pf progression to heart failure as a result of SCD prevention vs result of multiple ICD shocks)

-Criticism: cost effectiveness/need for other invasive/noninvasive markers of risk for further stratification

MUSTT Trial (NEJM, Dec 1999)

Why care?

No reduction in mortality with empirical antiarrhythmic therapy in patients with CAD and asymptomatic ventricular arrhythmias

Aim:

To investigate whether antiarrhythmic therapy guided by EPS might reduce risk of SCD

MUSTT: Methods

Inclusion Criteria:

-CAD

-LVEF of 40% or less

-asymptomatic nonsustained VT

Exclusion Criteria:

-h/o syncope or sustained VT/VF >48 hours after onset of MI

-unsustained VT in the setting of ischemia, metabolic disorders, or drug toxicity

MUSTT: Methods

Patients

EPS negative registry n 1435

induced VT/VF (n 704)

Antiarrhythmic ICD No therapyN 154 after at least one n 353

unsuccessful drug

n 161

MUSTT: Statistics

-intention to treat analysis

-primary end point: cardiac arrest or death from arrhythmia

-secondary end point: all cause mortality; cardiac causes; sustained VT

MUSTT: Results

Nonantiarrhythmic medical therapy:

-use of beta-blockers: more frequent in nonantiarrhthmic group

Antiarrhythmic therapy:

-medications (class I agents, 26%; amiodarone, 10%; sotalol, 9%) and ICD

Mean of 39 months of follow up

MUSTT: Results

Kaplan-Meier Curve: rate of cardiac arrest or death (primary end point) and overall mortality (secondary end point)

2yrs 5yrs primary secondary primary secondary

No therapy 18% 28% 32% 48%

EPG therapy 12% 22% 25% 42% p 0.04 p 0.06

MUSTT: Results

-Lower rates of arrhythmic events in EPG therapy largely attributed to ICD:

5 yr rate 5 yr rate primary end point overall mortalityEPG therapy with ICD 9% 24%

EPG therapy without ICD 37% 55% p<0.001 p<0.001

-No Difference in outcome between people receiving no therapy and treated with antiarrhythmc drugs

MUSTT: Discussion

-EPG antiarrhythmic therapy leads to absolute reduction in the risk of cardiac arrest or death of 7% at 5 years

-Survival benefit is solely due to use of ICD-ICD was shown to improve overall survival-Rate of cardiac arrest or death from

arrhythmia in group assigned to no antiarrhythmics is 18% per 2 years (similar to reported studies)

MUSTT: Discussion, Cont’d

-Patients who had at least one unsuccessful antiarrhythmic drug test have poorer prognosis if they did not receive ICD

-Antiarrhythmic drug therapy did not improve survival

-? Whether EPS is more useful in patients with EF of 30 to 40 %

Take Home Points

• Prophylactic ICD is most cost effective in patients with lower LVEF

• QRS width is important• EPS is important for risk stratification (although

negative EPS does not rule out risk of SCD)• ICD is superior to antiarrhythmic drugs in

preventing SCD in post MI patients with depressed EF

• Need for other methods of risk stratification in MADIT II patients (TWA)