Future of ICD Trials

David S. Cannom, M.D. Medical Director of Cardiology

Hospital of the Good Samaritan

Clinical Professor of Medicine a

Keck Medical School at USC

Los Angeles, California

July 13, 2020

ar

40 Years Ago ICD Trials Were

Necessary

● Sudden cardiac death had been identified as a

major unsolved public health issue

● Two widely different clinical approaches were

available for SCD survivors: serial drug testing

versus the newly available ICD

● Bernard Lown MD at Harvard and Michel

Mirowski MD and Morton Mower MD at Johns

Hopkins developed different clinical

approaches to the SCD patient

Bernard Lown

● Born in 1921 in Lithuania, the son of a rabbi

● Received his MD from Johns Hopkins in 1945; trained at

Yale and took his cardiology at the Peter Brent Brigham

Hospital with Samuel A. Levine

● Until the 1950s ventricular fibrillation could only be

treated with drugs. Defibrillation of the heart was first

done in 1956 by Paul Zoll with AC current which injured

the heart. In 1961, Lown used direct current to safely

reverse VF.

● In 1961 he founded Physicians for Social Responsibility to

address the mounting threat of nuclear war between the

USSR and USA; in 1985 he accepted the Nobel Peach

Prize

Bernard Lown and Evgeny Chazov

● Bernard Lown pioneered the study of sudden death in the

CCU in the 1960s and extrapolated his CCU experience to

targeting patients at risk for SCD

● Lown showed that CCU protocols in AMI patients could

reduce arrhythmic mortality by 30%. Lown’s approach was

to quantify VPBs in a CAD patient at risk for sudden death

and then attempt to supress the VPBs with antiarrhythmic

drugs

● Meds tried included high dose quinidine, procainamide,

propranalol, dispyramdie, metoprolol, mexiletine, ethmozine

● Lown knew that antiarrhythmic drugs in animals with an

acute MI varied in their efficacy

Lown and Wolf, Circulation 1971; XLIV

Grade of VPB Related to

Duration of Monitoring

Grade Observed

0 No ventricular ectopic beats

1 Occasional, isolated VPB

2 Frequent VPB (>1/min or 30/hr

3 Multiform VPB

4 Repetitive VPB

(a) Couplets

(b) Salvos

5 Early VPB

0

25

50

75

100

1 2 4 6 8 10 12

Hours of Monitoring

% P

ati

en

ts R

each

ing

Maxim

um

Gra

de

All Grades

Grade 4 and 5

Lown and Wolf, Circulation 1971; XLIV

0 12 24 36 48 60 72

Months

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

bab

ility

of

Su

rviv

al

ControlNo Control

EF

Arrhythmia Control

Total Yes No

<0.50 32 12 44

>0.50 29 6 35

Total 61 18 79

5.5%/yr

52.5%/yr

Long-Term Survival of Patients with Malignant Ventricular

Arrhythmia Treated with Antiarrhythmic Drugs Thomas B. Graboys, MD; Bernard Lown, MD; Philip J. Podrod, MD; Regis DeSilva, MB, FRCP

Boston, Massachusetts

• 79 VT/VF pts (60% CAD)

• Effective drug response = elimination

(4B,5 salvos or early VPCs) or

reduction (4A - couplets) of ectopy

• Control (61 pts) 5.5% annual SCD vs

52.5% no control AJC 1982;50:437-443

Protection Against SCD

“It is already becoming possible to protect the patient

who has been resuscitated from VF against recurrence

of cardiac arrest. Essential elements of a prophylactic

program involve the use of anti-arrhythmic drugs.

Therapy, however, needs to be individualized. The

objective of treatment is reduction in frequency or

complete abolition of advanced grades of VPCs rather

than suppression of all ectopic activity”

Circulation 60, No. 7, 1593-1599, 1979

Michel Mirowski, MD

● Born in Warsaw in 1924, had a classic education in Latin,

French, Hebrew

● Left Warsaw with his family in 1939, tried to enroll in Russian

Army, then went to Kiev where he worked manufacturing

cigarettes. Also worked in an airplane factory. All his family

had been killed by 1945.

● He went to Tel Aviv where he worked as shoe salesman; finally

in 1947 he entered medical school in Lyon and graduated in

1953.

● He went back to Tel Aviv and worked on the Heart Station. His

chief was Dr. Harry Heller who died suddenly in 1966

Michel Mirowski, MD

● He studied with Dr. Helen Taussig in Baltimore in 1960 for 2

years and published 14 papers.

● In 1968 became Director of the CCU at Sinai Hospital in

Baltimore which was an affiliate of Hopkins. There he met Dr.

Morton Mower who was a talented cardiologist and engineer.

They began work on the defibrillator in 1969. Dr. John Kastor

wrote that “Michels creativity and Mort Mowers tinker

capability fit well together”

● One of Mirowski’s favorite quotes was “don’t give up, don’t

give in and beat the bastards”

Drs Mirowski and Mower propose a

new approach

1970-71: discussions at Medtronic with prototype of device

1980

The 1st device

Lown & Axelrod – Circulation

Editorial 1972;46:637-639

Letters to Editor 1973;47;1135-1136

Fraught with multitude of technical difficulties

Sensing of VF a difficult problem, probably insurmountable

Electric discharges can damage heart

No method to test operational readiness

No way of identifying candidates

Once in body, no way of testing device

Drugs a better way to treat bouts of VF

Authors engage in minor polemics

Wasteful of societal resources

Concept lacks common sense

Arthur Moss MD defended M & M

M.Mower A.Moss M. Mirowski

Implanted Standby Defibrillators

“Since when have answers to such questions been

required before research is undertaken? Are Drs. Lown

and Axelrod so clairvoyant that they can see the

ultimate impracticality of someone else’s research

energies thereby prematurely labeling that work ‘an

imperfect solution in search of a plausible and practical

application?’ Fortunately, sincere investigators will

continue to attach problems even when the prospect of

solution is slight and when sensible people shake their

heads.”

Arthur J. Moss, M.D.

University of Rochester School of Medicine and Dentistry

Rochester, New York

EP Climate at Initiation of

Prophylactic ICD Trials (~1990)

● Uncertainty about role of ICD

(VT surgery, EPS-guided drug trials popular)

● All ICDs epicardial

(4-5% operative risk)

● No secondary prevention ICD trials completed

● Long hospital stays

● Many physicians thought such trials unethical

866 pts Post-MI; 1979-1981;

4 Variables Predicted Risk in Year after MI

Factor Relative Risk Chi-

Square P Value

Ejection fraction <0.40 2.4 12.3 <0.001

VPDs >10/hr 1.6 3.8 <0.05

Rales > Bibasilar 3.3 20.5 <0.001

NYHA class II-IV 1.9 8.1 <0.01

NEJM 1983;309:331-6

Moss, et al.

NEJM 1983;309:331

0

10

20

30

40

50

0 15 30 45 60 75

Radionuclide Ejection Fraction (%)

% O

ne

-Yea

r C

ard

iac M

ort

alit

y

(<20%)

n=799mean EF = 46%

(20-39%)

(40-59%)( 60%)>

n 21 244 382 152

MUSTT

SCD HeFT

MADIT II

MPIP

Major Implantable Cardioverter-Defibrillator Trials for

Prevention of SCD

Trial

Year

Pts.

(n)

Inclusion Criteria:

LVEF % <

Other Inclusion

Criteria

H.R.

95% C.I.

P

MADIT I 1996 196 35 Prior MI, NSVT and

+ EP

0.46 0.26 to 0.82 0.009

MADIT II 2002 1232 30 Prior MI 0.69 0.51 to 0.93 0.016

CABG-Patch 1997 900 36 + SAECG & CABG 1.07 0.81 to 1.42 0.63

DEFINTE 2004 485 35 NICM, PVCs, or

NSVT

0.65 0.40 to 1.06 0.08

DINAMIT 2004 674 35 6-40 days after MI

& Impaired HRV

1.08 0.76 to 1.55 0.66

SCD-HeFT 2005 1676 35 Prior MI or NICM 0.77 0.62 to 0.96 0.007

Characteristics of

the MADIT Family of Trials Trial Acronym MADIT-II MADIT-CRT MADIT-RIT

No. of Patients 732 1820 1500

Enrollment years 1997-2001 2004-2008 2009-2011

Randomized

Comparison

ICD vs. medical

management

CRT-D vs. ICD CRT-D and ICD

Inclusion criteria LVEF <30%

Prior MI

LVEF <30%

Ischemic or non-

ischemic

NYHA I-II

LVEF <35%

Ischemic or non-

ischemic

ICD or CRT-D

indication

Average follow-up

duration

20 months 40 months 17 months

Years 1997 2004 2011

Incidence of Sudden Cardiac Death

0 10 20 30 0 150,000 300,000

Percent Absolute Number

Incidence Events

Generalpopulation

High-risksubgroups

Any priorcoronary event

EF <30% orheart failure

Cardiac arrestsurvivor

Arrhyhmia riskmarkers, post MI

MADIT II SCD-HeFT

AVID, CIDS, CASH

MADIT I, MUSTT

● After MADIT I, II, & MADIT CRT, Drs Moss and

Kutiyifa were interested in other risk markers

besides EF and HF in a next generation of ICD

trials

● Diabetes as a risk factor in CAD patients in the

literature predicted a two fold increase in

mortality across all ejection fractions

● A trial hypothesis and sample size prediction

was developed over two years in an iterative

process led by Dr A. Moss with support of

industry

Planning for the next ICD trial

MADIT S-ICD

To test the hypothesis that post-MI diabetic

patients with relatively preserved ejection

fraction will have life-saving benefit from the

subcutaneous implantable cardioverter

defibrillator

Randomized, 2-arm study using Boston Scientific S-ICD devices

MADIT S-ICD Study Terminated

● Study Design:

» 2:1 Randomization (S-ICD:CMT)

● Planned Enrollment:

» 1800 men and women from 150 centers in the United States,

Europe, and Israel enrollment was discontinued June 20,

2018

● Participants:

» 40 men and women from 21 centers in the United States,

Europe, and Israel

» Follow-up continues per original study protocol

● Average length of follow-up:

» Planned follow-up for a minimum of 5 years

What Does the Future Hold 73 trials in progress;

No randomized ICD trials in new populations; Smaller topics studied Title Status Study

Results

Conditions Interventio

ns

Locations

Implantable

Cardioverter

Defibrillator (ICD

Registry)

Recruiting No

Results

Available

•Heart Failure

•Nonischemic

Cardiomyopathy

• Ischemic Cardiomyopathy

•Ventricular Arrhythmia

•Complications; Device,

Cardiac

American College of

Cardiology/National

Cardiovascular Data

Registry (NCDR),

Washington, District

of Columbia, United

States

Evaluation of Novel

Biomarkers to

Improve Risk

Stratification and

Patient Selection in

ICD Therapy

Active,

not

recruiting

No

Results

Available

•Ventricular Arrhythmias

•Cardiac Death

Hannover Medical

School, Hannover,

Germany

Pilot Randomized

Trial with Flecainide

in ARVC Patients

Not yet

recruiting

No

Results

Available

•Arrhythmogenic Right

Ventricular

Cardiomyopathy

•Drug:

Flecainide

Pill

•Drug:

Placebo

University of

Rochester Medical

Center, Rochester,

New York, United

States

● Randomized trials on the feasibility of risk stratification

with invasive electrophysiological study early after

myocardial infarction are warranted.

● More than a decade has passed since the publication

of landmark RCTs on primary prevention of SCD.

Patients profiles and medical treatments have changed

significantly since then: today’s patients are old and

have more co-morbidities such as AF, chronic kidney

disease and others. Thus new clinical trials are needed

to assess the potential benefit of primary prevention of

SCD with an ICD for todays’ patient population.

European Heart Journal 2015.36:2793-2867

Definition of Innovation

“Something is innovative when it is

new, better, and can be applied to a

large patient population. In the field of

medicine it has to be easier, accessible

and inexpensive to patients”

Thomas J. Fogarty M.D.

March, 2013