Sudden Cardiac Death in Patients with Left Ventricular ...fiaiweb.com/wp-content/uploads/2019/07/WEB-CRT-Update-Final.pdf · HFSA Late-Breaking Clinical Trials, September 24, 2003

Sudden Cardiac Death in Patients with Left

Ventricular Dysfunction: Focus on Primary Prevention

with ICDsAndrew E. Epstein, MD Professor of Medicine

Division of Cardiovascular DiseaseThe University of Alabama at Birmingham

Birmingham, Alabama

Moss et al. N Engl J Med 2002;346:877-83.

ICD

Conventional

P = 0.007

1.0

0.9

0.8

0.7

0.6

0.0

Probability of Survival

0 1 2 3 4Year

MADIT II: Probability of Survival in ICD vs Conventional Therapy Group

No. At Risk Defibrillator 742 502 (0.91) 274 (0.84) 110 (0.78) 9 Conventional 490 329 (0.90) 170 (0.78) 65 (0.69) 3

• Trial stopped at 20 months • Reduction in death rate with

ICD Rx: 12% at 1 yr, 28% at 2 yrs, 28% at 3 yrs

Comparison of Medical Therapy, Pacing and Defibrillation Therapies in Heart Failure (COMPANION) Trial

• NYHA Class III or IV • NSR, QRS ≥120 ms, PR interval >150 ms • LVEF ≤35%, LVEDD ≥60 mm • Optimal pharmacological therapy (OPT)

• β-blocker (for at least 3 months) • Diuretic, ACEI/ARB, spironolactone (1 month) • Digoxin

• HF hospitalization (or equivalent) in prior 12 months, >1 month prior to enrollment

COMPANION Design

• OPT • CRT w/ ICD Backup

+2

• OPT • CRT

+2

Randomization Stratification

Baseline Implant Follow-up Follow-up Follow-up

Follow-up Follow-up Follow-up

Implant Follow-up Follow-up Follow-up

• OPT

1

<5 Days 0 <2 Working Days One Week One Month Quarterly

Time Post-Randomization

Endpoints Primary: Combined all-cause mortality and all-cause hospitalization Secondary: Morbidity and survival Substudy: QoL

HFSA Late-Breaking Clinical Trials, September 24, 2003. Bristow MR, et al. N Engl J Med 2004;350:2140-2150.

0

20

40

60

80

100

Days from Randomization

Patie

nts

Even

t-fre

e (%

) OPT CRT HR .80 (CI: .68-.94) CRT-D HR .80 (CI: .67-.94)

0 120 240 360 480 600 720 840 960 1,080

12-Month Event Rates OPT: 68% CRT: 55% (AR=13%) CRT-D: 56% (AR=12%)

CRT vs OPT: RR=20%, P=.008 (Critical boundary=.014) CRT-D vs OPT: RR=20%, P=.007 (Critical boundary=.022)

COMPANION: Primary Endpoint: Mortality+Hospitalization

50

60

70

80

90

100

Days from Randomization

OPT CRT HR .76 (CI: .58-1.01) CRT-D HR .64 (CI: .48-.86)

0 120 240 360 480 600 720 840 960 1,080

12-Month Event Rates OPT: 19% CRT: 15% (AR=4%) CRT-D: 12% (AR=7%)

CRT vs OPT: RR=24%, P=.060 (Critical boundary=.014) CRT-D vs OPT: RR=36%, P=.003 (Critical boundary=.022)

Patie

nts

Even

t-fre

e (%

)COMPANION:

Secondary Endpoint: All-Cause Mortality

HFSA Late-Breaking Clinical Trials, September 24, 2003. Bristow MR, et al. N Engl J Med 2004;350:2140-2150.

CRT Improves QoL and NYHA Functional Class

Average Change in QoL Score (MLWHF)

-18

-13,5

-9

-4,5

0

MIR

ACLE

(1)

MUS

TIC

SR (2

)M

USTI

C AF

(3)

CONT

AK C

D (4

)M

IRAC

LE IC

D (5

)

ControlCRT

* * * *

* P<0.05

NYHA: Proportion Improving 1 or More Class

0 %

20 %

40 %

60 %

80 %

MIRACLE (1) MIRACLE ICD (5)

ControlCRT

**

*

1Abraham WT et al. N Engl J Med. 2002;346:1845-1853. 2Cazeau S. N Engl J Med. 2001;344:873-80. 3Leclercq C et al. Eur Heart J. 2002;23:1780-1787.4http://www.fda.gov/cdrh/pdf/P010012b.pdf. Accessed August 2, 2002. 5Young JB et al. JAMA. 2003;289:2685-2694.

Favors CRT Favors No CRT

0.1 0.5 1.0 2.0 3.0

Heart Failure Mortality in Meta Analysis of CRT Trials

Odds Ratio (95% CL)

CONTAK CD (n=490)

InSync ICD (n=554)

MIRACLE (n=532)

MUSTIC (n=58)Overall

Bradley et al. JAMA 2003; 289: 730

Sudden Cardiac Death in Heart Failure Trial: SCD-HeFT

CAD and DCM NYHA II and III

LVEF ≤0.35 No prior VT or VF

Conventional Rx +

Placebo

Conventional Rx +

Amiodarone

Conventional Rx +

ICD

Randomize

Double blind Endpoint: Total Mortality

0

.1

.2

.3

.4

Months of Follow-Up

Mor

talit

y

Amiodarone ICD Therapy Placebo

0 6 12 18 24 30 36 42 48 54 60

HR 97.5% CI P Value Amiodarone vs Placebo 1.06 .86, 1.30 .529 ICD Therapy vs Placebo .77 .62, 0.96 .007

SCD-HeFTMortality by Intention-to-Treat

Bardy GH, et al. N Engl J Med 2005;352:225-237.

CARE-HF 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 investigate the mechanisms underlying the observed effect to identify markers predicting success or failure of CRT

Cleland JG, et al. N Engl J Med 2005;352:1539-1549.

CARE-HF Primary Endpoint

(All-cause Mortality or Unplanned Hosp. for Major CVS Event)

348118232292404Medical Therapy768166273323409CRT

Number at risk 0 500 1000 15000.00

0.25

0.50

0.75

1.00

HR 0.63 (95% CI 0.51 to 0.77) P < .0001

Even

t-fre

e Su

rviv

al

Days

CRT

Medical Therapy


CARE-HF All-Cause Mortality

571192321365404Medical Therapy889213351376409CRT

Number at risk 0 500 1000 15000.00

0.25

0.50

0.75

1.00Ev

ent-f

ree

Surv

ival

Days

Medical Therapy

HR 0.64 (95% CI 0.48 to 0.85) P = .0019

CRT


Recovery of LV Function Post MI• 261 patients in HEART (ramipril) trial, all

with reperfusion therapy • Day 1, 9/261 had normal LV function (EF ≥0.55, 3.4%)

• 171/261 (66%) had improvement in EF (0.05 ± 0.10). Final EF 0.57 ± 0.96

• Of 252 patients with EF <0.55: • 13% complete recovery by day 14 • 22% complete recovery by day 90 • Additional 36% had partial recovery by

day 90 ➔ Early dysfunction often improves

Solomon et al. Ann Intern Med 2001;134:451-8

Reasons for Nonresponse• Inappropriate patient selection

• End stage • No dyssynchrony • No correctable dyssynchrony

• Too strict definition of response • Is prevention of disease progression “response”?

• More attention needs to paid to VV timing and AV delays

Procedural Outcomes and Complications in COMPANION Trial

0

3,8

7,5

11,3

15

CRT (n=617) CRT-D (n=595)

%

Implant death

Perforation Any LVlead AE

Lead implant failure

1.3% 1.8% 6.3% 13%0.8% 0.8% 4.7% 9%

Saxon et al. Circulation 2004:110:111.

Cardiac Resynchronization TherapyEntry Criteria Randomized Trials

Study (n) NYHA QRS EF Status

MIRACLE (524#) III, IV ≥130 < 35% Published

MUSTIC SR (58) III >150 < 35% Published

MUSTIC AF (43) III >200* < 35% Published

PATH CHF (42) III, IV ≥120 < 35% Published

CONTAK CD (581¥) III-IV ≥120 < 35% Published

MIRACLE ICD (362^) III-IV ≥130 < 35% Published

PATH CHF II (89) III, IV ≥120 < 35% Published

COMPANION (1520) III, IV ≥120 < 35% Published

CARE HF (800) III, IV ≥120† < 35% Published

MIRACLE ICD II (186) II ≥130 < 35% Presented

PACMAN (328) III ≥150 < 35% Enrolled

VecToR (420) II-IV ≥140 < 35% Enrolling

From WT Abraham

No Randomized Trials Used an Imaging

Dyssynchrony Study

Should all Patients with CHF get a CRT Device?

LBBB QRS >120ms NYHA III,IV EF <35%

NSR Optimal Med Rx

IVCD / RBBB QRS 100-120ms

NYHA II (I) EF 35-40%

AF Optimal Med Rx

Straight Shot Longer Shot

CRT / ICD

ECHO Dyssynchrony

YES No ??Courtesy of Kenneth A. Ellenbogen, MD

Pacemaker and ICD Malfunctions

Maisel WH, et al. JAMA 2006; 295:1901-1906.

Pacemakers n=8834 ICDs n=8489 Devices explanted and malfunction confirmed

• Over 200,000 ICDs are implanted or replaced annually in patients who are at risk for SD.

• In 2005 over 150,000 ICDs were the subject of recalls or safety alerts by their manufacturers.

• A recent Food and Drug Administration study suggested that ICD malfunctions are increasing.

• The Multicenter Registry is funded entirely by a grant from the Minneapolis Heart Institute Foundation, and is supported by the voluntary efforts of its participants.

The Multicenter Registry Investigators American College of Cardiology, 2006

Multicenter Experience With 1,355 Failed and Recalled Implantable Cardioverter Defibrillators

Objective

• The aim of the present study was to examine the failure modes and implant times of contemporary ICD pulse generators in that had failed, or were replaced due to manufacturers recalls.

• We also evaluated the causes and major adverse clinical events associated with ICD failure and replacement.



Methods

• 9 centers in the U. S. and Canada. • Failure reports entered via Internet since 4/99:

Manufacturer and model Dates of implant and failure Signs of failure and clinical consequence Cause of failure

• A pulse generator failed if it was not performing according to its intended use, or as described in the manufacturer’s published specifications. A normally functioning device that was replaced, removed, or abandoned as the result of a manufacturer’s recall was a failure.

PACE 2001; 24:82-87.

Methods (2)• Categories of ICD pulse generator failure included: Normal battery depletion (ERI)

Premature battery depletion (ERI ≤ 3 yrs) Electronic or housing malfunction Replacement for Recall-Advisory Unknown

• Cause of failure was determined by the reporting center based on clinical and technical evaluations and manufacturers reports.

PACE 2001; 24:82-87.

0

10

20

30

40

50

60

70

80

Normal Battery

Depletion

Recall Advisory

Premature Battery

Depletion

Electronic Housing

Malfunction

Unknown

Perc

ent o

f Pul

se G

ener

ator

s73%

10% 9%6% 2%

Causes of ICD Failure

1,355 Pulse Generators

N= 988 135 122 85 25The Multicenter Registry Investigators American College of Cardiology, 2006

ICD Types and Manufacturers

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

All Single Dual Single-R Dual-R CRT-D

Guidant Medtronic St. Jude

N= 1,355 791 35 93 388 48% = 58% 29%3% 7% 4%100%

All Dual Single Single-R Dual-R CRT-D


Causes of Failure for Each ICD Type

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%


Normal Battery Depletion

Recall Premature Battery Depletion

Electronic Housing


0

1

2

3

4

5

6

Dual Single Dual-R Single-R CRT-D All

Year

s

79135 93388 48 1,355N =

p < 0.001

5.14.8

3.4

2.5

1.9

4.1

Average Implant Time of Failed ICDs

% = 3% 58% 29% 7% 4% 100%The Multicenter Registry Investigators American College of Cardiology, 2006

Average Implant Time of Failed ICDs According to Cause of Failure

0

1

2

3

4

5

6

Years


Normal Battery Depletion

Recall Premature Battery Depletion

Electronic Housing


0

10

20

30

40

50

60

70

80

90

100

1 5 9 13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97 101 105

Years After Implant

Perc

ent F

unct

ioni

ng

1 2 3 4 5 6 7 80

ICDs with and w/o Rate Response

Years After Implantation 0 1 2 3 4 5 6 7 8

Rate Response

No Rate Response

P< 0.001


0 10 20 30 40 50 60 70 80 90 100

Percent

CRT-D

Single-R

Dual-R

Dual

Single

AlI

3 years4 years5 years

Proportion of Failed ICDs That Were Functioning 3, 4, & 5 Years After Implant

Percent Functioning

27%


Major Adverse Clinical Events• 20 patients had a major adverse clinical event. • 1 patient died due to short-circuiting during shock

delivery. • 1 patient died of a stroke following replacement of a

normally functioning recalled device. • 4 patients were rescued when their devices failed to

treat VT/VF during device testing. • 3 patients experienced syncope due to battery

depletion (2) and electronic component failure. • 11 patients received inappropriate shocks caused by

electronic and housing defects.


Limitations• Average implant time may significantly

underestimate device longevity when compared to actuarial survival data.

• The longevity of an ICD pulse generator is the result of a complex interplay between multiple hardware components, the ICD lead, and the individual patient’s needs for therapy, energy requirements for pacing and defibrillation, and diagnostic information including electrograms. We did not evaluate all these variables.


Conclusions• Based on this analysis of failed ICDs, the

performance of ICDs, particularly those offering advanced pacing capabilities, has been adversely affected by early battery depletion, electronic or housing failure and recalls.

• A comprehensive, independent national registry is needed to accurately estimate ICD longevity and determine the incidence of unexpected failure modes and adverse clinical events.


Complications Associated with ICD Replacement in Response to Advisories:Canadian Heart Rhythm Society Working Group on Device Advisories

• 17 Centers, 2915 recalled devices • 533 (18.3%) replaced

• 66% primary prevention

• Complications in 43 pts (8.1%) • Major requiring reoperation: 31 pts (5.8%) • Death: 2 pts • Minor complications: 12 pts (2.3%) • Of explanted devices, 3 (0.1%) had malfunction (early battery depletion),

none with clinical consequence.

Gould et al. JAMA 2006; 295:1907-1911.

Indications for ICD TherapyClass I • Cardiac arrest due to VF or VT not due to a transient or reversible

cause • Spontaneous sustained VT in association with structural heart disease • Syncope of undetermined origin with clinically relevant,

hemodynamically significant, sustained VT or VF induced at EP study when drug therapy is ineffective, not tolerated, or not preferred

• Nonsustained VT in patients with coronary disease, prior MI, LV dysfunction, and inducible VF or sustained VT at EP study that is not suppressible by a Class I antiarrhythmic drug.

Class II • Patients with LVEF ≤.30, at least 1 month post MI and at least 3 months

post coronary revascularization surgery

Gregoratos G, et al. Circulation. 2002;106:2145-2161.

Class II

• Medically refractory, NYHA Class III or IV heart failure despite optimal medical therapy

• Ischemic or nonischemic cardiomyopathy with

• QRS ≥130 ms

• LVEF ≤0.35

Indications for Resynchronization Therapy

Gregoratos G, et al. Circulation. 2002;106:2145-2161.

Summary• Multiple RCTs have shown that CRT:

• Is safe and well tolerated improves quality of life, functional status, and exercise capacity.

• Improves cardiac structure and function. • Reduces hospitalization and mortality with or without ICD backup.

• Studies needed to risk stratify, identify likely responders, and new groups who may benefit from CRT.

• Reliability/advisory issues recognized and need guidelines for management.

Documents

Sudden Cardiac Death in Patients with Left Ventricular ...fiaiweb.com/wp-content/uploads/2019/07/WEB-CRT-Update-Final.pdf · HFSA Late-Breaking Clinical Trials, September 24, 2003