ICD in Non-ischemic cardiomyopathy

ICD in Non-ischemic
cardiomyopathy
Presenter
Praveen Gupta
Moderator
Dr Raja Selvaraj
Department of cardiology
JIPMER
Pondicherry
20-06-2018

Introduction
 Multiple randomized reported role of the ICD in primary prevention of SCD in
patients with nonischemic DCM
 30% of deaths in patients with DCM are sudden
 Mortality in medically treated patients with DCM and a prior history of syncope
may exceed 30% at 2 years, whereas those treated with an ICD experience a high
frequency of appropriate ICD therapy

CAT trial
 Primary prevention trial
 DCM of recent onset (9 months) and impaired LV ejection fraction (EF 30%)
 NYHA class II or III
 Coronary artery disease (coronary stenosis 70%) had to be excluded by
angiography
 Without documented symptomatic ventricular tachyarrhythmias
 Randomly assigned to ICD therapy or to a control group
Bänsch D, Antz M, Boczor S, Volkmer M, Tebbenjohanns J, Seidl K, Block M, Gietzen F, Berger J, Kuck KH. Primary prevention of
sudden cardiac death in idiopathic dilated cardiomyopathy: the Cardiomyopathy Trial (CAT). Circulation. 2002 Mar 26;105(12):1453-
8.

CAT trial
 The primary end point of the trial was all-cause mortality at 1 year.
 A total of 104 patients were enrolled between July 1991 and March 1997. Fifty
patients were randomly assigned to ICD treatment and 54 to the control group.
sudden cardiac death in idiopathic dilated cardiomyopathy: the Cardiomyopathy Trial (CAT). Circulation. 2002 Mar 26;105(12):1453-
8.

sudden cardiac death in idiopathic dilated cardiomyopathy: the Cardiomyopathy Trial (CAT). Circulation. 2002 Mar
26;105(12):1453-8.

Result
 All-cause mortality rates were neither different between ICD treatment and control
group after 1 year (primary end point) nor during long-term follow-up
 Short- and long-term overall mortality rates in patients with DCM and significantly
impaired LV function were surprisingly low. Therefore, ICD therapy did not
provide any survival benefit in these patients.
 ICD therapy did not reveal any survival benefit in the setting of DCM of recent
onset and impaired LV function (EF 30%).
 Results of CAT do not favor prophylactic ICD implantation in patients with DCM
of recent onset and impaired LVEF without any further risk stratification
26;105(12):1453-8.

Discussion
 The lack of any survival benefit of ICD therapy is most likely due to the overall low
event rate in our cohort.
 Even if the study had been continued to include 1348 patients, the power to show
the expected difference of 6% would have been 50%. Thus, the trial was stopped
for futility after 1 year
26;105(12):1453-8.

Background and methology
 To compare total mortality in patients with NIDCM and asymptomatic NSVT
randomly assigned to therapy with amiodarone or an ICD
 Subjects were randomly assigned to receive either amiodarone or an ICD
 Inclusion criteria included a NIDCM
 an ejection fraction <0.35
 asymptomatic NSVT
 New York Heart Association functional class I to III
 age 18 years

 The primary end point of the study was total mortality.
 Secondary end points consisted of SCD, non-SCD, noncardiac death, syncope,
arrhythmia-free survival, quality of life, and costs

Result
 At the first interim analysis in September 2000, the study enrollment was
discontinued because OF inability to demonstrate statistical significance was
reached
 The one- and three-year survival rates among the 52 patients treated with
amiodarone compared with 51 patients treated with an ICD was not significant ( p <
0.8)
 There was a trend towards improved arrhythmia-free survival with amiodarone
therapy.
 The quality of life with each therapy was not statistically different.
 A trend towards a 60% cost savings was observed with amiodarone therapy

 Hypothesis that an ICD will reduce the risk of death in patients with nonischemic
cardiomyopathy and moderate-to-severe left ventricular dysfunction.
 Prospective,
 Randomized
 Investigator-initiated study
 Left ventricular ejection fraction of less than 36 percent, the presence of ambient
arrhythmias, a history of symptomatic heart failure, and the presence of
nonischemic dilated cardiomyopathy
Kadish A, Dyer A, Daubert JP, Quigg R, Estes NM, Anderson KP, Calkins H, Hoch D, Goldberger J, Shalaby A, Sanders WE. Prophylactic
defibrillator implantation in patients with nonischemic dilated cardiomyopathy. New England Journal of Medicine. 2004 May
20;350(21):2151-8.

Methology
 Patients were randomly assigned to one of two treatment groups, with 229 patients
in each group.
 Patients who were randomly assigned to the ICD group received a singlechamber
device
20;350(21):2151-8.

20;350(21):2151-8.

Result
 Fewer patients died in the ICD group than in the standard-therapy group (28 vs.
40), but the difference in survival was not significant (P=0.08 by the log-rank test)
 ICD significantly reduced the risk of sudden death from arrhythmia (hazard ratio,
0.20; P=0.006) and resulted in a reduction in the risk of death from any cause that
approached but did not reach statistical significance (hazard ratio, 0.65; P=0.08).
 Subgroup analyses revealed that the implantation of an ICD significantly reduced
the risk of death among patients who had NYHA class III heart failure and among
men
20;350(21):2151-8.

Discussion
 On the basis of our results, the routine implantation of a cardioverter–defibrillator
cannot be recommended for all patients with nonischemic cardiomyopathy and
severe left ventricular dysfunction.
 However, our findings of a reduction in sudden death from arrhythmia and an
apparent benefit of ICDs in subgroup analyses suggest that the use of these devices
should be considered on a case-bycase basis.
20;350(21):2151-8.

Background and methdology
 Designed to evaluate the hypothesis that amiodarone or, single-lead ICD would
decrease the risk of death from any cause in a broad population of patients with
mild-to-moderate heart failure.
 Placebo-controlled
 3-arm study
 Intention-to-treat analysis,
 2521 patients
 New York Heart Association (NYHA) class II or III CHF
 Left ventricular ejection fraction (LVEF) of 35 percent or less
Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson J, Johnson G, McNulty SE.
Amiodarone or an implantable cardioverter–defibrillator for congestive heart failure. New England Journal of Medicine. 2005 Jan
20;352(3):225-37.

Background and methdology
 Stable CHF due to ischemic or nonischemic
 To conventional therapy for CHF plus placebo (847 patients)
 Conventional therapy plus amiodarone (845 patients)
 Conventional therapy plus single-lead ICD (829 patients)
 Placebo and amiodarone were administered in a double-blind fashion.
 The primary end point was death from any cause
20;352(3):225-37.

Discussion
 ICD significantly decreased the relative risk of death by 23 percent, resulting in an
absolute reduction of 7.2 percentage points at five years among patients with CHF
 Amiodarone had no beneficial effect on survival
 ICD therapy had a significant benefit inn NYHA class II but not in NYHA class III
CHF
 Amiodarone therapy had no benefit in patients in NYHA class II and decreased
survival among patients in NYHA class III CHF, as compared with those who
received placebo
20;352(3):225-37.

 Large-scale, multicenter, controlled clinical trial
 comparing optimal pharmacologic therapy plus cardiac-resynchronization therapy
with a pacemaker,
 Optimal pharmacologic therapy plus cardiac-resynchronization therapy with
pacemaker–defibrillator,
 optimal pharmacologic therapy alone in a population with advanced heart failure
and intraventricular conduction delays

Methology
 Conducted at 128 U.S. centers
 New York Heart Association (NYHA) class III or IV heart failure
 Resulting from either ischemic or nonischemic cardiomyopathy
 left ventricular ejection fraction of 0.35 or less,
 QRS interval 120 msec and a PR interval of more than 150 msec, sinus rhythm,
 no clinical indication for a pacemaker or implantable defibrillator
 Hospitalization for the treatment of heart failure or the equivalent in the preceding
12 months

Discussion
 The primary composite end point of the COMPANION trial — the rate of death
from any cause or hospitalization for any cause — was reduced by approximately
20 percent in both groups that received cardiac-resynchronization therapy in
addition to optimal pharmacologic therapy, as compared with the group that
received optimal pharmacologic therapy alone.
Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW. Cardiac-
resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. New England Journal of Medicine. 2004
May 20;350(21):2140-50.

Discussion
 The addition of a defibrillator to cardiac-resynchronization therapy did not
appreciably affect the combined outcomes of death from or hospitalization for any
cause, which are heavily influenced by the hospitalization components.
 However, the addition of a defibrillator to cardiacresynchronization therapy
incrementally increased the survival benefit, resulting in a substantial, 36 percent
reduction in the risk of death (P=0.003), as compared with optimal pharmacologic
therapy
May 20;350(21):2140-50.

Discussion
 cardiac-resynchronization therapy with a pacemaker–defibrillator, as compared with optimal
pharmacologic therapy, was associated with a 27 percent reduction in the risk of death from
any cause in the subgroup with ischemic cardiomyopathy and a 50 percent reduction in risk in
the subgroup with nonischemic cardiomyopathy
May 20;350(21):2140-50.

Result
 Analysis of the 7 primary and secondary prevention trials in combination
demonstrated a statistically significant 31% survival benefit for ICD over medical
therapy (RR, 0.69; 95% CI, 0.56-0.86; P=.002).
 No individual trial was able to demonstrate a statistically significant benefit to ICD
therapy, likely due to lower than anticipated control group mortality and systematic
underpowering of these trials in the design pha
 ICD therapy could result in an absolute reduction of approximately 2% per year in
all-cause mortality.

Class I
 ICD therapy is indicated in patients with LVEF less than or equal to 35% due to
prior myocardial infarction who are at least 40 days post–myocardial infarction and
are in NYHA functional Class II or III. (Level of Evidence: A)
 ICD therapy is indicated in patients with nonischemic dilated cardiomyopathy who
have an LVEF less than or equal to 35% and who are in NYHA functional Class II
or III. (Level of Evidence: B)
Epstein, Andrew E., et al. "ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the
American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the
ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) developed in collaboration
with the American Association for Thoracic Surgery and Society of Thoracic Surgeons." Journal of the American College of Cardiology 51.21
(2008): e1-e62.

Introduction
Objective
 DANISH study to investigate the effect of ICD implantation in patients with HF
and reduced ejection fraction not caused by coronary artery disease who receive
contemporary HF therapy including CRT
 DANISH study will add insight into the rate of complications in a cohort where a
large proportion of patients will require implantation of multiple leads
42

Methods
Trial design
 Multicenter
 Randomized
 Unblinded
 Controlled
 Parallel
 2-group trial
43
Køber L, Thune JJ, Nielsen JC, Haarbo J, Videbæk L, Korup E, Jensen G, Hildebrandt P, Steffensen FH, Bruun NE, Eiskjær H.
Defibrillator implantation in patients with nonischemic systolic heart failure. New England Journal of Medicine. 2016 Sep
29;375(13):1221-30.

Inclusion criteria
 Clinical HF
 Non-ischemic etiology
 Optimal medical treatment
 NYHA functional class II or III (patients in NYHA class IV could be
included if planned for CRT)
 LVEF ≤35%
 NT-proBNP N200 pg/mL (23.6 pmol/L)
44
29;375(13):1221-30.

Primary analysis
 Time to death from any cause
45
29;375(13):1221-30.

Secondary outcomes
 Time to sudden cardiac death
 Time to cardiovascular death
 Time to resuscitated cardiac arrest or sustained ventricular tachycardia
 Change in quality of life from baseline (Quality of life is assessed by the
Minnesota Living with Heart Failure Questionnaire)
46
29;375(13):1221-30.

Result
 From February 7, 2008, to June 30, 2014,
 Total of 1116 patients were enrolled at five centers; 556 patients were
randomly assigned to the ICD group, and 560 patients were assigned to the
control group
 Follow-up data for all outcomes were available through June 30, 2016
 The median follow-up period was 67.6 months (interquartile range, 49 to
85), and no patients were lost to follow-up for the primary outcome
47
29;375(13):1221-30.

Result
• Primary outcome, death
from any cause, occurred in
120 patients (21.6%) in the
ICD group (4.4 events per
100 person-years) and in
131 patients (23.4%) in the
control group (5.0 events per
100 person-years)
• The hazard ratio for death
from any cause in the ICD
group, as compared with the
control group, was 0.87
(95% confidence interval
[CI] 0.68 to 1.12; P = 0.28)
49
Time-to-Event Curves for Death from Any Cause
29;375(13):1221-30.

Result
• Cardiovascular death
occurred in 77 patients
(13.8%) in the ICD
group and in 95
patients (17.0%) in the
control group (hazard
ratio, 0.77; 95% CI,
0.57 to 1.05; P = 0.10)
50
Time-to-Event Curves for Cardiovascular death
29;375(13):1221-30.

Result
 Sudden cardiac
death occurred in 24
patients (4.3%) in
the ICD group and
in 46 patients
(8.2%) in the control
(hazard ratio, 0.50;
95% CI, 0.31 to
0.82; P = 0.005)
51
Time-to-Event Curves for Sudden Cardiac Death
29;375(13):1221-30.

Discussion
 Implantation of an ICD in heart failure not caused by ischemic heart disease did
not provide an overall survival benefit, although the risk of sudden cardiac death
was halved with an ICD
 No difference of ICD between patients with CRT and without CRT
 Time-to-event curves diverge during initial 5 years and then converge
 Rationale for long-term studies
54
29;375(13):1221-30.

Discussion
 31% of deaths were due to noncardiovascular causes
 Important interaction with age
 Younger patients have a survival benefit with ICD
 This is not surprising in an elderly population, but it highlights the
importance of selecting patients for ICD implantation carefully
 Patients at higher risk more likely to benefit from ICD
55
29;375(13):1221-30.

Conclusion
 ICDs reduce all-cause mortality by 23% in patients with NICM.
 ICDs may still reduce all-cause mortality in patients who are also candidates of
CRT therapy, although the results did not meet statistical significance.
 It may be plausible that, because of the high use of CRT in the DANISH trial (60%
in each arm), ICD failed to demonstrate statistically significant effect on all-cause
mortality in patients with NICM.

Result
 Among patients without a CRT, the risk of all-cause mortality was 24% lower in those
assigned to ICD compared to those assigned to medical therapy (RR: 0.76; 95% CI: 0.63 to
0.91; p ¼ 0.003)
 Among patients with CRT, there was no statistically significant difference in mortality
between the CRT-D and CRT-P groups (RR: 0.74; 95%: CI: 0.47 to 1.16; p ¼ 0.19), the
relatively smaller sample size of this analysis prevents a definitive conclusion.
Narayanan MA, Vakil K, Reddy YN, Baskaran J, Deshmukh A, Benditt DG, Adabag S. Efficacy of implantable cardioverter-
defibrillator therapy in patients with nonischemic cardiomyopathy: a systematic review and meta-analysis of randomized
controlled trials. JACC: Clinical Electrophysiology. 2017 Sep 1;3(9):962-70.

Discussion
 In DANISH, 60% of the population had CRT.
 Aggressive use of heart failure therapy was pursued in DANISH, this does not necessarily
reflect the practice in the real-world
 Median age in DANISH was higher than in DEFINITE and SCD-HEFT.

Discussion
 A subgroup analysis of DANISH demonstrated mortality benefit with ICD therapy among
patients younger than 68 years
 Absence of benefit of ICD in DANISH could have been related to selection of an older
population with higher noncardiac mortality
 ICD therapy is of benefit among appropriately selected patients with NICM, particularly if
they are younger

Conclusion
 This systematic review and meta-analysis of published RCTs supports the use of ICD in
appropriately selected patients with NICM who are not eligible for CRT.
 Further research, perhaps an adequately powered trial, of NICM patients with CRT is essential
to assess the efficacy of CRT-D in comparison to CRT-P in NICM.

Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, Deal BJ, Dickfeld T, Field ME, Fonarow GC, Gillis AM. 2017 AHA/ACC/HRS Guideline for
Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart
Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Journal of the American College of Cardiology. 2017 Oct 30:24390.

Take home message
 ICD therapy is of benefit among appropriately selected patients with NICM, particularly if
they are younger
 Among patients with CRT, there was no statistically significant difference in mortality
between the CRT-D and CRT-P groups
 Further research on the efficacy of defibrillator therapy in patients with CRT
 Role of ARNI is to be further investigated with ICD AND CRT.

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