Presenter Dr Praveen Gupta
Moderator Dr Raja Selvaraj
MD(Ped) DNB(Card) Fellowship in Cardiac EP(Toronto)
Cardiac Electrophysiologist
Associate Professor of Cardiology
Jawaharlal Institute of Postgraduate Medical Education and Research
Pondicherry | India 605006
Date 19/12/2016
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• The trial was supported by unrestricted grants from Medtronic, St. Jude
Medical, TrygFonden, and the Danish Heart Foundation
• Kober disclosed relevant relationships with Sanofi and Novartis.
• McMurray disclosed relevant relationships with Cardiorentis, Amgen,
Novartis, Oxford University/Bayer, GlaxoSmithKline, Theracos, AbbVie,
AstraZeneca, Vifor-Fresnius Pharma, DalCor, Pfizer, Merck, and Bristol-
Myers Squibb.
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Introduction
Background
 ICD benefit well documented in ischemic heart diseases
 No trial showed a significant effect of ICD with non-ischemic HF
 Positive effect of ICD confined to New York Heart Association (NYHA) class II,
and no patients received concomitant CRT
 Large proportion of these patients now receive CRT, and the impact of ICD
implantation in this setting is not well known
 ICD implantation confers a risk of device-related complications
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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
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Methods
Trial design
 Multicenter
 Randomized
 Unblinded
 Controlled
 Parallel
 2-group trial
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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)
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Exclusion criteria
 Dysregulated permanent atrial fibrillation (resting heart rate N100
beats/min)
 Uncorrected congenital heart disease or valve obstruction
 Obstructive cardiomyopathy, active myocarditis, constrictive pericarditis,
untreated hypothyroidism or hyperthyroidism, adrenal insufficiency, and
active vasculitis due to collagen vascular disease
 On the urgent waiting list for a heart transplant (UNOS category 1A or 1B,
or equivalent)
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Exclusion criteria (Contd)
 Recipient of
 Major organ transplant
 Receiving or received cytotoxic or cytostatic chemotherapy and/or
radiation therapy for malignancy within 6 m before randomization or
clinical evidence of current malignancy, with the following exceptions:
basal or squamous cell carcinoma of the skin, cervical intraepithelial
neoplasia, prostate cancer (if stable localized disease, with a life
expectancy of N2.5 y in the opinion of the investigator)
 Known to be HIV positive, with an expected survival of b5 y due to HIV
 Renal failure treated with dialysis
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Exclusion criteria (Contd)
 Recent (within 3 m) history of alcohol or illicit drug abuse disorder, based
on self-report
 Any condition (eg, psychiatric illness) or situation that, in the investigator's
opinion, could put the participant at significant risk, confound the study
results, or interfere significantly with the participant's participation in the
study
 Lack of informed consent
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Intervention
 Randomization performed on web-based system, using permuted-block
 Non-ischemic etiology was determined by coronary angiogram, although a
normal computed tomography angiogram or nuclear myocardial perfusion
imaging study was acceptable
 Patients could be included despite having 1 or 2 coronary artery stenoses, if
the extent of coronary artery disease did not explain the reduced left
ventricular systolic function
 Decision to implant a CRT device made before randomization
 Single or dual chamber ICD was implanted
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Methods (Contd.)
 Follow-up –
 2 months
 Every 6 months
 Patients who receive ICD undergo regular follow-up by implantation center
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Primary analysis
 Time to death from any cause
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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)
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Statistical Analysis
 Study designed to have 80% power to detect a 25% difference in total mortality between the
treatment groups.
 At least 246 primary outcome events were required for the study to be conclusive, and we planned
to include 1000 patients.
 Because the event rate and enrollment rate were lower than expected, the steering committee decided
to prolong enrollment until June 30, 2014, or until 1200 patients were included (whichever came
first) and to follow the last randomly assigned patient for at least 2 years.
 Baseline characteristics compared between the groups with the use of chi-square and Wilcoxon tests
 Outcomes analyzed with the use of time-to-event methods
 Kaplan–Meier plots were calculated for total mortality, and cumulative incidence curves were
calculated for events with competing risk (sudden cardiac death and cardiovascular death)
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Statistical Analysis
 The analysis of the primary outcome was performed with a log-rank model
 The proportional-hazard assumption was assessed with Schoenfeld residuals
 Post hoc annual event rate ratios were derived from a Poisson regression
 Prespecified subgroup analyses of the primary outcome were performed for the variables
 All analyses were performed in the intention-to-treat population
 Two sided P values of 0.05 or less were considered to indicate statistical significance.
 Analyses were performed with SAS software, version 9.4 (SAS Institute), and R software, version
3.3.1 (R Project for Statistical Computing)
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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
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Cohort and baseline characteristics
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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)
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Time-to-Event Curves for Death from Any Cause

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)
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Time-to-Event Curves for Cardiovascular death

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)
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Time-to-Event Curves for Sudden Cardiac Death

Result
 The clinical outcome of resuscitated
cardiac arrest or sustained ventricular
tachycardia occurred with similar
frequency in the two groups
 Device infections in 4.9% in the ICD
and in 3.6% in the control (P = 0.29)
 Patients not receiving CRT, the risk of
device infection was higher in the
ICD group than it was in the control
group (5.1% vs 0.8%) ( hazard ratio,
6.35; 95% CI, 1.38 to 58.87; P =
0.006).
 Inappropriate shocks in 5.9% in the
ICD group
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Result
 With age there was a
significant treatment-by-
subgroup interaction (P =
0.009 )
 The rate of death from any
cause was significantly lower
among patients younger than
68 years of age than among
patients 68 years of age or
older (hazard ratio, 0.64; 95%
CI, 0.45 to 0.90; = 0.01).
 The effect of ICD implantation
was independent of CRT status
(P = 0.73 for the interaction)
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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
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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
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Discussion
 Lower likelihood of benefit in older patients might be used as an argument
for not implanting ICDs in frail patients
 Long-term data from the Multicenter Automatic Defibrillator Implantation
Trial (MADIT) II indicate that clinical risk scores may make it possible to
identify the patients with ischemic heart disease who will benefit most from
ICD implantation
 Such a method for identifying patients with nonischemic heart failure who
are at high risk for death from arrhythmia would be very useful
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Discussion
 The side effects associated with device implantation in our trial not trivial
 Device related infections were not infrequent, but we did have a high
proportion of patients in both groups who were receiving CRT (which
requires implantation of an additional lead in the coronary sinus).
 In addition, 10% of our patients already had a pacemaker and were
randomly assigned either to receive or not to receive an ICD upgrade; this
is a patient group that has not been included in most of the previous trials
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Thank you