Circulation: Heart Failure
RESEARCH LETTER

Diabetes and Implantable Cardioverter
Defibrillator in Nonischemic Systolic Heart
Failure: An Extended Follow-Up Analysis of
DANISH
Seiko Nakajima Doi, MD, PhD; Jens Jakob Thune , MD, PhD; Jens Cosedis Nielsen , MD, DMSc; Jens Haarbo, MD, DMSc;
Lars Videbæk , MD, PhD; Rasmus Rørth, MD, PhD; Søren Lund Kristensen , MD, PhD; Niels Eske Bruun , MD, DMSc;
Finn Gustafsson , MD, DMSc; Hans Eiskjær , MD, DMSc; Christian Hassager , MD, DMSc;
Jesper Hastrup Svendsen , MD, DMSc; Dan Eik Høfsten , MD, PhD; Christian Torp-Pedersen , MD, DMSc;
Steen Pehrson , MD, DMSc; Lars Køber , MD, DMSc; Jawad Haider Butt , MD

I
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ndividuals with heart failure (HF) and diabetes generally have more severe HF and more comorbidities thanthose with HF and no diabetes, and the former may
therefore have an increased risk of competing causes ofdeath to arrhythmic death.
In the DANISH trial (The Danish Study to Assess theEfficacy of Implantable Cardioverter Defibrillators [ICDs]
in Patients With Nonischemic Systolic Heart Failure onMortality), primary prophylactic ICD implantation, compared with usual care, significantly reduced the rate ofsudden cardiovascular death, but not all-cause mortality.1
We have previously examined the effect of ICD implantation according to diabetes status in the DANISH trial
and found no statistically significant interaction between
diabetes and the effect of ICD implantation.2 However,given that diabetes is a chronic disease, which can cause
various systemic adverse effects over the long term, weconducted an extended follow-up study of the DANISH
trial, adding 4 years of additional follow-up, to examine
the long-term effects of primary prophylactic ICD implantation, according to diabetes status.
The data that support the findings of this study areavailable from the corresponding author on reasonable
request. The design of the DANISH trial has been published and described previously.1,3 In brief, 1116 patientswith nonischemic HF with reduced ejection fraction(HFrEF) were enrolled from 5 ICD-implanting centers inDenmark and randomized in a 1:1 ratio to ICD implantation or usual care. In the present analysis with extended
follow-up, patients were followed from randomization
until death or May 18, 2020, whichever came first, andno patients were lost to follow-up. The primary outcome
was death from any cause, and secondary outcomes
were cardiovascular death and sudden cardiovasculardeath. The protocol was approved by the ethics committee in the Capital Region of Denmark (H-D-2007-0101),
and all participants gave written informed consent.
The effect of ICD implantation versus usual care
was evaluated using the Kaplan-Meier estimator, AalenJohansen estimator, and Cox proportional hazards
regression models, stratified according to center andstatus with respect to cardiac resynchronization therapy
implantation. Data were analyzed according to the intention-to-treat principle. A P-value of 0.05 was considered
statistically significant.
At baseline, 211 (18.9%) patients had diabetes. Baseline characteristics, including data on the managementof diabetes, are presented in our previous report.2 During a median follow-up of 9.5 years (interquartile range,7.9–10.9), there was a statistically significant interaction
between diabetes and the effect of ICD implantation ondeath from any cause; ICD implantation, compared withKey Words: clinical trial ◼ diabetes ◼ heart failure ◼ implantable cardioverter defibrillator
Correspondence to: Jawad H. Butt, MD, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark.
Email jawad_butt91@hotmail.com
For Sources of Funding and Disclosures, see page XXX.
© 2023 American Heart Association, Inc.
Circulation: Heart Failure is available at www.ahajournals.org/journal/circheartfailure

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ICD and Diabetes in Systolic HF

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Figure. Effect of implantable cardioverter defibrillator (ICD) implantation compared with usual care according to diabetes.
A through F, Cumulative incidence of death from any cause (using the Kaplan-Meier estimator), cardiovascular death, sudden cardiovasculardeath (using the Aalen-Johansen estimator, taking the competing risk of other causes of death into account) among patients with and without
ICD. G, Cox regression models were stratified according to center and cardiac resynchronization therapy implantation (preexisting or planned).
Because there was a difference between the ICD and control arm according to diabetes status at baseline with respect to certain key
variables, we also adjusted these analyses for age, log of NT-proBNP (N-terminal pro-B-type natriuretic peptide) level, estimated glomerular
filtration rate, and a history of hypertension, atrial fibrillation, and chronic obstructive pulmonary disease. In addition, an interaction term between
diabetes and treatment assignment was included as a covariate in the models.
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usual care, reduced the rate of death from any cause inpatients without diabetes, but not in those with diabetes (hazard ratio, 0.78 [95% CI, 0.62–0.97] versus 1.28
[0.87–1.89], respectively; Pinteraction=0.029). Although
there was no statistically significant interaction between
diabetes and the effect of ICD implantation on cardiovascular death (Pinteraction=0.058) and sudden cardiovasculardeath (Pinteraction=0.110), the potential differential effectof ICD implantation according to diabetes status was
also observed for these outcomes (cardiovascular death:hazard ratio 0.75 [0.57–0.98] versus 1.22 [0.80–1.85] inpatients without and with diabetes, respectively; sudden
cardiovascular death: hazard ratio 0.47 [0.28–0.79] versus 1.03 [0.46–2.32], respectively; Figure).
Due to the cumulative benefit of evidence-based, disease-modifying therapies, the incidence of sudden cardiac
death has declined in patients with HFrEF during the past
decades.4 The incidence is expected to decline even further with the addition of angiotensin receptor-neprilysininhibitors and sodium-glucose cotransporter-2 inhibitors
to the pharmacological armamentarium, although neitherof these drug classes were indicated for the treatment ofHFrEF during the enrollment period of the DANISH trial.
Our data confirm the findings from a previous metaanalysis of 4 landmark primary prevention ICD trials5 andextend those from our previous analysis by increasing thenumber of events and subsequently the statistical power.2
There may be several explanations for the differential
effects of ICD implantation in patients with and without
diabetes. An ICD can prevent sudden cardiovasculardeath caused by ventricular tachyarrhythmia, and severe
bradycardia, but cannot provide protection against othercauses of death, including sudden cardiovascular death
not caused by such arrhythmia. Because patients with diabetes have more severe HF and more comorbidities thanthose without diabetes, they may, perhaps, be less likely todie suddenly due to arrhythmias. Therefore, due to competing risk of nonarrhythmic causes of death, patients with
HF and diabetes may derive less benefit of ICD therapy
than those without diabetes. Furthermore, sodium-glucose
cotransporter-2 inhibitors, which were indicated for thetreatment of diabetes during follow-up in the DANISH
trial, have been shown to reduce the risk of sudden cardiacdeath in patients with HFrEF and may have contributed, atleast to some extent, to the lack of a beneficial effect of
ICD implantation in patients with diabetes. Nevertheless,the findings from the present report, along with previous
analyses from other trials, suggest that individuals with
nonischemic HFrEF without diabetes may derive benefit
from ICD implantation. However, this question can only beanswered definitively in a clinical trial specifically designed
and powered to answer this question.

ICD and Diabetes in Systolic HF

ARTICLE INFORMATION
AffiliationsDepartment of Cardiology, Copenhagen University Hospital - Rigshospitalet, Denmark (S.N.D., R.R., S.L.K., F.G., C.H., J.H.S., D.E.H., S.P., L.K., J.H.B.). Department ofClinical Medicine, University of Copenhagen, Denmark (J.J.T., N.E.B., F.G., C.H.,
J.H.S., D.E.H., L.K.). Department of Cardiology, Copenhagen University Hospital- Bispebjerg and Frederiksberg, Denmark (J.J.T.). Department of Cardiology, Aarhus University Hospital, Denmark (J.C.N., H.E.). Department of Clinical Medicine,Aarhus University, Denmark (J.C.N.). Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark (J.H.). Department ofCardiology, Odense University Hospital, Svendborg, Denmark (L.V.). Departmentof Cardiology, Aalborg University Hospital, Denmark (N.E.B.). Department of Cardiology, Zealand University Hospital, Roskilde, Denmark (N.E.B.). Department ofCardiology, Nordsjællands Hospital, Hillerød, Denmark (C.T.-P.). Department of
Public Health, University of Copenhagen, Denmark (C.T.-P.).

Acknowledgments
None.

Sources of Funding
Dr Doi was supported by the Japanese College of Cardiology Overseas ResearchFellowship.

Disclosures
Dr Butt reports advisory board honoraria from Bayer, consultant honoraria fromNovartis and AstraZeneca, and travel grants from AstraZeneca, outside thesubmitted work. Dr Nielsen reports grants from the Novo Nordisk Foundation (NNF16OC0018658 and NNF17OC0029148), outside the submittedwork. Dr Kristensen reports advisory honoraria from Bayer and AstraZeneca,
outside the submitted work. Dr Svendsen reports honoraria from Medtronic(speaker fee and membership of advisory committee) and research grant fromMedtronic, outside the submitted work. Dr Pehrson reports honoraria (speakerfees) from AstraZeneca, Bristol Myers Squibb, and Abbott, outside the submitted work. Dr Hassager reports grants from the Novo Nordisk Foundation, theLundbeck Foundation, and the Danish Heart Foundation, outside the submitted work. Dr Bruun reports grants from the Novo Nordisk Foundation, Health
Insurance Denmark, the Augustinus Foundation, and the Kaj Hansen Foundation, outside the submitted work. Dr Gustafsson reports research grants fromPfizer and the Novo Nordisk Foundation, advisory board honoraria from Bayer,Pfizer, Abbott, Ionis, and Alnylam, and speakers’ fee from AstraZeneca, Novartis, and Orion Pharma, outside the submitted work. The other authors reportno conflicts.

REFERENCES
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2. Rorth R, Thune JJ, Nielsen JC, Haarbo J, Videbaek L, Korup E, Signorovitch J,Bruun NE, Eiskjaer H, Hassager C, et al. The effect of implantable cardioverter-defibrillator in patients with diabetes and non-ischaemic systolic heart
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Circ Heart Fail. 2023;16:e010606. DOI: 10.1161/CIRCHEARTFAILURE.123.010606

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