Accepted Manuscript

COPD increases mortality in patients presenting with ventricular tachyarrhythmias

and aborted cardiac arrest

Jonas Rusnak, Michael Behnes, Tobias Schupp, Linda Reiser, Armin Bollow, Gabriel
Taton, Thomas Reichelt, Dominik Ellguth, Niko Engelke, Jorge Hoppner, Kathrin
Weidner, Ibrahim El-Battrawy, Kambis Mashayekhi, Christel Weiß, Martin Borggrefe,
Ibrahim Akin

PII: S0954-6111(18)30325-1
DOI: https://doi.org/10.1016/j.rmed.2018.10.019
Reference: YRMED 5552

To appear in: Respiratory Medicine

Received Date: 12 May 2018

Revised Date: 17 October 2018
Accepted Date: 19 October 2018

Please cite this article as: Rusnak J, Behnes M, Schupp T, Reiser L, Bollow A, Taton G, Reichelt T,
Ellguth D, Engelke N, Hoppner J, Weidner K, El-Battrawy I, Mashayekhi K, Weiß C, Borggrefe M, Akin I,
COPD increases mortality in patients presenting with ventricular tachyarrhythmias and aborted cardiac
arrest, Respiratory Medicine (2018), doi: https://doi.org/10.1016/j.rmed.2018.10.019.

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 ACCEPTED MANUSCRIPT
COPD Increases Mortality in Patients Presenting with Ventricular
Tachyarrhythmias and Aborted Cardiac Arrest

Jonas Rusnak MD1*; Michael Behnes MD1*; Tobias Schupp MS1; Linda Reiser MS1;
Armin Bollow MS1; Gabriel Taton MS1; Thomas Reichelt MS1; Dominik Ellguth MS1;
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Niko Engelke MS1; Jorge Hoppner MD ; Kathrin Weidner MD1; Ibrahim-El-Battrawy
MD1; Kambis Mashayekhi MD3; Christel Weiß PhD4; Martin Borggrefe MD1; Ibrahim

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Akin MD1

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First Department of Medicine, University Medical Centre Mannheim (UMM), Faculty of Medicine
Mannheim, University of Heidelberg, European Center for AngioScience (ECAS), and DZHK
(German Center for Cardiovascular Research) partner site Heidelberg/Mannheim, Mannheim,

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Germany. 2Department of Diagnostic and Interventional Radiology, University Heidelberg,
Heidelberg, Germany.
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Department of Cardiology and Angiology II, University Heart Center Freiburg • Bad Krozingen, Bad

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Krozingen, Germany.
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Institute of Biomathematics and Medical Statistics, University Medical Center Mannheim (UMM),
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Faculty of Medicine Mannheim, Heidelberg University, Mannheim, Germany.

*J.R. and M. Be. contributed equally to this study.

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No conflict of interest for all authors

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Brief Title:Ventricular tachyarrhythmias and SCA in patients with COPD

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Key words: sudden cardiac arrest, aborted cardiac arrest, ventricular tachyarrhythmia,
ventricular fibrillation, COPD, pulmonary disease
Word count: 3696
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Corresponding author: Michael Behnes, First Department of Medicine, University Medical Center
Mannheim (UMM), Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany, E-mail:
michael.behnes@umm.de
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Abstract

Objectives: The study sought to assess the prognostic impact of COPD in patients

presenting with ventricular tachyarrhythmias and sudden cardiac arrest (SCA) on admission.

Background: Data regarding the outcome of patients with COPD presenting with

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ventricular tachyarrhythmias and SCA is limited.

Methods: A large retrospective registry was used including all consecutive patients

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presenting with ventricular tachycardia (VT), fibrillation (VF) and SCA from 2002 to 2016.

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Patients with COPD were compared to patients without COPD applying multivariable Cox

regression models and propensity-score matching for evaluation of the primary prognostic

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endpoint defined as long-term all-cause mortality at 2 years. Secondary endpoints were all-
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cause mortality at index, at 30 days and after discharge, cardiac death at 24 hours,

rehospitalization related to cardiac causes and the composite endpoint of cardiac death at 24
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hours, recurrences of ventricular tachyarrhythmias and appropriate ICD therapy.

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Results: In 2,813 unmatched high-risk patients with ventricular tachyarrhythmias and

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SCA, COPD was present in 9% with slightly higher rates of early cardiac death (36% versus

28%), whereas VF was more common in non-COPD (39% versus 28%; p<0.05).
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Multivariable Cox regression models revealed that COPD was associated with the primary

endpoint of long-term all-cause mortality (HR=1.245; 95% CI 1.001-1.549), which was also
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proven after propensity score matching (58% versus 39%; log rank p=0.001; HR=1.778; 95%
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CI 1.312-2.410). The secondary endpoints of all-cause mortality at index, at 30 days, after

discharge, cardiac death at 24 hours, as well as the composite endpoint of cardiac death at 24

hours, recurrences of ventricular tachyarrhythmias and appropriate ICD therapy were higher

in COPD (p<0.05).

Conclusion: In high-risk patients presenting with ventricular tachyarrhythmias and SCA,

COPD was associated with higher all-cause mortality, cardiac death at 24 hours and higher

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rates of the composite endpoint of cardiac death at 24 hours, recurrences of ventricular

tachyarrhythmias and appropriate ICD therapies at 2 years.

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Condensed abstract

This study retrospectively examined the prognostic impact of COPD in 2,813 consecutive

patients admitted with ventricular tachyarrhythmias and SCA. Presence of COPD was

independently associated with higher all-cause mortality, cardiac death at 24 hours and higher

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rates of the composite endpoint of cardiac death at 24 hours, recurrences of ventricular

tachyarrhythmias and appropriate ICD therapy.

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Introduction

Sudden cardiac arrest (SCA) and sudden cardiac death (SCD) are commonly caused by
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ventricular tachyarrhythmias. Therefore, patients at increased risk of SCD should receive

implantable cardioverter defibrillators (ICD) to interrupt recurrences of ventricular

tachyarrhythmias. 2 Patients presenting with ventricular tachyarrhythmias or aborted SCA and

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arriving the emergency department reveal an increased risk for all-cause mortality and

recurrent cardiac arrest. 3-8

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Chronic obstructive pulmonary disease (COPD) is a leading cause of death with a

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decreasing prevalence in the Western world. Patients with COPD are associated with a

significantly higher number of adverse clinical events, including acute exacerbation with

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consecutive rehospitalization. COPD was recently shown to affect both cardiac structure and
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function 10-12
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Cardiac arrhythmias represent the most common cardiac manifestation related to COPD
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limiting the long-term prognosis of the affected patients. There is increasing evidence
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that the myocardium is more susceptible for arrhythmias in COPD patients, which is indicated
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16,17
by an increased frequency of ventricular ectopic and paired premature ventricular beats.

Although the underlying patho-mechanism is not fully understood yet, it is presumed that the
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COPD related increased arrhythmogenicity might be explained by recurrent hypercapnia and

recurrent hypoxemia at more advanced stages, as well as by alterations of the QTc interval
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and adverse side effects of bronchodilators. 15-19

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Several screening and community-based studies could demonstrate a higher

cardiovascular risk, increased mortality and incidence of ventricular tachyarrhythmias and

15,16,20-23
SCD in COPD patients. The community-based ARREST-registry demonstrated that

1,192 patients with out-of-hospital cardiac arrest (OHCA) due to VT or VF were associated

with a 40% increase of 30-day mortality in the presence of “generally determined” obstructive
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pulmonary disease. In 402 men mean-aged at 68 years without a prior history of acute
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myocardial infarction (AMI) and stroke, Engström et al. reported about higher rates of

coronary events and mortality in patients with lower forced expiratory volume (FEV) and

premature ventricular contractions (PVC) of Lown Class 2-5 at 14 years of follow-up (defined

as Lown Class 2: ≥ 720 PVC/24h; Lown Class 3: multiform, bigeminal or trigeminal PVC;

Lown Class 4a: couplets; Lown Class 4b: ventricular tachycardia; Lown Class 5: R-on-T

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type). 25

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However, no data is currently available, whether the presence of COPD itself may

independently increase mortality in real-life patients presenting consecutively on admission

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with ventricular tachyarrhythmias and SCA irrespective of the underlying etiology. Therefore,

this study evaluates the prognostic impact of COPD in consecutive patients presenting with

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ventricular tachyarrhythmias and SCA on admission.
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Methods

Study patients, design and data collection

The present study retrospectively included all consecutive patients presenting with

ventricular tachyarrhythmias or SCA on hospital admission from 2002 until 2016 at the First

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Department of Medicine, University Medical Centre Mannheim, Germany. Patients were

mostly resident in the city of Mannheim and the surrounding areas. This area is inhabited by

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nearly 500,000 people. Using the electronic hospital information system, all relevant clinical

data related to the index event was documented.

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Ventricular tachyarrhythmias comprised VT and VF as defined by current international

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2,26
guidelines. Sustained VT was defined by duration of >30 seconds or causing
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hemodynamic collapse within 30 seconds, non-sustained VT by duration <30 seconds both
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with wide QRS complex (≥120 milliseconds) at a rate greater than 100 beats per minute.
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Ventricular tachyarrhythmias were documented by 12-lead electrocardiogram (ECG), ECG

tele-monitoring, implantable cardioverter defibrillator (ICD) or in case of unstable course or

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during resuscitation by external defibrillator monitoring. Documented VF was treated by

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external defibrillation and in case of prolonged instability with additional intravenous anti-

arrhythmic drugs during cardiopulmonary resuscitation (CPR). 2

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Further data being documented contained baseline characteristics, prior medical history,
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prior medical treatment, length of index stay, detailed findings of laboratory values at
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baseline, data derived from all non-invasive or invasive cardiac diagnostics and device

therapies, such as coronary angiography, electrophysiological examination, ICD, pacemaker

or cardiac contractility modulation (CCM), as well as imaging modalities, such as

echocardiography or cardiac magnetic resonance imaging (cMRI). The overall presence of

ICDs comprised the total sum of all patients with either a prior implanted ICD before

admission, those undergoing new ICD implantation at index stay, as well as those with ICD

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implantation at the complete follow-up period after index hospitalization, referring to

conventional ICD, subcutaneous-ICD (s-ICD) and cardiac resynchronization therapy with

defibrillator function (CRT-D). Pharmacological treatment was documented according to the

discharge medication of patients surviving index hospitalization. Rates of overall ICDs and of

pharmacological therapies are referred to the number of surviving patients being discharged

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from index hospitalization.

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Every re-visit at the outpatient clinic or rehospitalization was documented, when related

to recurrent ventricular tachyarrhythmias and adverse cardiac events. Adverse cardiac events

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comprised acute heart failure, CPR, cardiac surgery, new implants or upgrades of cardiac

devices, worsening or improvement of left ventricular function.

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Documentation period lasted from index event until 2016. Documentation of all medical
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data was performed by independent cardiologists at the time of the patients´ clinical
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presentation at our institution, being masked to final data analyses.

The present study is derived from an analysis of the “Registry of Malignant Arrhythmias
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and Sudden Cardiac Death - Influence of Diagnostics and Interventions (RACE-IT)” and
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represents a single-center registry including consecutive patients presenting with ventricular

tachyarrhythmias and SCA being acutely admitted to the University Medical Center
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Mannheim (UMM), Germany (clinicaltrials.gov identifier: NCT02982473) from 2002 until

2016. The registry was performed according to the principles of the declaration of Helsinki
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and was approved by the medical ethics committee II of the Medical Faculty Mannheim,

University of Heidelberg, Germany, which waived the requirement for informed consent.

The medical center covers a general emergency department (ED) for emergency

admission of traumatic, surgical, neurological and cardiovascular conditions. Interdisciplinary

consultation is an in-built feature of this 24/7 service, and connects to a stroke unit, four

intensive care units with extracorporeal life support and a chest pain unit (CPU) to alleviate

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rapid triage of patients. The cardiologic department itself includes cardiac catheterization and

electrophysiologic laboratory, a hybrid operating room and telemetry units.

Definition of study groups, inclusion and exclusion criteria

For the present analysis risk-stratification was performed according to the presence of

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COPD according to latest GOLD guidelines. 19

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Documentation of COPD was derived from the electronic hospital information system.

Spirometric assessment was evaluated separately from symptom evaluation. Spirometric

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airflow limitation was graduated by FEV1 (% predicted): GOLD 1 = ≥80; GOLD 2 = 50-79;

GOLD 3 = 30-49; GOLD 4 = <30. Symptoms were graduated by exacerbation history and

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mMRC: GOLD A = mMRC 0-1 and 0-1 exacerbations without hospital admission; GOLD B
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= mMRC ≥2 and 0-1 exacerbations without hospital admission; GOLD C = mMRC 0-1 and
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≥2 exacerbations with hospital admission; GOLD D = mMRC ≥2 and ≥2 exacerbations with

hospital admission.
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Overall exclusion criteria comprised patients without complete follow-up data regarding
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mortality. Each patient was counted only once for inclusion when presenting with the first

episode of ventricular tachyarrhythmias or SCA.

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Study Endpoints
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The primary prognostic endpoint was all-cause mortality at long-term follow-up.

Secondary endpoints were all-cause mortality at 30 days, at index hospitalization, after

discharge, cardiac death at 24 hours and the composite endpoint of cardiac death at 24 hours,

recurrences of ventricular tachyarrhythmias and appropriate ICD therapy at long-term follow-

up. Cardiac death at 24 hours was defined as occurring <24 hours after onset of ventricular

tachyarrhythmias or an assumed unstable cardiac condition on index admission.

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Overall follow-up period lasted until 2016. All-cause mortality was documented using

our electronic hospital information system and by directly contacting state resident

registration offices (“bureau of mortality statistics”) across Germany. Identification of patients

was verified by place of name, surname, day of birth and registered living address. Lost to

follow-up rate was 1.7% (n=48) regarding survival until the end of the follow-up period.

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Statistical methods

Quantitative data are presented as mean ± standard error of mean (SEM), median and

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interquartile range (IQR), and ranges depending on the distribution of the data and were

compared using the Student’s t test for normally distributed data or the Mann-Whitney U test

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for nonparametric data. Deviations from a Gaussian distribution were tested by the
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Kolmogorov-Smirnov test. Spearman’s rank correlation for nonparametric data was used to
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test univariate correlations. Qualitative data are presented as absolute and relative frequencies

and compared using the Chi² test or the Fisher’s exact test, as appropriate.
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Firstly, overall data of consecutive patients on admission are given for the entire
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unmatched cohort to present the real-life character of healthcare supply at our institution in

between 2002 and 2016. Here, multivariable Cox regression models were applied for the
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evaluation of the primary prognostic endpoint within the total study cohort for the presence of

COPD. Then, multivariable Cox regression models were applied for the primary prognostic
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endpoint in the subgroups of females, males, LVEF ≥35%, LVEF <35%, ICD, non-ICD,

smokers, non-smokers, and in patients with and without beta-blocker therapy. Multivariable

Cox regression models were adjusted for the following covariables: age, sex, diabetes

mellitus, chronic kidney disease (glomerular filtration rate <60 mL/min per 1.73 m2), atrial

fibrillation, AMI, prior coronary artery disease (CAD), LVEF <35%, overall presence of ICD,

cardiogenic shock, CPR, smoking, presence of beta-blocker therapy and presence of COPD.

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Secondly, propensity score matching was applied. There is a relevant and increasing

demand from patients, clinicians and within the healthcare system in general for growing

evidence from non-randomized studies. There are simply too many medically relevant

hypotheses, which will never be investigated within randomized controlled trials because of

several reasons (ie, funding, recruitment, difficult study settings, high-risk patients, etc).

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Therefore, we felt that the method of propensity matching would be a reasonable additional

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statistical method beside multivariable Cox regression models for the purpose of the present

study evaluating the prognostic impact of COPD in high-risk patients presenting with

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ventricular tachyarrhythmias and SCA on admission. These high-risk patients are usually

excluded from randomized controlled trials. In randomized controlled trials patients with or

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without a specific treatment would have a 50% chance to be treated and balanced measured
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and unmeasured baseline characteristics would be expected. However, patients with different
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disease entities may not be randomized in real-life (such as COPD versus non-COPD)

because of different pathophysiologies and treatment recommendations. An observational

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study usually recruits consecutive real-life patients without randomization resulting in varying
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chances between 0% and 100% to receive imbalances in baseline characteristics and

treatments. Therefore, differences of outcomes in specific disease groups might be explained

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by heterogeneous distribution of baseline characteristics and applied therapies. To further

reduce this selection bias, we used 1:1 propensity-scores for COPD versus non-COPD, to
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assemble matched and well-balanced subgroups. One-to-one ratio for propensity score

matching was performed including the entire study cohort and in COPD patients, applying a

non-parsimonious multivariable logistic regression model using COPD as the dependent

variable. 27

Propensity scores were created according to the presence of the following independent

variables: age, chronic kidney disease (glomerular filtration rate <60 mL/min per 1.73 m2),

diabetes mellitus, cardiogenic shock, CPR, overall presence of ICD, CAD, gender, ST-
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segment-elevating myocardial infarction (STEMI), non-STEMI, LVEF <35%, beta blocker

therapy at discharge as well as smoking. Based on the propensity score values counted by

logistic regression, for each patient in the COPD group one patient in the control group with a

similar propensity score value was found (accepted difference of propensity score values

<5%). Uni-variable stratification was performed using the Kaplan–Meier method with

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comparisons between groups using univariable hazard ratios (HR) given together with 95%

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confidence intervals, according to the presence of COPD within the propensity-matched

cohorts.

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Long-term follow-up period of 2 years accorded to the median survival time of COPD

patients to guarantee complete follow-up of at least 50% of patients, which is needed to

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sufficiently address the main objective of this registry study. Patients not meeting long-term
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follow-up were censored.
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The result of a statistical test was considered significant for p<0.05, p<0.1 was defined as

a statistical trend. SAS, release 9.4 (SAS Institute Inc., Cary, NC, USA) and SPSS (Version
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25, IBM Armonk, New York, USA) were used for statistics.
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Results

Entire, unmatched real-life cohort

In the entire, unmatched real-life cohort including a total of 2,813 high-risk patients, the

prevalence of COPD was 9%. Most patients were in COPD stage 1A (supplemental table 1).

As shown in Table 1 (left columns), COPD patients had higher rates of early cardiac death,

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were older and more likely to be smoker, as well had higher rates of arterial hypertension,

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diabetes mellitus, prior chronic heart failure, prior CAD, pre-existing ICD, AF, chronic

kidney disease and hyperkalaemia (p<0.05). Furthermore, COPD patients were more often

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treated with aldosterone antagonists, digitalis and amiodarone (p<0.05). In contrast, non-

COPD patients revealed higher rates of VF, cardiac family history and STEMI (p<0.05).

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Table 2 (left columns) outlines significantly higher rates of the primary endpoint of
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long-term all-cause mortality in COPD patients at 2 years after presenting with ventricular
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tachyarrhythmias and SCA on hospital admission compared to non-COPD patients (64% vs.

47%, log rank p=0.001; HR=1.488; 95% CI 1.264 – 1.752; p=0.001). COPD was associated
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with higher rates of secondary endpoints, including cardiac death at 24 hours and all-cause
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mortality at index, at 30 days and after discharge (p<0.05). Furthermore, the presence of

COPD was associated with a higher rate of the composite endpoint of cardiac death at 24
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hours, recurrences of ventricular tachyarrhythmias and appropriate ICD therapy compared to

non-COPD patients (45% vs. 38%; HR=1.215; 95% CI 1.003 – 1.473; p=0.047).
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Multivariable Cox regression analyses within the entire, unmatched real-life cohort

revealed COPD patients to be significantly associated with the primary endpoint of long-term

all-cause mortality at 2 years (HR=1.245, 95% CI 1.001 – 1.549) (Table 3A). The presence of

COPD sustained significant impact on long-term all-cause mortality in the subgroups of

females, VF, smokers, and beta-blocker therapy at discharge (Table 3B).

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Propensity-matched Cohorts

After applying propensity-score matching for the comparison of COPD versus non-

COPD (181 matched pairs) comparable subgroups with similar rates of chronic kidney

disease (glomerular filtration rate <60 mL/min per 1.73 m2), diabetes mellitus, cardiogenic

shock, CPR, overall presence of ICD, CAD, gender, ST-segment-elevating myocardial

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infarction (STEMI), non-STEMI, LVEF <35%, beta blocker therapy at discharge as well as

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smoking were achieved (Table 1, right columns).

In COPD patients a slightly higher median age remained after matching, as well as

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higher rates of early cardiac death, atrial fibrillation, hyperkalaemia and pharmacological

treatment at discharge, which were not included within the matching process. In contrast, non-

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COPD patients revealed higher rates of VF, as well as higher rates of cardiac family history.
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Figure 1 illustrates the significantly adverse prognosis for the primary endpoint of long-
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term all-cause mortality in COPD compared with non-COPD patients when presenting with

ventricular tachyarrhythmias on hospital admission (primary endpoint, all-cause mortality at 2

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years: 58% versus 39%; log rank p=0.001; HR=1.778; 95% CI 1.312-2.410; p=0.001).
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Figure 2 shows significantly adverse prognosis for the composite endpoint of cardiac

death at 24 hours, recurrences of ventricular tachyarrhythmias and appropriate ICD therapy in

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COPD patients (secondary composite endpoint: 46% versus 35%; log rank p=0.018;

HR=1.457; 95% CI 1.050-2.020; p=0.024). Accordingly, cardiac death at 24 hours, all-cause

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mortality at 30 days and at index were significantly higher in COPD compared to non-COPD

patients (p<0.05), whereas rates of all-cause mortality after discharge were comparable in

both groups (Table 2, right columns).

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Discussion

The present study evaluates the differences of prognostic outcomes depending on the

presence of COPD in consecutive patients presenting with ventricular tachyarrhythmias and

SCA on admission.

This real-world data suggests that high-risk patients presenting with ventricular

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tachyarrhythmias and SCA on admission were associated with higher long-term all-cause

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mortality in the presence of COPD compared to patients without COPD. Prognostic

differences were demonstrated even within multivariable Cox regression models and after

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propensity-score matching. Furthermore, COPD was associated with higher rates of all-cause

mortality at index, at 30 days and cardiac death at 24 hours, as well as of the composite

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endpoint of cardiac death at 24 hours, recurrences of ventricular tachyarrhythmias and
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appropriate ICD therapies.
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Therefore, this study consistently identifies the presence of COPD as a robust predictor of

adverse outcomes in patients presenting with ventricular tachyarrhythmias and SCA. The
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major strength of the present study consists in the consecutive recruitment of patients with
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ventricular tachyarrhythmias and SCA straight from the admission scenario.

The exact pathomechanisms increasing the susceptibility of COPD patients to develop

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ventricular tachyarrhythmias or SCA is not well understood. However, a multi-factorial

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pathogenesis is most likely. COPD patients suffer from recurrent hypercapnia and at more
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advanced stages from recurrent hypoxemia, which increase oxidative stress in cardiac tissue.
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This facilitates the onset of premature ectopic beats, which are known to initiate
28,29
ventricular tachyarrhythmias. Furthermore, hypercapnia and hypoxemia do cause

pulmonary arteriolar constriction leading to pulmonary hypertension and right ventricular

hypertension, which in turn increase the transmural pressure and pressure on endocardial
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vessels resulting in alterations of the blood flow and local ischemia. Moreover, hypoxemia

induces catecholamine excess and heart rate corrected QT-interval (QTc) alterations may
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28,31-35
result in a higher risk for ventricular tachyarrhythmias. Hypoxemia-induced QTc

dispersion may also be caused by a direct effect on the electrogenic pump, high intracellular

calcium and a massive efflux of K+ enabling re-entrant mechanisms. 33,36,37

From a clinical point of view, several studies demonstrated that COPD patients are

endangered by an increased risk of SCD, which was shown both in community-based cohorts

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and selected COPD only cohorts. However, data on the outcome of consecutive

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patients presenting with ventricular tachyarrhythmias or SCA accompanied by a history of

COPD on admission has never been investigated yet. In contrast, further retrospective studies

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focused on screening cohorts, and compared the incidence of ventricular tachyarrhythmia and

SCD at long-term follow-up in patients with airway obstruction to those without. For

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instance, a retrospective study of 6351 patients undergoing 24 hours holter-ECG recordings,
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pulmonary function testing and echocardiographically assessed LVEF demonstrated that
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COPD was associated with a higher rate of VT occurrence irrespective of LV dysfunction.

Moreover, COPD patients with VT showed increased all-cause mortality at long-term follow-
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up. Additionally, the population-based cohort of the Rotterdam study showed that patients
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with COPD had a higher risk for future SCD in a follow-up period up to 24 years as well as

increased all-cause mortality. 15

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Studies evaluating patients presenting with newly diagnosed ventricular tachyarrhythmias

or aborted cardiac arrest in the presence of COPD are very rare and usually focus on short-
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term outcomes in terms of 30-day mortality, whereas data on long-term outcomes are not
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available. Therefore, the present study expands current knowledge of high-risk COPD

patients with an accurate stratification into the presence of VT, VF and SCA revealing

impaired long-and short-term survival. Furthermore, COPD was also associated with

increased rates of the composite endpoint of cardiac death at 24 hours, recurrences of

ventricular tachyarrhythmias and appropriate ICD therapy at long-term follow-up. This might

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reflect the increased susceptibility of COPD patients to develop recurrent ventricular

tachyarrhythmias and early cardiac death.

A Danish registry found a 23.4% rate of COPD patients in 33,228 patients with out-of-

hospital cardiac arrest (OHCA), of which 86% revealed a non-shockable rhythm, especially in
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more pronounced grades of COPD. This is in line with the present results showing

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respectively higher rates of non-shockable arrhythmia in patients with aborted death in the

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presence of COPD (19% versus 13%). Also, COPD patients were shown to lack improvement

of 30-day survival in the presence of COPD, despite a generally improved 30-day survival

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over time in overall patients suffering from OHCA. Besides this, a retrospective case-

control study including 100 patients with LVEF <35% and no prior history of ventricular

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arrhythmia, demonstrated that COPD patients with an activated ICD for primary prevention
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revealed significantly better survival compared to COPD patients without ICD at 2-years of

follow-up. 40 It may be speculated, that the indication for ICD implantation in COPD patients
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may be irrespective of the LV dysfunction, since the present study demonstrated impaired
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survival specifically in patients with LVEF ≥35%.

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In summary, this study demonstrates increasing long-term all-cause mortality at 2 years

in COPD compared to non-COPD patients presenting consecutively with ventricular

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tachyarrhythmias and SCA on admission. Respectively, increasing rates of secondary

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endpoints, including the composite endpoint of cardiac death at 24 hours, recurrences

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ventricular tachyarrhythmias and appropriate ICD therapies, as well as all-cause mortality at

index, at 30 days and after discharge were seen in COPD compared to non-COPD patients.

Therefore, the presence of COPD represents a robust predictor of all-cause mortality in

patients presenting with ventricular tachyarrhythmias and aborted SCA, as proven also in

several subgroups. The present results therefore add to the knowledge of previous COPD

studies highlighting the need for a better risk stratification of high risk COPD patients

presenting with ventricular tachyarrhythmias and aborted SCA focussing on improvement of

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effective diagnostics and therapies of COPD patients. Regarding the higher rates of the

composite endpoint of cardiac death at 24 hours, recurrences of ventricular tachyarrhythmias

and appropriate ICD therapies in COPD patients, we propose an early ICD implantation in

pre-selected COPD patients in combination with escalated COPD therapy according to current

guidelines for secondary prevention. However, this still needs to be evaluated in future

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prospective randomized trials.

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Study limitations

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This observational and retrospective registry-based analysis reflects a realistic picture of

consecutive health-care supply of high-risk patients presenting with ventricular

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tachyarrhythmias and SCA. Lost to follow-up rate regarding the evaluated primary endpoint
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of long-term all-cause mortality was minimal. Additionally, heterogeneity within the study
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population was controlled by a stepwise statistical approach including multivariable

adjustment for several important comorbidities and risk factors. Patients not surviving out of
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hospital CPR and not being transferred to the heart centre were not included in this study. Due
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to the long period of patient recruitment (2002 – 2014) time-varying variables might occur,

such as changes of diagnostic criteria and therapeutic options, which might have altered the
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survival of both COPD and non-COPD patients. All clinical data was documented reliably by

individual cardiologists and specialists in internal medicine and pneumology during routine
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clinical care being blinded to final data analyses, alleviating the use of an independent clinical

event committee.

Conclusions

The presence of COPD is an independent predictor of all-cause mortality as well as the

composite endpoint of cardiac death at 24 hours, recurrences of ventricular tachyarrhythmias

and appropriate ICD therapies in patients with ventricular tachyarrhythmias and SCA.
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Figure Legends

Figure 1: After propensity score matching, Kaplan–Meier survival curves still

demonstrated the association of COPD and non-COPD patients with the primary endpoint of

long-term all-cause mortality at 2 years.

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Figure 2: After propensity score matching, Kaplan-Meier survival curves still

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demonstrated the association of COPD compared to non-COPD patients with the composite

endpoint of cardiac death at 24 hours, recurrences of ventricular tachyarrhythmias and

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appropriate ICD therapies.

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 ACCEPTED MANUSCRIPT

Acknowledgments

None

Funding

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This research did not receive any specific grant from funding agencies in the public,

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commercial, or not-for-profit sectors.

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Conflict of interest

The authors declare that they do not have any conflict of interest.

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References

1. McElwee SK, Velasco A, Doppalapudi H. Mechanisms of sudden cardiac death. J

Nucl Cardiol. 2016;23(6):1368-1379.

2. Priori SG, Blomstrom-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the

management of patients with ventricular arrhythmias and the prevention of sudden

PT
cardiac death: The Task Force for the Management of Patients with Ventricular

RI
Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of

Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital

SC
Cardiology (AEPC). Eur Heart J. 2015;36(41):2793-2867.

3. Kuck KH, Cappato R, Siebels J, Ruppel R. Randomized comparison of antiarrhythmic

U
drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest
AN
: the Cardiac Arrest Study Hamburg (CASH). Circulation. 2000;102(7):748-754.
M

4. Connolly SJ, Gent M, Roberts RS, et al. Canadian implantable defibrillator study

(CIDS) : a randomized trial of the implantable cardioverter defibrillator against

D

amiodarone. Circulation. 2000;101(11):1297-1302.

TE

5. Connolly SJ, Hallstrom AP, Cappato R, et al. Meta-analysis of the implantable

cardioverter defibrillator secondary prevention trials. AVID, CASH and CIDS studies.
EP

Antiarrhythmics vs Implantable Defibrillator study. Cardiac Arrest Study Hamburg .

Canadian Implantable Defibrillator Study. Eur Heart J. 2000;21(24):2071-2078.

C
AC

6. Antiarrhythmics versus Implantable Defibrillators I. A comparison of antiarrhythmic-

drug therapy with implantable defibrillators in patients resuscitated from near-fatal

ventricular arrhythmias. N Engl J Med. 1997;337(22):1576-1583.

7. Myerburg RJ, Kessler KM, Estes D, et al. Long-term survival after prehospital cardiac

arrest: analysis of outcome during an 8 year study. Circulation. 1984;70(4):538-546.

8. Baum RS, Alvarez H, 3rd, Cobb LA. Survival after resuscitation from out-of-hospital

ventricular fibrillation. Circulation. 1974;50(6):1231-1235.

21
 ACCEPTED MANUSCRIPT
9. Lopez-Campos JL, Ruiz-Ramos M, Soriano JB. Mortality trends in chronic

obstructive pulmonary disease in Europe, 1994-2010: a joinpoint regression analysis.

Lancet Respir Med. 2014;2(1):54-62.

10. Maclay JD, MacNee W. Cardiovascular disease in COPD: mechanisms. Chest.

2013;143(3):798-807.

PT
11. Sin DD, Man SF. Chronic obstructive pulmonary disease as a risk factor for

RI
cardiovascular morbidity and mortality. Proc Am Thorac Soc. 2005;2(1):8-11.

12. Huiart L, Ernst P, Suissa S. Cardiovascular morbidity and mortality in COPD. Chest.

SC
2005;128(4):2640-2646.

13. Bhatt SP, Dransfield MT. Chronic obstructive pulmonary disease and cardiovascular

U
disease. Transl Res. 2013;162(4):237-251.
AN
14. Falk JA, Kadiev S, Criner GJ, Scharf SM, Minai OA, Diaz P. Cardiac disease in
M

chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2008;5(4):543-548.

15. Lahousse L, Niemeijer MN, van den Berg ME, et al. Chronic obstructive pulmonary
D

disease and sudden cardiac death: the Rotterdam study. Eur Heart J.
TE

2015;36(27):1754-1761.

16. Konecny T, Somers KR, Park JY, et al. Chronic obstructive pulmonary disease as a
EP

risk factor for ventricular arrhythmias independent of left ventricular function. Heart

Rhythm. 2017.
C
AC

17. Goudis CA. Chronic obstructive pulmonary disease and atrial fibrillation: An

unknown relationship. J Cardiol. 2017;69(5):699-705.

18. van den Berg ME, Stricker BH, Brusselle GG, Lahousse L. Chronic obstructive

pulmonary disease and sudden cardiac death: A systematic review. Trends Cardiovasc

Med. 2016;26(7):606-613.

22
 ACCEPTED MANUSCRIPT
19. Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global Strategy for the Diagnosis,

Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report.

GOLD Executive Summary. Am J Respir Crit Care Med. 2017;195(5):557-582.

20. Konecny T, Park JY, Somers KR, et al. Relation of chronic obstructive pulmonary

disease to atrial and ventricular arrhythmias. Am J Cardiol. 2014;114(2):272-277.

PT
21. Hawkins NM, Huang Z, Pieper KS, et al. Chronic obstructive pulmonary disease is an

RI
independent predictor of death but not atherosclerotic events in patients with

myocardial infarction: analysis of the Valsartan in Acute Myocardial Infarction Trial

SC
(VALIANT). Eur J Heart Fail. 2009;11(3):292-298.

22. Fuso L, Incalzi RA, Pistelli R, et al. Predicting mortality of patients hospitalized for

acutely exacerbated chronic

U
obstructive pulmonary disease. Am J Med.
AN
1995;98(3):272-277.
M

23. Nishiyama K, Shizuta S, Doi T, Morimoto T, Kimura T. Sudden cardiac death after

PCI and CABG in the bare-metal stent era: Incidence, prevalence, and predictors. Int J
D

Cardiol. 2010;144(2):263-266.
TE

24. Blom MT, Warnier MJ, Bardai A, et al. Reduced in-hospital survival rates of out-of-

hospital cardiac arrest victims with obstructive pulmonary disease. Resuscitation.

EP

2013;84(5):569-574.

25. Engstrom G, Wollmer P, Hedblad B, Juul-Moller S, Valind S, Janzon L. Occurrence

C
AC

and prognostic significance of ventricular arrhythmia is related to pulmonary function:

a study from "men born in 1914," Malmo, Sweden. Circulation. 2001;103(25):3086-

3091.

26. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 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

23
 ACCEPTED MANUSCRIPT
Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm

Society. Circulation. 2017.

27. Austin PC. An Introduction to Propensity Score Methods for Reducing the Effects of

Confounding in Observational Studies. Multivariate Behav Res. 2011;46(3):399-424.

28. Incalzi RA, Pistelli R, Fuso L, Cocchi A, Bonetti MG, Giordano A. Cardiac

PT
arrhythmias and left ventricular function in respiratory failure from chronic

RI
obstructive pulmonary disease. Chest. 1990;97(5):1092-1097.

29. Noda T, Shimizu W, Taguchi A, et al. Malignant entity of idiopathic ventricular

SC
fibrillation and polymorphic ventricular tachycardia initiated by premature

extrasystoles originating from the right ventricular outflow tract. J Am Coll Cardiol.

2005;46(7):1288-1294.
U
AN
30. Terzano C, Romani S, Conti V, Paone G, Oriolo F, Vitarelli A. Atrial fibrillation in
M

the acute, hypercapnic exacerbations of COPD. Eur Rev Med Pharmacol Sci.

2014;18(19):2908-2917.
D

31. Naksuk N, Kunisaki KM, Benditt DG, Tholakanahalli V, Adabag S. Implantable

TE

cardioverter-defibrillators in patients with COPD. Chest. 2013;144(3):778-783.

32. Stewart AG, Waterhouse JC, Howard P. The QTc interval, autonomic neuropathy and
EP

mortality in hypoxaemic COPD. Respir Med. 1995;89(2):79-84.

33. Sarubbi B, Esposito V, Ducceschi V, et al. Effect of blood gas derangement on QTc
C
AC

dispersion in severe chronic obstructive pulmonary disease: evidence of an

electropathy? Int J Cardiol. 1997;58(3):287-292.

34. Sievi NA, Clarenbach CF, Camen G, Rossi VA, van Gestel AJ, Kohler M. High

prevalence of altered cardiac repolarization in patients with COPD. BMC Pulm Med.

2014;14:55.

35. Yildiz P, Tukek T, Akkaya V, et al. Ventricular arrhythmias in patients with COPD

are associated with QT dispersion. Chest. 2002;122(6):2055-2061.

24
 ACCEPTED MANUSCRIPT
36. Coronel R. Heterogeneity in extracellular potassium concentration during early

myocardial ischaemia and reperfusion: implications for arrhythmogenesis. Cardiovasc

Res. 1994;28(6):770-777.

37. Silverman HS, Stern MD. Ionic basis of ischaemic cardiac injury: insights from

cellular studies. Cardiovasc Res. 1994;28(5):581-597.

PT
38. Granfeldt A, Wissenberg M, Hansen SM, et al. Severity of chronic obstructive

RI
pulmonary disease and presenting rhythm in patients with out-of-hospital cardiac

arrest. Resuscitation. 2018;126:111-117.

SC
39. Moller SG, Rajan S, Folke F, et al. Temporal trends in survival after out-of-hospital

cardiac arrest in patients with and without underlying chronic obstructive pulmonary

U
disease. Resuscitation. 2016;104:76-82.
AN
40. Razak E, Kamireddy S, Saba S. Implantable cardioverter-defibrillators confer survival
M

benefit in patients with chronic obstructive pulmonary disease. Pacing Clin

Electrophysiol. 2010;33(9):1125-1130.
D
TE
C EP
AC

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Table 1. Baseline characteristics comparing patients with and without COPD presenting with ventricular tachyarrhythmia.
before matching (n=2,813) after matching (n=362)
Non-COPD COPD Non-COPD COPD
Characteristic ACCEPTED
(n=2,556; 91%) MANUSCRIPT
(n=257;9%)
p value
(n=181; 50%) (n=181; 50%)
p value
Inclusion criteria, n (%)
Ventricular tachycardia 1227 (48) 137 (53) 0.105 104 (58) 106 (59) 0.831
Ventricular fibrillation 987 (39) 71 (28) 0.001 69 (38) 49 (27) 0.025
Early cardiac death 727 (28) 93 (36) 0.001 26 (14) 48 (27) 0.004
With VT 116 (5) 18 (7) 0.404 7 (4) 9 (5) 0.389
With VF 269 (11) 26 (10) 0.087 12 (7) 16 (9) 0.252
Without VA 342 (13) 49 (19) 0.305 8 (4) 26 (14) 0.070
Gender, n (%)
Male 1792 (70) 194 (75) 0.071 151 (83) 142 (79) 0.228
Age, median (range) 68 (14-100) 72 (37-91) 0.001 71 (21-100) 72 (46-89) 0.012
Cardiovascular risk factors, n (%)
Arterial hypertension 1379 (54) 175 (68) 0.001 129 (71) 132 (73) 0.725
Diabetes mellitus 652 (26) 98 (38) 0.001 64 (35) 69 (38) 0.586

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Hyperlipidemia 644 (25) 74 (29) 0.207 60 (33) 60 (33) 1.000
Smoking 577 (23) 126 (49) 0.001 84 (46) 92 (51) 0.400
Cardiac family history 222 (9) 9 (4) 0.004 25 (14) 5 (3) 0.001
Comorbidities, n (%)

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Prior chronic heart failure 536 (21) 94 (37) 0.001 74 (41) 81 (45) 0.457
Prior coronary artery disease 960 (38) 129 (50) 0.001 94 (52) 104 (58) 0.291
Prior myocardial infarction 552 (22) 61 (24) 0.428 65 (36) 49 (27) 0.070
Acute myocardial infarction 762 (39) 63 (25) 0.075 45 (25) 47 (26) 0.809

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STEMI 265 (10) 11 (4) 0.002 3 (2) 9 (5) 0.078
NSTEMI 497 (19) 52 (20) 0.761 42 (23) 38 (21) 0.612
Pre-existing ICD 227 (9) 41 (16) 0.001 24 (13) 33 (18) 0.194
Atrial fibrillation 438 (17) 103 (39) 0.001 54 (22) 81 (36) 0.003
Chronic kidney disease 1283 (50) 165 (64) 0.001 96 (54) 114 (63) 0.088

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Cardiogenic shock 520 (20) 47 (18) 0.433 33 (18) 29 (16) 0.577
Hyperkalemia 76 (3) 14 (5) 0.032 2 (1) 9 (5) 0.031
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Hypokalemia 132 (5) 15 (6) 0.644 9 (5) 10 (6) 0.814
Stroke 73 (3) 10 (4) 0.350 8 (4) 8 (4) 1.000
Left ventricular ejection function, n (%)
LVEF ≥55% 535 (30) 48 (26) 46 (30) 39 (25)
LVEF 54-35% 593 (34) 56 (30) 0.150 52 (33) 50 (32) 0.735
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LVEF <35% 631 (36) 80 (44) 57 (37) 32 (21)

Cardiac therapies at index, n (%)
Cardiopulmonary resuscitation 1,37 (54) 133 (52) 0.547 52 (33) 55 (36) 0.720
In hospital 602 (23) 71 (28) 33 (21) 24 (16)
0.096 0.114
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Out of hospital 771 (31) 62 (24) 19 (12) 31 (20)

Coronary artery disease, n (%)
Coronary angiography, overall 1,426 (56) 118 (46) 0.002 97 (63) 81 (52) 0.066
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Coronary artery disease 1,072 (75) 88 (74) 0.912 70 (72) 62 (77) 0.358
No evidence of CAD 354 (25) 30 (25) 27 (28) 22 (27)
1-vessel 322 (23) 30 (25) 27 (28) 22 (27)
0.416 0.810
2-vessel 336 (24) 20 (17) 19 (20) 15 (19)
3-vessel 414 (29) 38 (32) 24 (25) 25 (31)
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CTO 296 (21) 29 (25) 0.328 18 (19) 20 (25) 0.320

Presence of CABG 177 (12) 19 (16) 0.247 16 (17) 18 (22) 0.333
Intracoronary thrombus 127 (9) 7 (6) 0.254 5 (5) 3 (4) 0.729
PCI, n (%) 675 (47) 45 (38) 0.054 34 (35) 27 (33) 0.810
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Target lesions
RCA 247 (37) 17 (38) 0.873 18 (52) 8 (29) 0.067
LMT 48 (7) 5 (11) 0.320 0 (0) 1 (4) 0.442
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LAD 343 (51) 18 (40) 0.160 15 (44) 10 (37) 0.576

RIM 15 (2) 0 (0) 0.616 0 (0) 0 (0) -
LCX 163 (24) 13 (29) 0.474 6 (17) 12 (44) 0.022
Patients discharged, n (%) 1576 (62) 131 (51) 0.001 132 (85) 107 (69) 0.001
Overall ICDs, n (%) 760 (48) 78 (60) 0.013 84 (62) 67 (62) 0.965
Medication at discharge, n (%)
Beta-blocker 1256 (80) 98 (75) 0.185 107 (79) 86 (80) 0.856
ACE-inhibitor/ ARB 1133 (72) 100 (76) 0.275 107 (79) 85 (79) 0.996
Aldosterone antagonist 157 (10) 24 (18) 0.003 4 (3) 23 (21) 0.001
Digitalis 183 (12) 26 (20) 0.006 25 (18) 23 (21) 0.570
Amiodarone 229 (15) 30 (23) 0.010 27 (20) 24 (22) 0.651
Statin 946 (60) 81 (62) 0.685 80 (59) 68 (63) 0.511
ACE indicates angiotensin-converting enzyme; AMI, acute myocardial infarction; ARB, angiotensin receptor blocker; CABG, coronary
artery bypass grafting; CAD, coronary artery disease; CTO, chronic total occlusion; ICD; internal cardioverter defibrillator; LAD, left
artery descending; LVEF, left ventricular ejection fraction; LCX, left circumflex; LMT, left main trunk; PCI, percutaneous coronary
intervention; RCA, right coronary artery; RIM, ramus intermedius; STEMI/NSTEMI, (non) ST segment myocardial infarction; VF,
ventricular fibrillation; VT, ventricular tachycardia.
Bold type indicates statistical significance p<0.05.
Table 2. Primary and secondary endpoints. ACCEPTED MANUSCRIPT
before matching (n=2,813) after matching (n=362)
Non-COPD COPD P Non-COPD COPD P
(n=2,556; 91%) (n=257;9%) value (n=181; 50%) (n=181; 50%) value

Primary endpoint, n (%)

All cause-mortality, at 2 years 1197 (47) 164 (64) 0.001 70 (39) 104 (58) 0.001

Secondary endpoints, n (%)

Cardiac death, at 24 hours 714 (28) 89 (35) 0.023 26 (14) 48 (27) 0.004
All-cause mortality, at 30 days 960 (38) 123 (48) 0.001 43 (24) 71 (39) 0.002
All-cause mortality, at index 980 (38) 126 (49) 0.001 45 (25) 73 (40) 0.001
All-cause mortality, after discharge 217 (8) 38 (15) 0.001 25 (14) 31 (18) 0.383

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Composite endpoint * 980 (38) 116 (45) 0.033 63 (35) 83 (46) 0.032
Cardiac rehospitalization 190 (7) 24 (9) 0.272 21 (12) 21 (12) 1.000

Follow up times

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Hospitalization total; days (median (IQR)) 9 (3-18) 11 (4-23) 0.001 10 (6-21) 15 (7-26) 0.215
ICU time; days (median (IQR)) 4 (2-9) 4 (1-9) 0.001 2 (0-6) 4 (1-10) 0.001
Follow-up; days (mean; median (range)) 1227; 527 673; 46 1705; 1733 244; 846
(0-5106) (0-5091) 0.001 (0-5095) (0-5091) 0.001

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ICU, intensive care unit; IQR, interquartile range.

*composite endpoint comprising recurrences of ventricular tachyarrhythmias and appropriate ICD therapy and cardiac death at 24h.

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Table 3 A. Unmatched uni- and multivariable hazard ratios to predict the primary prognostic
endpoint of long-term all-cause mortality at 2 years (n = 2,813)
univariable multivariable
HR 95% CI HR 95% CI
Age 1.035 1.030-1.039 1.026 1.019-1.032
Male gender 0.880 0.785-0.987 1.113 0.940-1.318
Diabetes 1.394 1.244-1.562 1.062 0.906-1.246
CKD 3.226 2.842-3.662 1.810 1.511-2.169

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AF 1.088 0.970-1.221 0.894 0.764-1.046
CAD 0.885 0.794-0.986 1.184 0.982-1.427
AMI 1.363 1.218-1.525 0.898 0.756-1.067

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LVEF <35% 1.448 1.253-1.673 1.569 1.343-1.833
Cardiogenic shock 3.018 2.691-3.384 1.606 1.357-1.901
CPR 2.342 2.195-2.499 1.555 1.411-1.714

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Smoking 0.641 0.560-0.734 0.985 0.821-1.181
Beta-blocker at discharge 0.088 0.075-0.102 0.142 0.117-0.174
Overall ICD 0.183 0.154-0.218 0.438 0.352-0.545
COPD 1.488 1.264-1.752 1.245 1.001-1.549

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AF, atrial fibrillation; AMI, acute myocardial infarction; CAD, coronary artery disease; CI; confidence
interval; CKD, chronic kidney disease; CPR, cardiopulmonary resuscitation; HR; hazard ratio; ICD,
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implantable cardioverter defibrillator; LVEF, left ventricular ejection faction.

Bold type indicates statistical significance p<0.05.

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Table 3 B. Unmachted univariable and multivariable hazard ratios for the association of COPD with the primary
prognostic endpoint of long-term all-cause mortality at 2 years in pre-specified subgroups.
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univariable multivariable
n (%) HR 95% CI HR 95% CI
Females 827 (29) 1.576 1.146-2.169 1.695 1.040-2.763
Males 1986 (71) 1.473 1.218-1.782 1.147 0.897-1.468
VT 1364 (49) 1.654 1.252-2.185 1.192 0.841-1.688
VF 1058 (38) 1.827 1.389-2.403 1.454 1.000-2.115

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LVEF ≥35% 1232 (44) 2.175 1.661-2.849 1.219 0.910-1.633
LVEF <35% 711 (37) 1.280 0.929-1.764 - -
ICD 882 (31) 1.884 1.208-2.940 1.463 0.896-2.389

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Non-ICD 1931 (69) 1.530 1.283-1.824 1.248 0.976-1.595
Smokers 703 (25) 1.980 1.507-2.602 1.509 1.051-2.166
Non-smokers 2110 (75) 1.559 1.260-1.928 1.095 0.823-1.457

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Beta-blocker, at discharge 1354 (47) 2.216 1.465-3.352 1.617 1.245-2.506
No beta-blocker, at discharge 353 (13) 1.128 0.944-1.347 - -

CI; confidence interval; HR; hazard ratio; ICD, implantable cardioverter defibrillator; LVEF, left ventricular ejection

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faction; VF, ventricular fibrillation; VT, ventricular tachycardia.
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multivariable models were adjusted for age, gender, diabetes mellitus, chronic kidney disease, atrial fibrillation (AF),
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coronary artery disease (CAD), acute myocardial infarction (AMI), LVEF, cardio-pulmonary resuscitation (CPR),
cardiogenic shock, smoking, Beta-blocker therapy and ICD.
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after propensity score matching

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Log-rank p = 0.001
Non-COPD COPD
All-cause mortality,
(n=181; 50%) (n=181; 50%)
n (%)
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70 (39) 104 (58)

Patients at risk
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Non-COPD 181 128 121 116 110

COPD 181 93 79 77 69
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after propensity score matching

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Log-rank p = 0.018

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Non-COPD COPD
Composite endpoint,
(n=181; 50%) (n=181; 50%)
n (%)
63 (35) 83 (46)
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Patients at risk
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Non-COPD 181 133 124 118 116

COPD 181 108 102 96 87
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Highlights:
COPD Increases Mortality in Patients Presenting with
Ventricular Tachyarrhythmias and Aborted Cardiac Arrest

• COPD increases mortality in patients with ventricular tachyarrhythmias

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and SCA.
• COPD was associated with the primary endpoint of long-term all-cause

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mortality.
• Results showed consistency in multivariable regression and propensity

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score matching.
• COPD was associated with secondary endpoints such as cardiac death at
24 hours.
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