COPD increases cardiac mortality in patients presenting with ventricular tachyarrhythmias and aborted cardiac arrest

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. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

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

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Jonas Rusnak MD1*; Michael Behnes MD1*; Tobias Schupp MS1; Linda Reiser MS1; Armin Bollow MS1; Gabriel Taton MS1; Thomas Reichelt MS1; Dominik Ellguth MS1; 2 Niko Engelke MS1; Jorge Hoppner MD ; Kathrin Weidner MD1; Ibrahim-El-Battrawy MD1; Kambis Mashayekhi MD3; Christel Weiß PhD4; Martin Borggrefe MD1; Ibrahim Akin MD1 1

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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, Germany. 2Department of Diagnostic and Interventional Radiology, University Heidelberg, Heidelberg, Germany. 3 Department of Cardiology and Angiology II, University Heart Center Freiburg • Bad Krozingen, Bad Krozingen, Germany. 4 Institute of Biomathematics and Medical Statistics, University Medical Center Mannheim (UMM), Faculty of Medicine Mannheim, Heidelberg University, Mannheim, Germany.

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

Ventricular tachyarrhythmias and SCA in patients with COPD sudden cardiac arrest, aborted cardiac arrest, ventricular tachyarrhythmia, ventricular fibrillation, COPD, pulmonary disease Word count: 3696

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Brief Title: Key words:

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No conflict of interest for all authors

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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: [email protected]

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ACCEPTED MANUSCRIPT 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.

ventricular tachyarrhythmias and SCA is limited.

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

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

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regression models and propensity-score matching for evaluation of the primary prognostic endpoint defined as long-term all-cause mortality at 2 years. Secondary endpoints were allcause 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. Results: In 2,813 unmatched high-risk patients with ventricular tachyarrhythmias and SCA, COPD was present in 9% with slightly higher rates of early cardiac death (36% versus

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

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endpoint of long-term all-cause mortality (HR=1.245; 95% CI 1.001-1.549), which was also proven after propensity score matching (58% versus 39%; log rank p=0.001; HR=1.778; 95% 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 2

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

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tachyarrhythmias and appropriate ICD therapies at 2 years.

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ACCEPTED MANUSCRIPT 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

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independently associated with higher all-cause mortality, cardiac death at 24 hours and higher rates of the composite endpoint of cardiac death at 24 hours, recurrences of ventricular

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tachyarrhythmias and appropriate ICD therapy.

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ACCEPTED MANUSCRIPT Introduction Sudden cardiac arrest (SCA) and sudden cardiac death (SCD) are commonly caused by ventricular tachyarrhythmias.

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Therefore, patients at increased risk of SCD should receive

implantable cardioverter defibrillators (ICD) to interrupt recurrences of ventricular

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tachyarrhythmias. 2 Patients presenting with ventricular tachyarrhythmias or aborted SCA and arriving the emergency department reveal an increased risk for all-cause mortality and recurrent cardiac arrest. 3-8

decreasing prevalence in the Western world.

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

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significantly higher number of adverse clinical events, including acute exacerbation with consecutive rehospitalization. COPD was recently shown to affect both cardiac structure and function 10-12

Cardiac arrhythmias represent the most common cardiac manifestation related to COPD

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limiting the long-term prognosis of the affected patients.

13-15

There is increasing evidence

that the myocardium is more susceptible for arrhythmias in COPD patients, which is indicated by an increased frequency of ventricular ectopic and paired premature ventricular beats.

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

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recurrent hypoxemia at more advanced stages, as well as by alterations of the QTc interval and adverse side effects of bronchodilators. 15-19 Several screening and community-based studies could demonstrate a higher cardiovascular risk, increased mortality and incidence of ventricular tachyarrhythmias and SCD in COPD patients.

15,16,20-23

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 pulmonary disease.

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In 402 men mean-aged at 68 years without a prior history of acute 5

ACCEPTED MANUSCRIPT 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;

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Lown Class 4a: couplets; Lown Class 4b: ventricular tachycardia; Lown Class 5: R-on-T type). 25

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

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independently increase mortality in real-life patients presenting consecutively on admission with ventricular tachyarrhythmias and SCA irrespective of the underlying etiology. Therefore,

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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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ACCEPTED MANUSCRIPT Methods Study patients, design and data collection The present study retrospectively included all consecutive patients presenting with

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

data related to the index event was documented.

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

guidelines.

2,26

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Ventricular tachyarrhythmias comprised VT and VF as defined by current international Sustained VT was defined by duration of >30 seconds or causing

hemodynamic collapse within 30 seconds, non-sustained VT by duration <30 seconds both with wide QRS complex (≥120 milliseconds) at a rate greater than 100 beats per minute.

2

Ventricular tachyarrhythmias were documented by 12-lead electrocardiogram (ECG), ECG

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tele-monitoring, implantable cardioverter defibrillator (ICD) or in case of unstable course or during resuscitation by external defibrillator monitoring. Documented VF was treated by external defibrillation and in case of prolonged instability with additional intravenous anti-

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arrhythmic drugs during cardiopulmonary resuscitation (CPR). 2

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Further data being documented contained baseline characteristics, prior medical history, prior medical treatment, length of index stay, detailed findings of laboratory values at 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 7

ACCEPTED MANUSCRIPT 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

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pharmacological therapies are referred to the number of surviving patients being discharged from index hospitalization.

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

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to recurrent ventricular tachyarrhythmias and adverse cardiac events. Adverse cardiac events comprised acute heart failure, CPR, cardiac surgery, new implants or upgrades of cardiac

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devices, worsening or improvement of left ventricular function.

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

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

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

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2016. The registry was performed according to the principles of the declaration of Helsinki 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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ACCEPTED MANUSCRIPT 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

COPD according to latest GOLD guidelines. 19

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

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

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Spirometric assessment was evaluated separately from symptom evaluation. Spirometric airflow limitation was graduated by FEV1 (% predicted): GOLD 1 = ≥80; GOLD 2 = 50-79;

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GOLD 3 = 30-49; GOLD 4 = <30. Symptoms were graduated by exacerbation history and mMRC: GOLD A = mMRC 0-1 and 0-1 exacerbations without hospital admission; GOLD B = mMRC ≥2 and 0-1 exacerbations without hospital admission; GOLD C = mMRC 0-1 and ≥2 exacerbations with hospital admission; GOLD D = mMRC ≥2 and ≥2 exacerbations with

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hospital admission.

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

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episode of ventricular tachyarrhythmias or SCA.

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Study Endpoints

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 followup. 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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ACCEPTED MANUSCRIPT 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

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

Statistical methods

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Quantitative data are presented as mean ± standard error of mean (SEM), median and interquartile range (IQR), and ranges depending on the distribution of the data and were

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compared using the Student’s t test for normally distributed data or the Mann-Whitney U test for nonparametric data. Deviations from a Gaussian distribution were tested by the Kolmogorov-Smirnov test. Spearman’s rank correlation for nonparametric data was used to test univariate correlations. Qualitative data are presented as absolute and relative frequencies

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

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

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COPD. Then, multivariable Cox regression models were applied for the primary prognostic 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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ACCEPTED MANUSCRIPT 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

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several reasons (ie, funding, recruitment, difficult study settings, high-risk patients, etc). Therefore, we felt that the method of propensity matching would be a reasonable additional statistical method beside multivariable Cox regression models for the purpose of the present

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study evaluating the prognostic impact of COPD in high-risk patients presenting with ventricular tachyarrhythmias and SCA on admission. These high-risk patients are usually

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

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because of different pathophysiologies and treatment recommendations. An observational study usually recruits consecutive real-life patients without randomization resulting in varying chances between 0% and 100% to receive imbalances in baseline characteristics and

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treatments. Therefore, differences of outcomes in specific disease groups might be explained by heterogeneous distribution of baseline characteristics and applied therapies. To further

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reduce this selection bias, we used 1:1 propensity-scores for COPD versus non-COPD, to 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, ST11

ACCEPTED MANUSCRIPT 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

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<5%). Uni-variable stratification was performed using the Kaplan–Meier method with comparisons between groups using univariable hazard ratios (HR) given together with 95% confidence intervals, according to the presence of COPD within the propensity-matched

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cohorts.

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

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patients to guarantee complete follow-up of at least 50% of patients, which is needed to sufficiently address the main objective of this registry study. Patients not meeting long-term follow-up were censored.

The result of a statistical test was considered significant for p<0.05, p<0.1 was defined as

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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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ACCEPTED MANUSCRIPT 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).

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As shown in Table 1 (left columns), COPD patients had higher rates of early cardiac death, were older and more likely to be smoker, as well had higher rates of arterial hypertension, diabetes mellitus, prior chronic heart failure, prior CAD, pre-existing ICD, AF, chronic

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kidney disease and hyperkalaemia (p<0.05). Furthermore, COPD patients were more often treated with aldosterone antagonists, digitalis and amiodarone (p<0.05). In contrast, non-

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COPD patients revealed higher rates of VF, cardiac family history and STEMI (p<0.05). Table 2 (left columns) outlines significantly higher rates of the primary endpoint of long-term all-cause mortality in COPD patients at 2 years after presenting with ventricular tachyarrhythmias and SCA on hospital admission compared to non-COPD patients (64% vs.

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

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

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non-COPD patients (45% vs. 38%; HR=1.215; 95% CI 1.003 – 1.473; p=0.047). 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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ACCEPTED MANUSCRIPT Propensity-matched Cohorts After applying propensity-score matching for the comparison of COPD versus nonCOPD (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

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shock, CPR, overall presence of ICD, CAD, gender, ST-segment-elevating myocardial infarction (STEMI), non-STEMI, LVEF <35%, beta blocker therapy at discharge as well as smoking were achieved (Table 1, right columns).

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In COPD patients a slightly higher median age remained after matching, as well as higher rates of early cardiac death, atrial fibrillation, hyperkalaemia and pharmacological

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treatment at discharge, which were not included within the matching process. In contrast, nonCOPD patients revealed higher rates of VF, as well as higher rates of cardiac family history. Figure 1 illustrates the significantly adverse prognosis for the primary endpoint of longterm all-cause mortality in COPD compared with non-COPD patients when presenting with

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ventricular tachyarrhythmias on hospital admission (primary endpoint, all-cause mortality at 2 years: 58% versus 39%; log rank p=0.001; HR=1.778; 95% CI 1.312-2.410; p=0.001). Figure 2 shows significantly adverse prognosis for the composite endpoint of cardiac

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death at 24 hours, recurrences of ventricular tachyarrhythmias and appropriate ICD therapy in COPD patients (secondary composite endpoint: 46% versus 35%; log rank p=0.018;

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

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This real-world data suggests that high-risk patients presenting with ventricular tachyarrhythmias and SCA on admission were associated with higher long-term all-cause mortality in the presence of COPD compared to patients without COPD. Prognostic

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differences were demonstrated even within multivariable Cox regression models and after propensity-score matching. Furthermore, COPD was associated with higher rates of all-cause

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mortality at index, at 30 days and cardiac death at 24 hours, as well as of the composite endpoint of cardiac death at 24 hours, recurrences of ventricular tachyarrhythmias and appropriate ICD therapies.

Therefore, this study consistently identifies the presence of COPD as a robust predictor of

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

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The exact pathomechanisms increasing the susceptibility of COPD patients to develop ventricular tachyarrhythmias or SCA is not well understood. However, a multi-factorial

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pathogenesis is most likely.

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COPD patients suffer from recurrent hypercapnia and at more

advanced stages from recurrent hypoxemia, which increase oxidative stress in cardiac tissue. 10,17

This facilitates the onset of premature ectopic beats, which are known to initiate

ventricular tachyarrhythmias.

28,29

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 vessels resulting in alterations of the blood flow and local ischemia.

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Moreover, hypoxemia

induces catecholamine excess and heart rate corrected QT-interval (QTc) alterations may 15

ACCEPTED MANUSCRIPT result in a higher risk for ventricular tachyarrhythmias.

28,31-35

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

and selected COPD only cohorts.

15,16,20,31

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endangered by an increased risk of SCD, which was shown both in community-based cohorts However, data on the outcome of consecutive

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

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COPD on admission has never been investigated yet. In contrast, further retrospective studies focused on screening cohorts, and compared the incidence of ventricular tachyarrhythmia and

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

For

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

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up.

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Moreover, COPD patients with VT showed increased all-cause mortality at long-term followAdditionally, the population-based cohort of the Rotterdam study showed that patients

with COPD had a higher risk for future SCD in a follow-up period up to 24 years as well as

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increased all-cause mortality. 15

Studies evaluating patients presenting with newly diagnosed ventricular tachyarrhythmias

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or aborted cardiac arrest in the presence of COPD are very rare and usually focus on shortterm outcomes in terms of 30-day mortality, whereas data on long-term outcomes are not available.

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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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ACCEPTED MANUSCRIPT 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-ofhospital cardiac arrest (OHCA), of which 86% revealed a non-shockable rhythm, especially in 38

This is in line with the present results showing

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more pronounced grades of COPD.

respectively higher rates of non-shockable arrhythmia in patients with aborted death in the presence of COPD (19% versus 13%). Also, COPD patients were shown to lack improvement

over time in overall patients suffering from OHCA.

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of 30-day survival in the presence of COPD, despite a generally improved 30-day survival 39

Besides this, a retrospective case-

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control study including 100 patients with LVEF <35% and no prior history of ventricular arrhythmia, demonstrated that COPD patients with an activated ICD for primary prevention 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 survival specifically in patients with LVEF ≥35%. In summary, this study demonstrates increasing long-term all-cause mortality at 2 years

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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 endpoints, including the composite endpoint of cardiac death at 24 hours, recurrences 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 17

ACCEPTED MANUSCRIPT 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

prospective randomized trials.

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Study limitations

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

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

supply of

high-risk

patients

presenting

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consecutive

with

ventricular

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

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

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

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individual cardiologists and specialists in internal medicine and pneumology during routine 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. 18

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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

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long-term all-cause mortality at 2 years.

Figure 2: After propensity score matching, Kaplan-Meier survival curves still demonstrated the association of COPD compared to non-COPD patients with 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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Acknowledgments

Funding

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None

commercial, or not-for-profit sectors.

Conflict of interest

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

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

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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 p value p value ACCEPTED (n=2,556; 91%) MANUSCRIPT (n=257;9%) (n=181; 50%) (n=181; 50%) Inclusion criteria, n (%) 1227 (48) 137 (53) 104 (58) 106 (59) 0.105 0.831 Ventricular tachycardia 0.001 0.025 Ventricular fibrillation 987 (39) 71 (28) 69 (38) 49 (27) 0.001 0.004 26 (14) 48 (27) Early cardiac death 727 (28) 93 (36) 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 68 (14-100) 72 (37-91) 71 (21-100) 72 (46-89) 0.001 0.012 Age, median (range) Cardiovascular risk factors, n (%) 0.001 Arterial hypertension 1379 (54) 175 (68) 129 (71) 132 (73) 0.725 0.001 Diabetes mellitus 652 (26) 98 (38) 64 (35) 69 (38) 0.586 Hyperlipidemia 644 (25) 74 (29) 0.207 60 (33) 60 (33) 1.000 0.001 Smoking 577 (23) 126 (49) 84 (46) 92 (51) 0.400 0.004 0.001 Cardiac family history 222 (9) 9 (4) 25 (14) 5 (3) Comorbidities, n (%) 0.001 Prior chronic heart failure 536 (21) 94 (37) 74 (41) 81 (45) 0.457 0.001 Prior coronary artery disease 960 (38) 129 (50) 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 0.002 STEMI 265 (10) 11 (4) 3 (2) 9 (5) 0.078 NSTEMI 497 (19) 52 (20) 0.761 42 (23) 38 (21) 0.612 0.001 24 (13) 33 (18) 0.194 Pre-existing ICD 227 (9) 41 (16) 0.001 0.003 Atrial fibrillation 438 (17) 103 (39) 54 (22) 81 (36) 0.001 Chronic kidney disease 1283 (50) 165 (64) 96 (54) 114 (63) 0.088 Cardiogenic shock 520 (20) 47 (18) 0.433 33 (18) 29 (16) 0.577 0.032 0.031 Hyperkalemia 76 (3) 14 (5) 2 (1) 9 (5) 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 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 Out of hospital 771 (31) 62 (24) 19 (12) 31 (20) Coronary artery disease, n (%) 0.002 Coronary angiography, overall 1,426 (56) 118 (46) 97 (63) 81 (52) 0.066 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) 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 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 LAD 343 (51) 18 (40) 0.160 15 (44) 10 (37) 0.576 RIM 15 (2) 0 (0) 0.616 0 (0) 0 (0) 0.022 LCX 163 (24) 13 (29) 0.474 6 (17) 12 (44) 0.001 0.001 Patients discharged, n (%) 1576 (62) 131 (51) 132 (85) 107 (69) 0.013 Overall ICDs, n (%) 760 (48) 78 (60) 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 0.003 0.001 Aldosterone antagonist 157 (10) 24 (18) 4 (3) 23 (21) 0.006 Digitalis 183 (12) 26 (20) 25 (18) 23 (21) 0.570 0.010 Amiodarone 229 (15) 30 (23) 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.

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Table 2. Primary and secondary endpoints.

before matching (n=2,813) Non-COPD COPD P value (n=2,556; 91%) (n=257;9%)

Follow up times Hospitalization total; days (median (IQR)) ICU time; days (median (IQR)) Follow-up; days (mean; median (range))

(47)

164

(64)

0.001

70

(39)

104

(58)

0.001

714 960 980 217 980 190

(28) (38) (38) (8) (38) (7)

89 123 126 38 116 24

(35) (48) (49) (15) (45) (9)

0.023 0.001 0.001 0.001 0.033 0.272

26 43 45 25 63 21

(14) (24) (25) (14) (35) (12)

48 71 73 31 83 21

(27) (39) (40) (18) (46) (12)

0.004 0.002 0.001 0.383 0.032 1.000

0.001 0.001

10 (6-21) 2 (0-6)

15 (7-26) 4 (1-10)

0.215 0.001

0.001

1705; 1733 (0-5095)

244; 846 (0-5091)

0.001

9 (3-18) 4 (2-9) 1227; 527 (0-5106)

ICU, intensive care unit; IQR, interquartile range.

11 (4-23) 4 (1-9) 673; 46 (0-5091)

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Secondary endpoints, n (%) Cardiac death, at 24 hours All-cause mortality, at 30 days All-cause mortality, at index All-cause mortality, after discharge Composite endpoint * Cardiac rehospitalization

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

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P value

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Primary endpoint, n (%) All cause-mortality, at 2 years

after matching (n=362) Non-COPD COPD (n=181; 50%) (n=181; 50%)

ACCEPTED MANUSCRIPT 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

3.226

2.842-3.662

1.810

AF

1.088

0.970-1.221

0.894

1.511-2.169

CAD

0.885

0.794-0.986

1.184

AMI

1.363

1.218-1.525

0.898

LVEF <35%

1.448

1.253-1.673

1.569

Cardiogenic shock

3.018

2.691-3.384

1.606

CPR

2.342

2.195-2.499

1.555

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

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CKD

0.764-1.046

0.982-1.427 0.756-1.067

1.343-1.833 1.357-1.901

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1.411-1.714

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Bold type indicates statistical significance p<0.05.

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1.488 1.264-1.752 1.245 1.001-1.549 COPD 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, implantable cardioverter defibrillator; LVEF, left ventricular ejection faction.

ACCEPTED MANUSCRIPT 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. * univariable multivariable n (%)

HR

95% CI

HR

95% CI

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

LVEF ≥35%

1232 (44)

2.175

1.661-2.849

LVEF <35%

711 (37)

1.280

0.929-1.764

ICD

882 (31)

1.884

1.208-2.940

Non-ICD

1931 (69)

1.530

1.283-1.824

Smokers

703 (25)

1.980

1.507-2.602

Non-smokers

2110 (75)

1.559

1.260-1.928

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

-

-

1.000-2.115

0.910-1.633

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1.454

1.219 -

-

1.463

0.896-2.389

1.248

0.976-1.595

1.509

1.051-2.166

1.095

0.823-1.457

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multivariable models were adjusted for age, gender, diabetes mellitus, chronic kidney disease, atrial fibrillation (AF), 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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Patients at risk Non-COPD COPD

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after propensity score matching

181 181

Log-rank p = 0.001

All-cause mortality, n (%)

128 93

121 79

Non-COPD (n=181; 50%) 70 (39)

116 77

COPD (n=181; 50%) 104 (58)

110 69

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after propensity score matching

Log-rank p = 0.018

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Patients at risk Non-COPD COPD

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Composite endpoint, n (%)

181 181

133 108

124 102

Non-COPD (n=181; 50%) 63 (35)

118 96

COPD (n=181; 50%) 83 (46)

116 87

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Highlights: COPD Increases Mortality in Patients Presenting with Ventricular Tachyarrhythmias and Aborted Cardiac Arrest

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• COPD increases mortality in patients with ventricular tachyarrhythmias and SCA.

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

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• Results showed consistency in multivariable regression and propensity score matching.

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• COPD was associated with secondary endpoints such as cardiac death at

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24 hours.

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Conflict of Interest and Authorship Conformation Form Please check the following as appropriate:

All authors have participated in (a) conception and design, or analysis and interpretation of the data; (b) drafting the article or revising it critically for important intellectual content; and (c) approval of the final version.

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X

X This manuscript has not been submitted to, nor is under review at, another journal or other publishing venue.

The following authors have affiliations with organizations with direct or indirect financial interest in the subject matter discussed in the manuscript:

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X The authors have no affiliation with any organization with a direct or indirect financial interest in the subject matter discussed in the manuscript

Affiliation

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Author’s name