# Impact of diabetes on the management and outcomes in atrial fibrillation: an analysis from the ESC-EHRA EORP-AF Long-Term General Registry

Wern Yew Ding, Agnieszka Kotalczyk, Giuseppe Boriani, Francisco Marin, Carina Blomström-Lundqvist, Tatjana Potpara, Laurent Fauchier, Gregory.Y.H. Lip

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Wern Yew Ding, Agnieszka Kotalczyk, Giuseppe Boriani, Francisco Marin, Carina Blomström-Lundqvist, et al. Impact of diabetes on the management and outcomes in atrial fibrillation: an analysis from the ESC-EHRA EORP-AF Long-Term General Registry. European Journal of Internal Medicine, 2022, 10.1016/j.ejim.2022.04.026. [hal-03677270](https://hal.science/hal-03677270)

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Original article

# Impact of diabetes on the management and outcomes in atrial fibrillation: an analysis from the ESC-EHRA EORP-AF Long-Term General Registry

Wern Yew Ding<sup>a</sup>, Agnieszka Kotalczyk<sup>a,b</sup>, Giuseppe Boriani<sup>c</sup>, Francisco Marin<sup>d</sup>, Carina Blomström-Lundqvist<sup>e</sup>, Tatjana S. Potpara<sup>f,g</sup>, Laurent Fauchier<sup>h</sup>, Gregory.Y.H. Lip<sup>a,i,*</sup>, on behalf of the ESC-EHRA EORP-AF Long-Term General Registry Investigators<sup>1</sup>

## ARTICLE INFO

Keywords:

Cohort

Prevalence

Healthcare resource utilisation

Prognosis

MACE

Mortality

## ABSTRACT

**Background:** The prevalence of atrial fibrillation (AF) and diabetes mellitus is rising to epidemic proportions. We aimed to assess the impact of diabetes on the management and outcomes of patients with AF.

**Methods:** The EORP-AF General Long-Term Registry is a prospective, observational registry from 250 centres across 27 European countries. Outcomes of interest were as follows: i)rhythm control interventions; ii)quality of life; iii)healthcare resource utilisation; and iv)major adverse events.

**Results:** Of 11,028 patients with AF, the median age was 71 (63–77) years and 2537 (23.0%) had diabetes. Median follow-up was 24 months. Diabetes was related to increased use of anticoagulation but less rhythm control interventions. Using multivariable analysis, at 2-year follow-up, patients with diabetes were associated with greater levels of anxiety (p = 0.038) compared to those without diabetes. Overall, diabetes was associated with worse health during follow-up, as indicated by Health Utility Score and Visual Analogue Scale. Healthcare resource utilisation was greater with diabetes in terms of length of hospital stay (8.1 (±8.2) vs. 6.1 (±6.7) days); cardiology and internal medicine/general practitioner visits; and emergency room admissions. Diabetes was an independent risk factor of major adverse cardiovascular event (MACE; HR 1.26 [95% CI, 1.04–1.52]), all-cause mortality (HR 1.28 [95% CI, 1.08–1.52]), and cardiovascular mortality (HR 1.41 [95% CI, 1.09–1.83]).

**Conclusion:** In this contemporary AF cohort, diabetes was present in 1 in 4 patients and it served as an independent risk factor for reduced quality of life, greater healthcare resource utilisation and excess MACE, all-cause mortality and cardiovascular mortality. There was increased use of anticoagulation therapy in diabetes but with less rhythm control interventions.

## 1. Introduction

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, frequently associated with other conditions such as diabetes mellitus [1,2], and confers major healthcare costs [3]. Given the increasing number of AF patients with multi-morbidity, these patients

should be managed with a holistic or integrated management approach to AF patient care [4]. Such an approach has been associated with improved clinical outcomes [5,6].

The incidence of diabetes is rising to epidemic proportions, with recent estimates reporting that as many as 8.5% of adults in Europe are affected [7]. Of note, diabetes is an independent risk factor for

<footnote><sup>a</sup> Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom</footnote>

<footnote><sup>b</sup> Department of Cardiology, Congenital Heart Diseases and Electrotherapy, Medical University of Silesia, Silesian Centre for Heart Diseases, Zabrze, Poland</footnote>

<footnote><sup>c</sup> Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Policlinico di Modena, Modena, Italy</footnote>

<footnote><sup>d</sup> Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, University of Murcia, CIBERCV, Murcia, Spain</footnote>

<footnote><sup>e</sup> Department of Medical Science and Cardiology, Uppsala University, Uppsala, Sweden</footnote>

<footnote><sup>f</sup> School of Medicine, University of Belgrade, Belgrade, Serbia</footnote>

<footnote><sup>g</sup> Intensive Arrhythmia Care, Cardiology Clinic, Clinical Center of Serbia, Belgrade, Serbia</footnote>

<footnote><sup>h</sup> Service de Cardiologie, Centre Hospitalier Universitaire Trousseau, Tours, France</footnote>

<footnote><sup>i</sup> Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark</footnote>

<footnote>* Corresponding author at: William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX.
E-mail address: gregory.lip@liverpool.ac.uk (Gregory.Y.H. Lip).</footnote>

<footnote n="1">¹ Listed in Appendix.</footnote>
developing AF [8], with approximately 20% of diabetic patients having AF [9,10]. amongst patients with AF, diabetes is a known risk factor for thromboembolic complications [1]. Furthermore, the presence of diabetes in patients with AF has previously been reported to be linked to reduced quality of life, higher symptom burden, and increased risk of cardiovascular hospitalisations and mortality [11,12]. However, much of the relationship between AF and diabetes on quality of life, greater healthcare resource utilisation and outcomes remains ill-defined in contemporary cohorts.

In this study, we aimed to assess the impact of diabetes on the management and outcomes of patients with AF from the EURObservational Research Programme Atrial Fibrillation (EORP-AF) Long-Term General Registry.

## 2. Methods

### 2.1. Study design and population

The EORP-AF General Long-Term Registry is a prospective, observational, large-scale multicentre registry from 250 centres across 27 participating European countries. Details of the study design has previously been published [13]. Briefly, adults with AF who presented to cardiology services between October 2013 and September 2016 were enroled. All patients had electrocardiographic confirmation of AF within 12 months prior to enrolment. For this study, we included patients with known diabetes status. Informed consent was obtained from each patient. Institutional review board approval of the study protocol was obtained for every institution, and the study was performed in accordance with the European Union Note for Guidance on Good Clinical Practice CPMP/ECH/135/95 and the Declaration of Helsinki.

### 2.2. Data collection and definitions

Data on demographics, comorbidities, medication use and investigations were collected at study enrolment. Estimated glomerular filtration rate (eGFR) was assessed using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. AF classification was based on recommendations from the European Society of Cardiology [14]. Severity of AF-related symptoms was established with the European Heart Rhythm Association (EHRA) classification [15]. Thromboembolic risk was defined according to the CHA₂DS₂-VASc score and bleeding risk according to the HAS-BLED score.

### 2.3. Quality of life evaluation

Quality of life was evaluated at baseline, and 1-year and 2-year follow-ups using the EQ-5D-5 L questionnaire. This generic, validated, easy to use instrument consists of two parts: the EQ-5D descriptive system and the EQ visual analogue scale (VAS). The descriptive system is comprised of 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) with 5 possible levels for each dimension (no problems, slight problems, moderate problems, severe problems and extreme problems), generating $5^5 = 3125$ unique health states. Based on the United Kingdom trade-off value set [16], we translated each of the levels into a single numeric value, with lower values corresponding to better health. Thereafter, the value of each dimension was combined into a 5-digit health state which was translated into a single index, termed the Health Utility Score (HUS), by subtracting the total of these values from 1. The best possible health in each dimension (=11,111) corresponded to a HUS of 1.0 (perfect health). A HUS of 0 was equivalent to death. The VAS was used for patients to self-rate their current health status, ranging from 0 (worst health imaginable) to 100 (best health imaginable).

### 2.4. Study outcomes

Study outcomes were compared between patients with and without diabetes. The outcomes of interest included: i) rhythm control interventions, ii) quality of life, iii) healthcare resource utilisation, and iv) adverse events. Rhythm control interventions evaluated during follow-up were electrical cardioversion, pharmacological cardioversion, catheter AF ablation and surgical AF ablation. Healthcare resource utilisation was based on the occurrence and number of cardiology and internal medicine/general practitioner (GP) visits, as well as emergency room (ER) admissions. Adverse events assessed were major adverse cardiovascular events (MACEs; composite of any thromboembolic event, acute coronary syndrome and cardiovascular [CV] mortality), all-cause mortality, CV mortality, non-CV mortality, any thromboembolic event, ischaemic stroke, acute coronary syndrome, major bleeding and intracranial haemorrhage. Subgroup analysis of patients with diabetes was performed to evaluate the effects of treatment (insulin vs. oral anti-diabetics alone) on adverse events.

### 2.5. Statistical analysis

Continuous variables were described with mean and standard deviation (SD) or median and interquartile range (IQR), and tested for differences with Student's *t*-test and Mann-Whitney U test, respectively. Categorical variables were described as counts and/or percentages, and tested for differences with chi-squared test. A linear regression model was used to evaluate the effects of diabetes on quality of life, length of hospital stay and number of medical visits. The multivariable model was adjusted for CHA₂DS₂-VASc score, type of AF and EHRA classification. Additionally, quality of life during follow-up was adjusted for baseline values. A logistic regression model was used to evaluate the relationship between diabetes and occurrence of medical visits after adjustment for CHA₂DS₂-VASc score, type of AF and EHRA classification.

Differences in the cumulative risk of adverse events were assessed using Kaplan-Meier curves and survival distributions were compared using log-rank test. The association between diabetes and adverse events was investigated using Cox regression analysis. A multivariable model was performed to account for other risk factors of poor outcomes by adjusting for the following covariates: age, gender, estimated glomerular filtration rate, chronic obstructive pulmonary disease, coronary artery disease, heart failure, hypercholesterolaemia, hypertension, peripheral artery disease, previous haemorrhagic event, previous thromboembolism, sleep apnoea and use of anticoagulation.

Linear regression analyses were reported as Beta coefficient with 95% confidence interval (CI). Logistic regression analyses were reported as odds ratio (OR) with 95% CI. Cox regression analyses were reported as hazard ratio (HR) with 95% CI. A two-sided p value of less than 0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 24 (IBM Corp, Armonk, NY).

## 3. Results

### 3.1. Baseline characteristics

For this analysis, we included a total of 11,028 patients with AF, comprising 99.4% of the original EORP-AF General Long-Term Registry cohort. The median age was 71 (63 - 77) years with 4487 (40.7%) women and there were 2537 (23.0%) patients with DM. Baseline characteristics of the groups are shown in Table 1. Patients with diabetes were older and more likely to be women. Furthermore, the presence of diabetes was associated with elevated body mass index and left atrial diameter, and reduced eGFR. amongst patients with diabetes, there was a greater prevalence of comorbidities such as chronic obstructive pulmonary disease, coronary artery disease, heart failure, hypercholesterolaemia, hypertension, peripheral artery disease, previous haemorrhagic event, previous thromboembolism, previous ischaemic
<table><caption>**Table 1**
Baseline Characteristics and Medication Use.</caption><thead><tr><th>Baseline Characteristics</th><th>Diabetes (n = 2537)</th><th>No Diabetes (n = 8491)</th><th>p</th></tr></thead><tbody><tr><td>Age (years), median (IQR)</td><td>72 (66 - 78)</td><td>70 (62 - 77)</td><td>&lt;0.001</td></tr><tr><td>Women, n (%)</td><td>1091 (43.0%)</td><td>3396 (40.0%)</td><td>0.007</td></tr><tr><td>Heart rate, median (IQR)</td><td>80 (69 - 94)</td><td>78 (66 - 93)</td><td>0.006</td></tr><tr><td>sBP (mmHg), median (IQR)</td><td>133 (120 - 147)</td><td>130 (120 - 140)</td><td>&lt;0.001</td></tr><tr><td>dBP (mmHg), median (IQR)</td><td>80 (70 - 88)</td><td>80 (70 - 87)</td><td>0.641</td></tr><tr><td>BMI (kg/m²), median (IQR)</td><td>29.0 (26.0 - 32.9)</td><td>27.1 (24.5 - 30.5)</td><td>&lt;0.001</td></tr><tr><td>eGFR (mL/min/1.73m²), median (IQR)</td><td>62.6 (46.4 - 79.9)</td><td>71.7 (56.9 - 86.1)</td><td>&lt;0.001</td></tr><tr><td>LA diameter (mm), median (IQR)</td><td>46 (41 - 50)</td><td>44 (40 - 50)</td><td>&lt;0.001</td></tr><tr><td>LVEF (%), median (IQR)</td><td>55 (44 - 60)</td><td>56 (46 - 62)</td><td>&lt;0.001</td></tr><tr><td>LVH, n (%)</td><td>711 (33.1%)</td><td>1385 (16.6%)</td><td>&lt;0.001</td></tr><tr><td>AF classification, n (%)</td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>First-detected</td><td>343 (13.7%)</td><td>2243 (26.9%)</td><td></td></tr><tr><td>Paroxysmal</td><td>591 (23.6%)</td><td>1729 (20.7%)</td><td></td></tr><tr><td>Persistent</td><td>386 (15.4%)</td><td>369 (4.4%)</td><td></td></tr><tr><td>Long-standing persistent</td><td>106 (4.2%)</td><td>2613 (31.3%)</td><td></td></tr><tr><td>Permanent</td><td>1074 (43.0%)</td><td>1385 (16.6%)</td><td></td></tr><tr><td>EHRA classification, n (%)</td><td></td><td></td><td>0.002</td></tr><tr><td>I</td><td>1200 (47.3%)</td><td>3807 (44.8%)</td><td>0.029</td></tr><tr><td>II</td><td>822 (32.4%)</td><td>3044 (35.9%)</td><td>0.001</td></tr><tr><td>III</td><td>444 (17.5%)</td><td>1468 (17.3%)</td><td>0.806</td></tr><tr><td>IV</td><td>71 (2.8%)</td><td>171 (2.0%)</td><td>0.018</td></tr><tr><td>Symptoms</td><td>1337 (52.7%)</td><td>4684 (55.2%)</td><td>0.029</td></tr><tr><td>Palpitations</td><td>770 (30.4%)</td><td>2937 (34.6%)</td><td>&lt;0.001</td></tr><tr><td>Dyspnoea</td><td>813 (32.0%)</td><td>2548 (30.0%)</td><td>0.050</td></tr><tr><td>Fatigue</td><td>562 (22.2%)</td><td>1771 (20.9%)</td><td>0.161</td></tr><tr><td>Non-wellbeing</td><td>414 (16.3%)</td><td>1235 (14.5%)</td><td>0.028</td></tr><tr><td>Dizziness</td><td>272 (10.7%)</td><td>954 (11.2%)</td><td>0.469</td></tr><tr><td>Syncope</td><td>68 (2.7%)</td><td>226 (2.7%)</td><td>0.960</td></tr><tr><td>Chest pain</td><td>317 (12.5%)</td><td>903 (10.6%)</td><td>0.009</td></tr><tr><td>Fear/anxiety</td><td>167 (6.6%)</td><td>606 (7.1%)</td><td>0.336</td></tr><tr><td>Comorbidities, n (%)</td><td></td><td></td><td></td></tr><tr><td>COPD</td><td>321 (12.8%)</td><td>652 (7.7%)</td><td>&lt;0.001</td></tr><tr><td>Coronary artery disease</td><td>979 (41.4%)</td><td>2063 (25.7%)</td><td>&lt;0.001</td></tr><tr><td>Heart failure</td><td>1278 (50.8%)</td><td>3040 (36.1%)</td><td>&lt;0.001</td></tr><tr><td>Hypercholesterolaemia</td><td>1380 (56.7%)</td><td>2983 (36.7%)</td><td>&lt;0.001</td></tr><tr><td>Hypertension</td><td>1850 (73.5%)</td><td>4947 (58.7%)</td><td>&lt;0.001</td></tr><tr><td>Peripheral artery disease</td><td>317 (12.8%)</td><td>561 (6.7%)</td><td>&lt;0.001</td></tr><tr><td>Previous haemorrhagic event</td><td>164 (6.5%)</td><td>405 (4.8%)</td><td>0.001</td></tr><tr><td>Previous thromboembolism</td><td>331 (13.2%)</td><td>937 (11.1%)</td><td>0.004</td></tr><tr><td>Previous ischaemic stroke</td><td>187 (7.5%)</td><td>489 (5.8%)</td><td>0.003</td></tr><tr><td>Sleep apnoea</td><td>175 (7.2%)</td><td>314 (3.8%)</td><td>&lt;0.001</td></tr><tr><td>CHA<sub>2</sub>DS<sub>2</sub>-VASc, median (IQR)</td><td>4 (3 - 5)</td><td>3 (2 - 4)</td><td>&lt;0.001</td></tr><tr><td>HAS-BLED, median (IQR)</td><td>2 (1 - 3)</td><td>1 (1 - 2)</td><td>&lt;0.001</td></tr><tr><td>Medication Use, n (%)</td><td></td><td></td><td></td></tr><tr><td>Anti-thrombotic</td><td>2426 (95.7%)</td><td>7896 (93.0%)</td><td>&lt;0.001</td></tr><tr><td>Any antiplatelet</td><td>675 (26.6%)</td><td>1531 (18.0%)</td><td>&lt;0.001</td></tr><tr><td>Acetylsalicylic acid</td><td>603 (23.8%)</td><td>1377 (16.2%)</td><td>&lt;0.001</td></tr><tr><td>Clopidogrel</td><td>243 (9.6%)</td><td>452 (5.3%)</td><td>&lt;0.001</td></tr><tr><td>Any anticoagulant</td><td>2253 (88.8%)</td><td>7313 (86.2%)</td><td>0.001</td></tr><tr><td>Vitamin K antagonist</td><td>1405 (55.4%)</td><td>4118 (48.5%)</td><td>&lt;0.001</td></tr><tr><td>Any NOAC</td><td>792 (31.2%)</td><td>3063 (36.1%)</td><td>&lt;0.001</td></tr><tr><td>Apixaban</td><td>218 (8.6%)</td><td>849 (10.0%)</td><td>0.036</td></tr><tr><td>Dabigatran</td><td>175 (6.9%)</td><td>685 (8.1%)</td><td>0.055</td></tr><tr><td>Edoxaban</td><td>24 (0.9%)</td><td>79 (0.9%)</td><td>0.941</td></tr><tr><td>Rivaroxaban</td><td>375 (14.8%)</td><td>1450 (17.1%)</td><td>0.007</td></tr><tr><td>Anti-arrhythmic drugs</td><td>573 (22.7%)</td><td>2461 (29.1%)</td><td>&lt;0.001</td></tr><tr><td>Flecainide</td><td>37 (1.5%)</td><td>322 (3.8%)</td><td>&lt;0.001</td></tr><tr><td>Propafenone</td><td>54 (2.1%)</td><td>335 (4.0%)</td><td>&lt;0.001</td></tr><tr><td>Amiodarone</td><td>435 (17.2%)</td><td>1519 (18.0%)</td><td>0.411</td></tr><tr><td>Sotalol</td><td>44 (1.7%)</td><td>253 (3.0%)</td><td>0.001</td></tr><tr><td>Other treatments</td><td></td><td></td><td></td></tr><tr><td>ACE inhibitor</td><td>1243 (49.3%)</td><td>3463 (40.9%)</td><td>&lt;0.001</td></tr><tr><td>Aldosterone blocker</td><td>577 (22.9%)</td><td>1425 (16.9%)</td><td>&lt;0.001</td></tr><tr><td>Angiotensin receptor blocker</td><td>606 (24.0%)</td><td>1480 (17.5%)</td><td>&lt;0.001</td></tr><tr><td>Beta-blocker</td><td>1709 (68.3%)</td><td>5143 (61.5%)</td><td>&lt;0.001</td></tr><tr><td>Dihydropyridine CCB</td><td>569 (22.6%)</td><td>1282 (15.2%)</td><td>&lt;0.001</td></tr><tr><td>Digoxin</td><td>481 (19.1%)</td><td>1115 (13.2%)</td><td>&lt;0.001</td></tr><tr><td>Diuretic</td><td>1657 (65.7%)</td><td>4008 (47.4%)</td><td>&lt;0.001</td></tr><tr><td>Statin</td><td>1427 (56.5%)</td><td>3210 (38.0%)</td><td>&lt;0.001</td></tr></tbody></table>

ACE, angiotensin converting enzyme; AF, atrial fibrillation; BMI, body mass index; CCB, calcium-channel blocker; COPD, chronic obstructive pulmonary

disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; EHRA, European Heart Rhythm Association; IQR, interquartile range; LA, left atrium; LVEF, left ventricle ejection fraction; LVH, left ventricular hypertrophy; NOAC, non-vitamin K oral anticoagulant; sBP, systolic blood pressure.

stroke and sleep apnoea. The median CHA<sub>2</sub>DS<sub>2</sub>-VASc and HAS-BLED scores were increased amongst patients with diabetes.

## 3.2. Baseline medication use

The use of medications at baseline are summarised in Table 1. Patients with diabetes were more likely to receive anticoagulation therapy (88.8% vs. 86.2%), particularly in the form of vitamin K antagonist (55.4% vs. 48.5%), and other treatments such as angiotensin converting enzyme inhibitor, aldosterone blocker, angiotensin receptor blocker, beta-blocker, dihydropyridine calcium-channel blocker, digoxin, diuretic and statin. Differences in the rates of anticoagulation therapy between the groups were attenuated by accounting for those with an indication for treatment according to current European Society of Cardiology guidelines, though variations in the choice of vitamin K antagonist vs. non-vitamin K antagonist oral anticoagulants persisted. Anti-arrhythmic drugs were less frequently prescribed in patients with diabetes (22.7% vs. 29.1%).

## 3.3. Diagnostic investigations and rhythm control interventions

In terms of diagnostic investigations within 12 months prior to enrolment, trans-thoracic echocardiography (80.5% vs. 77.7%) and invasive coronary angiography (17.6% vs. 12.5%) were more commonly performed in patients with diabetes (Supplementary Figure 1). The presence of diabetes was associated with reduced trans-oesophageal echocardiography (10.2% vs. 12.4%), cardiac computed tomography (2.6% vs. 4.3%) and electrophysiology study (1.5% vs. 2.8%). The median follow-up duration was 24 (IQR 23 - 24 months). During this period, rhythm control interventions in the form of electrical cardioversion, pharmacological cardioversion and catheter AF ablation were undertaken less frequently amongst patients with diabetes (Supplementary Table 1).

## 3.4. Quality of life

At baseline, there were significant differences in all the quality of life indicators of the EQ-5D-5 L questionnaire between patients with and without diabetes (Table 2). These differences were not observed after adjustment for other confounders. At 1-year and 2-year follow-ups, there was reduced quality of life indicators amongst patients with diabetes compared to non-DM. Using multivariable analysis, at 1-year follow-up, patients with diabetes had a trend for worse mobility (p = 0.051), and were less able to attend to their self-care (p = 0.002) and usual activities (p = 0.023), and had greater levels of anxiety (p = 0.023) vs. those without diabetes. Using multivariable analysis, at 2-year follow-up, patients with diabetes had a trend to be less able to attend to their usual activities (p = 0.052) and had greater levels of anxiety (p = 0.038). Overall, diabetes was associated with worse HUS and VAS during follow-up.

## 3.5. Healthcare resource utilisation

After multivariable adjustment, the presence of diabetes was related to excess internal medicine/GP visits at 1-year follow-up (p = 0.001), ER admissions at 1-year follow-up (p < 0.001) and internal medicine/GP visits at 2-year follow-up (p = 0.005) (Table 3). The mean length of stay was greater in the group with diabetes at 8.1 (± 8.2) vs. 6.1 (± 6.7) days in the group without diabetes, p = 0.012 following adjustment for other risk factors. After multivariable adjustment, diabetes was associated with more cardiology visits at 1-year and 2-year follow-ups (p = 0.017
<table><caption>**Table 2**
Baseline and Follow-Up Quality of Life Indicators for Diabetes vs. No Diabetes.</caption><thead><tr><th>EQ-5D-5 L,<br>mean ± SD</th><th>Diabetes</th><th>No<br>Diabetes</th><th>p</th><th>Diabetes vs.<br>No Diabetes<br>Beta (95% CI)<sup>*</sup></th><th>p</th></tr></thead><tbody><tr><td><strong>Baseline</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Descriptive<br>indicators</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Mobility</td><td>0.057 ±<br>0.063</td><td>0.042 ±<br>0.060</td><td>&lt;0.001</td><td>-0.016<br>(-0.055 to<br>0.001)</td><td>0.151</td></tr><tr><td>Self-care</td><td>0.023 ±<br>0.042</td><td>0.016 ±<br>0.036</td><td>&lt;0.001</td><td>-0.016<br>(-0.003 to<br>0.001)</td><td>0.148</td></tr><tr><td>Usual<br>activities</td><td>0.040 ±<br>0.048</td><td>0.031 ±<br>0.044</td><td>&lt;0.001</td><td>-0.010<br>(-0.003 to<br>0.001)</td><td>0.371</td></tr><tr><td>Pain/<br>discomfort</td><td>0.053 ±<br>0.069</td><td>0.043 ±<br>0.065</td><td>&lt;0.001</td><td>-0.004<br>(-0.004 to<br>0.003)</td><td>0.747</td></tr><tr><td>Anxiety</td><td>0.049 ±<br>0.071</td><td>0.044 ±<br>0.066</td><td>0.005</td><td>-0.005<br>(-0.004 to<br>0.003)</td><td>0.680</td></tr><tr><td>Health Utility<br>Score</td><td>0.778 ±<br>0.214</td><td>0.823 ±<br>0.198</td><td>&lt;0.001</td><td>0.012<br>(-0.005 to<br>0.016)</td><td>0.277</td></tr><tr><td>Visual<br>analogue<br>Scale</td><td>66 ± 20</td><td>69 ± 21</td><td>&lt;0.001</td><td>0.005<br>(-0.925 to<br>1.397)</td><td>0.690</td></tr><tr><td><strong>EQ-5D-5 L,<br>mean ± SD</strong></td><td><strong>Diabetes</strong></td><td><strong>No<br>Diabetes</strong></td><td><strong>p</strong></td><td><strong>Diabetes vs.<br>No Diabetes<br>Beta (95% CI)<sup>†</sup></strong></td><td><strong>p</strong></td></tr><tr><td><strong>1-Year</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Follow-Up</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Descriptive<br>indicators</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Mobility</td><td>0.057 ±<br>0.064</td><td>0.037 ±<br>0.054</td><td>&lt;0.001</td><td>0.025 (0.000<br>to 0.007)</td><td><strong>0.051</strong></td></tr><tr><td>Self-care</td><td>0.024 ±<br>0.041</td><td>0.014 ±<br>0.032</td><td>&lt;0.001</td><td>0.040 (0.001<br>to 0.005)</td><td><strong>0.002</strong></td></tr><tr><td>Usual<br>activities</td><td>0.041 ±<br>0.047</td><td>0.027 ±<br>0.040</td><td>&lt;0.001</td><td>0.030 (0.000<br>to 0.006)</td><td><strong>0.023</strong></td></tr><tr><td>Pain/<br>discomfort</td><td>0.052 ±<br>0.071</td><td>0.038 ±<br>0.060</td><td>&lt;0.001</td><td>0.021<br>(-0.001 to<br>0.007)</td><td>0.117</td></tr><tr><td>Anxiety</td><td>0.047 ±<br>0.068</td><td>0.037 ±<br>0.059</td><td>&lt;0.001</td><td>0.031 (0.001<br>to 0.009)</td><td><strong>0.023</strong></td></tr><tr><td>Health Utility<br>Score</td><td>0.700 ±<br>0.317</td><td>0.793 ±<br>0.273</td><td>&lt;0.001</td><td>-0.137<br>(-0.109 to<br>-0.077)</td><td>&lt;0.001</td></tr><tr><td>Visual<br>analogue<br>Scale</td><td>66 ± 20</td><td>71 ± 19</td><td>&lt;0.001</td><td>-0.029<br>(-2.588 to<br>-0.101)</td><td><strong>0.034</strong></td></tr><tr><td><strong>2-Year</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Follow-Up</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Descriptive<br>indicators</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Mobility</td><td>0.058 ±<br>0.066</td><td>0.040 ±<br>0.056</td><td>&lt;0.001</td><td>0.015<br>(-0.002 to<br>0.006)</td><td>0.294</td></tr><tr><td>Self-care</td><td>0.026 ±<br>0.043</td><td>0.015 ±<br>0.034</td><td>&lt;0.001</td><td>0.024 (0.000<br>to 0.005)</td><td>0.107</td></tr><tr><td>Usual<br>activities</td><td>0.043 ±<br>0.048</td><td>0.029 ±<br>0.041</td><td>&lt;0.001</td><td>0.029 (0.000<br>to 0.006)</td><td><strong>0.052</strong></td></tr><tr><td>Pain/<br>discomfort</td><td>0.051 ±<br>0.068</td><td>0.038 ±<br>0.061</td><td>&lt;0.001</td><td>0.011<br>(-0.003 to<br>0.006)</td><td>0.487</td></tr><tr><td>Anxiety</td><td>0.045 ±<br>0.065</td><td>0.035 ±<br>0.057</td><td>&lt;0.001</td><td>0.032 (0.000<br>to 0.009)</td><td><strong>0.038</strong></td></tr><tr><td>Health Utility<br>Score</td><td>0.610 ±<br>0.374</td><td>0.722 ±<br>0.342</td><td>&lt;0.001</td><td>-0.135<br>(-0.132 to<br>-0.090)</td><td>&lt;0.001</td></tr><tr><td>Visual<br>analogue<br>Scale</td><td>66 ± 20</td><td>72 ± 19</td><td>&lt;0.001</td><td>-0.037<br>(-3.171 to<br>-0.309)</td><td><strong>0.017</strong></td></tr></tbody></table>

*Adjusted for CHA₂DS₂-VASC score, type of atrial fibrillation and European Heart Rhythm Association classification.

† Adjusted for CHA₂DS₂-VASC score, type of atrial fibrillation, European Heart Rhythm Association classification and respective 5Q-5D-5 L scores at baseline. CI, confidence interval.

<table><caption>**Table 3**
Healthcare Resource Utilisation according to Diabetes vs. No Diabetes.</caption><thead><tr><th>Any Visits or<br>Admissions,%</th><th>Diabetes</th><th>No<br>Diabetes</th><th>p</th><th>Diabetes vs.<br>No Diabetes<br>OR (95% CI)*</th><th>p</th></tr></thead><tbody><tr><td>Cardiology visits<br>1Y</td><td>54.4</td><td>57.7</td><td>0.003</td><td>1.02 (0.93 -<br>1.13)</td><td>0.664</td></tr><tr><td>IM/GP visits 1Y</td><td>13.6</td><td>11.9</td><td>0.026</td><td>1.29 (1.11 -<br>1.49)</td><td><strong>0.001</strong></td></tr><tr><td>ER admissions 1Y</td><td>23.5</td><td>17.3</td><td>&lt;0.001</td><td>1.29 (1.13 -<br>1.48)</td><td>&lt;0.001</td></tr><tr><td>Cardiology visits<br>2Y</td><td>68.4</td><td>68.1</td><td>0.831</td><td>1.04 (0.92 -<br>1.19)</td><td>0.512</td></tr><tr><td>IM/GP visits 2Y</td><td>23.1</td><td>21.9</td><td>0.186</td><td>1.18 (1.05 -<br>1.33)</td><td><strong>0.005</strong></td></tr><tr><td>ER admissions 2Y</td><td>16.5</td><td>14.3</td><td>0.022</td><td>1.05 (0.89 -<br>1.24)</td><td>0.539</td></tr><tr><th>Number of Visits<br>or Admissions,<br>mean ± SD</th><th>Diabetes</th><th>No<br>Diabetes</th><th>p</th><th>Diabetes<br>vs. No<br>Diabetes<br>Beta (95% CI)*</th><th>p</th></tr><tr><td>Cardiology visits<br>1Y</td><td>1.4 ± 2.0</td><td>1.4 ± 1.9</td><td>0.407</td><td>0.025<br>(0.020 to<br>0.211)</td><td><strong>0.017</strong></td></tr><tr><td>IM/GP visits 1Y</td><td>0.7 ± 2.4</td><td>0.6 ± 2.0</td><td>0.012</td><td>0.031<br>(0.052 to<br>0.260)</td><td><strong>0.003</strong></td></tr><tr><td>ER admissions 1Y</td><td>1.7 ± 1.3</td><td>1.7 ± 1.4</td><td>0.649</td><td>0.037<br>(-0.056 to<br>0.281)</td><td>0.190</td></tr><tr><td>Cardiology visits<br>2Y</td><td>1.0 ± 1.0</td><td>1.0 ± 1.0</td><td>0.148</td><td>0.024<br>(0.007 to<br>0.089)</td><td><strong>0.022</strong></td></tr><tr><td>IM/GP visits 2Y</td><td>0.9 ± 2.6</td><td>0.8 ± 2.6</td><td>0.105</td><td>0.018<br>(-0.013 to<br>0.238)</td><td>0.079</td></tr><tr><td>ER admissions 2Y</td><td>1.5 ± 1.1</td><td>1.5 ± 1.2</td><td>0.984</td><td>0.000<br>(-0.176 to<br>0.174)</td><td>0.993</td></tr></tbody></table>

*Adjusted for CHA₂DS₂-VASC score, type of atrial fibrillation and European Heart Rhythm Association classification. 1Y, 1-year follow-up; 2Y, 2-year follow-up; CI, confidence interval; ER, emergency room; GP, general practitioner; IM, internal medicine; SD, standard deviation; OR, odds ratio.

and *p* = 0.022, respectively), and internal medicine/GP visits at 1-year follow-up (*p* = 0.003).

### 3.6. Adverse events

In the univariate model, patients with diabetes had significantly worse outcomes in terms of MACE (HR 1.58 [95% CI, 1.35 - 1.85]), all-cause mortality (HR 1.59 [95% CI, 1.38 - 1.84]), CV mortality (HR 1.79 [95% CI, 1.44 - 2.24]), non-CV mortality (HR 1.33 [95% CI, 1.00 - 1.77]) and acute coronary syndrome (HR 1.54 [95% CI, 1.16 - 2.04]) (Table 4). There was no statistical difference between the groups for any thromboembolic event, ischaemic stroke, major bleeding and intracranial haemorrhage.

Kaplan-Meier analyses are shown in Fig. 1. Using multivariable analysis, diabetes was independently associated with excess MACE (HR 1.26 [95% CI, 1.04 - 1.52]), all-cause mortality (HR 1.28 [95% CI, 1.08 - 1.52]) and CV mortality (HR 1.41 [95% CI, 1.09 - 1.83]), but not non-CV mortality, any thromboembolic event, ischaemic stroke, acute coronary syndrome, major bleeding and intracranial haemorrhage.
<table><caption>**Table 4**
Major Adverse Events at 2-Year Follow-Up by the Presence of Diabetes.</caption><thead><tr><th rowspan="2">Major adverse events</th><th>Diabetes</th><th>No Diabetes</th><th>Univariate</th><th>Multivariable*</th></tr><tr><th>%</th><th></th><th>HR (95% CI)</th><th>HR (95% CI)</th></tr></thead><tbody><tr><td>MACE</td><td>10.2</td><td>6.6</td><td>1.58 (1.35 - 1.85)</td><td>1.26 (1.04 - 1.52)</td></tr><tr><td>All-cause mortality</td><td>11.9</td><td>7.6</td><td>1.59 (1.38 - 1.84)</td><td>1.28 (1.08 - 1.52)</td></tr><tr><td>CV mortality</td><td>5.0</td><td>2.9</td><td>1.79 (1.44 - 2.24)</td><td>1.41 (1.09 - 1.83)</td></tr><tr><td>Non-CV mortality</td><td>2.8</td><td>2.1</td><td>1.33 (1.00 - 1.77)</td><td>1.16 (0.84 - 1.60)</td></tr><tr><td>Any thromboembolic event</td><td>2.3</td><td>1.9</td><td>1.20 (0.87 - 1.65)</td><td>1.25 (0.85 - 1.83)</td></tr><tr><td>Ischaemic stroke</td><td>1.3</td><td>1.0</td><td>1.23 (0.80 - 1.90)</td><td>1.21 (0.72 - 2.04)</td></tr><tr><td>Acute coronary syndrome</td><td>3.1</td><td>2.1</td><td>1.54 (1.16 - 2.04)</td><td>1.06 (0.76 - 1.50)</td></tr><tr><td>Major bleeding</td><td>1.0</td><td>0.9</td><td>1.06 (0.65 - 1.74)</td><td>0.75 (0.43 - 1.33)</td></tr><tr><td>Intracranial haemorrhage</td><td>0.2</td><td>0.3</td><td>0.65 (0.25 - 1.69)</td><td>0.62 (0.23 - 1.72)</td></tr></tbody></table>

* Adjusted for age, gender, estimated glomerular filtration rate, chronic obstructive pulmonary disease, coronary artery disease, heart failure, hypercholesterolaemia, hypertension, peripheral artery disease, previous haemorrhagic event, previous thromboembolism, sleep apnoea and use of anticoagulation. MACE represents a composite of any thromboembolic event, acute coronary syndrome and CV mortality. CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MACE, major adverse cardiovascular event.

Subgroup analysis of patients with diabetes who were treated with either insulin or oral anti-diabetics alone found higher rates of MACE, all-cause mortality, CV mortality and acute coronary syndrome amongst insulin users (Supplementary Table 2). However, these effects were attenuated after adjusting for confounders with no statistical differences between the groups for any of the adverse outcomes.

## 4. Discussion

In this large cohort study of AF patients who were prospectively recruited from 250 centres across 27 participating European countries, our principal findings are as follows: (i) 1 in 4 patients with AF had diabetes, and they were older with greater burden of comorbidities as

compared to patients without diabetes; (ii) the presence of diabetes was associated with increased use of anticoagulation but less rhythm control interventions whether in the form of anti-arrhythmic drugs, cardioversion or AF ablation; (iii) diabetes was linked to reduced quality of life, particularly in that patients were less able to attend to their usual activities and had greater levels of anxiety; (iv) healthcare resource utilisation was higher amongst those with diabetes in terms of outpatient visits, ER admissions and length of in-hospital stay; and (v) diabetes was an independent risk factor of MACE, all-cause mortality, and CV mortality over a 2-year follow-up period.

Similar to the previous studies, we found a high incidence of diabetes amongst AF patients (23%); driven by an age-dependant increase in both diabetes and AF [9,10,17]. Consequently, as these patients were overburdened with multi-morbidity, they were exposed to an elevated risk of thromboembolic events as compared to patients without diabetes. In response, there was greater use of anticoagulation therapy in diabetes patients, despite their excess risk of major bleeding. Vitamin K antagonist was more frequently prescribed in patients with diabetes; this was likely related to the severity of renal impairment in this group rather than the presence of diabetes per se, as both non-vitamin K antagonist oral anticoagulants and vitamin K antagonist have been shown to be effective amongst these patients. Of note, a recent study showed that patients with diabetes had poorer time-in-therapeutic range (TTR) than patients without diabetes, and that lower TTR was associated with a higher risk of adverse events [18]. This highlights the need for closer monitoring in patients with diabetes. Furthermore, AF is commonly asymptomatic and improved diagnosis focuses on better monitoring [19, 20]. The importance of proper evaluation and characterisation of AF patients, including assessment of comorbidities such as diabetes, has been emphasised [21].

Rhythm control interventions during follow-up were less commonly pursued in patients with diabetes likely as a result of their older age and the perceived lower success rate. This is in keeping with the European Society of Cardiology guidelines where a rhythm control strategy is recommended for symptomatic, preferably younger patients to improve the quality of life [4]. Although patients with AF universally have impaired quality of life [22], we found that the coexistence of diabetes was related to poorer quality of life indicators in terms of mobility, self-care, usual activities, pain/discomfort and anxiety; resulting in a worse overall health. At 2-year follow-up, the presence of diabetes was an independent risk factor for poor health due to limitations in usual

<figure><img src="image_3.png" /><figcaption>**Fig. 1.** Kaplan-Meier analysis of MACE, all-cause mortality and CV mortality over 24 months of follow-up in atrial fibrillation patients with and without diabetes. Diabetes = red line, No diabetes = blue line. MACE represents a composite of any thromboembolic event, acute coronary syndrome and CV mortality. CV, cardiovascular; DM, diabetes mellitus; MACE, major adverse cardiovascular event.</figcaption></figure>
activities and greater levels of anxiety.

Consistent with other registries, we found that hospital re-admissions were common in AF patients [11,23], with an excess number of ER admissions and outpatients clinic visits (IM/GP and cardiology type) amongst those with diabetes. This finding may be partly driven by the higher prevalence of other comorbidities (such as chronic obstructive pulmonary disease, heart failure and coronary artery disease) amongst these patients. Likewise, a recent study of 20,172 patients with AF from the Chinese Atrial Fibrillation Registry showed that diabetes was a risk factor for hospitalisation [24]. Other risk factors reported by Dong et al. were concomitant heart failure, coronary artery disease, ischaemic stroke/transient ischaemic attack, chronic obstructive pulmonary disease and renal failure. Notably, the number of AF-related hospitalisations is acknowledged as a significant healthcare burden that is predicted to rise over the next 2 decades [3]. Overall, a multidisciplinary approach to the management of comorbidities is crucial to improve quality of life and reduce the hospitalisation rate in patients with AF and diabetes [25].

Herein, we demonstrated that amongst AF patients, diabetes was an independent risk factor of MACE, all-cause mortality and CV mortality (but not non-CV mortality, any thromboembolic event, ischaemic stroke, acute coronary syndrome and major bleeding). Similarly, the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation) study showed that patients with diabetes and AF had an increased risk of CV events (coronary events, stroke and heart failure), all-cause mortality and CV mortality, as compared to the non-AF group [26]. A study of 9749 patients with AF from the ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registry found that diabetes was an associated with increased all-cause mortality and CV mortality, after accounting for other risk factors [11]. These high-risk patients may benefit from SGLT2 (sodium-glucose cotransporter 2) inhibitors which have been shown to reduce adverse events [27], potentially through their mechanistic effects on interstitial myocardial fibrosis and aortic stiffness [28].

## 4.1. Limitations

The primary limitations of this study are its observational design and the potential for residual confounders. Furthermore, as patients were enroled from cardiology practices in Europe, the results may not be generalisable to the wider population. As we did not account for new cases of diabetes during the follow-up period, the true prevalence of diabetes may have been underestimated [29]. The inclusion of patients who may have developed diabetes following enrolment in the group without diabetes may have reduced the detrimental effects of diabetes observed in our study. Regarding antidiabetic therapies, we had limited information on the type of oral medications or insulin that were prescribed. Moreover, we lacked data on the quality of glucose control, and type or duration of diabetes. The former was potentially important as poor glucose control, indicated by increasing levels of haemoglobin A1c, have been associated with a higher risk of thromboembolic events [30].

## 5. Conclusions

In this contemporary European cohort of AF patients, diabetes was present in 1 in 4 patients and it served as independent risk factor for reduced quality of life, greater healthcare resource utilisation and excess MACE, all-cause mortality and CV mortality over a 2-year follow-up period. There was increased use of anticoagulation therapy amongst patients with AF and diabetes but they were less likely to receive rhythm control interventions.

## Funding

Since the start of EORP, the following companies have supported the programme: Abbott Vascular Int. (2011–2021), Amgen Cardiovascular

(2009–2018), AstraZeneca (2014–2021), Bayer (2009–2018), Boehringer Ingelheim (2009–2019), Boston Scientific (2009–2012), The Bristol Myers Squibb and Pfizer Alliance (2011–2016), The Alliance Daiichi Sankyo Europe GmbH and Eli Lilly and Company (2011–2017), Edwards (2016–2019), Gedeon Richter Plc. (2014–2017), Menarini Int. Op. (2009–2012), MSD-Merck & Co. (2011–2014), Novartis Pharma AG (2014–2020), ResMed (2014–2016), Sanofi (2009–2011), SERVIER (2010–2021), Vifor (2019–2022).

## Disclosures

GB: small speaker's fees from Medtronic, Boston, Biotronik, Boehringer, and Bayer outside of the submitted work. FM: receiving grants from Ferrer, and personal fees from Bayer, Pfizer/BMS. Boehringer-Ingelheim and Astra-Zeneca outside the submitted work. CBL: receiving grants from Medtronic, Cardiome, and personal fees from Bayer, Sanofi, Boston Scientific, and Merck Sharp & Dohme outside the submitted work. TSP: Consultant for Bayer and Pfizer, no fees. LF: consultant or speaker fees of small amounts for Bayer, BMS/Pfizer, Boehringer Ingelheim, Medtronic and Novartis outside of this work. GYHL: consultant and speaker for BMS/Pfizer, Boehringer Ingelheim and Daiichi-Sankyo. No fees are received personally. Other authors declare no conflict of interest.

## Data availability statement

The data underlying this article will be shared on reasonable request to the corresponding author.

## Contributorship statement

WYD and GYHL contributed to the design of the study; WYD analysed and interpreted the data, and drafted the manuscript; GB, FM, CB-L, TSP, LF and GYHL revised the manuscript critically for important intellectual content.

## Acknowledgements

None.

## Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ejim.2022.04.026.

## Appendix

**EURObservational Research Programme Atrial Fibrillation (EORP-AF) Long-Term General Registry Committees and Investigators (ESC Member Countries)**

**Executive committee:** G.Boriani (Chair), G.Y.H. Lip, L. Tavazzi, A. P. Maggioni, G-A. Dan, T. Potpara, M. Nabauer, F. Marin, Z. Kalarus, L. Fauchier.

**Steering Committee (National Coordinators):** A. Goda, G. Mairesse, T.Shalganov, L. Antoniades, M. Taborsky, S. Riahi, P. Muda, I. García Bolao, O. Piot, M. Nabauer, K. Etsadashvili, E.Simantirakis, M. Haim, A. Azhari, J. Najafian, M. Santini, E. Mirrakhimov, K.a Kulzida, A. Erglis, L. Poposka, M. Burg, H. Crijns, Ö. Erküner, D. Atar, R. Lenarczyk, M. Martins Oliveira, D. Shah, G-A. Dan, E. Serdechnaya, T. Potpara, E. Diker, G.Y.H. Lip, D. Lane.

**Participants:** ALBANIA Durrès: E. Zëra, Tirana: U. Ekmekçiu, V. Paparisto, M. Tase, Tirana: H. Gjergo, J. Dragoti, A. Goda, BELGIUM Bastogne: M. Ciutea, N. Ahadi, Z. el Husseini, M. Raepers, Gilly: J. Leroy, P. Haushan, A. Jourdan, Haine Saint Paul: C. Lepiece, Hasselt: L. Desteghe, J. Vijgen, P. Koopman, G. Van Genechten, H. Heidbuchel, Kortrijk: T. Boussy, M. De Coninck, H. Van Eeckhoutte, N. Bouckaert, La
Louviere: A. Friart, J. Boreux, C. Arend, Liege: P. Evrard, Liège: L. Stefan, E. Hoffer, J. Herzet, M. Massoz, Liège: C. Celentano, M. Sprynger, L. Pierard, Liège: P. Melon, Overpelt: B. Van Hauwaert, C. Kuppens, D. Faes, D. Van Lier, A. Van Dorpe, Waremme: A. Gerardy, Yvoir: O. Deceuninck, O. Xhaet, F. Dormal, E. Ballant, D. Blommaert, **BULGARIA** Pleven: D. Yakova, M. Hristov, T. Yncheva, N. Stancheva, S. Tsisheva, Plovdiv: M. Tokmakova, F. Nikolov, D. Gencheva, Sofia: T. Shalganov, B. Kunev, M. Stoyanov, Sofia: D. Marchov, V. Gelev, V. Traykov, Varna: A. Kisheva, H. Tsvyatkov, R. Shtereva, S. Bakalska-Georgieva, S. Slavcheva, Y. Yotov, **CZECH REPUBLIC** Ústí nad Labem: M. Kubíčková, **DENMARK** Aalborg: A. Marni Joensen, A. Gammelmark, L. Hvilsted Rasmussen, P. Dinesen, S. Riahi, S. Krogh Venø, B. Sorensen, A. Korsgaard, K. Andersen, C. Fragtrup Hellum, Esbjerg: A. Svenningsen, O. Nyvad, P. Wiggers, Herning: O. May, A. Aarup, B. Graversen, L. Jensen, M. Andersen, M. Svejgaard, S. Vester, S. Hansen, V. Lynggaard, Madrid: M. Ciudad, Tallinn: R. Vettus, Tartu: P. Muda, **ESTONIA** Elche, Alicante: A. Maestre, Toledo: S. Castaño, **FRANCE** Abbeville: S. Cheggour, Abbeville: J. Poulard, V. Mouquet, S. Leparrée, Aix-en-Provence: J. Bouet, J. Taieb, Amiens: A. Doucy, H. Duquenne, Angers: A. Furber, J. Dupuis, J. Raultureau, Aurillac: M. Font, P. Damiano, Avignon Cedex: M. Lacrimini, Brest: J. Abalea, S. Boismal, T. Menez, J. Mansourati, Chartres: G. Range, H. Gorka, C. Laure, C. Vassalière, Creteil: N. Elbaz, N. Lellouche, K. Djouadi, Montpellier: F. Roubille, D. Dietz, J. Davy, Nimes: M. Granier, P. Winum, C. Leperchois-Jacquey, Paris: H. Kassim, E. Marijon, J. Le Heuzey, Paris: J. Fedida, M. Maupain, C. Himbert, E. Gandjbakhf, H. Hidden-Lucet, G. Duthoit, N. Badenboe, T. Chastre, X. Waintraub, M. Oudihat, J. Lacoste, C. Stephan, Pau: H. Bader, N. Delarche, L. Giry, Pessac: D. Arnaud, C. Lopez, F. Boury, I. Brunello, M. Lefèvre, R. Minigam, M. Haissaguerre, Rennes: M. Le Bidan, D. Pavin, V. Le Moal, C. Leclercq, Saint Denis: O. Piot, T. Beitar, Saint Etienne: I. Martel, A. Schmid, N. Sadki, C. Romeyer-Bouchard, A. Da Costa, Tours: I. Arnault, M. Boyer, C. Piat, L. Fauchier, **FYR MACEDONIA** Bitola: N. Lozance, S. Nastevska, Ohrid: A. Doneva, B. Fortomaroska Milevska, B. Sheshoski, K. Petroska, N. Taneska, N. Bakrecheski, Skopje: K. Lazarovska, S. Jovevska, V. Ristovski, A. Antovski, Skopje: E. Lazarova, I. Kotlar, J. Taleski, L. Poposka, S. Kedev, Skopje: N. Zlatanovik, Štip: S. Jordanova, T. Bajraktarova Proseva, S. Doncovska, **GEORGIA** Tbilisi: D. Maisuradze, A. Esakia, E. Sagirashvili, K. Lartsuliani, N. Natelashvili, N. Gumberidze, R. Gvenetadze, **Tbilisi:** K. Men sadashvili, N. Gotonelia, N. Kuridze, **Tbilisi:** G. Papiashvili, I. Menabde, **GERMANY** Aachen: S. Glöggler, A. Napp, C. Lebherz, H. Romero, K. Schmitz, M. Berger, M. Zink, S. Köster, J. Sachse, E. Vonderhagen, G. Soiron, K. Mischke, Bad Reichenhall: R. Reith, M. Schneider, Berlin: W. Rieker, Biberach: D. Boscher, A. Taschareck, A. Beer, Boppard: D. Oster, Brandenburg: O. Ritter, J. Adamczewski, S. Walter, Chemnitz: A. Frommhold, E. Luckner, J. Richter, M. Schellner, S. Landgraf, S. Bartholome, Chemnitz: R. Naumann, J. Schoeler, Dachau: D. Westermeier, F. William, K. Wilhelm, M. Maerkl, Detmold: R. Oekinghaus, M. Denart, M. Kriete, U. Tebbe, Ebersbach: T. Scheibnner, Erlangen: M. Gruber, A. Gerlach, C. Beckendorf, L. Anneken, M. Arnold, S. Lengerer, Z. Bal, C. Uecker, H. Förtsch, S. Fechner, V. Mages, Friedberg: E. Martens, H. Methe, Göttingen: T. Schmidt, Hamburg: B. Schaeffer, B. Hoffmann, J. Moser, K. Heitmann, S. Willems, S. Willems, Hartmannsdorf: C. Klaus, I. Lange, Heidelberg: M. Durak, E. Esen, Itzehoe: F. Mibach, H. Mibach, Kassel: A. Utech, Kirchzarten: M. Gabelmann, R. Stumm, V. Ländle, Koblenz: C. Gartner, C. Goerg, N. Kaul, S. Messer, D. Burkhardt, C. Sander, R. Orthen, S. Kaes, Köln: A. Baumer, F. Dodos, Königsbrück: A. Barth, G. Schaeffer, Leisnig: J. Gaertner, J. Winkler, Leverkusen: A. Fahrig, J. Aring, I. Wenzel, Limburg: S. Steiner, A. Kliesch, E. Kratz, K. Winter, P. Schneider, Ludwigsburg: A. Haag, I. Mutscher, R. Bosch, Markkleebberg: J. Taggeselle, S. Meixner, Meissen: A. Schnabel, Meppen: A. Shamalla, H. Hötz, A. Korinth, Merzig: C. Rheinert, Moosburg: G. Mehltretter, Mühlendorf: B. Schön, N. Schön, A. Starflinger, E. Englmann, Munich: G. Baytok, T. Laschinger, G. Ritscher, Munich: A. Gerth, Münster: D. Dechering, L. Eckardt, Nienburg: M. Kuhlmann, N. Proskynitopoulos, Paderborn: J. Brunn, K. Foth, Pirna: C. Axthelm, H. Hohensee, K. Eberhard, S. Turbanisch,

Plauen: N. Hassler, A. Koestler, Riesa: G. Stenzel, Riesa: D. Kschiwan, M. Schwefer, S. Neiner, S. Hettwer, Rotenburg a.d. Fulda: M. Haeussler-Schuchardt, R. Degenhardt, S. Sennhenn, S. Steiner, Starnberg: M. Brendel, Westerstede: A. Stoehr, W. Widjaja, S. Loehndorf, A. Logemann, J. Hoskamp, J. Grundt, Zorneding: M. Block, Zwiesel: R. Ulrych, A. Reithmeier, V. Panagopoulos, **ITALY** Bologna: C. Martignani, D. Bernucci, E. Fantecchi, I. Diemberger, M. Ziacchi, M. Biffi, P. Cimaglia, J. Frisoni, G. Boriani, Firenze: I. Giannini, S. Boni, S. Fumagalli, S. Pupo, A. Di Chiara, P. Mirone, Modena: E. Fantecchi, G. Boriani, F. Pesce, C. Zoccali, V.L.Malavasi, **KAZAKHSTAN** Almaty: A. Mussagaliyeva, B. Ahyt, Z. Salihova, K. Koshum-Bayeva, **KYRGYZSTAN** Bishkek: A. Kerimkulova, A. Bairamukova, E. Mirrakhimov, **LATVIA** Riga: B. Lurina, R. Zuzans, S. Jegere, I. Mintale, K. Kupics, K. Jubele, A. Erglis, O. Kalejs, **MALTA** Birkirkara: K. Vanhear, M. Burg, M. Cachia, E. Abela, S. Warwicker, T. Tabone, R. Xuereb, **MONTENEGRO** Podgorica: D. Asanovic, D. Drakalovic, M. Vukmirovic, N. Pavlovic, L. Music, N. Bulatovic, A. Boskovic, **NETHERLANDS** Almere: H. Uiterwaal, N. Bijsterveld, Amsterdam: J. De Groot, J. Neefs, N. van den Berg, F. Piersma, A. Wilde, Delfzijl: V. Hagens, Enschede: J. Van Es, J. Van Opstal, B. Van Rennes, H. Verheij, W. Breukers, Heerenveen: G. Tjeerdsma, R. Nijmeijer, D. Wegink, R. Binnema, Hengelo: S. Said, Maastricht: Ö. Erküner, S. Philippens, W. van Doorn, H. Crijns, Rotterdam: T. Szilá-Torok, R. Bhagwandien, P. Janse, A. Muskens, s-Hertogenbosch: M. van Eck, R. Gevers, N. van der Ven, Venlo: A. Duygun, B. Rahel, J. Meeder, **NORWAY** Oslo: A. Vold, C. Holst Hansen, I. Engset, D. Atar, **POLAND** Bytom: A. Dyduch-Fejklowicz, E. Koba, M. Cichocka, Czeszyn: A. Sokal, A. Kubicius, E. Pruchniewicz, Gliwice: A. Kowalik-Sztylc, W. Czapla, Katowice: I. Mróz, M. Kozlowski, T. Pawlowski, M. Tendera, Katowice: A. Winiarska-Filipek, A. Fidyk, A. Slowikowski, M. Haberka, M. Lachor-Broda, M. Biedron, Z. Gasior, Kielce: M. Kołodziej, M. Janion, Kielce: I. Gorczyca-Michta, B. Wozakowska-Kaplon, Łódź: M. Stasiak, P. Jakubowski, T. Ciurus, J. Drozdz, Łódź: M. Simiera, P. Zajac, T. Wcislo, P. Zycinski, J. Kasprzak, Nysa: A. Olejnik, E. Harc-Dyl, J. Miarka, M. Pasieka, M. Zieminska-Łuć, W. Bujak, Opoczno: A. Śliwiński, A. Grech, J. Morka, K. Petrykowska, M. Prasał, Opole: G. Hordyński, P. Feusette, P. Lipski, A. Wester, Radlin: W. Streb, Rzeszów: J. Romanek, P. Woźniak, M. Chlebuś, P. Szafarz, W. Stanik, Szczecin: M. Zakrzewski, J. Kaźmierczak, Szczecin: A. Przybylska, E. Skorek, H. Blaszczyk, M. Stępień, S. Szabowski, W. Krysiak, M. Szymańska, Tarnów: J. Karasiński, J. Blicharz, M. Skura, Warsaw: K. Hałas, L. Michalczyk, Z. Orski, K. Krzyżanowski, A. Skrobowski, Warsaw: L. Zieliński, M. Tomaszewska-Kiecana, M. Dłużniewski, Warsaw: M. Kiliszek, M. Peller, M. Budnik, P. Balsam, G. Opolski, A. Tymińska, K. Ozierański, A. Wancerz, Warsaw: A. Borowiec, E. Majos, R. Dabrowski, H. Szwed, Zabrze: A. Musialik-Lydka, Zabrze: A. Leopold-Jadczyk, E. Jedrzejczyk-Patej, M. Koziel, R. Lenarczyk, M. Mazurek, Z. Kalarus, Zabrze: K. Krzemien-Wolska, P. Starosta, E. Nowalany-Kozielska, Zakopane: A. Orzechowska, M. Szpot, M. Staszel, **PORTUGAL** Almada: S. Almeida, H. Pereira, L. Brandão Alves, R. Miranda, L. Ribeiro, Carnaxide Lisboa: F. Costa, F. Morgado, P. Carmo, P. Galvao Santos, R. Bernardo, P. Adragão, Santarém: G. Ferreira da Silva, M. Peres, M. Alves, M. Leal, Vila Real: A. Cordeiro, P. Magalhães, P. Fontes, S. Leão, Viseu: A. Delgado, A. Costa, B. Marmelo, B. Rodrigues, D. Moreira, J. Santos, L. Santos, **ROMANIA** Arad: A. Terchet, D. Darabantiu, S. Mercea, V. Turcin Halka, A. Pop Moldovan, Brasov: A. Gabor, B. Doka, G. Catanescu, H. Rus, L. Oboroceanu, E. Bobescu, Bucharest: R. Popescu, A. Dan, A. Buzea, I. Daha, G. Dan, I. Neuhoff, Bucharest: M. Baluta, R. Ploesteanu, N. Dumitrache, M. Vintila, Bucharest: A. Daraban, C. Japie, E. Badila, H. Tewelde, M. Hostioc, S. Frunza, E. Tintea, D. Bartos, Bucharest: A. Ciobanu, I. Popescu, N. Toma, C. Gherghinescu, D. Cretu, N. Patrascu, C. Stoicescu, C. Udroiu, G. Bicescu, V. Vintila, D. Vinereanu, M. Cinteza, R. Rimbas, Iași: M. Grecu, Oradea: A. Cozma, F. Boros, M. Ille, O. Tica, R. Tor, A. Corina, A. Jee-wooth, B. Maria, C. Georgiana, C. Natalia, D. Alin, D. Dinu-Andrei, M. Livia, R. Daniela, R. Larisa, S. Umaar, T. Tamara, M. Ioachim Popescu, Târgu Mureș: D. Nistor, I. Sus, O. Coborosanu, Timișoara: N. Alina-Ramona, R. Dan, L. Petrescu, Timișoara: G. Ionescu, I. Popescu, C.
Vacarescu, E. Goanta, M. Mangea, A. Ionac, C. Mornos, D. Cozma, S. Pescariu, RUSSIAN FEDERATION Arkhangelsk: E. Solodovnicova, I. Soldatova, J. Shutova, L. Tjuleneva, T. Zubova, V. Uskov, Arkhangelsk: D. Obukhov, G. Rusanova, Arkhangelsk: I. Soldatova, N. Isakova, S. Odinsova, T. Arhipova, Arkhangelsk: E. Kazakevich, E. Serdechnaya, O. Zavyalova, Saint-Petersburg: T. Novikova, Saint-Petersburg: I. Riabaia, M. Zhigalov, Saint-Petersburg: E. Drozdova, I. Luchkina, Y. Monogarova, Vladivostok: D. Hegya, L. Rodionova, L. Rodionova, V. Nevzorova, Vladivostok: I. Soldatova, O. Lusanova, SERBIA Belgrade: A. Arandje-lovic, D. Toncev, L. Vukmirovic, M. Radisavljevic, M. Milanov, N. Sekularac, Belgrade: M. Zdravkovic, S. Hinic, S. Dimkovic, T. Acimovic, J. Saric, S. Radovanovic, Belgrade: A. Kocijancic, B. Obrenovic-Kircanski, D. Kalimanovska Ostric, D. Simic, I. Jovanovic, I. Petrovic, M. Polovina, M. Vukicevic, M. Tomasevic, N. Mujovic, N. Radivojevic, O. Petrovic, S. Aleksandric, V. Kovacevic, Z. Mijatovic, B. Ivanovic, M. Tesic, T. Potpara, A. Ristic, B. Vujisic-Tesic, M. Nedeljkovic, Belgrade: A. Karadzic, A. Uscumlic, M. Prodanovic, M. Zlatar, M. Asanin, Belgrade: B. Bisenic, V. Vasic, Z. Popovic, Belgrade: D. Djikic, M. Sipic, V. Peric, B. Dejanovic, N. Milosevic, Belgrade: S. Backovic, A. Stevanovic, A. Andric, B. Pencic, M. Pavlovic-Kleut, V. Celic, Kragujevac: M. Pavlovic, M. Petrovic, M. Vuleta, N. Petrovic, S. Simovic, Z. Savovic, S. Milanov, G. Davidovic, V. Iric-Cupic, Nis: D. Djordjevic, M. Damjanovic, S. Zdravkovic, V. Topic, D. Stanojevic, M. Randjelovic, R. Jankovic-Tomasevic, V. Atanaskovic, S. Antic, M. Pavlovic, Niška Banja: D. Simonovic, M. Stojanovic, S. Stojanovic, V. Mitic, V. Ilic, D. Petrovic, M. Deljanin Ilic, S. Ilic, V. Stoickov, Pirot: S. Markovic, Sabac: A. Mijatovic, D. Tanasic, D. Petrovic, G. Radakovic, J. Peranovic, M. Pavlovic, N. Panic-Jelic, O. Vujadinovic, P. Pajic, S. Bekic, S. Kovacevic, SPAIN Alicante: A. García Fernandez, Benalmadena: A. Perez Cabeza, Córdoba: M. Anguita, Granada: L. Tercedor Sanchez, Huarte: E. Mau, J. Loayssa, M. Ayarra, M. Carpintero, Madrid: I. Roldán Rabadan, Murcia: M. Leal, Murcia: M. Gil Ortega, Murcia: A. Tello Montoliu, E. Orenes Piñero, S. Manzano Fernández, F. Marín, A. Romero Aniorte, A. Veliz Martínez, M. Quintana Giner, Pamplona: G. Ballesteros, M. Palacio, O. Alcalde, O. García-Bolao, San Juan de Alicante: V. Bertomeu Gonzalez, Santiago de Compostela: F. Otero-Raviña, J. García Seara, J. Gonzalez Juanatey, SWITZERLAND Geneva: N. Dayal, P. Maziarski, P. Gentil-Baron, D. Shah, TURKEY Adana: M. Koç, Afyon: E. Onrat, I. E. Dural, Ankara: K. Yilmaz, B. Özin, Ankara: S. Tan Kurklu, Y. Atmaca, Ankara: U. Canpolat, L. Tokgozoglu, Ankara: A. K. Dolu, B. Demirtas, D. Sahin, Ankara: O. Ozcan Celebi, E. Diker, Antalya: G. Gagirci, Bayraklı/Izmir: U.O.Turk, Bursa: H. Ari, Diyarbakır: N. Polat, N. Toprak, Gaziantep: M. Sucu, Görükle-Bursa: O. Akin Serdar, Istanbul: A. Taha Alper, Istanbul: A. Kepez, Istanbul: Y. Yuelsel, Kurupelit - Samsun: O. Uzunselvi, S. Yuksel, M. Sahin, Merkez/Düzce: O. Kayapinar, Mersin: T. Ozcan, Sivas: H. Kaya, M. B. Yilmaz, Trabzon: M. Kutlu, Yüreğir-Adana: M. Demir, UNITED KINGDOM Barnstaple: C. Gibbs, S. Kaminskiene, M. Bryce, A. Skinner, G. Belcher, J. Hunt, L. Stancombe, B. Holbrook, C. Peters, S. Tettersell, Birmingham: A. Shantsila, D. Lane, K. Senoo, M. Proietti, K. Russell, P. Domingos, S. Hussain, J. Partridge, R. Haynes, S. Bahadur, R. Brown, S. McMahon, G. Y H Lip, Blackburn: J. McDonald, K. Balachandran, R. Singh, S. Garg, H. Desai, K. Davies, W. Goddard, Blackpool: G. Galasko, I. Rahman, Y. Chua, O. Payne, S. Preston, O. Brennan, L. Pedley, C. Whiteside, C. Dickinson, J. Brown, K. Jones, L. Benham, R. Brady, Carlisle: L. Buchanan, A. Ashton, H. Crowther, H. Fairlamb, S. Thornthwaite, C. Relph, A. McSkeane, U. Poultney, N. Kelsall, P. Rice, T. Wilson, Chertsey: M. Wrigley, R. Kaba, T. Patel, E. Young, J. Law, Cramlington: C. Runnett, H. Thomas, H. McKie, J. Fuller, S. Pick, Exeter: A. Sharp, A. Hunt, K. Thorpe, C. Hardman, E. Cusack, L. Adams, M. Hough, S. Keenan, A. Bowring, J. Watts, Great Yarmouth: J. Zaman, K. Goffin, H. Nutt, Harrogate: Y. Beerachee, J. Featherstone, C. Mills, J. Pearson, L. Stephen, Huddersfield: S. Grant, A. Wilson, C. Hawksworth, I. Alam, M. Robinson, S. Ryan, Macclesfield: R. Egdell, E. Gibson, M. Holland, D. Leonard, Maidstone: B. Mishra, S. Ahmad, H. Randall, J. Hill, L. Reid, M. George, S. McKinley, L. Brockway, W. Milligan, Manchester: J. Sobolewska, J. Muir, L. Tuckis, L. Winstanley, P. Jacob, S. Kaye, L. Morby,

Nottingham: A. Jan, T. Sewell, Poole: C. Boos, B. Wadams, C. Cope, P. Jefferey, Portsmouth: N. Andrews, A. Getty, A. Suttling, C. Turner, K. Hudson, R. Austin, S. Howe, Redhill: L. Iqbal, N. Gandhi, K. Brophy, P. Mirza, E. Willard, S. Collins, N. Ndlovu, Rhyl: E. Subkovas, V. Karthikeyan, L. Waggett, A. Wood, A. Bolger, J. Stockport, L. Evans, E. Harman, J. Starling, L. Williams, V. Saul, Salisbury: M. Sinha, L. Bell, S. Tudgay, S. Kemp, J. Brown, L. Frost, Shrewsbury: T. Ingram, A. Loughlin, C. Adams, M. Adams, F. Hurford, C. Owen, C. Miller, E. Donaldson, H. Tivenan, H. Button, South Shields: A. Nasser, O. Jhagra, B. Stidolph, C. Brown, C. Livingstone, M. Duffy, P. Madgwick, Southampton: P. Roberts, E. Greenwood, L. Fletcher, M. Beveridge, S. Earles, Taunton: D. McKenzie, D. Beacock, M. Dayer, M. Seddon, D. Greenwell, F. Luxton, F. Venn, H. Mills, J. Rewbury, K. James, K. Roberts, L. Tonks, Torquay: D. Felmeden, W. Taggu, A. Summerhayes, D. Hughes, J. Sutton, L. Felmeden, Watford: M. Khan, E. Walker, L. Norris, L. O'Donohoe, Weston-super-Mare: A. Mozid, H. Dymond, H. Lloyd-Jones, G. Saunders, D. Simmons, D. Coles, D. Cotterill, S. Beech, S. Kidd, Wolverhampton: B. Wrigley, S. Petkar, A. Smallwood, R. Jones, E. Radford, S. Milgate, S. Metherell, V. Cottam, Yeovil: C. Buckley, A. Broadley, D. Wood, J. Allison, K. Rennie, L. Balian, L. Howard, L. Pippard, S. Board, T. Pitt-Kerby.

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