European Journal of Internal Medicine xxx (xxxx) xxx–xxx

Contents lists available at ScienceDirect

European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Predicting spontaneous conversion to sinus rhythm in symptomatic atrial

fibrillation: The ReSinus score
Jan Niederdöckl1, Alexander Simon2, Filippo Cacioppo1, Nina Buchtele3,4, Anne Merrelaar1,
Nikola Schütz1, Sebastian Schnaubelt1, Alexander O Spiel1,2, Dominik Roth1,
Christian Schörgenhofer3, Harald Herkner1, , Hans Domanovits1, Michael Schwameis1
⁎

1
Department of Emergency Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
2
Zentrale Notaufnahme, Wilhelminenspital, Montleartstr.37, 1160 Vienna, Austria
3
Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
4
Department of Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria

ARTICLE INFO ABSTRACT

Keywords: Background: The optimal management of patients presenting to the Emergency Department with hemodyna-
symptomatic atrial fibrillation mically stable symptomatic atrial fibrillation remains unclear. We aimed to develop and validate an easy-to-use
spontaneous conversion score to predict the individual probability of spontaneous conversion to sinus rhythm in these patients
prediction score Methods: This retrospective cohort study analyzed 2426 cases of first-detected or recurrent hemodynamically
derivation
stable non-permanent symptomatic atrial fibrillation documented between January 2011 and January 2019 in
validation
an Austrian academic Emergency Department atrial fibrillation registry. Multivariable analysis was used to
develop and validate a prediction score for spontaneous conversion to sinus rhythm during Emergency
Department visit. Clinical usefulness of the score was assessed using decision curve analysis
Results: 1420 cases were included in the derivation cohort (68years, 57-76; 43% female), 1006 cases were
included in the validation cohort (69years, 58-76; 47% female). Six variables independently predicted sponta-
neous conversion. These included: duration of atrial fibrillation symptoms (<24hours), lack of prior cardio-
version history, heart rate at admission (>125bpm), potassium replacement at K+ level ≤3.9mmol/l, NT-
proBNP (<1300pg/ml) and lactate dehydrogenase level (<200U/l). A risk score weight was assigned to each
variable allowing classification into low (0-2), medium (3-5) and moderate (6-8) probability of spontaneous
conversion. The final score showed good calibration (p=0.44 and 0.40) and discrimination in both cohorts (c-
indices: 0.74 and 0.67) and clinical net benefit
Conclusion: The ReSinus score, which predicts spontaneous conversion to sinus rhythm, was developed and
validated in a large cohort of patients with hemodynamically stable non-permanent symptomatic atrial fi-
brillation and showed good calibration, discrimination and usefulness
Registration: NCT03272620

1. Introduction
In patients with symptomatic atrial fibrillation rates of spontaneous
conversion are high.1-3 In real-world emergency cohorts optimal man-
agement is unclear; however, treatment with early cardioversion is a
common practice, although the individual probability of a patient
converting to sinus rhythm spontaneously is uncertain. Deferred car-
dioversion in patients with a low probability of spontaneous conversion
may result in an unjustified treatment delay and increased risk of
stroke, heart failure and progression to persistent atrial fibrillation,4-6
Conversely, patients who are likely to convert to sinus rhythm spon-
taneously, but undergo early pharmacological or electrical cardiover-
sion may be unnecessarily hospitalized and exposed to the risk of post-
conversion arrhythmias and complications by general anesthesia or
antiarrhythmic drugs.7, 8
Given the rising prevalence9 and economic burden10 of atrial fi-
brillation, several decision aids have been developed to facilitate the
estimation of a patients’ individual stroke, bleeding and mortality risk,
thus guiding safe and effective long-term management.11, 12 A tool to
estimate the individual probability of spontaneous conversion of

⁎
Corresponding author. Tel.: +4314040019640, Fax: +4314040019650.
E-mail address: harald.herkner@meduniwien.ac.at (H. Herkner).

https://doi.org/10.1016/j.ejim.2020.07.022
Received 20 February 2020; Received in revised form 14 July 2020; Accepted 31 July 2020
0953-6205/ © 2020 The Author(s). Published by Elsevier B.V. on behalf of European Federation of Internal Medicine. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).

Please cite this article as: Jan Niederdöckl, et al., European Journal of Internal Medicine, https://doi.org/10.1016/j.ejim.2020.07.022
J. Niederdöckl, et al.
patients presenting with symptomatic atrial fibrillation, however, is not
available. Ideally, informed decisions of patients and clinicians should
be based on this information.
In this study we developed and validated an easy-to-use score to
estimate the individual probability of spontaneous conversion to sinus
rhythm in adult patients with hemodynamically stable non-permanent
symptomatic atrial fibrillation.
2. Material and methods
2.1. Study design/setting
This retrospective cohort study is based on an atrial fibrillation
registry including consecutive adult patients with atrial fibrillation
treated at the Emergency Department at the Medical University of
Vienna, an academic tertiary care facility. The Emergency Department
comprises an outpatient care section and an affiliated critical care unit
covering more than 90 000 patients overall 13 and about 600 patients
with atrial fibrillation per year. Patients presenting with atrial fi-
brillation and hypokalemia (less than 3.5mmol/l) or low-normal po-
tassium levels (3.5-3.9mmol/l) receive potassium replacement with
Elozell Spezial intravenous solution (containing 24 mmol potassium
and 12mmol magnesium per 250ml) based on provider-dependent
practice. Acute rate and rhythm control therapy is based on current
European Society of Cardiology (ESC) guidelines 14 and depends on the
patient's left ventricular function, hemodynamics, drug history in-
cluding anticoagulation status and comorbidities. Rate control medi-
cation includes beta-adrenergic receptor blockers (metoprolol, es-
molol), verapamil and cardiac gylcosides (digoxin, digitoxin).
Pharmacological cardioversion is performed mainly with vernakalant,
ibutilide and amiodarone. Standard biphasic defibrillators are used for
synchronized direct current electrical cardioversion.
The study was approved by the Ethics Committee of the Medical
University of Vienna and conducted in accordance with ICH-GCP
guidelines and Helsinki Declaration. Patients or the public were not
involved in the design, or conduct, or reporting, or dissemination of our
research. The study is registered with clinicaltrials.gov
(NCT03272620).
2.2. Atrial fibrillation registry
The atrial fibrillation registry has previously been described in de-
tail.15 In brief, the registry started in January 2011 and prospectively
includes all cases of atrial fibrillation confirmed by 12-lead electro-
cardiography. Prior to inclusion informed consent is obtained. Demo-
graphics, past medical history including comorbidities, concomitant
medication and previous attempts at electrical cardioversion, the
CHA2DS2VASC score, results from blood gas analysis, blood count,
chemistry, coagulation variables, thyroid function, troponin and NT-
proBNP levels are obtained. Additionally, vital signs including heart
rate, blood pressure and oxygen saturation, symptoms attributable to
atrial fibrillation, the time of symptom onset, the type of atrial fi-
brillation, and treatments including electrolyte substitution, rate con-
trol medication and cardioversion attempts are documented by study
fellows.
2.3. The ReSinus score
The score was developed and validated in cases of hemodynamically
stable first-detected or recurrent non-permanent symptomatic atrial
fibrillation entered into the atrial fibrillation registry between January
2011 and January 2019 (Figure 1).
AF, atrial fibrillation.
Patients with a history of permanent atrial fibrillation and atrial
fibrillation events occurring in the context of critical illness were ex-
cluded before cohort allocation. Initially, internal validation was
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European Journal of Internal Medicine xxx (xxxx) xxx–xxx
planned using a random sample for model derivation and one for va-
lidation in a 1:1 sample ratio. However, owing to the considerations of
Steyerberg and Verguowe16 on the benefits of temporal validation we
restricted the validation sample to the most contemporary cases at a
sample size sufficient to handle up to 10 independent predictors in the
model. Accordingly, we aimed at a sample size of approximately 1000
patients for the validation set. Temporal validation assesses the per-
formance of a model by applying it to the most recent data from the
population it was initially derived. Thus, it refers to the generalizability
and transportability of study findings to plausibly related populations
and is considered a more robust test for prediction models. A compar-
ison of the set of excluded patients (n=345) with the set of patients
finally included in the validation cohort (n=1006) is available with the
supplement (Supp. Table 4).
Spontaneous conversion was defined as return to sinus rhythm
during Emergency Department visit without any attempt at pharma-
cological or electrical cardioversion. Rate-control therapy as well as
electrolyte replacement was not rated as an attempt at cardioversion.
Patients who converted spontaneously did not receive any anti-ar-
rhythmic drugs prior to restoration of sinus rhythm.
2.4. Statistical methods
Variables are presented as absolute values (n), relative frequencies
(%) and median (25-75% interquartile ranges, IQR). Between-group
comparisons were performed using the Mann-Whitney U test for con-
tinuous variables or the chi-squared test/Fisher's exact test for nominal
variables. Univariable logistic regression with spontaneous conversion
to sinus rhythm as a dependent variable was performed on available
cases. Several candidate predictors for spontaneous conversion, which
were judged to be clinically plausible, were tested. Only variables
available within one hour upon admission were used to allow the
creation of a risk score readily useable in clinical practice. Continuous
variables in univariable analysis were categorized by selecting clinically
relevant cut-offs, which were the closest to the statistically optimal cut-
offs, and examined for linear and non-linear associations including re-
stricted cubic splines. Categorization of variables yielded at parsimony
and dichotomy, and cut-offs were optimized for maximum discrimina-
tion in the derivation cohort.
Variables significant in univariable analysis were entered in a
multivariable logistic regression model to calculate adjusted odds ratio
(OR) with 95% confidence intervals (95% CI). A stepwise process was
used, aiming at the most parsimonious model. Interaction was assessed
using the likelihood ratio test. In case of interaction the interaction
terms were used in subsequent models. Multicollinearity between the
variables in the final model was assessed as ill-conditioning, i.e. the
impact of small random changes (perturbations) to variables on para-
meter estimates. Firth regression penalizing the log-likelihood with
one-half of the logarithm of the determinant of the information matrix
was used for the final model to avoid overfitting to the derivation data.
These adjusted coefficients of significant multivariable predictors were
then divided by the lowest coefficient value in the model and rounded
to the nearest integer. From these values a risk score weight was as-
signed to each predictor in the model. The sum of risk scores for each
patient was subsequently calculated.
Calibration was assessed by performing the Hosmer–Lemeshow
goodness-of-fit test and by plotting observed vs. predicted incidence
rate across categories of the developed score. In the derivation set, as
well as in the validation set, the predictive performance of the risk score
was assessed using the c-statistic, which was 1000-fold cross-validated
by bootstrapping in order to evaluate the discriminative ability.
To test the robustness of the model according to the time to cardi-
oversion we performed a sensitivity analysis restricting the observation
time from admission to restoration of sinus rhythm to two hours.
Clinical usefulness was evaluated using decision curve analysis.17 In
this context, clinical net benefit is the relationship between the benefit
J. Niederdöckl, et al.
Figure 1. Study flow chart. Out of 3012 cases of symptomatic atrial fibrillation documented between 2011 and 2019, a total of 2426 cases of hemodynamically stable
first-detected or recurrent non-permanent symptomatic atrial fibrillation were eligible for analysis. Owing to the benefits of temporal validation the validation sample
was restricted to the most contemporary cases at a sample size sufficient to handle up to 10 independent predictors in the model. 1420 cases were finally included in
the derivation cohort and 1006 cases were included in the validation cohort.
of treating those, who need treatment, and the harm of treating those,
who do not need treatment. Decision curve analysis allows the eva-
luation of clinical net benefit of a prognostic tool over a range of
threshold probabilities of having a positive outcome. Clinical net ben-
true positives false positives p
efit is calculated as n n
( 1 tp ) , where n is the total
t
number of patients, and ptis the threshold probability of having a po-
sitive outcome. True and false positives are calculated using pt as the
cut-point for determining a positive or negative result. This calculation
is repeated over a range of clinically meaningful threshold prob-
abilities.18
The analyses followed the framework of derivation and validation of
prediction models proposed by Steyerberg and Vergouwe.16 Reporting
followed the TRIPOD statement.19 Missing data were included as se-
parate categories for each variable as appropriate. Stata 14 (StataCorp,
College Station, TX, USA) was used for data analysis. Generally, a two-
sided p-value <0.05 was considered statistically significant.
3. Results
Out of 3012 cases of symptomatic atrial fibrillation entered into the
registry between 2011 and 2019, 2426 cases of hemodynamically stable
first-detected or recurrent non-permanent symptomatic atrial fibrilla-
tion were eligible for analysis. 1420 cases were included in the deri-
vation cohort (median age 68 years, IQR 57 - 76; 43% female) and 1006
cases were included in the validation cohort (median age 69 years, IQR
58 - 76; 47% female). Table 1 provides an overview of demographics,
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European Journal of Internal Medicine xxx (xxxx) xxx–xxx
baseline characteristics and clinical course of both study cohorts.
968 patients (67.3%) in the derivation cohort and 717 patients
(71.3%) in the validation cohort who did not convert spontaneously
underwent an attempt of pharmacological/electrical cardioversion.
The median duration from admission to restoration of sinus rhythm
was significantly longer in patients who were cardioverted than in those
who converted spontaneously to sinus rhythm: 4.1 vs. 2.1 hours in the
derivation cohort (p<0.001) and 3.7 vs. 1.5 hours in the validation
cohort (p=0.040) (Supp. Table 5).
3.1. Derivation of the ReSinus score
Spontaneous conversion to sinus rhythm occurred in 186 patients
(13%). Clinical and laboratory characteristics of patients in the deri-
vation cohort stratified by the occurrence of spontaneous conversion
are shown in Table 2.
Univariable analysis identified six variables independently asso-
ciated with spontaneous conversion to sinus rhythm. The identified
values of predictors were doubled and rounded to the nearest integer
(Table 3).
The weighted score included the duration of atrial fibrillation re-
lated symptoms (<24 hours; 2 points), a lack of prior cardioversion
history (2 points), heart rate at admission (>125 beats per minute; 1
point), potassium replacement at K+ level ≤3.9mmol/l (1 point), NT-
proBNP (<1300 pg/ml; 1 point) and lactate dehydrogenase level
(<200 U/l; 1 point), totaled to a maximum score of 8 points. The factor
J. Niederdöckl, et al. European Journal of Internal Medicine xxx (xxxx) xxx–xxx

Table 1
Demographics and baseline characteristics of the derivation and the validation cohort
Derivation cohort Validation cohort p=
n=1420 n=1006
available* (n) available* (n)

Clinical Characteristics
Age, years (IQR) 68 (57 - 76) 1420 69 (58 - 76) 1420 0.190
Female gender, n (%) 615 (43) 472 (47) 0.065
BMI, kg/m˄2 (IQR) 28 (25 - 30) 1420 28 (24 - 30) 984 0.824
BP systolic, mmHG (IQR) 134 (120 - 150) 1290 134 (120 - 150) 967 0.876
BP diastolic, mmHG (IQR) 82 (72 - 95) 1279 85 (75 - 95) 962 0.034
Heart rate, bpm (IQR) 130 (111 - 147) 845 130 (111 - 146) 625 0.762
Comorbidities
Lone AF, n (%) 86 (6) 72 (7) 0.311
Heart failure, n (%) 242 (17) 174 (17) 0.894
Hypertension, n (%) 873 (61) 593 (59) 0.185
DM, n (%) 327 (23) 130 (13) 0.433
TIA, n (%) 38 (3) 12 (1) 0.016
Stroke, n (%) 93 (7) 49 (5) 0.061
CAD, n (%) 243 (17) 166 (17) 0.711
Previous myocardial infarcton, n (%) 110 (8) 91 (9) 0.276
PAD, n (%) 59 (4) 39 (4) 0.733
COPD, n (%) 114 (8) 72 (7) 0.452
Valvular pathology, n (%) 349 (25) 235 (23) 0.445
Hyperlipidaemia, n (%) 452 (32) 301 (30) 0.331
Hyperthyreosis, n (%) 56 (4) 46 (5) 0.580
Hypothyreosis, n (%) 221 (16) 163 (16) 0.759
Current smoker, n (%) 77 (5) 44 (4) 0.749
AF history
First AF episode, n (%) 217 (15) 183 (18) 0.505
Previous AF episodes, n (%) 3 (0 - 8) 691 3 (0 - 8) 506 0.373
Previous electrical CV, n (%) 398 (28) 298 (30) 0.392
Ablation, n (%) 229 (16) 180 (18) 0.227
Duration of AF symptoms, h (IQR) 6 (2 - 21) 760 6 (2 - 19) 558 0.997
CHA2DS2-VASc (IQR) 3 (1 - 4) 1339 2 (1 - 4) 961 0.029
Medication
Phenprocoumon, n (%) 355 (25) 198 (20) 0.002
DOACS, n (%) 245 (17) 213 (21) 0.015
Cardiac glycosides, n (%) 56 (4) 38 (4) 0.834
Beta blocker, n (%) 625 (44) 437 (43) 0.779
Amiodarone, n (%) 255 (18) 147 (15) 0.039
AT-2 Blocker, n (%) 316 (22) 266 (16) 0.025
ACE Blocker, n (%) 284 (20) 174 (17) 0.102
Pre-Treatment
Potassium replacement, n (%) 712 (50) 377 (37) 0.171
Laboratory
Haematocrit, % (IQR) 41 (38 - 45) 1351 42 (38 - 45) 941 0.134
WBC, G/l (IQR) 8 (7 - 10) 1363 8 (7 - 10) 950 0.860
Creatinine, mg/dl (IQR) 1 (1 - 1) 1361 1 (1 - 1) 954 0.350
Potassium, mmol/l (IQR) 4.0 (3.8 - 4.3) 1321 4.0 (3.8 - 4.3) 930 0.973
LDH, U/l (IQR) 196 (167 - 238) 1117 198 (169 - 240) 792 0.435
NT-proBNP, pg/ml (IQR) 943 (303 - 2393) 1172 981 (312 - 2739) 831 0.355
hs-Troponin T, ng/l (IQR) 14 (8 - 25) 1090 14 (8 - 27) 821 0.663
CRP, mg/dl (IQR) 0 (0 - 1) 1318 0 (0 - 1) 927 0.750
Lactate, mmol/l (IQR) 1 (1 - 2) 1238 2 (1 - 2) 870 0.226
INR, (IQR) 2 (1 - 3) 738 1 (1 - 2) 527 <0.001
TSH, μU/ml (IQR) 2 (1 - 3) 980 2 (1 - 3) 691 0.492

*Number of patients who had the variable available. Missing data for some score variables in both cohorts ranged from 0 to 21%.
ACE (angiotensin converting enzyme), AF (atrial fibrillation), AT (angiotensin), BMI (body mass index), BP (blood pressure), CAD (coronary artery disease), COPD
(chronic obstructive pulmonary disease), CRP (C-reactive protein), CV (cardioversion), DM (diabetes mellitus), DOAC (direct oral anticoagulants), hs (high-sensitive),
INR (international normalized ratio), LA (left atrium), LDH (lactate dehydrogenase), NT-proBNP (N-terminal-pro brain natriuretic peptide), PAD (peripheral artery
disease), RA (right atrium), TIA (transient ischemic attack), TSH (thyroid stimulating hormone), WBC (white blood cells).
The frequency distribution of individual DOACS, glycosides and beta-blockers is available with the supplement (Supp. Table 1).

‘potassium replacement at K+ level ≤3.9mmol/l’ included all patients
who received potassium substitution unless potassium level exceeded
3.9mmol/l. The observed incidence of short-term spontaneous conver-
sion was 50% for patients with 8 points and 0% for patients with 0
points. The odds ratio associated with every increase of one score point
was 1.61 (95% CI 1.47–1.76; p < 0.001).
The final model showed good discrimination (c-index 0.74; 95% CI
0.70–0.77). The p-value of the Hosmer-Lemeshow goodness-of-fit test
was 0.43. The predicted and observed incidence of short-term sponta-
neous conversion to sinus rhythm across the groups built by final score
values showed good calibration (p=0.43) (Figure 2).
The cumulative final score value of each patient allowed classifi-
cation into low (0-2), medium (3-5) and moderate (6-8) probability of
spontaneous conversion. The rates of short-term spontaneous conver-
sion to sinus rhythm across these three classes were 3.8%, 12.3%,
33.8% respectively (Figure 3).
3.2. Validation of the ReSinus score
The observed incidence of spontaneous conversion in the validation

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Table 2
Clinical and biomarker characteristics among patients with and without spontaneous conversion
Spontaneous No Spontaneous p=
Conversion n=186 Conversion n=1234
available* (n) available* (n)

Clinical Characteristics
Age, years (IQR) 68 (56 - 76) 186 68 (58 - 75) 1234 0.490
Male gender, n (%) 108 (58) 697 (56) 0.626
BMI, kg/m˄2 (IQR) 28 (25 - 30) 186 28 (2 - 30) 1234 0.315
BP systolic, mmHG (IQR) 133 (120 - 150) 168 134 (11 - 150) 1122 0.728
BP diastolic, mmHG (IQR) 82 (72 - 95) 167 82 (7 - 95) 1112 0.825
Heart rate, bpm (IQR) 136 (117 - 149) 142 129 (110 - 146) 703 0.012
Comorbidities
Lone AF, n (%) 9 (5) 77 (6) 0.405
Heart failure, n (%) 19 (10) 223 (18) 0.008
Hypertension, n (%) 128 (69) 754 (61) 0.022
DM, n (%) 20 (11) 177 (14) 0.217
TIA, n (%) 5 (3) 33 (3) 0.964
Stroke, n (%) 12 (6) 81 (7) 0.996
CAD, n (%) 33 (18) 210 (17) 0.769
Previous myocardial 14 (8) 96 (8) 0.896
infarction, n (%)
PAD, n (%) 4 (2) 55 (4) 0.137
COPD, n (%) 12 (6) 102 (8) 0.329
Valvular pathology, n (%) 46 (25) 303 (25) 0.999
Hyperlipidaemia, n (%) 67 (36) 385 (31) 0.166
Hyperthyreosis, n (%) 6 (3) 50 (4) 0.674
Hypothyreosis, n (%) 37 (20) 184 (15) 0.083
Current smoker, n (%) 22 (12) 135 (11) 0.868
AF history
First AF episode, n (%) 40 (22) 177 (14) 0.027
Previous AF episodes, n 2 (0 - 5) 97 3 (0 - 8) 594 0.058
(IQR)
Previous electrical CV, n 38 (20) 360 (29) 0.018
(IQR)
Ablation, n (%) 31 (17) 198 (16) 0.802
Duration of AF symptoms, h 4 (2 - 8) 133 7 (2 - 24) 627 <0.001
(IQR)
CHA2DS2-VASc (IQR) 3 (2 - 4) 182 2 (1 - 4) 1157 0.366
Medication
Phenprocoumon, n (%) 38 (20) 317 (26) 0.140
DOACS, n (%) 35 (19) 210 (17) 0.545
Cardiac glycosides, n (%) 6 (3) 50 (4) 0.589
Beta blocker, n (%) 92 (49) 533 (43) 0.108
Amiodarone, n (%) 22 (12) 233 (19) 0.022
AT-2 Blocker, n (%) 54 (29) 262 (21) 0.018
ACE Blocker, n (%) 46 (25) 238 (19) <0.001
Pre-Treatment
Potassium replacement, n 124 (67) 588 (48) <0.001
(%)
Laboratory
Haematocrit, % (IQR) 41 (37 - 44) 180 42 (38 - 45) 1171 0.237
WBC, G/l (IQR) 8 (7 - 10) 183 8 (7 - 10) 1180 0.950
Creatinine, mg/dl (IQR) 1 (1 - 1) 183 1 (1 - 1) 1178 0.094
Potassium, mmol/l (IQR) 3.9 (3.7 - 4.1) 181 4.0 (3.8 - 4.3) 1140 <0.001
LDH, U/l (IQR) 190 (163 - 220) 173 198 (167 - 241) 944 0.012
NT-proBNP, pg/ml (IQR) 516 (22 - 1282) 164 1042 (334 - 2574) 1008 <0.001
hs-Troponin T, ng/l (IQR) 15 (8 - 25) 143 14 (8 - 25) 947 0.406
CRP, mg/dl (IQR) 0 (0 - 1) 176 0 (0 - 1) 1142 0.752
Lactate, mmol/l (IQR) 1 (1 - 2) 177 1 (1 - 2) 1061 0.374
INR, (IQR) 1 (1 - 2) 97 2 (1 - 3) 641 <0.001
TSH, μU/ml (IQR) 2 (1- 3) 136 2 (1 - 3) 844 0.456

*Number of patients who had the variable available. Missing data for some score variables in both cohorts ranged from 0 to 21%.
ACE (angiotensin converting enzyme), AF (atrial fibrillation), AT (angiotensin), BMI (body mass index), BP (blood pressure), CAD (coronary artery disease), COPD
(chronic obstructive pulmonary disease), CRP (C-reactive protein), CV (cardioversion), DM (diabetes mellitus), DOAC (direct oral anticoagulants), hs (high-sensitive),
INR (international normalized ratio), LA (left atrium), LDH (lactate dehydrogenase), NT-proBNP (N-terminal-pro brain natriuretic peptide), PAD (peripheral artery
disease), RA (right atrium), TIA (transient ischemic attack), TSH (thyroid stimulating hormone), WBC (white blood cells).
The frequency distribution of individual DOACS, glycosides and beta-blockers is available with the supplement (Supp. Table 2).

cohort according to their classification (low, medium, moderate) was
7.9%, 9.1% and 19.6%. The score showed good calibration (p=0.40)
and discrimination (c statistic 0.67; 95% CI 0.63–0.72) (Figure 2).
The sensitivity analysis censoring the observation time at two hours
suggested robustness of the model (Supp. Table 3).
The decision curve analysis indicated a substantial clinical net
benefit of using the ReSinus score over the full spectrum of possible
thresholds (Figure 4).
Figure 5 provides an easy-to-use template for pragmatic calculation
of the ReSinus score in the clinical setting. Online calculation of the
score is available at www.meduniwien.ac.at/notfall/resinus.

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Table 3
Independent predictors of spontaneous conversion to sinus rhythm
Predictor Coefficient 95% CI p= Weighted Score

Duration of AF symptoms <24 h 0.89 ( 0.53 - 1.25 ) <0.001 2

No previous electrical CV 0.75 ( 0.35 - 1.15 ) <0.001 2
Heart rate > 125 bpm 0.55 ( 0.22 - 0.88 ) <0.001 1
Potassium replacement at K+ level ≤3.9mmol/l 0.55 ( 0.21 - 0.89 ) 0.002 1
NT-proBNP < 1300 pg/ml 0.54 ( 0.19 - 0.88 ) 0.003 1
LDH < 200 U/l 0.45 ( 0.11 - 0.78 ) 0.009 1

Firth regression was used to penalize the log-likelihood of the model to avoid overfitting to the derivation data. AF (atrial fibrillation), CV (cardioversion), NT-
proBNP (N-terminal-pro brain natriuretic peptide), LDH (lactate dehydrogenase).

Figure 2. Observed and predicted incidence of spontaneous conversion in (A) the derivation cohort and (B) the validation cohort. Calibration was visualized by
plotting observed vs. predicted incidence rate across categories of the developed score in the derivation set (A), as well as in the validation set (B). The dotted line
represents perfect calibration, the solid line represents actual calibration.

4. Discussion
In this study we developed and validated an easy-to-use risk score to
estimate the individual probability of spontaneous conversion to sinus
rhythm in patients with hemodynamically stable non-permanent
symptomatic atrial fibrillation. The score includes both clinical and
laboratory information and was developed from a cohort of patients
treated in a real-world emergency setting. To allow for the creation of a
risk score readily applicable in clinical practice, only variables available
within one hour of admission were used. Six independent predictors of
spontaneous conversion to sinus rhythm were identified including four
clinical (actual heart rate, duration of atrial fibrillation related symp-
toms, clinical history of previous cardioversion, potassium replace-
ment) and two routine laboratory variables (NT-proBNP and LDH
level). The final score was well calibrated, showed good discriminative
ability and clinical usefulness.

Figure 3. Observed incidence of spontaneous conversion across low (0-2), medium (3-5) and moderate (6-8) probability categories for spontaneous conversion in the
(A) derivation cohort and (B) the validation cohort.

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J. Niederdöckl, et al. European Journal of Internal Medicine xxx (xxxx) xxx–xxx

Figure 4. Decision curve analysis showing clinical usefulness of

the ReSinus score. X-axis depicts threshold probability of sponta-
neous conversion. Y-axis depicts clinical net benefit of three dif-
ferent strategies: Dashed line: ReSinus score. Solid line: assume all
patients will convert. Thin line: assume no patient will convert.
ReSinus score has a positive net benefit over the whole spectrum
of threshold probabilities. This was especially true in the clinically
relevant probability range from 5 to 30%, which corresponds to
the spontaneous conversion rates observed in our and many other
studies.

Figure 5. Stratification according to the probability of spontaneous conversion using the ReSinus score. Work along criteria A-F from the middle to the edge. Each
corresponding answer leads to the adjacent field of the next circle (blue = true; white = false). The final score can be read directly from the outermost circle. The
individual probability of spontaneous conversion according to the score is given by the bar on the right side. AF (atrial fibrillation), CV (cardioversion), NT-proBNP
(N-terminal-pro brain natriuretic peptide), LDH (lactate dehydrogenase).

4.1. Clinical predictors
Atrial fibrillation is considered a continuous process of electro-
anatomical remodeling promoting electrical dissociation, heterogenic
conduction and arrhythmic atrial contractions.20, 21 With progressive
disease, accumulating structural changes in atrial myocytes promote
further episodes of atrial fibrillation, which facilitates electro-physio-
logic conditions that perpetuate atrial arrhythmia and limit the prob-
ability of spontaneous conversion.22-24 It has been shown experimen-
tally that the duration of atrial fibrillation negatively affects its
spontaneous conversion probability.25 Accordingly, in the ReSinus
score the duration of atrial fibrillation was assigned the highest risk
score weight alongside a lacking history of cardioversion. Several
variables of the ReSinus score reflect advanced heart disease and may
indicate structural atrial alterations. In this context, a history of pre-
vious cardioversion attempts may suggest the presence of structural
changes, which impede spontaneous conversion and prompt the need
for cardioversion. Likewise, a low heart rate may indicate that the
disease is already advanced. Data on the relation between heart rate
and the probability of spontaneous conversion in atrial fibrillation are
lacking. However, a higher heart rate has previously been shown to
favor successful cardioversion and is associated with both a lower rate
of progression 26 and a lower rate of recurrence in atrial fibrillation. In
more advanced disease, remodeling processes within atria and the AV-

7
J. Niederdöckl, et al.
node, as well as negative chrono-and dromotropic treatment, may
promote lower ventricular conduction rates, which may thus be asso-
ciated with a lower probability of spontaneous conversion.
4.2. Laboratory predictors
The final score includes two biomarkers. NT-pro BNP has previously
been shown to be associated with atrial appendage dysfunction27 and
the risk of both new-onset and recurrent atrial fibrillation.28-32 Atrial
natriuretic peptide is specifically expressed in the atria and may thus be
an even more sensitive indicator of structural atrial disease33 but this is
not yet routinely available in clinical practice. Lactate dehydrogenase
in contrast is a widely used unspecific marker of tissue damage, which
is elevated in various medical conditions. It has recently been shown
that lactate cascades play a crucial role in the process of atrial re-
modeling and in the maintenance of atrial fibrillation.34 We can only
speculate as to whether elevated LDH levels in our study patients reflect
atrial alterations associated with atrial fibrillation or other comorbid-
ities. It is, however, evident that in atrial fibrillation biomarker-guided
management lags behind that of other major cardiovascular diseases
including myocardial infarction and heart failure, where both diagnosis
and treatment rely on laboratory values. The inclusion of biomarkers
into prediction models for the assessment of bleeding, stroke and death
risk in patients with atrial fibrillation has substantially improved their
accuracy and usefulness.35-37 It is conceivable that the inclusion of
further biomarkers not yet readily available in clinical practice would
likewise improve the performance of the ReSinus score.
4.3. Application of the ReSinus score
The ReSinus score was developed and validated in a real-world
cohort of patients with non-permanent symptomatic atrial fibrillation
presenting to the Emergency Department. Atrial fibrillation is among
the most frequent arrhythmias encountered in the acute care sector and
places an increasingly critical economic burden on health care sys-
tems,38, 39 mainly driven by treatment associated complications and
costs of hospitalization.14 Emergency department visits and hospitali-
zations for atrial fibrillation are increasing,10, 40 stressing the im-
portance of strategies aimed at personalizing acute management deci-
sions to reduce hospital admissions for unnecessary cardioversions,
treatment complications and associated health care costs.
2016 ESC guidelines suggest immediate cardioversion in patients
with recent-onset atrial fibrillation and related symptom burden or
cardiorespiratory compromise. In hemodynamically stable patients
with symptomatic atrial fibrillation, however, decisions as to whether
immediate restoration of sinus rhythm in the individual patient is ne-
cessary, or whether spontaneous conversion can be expected, remains
challenging in clinical practice because no objective decision guidance
is available. An easy-to-use decision tool may offer the opportunity to
personalize patient treatment already in a very early phase, facilitate
shared decision-making processes, fasten acute therapeutic manage-
ment and may reduce the length of stay in crowded Emergency
Departments. The ReSinus score may especially support decisions on
early cardioversion in patients in whom timely spontaneous conversion
to sinus rhythm is unlikely to occur. Conversely, in patients with high
probability of spontaneous conversion, the ReSinus score could
strengthen delayed-cardioversion approaches as suggested by
Pluymaekers et al and help avoiding treatment associated complica-
tions.3
4.4. Strengths and Limitations
The particular strength of this study is its real-world-cohort struc-
ture. This suggests robust results that could prove valid beyond highly
selected study populations. The Emergency Department at the Medical
University of Vienna comprises an outpatient care section and an
8
European Journal of Internal Medicine xxx (xxxx) xxx–xxx
affiliated critical care unit allowing fast diagnostic work-up and the
opportunity to rapidly perform cardioversion at any time. As this was a
registry-based study, time to cardioversion attempts and observation
periods were not standardized. It is thus conceivable that patients as-
signed to the non-spontaneous conversion cohort would have converted
spontaneously over the following hours or days if they had not under-
gone early cardioversion to restore sinus rhythm. Some related bias
cannot be excluded and should be considered when interpreting our
findings. However, sensitivity analysis restricting the observational
time-window from admission to two hours suggested robustness of the
model. Furthermore, the median duration from admission to restoration
of sinus rhythm was significantly longer in patients who were finally
cardioverted than in those who converted spontaneously. At our in-
stitution, cardioversion of hemodynamically stable symptomatic AF
patients, who do not early convert spontaneously, is performed as soon
as exam results are available and a trial of fluid and/or potassium
challenge has been performed to improve the probability of sponta-
neous conversion. This might be a common approach and reflect real-
world practice in emergency settings, where ED-overcrowding and
limited space for observation are common conditions. Yet, a future
prospective trial should include a predefined observation schedule and
follow-up period. In addition, the single-center design limits our results’
generalizability to different settings and populations. We followed the
methodological guidance by Steyerberg and Verguowe and used the
most contemporaneous set for validating our score. Geographical or
strong external validation may provide more robust model validation,
but was not be performed in this single-center study. Further validation
of the developed score is needed to conclusively assess its performance.
As not only hypokalemia but also potassium levels in the low-
normal range may be considered target conditions for potassium re-
placement, we included the combined information of low/low-normal
potassium level (≤3.9mmol/l) and potassium substitution in the
model. Patients with potassium levels exceeding 3.9mmol/l were not
counted as potassium replacement. This needs to be noted, as clinical
practice on potassium substitution in atrial fibrillation may vary be-
tween institutions and clinicians.
Finally, possible bias arising from missing data cannot be fully ex-
cluded. For some of the score variables data were missing in the deri-
vation and in the validation set. We avoided strong assumptions on the
missing data and included these as separate categories into our models.
Yet, it needs to be acknowledged that this does not exclude bias asso-
ciated with data missing not at random. Our results thus should be
interpreted with appropriated caution.
5. Conclusions
The ReSinus score, which uses clinical and routine laboratory
variables to predict spontaneous conversion to sinus rhythm, was de-
veloped and validated in a large cohort of patients with hemodynami-
cally stable non-permanent symptomatic atrial fibrillation, showed
good calibration, discrimination and clinical usefulness. Once vali-
dated, its implementation in clinical practice may aid physicians in
guiding early cardioversion decisions while reducing the risk of over-
treatment.
Authors
Jan Niederdoeckl, Alexander Simon, Filippo Cacioppo, Nina
Buchtele, Anne Merrelaar, Nikola Schütz, Sebastian Schnaubelt,
Alexander O. Spiel, Dominik Roth, Christian Schörgenhofer, Harald
Herkner, Hans Domanovits, Michael Schwameis
Declaration of interests
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to
J. Niederdöckl, et al.
influence the work reported in this paper.
The authors declare the following financial interests/personal re-
lationships which may be considered as potential competing interests:
Declarations of interest
none
Supplementary materials
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.ejim.2020.07.022.
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