Impact of frailty on the effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation: a nationwide cohort study

Abstract

Aims:
Data on non-vitamin K antagonist oral anticoagulants (NOACs) use in patients with atrial fibrillation (AF) and frailty are scarce. Therefore, the impact of frailty on AF-related outcomes and benefit-risk profiles of NOACs in patients with frailty were investigated.

Methods and results:
AF patients initiating anticoagulation between 2013-2019 were included using Belgian nationwide data. Frailty was assessed with the Claims-based Frailty Indicator. Among 254 478 anticoagulated AF patients, 71 638 (28.2%) had frailty. Frailty was associated with higher all-cause mortality risks (adjusted hazard ratio (aHR) 1.48, 95% confidence interval (CI) (1.43-1.54)), but not with thromboembolism or bleeding. Among subjects with frailty (78 080 person-years of follow-up), NOACs were associated with lower risks of stroke or systemic embolism (stroke/SE) (aHR 0.77, 95%CI (0.70-0.86)), all-cause mortality (aHR 0.88, 95%CI (0.84-0.92)) and intracranial bleeding (aHR 0.78, 95%CI (0.66-0.91)), a similar major bleeding risk (aHR 1.01, 95%CI (0.93-1.09)) and higher gastrointestinal bleeding risk (aHR 1.19, 95%CI (1.06-1.33) compared to VKAs. Major bleeding risks were lower with apixaban (aHR 0.84, 95%CI (0.76-0.93)), similar with edoxaban (aHR 0.91, 95%CI (0.73-1.14)), and higher with dabigatran (aHR 1.16, 95%CI (1.03-1.30)) and rivaroxaban (aHR 1.11, 95%CI (1.02-1.21)) compared to VKAs. Apixaban was associated with lower major bleeding risks compared to dabigatran (aHR 0.72, 95%CI (0.65-0.80)), rivaroxaban (aHR 0.78, 95%CI (0.72-0.84)) and edoxaban (aHR 0.74, 95%CI (0.65-0.84)), but mortality risk was higher compared to dabigatran and edoxaban.

Conclusion:
Frailty was an independent risk factor of death. NOACs had better benefit-risk profiles than VKAs in patients with frailty, especially apixaban, followed by edoxaban.

Full text

European Heart Journal - Quality of Care and Clinical Outcomes (2023) 0, 1–11
https://doi.org/10.1093/ehjqcco/qcad019 ORIGINAL ARTICLE
Impact of frailty on the effectiveness and
safety of non-vitamin K antagonist oral
anticoagulants (NOACs) in patients with atrial
brillation: a nationwide cohort study
Maxim Grymonprez 1, Mirko Petrovic2,TineL.DeBacker
3,
Stephane Steurbaut4,5and Lies Lahousse 1,6,∗
1Department of Bioanalysis, Pharmaceutical Care Unit, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium; 2Department of
Geriatrics, Ghent University Hospital, C. Heymanslaan 10, 9000 Ghent, Belgium; 3Department of Cardiology, Ghent University Hospital, C. Heymanslaan 10, 9000 Ghent, Belgium;
4Centre for Pharmaceutical Research, Research group of Clinical Pharmacology and Clinical Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Jette, Belgium; 5Department
of Hospital Pharmacy, UZ Brussel, Laarbeeklaan 101, 1090 Jet te, Belgium; and 6Department of Epidemiology, Erasmus Medical Center, PO Box 2040, Rotterdam 3000 CA,
The Netherlands
Received 24 January 2023; revised 4 March 2023; accepted 17 March 2023; online publish-ahead-of- print 20 March 2023
Aims Data on non-vitamin K antagonist oral anticoagulants (NOACs) use in patients with atrial brillation (AF) and frailty are
scarce. Therefore, the impact of frailty on AF-related outcomes and benet–risk proles of NOACs in patients with
frailty were investigated.
............................................................................................................................................................................................
Methods and
results
AF patients initiating anticoagulation between 2013 and 2019 were included using Belgian nationwide data. Frailty was
assessed with the Claims-based Frailty Indicator. Among 254 478 anticoagulated AF patients, 71 638 (28.2%) had frailty.
Frailty was associated with higher all-cause mortality risks [adjusted hazard ratio (aHR) 1.48, 95% condence interval
(CI) (1.43–1.54)], but not with thromboembolism or bleeding. Among subjects with frailty (78 080 person-years of
follow-up), NOACs were associated with lower risks of stroke or systemic embolism (stroke/SE) [aHR 0.77, 95%CI
(0.70–0.86)], all-cause mortality [aHR 0.88, 95%CI (0.84–0.92)], and intracranial bleeding [aHR 0.78, 95%CI (0.66–0.91)],
a similar major bleeding risk [aHR 1.01, 95%CI (0.93–1.09)], and higher gastrointestinal bleeding risk [aHR 1.19, 95%CI
(1.06–1.33)] compared with VKAs. Major bleeding risks were lower with apixaban [aHR 0.84, 95%CI (0.76–0.93)], similar
with edoxaban [aHR 0.91, 95%CI (0.73–1.14)], and higher with dabigatran [aHR 1.16, 95%CI (1.03–1.30)] and rivaroxaban
[aHR 1.11, 95%CI (1.02–1.21)] compared with VKAs. Apixaban was associated with lower major bleeding risks compared
with dabigatran [aHR 0.72, 95%CI (0.65–0.80)], rivaroxaban [aHR 0.78, 95%CI (0.72–0.84)] and edoxaban [aHR 0.74,
95%CI (0.65–0.84)], but mortality risk was higher compared with dabigatran and edoxaban.
............................................................................................................................................................................................
Conclusion Frailty was an independent risk factor of death. Non-vitamin K antagonist oral anticoagulants had better benet–risk
proles than VKAs in patients with frailty, especially apixaban, followed by edoxaban.
∗Corresponding author. Tel: +32 9 264 81 14, Fax: +32 9 264 81 97, Email: Lies.lahousse@ugent.be
© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative
Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium,
provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
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2M. Grymonprez et al.
Graphical
Abstract
AF: atrial brillation; aHR: adjusted hazard ratio; Api: apixaban; CI: condence interval; Dabi: dabigatran; Edo: edoxaban;
IPTW: inverse probability of treatment weighting; NOAC: non-vitamin K antagonist oral anticoagulant; OAC: oral
anticoagulant; Ref: reference category; Riva: rivaroxaban; SE: systemic embolism; VKA: vitamin K antagonist.
............................................................................................................................................................................................
Key words Atrial brillation rFrailty rAnticoagulant rThromboembolism rBleeding rDeath
Introduction
Frailty is a complex clinical syndrome associated with reduced re-
silience to stressor events due to age- and comorbidity-related decline
in multiple physiological organ systems.1–3The most frequently ap-
plied denitions of frailty include the Frailty Phenotype by Fried et al.4
and Frailty Index by Rockwood et al.,5although other tools such as
the Anamnestic Frailty Phenotype6have been proposed for clinical
practice.3Frailty is up to four times more prevalent in patients with
atrial brillation (AF) as compared with non-AF patients regardless
of age.1,2,7,8Frailty is also a prognostic factor, as it was found to be
an independent risk factor for falls, hospitalizations, and death.4,9–16
However, it is currently not known whether frailty is also associated or
not with an increased risk of thromboembolism or bleeding in AF pa-
tients initiating anticoagulation. Prior studies9–16 rendered conicting
results, but were often limited by small sample sizes, short follow-up
durations, heterogeneous frailty measures, inclusion of anticoagulated
and non-anticoagulated AF patients, and limited adjustment for con-
founders (e.g. only age and sex).
Moreover, the use of oral anticoagulants (OACs) in patients with
AF and frailty is a matter of concern for physicians, faced with the
challenge of balancing the benets of stroke reduction against the
risk of bleeding.17 Consequently, increased rates of non-initiation,
inappropriate underdosing, low therapy adherence, and early discon-
tinuation of non-vitamin K antagonist oral anticoagulants (NOACs)
have been observed in patients with AF and frailty.8–10,16,18–20 Data
on the benet–risk prole of NOACs in patients with frailty is,
however, particularly scarce, which was identied as an important
research gap.17 Although randomized controlled trials (RCTs) have
demonstrated that NOACs are associated with an at least comparable
efficacy and safety compared with vitamin K antagonists (VKAs),21–24
resulting in a rapid transition of VKAs to NOACs for stroke preven-
tion in AF,25–27 patients with frailty were largely under-represented in
these trials.17 To the best of our knowledge, only four studies1,7,12,28
have investigated the effectiveness and safety of individual NOACs
compared with VKAs in AF patients with frailty, among which only
one study7explored outcomes between three different NOACs (i.e.
not including edoxaban yet). Consequently, there is an urgent need for
a critical appraisal of the benet–risk prole of all marketed NOACs
in patients with frailty to guide physicians in their choice of (N)OAC.
Therefore, in the present study, we aimed to investigate (1) the
impact of frailty on clinical outcomes in AF patients initiating anticoag-
ulation, and (2) the long-term comparative effectiveness and safety of
dabigatran, rivaroxaban, apixaban, and edoxaban in comparison with
VKAs, and between individual NOACs in patients with both AF and
frailty.
Methods
Source population
Details on the study methodology have been published before and are
provided in the supplemental materials.19,27 ,29 In brief, two nationwide
databases provided the source population, namely the InterMutualis-
tic Agency (IMA) database and Minimal Hospital Dataset (MHD). The
IMA centralizes all claims data from Belgian health insurance funds on
reimbursed ambulatory and hospital care, including demographic charac-
teristics, medical procedures, and drug prescription claims, and represents
all legal residents in Belgium.30 The MHD aggregates hospital discharge
diagnoses of every hospital admission (hospitalizations, day-care stays,
and emergency room contacts), coded in International Classication of
Diseases (ICD) codes (ICD-9 up to 2014, ICD-10 from 2015 onwards).31
Every individual of the study population could be identied in both
databases. This study was approved by the Belgian Commission for the
Protection of Privacy (approval code IVC/KSZG/20/344).32 The Strength-
ening the Reporting of Observational Studies in Epidemiology (STROBE)
reporting guideline was followed (see Supplementary material online,
Tabl e S 1).33
Study population
From 1 January 2013 to 1 January 2019, persons aged ≥45 years with
≥1 year coverage by health insurance funds were included from the
IMA database on the rst date of lling an OAC prescription (=index
date) (Online Appendix Figure S1). Non-vitamin K antagonist oral anti-
coagulant users, namely dabigatran (approved in Belgium since August
2012), rivaroxaban (approved since September 2012), apixaban (approved
since September 2013), and edoxaban (approved since October 2016),
and VKA users (warfarin, acenocoumarol, and phenprocoumon) were
included.27 Only OAC-naïve subjects were considered, excluding subjects
with an OAC prescription lled ≤1 year before the index date. Subjects
were not required to have an ICD-coded hospital discharge diagnosis of
AF to be included, as this would create selection bias due to limiting the
study population to hospitalized AF subjects and excluding AF subjects
treated exclusively in primary or ambulatory care.29,34
To avoid competing treatment indications for OACs, persons were
excluded in case of total hip or knee replacement, or diagnosis of deep vein
thrombosis or pulmonary embolism ≤6 months before the index date (see
Supplementary material online, Ta b le S 2 and Figure S1). Moreover, only AF
patients eligible for NOACs and VKAs were examined, excluding subjects
with valvular AF (mechanical prosthetic heart valve or moderate/severe
mitral stenosis) or end-stage renal disease (chronic kidney disease (CKD)
stage V and/or dialysis). Lastly, subjects with two or more prescription
claims of different OAC types or doses on the index date, or treated with
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NOACs in AF patients with frailty 3
NOAC doses not approved for stroke prevention in AF (e.g. rivaroxaban
10 mg) were excluded.
Frailty
Frailty was identied using the validated Johns Hopkins Claims-based
Frailty Indicator (CFI),35 in line with prior research,1,7since a clinical frailty
assessment based on Fried’s Frailty Phenotype4or Rockwood’s Frailty
Index5was more difficult using administrative healthcare data (e.g. need
for data on grip strength, walking speed…). The CFI was developed to
identify explicitly a frail population and might be applied in large datasets
for confounding adjustment or risk prediction.35 This algorithm weighs
21 variables using only administrative claims data, including demograph-
ics, cognitive and physical dysfunction, and the Charlson Comorbidity
Index (CCI), to classify individuals as frail or not frail in accordance with
Fried’s Frailty Phenotype (summarized in Supplementary material online,
Tabl e S 2).1,4,7,35 Acut-offof≥0.20 (range 0–1) has been shown to truly
identify frail patients (specicity 91%).1,7,35 However, as the CFI does not
allow to identify robust and pre-frail subjects (zero or one to two criteria
of the Frailty Phenotype,4respectively), these patients are categorized as
non-frail.35
Outcomes
Effectiveness outcomes included stroke or systemic embolism (stroke/SE),
ischemic stroke, and all-cause mortality. Safety outcomes included major,
intracranial, and gastrointestinal bleeding. Major bleeding was dened as
a hospitalized bleeding event in a critical area or organ (e.g. intracranial),
fatal bleeding, or bleeding event with a medical procedure code for blood
transfusion ≤10 days after admission.29,36 This denition is adapted from
the International Society on Thrombosis and Haemostasis,37 considering
that no data on haemoglobin levels or number of blood transfusion units
were available.36,37 Outcomes were identied using ICD-coded hospital
discharge diagnoses and medical procedure codes (see Supplementary
material online, Tabl e S 3).19 The incident date of outcomes was dened as
the date of hospital admission for ICD codes and date of registration for
medical procedure codes, whichever occurred rst.
Follow-up
Patients were followed from OAC initiation until the rst occurrence of
the investigated outcome, discontinuation (>60-day gap of drug supply)
or switch of treatment, death, emigration, or end of the study period
(1 January 2019), whichever came rst (on-treatment analysis).19
Covariates
Baseline characteristics were assessed on the index date and included age,
sex, comorbidities, medication history, and clinical risk scores. Comorbidi-
ties were identied with specic ICD-coded diagnoses, medical procedure
codes, and/or medication prescription claims ≤1 year before the index
date (see Supplementary material online, Ta ble S 2 ). Medication history
was identied with medication prescription claims, considering recent use
≤6 months before the index date. The CHA2DS2-VASc score, modied
HAS-BLED score (without the ‘labile INR’ criterion), and age-adjusted CCI
were calculated.26 ,38
Statistical analyses
Mean and standard deviation were presented for continuous variables
if normally distributed, whereas median and interquartile range (IQR) if
skewed. For categorical variables, number and percentage were described.
Crude event rates per outcome were calculated as the total number of
events per 100 person-years at risk. Outcomes were compared between
AF patients initiating anticoagulation with vs. without frailty using Cox pro-
portional hazard regression models. Additionally, models were adjusted
for age and sex (age- and sex-adjusted model); and for age, sex, type of
OAC used, baseline comorbidities, and medication history (multivariable
adjusted model with covariates described in Tabl e 1 ). Only statistically
signicant factors using a two-sided P-value of <0.05 were retained in
the multivariable adjusted model with backward elimination.
Moreover, outcomes were compared between NOACs and VKAs, and
between individual NOACs in patients with AF and frailty using stabilized
inverse probability of treatment weighting (IPTW). In comparisons with
apixaban and edoxaban, the study population was restricted to subjects
having initiated treatment from September 2013 and from October 2016
onwards respectively, to avoid violations of the positivity assumption.39
Propensity scores (PS) were calculated with logistic regression models, in-
cluding the 39 confounding covariates described in Tab l e 1 (demographics,
comorbidities, medication history, and risk scores), stratied by calendar
year. Based on the PS, stabilized weights were calculated and truncated
at the 0.5th and 99.5th percentile. Covariate balance before and after
weighting was checked using standardized mean differences with a ≥0.1
threshold to indicate imbalance. Weighted Cox proportional hazard re-
gression models were used to calculate adjusted hazard ratios (aHRs) with
95% condence intervals (CIs). The proportional hazard assumption was
assessed using scaled Schoenfeld residuals. A two-sided P-value of <0.05
was considered statistically signicant. All analyses were performed in R
(R version 3.6.0).
Subgroup analyses
As an interaction between frailty and polypharmacy on the risk of death
has been demonstrated before,40 Cox proportional hazard regression
models, which compared outcomes between AF patients with vs. without
frailty, were additionally stratied by the number of concomitantly used
drugs (<5, 5–9 and ≥10 drugs). Moreover, the effectiveness and safety of
OACs were also investigated in AF patients with frailty stratied by age
(<85 and ≥85 years old).
Sensitivity analyses
Sensitivity analyses were performed to check the robustness of results on
the effectiveness and safety of OACs in AF patients with frailty. First, to ex-
amine whether estimates were affected by differential censoring between
treatment groups (e.g. due to differences in discontinuation or switching
rates), analyses were repeated using an intention-to-treat approach, den-
ing the end of follow-up as the rst occurrence of an outcome, death,
emigration, or end of study period, whichever occurred rst. Second, to
take competing risks into account, cause-specic aHRs were calculated,
treating death as a competing risk. Third, to reduce misclassication bias,
only subjects with an ICD-coded hospital discharge diagnosis of AF before
or up to 90 days after the index date were investigated.34 Fourth, the study
population was restricted to subjects having initiated treatment between
1 October 2016 and 1 January 2019, when all NOACs were commercially
available in Belgium, to avoid time-period bias and account for the shorter
follow-up of edoxaban compared with other NOACs. Lastly, although data
were lacking on other causes of death, the risk of AF-related mortality
was investigated as an exploratory analysis, by only considering deaths
occurring within 60 days after an event of thromboembolism, bleeding, or
myocardial infarction.29
Results
Baseline characteristics
A total of 254 478 newly treated AF patients were included (Figure 1).
Baseline characteristics of the 71 638 (28.2%) subjects with frailty and
182 840 (71.8%) subjects without frailty are summarized in Table 1.
Patients with frailty were older (85.7 ±5.6 vs. 70.8 ±9.5 years)
and more frequently female (66.3% vs. 40.1%), had a higher preva-
lence of cardiovascular comorbidities, used more drugs concomitantly
(8.3 ±4.6 vs. 6.0 ±3.9), and had higher CHA2DS2-VASc (4.9 ±1.6
vs. 2.9 ±1.6) and HAS-BLED scores (3.1 ±1.3 versus 2.2 ±1.2) than
patients without frailty.
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4M. Grymonprez et al.
Table 1 Baseline characteristics of OAC-naïve AF patients with and without frailty at baseline
Frailty SMD*
.............................................................................. .............................
No frailty Overall frail VKA NOAC Before After
Patient characteristics (n=182 840) (n=71 638) (n=13 524) (n=58 114) IPTW IPTW
............................................................................................................................................................................................................
Age (years) 70.8 ±9.5 85.7 ±5.6 85.1 ±6.0 85.9 ±5.5 0.144 0.027
Female 73 264 (40.1%) 47 510 (66.3%) 8803 (65.1%) 38 707 (66.6%) 0.032 0.012
Follow-up (years) 0.7 [0.2–2.1] 0.6 [0.1–1.6] 0.2 [0.1–1.0] 0.7 [0.2–1.7] NA NA
Comorbidities
Hypertension 110 426 (60.4%) 54 450 (76.0%) 10 406 (76.9%) 44 044 (75.8%) 0.024 0.002
Coronary artery disease 30 493 (16.7%) 17 350 (24.2%) 4128 (30.5%) 13 222 (22.8%) 0.171 0.011
Congestive heart failure 17 253 (9.4%) 22 640 (31.6%) 4698 (34.7%) 17 941 (30.9%) 0.076 0.001
Valvular heart disease 19 585 (10.7%) 16 576 (23.1%) 3600 (26.6%) 12 976 (22.3%) 0.095 0.018
Peripheral artery disease 12 532 (6.9%) 8404 (11.7%) 2089 (15.4%) 6315 (10.9%) 0.116 0.008
Dyslipidemia 104 247 (57.0%) 39 668 (55.4%) 7763 (57.4%) 31 905 (54.9%) 0.050 0.011
Chronic kidney disease 12 467 (6.8%) 17 028 (23.8%) 4311 (31.9%) 12 717 (21.9%) 0.214 0.023
Chronic liver disease 5450 (3.0%) 3007 (4.2%) 704 (5.2%) 2303 (4.0%) 0.039 0.010
Chronic lung disease 19 204 (10.5%) 12 841 (17.9%) 2724 (20.1%) 10 117 (17.4%) 0.056 0.007
Obstructive sleep apnea 7385 (4.0%) 1388 (1.9%) 342 (2.5%) 1046 (1.8%) 0.040 0.010
Cancer 16 399 (9.0%) 8788 (12.3%) 1763 (13.0%) 7025 (12.1%) 0.017 0.022
Upper GI tract disorder** 10 506 (5.7%) 8672 (12.1%) 1966 (14.5%) 6707 (11.5%) 0.074 0.007
Lower GI tract disorder** 11 611 (6.4%) 6045 (8.4%) 1276 (9.4%) 4769 (8.2%) 0.025 0.003
Diabetes mellitus 52 834 (28.9%) 29 869 (41.7%) 6171 (45.6%) 23 698 (40.8%) 0.092 0.066
Anemia 9483 (5.2%) 11 629 (16.2%) 2828 (20.9%) 8801 (15.1%) 0.129 0.017
Thyroid disease 23 156 (12.7%) 13 753 (19.2%) 2845 (21.0%) 10 908 (18.8%) 0.050 0.006
Depression 27 540 (15.1%) 29 696 (41.5%) 6047 (44.7%) 23 649 (40.7%) 0.081 0.026
Dementia 1845 (1.0%) 11 717 (16.4%) 2357 (17.4%) 9359 (16.1%) 0.022 0.015
Parkinson’s disease 2087 (1.1%) 5469 (7.6%) 1047 (7.7%) 4422 (7.6%) 0.005 0.003
History of falling 5979 (3.3%) 14 194 (19.8%) 2547 (18.8%) 11 648 (20.0%) 0.049 0.065
Prior stroke/SE 17 430 (9.5%) 17 965 (25.1%) 3519 (26.0%) 14 446 (24.9%) 0.008 0.017
Prior MB/CRNMB 7219 (3.9%) 7060 (9.9%) 1604 (11.9%) 5456 (9.4%) 0.055 0.010
Medication history
Number of concomitant drugs 6.0 ±3.9 8.3 ±4.6 8.9 ±4.9 8.2 ±4.5 0.143 0.028
Beta blockers 105 473 (57.7%) 46 344 (64.7%) 8256 (61.0%) 38 088 (65.5%) 0.093 0.016
Verapamil, diltiazem 7091 (3.9%) 2812 (3.9%) 568 (4.2%) 2244 (3.9%) 0.017 0.014
Digoxin 12 723 (7.0%) 9808 (13.7%) 1528 (11.3%) 8280 (14.2%) 0.088 0.004
Class I AAD 19 586 (10.7%) 3715 (5.2%) 511 (3.8%) 3204 (5.5%) 0.082 0.002
Class III AAD 42 953 (23.5%) 18 498 (25.8%) 3308 (24.5%) 15 190 (26.1%) 0.039 0.026
Acetylsalicylic acid 68 253 (37.3%) 31 728 (44.3%) 5896 (43.6%) 25 832 (44.5%) 0.017 0.004
P2Y12 inhibitor 9607 (5.3%) 5074 (7.1%) 1023 (7.6%) 4051 (7.0%) 0.023 0.028
Proton pump inhibitor 66 579 (36.4%) 35 669 (49.8%) 7136 (52.8%) 28 533 (49.1%) 0.073 0.022
NSAID 48 345 (26.4%) 14 637 (20.4%) 2755 (20.4%) 11 882 (20.4%) 0.002 0.022
Oral corticosteroids 34 727 (19.0%) 17 412 (24.3%) 3609 (26.7%) 13 803 (23.8%) 0.068 <0.001
SSRI/SNRI 15 304 (8.4%) 16 023 (22.4%) 3244 (24.0%) 12 779 (22.0%) 0.047 0.026
Clinical risk score
CHA2DS2-VASc score 2.9 ±1.6 4.9 ±1.6 5.1 ±1.7 4.9 ±1.6 0.089 0.004
HAS-BLED score 2.2 ±1.2 3.1 ±1.3 3.3 ±1.4 3.1 ±1.2 0.125 0.011
Charlson Comorbidity Index 3.7 ±2.0 6.0 ±2.2 6.2 ±2.4 5.9 ±2.1 0.080 0.023
Data shown as mean ±standard deviation, median and [interquartile range], or counts and percentages. NOAC users without frailty (25.3% reduced dose) included 20 492
dabigatran, 53 849 rivaroxaban, 43 575 apixaban, and 17 042 edoxaban users; NOAC users with frailty (64.8% reduced dose) included 7652 dabigatran, 20 572 rivaroxaban,
23 350 apixaban, and 6540 edoxaban users. VKA users without frailty included 22 641 acenocoumarol, 13 157 warfarin, and 12 084 phenprocoumon users; VKAuserswith
frailty included 7009 acenocoumarol, 3702 warfarin, and 2813 phenprocoumon users.
*Absolute SMDs illustrated for comparison of NOACs vs. VKAs in patients with frailty before and after stabilized inverse probability of treatment weighting.
** Upper and lower gastrointestinal tract disorders were dened as gastroesophageal reux disease or peptic ulcer disease; and diverticulosis, angiodysplasia, colorectal
polyposis or hemorrhoids, respectively.
AAD: antiarrhythmic drug; AF: atrial brillation; CRNMB: clinically relevant non-major bleeding; GI: gastrointestinal; MB: major bleeding; NA: not applicable; NOAC:
non-vitamin K antagonist oral anticoagulant; NSAID: non-steroidal anti-inammatory drug; OAC: oral anticoagulant; SE: systemic embolism; SMD: standardized mean difference;
SNRI: serotonin and norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; and VKA: vitamin K antagonist.
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NOACs in AF patients with frailty 5
Figure 1 Flowchart of the study population. AF: atrial brillation; CKD: chronic kidney disease; DVT: deep vein thrombosis; IMA: InterMutualistic
Agency; NOAC: non-vitamin K antagonist oral anticoagulant; OAC: oral anticoagulant; PE: pulmonary embolism; and VKA: vitamin K antagonist.
Among subjects with frailty, the 58 114 NOAC and 13 524 VKA
users were on average 85.9 ±5.5 and 85.1 ±6.0 years old, con-
comitantly used 8.2 ±4.5 and 8.9 ±4.9 drugs and had a mean
CHA2DS2-VASc score of 4.9 ±1.6 and 5.1 ±1.7 before weighting,
respectively (Table 1). Baseline characteristics of the 7652 dabigatran,
20 572 rivaroxaban, 23 350 apixaban and 6540 edoxaban users with
frailty (reduced dose used in 91.0%, 66.7%, 56.0%, and 59.7% of sub-
jects, respectively) are summarized in Supplementary material online,
Table S4. After weighting, covariate balance was achieved (Table 1, see
Supplementary material online, Figure S2).
Frailty vs. no frailty
During a median follow-up of 0.6 years (IQR [0.1–1.6]; 78 080
person-years) and 0.7 years (IQR [0.2–2.1]; 250 715 person-years)
among anticoagulated patients with and without frailty, respectively,
7380 persons had an event of stroke/SE (event rates 3.60 vs. 1.88
per 100 person-years), 24 853 subjects died (19.53 vs. 3.83 per
100 person-years), and 14 716 had a major bleeding (6.91 vs. 3.95
per 100 person-years) (Table 2). Crude, age- and sex-adjusted, and
multivariable adjusted HRs of outcomes are summarized in Table 3.
Before adjustment, the risks of stroke/SE [unadjusted HR 1.80, 95%CI
(1.72–1.89)], all-cause mortality [unadjusted HR 4.87, 95%CI (4.75–
5.00)], and major bleeding [unadjusted HR 1.66, 95%CI (1.61–1.72)]
were higher among AF patients with vs. without frailty, which was
consistent after adjusting for age and sex. After multivariable adjust-
ment, frailty was associated with a signicantly higher risk of all-cause
mortality [aHR 1.48, 95%CI (1.43–1.54)] compared with AF patients
without frailty, while the risks of stroke/SE [aHR 1.03, 95%CI (0.96–
1.10)] and major bleeding [aHR 1.03, 95%CI (0.98–1.08)] were not
signicantly different.
Non-vitamin K antagonist oral
anticoagulant vs. vitamin K antagonist
in patients with frailty
The unadjusted number of events and event rates among subjects
with AF and frailty are summarized in Table 2. After multivariable
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6M. Grymonprez et al.
Table 2 The number of events and crude event rates per 100 person-years of outcomes
No frailty Frailty
....................................................................................................................................................
Overall VKA NOAC Dabigatran Rivaroxaban Apixaban Edoxaban
Outcome
events
(per 100 PY)
events
(per 100 PY)
events
(per 100 PY)
events
(per 100 PY)
events
(per 100 PY)
events
(per 100 PY)
events
(per 100 PY)
events
(per 100 PY)
............................................................................................................................................................................................................
Effectiveness
Stroke/SE 4635 (1.88) 2745 (3.60) 493 (4.69) 2252 (3.43) 353 (3.68) 899 (3.35) 848 (3.38) 152 (3.66)
Ischemic stroke 2276 (0.92) 1619 (2.11) 299 (2.81) 1320 (1.99) 243 (2.51) 518 (1.92) 475 (1.87) 84 (2.01)
All-cause mortality 9601 (3.83) 15 252 (19.53) 2512 (23.28) 12 740 (18.93) 1522 (15.38) 4990 (18.21) 5348 (20.74) 880 (20.92)
Safety
Major bleeding 9543 (3.95) 5173 (6.91) 783 (7.60) 4390 (6.80) 658 (6.95) 1861 (7.12) 1464 (5.88) 407 (10.02)
Intracranial bleeding 2649 (1.07) 1153 (1.49) 209 (1.97) 944 (1.42) 147 (1.51) 389 (1.44) 347 (1.36) 61 (1.46)
Gastrointestinal bleeding 4802 (1.95) 2851 (3.73) 379 (3.57) 2472 (3.75) 395 (4.08) 1074 (4.02) 755 (2.98) 248 (6.01)
NOAC: non-vitamin K antagonist oral anticoagulant; PY: person-year; SE: systemic embolism; and VKA: vitamin K antagonist.
Table 3 Crude, age- and sex-adjusted, and multivariable adjusted hazard ratios with 95% condence intervals of
outcomes compared between anticoagulated AF patients with vs. without frailty using Cox proportional hazard
regression models
Frailty vs. no frailty
......................................................................................................................................................
Crude
HR (95%CI)
Age- and sex-adjusted
HR (95%CI)*
Multivariable adjusted
HR (95%CI)**
............................................................................................................................................................................................................
Effectiveness
Stroke/SE 1.80 (1.72–1.89) 1.68 (1.58–1.79) 1.03 (0.96–1.10)
Ischemic stroke 2.15 (2.02–2.29) 1.72 (1.58–1.88) 1.02 (0.93–1.13)
All-cause mortality 4.87 (4.75–5.00) 2.95 (2.85–3.05) 1.48 (1.43–1.54)
Safety
Major bleeding 1.66 (1.61–1.72) 1.49 (1.43–1.56) 1.03 (0.98–1.08)
Intracranial bleeding 1.30 (1.21–1.39) 1.39 (1.27–1.52) 0.96 (0.87–1.07)
Gastrointestinal bleeding 1.84 (1.76–1.93) 1.49 (1.40–1.59) 1.06 (0.99–1.13)
*Adjusted for age and sex.
** Adjusted for age, sex, OAC type, baseline comorbidities, and medication history with backward elimination.
AF: atrial brillation; CI: condence interval; HR: hazard ratio; OAC: oral anticoagulant; and SE: systemic embolism.
adjustment, NOACs in AF patients with frailty were associated with
signicantly lower risks of stroke/SE [aHR 0.77, 95%CI (0.70–0.86)], is-
chemic stroke [aHR 0.74, 95%CI (0.65–0.85)], and all-cause mortality
[aHR 0.88, 95%CI (0.84–0.92)] compared with VKAs (see Supplemen-
tary material online, Table S5 and Figure 2).
Likewise, dabigatran, rivaroxaban, apixaban, and edoxaban were
each associated with signicantly lower risks of stroke/SE, ischemic
stroke, and all-cause mortality compared with VKAs, although the
risks of stroke/SE with edoxaban [aHR 0.84, 95%CI (0.60–1.19)]
and risks of ischemic stroke with dabigatran [aHR 0.95, 95%CI
(0.79–1.13)] and edoxaban [aHR 0.79, 95%CI (0.50–1.25)] were not
signicantly different.
In terms of safety, NOACs were associated with a similar risk of
major bleeding [aHR 1.01, 95%CI (0.93–1.09)] compared with VKAs,
driven by a lower risk of intracranial bleeding [aHR 0.78, 95%CI
(0.66–0.91)] but higher risk of gastrointestinal bleeding [aHR 1.19,
95%CI (1.06–1.33)].
Compared with VKAs, the risk of major bleeding was signicantly
lower with apixaban [aHR 0.84, 95%CI (0.76–0.93)], non-signicantly
different with edoxaban [aHR 0.91, 95%CI (0.73–1.14)], but signif-
icantly higher with dabigatran [aHR 1.16, 95%CI (1.03–1.30)] and
rivaroxaban [aHR 1.11, 95%CI (1.02–1.21)]. While trends towards
lower risks of intracranial bleeding were observed with other NOACs,
only apixaban was associated with a signicantly lower risk compared
with VKAs [aHR 0.76, 95%CI (0.62–0.93)]. Dabigatran [aHR 1.46,
95%CI (1.25–1.71)] and rivaroxaban [aHR 1.33, 95%CI (1.18–1.50)]
were associated with signicantly higher risks of gastrointestinal bleed-
ing compared with VKAs, while risks were not signicantly different
with apixaban [aHR, 95%CI 0.91 (0.79–1.04)] and edoxaban [aHR
1.11, 95%CI (0.82–1.51)].
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NOACs in AF patients with frailty 7
Figure 2 The (A) effectiveness and (B) safety of NOACs vs. VKAs in AF patients with frailty after IPTW. The weighted number of subjects at
risk in the pseudopopulation, weighted number of events, weighted event rates per 100 PY, and aHRs with 95%CIs after IPTW are illustrated.
aHR: adjusted hazard ratio; CI: condence interval; IPTW: inverse probability of treatment weighting; NOAC: non-vitamin K antagonist oral
anticoagulant; PY: person-years; Ref: reference category; SE: systemic embolism; VKA: vitamin K antagonist; and vs.: versus.
Comparisons between NOACs
in patients with frailty
No signicant differences in the risks of stroke/SE and ischemic stroke
were observed between individual NOACs in patients with frailty,
except for a signicantly higher risk of ischemic stroke with dabi-
gatran compared with rivaroxaban [aHR 1.21, 95%CI (1.03–1.42)]
(see Supplementary material online, Table S6 and Figure 3). Dabi-
gatran [aHR 0.91, 95%CI (0.86–0.97)] and edoxaban [aHR 0.85,
95%CI (0.77–0.94)] were associated with signicantly lower risks
of all-cause mortality compared with rivaroxaban, while apixaban
was associated with higher mortality risks compared with dabi-
gatran [aHR 1.18, 95%CI (1.10–1.26)] and edoxaban [aHR 1.20,
95%CI (1.11–1.30)]. No signicant differences in the risk of death
were observed between dabigatran and edoxaban, or apixaban and
rivaroxaban.
Apixaban was associated with signicantly lower risks of major
bleeding in AF patients with frailty compared with dabigatran [aHR
0.72, 95%CI (0.65–0.80)], rivaroxaban [aHR 0.78, 95%CI (0.72–0.84)],
and edoxaban [aHR 0.74, 95%CI (0.65–0.84)], driven by signicantly
lower risks of gastrointestinal bleeding [aHR 0.63, 95%CI (0.55–0.72);
aHR 0.68, 95%CI (0.62–0.76); and aHR 0.64, 95%CI (0.54–0.76),
respectively]. No signicant differences in the risk of major bleed-
ing were observed between other NOACs. The risk of intracranial
bleeding was similar between individual NOACs.
Subgroup analyses
Results were consistent on the impact of frailty on clinical outcomes in
AF patients stratied by the number of concomitantly used drugs and
condence intervals largely overlapping (e.g. aHR 1.60 (1.45–1.75),
aHR 1.46 (1.37–1.55), and aHR 1.33 (1.24–1.42) for the risk of death
in AF patients with vs. without frailty using <5, 5–9, and ≥10 drugs,
respectively) (see Supplementary material online, Table S7).
Moreover, comparable trends were observed on the effectiveness
and safety of OACs in AF patients with frailty <85 and ≥85 years old
(see Supplementary material online, Table S8 and Figure S3). However,
in AF patient with frailty <85 years old, no signicant differences in the
risks of major bleeding with dabigatran [aHR 1.02, 95%CI (0.86–1.21)]
and rivaroxaban [aHR 1.09, 95%CI (0.96–1.24)] compared with VKAs,
and of all-cause mortality with apixaban compared with edoxaban
[aHR 1.09, 95%CI (0.95–1.26)] were observed.
Sensitivity analyses
Trends on the benet–risk prole of NOACs in patients with frailty
were consistent with an intention-to-treat approach (mean follow-
up of 2.0 ±1.6 years; 145 037 person-years) (see Supplementary
material online, Table S9 and Figure S4); when treating death as a
competing risk (see Supplementary material online, Table S10 and
Figure S5); and when restricting the study population to subjects
with an ICD-coded hospital discharge diagnosis of AF (n =45 695)
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8M. Grymonprez et al.
Figure 3 The (A) effectiveness and (B) safety compared between individual NOACs types in AF patients with frailty after IPTW. The weighted
number of subjects at risk in the pseudopopulation, weighted number of events, weighted event rates per 100 PY, and aHRs with 95%CIs after
IPTW are illustrated.
aHR: adjusted hazard ratio; CI: condence interval; IPTW: inverse probability of treatment weighting; NOAC: non-vitamin K antagonist oral
anticoagulant; PY: person-years; Ref: reference category; SE: systemic embolism; and vs.: versus.
(see Supplementary material online, Table S11 and Figure S6)orto
subjects having initiated treatment between October 2016 and Jan-
uary 2019 (n =27 812) (see Supplementary material online, Table S12
and Figure S7). However, no signicant differences in the risks of
stroke/SE, ischemic stroke, and intracranial bleeding were observed
between individual NOACs and VKAs in the latter analysis. Moreover,
NOACs were associated with a signicantly lower risk of AF-related
mortality compared with VKAs [aHR 0.83, 95%CI (0.74–0.94)], while
risks were not signicantly different between individual NOACs (see
Supplementary material online, Table S13).
Discussion
In this nationwide cohort study including more than 250 000 AF
patients during 328 796 person-years of on-treatment follow-up,
we have demonstrated that frailty, identied in 28% of AF patients
initiating anticoagulation, was an independent risk factor for all-cause
mortality, but not for thromboembolism or bleeding. Among AF
patients with frailty, NOACs were associated with signicantly lower
risks of stroke/SE and all-cause mortality, and a similar risk of major
bleeding compared with VKAs. Despite a comparable effectiveness
between individual NOACs, potential differences in safety were iden-
tied, with apixaban being associated with the most favourable safety
prole across NOACs in patients with frailty due to a lower gas-
trointestinal bleeding risk, followed by edoxaban. However, the higher
observed mortality risk with apixaban compared with dabigatran and
edoxaban, warrants caution.
Frailty has been associated with several adverse health outcomes
irrespective of AF, including falls, fractures, hospitalizations, cogni-
tive impairment, worsening mobility, and disability in activities of
daily living.4,9,15 As illustrated by the 48% increased risk of all-cause
mortality in this study, frailty is also an independent risk factor of
death in patients with AF.9–16 Although condence intervals were
largely overlapping, increased mortality risks seemed somewhat more
pronounced in frail AF patients using fewer than ve drugs (60%
increased risk), which may reect a subgroup of patients with general
undertreatment (e.g. non-ABC-concordant management of AF)41 ,42
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NOACs in AF patients with frailty 9
or discontinuation of non-essential drugs due to limited life ex-
pectancy. Regarding thromboembolic or bleeding risks, results of
previous studies were more conicting, as some studies10,12 ,13 did
demonstrate higher risks of thromboembolism and/or major bleed-
ing in frail compared with non-frail AF patients, while others did
not.9,11,14–16 Despite higher crude and age- and sex-adjusted risks,
frailty was not signicantly associated with more thromboembolism
or major bleeding after multivariable adjustment in the present study
of anticoagulated patients with AF. While the overall vulnerability
of AF patients with frailty necessitates close monitoring, previous
research suggested that the presence of frailty is no formal con-
traindication for anticoagulation in AF patients,16,17 since OAC use
in AF patients with frailty has been shown to reduce the risk of
thromboembolism and death compared with no OAC use, without
signicantly increasing the risk of major bleeding.9–11
In AF patients with frailty, NOAC use was associated with a 22%,
26%, and 12% reduced risk of stroke/SE, ischemic stroke, and all-cause
mortality, respectively, compared with VKAs, while the risk of major
bleeding was similar due to a 22% lower risk of intracranial bleeding
but 19% higher risk of gastrointestinal bleeding. However, differential
safety proles were observed, as apixaban was associated with a 16%
lower risk of major bleeding compared with VKAs, edoxaban with
a 9% non-signicantly lower risk, while dabigatran and rivaroxaban
with a 16% and 11% signicantly higher risk, respectively. Likewise,
apixaban was associated with lower risks of major and gastrointestinal
bleeding compared with dabigatran, rivaroxaban, and edoxaban, while
no differences were observed in other comparisons between NOACs.
Similar differences in safety between NOACs, especially regarding
the risk of gastrointestinal bleeding, have been demonstrated in the
general AF population.43,44 However, data on NOAC use in AF pa-
tients with frailty are scarce, due to the exclusion of patients with
an estimated life expectancy of <1–2 years in phase III RCTs.21–24
To date, only one post-hoc analysis of phase III RCTs, namely the
ENGAGE AF-TIMI 48 trial, has been performed on this topic, which
demonstrated that edoxaban was associated with a signicantly lower
risk of major bleeding in patients with mild-moderate frailty and a sim-
ilar risk in patients with severe frailty compared with warfarin, while
no differences in the risks of stroke/SE or death were observed.12
In the limited observational data on patients with frailty, NOACs
were associated with similar1to lower7,28 risks of stroke/SE and
lower28 risks of death compared with VKAs.45 Differences in safety
were also observed for individual NOACs, as the risk of major
bleeding was lower with apixaban,1,7,28 similar1,28 to lower7with
dabigatran, and similar1,28 to higher7with rivaroxaban compared with
VKAs. To the best of our knowledge, only one study compared
outcomes between NOACs (however not including edoxaban) in
frail patients, rendering similar ndings as observed in our study,
since apixaban was also associated with lower risks of major and
gastrointestinal bleeding compared with dabigatran and rivaroxaban.7
Although results should be considered as hypothesis-generating and
interpreted with caution, these ndings may help clinicians in choosing
to anticoagulate with a NOAC compared with VKAs in AF patients
with frailty.
Of note, the risk of ischemic stroke was not signicantly different
with dabigatran compared with VKAs, which was also observed in
prior research.7,28 However, it should be mentioned that results are
likely driven by the predominant use of reduced dose dabigatran
(110 mg twice daily) in patients with frailty (91% of patients). In
the RE-LY trial, reduced dose dabigatran was indeed associated with
similar risks of stroke/SE compared with VKAs, which was not the
case with standard dose dabigatran (150 mg twice daily).21 Moreover,
the non-signicantly lower risks of stroke/SE and ischemic stroke with
edoxaban compared with VKAs may be due to less events during
the much shorter follow-up duration of edoxaban users, given that
edoxaban has only been approved in Belgium since October 2016.
Exemplary, when analyses were restricted to the subgroup of patients
having initiated therapy from October 2016 onwards, the risks of
stroke/SE and ischemic stroke were no longer signicantly lower with
other NOACs compared with VKAs due to a lack of power.
Remarkably, signicantly higher risks of all-cause mortality were
observed with apixaban compared with dabigatran and edoxaban,
especially in the oldest AF patients with frailty, while thromboembolic
and intracranial bleeding risks were similar, and major and gastroin-
testinal bleeding risks were lower with apixaban. This may indicate that
the higher mortality risks in apixaban users with frailty were driven by
higher risks of non-AF-related death and selective prescribing of apixa-
ban to more vulnerable older AF patients with frailty (than dabigatran
and edoxaban). Exemplary, no signicant differences in the risk of
AF-related mortality, dened as deaths occurring within 60 days after
an event of thromboembolism, bleeding, or myocardial infarction,
were observed between individual NOACs. Moreover, apixaban users
were older, had more comorbidities and more polypharmacy than
other NOAC users (see Supplementary material online, Table S4).
Although confounding by indication was minimized using IPTW, any
inuence of unmeasured confounding (e.g. underweight, sarcopenia,
or renal dysfunction) or selective prescribing cannot be excluded.
While awaiting more research to replicate these exploratory ndings,
caution should be warranted given the remarkably high mortality rates
in patients with frailty (19.5% per year).
Based on the results of the present study, anticoagulation is rec-
ommended in AF patients with frailty and NOACs are still preferred
over VKAs. However, physicians should also tackle modiable bleeding
risk factors,46 initialize fall prevention,47 optimize therapy adherence,19
execute a thorough medication review as a part of comprehen-
sive geriatric assessment48 to switch or discontinue unnecessary,
interacting or contraindicated comedication,46,49 ,50 and perform an
individualized benet–risk assessment with shared decision making in
each AF patient with frailty.17
Strengths and limitations
Strengths of this nationwide cohort study include the large sam-
ple size, long-term follow-up duration up to 6 years, use of an
on-treatment analysis to reduce exposure misclassication, and ad-
justment for several confounders using stabilized IPTW.
Several limitations should be mentioned. First, coding errors and
misclassication bias may be present due to the observational design
using healthcare databases. However, by identifying comorbidities
based on ICD, medical procedure codes and/or medication pre-
scription claims assessed in ambulatory and hospital care, missing
data, and misclassication of characteristics were reduced. Second,
frailty was identied with the validated CFI35 using administrative
claims data, but a clinical frailty assessment based on Fried’s Frailty
Phenotype4or Rockwood’s Frailty Index5was not possible. More-
over, pre-frailty could not be identied. Third, due to the specic
inclusion of AF patients initiating anticoagulation, results cannot be
extrapolated to AF patients with frailty who do not initiate antico-
agulation. Fourth, although we thoroughly adjusted for confounders,
there is a risk of unmeasured confounding due to missing lifestyle
characteristics (e.g. weight, smoking) and laboratory values (e.g. renal
function, INR). In line, (in)appropriate NOAC dosing and time in
therapeutic range of VKA users could not be assessed. Moreover,
lack of data on residency precluded the possibility to assess differ-
ences between counties or hospitals. Fifth, although persons with
competing treatment indications were excluded, subjects were not
required to have an ICD-coded hospital discharge diagnosis of AF
to be included to reduce selection bias.34 Nevertheless, trends were
consistent when specically investigating subjects with an ICD-coded
diagnosis of AF ≤1 year before or ≤90 days after the index date.
Sixth, the follow-up duration of edoxaban users was considerably
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10 M. Grymonprez et al.
shorter than other NOACs due to variable approval dates. Never-
theless, effect estimates were consistent when restricting the study
population to subjects having initiated treatment since October 2016.
Seventh, although the risk of AF-related mortality was explored, data
were lacking on other causes of death, which would have been of
interest to explore why differences in the risk of all-cause mortality
between individual NOACs were observed. Lastly, anticoagulant use
was assessed based on dispensing data to account for discontinuation
or switch of treatment, not on the patients’ actual intake. However,
ndings were consistent using an intention-to-treat approach.
Conclusion
In conclusion, frailty was an independent risk factor for all-cause
mortality in AF patients initiating anticoagulation, but not for throm-
boembolism or bleeding. Among patients with frailty, NOACs were
associated with a superior effectiveness and non-inferior safety com-
pared with VKAs. Although effectiveness was comparable between
individual NOACs, safety outcomes differed with apixaban being asso-
ciated with the most favourable safety prole across NOACs followed
by edoxaban, driven by lower risks of gastrointestinal bleeding. How-
ever, the potentially increased mortality risk with apixaban compared
with dabigatran and edoxaban warrants caution, while awaiting fur-
ther research.
Supplementary material
Supplementary material is available at European Heart Journal—
Quality of Care and Clinical Outcomes online.
Acknowledgements
We would like to thank the administrators, data managers, statisti-
cians, and other staff of the InterMutualistic Agency (IMA) and Minimal
Hospital Dataset (MHD) for providing the data, especially Birgit Gielen
(IMA), David Jaminé (IMA), Iris Grant (IMA), Dirk De Kesel (IMA),
Sarah Bel (IMA), Jérôme Paque (IMA), Remi Vandereyd (IMA), Xavier
Rygaert (IMA), Delen Verhelst (MHD), Karin Smets (MHD), and
Francis Windey (MHD). Moreover, we would like to thank eHealth
for the deterministic linkage of both databases. Lastly, we would like
to thank Stephan Devriese (Belgian Health Care Knowledge Centre,
KCE) for performing the small-cell risk analysis.
Author contributions
M.G. and L.L. contributed to the concept and design of the study. M.G.
performed the statistical analysis, interpretation, and writing under
the supervision of L.L. M.P., T.D.B., S.S., and L.L. revised the manuscript
critically. All authors contributed to the article and approved the nal
manuscript.
Funding
Research Foundation Flanders (FWO) (Grant number 11C0820N to
Maxim Grymonprez).
Conicts of interests: Outside this manuscript, T.D.B. has served
as a chairperson during a lecture for Bayer and Daiichi Sankyo and
participated in an expert meeting for Pzer. Outside this manuscript,
L.L. has been consulted as expert for AstraZeneca. Outside this
manuscript, M.P. and S.S. have given a lecture sponsored by B.M.S.,
L.L. a lecture sponsored by Chiesi, and S.S., L.L. and M.G. lectures
sponsored by IPSA vzw, a non-prot organization facilitating lifelong
learning for health care providers. Neither author has received any
fees personally.
Data availability
Requests for the data underlying this article should be directed to
the administrators of the InterMutualistic Agency (IMA) database or
Minimal Hospital Dataset and are subject to approval.
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