Circulation: Cardiovascular Quality and Outcomes

ORIGINAL ARTICLE

Rivaroxaban Versus Apixaban for Stroke

Prevention in Atrial Fibrillation
An Instrumental Variable Analysis of a Nationwide Cohort

See Editorial by Yao and Noseworthy Anders N. Bonde, MD,

PhD
BACKGROUND: The comparative effectiveness of non-vitamin K Torben Martinussen, PhD
antagonist oral anticoagulants (NOACs) is uncertain, as they have not Christina J.-Y. Lee, MD,
been compared directly in randomized trials. Previous observational PhD
comparisons of NOACs are likely to be biased by unmeasured Gregory Y.H. Lip, MD
confounders. We sought to compare the efficacy and safety of Laila Staerk, MD, PhD
rivaroxaban and apixaban for stroke prevention in patients with atrial Casper N. Bang, MD, PhD
fibrillation (AF), using practice variation in preference for NOAC as an Jay Bhattacharya, MD,
instrumental variable. PhD
Gunnar Gislason, MD, PhD
METHODS AND RESULTS: Patients started on apixaban or rivaroxaban Christian Torp-Pedersen,
after newly diagnosed AF were identified using Danish nationwide registries. MD, DMSc
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Patients were categorized according to facility preferences for type of Jonas Bjerring Olesen,
NOAC, independent of actual treatment, measured as fraction of the prior MD, PhD
20 patients with AF initiated on rivaroxaban in the same facility. Facility Mark A. Hlatky, MD
preference for NOAC was used as an instrumental variable. The occurrence
of stroke/thromboembolism, major bleeding, myocardial infarction, and
all-cause mortality over 2 years of follow-up were investigated using
adjusted Cox regressions. We analyzed 6264 patients with AF initiated
on rivaroxaban or apixaban. NOAC preference was strongly related to
actual choice of treatment but not associated with any other measured
baseline characteristics. Patients treated in facilities that had preference for
rivaroxaban had more major bleeding: compared with patients treated in
facilities that used rivaroxaban in 0% to 20% of cases, the adjusted hazard
ratio for bleeding was 1.06 when treated in a facility with 25% to 40% use;
1.41 with 45% to 60% use; 1.51 with 65% to 80% use; and 1.81 with
0% to 100% use (Ptrend=0.01). Higher facility preference for rivaroxaban was
not significantly associated with increased risk of stroke/thromboembolism
(Ptrend=0.06), myocardial infarction (Ptrend=0.65), or all-cause mortality
(Ptrend=0.89). When we used the instrumental variable to model the causal
relationship between choice of NOAC and major bleeding, relative risk with
rivaroxaban was 1.89 (95% CI, 1.06–2.72) compared with apixaban.
Key Words:  atrial fibrillation
CONCLUSIONS: Using instrumental variable estimation in a cohort of ◼ follow-up ◼ myocardial infarction
◼ rivaroxaban ◼ stroke
patients with AF, rivaroxaban was associated with higher risk of major
bleeding compared with apixaban. No significant associations to other © 2020 American Heart Association, Inc.

outcomes were found in main analyses. https://www.ahajournals.org/journal/

circoutcomes

Circ Cardiovasc Qual Outcomes. 2020;13:e006058. DOI: 10.1161/CIRCOUTCOMES.119.006058 April 2020 58

 Bonde et al; Rivaroxaban vs Apixaban for Atrial Fibrillation
WHAT IS KNOWN
• No randomized trial has compared apixaban
and rivaroxaban for stroke prevention in atrial
fibrillation.
• Bias due to selective prescribing could have influ-
enced results in previous observational compari-
sons of rivaroxaban and apixaban.
WHAT THE STUDY ADDS
• When using an instrumental variable approach
where patients were assigned into exposure
groups before physician contact regarding atrial
fibrillation, rivaroxaban was associated with 1.89
(95% CI, 1.06–2.72) higher relative 2-year risk of
major bleeding compared with apixaban.
• Previous observational comparisons could have
underestimated bleeding risk with rivaroxaban
versus apixaban due to unmeasured confounding.
A
trial fibrillation (AF) affects >30 million people
worldwide,1 and most patients receive lifelong
oral anticoagulation to prevent stroke or systemic
embolism.2,3 During the past decade, non-vitamin K an-
tagonists (NOACs) have proven to be either superior or
noninferior to warfarin for stroke prevention in AF, both
in large randomized controlled trials and in real-world ob-
servational studies.4–10 NOACs now account for the major-
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ity of new prescriptions for oral anticoagulation in patients
with AF in several countries, including the United States,
United Kingdom, and Denmark.11–13 Rivaroxaban and apix-
aban are currently the most widely initiated NOACs,11 but
no head-to-head randomized trial has directly compared
these 2 drugs. Both drugs are factor Xa inhibitors, but they
have different pharmacokinetic profiles that could affect
their safety and efficacy.14 Although several observational
studies have compared apixaban and rivaroxaban in pa-
tients with AF,6–10 these studies are susceptible to treatment
selection bias due to unmeasured patient characteristics of
importance for choice of treatment. Apixaban is likely to be
preferred over rivaroxaban among patients with low renal
function and high bleeding risk, and these characteristics
are only partly recorded in registries. Instrumental variable
(IV) methods, in which a factor (the instrument) predicts
treatment choice but has no direct effect on outcomes,
can address unmeasured confounding.15,16 We used an IV
approach to compare the safety and efficacy of apixaban
versus rivaroxaban for stroke prevention in patients with
AF, using facility variation in the choice of NOACs as the IV.
METHODS
Data Sources
Danish citizens have a unique personal registration number
that allows linkage of administrative registries. Nationwide, all
hospitalizations are registered in the Danish National Patient
Circ Cardiovasc Qual Outcomes. 2020;13:e006058. DOI: 10.1161/CIRCOUTCOMES.119.006058
Registry using International Classification of Disease-10
codes,17 all drugs claimed at a Danish pharmacy are regis-
tered in the Danish prescription registry using Anatomical
Therapeutic Chemical codes,18 and vital status and yearly
income are available through Statistics Denmark.19
Study Population
We identified patients with AF discharged between 2014
and 2017 from a Danish hospital, who had no prior use of
oral anticoagulants and were prescribed either apixaban or
rivaroxaban. AF diagnoses have been validated in the Danish
National Patient Registry and have a positive predictive value
of 95%.20 We excluded patients with AF discharged from facil-
ities that treated <50 patients with AF during the study period
to ensure sufficient numbers to determine facility prescribing
patterns. By facility, we refer to a subdivision of a hospital,
where physicians goes to the same daily meetings, usually
talk to each other at a daily basis, and, overall, takes care of
the same patients, and for this reason, have a high chance
of developing preference for one kind of drug. We excluded
patients with AF discharged from surgical, acute medicine or
neurology units because AF diagnosis is likely to be noncom-
parable to AF diagnoses from general internal medicine or
cardiology units. Patients with AF discharged from neurology
units are likely to have AF diagnosed during rhythm monitor-
ing after a stroke, whereas patients with AF discharged from
surgical units or acute medicine units are more likely to have
so-called secondary AF, where the indication for OAC is still
debated. We excluded valvular AF,21 because NOACs are not
indicated this population. Finally, we excluded patients above
80 years old because on the European label this is a dose
reduction criteria for apixaban but not rivaroxaban.
Facility Preference for Rivaroxaban Over
Apixaban
We determined facility preference for the use of rivaroxaban
versus apixaban over time by sorting patients into groups of
20 based on the date of discharge at each facility (Figure 1).
For each group, we calculated the fraction of patients pre-
scribed rivaroxaban (eg, 3 out of 20 patients discharged on
rivaroxaban=15%). This fraction represents our IV—facility-
level preference for rivaroxaban prescribing—for the follow-
ing 20 patients discharged from the same facility, independent
of the treatment they received. The fraction of patients initi-
ated on rivaroxaban among the following 20 patients with AF
(patient 21–40 from facility) was used to determine the IV for
the following 20 patients with AF (patient 41–60 from facil-
ity), and so on. The first 20 patients during the study period
from each facility were used only to assess practice patterns,
not outcomes. Finally, we categorized patients into 5 groups
based on preference for rivaroxaban among the previous 20
patients: 0% to 20%, 25% to 40%, 45% to 60%, 65% to
80%, and 85% to 100%.
Comorbidities, Comedication
As in previous studies,6,22 comorbidities for each patient
were determined based on hospital discharge diagnoses
during the 5 years before study entry, and comedications
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 Bonde et al; Rivaroxaban vs Apixaban for Atrial Fibrillation
were determined based on pharmacy claims during the 180
days before entry.
Outcomes and Follow-Up
Outcomes were (1) stroke/thromboembolism (TE), defined
as hospitalization for stroke (ischemic stroke or unclassified
stroke) or arterial systemic embolism; (2) major bleeding,
defined as hospitalization for intracranial, intraocular, uro-
genital, airway, or gastrointestinal bleeding; (3) hospitaliza-
tion with myocardial infarction; or (4) all-cause mortality.
The diagnosis of stroke has been validated in the Danish
registries with a positive predictive value of 95% to 100%,23
the diagnosis of hospitalized major bleeding has a positive
predictive value of 89% to 99% in registries,24 and hospital-
ization for myocardial infarction have a positive predictive
value of 97%.20 We tracked patients from the date of their
first prescription for apixaban or rivaroxaban until death
or first occurrence of an outcome event of interest, with
censoring after 2 years after treatment initiation, June 30,
2017, or loss to follow-up by emigration. Table I in the Data
Supplement lists all International Classification of Disease
and Anatomical Therapeutic Chemical codes used to define
the study population, the baseline variables, and outcomes.
Statistical Analysis
We employed facility-level preference for rivaroxaban over
apixaban for stroke prevention in AF among the previous 20
patients discharged from the same facility as an IV. IV analysis
identifies a treatment effect in the presence of confounding
by indication under the following assumptions (Figure I in the
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Data Supplement): (1) the IV is associated with the treatment,
(2) the IV is unrelated to unmeasured confounders, and (3) the
IV is only related to the outcome through the treatment.15,16
Assumption 1 was tested using linear regression of rivaroxa-
ban treatment on and the IV (facility preference for rivaroxa-
ban) and all baseline characteristics as explanatory variables.
Assumption 2 cannot be directly tested, but we examined
the plausibility of the assumption with trend tests for associa-
tion between the IV and all measured baseline characteristics,
using the Cochran-Armitage trend test for binary variables,
and linear regression for continuous variables. The assumption
was considered reasonable in absence of any important asso-
ciations to measured baseline characteristics. Furthermore,
we examined the plausibility of the second assumption using
4 negative control outcomes: hospitalization cancer, dehydra-
tion, urogenital tract infection, and fracture,25 as the instru-
ment would most likely be associated with one or several of
those outcomes in presence of strong unmeasured confound-
ing between IV and primary outcomes. Assumption 3 cannot
be tested directly either, but in presence of a direct effect of
IV on outcomes (eg, if rivaroxaban preference was a general
marker of quality of care after inclusion), we would have been
more likely to see an effect of IV on negative control outcomes.
We chose 4 outcomes that are related to general fragility but
not thought to be causally related to the use of rivaroxaban
or apixaban. Two-year absolute risks for the outcomes were
plotted according to facility preference for rivaroxaban on a
continuous scale, and corresponding P values for trends were
calculated using a linear regression with number of patients
with each value of the IV as sampling weigh. Adjusted hazard
Circ Cardiovasc Qual Outcomes. 2020;13:e006058. DOI: 10.1161/CIRCOUTCOMES.119.006058
ratios (HRs) were calculated according to the IV as a categori-
cal variable using Cox regression, and P values for trend in
the adjusted models were calculated with the IV included as
a continuous variable. The Cox models were adjusted for all
measured medications, comorbidities, income quartile, age,
sex, and inclusion year. Proportional hazards were tested
using Kolmogorov-type Supremum tests and found valid for
all models. We used IV estimation in additive hazards models
to estimate the average causal treatment effect among the
treated, using the continuous version of the instrument value,
as described by Martinussen et al26 (see Methods in the Data
Supplement for further description and attached R code).
The assumed Cox model structure can be seen as a fourth
IV assumption, which is necessary to enhance estimation of
a potential causal effect in the analyses. Specifically, we esti-
mated the cumulative incidence function concerning the risk
of major bleeding when receiving apixaban, and similarly for
those receiving apixaban, had all the patients, contrary to the
fact, received rivaroxaban. The 95% CIs were calculated using
1000 bootstrap samples. Two-stage least squares regression
is commonly used in IV analysis but was not used for causal
estimates in our study, since 2-stage least squares regression
regression does not give meaningful results in a setting with
time-to-event as outcome. We performed several sensitivity
analyses. (1) We examined the association between the IV
and outcomes when censoring at discontinuation of initial
NOAC. (2) We included patients aged>80 years in the study
population. (3) We matched patients according to internal
medicine or cardiology discharge unit using a near-far match-
ing algorithm,27 where 2 patient groups were matched to be
near on unit type and measured baseline characteristics, and
far (different) on the IV. After matching, we examined cumu-
lative incidence and adjusted HR of events in the 2 groups. (4)
We re-estimated our IV and risk of events using groups of 10
and 30 patients instead of groups of 20 patients. (5) We cre-
ated an instrument value for a new AF population, including
also patients initiated on other OACs (VKA, dabigatran, or
edoxaban), using the same method as in the main analysis,
and examined use of other OACs and baseline characteristics
across facility preference for rivaroxaban as a fraction of all
available OACs. A 2-sided P value <0.05 was considered sta-
tistically significant. All analyses were performed using SAS
software, version 9.4 (SAS Institute) and R version 3.4.1.28
Ethics and Data Sharing
No ethical approval is required for registry-based studies in
Denmark. Data were anonymized without the possibility for
identification of individual patients. The study was approved
by the Danish Data Protection Agency (ref.no: 2007-58-0015/
GEH-2014-012 I-Suite no:02729).
Additional details and analyses are available from the cor-
responding author on request.
RESULTS
Study Population
We included 6264 patients with nonvalvular AF initiated
on either apixaban or rivaroxaban for analysis (Figure 1).
Thirty different facilities across Denmark met the crite-
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 Bonde et al; Rivaroxaban vs Apixaban for Atrial Fibrillation
Figure 1. A, Our method for designing the instrument, with an example.
B, Flowchart for selection of the study population. AF indicates atrial fibrillation.
ria for inclusion. The study population had a median
age of 70 years (interquartile range, 64–75), and 3608
(57.6%) were male. In the total study population, 3369
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(54%) received apixaban, and 2895 (46%) received
rivaroxaban. No patients received both apixaban and
rivaroxaban. Standard dose NOAC was initiated among
5431 (87%) patients, 1678 (27%) received co-therapy
with aspirin, and 533 (8.5%) received co-therapy with
an adenosine diphosphate receptor inhibitor. Facility
preferences for NOACs varied widely and was evenly
distributed in our study population (Figure  2), ranging
from 0% of previous 20 patients initiated on rivaroxa-
ban (n=205) to 100% of previous patients initiated on
rivaroxaban (n=139). There was a dose-response rela-
tionship between the IV and actual choice of treatment
(Figure  2). After controlling for all measured baseline
characteristics, the IV was highly associated with the
actual choice of treatment (odds ratio, 37.93 [95% CI,
30.27–47.52], F-value for IV=1427.1). Older age, dia-
betes mellitus, previous bleeding, and chronic kidney
disease were significantly associated with a lower risk of
receiving rivaroxaban for the individual patient (Table II
in the Data Supplement), but the IV was not significant-
ly associated with age, sex, income, prior stroke, prior
bleeding, or any other baseline variable, except for actu-
al choice of treatment (Table 1). In the group where 0%
to 20% of the last 20 patients received rivaroxaban, 279
(19.8%) patients received rivaroxaban, whereas 774
(81.0%) received rivaroxaban in the group where 80%
to 100% of the last 20 patients received rivaroxaban.
Circ Cardiovasc Qual Outcomes. 2020;13:e006058. DOI: 10.1161/CIRCOUTCOMES.119.006058
Between 2014 and 2017, 2920 patients with AF from
included facilities were discharged with dabigatran, 70
patients with AF discharged with edoxaban, and 5764
patients with AF were discharged with VKA.
Risk of Events According to Facility
Preference for Rivaroxaban Over
Apixaban
Higher percentage of the last 20 patients with AF from
facility discharged with rivaroxaban (the IV) was asso-
ciated with gradually higher unadjusted 2-year risk of
major bleeding (Figure  3). After adjustment for mea-
sured baseline characteristics, the IV was associated
with a higher hazard ratio (HR) for major bleeding
(Ptrend=0.013), but the IV was not significantly associ-
ated with higher HR for stroke/TE (Ptrend=0.06), myo-
cardial infarction (Ptrend=0.86), or all-cause mortality
(Ptrend=0.91). When using an IV value of 0% to 20% as
reference group, increasing preference for rivaroxaban
was significantly associated with an increased risk of
major bleeding  (Table 2): the HR was 1.06 (95% CI,
0.60–1.87) for 25% to 40%, 1.41 (95% CI, 0.84–2.37)
for 45% to 60%, 1.51 (95% CI, 0.83–2.74) for 65% to
80%, and 1.81 (95% CI, 1.01–3.25) for 85% to 100%.
When we used IV estimation to model the 2-year risk
of major bleeding, the cumulative incidence was 5.5%
(95% CI, 3.1–7.7) with use of rivaroxaban and 2.9%
(95% CI, 2.3–3.6) with use of apixaban (Figure II in the
Data Supplement), and the relative risk with rivaroxa-
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 Bonde et al; Rivaroxaban vs Apixaban for Atrial Fibrillation
Figure 2. Facility preferences for non-vitamin K antagonist oral anticoagulants.
AF indicates atrial fibrillation; and OAC, oral anticoagulation.
ban versus apixaban was 1.89 (95% CI, 1.06–2.72). We
did not model the risk with stroke/TE, MI, or all-cause
mortality since there was no definitive evidence for a
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relation between the IV and these outcomes.
Sensitivity Analyses
We repeated main analyses after censoring patients on
first switch or discontinuation of initial NOAC (Table III
in the Data Supplement) with results similar to the main
results. The IV was significantly related with a higher
adjusted HR of major bleeding (Ptrend=0.007) in this analy-
sis, and the IV was also associated with a higher HR for
stroke/TE (Ptrend=0.027). When we changed the number
of patients in each of the groups used to create the IV
from 20 to either 10 or 30, the results were similar to
main analyses (Table IV in the Data Supplement). The IV
was less valid when we included patients aged >80 years
in the study cohort (Table V in the Data Supplement),
but we had results similar to main analyses (Table VI in
the Data Supplement). In a sensitivity analysis where 2
groups were matched to be similar on the number of
patients discharged from a general internal medicine unit
or cardiology unit, but dissimilar on IV, the 2 groups had
comparable baseline characteristics (Table VII in the Data
Supplement). The group that was likely to be prescribed
rivaroxaban had a higher risk of major bleeding (HR, 1.72
[95% CI, 1.02–2.89]) and stroke/TE (HR, 1.98 [95% CI,
1.16–3.36]) compared with the matched group, which
was unlikely to be prescribed rivaroxaban (Figure III in the
Circ Cardiovasc Qual Outcomes. 2020;13:e006058. DOI: 10.1161/CIRCOUTCOMES.119.006058
Data Supplement). The IV was not significantly related to
higher risk of hospitalization for cancer (Ptrend=0.34), uro-
genital tract infection (Ptrend=0.71), fracture (Ptrend=0.14),
or dehydration (Ptrend=0.49; Figure IV in the Data Sup-
plement). Rivaroxaban had no significant relation to
outcomes when we used actual treatment initiation as
exposure (Table VIII in the Data Supplement). No impor-
tant systematic differences in baseline characteristics or
in use of other OACs (dabigatran, edoxaban, or VKA)
across facility preference for rivaroxaban was introduced
when examining rivaroxaban preference as a fraction of
all available OACs (Table IX in the Data Supplement).
DISCUSSION
No clinical guideline recommends one specific NOAC
over other NOACs for stroke prevention in AF, and there
are wide variations in preferences for choice of NOAC.
Consequently, similar patients are likely to receive differ-
ent NOACs based only on the facility in which they were
treated. Facility preference for using rivaroxaban served as
an IV in this study and allowed us to compare the safety
and efficacy of apixaban and rivaroxaban for stroke pre-
vention in patients with AF. We found that increased facil-
ity preference for the use of rivaroxaban had a significant,
graded association with increased risk of major bleeding,
but was not significantly associated with stroke/TE, myo-
cardial infarction or mortality in our main analyses. We
also demonstrated the preference for rivaroxaban was
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 Bonde et al; Rivaroxaban vs Apixaban for Atrial Fibrillation

Table 1.  Baseline Characteristics According to the Instrumental Variable (Percent of Previous 20 Patients With AF From Facility Initiated on
Rivaroxaban)

Percent of Previous 20 Patients With Atrial Fibrillation From Facility Initiated on Rivaroxaban
P Value
0%–20% 25%–40% 45%–60% 65%–80% 85%–100% for Trend
No. of patients 1406 1421 1551 930 956
Received rivaroxaban, n (%) 279 (19.8) 499 (35.1) 711 (45.8) 632 (68.0) 774 (81.0) <0.001
Standard dose, n (%) 1216 (86.5) 1232 (86.7) 1366 (88.1) 793 (85.3) 824 (86.2) 0.62
Median age (interquartile range) 70.00 69.00 70.00 70.00 70.00 0.11
(63.25–74.00) (63.00–74.00) (64.00–74.00) (64.00–75.00) (63.00–75.00)
Male, n (%) 797 (56.7) 795 (55.9) 903 (58.2) 539 (58.0) 574 (60.0) 0.07
Income group, n (%)
 1st quartile (lowest) 391 (28.8) 348 (24.5) 408 (26.3) 238 (25.6) 181 (18.9)
 2nd quartile 349 (24.8) 351 (24.7) 356 (23.0) 220 (23.7) 290 (30.3)
 3rd quartile 333 (23.7) 365 (25.7) 359 (23.2) 260 (28.0) 249 (26.1)
 4th quartile (highest) 333 (23.7) 357 (25.1) 428 (27.6) 212 (22.8) 236 (24.7) 0.88
Comorbidity, n (%)
 Prior stroke 99 (7.0) 115 (8.1) 134 (8.6) 69 (7.4) 74 (7.7) 0.56
 Prior bleeding 136 (9.7) 141 (9.9) 163 (10.5) 91 (9.8) 97 (10.1) 0.51
 Heart failure 258 (18.3) 245 (17.2) 270 (17.4) 163 (17.5) 202 (21.1) 0.09
 Vascular disease 135 (9.6) 127 (8.9) 161 (10.4) 100 (10.8) 95 (9.9) 0.25
 Diabetes mellitus 198 (14.1) 183 (12.9) 188 (12.1) 145 (15.6) 134 (14.0) 0.77
 Liver disease 34 (2.4) 17 (1.2) 19 (1.2) 17 (1.8) 20 (2.1) 0.72
 Chronic kidney disease 55 (3.9) 34 (2.4) 58 (3.7) 32 (3.4) 17 (1.8) 0.74
 Alcohol abuse 88 (6.3) 52 (3.7) 63 (4.1) 41 (4.4) 44 (4.6) 0.10
Comedication, n (%)
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 Adenosine diphosphate inhibitor 113 (8.0) 122 (8.6) 131 (8.4) 85 (9.1) 82 (8.6) 0.75
 Aspirin 361 (25.7) 381 (26.8) 415 (26.8) 254 (27.3) 267 (27.9) 0.15
 Statin 471 (33.5) 491 (34.6) 499 (32.2) 321 (34.5) 309 (32.3) 0.51

β-Blocker
  414 (29.4) 430 (30.3) 468 (30.2) 259 (27.8) 300 (31.4) 0.63

 Renin-angiotensin inhibitor 571 (40.6) 589 (41.4) 637 (41.1) 393 (42.3) 387 (40.5) 0.99
 Nonsteroid anti-inflammatory drug 210 (14.9) 220 (15.5) 250 (16.1) 133 (14.3) 148 (15.5) 0.83
AF indicates atrial fibrillation.

unrelated to other, contrafactual outcomes (hospitaliza-
tions for cancer, dehydration, fracture, or urogenital tract
infection), which suggests that the observed relationships
were specific to rivaroxaban, and not due to general fra-
gility of patients seen at these facilities.
Unmeasured Confounding in
Observational Comparisons of
Rivaroxaban and Apixaban
Observational registries have been used to compare rivar-
oxaban with apixaban for stroke prevention in AF, but all
have used individual-level treatment as the exposure.6–10
Treatment selection at the individual patient level is sus-
ceptible to confounding, since the choice of NOAC is
determined by clinical factors that registries do not typical-
ly record, and apixaban is often likely to be preferred over
rivaroxaban among patients at high bleeding risk and with
reduced renal function.29 Important risk factors for bleed-
ing, such as levels of creatinine, hemoglobin, body mass
index, blood pressure, and liver function, are not usually
available in registries,6–10 and exact renal function has not,
to our knowledge, been available in any previous com-
parison. Using surrogate markers for bleeding risk and
reduced renal function, such as hospital discharge diag-
noses, is likely to cause residual confounding; for instance,
variation in renal function among patients with or without
chronic kidney disease diagnosis is still likely to influence
treatment decision and outcomes. Common methods
to address confounding, such as propensity scores, and
g-formula or regression adjustments, cannot remove bias
due to unmeasured confounders. Rivaroxaban had no sig-
nificant association to major bleeding when we compared
rivaroxaban and apixaban using individual-level treatment
as exposure in the present study, suggesting that unmea-
sured confounding could have caused systematic under-

Circ Cardiovasc Qual Outcomes. 2020;13:e006058. DOI: 10.1161/CIRCOUTCOMES.119.006058 April 2020 63

 Bonde et al; Rivaroxaban vs Apixaban for Atrial Fibrillation
Figure 3. Risk of events according to facility preference for rivaroxaban over apixaban.
The size of the dots in the figure represents the relative number of patients with each value of the instrumental variable. AF indicates atrial fibrillation.
estimation of the true bleeding risk with rivaroxaban in
previous comparisons. In contrast, an IV can, under some
important assumptions, adjust for unmeasured confound-
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ing between exposure groups.15,16 In our study, the indi-
vidual patient’s renal function or bleeding risk, could not
have any importance for the IV, since preference for choice
of NOAC was determined among the previous 20 patients
from the same facility, that is, our IV was assigned to the
patient before any contact with the prescribing physician.
Validity of the IV Assumptions in the
Present Analysis
The IV method allowed us to adjust for any measured and
unmeasured confounding caused by physician-choice of
treatment for the individual patient, but this method also
rely on certain assumptions of importance for the validity
of the results. First, we assume no direct effect of our IV on
outcomes. If rivaroxaban preference was a marker of qual-
ity of care (eg, rivaroxaban was cheaper than apixaban
and used more widely among facilities that are trying to
reduce costs), we could have falsely created an association
between rivaroxaban and outcomes in our IV model. The
price of rivaroxaban and apixaban are similar in Denmark,
and we have no reason to think that facilities with prefer-
ence for rivaroxaban are in any way different than facili-
ties with preference for apixaban, although we can only
test this assumption using the measured variables in our
dataset. Further, we found differences in negative control
outcomes across rivaroxaban preference, suggesting that
Circ Cardiovasc Qual Outcomes. 2020;13:e006058. DOI: 10.1161/CIRCOUTCOMES.119.006058
quality of care was, in other aspects than OAC prefer-
ence, not systematically different across facility preference
for rivaroxaban. Second, we assume no unmeasured con-
founding between IV and outcomes. We could not directly
test this assumption, but the fact that the instrument was
not significantly related to age, sex, income, prior bleed-
ing, or use of platelet inhibitors, or any other measured
baseline variable, does make systematic unmeasured con-
founding less likely. The instrument would also have been
associated to one or several of the negative control out-
comes if strong unmeasured confounding was present, as
some of the risk factors for bleeding are also risk factors
for the negative control outcomes.
Bleeding Risk With Rivaroxaban
Compared With Apixaban
Despite the possibility for unmeasured confounding in
previous studies, our results are generally consistent with
other cohort studies of bleeding risk with rivaroxaban and
apixaban when used for stroke prevention in AF.5–7,9,10 A
meta-analysis of registry-based studies that compared
bleeding risk with apixaban versus rivaroxaban, showed
a 48% lower risk of bleeding with apixaban compared
with rivaroxaban.5 Network meta-analyses using extrapo-
lation of data from trials with warfarin as comparator, also
showed increased risk of bleeding with rivaroxaban versus
apixaban,30,31 but different inclusion criteria and differ-
ences in quality of anticoagulation control with warfarin
between the NOAC trials makes these analyses difficult.
April 2020 64
 Bonde et al; Rivaroxaban vs Apixaban for Atrial Fibrillation

Table 2.  Hazard Ratio of Event According to the Instrument Value (Percent of Previous 20 Patients With AF
From Facility Initiated on Rivaroxaban)

Percent of Previous 20 Patients Incidence Rate

With AF From Facility Initiated (Events/100 Adjusted Hazard
on Rivaroxaban Person-Years Events Person-Years) Ratio (95% CI)
Stroke/thromboembolism
 0%–20% 1677.2 27 1.6 1.00 (ref)
 25%–40% 1644.6 21 1.3 0.83 (0.47–1.48)
 45%–60% 1827.0 38 2.1 1.29 (0.79–2.13)
 65%–80% 878.8 24 2.7 1.70 (0.97–2.97)
 88%–100% 787.5 18 2.3 1.42 (0.77–2.63)
 P value for trend 0.06
Major bleeding
 0%–20% 1678.3 24 1.4 1.00 (ref)
 25%–40% 1639.6 25 1.5 1.06 (0.60–1.87)
 45%–60% 1828.2 37 2.0 1.41 (0.84–2.37)
 65%–80% 888.1 21 2.4 1.51 (0.83–2.74)
 85%–100% 788.8 24 3.0 1.81 (1.01–3.25)
 P value for trend 0.013
Myocardial infarction
 0%–20% 1682.2 16 1.0 1.00 (ref)
 25%–40% 1649.3 16 1.0 1.01 (0.50–2.03)
 45%–60% 1843.4 20 1.1 1.09 (0.56–2.12)
 65%–80% 895.7 4 0.4 0.40 (0.13–1.22)
 85%–100% 792.3 12 1.5 1.33 (0.61–2.93)
 P value for trend 0.86
Downloaded from http://ahajournals.org by on May 14, 2020

All-cause mortality
 0%–20% 1694.7 108 6.4 1.00 (ref)
 25%–40% 1661.6 75 4.5 0.74 (0.55–1.00)
 45%–60% 1858.6 102 5.4 0.88 (0.67–1.16)
 65%–80% 899.2 61 6.8 0.94 (0.68–1.29)
 85%–100% 800.2 53 6.6 0.91 (0.65–1.28)
 P value for trend 0.91

AF indicates atrial fibrillation.

Higher peaks of factor Xa inhibition related to the once-
daily dose regimen is a likely explanation for the higher risk
of bleeding with rivaroxaban relative to apixaban, which
has a twice-daily dose regimen.14 Another possible expla-
nation is higher adherence with rivaroxaban, which has
been found in some, but not all, real-world studies.32,33 In
our study, rivaroxaban was more strongly associated with
bleeding and stroke risk after censoring patients on the
first discontinuation of the study drug, which suggests that
higher adherence is not a likely explanation for increased
bleeding risk with rivaroxaban in our population.
Our study adds important new evidence to the grow-
ing literature on the efficacy and safety of apixaban and
rivaroxaban in clinical practice. We show a graded rela-
tionship between the use of rivaroxaban and increased
bleeding risk. Graded associations are important indica-
tors for causality, and our study is the first to show such
a relationship between the use of rivaroxaban and bleed-
ing risk. Our study is also the first to address unmeasured
confounding by use of an IV, which reduces bias due to
confounding by indication. In the absence of known dif-
ferences in efficacy between apixaban and rivaroxaban,
higher bleeding risk with rivaroxaban should be taken
into account when choosing between apixaban and riva-
roxaban for stroke prevention in AF.
Limitations
Our study had several limitations. First, our study design
did not allow for >2 exposure groups, and future studies
will determine the safety and efficacy of dabigatran
or edoxaban compared with rivaroxaban or apixaban.
Furthermore, exclusion of patients with AF initiated on
other kinds anticoagulation could have created bias, if

Circ Cardiovasc Qual Outcomes. 2020;13:e006058. DOI: 10.1161/CIRCOUTCOMES.119.006058 April 2020 65

 Bonde et al; Rivaroxaban vs Apixaban for Atrial Fibrillation
our IV was also systematically associated to inclusion
or exclusion of certain patient groups34; however, we
found no systematic differences in baseline character-
istics when recreating the IV with patients on dabiga-
tran, edoxaban, and VKA included. Second, we excluded
patients >80 years of age, because of different dosing
recommendations between apixaban and rivaroxaban in
this age group. However, sensitivity analyses where we
included these patients generated results similar to our
main results. Third, we excluded patients with AF treated
at surgical, acute medicine, or neurological units because
of likely unmeasured differences in the clinical profiles of
patients with AF treated by these units. Our results might
not generalize to AF diagnosed during rhythm monitor-
ing after stroke or to postoperative AF. Fourth, we includ-
ed both patients discharged from cardiology units and
general internal medicine units, and these patients could
differ in unmeasured characteristics; however, matching
patients on type of unit did not change our results. Fifth,
systematic differences in unmeasured patient character-
istics between facilities with preferences for rivaroxaban
and facilities with preference for apixaban could create
a false association between our IV and the outcomes;
however, as there were no association between our IV
and measured baseline characteristics or negative con-
trol outcomes, we have no reason to believe that such
systematic differences are likely. Sixth, it is possible that
too few patients were included in our study to detect
Downloaded from http://ahajournals.org by on May 14, 2020
differences in stroke/TE, MI, or all-cause mortality using
IV estimation. Seventh, the estimated treatment effects
in our models will only apply to patients that are possible
candidates for both apixaban and rivaroxaban where the
IV is of importance for treatment decision.
Conclusions
Using IV estimation in a nationwide cohort of patients
with AF, rivaroxaban was associated with higher risk of
major bleeding compared with apixaban. We found no
significant associations to stroke/TE, MI, or all-cause
mortality in main analyses.
ARTICLE INFORMATION
Received September 16, 2019; accepted February 27, 2020.
The Data Supplement is available at https://www.ahajournals.org/doi/
suppl/10.1161/CIRCOUTCOMES.119.006058.
Correspondence
Anders N. Bonde, MD, Department of Cardiology, Research Unit 1, Co-
penhagen University Hospital Herlev-Gentofte, Hellerup, Denmark. Email
andersnissenbonde@gmail.com
Affiliations
Department of Cardiology, Copenhagen University Hospital Herlev-Gentofte,
Hellerup, Denmark (A.N.B., C.J.-Y.L., L.S., G.G., C.T.-P., J.B.O.). Department
of Health Research and Policy, Stanford University School of Medicine, CA
(A.N.B., J.B., M.A.H.). Department of Public Health, Section of Biostatistics,
Circ Cardiovasc Qual Outcomes. 2020;13:e006058. DOI: 10.1161/CIRCOUTCOMES.119.006058
University of Copenhagen, Denmark (T.M.). Department of Health Science
and Technology, Aalborg University (C.J.-Y.L.). Department of Cardiology and
Epidemiology/Biostatistics, Aalborg University Hospital (C.J.-Y.L.). Liverpool
Centre for Cardiovascular Science, University of Liverpool, Liverpool Heart
and Chest Hospital, United Kingdom (C.J.-Y.L.). Department of Cardiology,
Zealand University Hospital Roskilde, Denmark (C.N.B., C.T.-P.). Department
of Cardiovascular Epidemiology and Research, The Danish Heart Foundation,
Copenhagen (C.N.B., G.G.).
Sources of Funding
This study was funded by an unrestricted grant from the Capital Region of Den-
mark, Foundation for Health Research for Dr Jonas Bjerring Olesen. Dr Bonde
received unrestricted travel grants from AP Møller fonden, Julie Von Müllens
fond, Oticonfonden, L.F. Foghts Fond, Anita og Tage Therkelsens fond, Knud
Højgaards fond, and Det Classenske Fideicommis. The study sponsors did not
influence the study design, interpretation of results, or the decision to submit
the manuscript for publication.
Disclosures
Dr Lip was a consultant for Bayer/Janssen, BMS/Pfizer, Medtronic, Boehringer
Ingelheim, Novartis, Verseon, and Daiichi-Sankyo. He was speaker for Bayer,
BMS/Pfizer, Medtronic, Boehringer Ingelheim, and Daiichi-Sankyo. No fees are
directly received personally. Dr Gislason has received research grants from BMS,
Boehringer Ingelheim, Pfizer, and Bayer. Dr Torp-Pedersen has received grants
from Bayer and Novo Nordisk. Dr Olesen was a speaker for Bristol-Myers Squibb,
Boehringer Ingelheim, Bayer, and AstraZeneca. He was a consultant for Bristol-
Myers Squibb, Boehringer Ingelheim, Novartis Healthcare, and Novo Nordisk.
Funding for research from Bristol-Myers Squibb and The Capital Region of Den-
mark, Foundation for Health Research. The other authors report no conflicts.
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