Research

JAMA Cardiology | Original Investigation

Effectiveness and Safety of Standard-Dose Nonvitamin K

Antagonist Oral Anticoagulants and Warfarin Among Patients
With Atrial Fibrillation With a Single Stroke Risk Factor
A Nationwide Cohort Study
Gregory Y. H. Lip, MD; Flemming Skjth, MSc, PhD; Peter Brnnum Nielsen, MSc, PhD;
Jette Nordstrm Kjldgaard, BSc; Torben Bjerregaard Larsen, MD, PhD

Supplemental content
IMPORTANCE The randomized clinical trials comparing nonvitamin K antagonist oral
anticoagulants (NOACs) vs warfarin largely focused on recruiting high-risk patients with atrial
fibrillation with more than 2 stroke risk factors, with only the trials testing dabigatran or
apixaban including few patients with 1 stroke risk factor. Despite this, regulatory approvals of
all NOACs have been based on stroke prevention for patients with atrial fibrillation with 1 or
more stroke risk factors.

OBJECTIVE To compare the effectiveness and safety study of standard-dose NOACs

(dabigatran at 150 mg twice daily, rivaroxaban at 20 mg once daily, and apixaban at 5 mg
twice daily) and warfarin in patients with atrial fibrillation with 1 low-risk, nonsex-related
stroke risk factor.

DESIGN, SETTING, AND PARTICIPANTS This nationwide observational cohort study used data
from Danish registries to determine the inverse probability of treatment-weighted
comparative effectiveness and safety of standard-dose NOACs (dabigatran at 150 mg twice
daily, rivaroxaban at 20 mg once daily, and apixaban at 5 mg twice daily) compared with
treatment with warfarin among 14 020 patients with atrial fibrillation with 1 low-risk, nonsex-
related stroke risk factor.

MAIN OUTCOMES AND MEASURES Rates of ischemic stroke/systemic embolism, death, and
bleeding.

RESULTS Of 14 020 participants, 5151 (36.7%) were women, and the median age for
participants was 66.5 years. For the principal effectiveness end point of ischemic
stroke/systemic embolism, no significant differences of the NOACs compared with treatment
with warfarin across strata were evident. For the end point of any bleeding, this was
significantly lower for treatment with apixaban (hazard ratio [HR], 0.35; 95% CI, 0.17-0.72)
and dabigatran (HR, 0.48; 95% CI, 0.30-0.77) compared with warfarin in the main analysis, Author Affiliations: Aalborg
Thrombosis Research Unit,
and was not significantly different for treatment with rivaroxaban vs warfarin (HR, 0.84; 95%
Department of Clinical Medicine,
CI, 0.49-1.44). There was broad consistency across most subgroups in the sensitivity analyses Faculty of Health, Aalborg University,
and whether 1- or 2.5-year follow-up periods were analyzed. However, falsification end points Aalborg, Denmark (Lip, Skjth,
generally did not falsify, indicating the possible presence of residual confounding across these Nielsen, Kjldgaard, Larsen);
Institute of Cardiovascular Sciences,
comparisons, presumably related to selective prescribing and unobserved covariates. University of Birmingham,
Birmingham, England (Lip); Unit of
CONCLUSIONS AND RELEVANCE In this Danish cohort study of patients with atrial fibrillation Clinical Biostatistics, Aalborg
and a single stroke risk factor, there was no difference between NOACs compared with University Hospital, Aalborg,
treatment with warfarin in terms of the risk of having an ischemic stroke/systemic embolism. Denmark (Skjth); Department of
Cardiology, Aalborg University
For any bleeding, this was lower for treatment with apixaban and dabigatran compared with Hospital, Aalborg, Denmark (Nielsen,
warfarin. These data do not allow for a definitive statement of the comparative effectiveness Kjldgaard, Larsen).
or safety of NOACs because of the possible residual confounding that was unmasked with Corresponding Author: Gregory Y.
falsification outcomes. H. Lip, MD, University of Birmingham
Institute of Cardiovascular Sciences,
City Hospital, Birmingham,
JAMA Cardiol. doi:10.1001/jamacardio.2017.1883 West Midlands B18 7QH, England
Published online June 14, 2017. (g.y.h.lip@bham.ac.uk).

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 Research Original Investigation Effectiveness and Safety of Standard-Dose Nonvitamin K Antagonist Oral Anticoagulants and Warfarin
I
n the respective randomized clinical trials of nonvitamin
K antagonist oral anticoagulants (NOACs) for stroke pre-
vention in atrial fibrillation (AF), the focus was on recruit-
ing patients with AF with 2 or more stroke risk factors, and only
the trials testing treatment with dabigatran or apixaban in-
cluded a minority of patients with 1 stroke risk factor.1,2 To our
knowledge, specific randomized clinical trials including pa-
tients with AF with only 1 stroke risk factor have not been per-
formed, and there is a low likelihood for such trials to be
conducted. The objective of this study was to investigate the
comparative effectiveness and safety of standard-dose
NOACs (dabigatran at 150 mg twice daily, rivaroxaban at 20 mg
once daily, and apixaban at 5 mg twice daily) compared with
treatment with warfarin among such patients in the Danish
registries.
Methods
We conducted an observational cohort study of Danish citi-
zens initiating OAC treatment for stroke prevention in AF with
1 stroke risk factor. To align with previous randomized clini-
cal trials, we focused on standard-dose NOAC agents only
and used Danish nationwide databases (eMethods in the
Supplement).3-5
The study was based on new users of OACs with no his-
tory of treatment for other indications than AF. For this analy-
sis, we only recruited patients with 1 nonsex-related stroke risk
factor that was assigned 1 point in the CHA2DS2-VASc score (ie,
congestive heart failure or left ventricular disease, hyper-
tension, 65 years age <75 years, and diabetes or vascular
diseases such as myocardial infarction, aortic plaque or
peripheral aortic disease), thus excluding patients with prior
strokes, systemic embolisms/transient ischemic attacks, or
those who were younger than 75 years.
Nonvitamin K antagonist oral anticoagulants were re-
stricted to standard doses: apixaban at 5 mg twice daily, dabi-
gatran at 150 mg twice daily, and rivaroxaban at 20 mg once
daily. To establish an OAC-naive cohort, we excluded pa-
tients previously treated with OAC-inclusive doses approved
for other indications within 1 year. Eventually, we excluded pa-
tients with prior diagnoses of valvular AF or a venous throm-
boembolism. Also, patients with contraindications for stan-
dard NOAC dose regimens because of renal impairment were
excluded. This population formed the main cohort for the
analyses. Sensitivity analyses were reported on the subgroup
with prior diagnoses of AF. To increase homogeneity6 across
patient groups, we also performed a sensitivity analysis in
which patients with prior heart failure, chronic pulmonary dis-
ease, or cancer were excluded.
End Points and Variable Definitions
Clinical end points were extracted from hospital discharge
codes with follow-up until April 30, 2016 (eTable 1 in the
Supplement). Primary and secondary discharge codes from
nonemergency wards were extracted. We only analyzed end
points obtained as discharge codes from hospitalizations and
did not include codes from ambulatory visits.
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Key Points
Question What is the effectiveness and safety study of
standard-dose nonvitamin K antagonist oral anticoagulants
(NOACs) and warfarin among patients with atrial fibrillation with 1
stroke risk factor?
Findings In this nationwide observational cohort study, no
significant differences of the NOACs compared with warfarin
across strata were evident for the principal effectiveness end point
of ischemic stroke/systemic embolism. The end point of any
bleeding was significantly lower for patients treated with
apixaban and dabigatran and not significantly different for
patients treated with rivaroxaban vs warfarin; however, there was
possible residual confounding across these comparisons that was
unmasked with falsification outcomes.
Meaning Our data show no significant differences of the NOACs
compared with treatment with warfarin for ischemic
stroke/systemic embolism, but for any bleeding, this was lower
for treatment with apixaban and dabigatran.
Efficiency was investigated by the occurrence of ischemic
stroke or systemic embolism. All-cause death was included as
a lone end point. The safety of the treatments was investigated
by the following bleeding events: intracranial, gastrointesti-
nal, traumatic intracranial, and clinically relevant nonmajor
bleeding reported in total as any bleeding and more specifi-
cally for intracranial (including traumatic) and gastrointesti-
nal bleeding (see eTable 1 in the Supplement for International
Statistical Classification of Diseases and Related Health Prob-
lems, Tenth Revision [ICD-10] discharge codes).7,8
A patients baseline comorbidities and comedications when
treatment was initiated were ascertained (Table 1) (eTable 1 in
the Supplement). The overall risk of bleeding was assessed by
the hypertension, abnormal renal and liver function, stroke,
bleeding, labile international normalized ratio, elderly, drugs
or alcohol (HAS-BLED) score (eTable 2 in the Supplement).9 The
Danish registries are well-validated with a sufficiently high
positive predictive value (>80%) of included comorbidities and
outcomes.10
Statistical Analysis
A time to event analysis was used to compare the risk of an end
point between treatment groups, measuring risk time from the
patient receiving their initial prescription and until the rel-
evant event, emigration, death, or end of follow-up (which-
ever came first). An intent-to-treat approach was applied for
the main analyses. This was supplemented by a continuous
treatment analysis by censoring the follow-up if the patient was
prescribed another treatment than what was initiated.
Crude incidence rates were calculated as the number of
events divided by the person-time. Cox regressions with a ro-
bust variance estimator were used to compare event rates be-
tween the treatment groups, with warfarin as the primary ref-
erence. To address confounding by indication of treatment, an
inverse probability of treatment weighted (IPTW) analysis was
applied.11,12 We used weights that enabled estimates represent-
ing mean population treatment effects. The underlying pro-
pensity models included the following treatment predictors: age
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 Effectiveness and Safety of Standard-Dose Nonvitamin K Antagonist Oral Anticoagulants and Warfarin Original Investigation Research

Table 1. Participant Characteristics at Treatment Initiation According to Treatment

No. (%)
Characteristic Apixaban Dabigatran Rivaroxaban Warfarin All
No. of patients 1470 3272 1604 7674 14 020
Women 589 (40.1) 1160 (35.5) 609 (38.0) 2793 (36.4) 5151 (36.7)
Age, median (IQR) 67.4 (62.5-70.9) 66.2 (61.3-69.8) 67.2 (62.4-70.7) 66.2 (60.5-70.4) 66.5 (61.1-70.4)
Heart failure or LVD 31 (2.1) 90 (2.8) 17 (1.1) 232 (3.0) 370 (2.6)
Hypertension 411 (28.0) 1134 (34.7) 471 (29.4) 2430 (31.7) 4446 (31.7)
65 age <75 y 963 (65.5) 1884 (57.6) 1037 (64.7) 4435 (57.8) 8319 (59.3)
Diabetes 44 (3.0) 96 (2.9) 41 (2.6) 271 (3.5) 452 (3.2)
Vascular disease 21 (1.4) 68 (2.1) 38 (2.4) 306 (4.0) 433 (3.1)
Prior AF diagnosis 1042 (70.9) 2300 (70.3) 1037 (64.4) 4114 (53.6) 8489 (60.5)
Cancer 206 (14.0) 345 (10.5) 217 (13.5) 1079 (14.1) 1847 (13.2)
HAS-BLED score, mean (SD)a 1.5 (0.6) 1.5 (0.6) 1.5 (0.6) 1.5 (0.7) 1.5 (0.7)
Hepatic dysfunction <0.3 (<5) <0.1 (<5) 0.3 (5) 0.4 (29) 0.3 (39)
Alcohol 38 (2.6) 83 (2.5) 55 (3.4) 264 (3.4) 440 (3.1)
CPD 128 (8.7) 237 (7.2) 115 (7.2) 665 (8.7) 1145 (8.2)
Previous bleeding 128 (8.6) 224 (6.8) 128 (8.0) 521 (6.8) 999 (7.1)
Aspirin 342 (23.3) 960 (29.3) 437 (27.2) 2316 (30.2) 4055 (28.9)
Ticagralor <0.3 (<5) 0.4 (12) <0.2 (<5) 0.4 (31) 0.3 (49)
Clopidogrel 28 (1.9) 55 (1.7) 34 (2.1) 181 (2.4) 298 (2.1)
-blockers 914 (62.2) 2175 (66.5) 931 (58.0) 4408 (57.4) 8428 (60.1)
NSAIDs 339 (23.1) 806 (24.6) 386 (24.1) 2053 (26.8) 3584 (25.6)
Statins 359 (24.4) 817 (25.0) 387 (24.1) 2053 (26.8) 3616 (25.8)
ACE/ARB inhibiters 396 (26.8) 1000 (30.6) 430 (26.8) 2118 (26.8) 3944 (28.1)
Loop diuretics 97 (6.6) 200 (6.1) 94 (5.9) 680 (8.9) 1071 (7.6)
Concomitant cardiovascular
drugs, No.b
None 641 (43.6) 1288 (39.4) 627 (39.1) 3019 (39.3) 5575 (39.8)
1 341 (23.2) 727 (22.2) 394 (24.6) 1713 (22.3) 3175 (22.6)
2 259 (17.6) 602 (18.4) 298 (18.6) 1403 (18.3) 2562 (18.3)
3 127 (8.6) 369 (11.3) 177 (11.0) 901 (11.7) 1574 (11.2)
4 102 (6.9) 286 (8.7) 108 (6.7) 638 (8.3) 1134 (8.1)
a
Abbreviation: ACE/ARB, angiotensin converting enzyme inhibitor/angiotensin HAS-BLED: score ranging from 0 to 9, which reflects the risk of bleeding in
receptor blocker; AF, atrial fibrillation; CPD, chronic pulmonary disease; patients with atrial fibrillation undergoing anticoagulant therapy (eTable 2 in
HAS-BLED, hypertension, abnormal renal and liver function, stroke, bleeding, the Supplement).
labile international normalized ratio, elderly, drugs or alcohol; IQR, interquartile b
Cardiovascular drugs covers all Anatomical Therapeutic Chemical codes in
range; NSAIDs, non-steroidal anti-inflammatory drugs; LVD, left ventricle groups B and C.
disease.

(continuous); binary indicators for sex, prior bleeding, vascu-
lar disease, hypertension, diabetes, renal disease, chronic pul-
monary disease, heart failure, cancer, and a recent prescrip-
tion for aspirin, -blockers, nonsteroidal anti-inflammatory
drugs, statins, or loop diuretics; and the HAS-BLED score.
Balances between treatment populations were evaluated
by the standardized differences of all baseline covariates, using
a threshold of 0.1 to indicate an imbalance.13
To evaluate the potential for residual confounding,
falsification analysis was performed by applying the
propensityweighted cohort in the analyses on (falsifica-
tion) end points that a priori should be expected not to be
associated with the effects of treatment.14 For this study, we
considered pneumonia, hip fractures, cancer, and urinary
tract infections.
We repeated the analyses on the subgroup with a hospi-
tal discharge diagnosis for AF either before or within 30 days
of first receiving a prescription. In addition, as there may be
confounding because of differences in the health status of pa-
tients, we also reported results of analyses in which patients
with high-mortality conditions (heart failure, cancer, or chronic
pulmonary disorder) at the time treatment was initiated were
excluded. Eventually, the results of the IPTW analysis were
compared with a trimmed analysis that removed 5% of the ex-
treme weights as well as with an ordinary crude and adjusted
analysis (data not shown).
The analyses on the entire population were supple-
mented by stratified analyses on the populations with 1 of the
frequent risk factors who were older than 65 and patients with
hypertension; additionally, the results of the analyses were re-
ported for men and women separately. Stata/MP, version 14
(StataCorp) and R version 3.1.1 (The R Foundation) were used
for the statistical analysis. A 2-tailed P value of less than .05
was considered statistically significant.

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 Research Original Investigation Effectiveness and Safety of Standard-Dose Nonvitamin K Antagonist Oral Anticoagulants and Warfarin

Table 2. Number of Events and Crude and Weighted Event Rates According to Treatmenta

Apixaban Dabigatran Rivaroxaban Warfarin

Rate Rate Rate Rate
Events Crude Weighted Events Crude Weighted Events Crude Weighted Events Crude Weighted
1-y Follow-up
Ischemic stroke/SE 10 0.68 0.83 22 0.70 0.65 14 1.09 1.20 57 0.79 0.81
All-cause death 19 1.62 1.52 51 1.62 1.84 26 2.01 1.67 249 3.45 3.11
Any bleeding 8 0.68 0.57 23 0.74 0.73 17 1.33 1.38 109 1.52 1.53
Intracranial/gastrointestinal <5 0.09 0.06 6 0.19 0.16 <5 0.23 0.29 39 0.54 0.54
bleeding
2.5-y Follow-up
Ischemic stroke/SE 14 0.85 0.85 41 0.61 0.58 16 0.75 0.81 109 0.70 0.69
All-cause death 22 1.32 1.21 91 1.33 1.48 49 2.28 2.10 428 2.71 2.47
Any bleeding 11 0.67 0.56 44 0.65 0.65 22 1.04 1.09 202 1.30 1.31
Intracranial/gastrointestinal <5 0.12 0.12 17 0.25 0.21 6 0.28 0.30 72 0.46 0.45
bleeding
Abbreviations: IPTW, inverse probability of treatment weighed; SE, systemic embolism.
a
Crude rates are events divided by person time per 100 years; weighted rates are based on IPTW population and express population mean treatment rates per 100
years. Main analysis.

Ethical Considerations
No ethical approval is required for anonymous register stud-
ies in Denmark. The study was approved by the Danish Data
Protection Agency (J. No. File No. 2012-41-0633).
Results
We identified 240 360 unique OAC users in the inclusion
period, 59% of whom (n = 142 307) either prevalently used
vitamin K antagonists or had an indication for treatment
because of other reasons than nonvalvular AF. Of the
remaining OAC users (n = 98 053), we excluded 22%
(n = 21 456) because of treatment with reduced-dose NOACs
or because of the presence of prior discharge codes for renal
impairment. Thus, the study population covers 76 597 new
users of OAC treatment for AF, with either standard-dose
NOACs or warfarin. Of these, 82% (n = 62 57 7) were
excluded because they had either 0 or more than 1 nonsex-
related stroke risk factor or because their risk factors had
scored a 2-point CHA2DS2-VASc score.
The final study population (n = 14 020) was distributed
according to treatment type: warfarin (n = 7674 [54.7%]),
dabigatran (n = 3272 [23.3%]), rivaroxaban( n = 1604
[11.4%]), and apixaban (n = 1470 [10.5%]) (eFigure 1 in the
Supplement). The mean (SD) follow-up was 2.6 (1.6) years,
with the shortest follow-up for the group treated with
apixaban (mean [SD] follow-up, 1.1 [0.7] years) reflecting its
later market introduction.
Baseline information about the initial study population
before weighing is shown in Table 1. The 5151 women (36.7%)
included in the study population were separated into treat-
ment groups: 1160 (35.5%) were treated with dabigatran, 589
(40.1%) were treated with apixaban, 2793 (36.4%) were treated
with warfarin, and 609 (38.0%) were treated with rivaroxa-
ban. All patients had 1 nonsex-related and 1 point-valued stroke
risk factor according to the CHA2DS2-VASc score. The domi-
nant factor for inclusion was being 65 to 74 years (n = 8319,
59.3%). Patients initiated with dabigatran or warfarin were
slightly younger; 1884 patients (57.6%) were treated with dabi-
gatran and 4435 (57.8%) were older than 65 years compared
with 963 patients (65.5%) treated with apixaban and 1037 pa-
tients (64.7%) treated with rivaroxaban who were older than
65 years. Hypertension, which affected 4446 participants
(31.7%), was lowest among the 411 patients (28.0%) initiated
with apixaban and 471 patients (29.4%) treated with rivaroxa-
ban and highest among the 1134 patients (37.4%) using dabi-
gatran. The remaining 1255 patients (8.9%) were included
because they received a diagnosis of vascular diseases (eg, myo-
cardial infarction, peripheral artery disease, or aortic plaques),
diabetes, or heart failure. Diabetes was the primary reason
among the NOACs, whereas they were distributed more evenly
among patients treated with warfarin. Notably, 8750 patients
(62.4%) had a prescription history with either 0 or only 1
drug within the Anatomical Therapeutic Chemical chapters
B or C, which cover multiple cardiovascular indications.
Apixaban had the highest proportion (n = 982, 66.8%) and
warfarin (n = 4732, 61.6%) and dabigatran (n = 2015, 61.6%)
had a lower proportion. Approximately 1134 patients (8%)
were intensively treated, with 4 or more different drugs pre-
scribed, ranging from 108 patients (6.7%) in the group
treated with rivaroxaban to 286 patients (8.7%) in the group
treated with dabigatran.
After weighing the study populations using the IPTW
method, all baseline differences were less than 0.08 standard-
ized differences at maximum (eFigure 2 in the Supplement).
An inspection of individual propensity score distributions
showed a sufficient overlap between treatment populations to
obtain a valid comparison (eFigures 3-5 in the Supplement).
Effectiveness: Stroke and Systemic Embolism
Event count and crude or weighted rates for the different
NOACs and warfarin are shown in Table 2, for 1 and 2.5 years
follow-up. Falsification analysis, described below, found that

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 Effectiveness and Safety of Standard-Dose Nonvitamin K Antagonist Oral Anticoagulants and Warfarin Original Investigation Research

Figure 1. Propensity Weighted Cox Hazard Ratios for 1-Year Follow-Up for Nonvitamin K Antagonist Anticoagulants Compared With Warfarian for
Effectiveness, Safety, and Death End Points.

Ischemic
Strata/ Stroke/SE Favors Favors Any Bleeding Favors Favors Death Favors Favors
Treatment HR (95% CI) Alternative Warfarin HR (95% CI) Alternative Warfarin HR (95% CI) Alternative Warfarin
Entire cohort with AF
(main analysis)
Apixaban 1.01 (0.51-2.01) 0.35 (0.17-0.72) 0.47 (029-0.76)
Dabigatran 0.81 (0.49-1.34) 0.48 (0.30-0.77) 0.59 (0.43-0.81)
Rivaroxaban 1.46 (0.79-2.70) 0.84 (0.49-1.44) 0.52 (0.34-0.79)
Cohort hospitalized with AF
(sensitivity analysis)
Apixaban 1.06 (0.51-2.19) 0.46 (0.22-0.97) 0.58 (0.33-1.02)
Dabigatran 0.69 (0.39-1.23) 0.46 (0.27-0.77) 0.69 (0.47-1.02)
Rivaroxaban 1.27 (0.64-2.52) 0.72 (0.38-1.37) 0.62 (0.36-1.08)
Low mortality cohort
(sensitivity analysis)
Apixaban 1.39 (0.65-2.95) 0.31 (0.12-0.78) 0.74 (0.39-1.43)
Dabigatran 1.03 (0.59-1.80) 0.44 (0.25-0.77) 0.92 (0.58-1.47)
Rivaroxaban 1.28 (0.61-2.68) 0.72 (0.37-1.37) 0.39 (0.17-0.91)
Age >65 y (supplementary analysis)
Apixaban 0.89 (0.37-2.13) 0.41 (0.17-0.96) 0.56 (0.33-0.96)
Dabigatran 0.96 (0.53-1.76) 0.55 (0.31-0.99) 0.59 (0.40-0.86)
Rivaroxaban 1.07 (0.49-2.23) 0.76 (0.41-1.42) 0.69 (0.44-1.08)
Hypertension
(supplementary analysis)
Apixaban 1.46 (0.47-4.54) 0.47 (0.11-2.02) 0.45 (0.14-1.42)
Dabigatran 0.83 (0.31-2.23) 0.47 (0.19-1.16) 0.49 (0.24-1.04)
Rivaroxaban 1.50 (0.41-5.46) 0.79 (0.23-2.65) 0.11 (0.01-0.82)
Men (supplementary analysis)
Apixaban 0.96 (0.39-2.36) 0.44 (0.19-0.98) 0.56 (0.31-1.01)
Dabigatran 0.90 (0.49-1.66) 0.50 (0.29-0.86) 0.61 (0.42-0.90)
Rivaroxaban 1.01 (0.43-2.37) 0.95 (0.53-1.71) 0.67 (0.40-1.12)
Women (supplementary analysis)
Apixaban 1.20 (0.40-3.59) 0.14 (0.02-1.04) 0.29 (0.13-0.68)
Dabigatran 0.72 (0.28-1.84) 0.46 (0.19-1.12) 0.57 (0.32-1.02)
Rivaroxaban 2.17 (0.89-5.31) 0.29 (0.07-1.25) 0.34 (0.16-0.75)

0.2 1.0 6.0 0.01 0.1 1.0 3.0 0.01 0.1 1.0 3.0
Ischemic Stroke/SE Any Bleeding Death
HR (95% CI) HR (95% CI) HR (95% CI)

The corresponding results for a follow-up of 2.5 years are provided in eFigure 8. AF indicates atrial fibrillation; SE, systemic embolism.

these end points did not falsify, indicating residual confound-
ing. Survival analyses are first described below.
For the principal effectiveness end point of ischemic stroke/
systemic embolism, 103 events (80.5% as primary diagnoses)
were observed within the first year, representing a rate be-
tween 0.65 and 1.20 per 100 person-years among the IPTW
population. The estimated effect sizes in terms of hazard ra-
tios (HR) of the NOACs ranged between 0.81 (95% CI, 0.49-
1.34) and 1.46 (0.79-2.70), with all treatment groups display-
ing statistically nonsignificant differences compared with
warfarin (Figure 1). The primary effectiveness outcome was al-
most exclusively composed of ischemic stroke, and only 3
events were systemic embolism (data not shown).
In sensitivity analyses restricted to patients with a his-
tory of AF discharge codes or to the cohort with a low mortal-
ity for the composite end point of ischemic stroke/systemic em-
bolism at 1 year, the findings from the main analysis were
generally in agreement, and no statistically significant differ-
ences between NOAC agents compared with warfarin were
observed. The number of events and the event rates for the sen-
sitivity analyses on the configuration of the study cohorts are
provided in Table 3.
All-Cause Mortality
There was an apparent significant lower risk of all-cause mor-
tality, death, across all treatment groups compared with war-
farin, although effect sizes shifted toward unity and became
nonsignificant when restricted to patients who were hospi-
talized with AF (Figure 1).
When restricting the study population to patients with-
out conditions associated with increased mortality (ie, exclud-
ing patients with heart failure, chronic pulmonary disease, or
cancer), all effect estimates were lower for NOAC agents com-
pared with warfarin, while only treatment with rivaroxaban
reached a statistically significant lower death rate (HR, 0.39;
95% CI, 0.17-0.91).
Excluding approximately 3084 patients (22%) with a
conjectured high mortality risk resulted in a pronounced

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 Research Original Investigation Effectiveness and Safety of Standard-Dose Nonvitamin K Antagonist Oral Anticoagulants and Warfarin

Table 3. Number of Events and Crude and Weighted Event Rates at 1-Year Follow-up According to Treatment for Main End Points
and Selected Study Cohortsa

Apixaban Dabigatran Rivaroxaban Warfarin

Rate Rate Rate Rate
End
Point/Cohort Events Crude Weighted Events Crude Weighted Events Crude Weighted Events Crude Weighted
Ischemic Stroke/SE
Main analysis 10 0.86 0.83 22 0.70 0.65 14 1.09 1.20 57 0.79 0.81
cohort
Cohort 9 1.01 1.07 17 0.69 0.66 11 1.25 1.29 41 0.94 0.96
hospitalized
with AF
Low mortality 9 1.00 1.00 19 0.75 0.79 10 0.97 0.92 38 0.68 0.70
cohort
All-Cause Death
Main analysis 19 1.62 1.52 51 1.62 1.84 26 2.01 1.67 249 3.45 3.11
cohort
Cohort 14 1.56 1.40 36 1.46 1.60 15 1.69 1.50 107 2.44 2.33
hospitalized
with AF
Low mortality 11 1.21 0.96 26 1.02 1.14 6 0.58 0.50 69 1.24 1.24
cohort
Any Bleeding
Main analysis 8 0.68 0.57 23 0.74 0.73 17 1.33 1.38 109 1.52 1.53
cohort
Cohort 8 0.90 0.79 18 0.74 0.72 12 1.36 1.24 69 1.58 1.59
hospitalized
with AF
Low mortality 5 0.55 0.44 15 0.59 0.58 11 1.06 1.02 70 1.26 1.32
cohort
Abbreviations: AF, atrial fibrillation; IPTW, inverse probability of treatment weighed; SE, systemic embolism.
a
Crude rates are events divided by person time per 100 years; weighted rates are based on IPTW population and express population mean treatment rates per 100
years.

reduction in the absolute number of deaths (from 345 to 112)
across treatment groups (eFigure 1 in the Supplement). The re-
sults of the supplementary analyses generally align with the
main analysis, but should be interpreted with caution in light
of the sensitivity analysis on the group with low mortality rates.
Bleeding Events
A total of 157 events (90% primary diagnoses) of the com-
bined end point of any bleeding were observed during the
first year of follow-up. The weighted event rates ranged be-
tween 0.57 (apixaban) to 1.53 (warfarin).
When compared with warfarin, apixaban and dabigatran
were associated with lower bleeding events (HR, 0.35; 95% CI,
0.17-0.72; and HR, 0.48; 95% CI, 0.30-0.77, respectively)
(Figure 1). This was statistically nonsignificant for the
comparison of rivaroxaban vs warfarin (HR, 0.84; 95% CI,
0.49-1.44).
In sensitivity analyses restricted to patients with AF with
an AF hospital discharge code or to the cohort with low mor-
tality rates, the rates were overall lower in the latter cohort,
although altogether the direction of associations from the
main analysis was generally maintained. For the supplemen-
tary subgroup analyses, the smaller sample sizes led to more
uncertain effect estimates, although they were aligned with
the main analyses (eTables 3-8 and eFigures 6 and 7 in the
Supplement).
After analyzing the outcomes of intracranial (including
traumatically induced) bleeding and gastrointestinal bleed-
ing, few events were observed among the populations treated
with NOACs (ie, no more than 6 events in each treatment group)
(Table 2). Fifty five bleeding events (35%) were observed. When
compared with warfarin, each NOAC exhibited a lower rela-
tive risk of intracranial bleeding with estimates (ie, HRs) rang-
ing from 0.11 (95% CI, 0.01-0.78) to 0.53 (95% CI, 0.15-1.87).
The low event numbers resulted in wide confidence inter-
vals, which preclude any statistically significant conclusions.
Results for a follow-up of 2.5 years (eFigure 8 in the Supple-
ment) aligned with these results, as did the trimmed IPTW
analyses when compared with the adjusted Cox regression on
the unweighted population (data not shown).
Falsification Analysis
For the falsification outcomes analyses on the associated treat-
ment-exposure relationship, the a priori null-hypothesis of
neutral associations was generally rejected, indicating a pos-
sible persistent bias. In the subgroup analysis of the cohort hos-
pitalized with AF and the cohort with low mortality rates, the
associations between exposure and studied falsification out-
comes were neutral, indicating a low likelihood of persistent
bias (Figure 2, eFigure 8, and eTable 9 in the Supplement).
Discussion
In this study of patients with AF with 1 nonsex-related
CHA2DS2-VASc risk factor, our principal findings were as fol-
lows: (1) for ischemic stroke/systemic embolism, no signifi-
cant differences of the NOACs compared with warfarin were

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 Effectiveness and Safety of Standard-Dose Nonvitamin K Antagonist Oral Anticoagulants and Warfarin Original Investigation Research

Figure 2. Inverse Probability of Treatment Weighted Cox Hazard Ratios for 1-Year Follow-up for Nonvitamin K Antagonist Oral Anticoagulants
Compared With Warfarin for Falsification Analysis

Cancer Favors Favors Hip Fractures Favors Favors

Strata/Treatment HR (95% CI) Alternative Warfarin Strata/Treatment HR (95% CI) Alternative Warfarin
Entire AF cohort (main analysis) Entire AF cohort (main analysis)
Apixaban 0.67 (0.480.93) Apixaban 0.64 (0.401.02)
Dabigatran 0.66 (0.53-0.82) Dabigatran 0.69 (0.510.93)
Rivaroxaban 0.68 (0.510.90) Rivaroxaban 0.67 (0.451.00)
AF hospitalized cohort (sensitivity analysis) AF hospitalized cohort (sensitivity analysis)
Apixaban 0.73 (0.501.05) Apixaban 0.69 (0.411.17)
Dabigatran 0.72 (0.550.93) Dabigatran 0.75 (0.521.08)
Rivaroxaban 0.73 (0.511.05) Rivaroxaban 0.71 (0.421.20)
Low mortality cohort (sensitivity analysis) Low mortality cohort (sensitivity analysis)
Apixaban 0.76 (0.481.21) Apixaban 0.75 (0.401.40)
Dabigatran 0.72 (0.511.00) Dabigatran 1.02 (0.661.57)
Rivaroxaban 0.74 (0.471.17) Rivaroxaban 0.51 (0.241.08)

0.1 1.0 10 0.1 1.0 10

Cancer HR (95% CI) Hip Fractures HR (95% CI)

Urinary Tract
Pneumonia Favors Favors Infection Favors Favors
Strata/Treatment HR (95% CI) Alternative Warfarin Strata/Treatment HR (95% CI) Alternative Warfarin
Entire AF cohort (main analysis) Entire AF cohort (main analysis)
Apixaban 0.94 (0.701.27) Apixaban 0.64 (0.411.00)
Dabigatran 0.69 (0.550.87) Dabigatran 0.73 (0.560.96)
Rivaroxaban 0.63 (0.470.86) Rivaroxaban 0.71 (0.501.03)
AF hospitalized cohort (sensitivity analysis) AF hospitalized cohort (sensitivity analysis)
Apixaban 0.93 (0.671.29) Apixaban 0.63 (0.381.04)
Dabigatran 0.74 (0.570.96) Dabigatran 0.83 (0.601.16)
Rivaroxaban 0.79 (0.551.14) Rivaroxaban 0.86 (0.551.36)
Low mortality cohort (sensitivity analysis) Low mortality cohort (sensitivity analysis)
Apixaban 1.11 (0.751.63) Apixaban 0.85 (0.481.51)
Dabigatran 0.93 (0.681.27) Dabigatran 1.01 (0.691.48)
Rivaroxaban 0.53 (0.320.88) Rivaroxaban 0.68 (0.381.22)

0.1 1.0 10 0.1 1.0 10

Pneumonia HR (95% CI) Urinary Tract Infection HR (95% CI)

AF indicates atrial fibrillation.

evident; (2) death was significantly lower for all 3 NOACs com-
pared with warfarin, but this appears mainly driven by intrin-
sic selective prescription patterns that warrant cautious inter-
pretation; and (3) any bleeding was significantly lower for
apixaban and dabigatran compared with warfarin and showed
nonsignificant differences between rivaroxaban and warfa-
rin. Nonetheless, the falsification end points generally did not
falsify, indicating some residual confounding across these com-
parisons that was presumably related to selective prescribing
and unobserved comorbidities.
In patients with a CHADS2 score of 0 to 1, ancillary analy-
ses from the RELY, ARISTOTLE, and AVERROES clinical trials
show that there was no significant interaction for the efficacy
and safety data on NOACs (ie, dabigatran or apixaban) com-
pared with warfarin or aspirin.15-17 However, the randomized
clinical trials for rivaroxaban (ROCKET-AF) or edoxaban
(ENGAGE-AF) did not include patients with 1 stroke risk fac-
tor; for example, the inclusion criteria for ROCKET-AF was con-
fined to patients with a CHADS2 score of 2 or more or having
experienced a prior stroke, and even those with a CHADS2 score
of 2 were capped at 10%.18,19 Hence, the relative effective-
ness and safety of these 2 NOAC agents (ie, rivaroxaban or
edoxaban, compared with warfarin) can benefit from obser-
vational cohort studies. As mentioned, the lack of clinical trial
data has led to some guidelines that express a preference
for treatment with dabigatran or apixaban for patients with 1
stroke risk factor, with the other NOACs or warfarin as
alternatives.20,21 However, the current analysis cannot firmly
support these preferences, and prescribing physicians are also
encouraged to evaluate each patient with AF individually to
select the preferred agent.22
Many guidelines have expressed a preference for NOACs
over warfarin for treating patients with AF with 1 or more stroke
risk factors. The current threshold for OAC for stroke preven-
tion has been quoted as a stroke rate of 1.7%year for warfarin,
and 0.9%/year for an NOAC, reflecting the change in tipping
point for treatment with the availability of NOACs.23 Even this
treatment threshold of 1.7%/year with warfarin could be low-
ered with good-quality anticoagulation control with a time in
therapeutic range of more than 70%.24 Given the lack of spe-
cific randomized clinical trial data in an exclusive patient popu-
lation with 1 stroke risk factor, guidelines have suggested that
OACs should be considered (grade IIa recommendation) for
those with 1 risk factor (CHA2DS2-VASc score of 1 in men or 2

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 Research Original Investigation Effectiveness and Safety of Standard-Dose Nonvitamin K Antagonist Oral Anticoagulants and Warfarin
in women) whereas OACs are recommended (grade I recom-
mendation) for patients with 2 or more stroke risk factors.25
Nevertheless, there has been controversy regarding the ac-
tual stroke event rates with 1 stroke risk factor, given the likely
differences of risk associated with different risk factors. Also,
different study settings (eg, hospitalized vs community), races/
ethnicities (Asian vs non-Asian) and methods of analyses may
be relevant factors.26,27 Indeed, some studies28,29 putatively
reporting low event rates excluded patients who ever took
OACs, hence conditioning analyses on the future, and artifi-
cially biasing results toward low event rates.26 Even 1 stroke
risk factor has a positive net clinical benefit for OAC treat-
ment compared with aspirin or no treatment.30 Also, stroke risk
among patients with AF not a static phenomenon, and clini-
cal scores like the CHA2DS2-VASc scores are reductionist and
a simplification.27
The observation on the lower risk of death among pa-
tients who received NOAC treatment compared with warfa-
rin requires attention. This difference in conclusion is likely
because of selective prescribing by physicians; these analy-
ses could suggest that rivaroxaban may be preferred for frailer
patients compared with the other treatment alternatives.
Causes of death available in real-world data analyses are in gen-
eral not adjudicated and either cerebral imaging or post mor-
tems are not mandated. It is evident that some deaths could
be because of fatal strokes, as there is an increased risk of stroke
in AF. Nonetheless, both stroke and death has been shown to
be significantly reduced by treatment with warfarin vs
placebos/controls.31 For mortality rates, there is even an added
10% reduction with treatment with NOACs over warfarin.32
Our falsification end points generally did not falsify, indi-
cating the presence of residual confounding across these com-
parisons. Indeed, there are multiple considerations that indi-
cate confounding. For example, there are important variables
that are known to influence treatment selection that are not
present in the data set, such as body mass index (calculated
as weight in kilograms divided by height in meters squared),
actual blood pressures, heart rate, smoking status, estimated
glomerular filtration rate, hematocrit, New York Heart Asso-
ciation class, left ventricle ejection fraction, and type of AF.
For the results to be totally unconfounded, these factors would
need to be unrelated to the treatment assignment. Successful
falsification does not prove a lack of confounding, as the
sources of confounding may be different for different out-
comes. However, the failure to falsify (as in our study) raises
the likelihood that unmeasured confounders exist, and may
well be relevant to our outcomes of interest and, perhaps add
bias toward NOACs.
Indeed, our analyses indicate that some selective prescrib-
ing may contribute to an important bias of the rates, and cau-
tion concerning conclusions on effects associated with death
is warranted. Indeed, the analyses on falsification outcomes
could not provide a reassurance of unbiased estimates, rec-
ognizing the findings of positive associations in the 4 investi-
gations of false outcomes. However, when investigating fal-
sified outcomes among the cohort with low mortality rates, we
observed neutral associations when contrasting exposure
groups, while the associations on treatment exposure and
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effectiveness or safety outcomes were generally maintained.
While these (sensitivity) analyses do not guarantee that our
analyses are completely unbiased, it does provide some reas-
surance and indicates that the observed associations may be
true associations.
Concisely, observational studies are inherently subject to
confounding and may lead to biased estimates. However, we
systematically and analytically investigated confounding and
biases in sensitivity analyses and falsification outcomes, and
in general, our approaches pointed toward causal associa-
tions between treatment exposure and effectiveness and safety
outcomes.
The main analysis of the end point of any bleeding in-
dicated that it was significantly lower for apixaban and dabi-
gatran compared with warfarin but was nonsignificant for the
comparison of rivaroxaban vs warfarin. Again, this is broadly
consistent with prior analyses.33-35 Ancillary analyses of ran-
domized clinical trial cohorts for the minority of patients with
a CHADS2 score of 0 to 1 show consistency between the effect
sizes of NOAC vs warfarin and the main trial observations.15-17
There was broad consistency across most subgroups in our sen-
sitivity analyses and whether 1- or 2.5-year follow-up periods
were analyzed.
Limitations
The main limitation of this study relates to the observational
nature of the data, and residual or unmeasured confounding
probably persists. A propensity weighing approach to ac-
count for baseline differences were used; however, the full ex-
tent and effect of different prescribing behavior may not be fully
captured and may have caused biased effect estimates. In-
deed, because we investigated rare outcomes, even a few er-
roneously coded outcomes could shift the direction of asso-
ciations. Nevertheless, the outcomes ascertained have been
previously validated with a high-positive predictive value (eg,
97%-100% for ischemic stroke).36
The presented sensitivity analysis on the cohort with low
mortality rates suggests selective prescribing and warrants cau-
tion on the conclusions drawn on mortality rates. Indeed, end
points were not adjudicated (unlike among a clinical trial co-
hort) and postmortems were not mandated, which leaves the
possibility that some deaths could be because of fatal strokes
uncertain. Information on the time in therapeutic range among
people treated with warfarin was not available, nor did we have
detailed information on laboratory (eg, serum creatinine), an-
thropometric, or socioeconomic data. Thus, our confounder
adjustment was partially determined by the information avail-
able in the registries. Patient adherence to the NOACs and pre-
scribing practices was not considered, but may be a potential
driver of the differences between drugs, and differences in a
patients medical experience may influence his or her adher-
ence to treatment. Our data apply to a predominantly white
European population, and differential efficacy and safety ben-
efits may be evident among Asian and non-Asian people.37,38
Indeed, these limitations could nullify the possible benefits of
NOACs, notwithstanding that our data show that at the very
minimum, the NOACs have a similar effectiveness to warfa-
rin with trends toward a better safety profile.
jamacardiology.com
 Effectiveness and Safety of Standard-Dose Nonvitamin K Antagonist Oral Anticoagulants and Warfarin
Conclusions
In this Danish observational cohort study of patients with AF
and a single stroke risk factor, there was no difference be-
tween NOACs compared with warfarin in the risk of patients
ARTICLE INFORMATION
Accepted for Publication: April 28, 2017.
Published Online: June 14, 2017.
doi:10.1001/jamacardio.2017.1883
Author Contributions: Drs Lip and Skjth had full
access to all of the data in this study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Lip, Skjth, Nielsen, Larsen.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Lip, Skjth, Nielsen.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Skjth, Nielsen.
Obtained funding: Lip, Larsen.
Administrative, technical, or material support: Lip,
Nielsen, Kjaeldgaard, Larsen.
Supervision: Lip, Larsen.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr Lip
has received consulting fees from Bayer/Janssen,
BMS/Pfizer, Biotronik, Medtronic, Boehringer
Ingelheim, Microlife and Daiichi-Sankyo. Speaker for
Bayer, BMS/Pfizer, Medtronic, Boehringer
Ingelheim, Microlife, Roche, and Daiichi-Sankyo. Dr
Larsen has served as an investigator for Janssen
Scientific Affairs, LLC, and Boehringer Ingelheim
and received speaking fees from Bayer, BMS/Pfizer,
Boehringer Ingelheim, MSD, and AstraZeneca. Mr
Nielsen has received speaking fees from Boehringer
Ingelheim, consulting fees from Bayer; and grant
support from BMS/Pfizer. Dr Skjth has received
consulting feed from Bayer. No other disclosures
are reported.
Funding/Support: The Obel Family Foundation
partially funded this research through an
unrestricted grant. The Danish Health Data
Authority provided the data material.
Role of the Funder/Sponsor: The Obel Family
Foundation had no role in the design and conduct
of the study; collection, management, analysis, and
interpretation of the data; and preparation, review,
or approval of the manuscript.
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E10 JAMA Cardiology Published online June 14, 2017 (Reprinted) jamacardiology.com

2017 American Medical Association. All rights reserved.

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