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REVIEW ARTICLE
Safety and efficacy of nonvitamin K antagonist oral
anticoagulants versus warfarin in diabetic patients with atrial
fibrillation: A study‐level meta‐analysis of phase III randomized
trials
Giuseppe Patti |Giuseppe Di Gioia |Ilaria Cavallari |Antonio Nenna
Department of Cardiovascular Sciences,
Campus Bio‐Medico University of Rome,
Rome, Italy
Correspondence
Giuseppe Patti, Department of Cardiovascular
Sciences, Campus Bio‐Medico University of
Rome, Via Alvaro del Portillo, 200, 00128
Rome, Italy.
Email: g.patti@unicampus.it
Summary
In patients with atrial fibrillation (AF), the safety and efficacy of nonvitamin K antagonist oral
anticoagulants (NOACs) vs warfarin according to diabetes mellitus (DM) status are not completely
characterized. We performed a meta‐analysis to clarify whether in these patients the strategy of
oral anticoagulation should be tailored to diabetes status. In this study‐level meta‐analysis, we
included 4 randomized phase III trials comparing NOACs and warfarin in patients with
nonvalvular AF; a total of 18 134 patients with DM and 40 454 without DM were overall consid-
ered. Incidence of the following outcome measures was evaluated during the follow‐up: stroke or
systemic embolism, ischemic stroke, major bleeding, intracranial bleeding, and vascular death. Use
of NOACs compared with warfarin reduced stroke/systemic embolism in diabetic (Risk Ratios
[RR] 0.80, 95% CI 0.68‐0.93; P= .004) and nondiabetic patients (RR 0.83, 0.73‐0.93; P= .001)
(Pfor interaction .72). No interaction between diabetes status and benefits of NOACs was found
for the occurrence of ischemic stroke, major bleeding, or intracranial bleeding (Pfor interaction
>.05 for each comparison). Reduction of vascular death rates with NOACs was significant in dia-
betic patients (4.97% vs 5.99% with warfarin; RR 0.83, 0.72‐0.96; P= .01), in whom absolute the
reduction of this outcome measure was higher than in nondiabetics (1.02% vs 0.27%), although
no interaction was present (P= .23). Results of this meta‐analysis support the safety and efficacy
of NOACs compared with warfarin in diabetic patients with nonvalvular AF.
KEYWORDS
adult diabetes, anticoagulation, atrial fibrillation, bleeding, stroke
1|INTRODUCTION
Atrial fibrillation (AF) is the most common arrhythmia and the preva-
lent risk factor for cardioembolic stroke,
1
and patients with diabetes
mellitus (DM) more frequently develop AF than those without DM.
2,3
The presence of DM increases the incidence of long‐term nonfatal
cardiovascular events, bleeding complications, and cardiovascular
death,
4
and a 70% relative increase of AF‐related thromboembolic
events has been demonstrated in diabetic vs nondiabetic patients
5
;
thus, DM has been included in the contemporary scores for the predic-
tion of the thromboembolic risk, such as CHADS
2
and CHA
2
DS
2
‐
VASc.
6,7
Accordingly, even in the absence of other risk factors for
thromboembolic events, current guidelines recommend to initiate oral
anticoagulation in patients with AF and concomitant DM.
8
Nonvitamin K antagonist oral anticoagulants (NOACs) represent
an important innovation in the antithrombotic strategies aimed to
prevent thromboembolic complications (ie, stroke and systemic
embolism) in patients with nonvalvular AF; these newer agents are
characterized by rapid onset and offset of action, predictable dose‐
response, fixed doses, no need for monitoring, low interactions with
other drugs, and no interaction with foods. In randomized phase III
trials, the use of NOACs has been overall associated with a 19%
relative reduction of the combined end point including any stroke or
systemic embolism and 14% relative reduction of major bleeding vs
warfarin treatment.
9–13
Given the diabetes‐related propensity for both
thromboembolic and hemorrhagic events, the issue of whether NOACs
maintain their efficacy in preventing thromboembolic complications
and their better safety profile compared with warfarin also in the
Received: 31 July 2016 Revised: 1 November 2016 Accepted: 14 December 2016
DOI 10.1002/dmrr.2876
Diabetes Metab Res Rev. 2017;e2876.
https://doi.org/10.1002/dmrr.2876
Copyright © 2016 John Wiley & Sons, Ltd.wileyonlinelibrary.com/journal/dmrr 1of8
high‐risk setting of diabetic patients is clinically relevant. In phase III
trials, no interaction between diabetes status and pharmacological
approach (NOACs vs warfarin) was present regarding the main out-
come measures; however, those individual studies may be underpow-
ered to specifically evaluate clinical results of NOACs in subgroups of
patients, especially for end points at low incidence, and pooled analy-
ses of data from multiple investigations may help to clarify this issue.
Therefore, we performed a meta‐analysis on randomized trials compar-
ing NOACs and warfarin in patients with nonvalvular AF to add more
robust evidence on the differential degree of effectiveness and safety
of these newer agents in patients with DM compared with those
without DM, especially for rarer adverse events (ie, intracranial bleed-
ing, ischemic stroke, or vascular death); as a consequence, we also
established the absolute risk reduction of the outcome measures with
NOACs vs warfarin according to diabetes status.
2|MATERIALS AND METHODS
2.1 |Study selection
For the purpose of this meta‐analysis, we have included controlled
randomized trials comparing NOACs vs warfarin in patients with
nonvalvular AF.
9–12
MEDLINE and PubMed databases up to June 30,
2016, and reviewed cited references to identify randomized studies
were used. Search key words were “atrial fibrillation,”“diabetes,”and
“randomized trial”combined with the words “stroke,”“systemic embo-
lism,”“bleeding,”“warfarin,”and “nonvitamin K antagonist”or “NOAC”
or “novel oral anticoagulants”. Published abstracts from meetings of
the American College of Cardiology, American Heart Association, and
European Society of Cardiology within 5 years were also hand
reviewed. Editorials and reviews from major medical journals published
within the last 2 years were also considered for further information on
trials of interest. Expert slide presentations and internet‐based sources
of information on the results of clinical trials in cardiology (http://
www.cardiosource.com and http://www.theheart.org) were also
searched. Studies were excluded when raw data were not available.
Only studies published in English language were considered.
2.2 |Data extraction and quality assessment
This meta‐analysis follows the guidelines of the Cochrane Handbook
for Systematic Reviews of Interventions 4.2.5.
14
Analysis was per-
formed at the study level. Authors G.P. and G.D.G. independently
extracted the data, and disagreements were resolved by consensus.
When information about an outcome of interest was not available,
the study was not utilized for such end point. Studies were evaluated
for the adequacy of allocation concealment, blinding of care providers
and patients, adequate description of withdrawals and dropouts, and
performance of the analysis according to the intention‐to‐treat
principle. The quality of the included studies was quantified by the
Jadad score,
15
and all the trials provided a Jadad quality score of 5,
but Randomized Evaluation of Long‐Term Anticoagulation Therapy
(RE‐LY) (it gave a score 4, because treatment in the warfarin arm was
unblinded).
2.3 |Data synthesis and analysis
Review Manager 5.2 software (available from The Cochrane Collabora-
tion at http//www.cochrane.org) was used for all analyses. The
DerSimonian‐Laird method for random effects was used to estimate
pooled Risk Ratios (RR).
16
We evaluated heterogeneity of the included
trials with Q statistics and the extent of inconsistency between results
with I
2
statistics.
17
The possibility of publication bias was tested by fun-
nel plot analysis.
18
Data are presented as RR with 95% confidence inter-
vals (CI), with 2‐tailed Pvalues and statistical significance set at P<.05.
3|RESULTS
Overall, 137 screened citations met the search criteria. From
MEDLINE and PubMed databases, 121 citations were retrieved, while
16 were identified from other sources. After excluding 12 duplicate
citations, 125 citations were evaluated. Most of these citations
(n = 111) were excluded at the level of title or abstract, mostly because
of study design or reviews, letter, or comments; 14 studies were
evaluated in a closer inspection, and 10 were then discarded. Thus, a
total of 4 randomized studies, corresponding to the phase III trials for
the currently available NOACs, were included in the analysis.
9–12
The
progress through the different steps of the search results is illustrated
in Figure 1.
From the 4 trials,
9–12
a total of 18 134 patients with DM (9123 on
NOACs and 9011 on warfarin) and 40 454 without DM (20 216 on
NOACs and 20 238 on warfarin) were included. Table 1 summarizes
the main characteristics of the 4 NOACs and related trials included in
the analysis. Rivaroxaban in ROCKET‐AF was used at the dose of
20 mg QD, reduced to 15 mg QD in patients with creatinine clearance
30‐49 ml/min; apixaban in ARISTOTLE was utilized at the dose of 5 mg
BID, reduced to 2.5 mg BID in presence of at least 2 of the following
conditions: age ≥80 years, body weight ≤60 kg, serum creati-
nine ≥1.5 mg/dl. For the purpose of this meta‐analysis, we used data
on the 150 mg BID dose of dabigatran from RE‐LY and on the 60 mg
QD dose of edoxaban from ENGAGE AF; the latter reduced to
30 mg QD in presence of at least 1 of the following situations:
creatinine clearance 30‐50 ml/min, body weight ≤60 kg, concomitant
therapy with verapamil, quinidine, or dronedarone.
The following end points were separately evaluated and compared
in the 2 groups (NOAC vs warfarin) according to presence or absence
of diabetes: incidence of any stroke or systemic embolism, ischemic
stroke, major bleeding by International Society on Thrombosis and
Haemostasis definition, intracranial bleeding, vascular death, and any
cause of death. There was substantial uniformity in the definition of
the abovementioned end points across the 4 trials. Efficacy analyses
were generally based on the intention‐to‐treat population of the
studies, whereas safety analyses on the on‐treatment population.
3.1 |Efficacy outcome measures
Incidence of stroke/systemic embolism was 3.55% in diabetic patients
vs 3.40% in those without DM (Figure 2). Use of NOACs vs warfarin
significantly reduced this composite efficacy end point both in diabetic
(3.15% vs 3.95%; RR 0.80, 95% CI 0.68‐0.93; P= .004) and in
2of8 PATTI ET AL .
nondiabetic patients (3.08% vs 3.73%; RR 0.83, 0.73‐0.93; P= .001),
without heterogeneity among the studies and without interaction
between diabetes status and NOACs effect (P= .72) (Figure 3). Abso-
lute risk reduction of stroke/systemic embolism was also similar in
patients with or without DM (0.80% vs 0.65%).
Data regarding the occurrence of ischemic stroke according to dia-
betes status are available from RE‐LY and ROCKET‐AF trials.
9,10
Risk
Ratios for ischemic stroke with NOACs vs warfarin were 0.88 (95%
CI 0.68‐1.13) in diabetic and 0.90 (95% CI 0.67‐1.20) in nondiabetic
patients (Pfor interaction .97) (Figure 4).
3.2 |Safety outcome measures
Rates of major bleeding were 6.35% in patients with DM vs 5.40%
in those without DM (P< .0001) (Figure 2). There was no signifi-
cant interaction between prevention of major bleeding by NOACs
and presence/absence of diabetes (DM: RR 0.94, 95% CI
0.81‐1.11; no DM: RR 0.83, 0.67‐1.03) (Pfor interaction .34)
(Figure 5); absolute risk reduction of major bleeding with NOACs
was 0.43% in diabetic patients and 1.08% in the subgroup without
DM.
FIGURE 1 Flow diagram demonstrating the study selection process in the meta‐analysis
TABLE 1 Main characteristics of the 4 NOACs and related trials
RE‐LY ROCKET‐AF ARISTOTLE ENGAGE AF
NOAC used Dabigatran Rivaroxaban Apixaban Edoxaban
Effect anti‐IIa anti‐Xa anti‐Xa anti‐Xa
Renal elimination 80% 33% 25% 50%
Dose 150/110 mg BID 20 mg QD 5 mg BID 60/30 mg QD
Target INR (warfarin arm) 2‐32‐32‐32‐3
Type of study PROBE 2 × blind 2 × blind 2 × blind
No. of patients 18 113 14 264 18 201 21 105
Mean CHADS
2
score 2.1 3.5 2.1 2.8
TTR (%) 64 58 62 68
Diabetic patients 23% 40% 25% 36%
Median follow‐up duration 2 y 1.9 y 1.8 y 2.8 y
Abbreviations: AF, atrial fibrillation; NOAC, nonvitamin K antagonist oral anticoagulant; PROBE, prospective, randomized, open‐label, blinded end‐point
evaluation; TTR, time in therapeutic range.
PATTI ET AL.3of8
Results on intracranial bleeding are available from RE‐LY,
ROCKET‐AF, and ARISTOTLE studies.
9–11
Incidence of intracranial
bleeding was significantly decreased by NOACs both in diabetic
(0.73% vs 1.29%; RR 0.57, 95% CI 0.40‐0.81; P= .002) and in nondia-
betic patients (0.62% vs 1.35%; RR 0.47, 0.32‐0.68; P< .0001) (Pfor
interaction 0.47) (Figure 6).
3.3 |Death
Data on vascular death according to diabetes status have been
presented or published from RE‐LY, ROCKET‐AF, and ARISTOTLE
trials.
9–11
Occurrence of this outcome measure during follow‐up was
higher in diabetic patients compared with those without DM (5.48%
vs 4.14%; P< .0001) (Figure 2). Decrease of vascular death by NOACs
was significant in diabetic patients (4.97% vs 5.99% in the warfarin
group; RR 0.83, 0.72‐0.96; P= .01); among patients without DM, rates
of vascular death were 4.00% in those receiving NOAC and 4.27% in
patients on warfarin (RR 0.94, 0.81‐1.08; P= .38) (Figure 7). Interaction
between NOACs effect and diabetes status was not significant
(P= .23), but, given the more elevated baseline risk of diabetic patients,
in the latter the absolute reduction of vascular death with NOACs was
higher (1.02% vs 0.27% in nondiabetic patients).
Data on the incidence of any cause of death are available from
RE‐LY and ARISTOTLE.
9,11
Overall mortality was higher in the diabetic
population (8.85% vs 6.74; P< .0001) (Figure 2). Risk Ratios for any
cause of death with NOACs vs warfarin were 0.88 (95% CI 0.76‐
1.02) in diabetic and 0.90 (95% CI 0.82‐0.99) in nondiabetic patients
(Pfor interaction 0.61) (Figure 7); the absolute reduction of this
FIGURE 2 Pooled rates of the study end
points regardless of the assigned treatment
(warfarin or NOAC) in patients with and
without diabetes mellitus. NOAC indicates
nonvitamin K antagonist oral anticoagulant;
SEE = Systemic embolic event
FIGURE 3 Risk ratios (with 95% confidence interval) of stroke/systemic embolism according to the diabetes status in patients receiving NOACs or
warfarin. AF indicates atrial fibrillation; NOAC, nonvitamin K antagonist oral anticoagulant
4of8 PATTI ET AL .
outcome measure in favor of NOACs was slightly more elevated in
diabetic patients (1.14% vs 0.70% in nondiabetics).
4|DISCUSSION
This study‐level meta‐analysis robustly indicates that in patients with
nonvalvular AF, the prevention of thromboembolic and major bleeding
complications by NOACs compared with warfarin is irrespective of
diabetes status; importantly, in patients with DM, the use of NOACs
instead of warfarin was associated with higher absolute reduction of
vascular death, although no significant heterogeneity by diabetes
status was present for this outcome measure.
The presence of DM carries a higher risk of cardiovascular events
and cardiovascular mortality, as well as of AF‐related thromboembolic
events, especially in patients not receiving long‐term anti-
coagulation
4,5,19
; this is mediated by a prothrombotic milieu because
of enhanced platelet reactivity, impaired response to antiplatelet
agents, changes in vascular function, more pronounced coagulation
mechanisms (ie, higher levels and activity of coagulation factors), and
FIGURE 4 Risk ratios (with 95% confidence interval) of ischemic stroke according to the diabetes status in patients receiving NOACs or warfarin.
AF indicates atrial fibrillation; NOAC, nonvitamin K antagonist oral anticoagulant
FIGURE 5 Risk ratios (with 95% confidence interval) of major bleeding according to the diabetes status in patients receiving NOACs or warfarin.
AF indicates atrial fibrillation; NOAC, nonvitamin K antagonist oral anticoagulant
PATTI ET AL.5of8
impaired fibrinolysis.
20–23
Of note, this prothrombotic status is partic-
ularly enhanced in patients with long‐lasting disease or in those receiv-
ing insulin therapy.
23,24
This meta‐analysis indicates that the utilization
of anticoagulant therapy (NOACs or warfarin) in diabetic patients
lowers the incidence of thromboembolic complications to values simi-
lar to nondiabetic patients; accordingly, a routine long‐term use of oral
FIGURE 6 Risk ratios (with 95% confidence interval) of intracranial bleeding according to the diabetes status in patients receiving NOACs or
warfarin. AF indicates atrial fibrillation; NOAC, nonvitamin K antagonist oral anticoagulant
FIGURE 7 Risk ratios (with 95% confidence interval) of vascular death and any cause death according to the diabetes status in patients receiving
NOACs or warfarin. AF indicates atrial fibrillation; NOAC, nonvitamin K antagonist oral anticoagulant
6of8 PATTI ET AL .
anticoagulation in patients with AF and concomitant DM appears
clinically relevant. Moreover, various observational data and post hoc
analyses have identified DM as a risk factor also for bleeding events
in patients with AF receiving oral anticoagulation,
25,26
although in the
current risk scores DM is not considered an independent predictor of
bleeding complications.
27,28
The high prevalence of concomitant
diseases predisposing to hemorrhagic complications as well as a poorer
time in therapeutic range (TTR) during warfarin therapy
29
might
explain the link between DM and increased propensity for bleeding.
In our study, the presence of DM was overall associated with a signif-
icant 1% absolute increase of major bleeding, whereas incidence of
intracranial hemorrhage in patients with and without diabetes was
not different; this may be explained by the hypercoagulable state and
diabetic microangiopathy making the cerebral vessels less prone to
rupture.
30
In randomized studies, the use of warfarin compared with no
antithrombotic treatment or antiplatelet therapy significantly
reduced the rates of thromboembolic complications in patients with
AF
31
; accordingly, European guidelines
8
recommend long‐term oral
anticoagulant therapy in all patients with CHA
2
DS
2
‐VASc score ≥1.
In single phase III trials, the benefit of NOACs in reducing thrombo-
embolic and bleeding events vs warfarin appeared to be maintained
both in patients with and without DM. However, individual studies
may be underpowered for subgroup analyses, especially when set-
tings of patients at low prevalence and events at low incidence are
considered; therefore, pooled analyses on large populations may
add robust evidence regarding the differential degree of effective-
ness and safety of NOACs compared with warfarin in diabetic vs non-
diabetic patients. In this study‐level meta‐analysis including >58 000
patients, we found that, compared with warfarin, the use of NOACs
led to similar relative and absolute reduction of stroke/systemic
embolism in patients with and without diabetes mellitus; comparable
results were also observed with regard to incidence of ischemic
stroke. Furthermore, we found no interaction between diabetes sta-
tus and decrease of major or intracranial bleeding by NOACs; of note,
the relative decrease of intracranial bleeding was striking both in dia-
betic (43%) and in nondiabetic (53%) patients. Interestingly, although
patients with diabetes had higher rates of major bleeding, the abso-
lute reduction with NOACs was smaller compared with nondiabetics;
we can speculate that this occurred because the presence of diabetes
“per se”predisposes to bleeding complications, and therefore,
diabetic patients have a higher incidence of hemorrhagic events
during anticoagulant therapy regardless of the type and level of
drug‐related interference with the coagulation cascade. Of note,
even in the context of a trial (ie, ENGAGE AF) with better TTR in
the warfarin arm, the use of edoxaban was associated with significant
decrease in major bleeding; and this was irrespective of diabetes
status.
12
Conversely, in ROCKET‐AF, where the population on
warfarin had overall a lower TTR, the rates of major bleeding were
essentially similar in patients receiving warfarin and rivaroxaban;
and this occurred regardless of presence or absence of diabetes.
10
Moreover, the relative decrease of major hemorrhagic events with
apixaban in ARISTOTLE
11
was numerically lower in the diabetic
subgroup. Finally, no reduction of major bleeding with dabigatran vs
warfarin was observed in diabetic patients of RE‐LY
9
; dabigatran is
preferentially eliminated by the kidney, and those results may be
explained by a higher proportion of patients with chronic renal failure
in the diabetic population.
Finally, the presence of diabetes in our study was associated with
a 32% higher relative risk and a 1.3% absolute elevation of death due
to vascular causes during the follow‐up. In diabetic patients receiving
NOACs, there was a significant 17% relative reduction of vascular
death vs warfarin use; given the high baseline risk profile of the
diabetic subpopulation, such reduction here translated into higher
absolute decrease of vascular death (1.02% vs 0.27% in patients
without diabetes). Importantly, the number needed to treat for this
outcome measure with NOACs was 98 in diabetic patients and 370
in nondiabetics.
This meta‐analysis has strengths and limitations. Our findings
derive from a large number of patients and are statistically robust,
without heterogeneity among the studies; moreover, the trials
included in our analysis used uniform definitions of the outcome
measures and had similar follow‐up durations. This is a study‐level
meta‐analysis, and we had no access to individual patients’data;
therefore, we were not able to identify subgroups of patients achieving
the higher benefit with NOACs and to evaluate possible interaction
between NOACs effects and duration of diabetes, glycemic control,
and condition of insulin dependence.
In conclusion, we believe that results of this meta‐analysis may be
useful in clinical practice as they support the safety and efficacy of
NOACs compared with warfarin in diabetic patients with nonvalvular AF.
ACKNOWLEDGEMENT
G.P. conceived and designed the study; G.P. and G.D.G. contributed to
data collection; G.P., A.N., and I.C. performed analysis and interpreta-
tion of the results; G.P. drafted the paper; critical revision of the paper
for important intellectual content was done by all authors.
G.P. takes full responsibility for the work as a whole, including the
study design, access to data, and the decision to submit and publish the
manuscript.
CONFLICT OF INTEREST
G.P. is a speaker/consultant/advisory board for Bayer, Boehringer‐
Ingelheim, BMS‐Pfizer, Daiichi Sankyo, Eli Lilly, Astra Zeneca, and
MSD. G.D.G, I.C., and A.N. have no disclosure.
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A. Safety and efficacy of nonvitamin K antagonist oral antico-
agulants versus warfarin in diabetic patients with atrial fibrilla-
tion: A study‐level meta‐analysis of phase III randomized trials,
Diabetes Metab Res Rev. 2017;e2876. https://doi.org/10.1002/
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