Comparative Efficacy and Safety of Novel Oral Anticoagulants In

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Journal of Cardiology 66 (2015) 466–474

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Original article

Comparative efﬁcacy and safety of novel oral anticoagulants in

patients with atrial ﬁbrillation: A network meta-analysis with the

adjustment for the possible bias from open label studies

a b b

Takeshi Morimoto (MD, PhD, MPH) , Bruce Crawford (MS) , Keiko Wada (MS) ,

Shinichiro Ueda (MD, PhD) *

Division of General Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan

Adelphi Values, Tokyo, Japan

Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus School of Medicine, Okinawa, Japan

A R T I C L E I N F O A B S T R A C T

Article history: Background: This study was designed to compare efﬁcacy and safety among novel oral anticoagulants

Received 22 January 2015

(NOACs), which have not been directly compared in randomized control trials to date.

Received in revised form 7 May 2015

Method: We performed network meta-analyses of randomized control trials in preventing thrombo-

Accepted 13 May 2015

embolic events and major bleeding in patients with atrial ﬁbrillation. PubMed, Embase, and the

Available online 7 July 2015

Cochrane Database of Systematic Reviews for published studies and various registries of clinical trials for

unpublished studies were searched for 2002–2013. All phase III randomized controlled trials (RCTs) of

Keywords:

NOACs (apixaban, edoxaban, dabigatran, rivaroxaban), idraparinux, and ximelagatran were reviewed.

Network meta-analysis

Results: A systematic literature search identiﬁed nine phase III RCTs for primary analyses. The efﬁcacy of

Novel oral anticoagulants

each NOAC was similar with respect to our primary composite endpoint following adjustment for open

Atrial ﬁbrillation

label designs [odds ratios (ORs) versus vitamin K antagonists: apixaban 0.79; dabigatran 150 mg 0.77;

edoxaban 60 mg 0.87; rivaroxaban 0.86] except for dabigatran 110 mg and edoxaban 30 mg. Apixaban

and edoxaban 30 mg and 60 mg had signiﬁcantly fewer major bleeding events than dabigatran 150 mg,

ricvaroxaban, and vitamin K antagonists. All NOACs were similar in reducing secondary endpoints with

the exception of dabigatran 110 mg and 150 mg which were associated with a signiﬁcantly greater

incidence of myocardial infarction compared to apixaban, edoxaban 60 mg, and rivaroxaban.

Conclusions: Our indirect comparison with adjustment for study design suggests that the efﬁcacy of the

examined NOACs is similar across drugs, but that some differences in safety and risk of myocardial

infarction exist, and that open label study designs appear to overestimate safety and treatment efﬁcacy.

Differences in study design should be taken into account in the interpretation of results from RCTs of

NOACs.

Introduction in the efﬁcacy and safety among individual drugs have not yet been

formally tested. Moreover, study design has varied widely among

The introduction of novel oral anticoagulants (NOACs) has clinical trials of NOACs, potentially inﬂuencing individual study

ushered in a new era in treatment strategies for the prevention of results as well as confounding cross-study analyses.

stroke and systemic embolism in patients with atrial ﬁbrillation. An example of the former includes the Stroke Prevention Using

However, as all approved NOACs were compared with vitamin K Oral Thrombin Inhibitor in Atrial Fibrillation Trial (SPORTIF) III [1]

antagonists in their respective phase III trials, possible differences and SPORTIF V [2] studies, which reported divergent results in

open design and double-blind comparisons of ximelagatran and

warfarin. This potential study design effect is further supported by

a pair of systematic reviews. Schulz et al. assessed the methodo-

* Corresponding author at: Department of Clinical Pharmacology & Therapeutics,

logical quality of 33 meta-analyses, containing 250 controlled

University of the Ryukyus School of Medicine, 207 Uehara, Nishihara-cho, Okinawa

trials, to evaluate study differences impacting treatment efﬁcacy

903-0215, Japan. Tel.: +81 98 895 1195; fax: +81 98 895 1447.

E-mail address: [email protected] (S. Ueda). and found that trials that were not adequately blinded signiﬁcantly

http://dx.doi.org/10.1016/j.jjcc.2015.05.018

T. Morimoto et al. / Journal of Cardiology 66 (2015) 466–474 467

overestimated treatment effects [3]. Ju¨ ni et al. conducted a meta- ximelagatran. We included all English language studies published

analysis to evaluate the extent of potential bias related to open between January 1, 2002 and December 31, 2013. The population

versus blinded studies and found similar results [4]. of interest was patients with atrial ﬁbrillation. Retrieved studies

In addition to concerns of study design, patient factors may also were limited to phase III RCTs. Complete search strategy details are

complicate comparisons of NOAC ﬁndings. White et al. reported provided in Appendix 1 as Table A1.

that clinical outcomes, including risk of death, stroke and systemic

embolism, myocardial infraction, and major bleeding, were Data extraction and synthesis

correlated to international normalized ratio (INR) control in

patients with atrial ﬁbrillation taking a vitamin K antagonist Two investigators (TM, SU) independently assessed articles

(warfarin) [5]. Such a patient condition-mediated outcome identiﬁed by the literature search for inclusion, and articles

variability in response to vitamin K antagonist therapy could pose fulﬁlling inclusion criteria were compiled for data extraction and

a potential stumbling block for inter-study analyses. synthesis.

In order to adjust for potential study design biases and outcome A network meta-analysis was conducted by a statistician (BC)

variability due to patient condition and to effectively compare the taking into account study bias and correcting for indirect

safety and efﬁcacy of NOACs and vitamin K antagonists using the comparisons. This approach was based on an empirical estimate

available data, we conducted an indirect comparison by network of bias from meta-epidemiological studies comparing results of

meta-analysis of the available literature. The novelty of our open studies with those of double-blind studies addressing the

analysis is indirect comparison of NOACs based on results adjusted same research question (treatment and disease). The mean

for un-blindness, which might have been relevant in the empirical bias (and its distribution) was obtained by calculating

assessment of efﬁcacy and safety of NOACs compared to warfarin. the ratio of the odds ratios (ORs), that is, dividing the OR from the

open studies by the OR of the double-blind studies. A ratio of less

Methods than 1 indicates an overestimation of effect by the open studies.

This method incorporates not only the magnitude but also the

Study design uncertainly of the bias (its distribution). We used the method

described by Ju¨ ni et al. [4] to estimate the pooled ORs for taking

We conducted a network meta-analysis to compare NOACs in study design into account. Statistical techniques for network

preventing thromboembolic events in patients with atrial ﬁbrilla- analyses have been described elsewhere [6]. In brief, to obtain the

tion. In our present study, we deﬁned apixaban, betrixaban, OR for two treatments A versus B (ORAB), we divided the OR for A

dabigatran, edoxaban, and rivaroxaban as NOACs; ximelagatran as versus C by the OR for B versus C. Conﬁdence intervals were

p 2 2

an oral anticoagulant; and warfarin, idraparinux, and aspirin as calculated as EXPðlnðORABÞ 1:96 ½SEAC þ SEBCÞ where the SE is

comparators. Our literature search included all phase III random- from the log-odds. Network analyses require the same assump-

ized controlled trials (RCTs) of NOACs for the primary analysis. In tions as traditional meta-analyses in that studies are assumed to be

instances where two doses were examined in one trial, we independent and should be performed under similar conditions.

considered both doses as independent interventions. Adjustments for open and blinded studies were made to account

Neither the approval of an institutional review board nor for this difference; however, other study differences that could

informed consent was required due to the nature of our study impact outcomes were evaluated and are discussed in the

design. limitations. Microsoft Excel 2010 for Windows was used for

statistical analyses and graphical presentation.

Patients and endpoints We ﬁrst estimated the pooled ORs of the NOACs compared to

vitamin K antagonists with and without an adjustment of study

We included patients with either chronic or paroxysmal atrial design on the primary and safety endpoints. If a study design

ﬁbrillation, irrespective of cause. No criteria were enforced for effect was observed, we thereafter used the bias adjustment

gender or age. method to estimate the pooled ORs for primary and secondary

The primary endpoint was a composite of stroke and systemic endpoints. We compared the pooled ORs of each NOAC to those

embolism. Stroke was deﬁned to include ischemic, hemorrhagic, of every other NOAC as well as those of aspirin and vitamin K

and uncertain stroke, but not transient ischemic attack; systemic antagonists. The choice of a ﬁxed or random effect model was

embolism included any embolism other than cerebrovascular or of based on the goodness of ﬁt of the model to the data. The

a cardiac origin. Secondary endpoints included stroke and Cochrane x (i.e. Q-statistic) was used for model ﬁt in assessing

myocardial infarction. We included major bleeding as a safety whether a ﬁxed or random effects model was used for each

endpoint. Other endpoints of interest included: all-cause death, endpoint.

ischemic stroke (including stroke of unknown origin), hemorrhagic As a sensitivity analysis, we added phase II studies to the main

stroke, and intracranial hemorrhage. analyses (phase III studies) and recalculated treatment effects to

assess the robustness of the main analyses.

Literature search

Results

One investigator (KW) conducted the literature search through

PubMed, Embase, and the Cochrane Database of Systematic Reviews Literature search

for published studies meeting inclusion criteria. We also reviewed

registries of clinical trials (TrialResults-center, clinicalstudyresult- Our literature search identiﬁed 139 articles, of which nine were

s.org, clinicaltrials.gov, the World Health Organization International selected for the primary analyses (Fig. 1). One of these nine articles

Clinical Trials Registry Platform), ISI Web of Knowledge, the US Food was an unpublished RTC of idraparinux [7], which was identiﬁed

and Drug Administration, and the European Medicines Agency sites while conducting a manual search for clinical trials in TrialResults-

for unpublished studies. References from retrieved articles found center. Three articles were excluded from the primary analyses

were also examined. because they were phase II RCTs; however, they were later

Our search included terms for the following interventions: included for sensitivity analyses. The agreement for inclusion and

apixaban, betrixaban, dabigatran, edoxaban, rivaroxaban, and exclusion between investigators was 100%.

468 T. Morimoto et al. / Journal of Cardiology 66 (2015) 466–474

Records identified through database Additional records identified through

searching other sources (n = 13 6) (n = 3)

Identification

Records aft er duplicates removed

(n = 10 3)

Records screen ed Records excluded

(n = 10 3) (n = 75) Screening

Full-text articles excluded,

Full-text articles assesse d for eligibility

with reason s

(n = 28 )

(n = 16 )

Eligibility Studies included in qualitative synthesis

(n = 12 )

Studies included in quantitative synthesis (secondary meta-analysis) Pha se I&II studies

(n = 12) exclude d

(n = 3)

Studies included in quantitative synthesis (primary meta-analysis) Included

(n = 9)

Fig. 1. Flowchart of literature review.

The number of trials examining each drug were: two for pooled ORs for the composite endpoint increased from 0.67 (95% CI

apixaban [8,9], zero for betrixaban, one for dabigatran [10], one for 0.37–1.21) to 0.78 (95% CI 0.42–1.44) for idraparinux, from 0.99

edoxaban [11], one for idraparinux [7], two for rivaroxaban [12,13], (95% CI 0.59–1.65) to 1.07 (95% CI 0.79–1.46) for ximelagatran,

and two for ximelagatran [1,2] (Table 1). When multiple doses from 0.91 (95% CI 0.74–1.12) to 1.06 (95% CI 0.83–1.36) for

were examined in a trial (i.e. dabigatran 110 mg and 150 mg twice dabigatran 110 mg, and from 0.66 (95% CI 0.37–1.21) to 0.77 (95%

daily in RE-LY; and edoxaban 30 mg and 60 mg once daily in CI 0.59–1.00) for dabigatran 150 mg (Fig. 2B). Pooled ORs from all

ENGAGE [11]), they were treated as independent interventions. double-blind studies were the same.

The comparator included aspirin and two types of vitamin K This trend was also observed in the ORs for major bleeding:

antagonists (warfarin and acenocoumarol). Three studies were of Pooled ORs for major bleeding increased from 2.62 (95% CI 1.70–

open label design [1,7,10], and thus the pooled ORs for dabigatran 4.03) to 3.04 (95% CI 1.93–4.80) for idraparinux, from 0.73 (95% CI

110 mg, dabigatran 150 mg, ximelagatran, and idraparinux were 0.55–0.96) to 0.76 (95% CI 0.58–1.01) for ximelagatran, from 0.80

subject to adjustment. The three phase II studies (all open label) (95% CI 0.69–0.93) to 0.93 (95% CI 0.76–1.15) for dabigatran

included for sensitivity analyses examined apixaban [14] and 110 mg, and from 0.93 (95% CI 0.81–1.08) to 1.08 (95% CI 0.88–

dabigatran [15,16]. 1.33) for dabigatran 150 mg following adjustment (Fig. 2D).

Deﬁnitions of each component of the primary composite Therefore, we used adjusted pooled ORs for all additional analyses.

endpoint varied across studies but were generally similar

(Appendix 2 Table A2). The deﬁnition of major bleeding was also Comparisons of NOACs

similar with the exception of the study examining apixaban, which

limited the drop in hemoglobin greater than 2 g/dL within 24 h Aspirin was consistently inferior to all NOACs with respect to

[17]. the primary composite endpoint [ORs 1.70 (95% CI 1.08–2.69) to

2.35 (95% CI 1.48–3.75)]. All NOACs were found to perform

Effect of study design similarly (Fig. 3A–F), except for dabigatran 110 mg and edoxaban

30 mg. Particularly, edoxaban 30 mg was signiﬁcantly inferior to

Pooled ORs for the composite endpoint compared to vitamin K apixaban (OR 1.45, 95% CI 0.55–0.88), rivaroxaban (OR 1.34, 95% CI

antagonists ranged from 0.66 (95% CI 0.53–0.82) to 1.81 (95% CI 0.08–1.44), and dabigatran 150 mg (OR 1.49, 95% CI 1.10–2.02). In

1.23–2.65) (Fig. 2A). Pooled ORs for major bleeding compared to terms of major bleeding, idraparinux was consistently inferior to

vitamin K ranged from 0.62 (95% CI 0.39–0.98) to 2.62 (95% CI all NOACs [ORs 2.81 (95% CI 1.7–4.63) to 6.52 (95% CI 4.03–10.57)]

1.70–4.03) (Fig. 2C). When taking study design into account, the (Fig. 4A–F). Apixaban and edoxaban 30 mg were signiﬁcantly Table 1 Summary of included studies.

Study Study design – Follow-up Intervention Dose Patients, n CHADS2 No history Secondary Stroke Systemic Myocardial Major All-cause double blind period and dose regimen (mean) of vitamin K prevention (%) embolism infarction bleeding mortality antagonist (%) Event, n Event, n Event, n Event, n Event, n

AMADEUS [7] No 0.9 years (mean) Idraparinux 2.5 mg (SC) Once a week 2283 24.0 22.6 0 16 74 62 Vitamin K antagonist Once daily 2293 24.1 25.1 2 13 29 61 T.

ARISTOTLE [8] Yes 1.8 years (median) Apixaban 5 mg Twice daily 9120 2.1 42.9 19.2 199 15 90 327 603 Morimoto Vitamin K antagonist Once daily 9081 2.1 42.8 19.7 250 17 102 462 669 AVERROES [9] Yes 1.1 years (mean) Apixaban 5 mg Twice daily 2808 2.0 85.7 13.8 49 2 24 44 111 Aspirin (81–324 mg) Once daily 2791 2.1 84.7 13.4 105 13 28 39 140

ENGAGE [11] Yes 2.8 years (median) Edoxaban 60 mg Once daily 7035 2.8 41.2 28.1 281 15 133 418 773 et

Edoxaban 30 mg Once daily 7034 2.8 40.8 28.5 360 29 169 254 737 al.

Vitamin K antagonist Once daily 7036 2.8 41.2 28.3 317 23 141 524 839 Journal JROCKET [13] Yes 1.3 years (mean) Rivaroxaban 15 mg Once daily 640 3.27 9.7 63.8 10 1 1 7 Vitamin K antagonist Once daily 640 3.22 10.3 63.4 21 1 3 5

RELY [10] No 2.0 years (median) Dabigatran 150 mg Twice daily 6076 2.2 49.8 20.3 122 89 375 438 Cardiology Dabigatran 110 mg Twice daily 6015 2.1 49.9 19.9 171 86 322 446 Vitamin K antagonist Once daily 6022 2.1 51.4 19.8 185 63 397 487 ROCKET AF [12]* Yes 1.9 years (median) Rivaroxaban 20 mg Once daily 7131 3.48 37.7 54.9 184 5 101 395 208

Vitamin K antagonist Once daily 7133 3.46 37.5 54.6 221 22 126 386 250 66

SPORTIF III [1] No 1.4 years (mean) Ximelagatran 36 mg Twice daily 1704 25.6 24.5 4 24 29 78 (2015) Vitamin K antagonist Once daily 1703 27.5 23.8 2 13 41 79 SPORTIF V [2] Yes 1.7 years (mean) Ximelagatran 36 mg Twice daily 1960 17.5 18.8 6 26 63 116

Vitamin K antagonist Once daily 1962 15.3 17.7 1 37 84 123 466–474 Phase II studies for sensitivity analyses ARISTOTLE-J [14] No 12 weeks Apixaban 5 mg Twice daily 74 2.1 12.7 35.1 0 0 Vitamin K antagonist Once daily 74 1.9 16.0 27.0 3 1 PETRO [15] No 12 weeks Dabigatran 150 mg Twice daily 166 17.5 0 0 Vitamin K antagonist Once daily 70 18.6 0 0 Phase II No 12 weeks Dabigatran 150 mg Twice daily 58 Dabigatran [16] Vitamin K antagonist Once daily 62

CHADS2, risk score based on congestive heart failure, hypertension, age75 years, diabetes mellitus, and previous stroke or transient ischemic attack. SC, subcutaneously. 469 470 Fig.

3. edoxaban Odds

ratios

aiarn150 Dabigatran Rivaroxaban 110 Dabigatran X Ximelagatra Idraparinux 110 Dabigatran aiarn150 Dabigatran V Vitamin K antagonis 60 Edoxaban A Idraparinux dxbn30 Edoxaban Rivaroxaban A dxbn60 Edoxaban A mg, i pi i spirin spirin

m t a xaba D e m Composite endpoint

Major bleeding

A and a i of n g

n a K

composite Fig. t

a rivaroxaban,

n n n dxbn30 Edoxaban Aspirin aiarn150 Dabigatran 110 Dabigatran Api Api I Ximelagatra Ximelagatra dxbn60 Edoxaban aiarn110 Dabigatran aiarn150 Dabigatran Idraparinux Aspirin Rivaroxaban Rivaroxaban E E d t mg mg mg a

Reference: d d

r 2. g a o o mg mg mg mg xaba xaba o 0 p x x 012

a a a Differences Reference i b b r s i

t t n a a C A n n

0.67 0.94 0.87 0.69 0.76 0.75 0.68 0.93 n n u endpoint 0.98 0.97

6 3

n n 0 0 Edo

mg mg 1 m m respectively. Reference: Reference:

1.10 1.26 1.08

1.36 mg mg mg mg 1.34 g g : Apix 1.45 0 Odds ratios 1.58 xab Odds ratios

0.47 n30mg an aba odds 0.62

2 direct 0.69

0.73 0.78 0.93 0.80 2.28

Not adjust Not adjust n Vit Vit

0.91 0.66 0.99 0.67 0.86 0.87 0.79 1234 ratios 1.03

ami ami oral Odds ratios

3 3 123 n K an n K an n K Odds ratios

anticoagulants. of 1.14 ed ed T.

direct

Morimoto tago tago 4 4

1.81 dxbn60 Edoxaban Rivaroxaban Idraparinux 30 Edoxaban Api Aspirin aiarn150 Dabigatran V X Ximelagatra Rivaroxaban Api Vitamin K antagonis aiarn150 Dabigatran Aspirin Idraparinux dxbn30 Edoxaban aiarn110 Dabigatran

i i

2.62 m t oral nist nist a

xaba e m

xaba B l a i

n E g

anticoagulants n a K et

t n

A, r

al.

Reference: Dabiga Reference: B, t mg mg n a

g Reference: / mg

C, mg

o Journal 0 012 mg mg n

D, i s t

E, t 0.94 0.81 0.73 0.82 0.72 0.75 0.98 0.89 0.88 0.91

and

1 between Edo

1.01 1.08 1.15 1.22

1.23 1.31 Cardiology

Odds ratios are Odds ratios 1.70 xab 5

rn11 tran

referenced I Ximelagatra Rivaroxaban Aspirin Api dxbn60 Edoxaban aiarn150 Dabigatran aiarn110 Dabigatran aiarn150 Dabigatran Aspirin Rivaroxaban Api Ximelagatra 110 Dabigatran Idraparinux 30 Edoxaban E E n60mg an d 2.07 2 d d

bias a o o xaba xaba p x x

a a a 0 mg 66 r b b D

B i n a a corrected n n

u n n (2015)

3 3 6 3

n n 0 0 to mg mg Reference: Reference: m m

apixaban, mg mg mg mg g g

0 466–474

0 and

4 4 0.47 aiarn150 Dabigatran Vitamin K antagonis Idraparinux 30 Edoxaban 110 Dabigatran Ximelagatra Api dxbn60 Edoxaban Aspirin 0.62 0.69 Api dxbn60 Edoxaban Idraparinux aiarn110 Dabigatran dxbn30 Edoxaban Vitamin K antagonis Rivaroxaban Aspirin X

0.76 0.78

Bias adj Bias adj i

m not xaba

xaba F Vit Vit

dabigatran 0.86 0.78 0.87 0.77 0.79 C l a 1

g n corrected

ami ami

1.08 0.93 1.03 n a Odds ratios

123 r

a Odds ratios usted usted n

1.07 1.06 Referen n K an n K n K an n K 1.14 n mg mg mg mg mg mg Reference: 012 0 mg

110 234

t tago tago referenced

1.81

t ce: Dabiga 0.93 0.91 1.02 0.90

mg, nist nist 1

1.17 Rivaroxaba 1.26 1.34 1.24 1.30 1.01 1.11 1.14 1.38 1.49 1.03

1.40 dabigatran Odds ratios 3.04 Odds ratios rn15 tran

to 2.11 2

warfarin.

2.35 0 mg n

150 3 3

mg,

edoxaban 4 5 4

mg,

T. Morimoto et al. / Journal of Cardiology 66 (2015) 466–474 471

lower in risk of major bleeding compared to dabigatran 110 mg Vitamin K antagonists, apixaban, edoxaban 60 mg, and

[OR 0.74 (95% CI 0.58–0.96) and OR 0.50 (95% CI 0.39–0.65), rivaroxaban were superior in reducing myocardial infarction

respectively] (Fig. 4B), dabigatran 150 mg [OR 0.64 (95% CI 0.5– compared to both dabigatran 110 mg and 150 mg, with ORs

0.82) and OR 0.43 (95% CI 0.33–0.56)] (Fig. 4C), rivaroxaban [OR ranging from 0.48 (95% CI 0.31–0.75) to 0.63 (95% CI 0.44–0.90)

0.68 (95% CI 0.55–0.83) and OR 0.45 (95% CI 0.37–0.56)] (Fig. 4F), (Fig. 5B and C). Rivaroxaban was also signiﬁcantly lower in risk of

and vitamin K antagonists [OR 0.69 (95% CI 0.60–0.80) and OR 0.47 myocardial infarction than edoxaban 30 mg (OR 0.66, CI 95% 0.47–

(95% CI 0.40–0.54)] (Fig. 2D). In addition, edoxaban 30 mg was 0.93) (Fig. 6D). Otherwise, vitamin K antagonists and all other

signiﬁcantly lower in risk of major bleeding compared to apixaban NOACs were observed to have a similar effect on myocardial

(OR 0.67, CI 95% 0.54–0.83) (Fig. 4A), and edoxaban 60 mg (OR 0.59, infarction (Fig. 6A, D–F).

CI 95% 0.48–0.73) (Fig. 4E). While the risk of major bleeding was

similar among ximelagatran, dabigatran 110 mg and 150 mg, and Other endpoints and sensitivity analyses

rivaroxaban (Fig. 4B, C, and F), aspirin was superior to vitamin K

antagonists, dabigatran 150 mg, and rivaroxaban (Figs. 2D, 4C and In terms of all-cause mortality, vitamin K antagonists were

F). signiﬁcantly inferior to apixaban and edoxaban 30 mg with ORs of

With respect to secondary endpoints, aspirin was consistently 1.12 (CI 95% 1.00–1.26) (Appendix 3 Fig. A3 A) and 1.16 (95% CI

inferior with ORs ranging from 1.61 (95% CI 1.01–2.58) to 2.31 (95% 1.04–1.28) (Appendix 3 Fig. A3 D), respectively. All other NOACs as

CI 1.43–3.72) (Fig. 5A–C, E and F) to all NOACs except edoxaban well as aspirin and, idraparinux were similar in effect on all-cause

30 mg (Fig. 5D) and vitamin K antagonists (data not shown) in mortality (Appendix 3 Fig. A3 A–F). When we considered ischemic

reducing stroke. Vitamin K antagonists were also inferior to stroke and stroke of unknown origin, aspirin was found to be

apixaban (Fig. 5A), dabigatran 150 mg (Fig. 5C), and rivaroxaban inferior to all NOACs and vitamin K antagonists, with the exception

(Fig. 5F) in reducing stroke, with pooled ORs of 1.27 (95% CI 1.05– of dabigatran 110 mg and edoxaban 30 mg (Appendix 4 Fig. A4 A–

1.53), 1.33 (95% CI 1.01–1.75), and 1.25 (95% CI 1.03–1.51), F). Moreover, apixaban and rivaroxaban were found to be superior

respectively. Edoxaban 30 mg had higher risk of stroke compared to dabigatran 110 mg in reducing ischemic stroke and stroke of

to apixaban, dabigatran 150 mg, edoxaban 60 mg, and rivaroxaban unknown origin (Appendix 4 Fig. A4 A and C). With respect to

(Fig. 5D) with pooled ORs of 1.45 (95% CI 1.14–1.85; Fig. 5A), 1.52 intracranial hemorrhage, idraparinux was consistently inferior to

(95% CI 1.11–2.08; Fig. 5C), 1.30 (95% CI 1.03–1.62; Fig. 5E), and the NOACs and vitamin K antagonists (Appendix 6 Fig. A6 A–F, data

1.43 (95% CI 1.12–1.83; Fig. 5F), respectively. not shown for vitamin K antagonists).

ABReference: Apixaban Reference: Dabigatran 110 mg C Reference : Dabigatran 150 mg

0.89 0.66 0.57 Aspirin Aspirin Aspirin

1.34 0.74 0.64

Dabigatran 110 mg Apixaban Api xaban

1.56 1.16 0.86

Dabigatran 150 mg Dabigatran 150 mg Dabigatran 110 mg

0.67 0.50 0.43

Edoxaban 30 mg Edoxaban 30 mg Edoxaban 30 mg

1.13 0.84 0.72

Edoxaban 60 mg Edoxaban 60 mg Edoxaban 60 mg 4.38 3.26 2.81 Idraparinux Idraparinux Idraparinux 1.48 1.10 0.95 Rivaroxaban Rivaroxaban Rivaroxaban

1.44 1.07 0.92

Vitamin K antagonist Vitamin K antagonist Vitamin K antagonis t

1.10 0.82 0.71

Ximelagatra n Ximelagatran Ximelagatran

0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8

Odds ratios Odds ratios Odds ratios

D Reference: Edoxaban 30mg E R eference: Edoxaban 60mg F Reference: Rivaroxaban

1.33 0.79 0.60

Aspirin Aspirin Aspirin

1.49 0.88 0.68

Api xaban Apixaban Apixaban

2.00 1.19 0.91

Dabigatran 110 mg Dabigatran 110 mg Dabigatran 110 mg

2.33 1.38 1.06

Dabigatran 150 mg Dabigatran 150 mg Dabigatran 150 mg

1.68 0.59 0.45

Edoxaban 60 mg Edoxaban 30 mg Edoxaban 30 mg

6.52 3.87 0.76 Idraparinux Idraparinux Edoxaban 60 mg 2.20 1.31 2.96 Rivaroxaban Rivaroxaban Idraparinux

2.15 1.27 0.97

Vitamin K antagonis t Vitamin K antagonist Vitamin K antagonist

1.64 0.74

0.97

Ximelagatra n Ximelagatran Ximelagatran

0 1 2 3 4 5 6 7 11 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8

Odds ratios Odds ratios Odds ratios

Fig. 4. Odds ratios of major bleeding of direct oral anticoagulants. A, B, C, D, E, and F are referenced to apixaban, dabigatran 110 mg, dabigatran 150 mg, edoxaban 30 mg,

edoxaban 60 mg, and rivaroxaban, respectively.

472 T. Morimoto et al. / Journal of Cardiology 66 (2015) 466–474

A Reference : Apixaban B Reference: Dabigatran 110 mg C Reference: Dabigatran 150 mg 2.20 1.61 Aspirin Aspirin Aspirin 2.31

1.36 0.73 1.05

Dabigatran 110 mg Apixaban Api xaban

0.95 0.70 1.43

Dabigatran 150 mg Dabigatran 150 mg Dabigatran 110 mg

1.45 1.07 1.52

Edoxaban 30 mg Edoxaban 30 mg Edoxaban 30 mg

1.12 0.82 1.17

Edoxaban 60 mg Edoxaban 60 mg Edoxaban 60 mg 1.02 0.75 1.07 Rivaroxaban Rivaroxaban Rivaroxaban

1.27 0.93 1.33

Vitamin K antagonis t Vitamin K antagonist Vitamin K antagonist

0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

Odds ratios Odds ratios Odds ratios

D Reference: Edoxaban 30mg E Reference: Edoxaban 60mg F Reference: Rivaroxaban

1.52 1.97 2.16 Aspirin Aspirin Aspirin

0.69 0.89 0.98

Api xaban Apixaban Apixaban

0.94 1.22 1.34

Dabigatran 110 mg Dabigatran 110 mg Dabigatran 110 mg

0.66 0.85 0.94

Dabigatran 150 mg Dabigatran 150 mg Dabigatran 150 mg

0.77 1.30 1.43

Edoxaban 60 mg Edoxaban 30 mg Edoxaban 30 mg

0.70 0.91 1.10 Rivaroxaban Rivaroxaban Edoxaban 60 mg

0.87 1.13 1.25

Vitamin K antagonis t Vitamin K antagonist Vitamin K antagonist

0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

Odds ratios Odds ratios Odds ratios

Fig. 5. Odds ratios of stroke of direct oral anticoagulants. A, B, C, D, E, F, and G are referenced to vitamin K antagonist, apixaban, dabigatran 110 mg, dabigatran 150 mg,

edoxaban 30 mg, edoxaban 60 mg, and rivaroxaban, respectively.

Pooled ORs and statistical signiﬁcances remained unchanged O’Neal et al. recently reported the lack of a differentiating pattern

following sensitivity analyses with the addition of the three of results across phase III NOACs studies between blinded and

identiﬁed phase II studies. unblinded designs [22], their results do not necessarily exclude the

possibility of biased results stemming from open label study

Discussion designs.

While similarities were observed among most NOACs in terms

Our network meta-analysis with adjustment for study design of the primary efﬁcacy endpoint, our network meta-analysis

indicates that the relative efﬁcacies of NOACs in preventing stroke suggests some key differences between dabigatran and edoxaban

and systemic embolism in patients with atrial ﬁbrillation are at lower doses and other NOACs in the primary efﬁcacy endpoint

nearly indistinguishable apart from those of dabigatran and as well as among some NOACs in secondary and safety endpoints.

edoxaban at lower doses. In light of our ﬁndings, it appears likely For example, the RE-LY study [10] demonstrated that treatment

that unblinded clinical trials such as the RE-LY study [10] with dabigatran at 150 mg twice daily was associated with an

overestimate the effects of tested drugs. Safety endpoints usually increased risk of myocardial infarction compared to vitamin K

include ‘‘soft’’ endpoints and, thus, are easily biased by unblinded antagonists, and this was conﬁrmed by a recent meta-analysis

study design. Indeed, although dabigatran 110 mg had a lower risk [23] as well as in line with the ﬁndings of our own indirect

of bleeding than vitamin K antagonist in unadjusted analysis comparison wherein treatment with dabigatran (both 110 mg and

(Fig. 2C), this was no longer the case following adjustment for open 150 mg doses) was associated with a higher risk of myocardial

label study bias (Fig. 2D). infarction compared to apixaban, rivaroxaban, and edoxaban

Blinding is one of the best ways of minimizing biased outcomes 60 mg. Although results should be interpreted with caution

in clinical trials [3,18,19] and is of particular importance in because of very few events, a recent clinical trial also suggested a

pharmaceutical-industry funded trials comparing sponsor pro- higher risk for myocardial infarction in dabigatran-treated

ducts with standard treatments [20]. Although blinding the phase patients with venous thromboembolism as compared to warfa-

III trials is difﬁcult and costly, the efﬁcacy of newly developed rin-treated patients [24]. Populations tested in such studies,

drugs should be assessed in rigid, reliable study designs to avoid however, are not necessarily appropriate for the assessment of

the introduction of biases. Use of open label study designs is risk of myocardial infarction. Recent two ‘‘new users’’ large cohort

justiﬁed only in pragmatic trials comparing effectiveness of studies showed equivalent or even lower risk of myocardial

treatment strategies using already approved drugs [e.g. Anglo- infarction in patients with dabigatran compared to those with

Scandinavian Cardiac Outcomes Trial (ASCOT)] [21]. Although warfarin [25,26].

T. Morimoto et al. / Journal of Cardiology 66 (2015) 466–474 473

A Reference : Apixaban B Reference: Dabigatran 110 mg C Reference: Dabigatran 150 mg 1.18 0.65 0.63 Aspirin Aspirin Aspirin

1.82 0.55 0.54

Dabigatran 110 mg Apixaban Api xaban

1.86 1.02 0.98

Dabigatran 150 mg Dabigatran 150 mg Dabigatran 110 mg

1.37 0.75 0.74

Edoxaban 30 mg Edoxaban 30 mg Edoxaban 30 mg

1.07 0.59 0.58

Edoxaban 60 mg Edoxaban 60 mg Edoxaban 60 mg 1.64 0.90 0.88 Idraparinux Idraparinux Idraparinux 0.90 0.50 0.48 Rivaroxaban Rivaroxaban Rivaroxaban

1.14 0.63 0.61

Vitamin K antagonist Vitamin K antagonis t Vitamin K antagonist

1.35 0.74 0.72

Ximelagatran Ximelagatran Ximelagatran

0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5

Odds ratios Odds ratios Odds ratios

D Reference: Edoxaban 30mg E Reference: Edoxaban 60mg F Reference: Rivaroxaban 1.09 0.86 1.30

Aspirin Aspirin Aspirin

0.73 0.93 1.11

Api xaban Apixaban Apixaban

1.33 1.69 2.01

Dabigatran 110 mg Dabigatran 110 mg Dabigatran 110 mg

1.36 1.74 2.07

Dabigatran 150 mg Dabigatran 150 mg Dabigatran 150 mg

0.78 1.28 1.52

Edoxaban 60 mg Edoxaban 30 mg Edoxaban 30 mg

1.20 1.53 1.19 Idraparinux Idraparinux Edoxaban 60 mg 0.66 0.84 1.82 Rivaroxaban Rivaroxaban Idraparinux

0.83 1.06 1.26

Vitamin K antagonis t Vitamin K antagonist Vitamin K antagonist

0.98 1.26 1.50

Ximelagatran Ximelagatran Ximelagatran

0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5

Odds ratios Odds ratios Odds ratios

Fig. 6. Odds ratios of myocardial infarction of direct oral anticoagulants. A, B, C, D, E, F, and G are referenced to vitamin K antagonist, apixaban, dabigatran 110 mg, dabigatran

150 mg, edoxaban 30 mg, edoxaban 60 mg, and rivaroxaban, respectively.

Furthermore, whilst dabigatran at either dose, rivaroxaban, and adjustment for open label study bias was applied to allow us to

vitamin K antagonists performed similarly with respect to major control for the over-estimation of treatment effect in these studies.

bleeding following adjustment, treatment with apixaban or However, this strategy carries its own limitations. Although much

edoxaban at either dose was associated with a lower risk of major work has been done to investigate the inherent treatment effect

bleeding than other NOACs and vitamin K antagonists. However, bias from open label studies, the results of these efforts are limited

inter-study comparison regarding our safety endpoint should be in that validation of these methods remains insufﬁcient despite

interpreted with caution, as the deﬁnition of major bleeding varied their approximation to blinded studies. We selected the method

among studies (Appendix 2 Table A2). used by Ju¨ ni et al. as it incorporates multiple different studies in a

In terms of statistical heterogeneity, which is often a problem in meta-analysis rather than a single open-blinded comparison, and

meta-analysis, we closely reviewed studies to ensure they were as should therefore provide a broader representation of the inherent

comparable as possible to reduce the inﬂuence of heterogeneity. bias from open-label studies.

No dose-ﬁnding studies were included and we restricted our

primary analysis to only Phase III studies and Phase II studies were Conclusion

restricted to approved doses (same as Phase III studies) and

assessed in a sensitivity analysis only. Indirect comparison of phase III trials of NOACs suggests that

newly approved NOACs are of near equivalent efﬁcacy following

Limitation of the study adjustment by study design apart from dabigatran and edoxaban at

lower doses; however, some differences in safety and risk of

While useful in making comparisons where such experiments myocardial infarction remain. Furthermore, open label study

are infeasible or have yet to be conducted, a number of limitations designs appear to overestimate efﬁcacy and safety. Differences in

exist with regard to the conduct of network analyses. Study study design should be taken into account in interpretation and

differences, including the heterogeneity of populations, endpoint implementation of results from RCTs of NOACs.

deﬁnitions, study designs, and therapeutic doses, all constrain the

strength of network analytic ﬁndings. In our study, we adjusted for Contributors

open label study bias but did not adjust for the greater severity of

the ROCKET study population (as evidenced by a higher CHADS2 TM and SU developed the study design. BC and KW performed

score) nor the difference in ‘‘major bleeding’’ deﬁnition in the literature search, data extraction and analyzed the data according

apixaban studies. To allow for a more ‘‘fair’’ comparison, the to the study design under the supervision of TM and SU. TM and SU

474 T. Morimoto et al. / Journal of Cardiology 66 (2015) 466–474

K antagonists for prevention of thromboembolism in patients with atrial

drafted the ﬁrst version of manuscript. All authors contributed to

ﬁbrillation: a randomised, open-label, non-inferiority trial. Lancet 2008;371:

the interpretation of the data and revision of the manuscript. SU is 315–21.

guarantor. [8] Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-

Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz

JA, Flaker G, et al. Apixaban versus warfarin in patients with atrial ﬁbrillation.

Funding

N Engl J Med 2011;365:981–92.

[9] Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G,

Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko

This work was supported by Bayer, Osaka, Japan. Representa-

A, et al. Apixaban in patients with atrial ﬁbrillation. N Engl J Med 2011;364:

tives of Bayer participated in the study design, interpretation of

806–17.

data, and approval of the ﬁnal manuscript. However, the authors [10] Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G,

maintained leading roles in all aspects of study design, data Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko

A, et al. Dabigatran versus warfarin in patients with atrial ﬁbrillation. N Engl J

collection and interpretation, and drafting of the manuscript.

Med 2009;361:1139–51.

[11] Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo

Disclosure AL, Ezekowitz MD, Weitz JI, Sˇpinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J,

Shi M, et al. Edoxaban versus warfarin in patients with atrial ﬁbrillation. N Engl

J Med 2013;369:2093–104.

Competing interests: All authors have completed the ICMJE

[12] Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G,

uniform disclosure at www.icmje.org/coi_disclosure.pdf and Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz

SD, Fox KA, et al. Rivaroxaban versus warfarin in nonvalvular atrial ﬁbrillation.

declare: ﬁnancial support for the submitted work from Bayer,

N Engl J Med 2011;365:883–91.

Osaka, Japan; TM has received research grants and personal fee

[13] Hori M, Matsumoto M, Tanahashi N, Momomura S, Uchiyama S, Goto S, Izumi

from Kowa, personal fee from Boehringer Ingelheim, Edward T, Koretsune Y, Kajikawa M, Kato M, Ueda H, Iwamoto K, Tajiri M, J-ROCKET AF

study investigators. Rivaroxaban vs. warfarin in Japanese patients with atrial

Lifescience, Esai, Pﬁzer; BC and KW have received a ﬁnancial

ﬁbrillation. Circ J 2012;76:2104–11.

support from Bayer to Adelphi Values for the submitted work; SU

[14] Ogawa S, Shinohara Y, Kanmuri K. Safety and efﬁcacy of the oral direct factor

has received research grants and personal fee from Pﬁzer, Takeda, xa inhibitor apixaban in Japanese patients with non-valvular atrial ﬁbrillation

– The ARISTOTLE-J study. Circ J 2011;75:1852–9.

MSD, Bayer, Dai-ichi Sankyo, Dainippon Sumitomo, Tanabe

[15] Ezekowitz MD, Reilly PA, Nehmiz G, Simmers TA, Nagarakanti R, Parcham-

Mitsubishi and Personal fees from Astellas, Novartis, Boehringer

Azad K, Pedersen KE, Lionetti DA, Stangier J, Wallentin L. Dabigatran with or

Ingelheim; no other relationships or activities that could appear to without concomitant aspirin compared with warfarin alone in patients with

have inﬂuenced the submitted work. nonvalvular atrial ﬁbrillation (PETRO Study). Am J Cardiol 2007;100:1419–26.

[16] Boehringer Ingelheim Pharmaceuticals. A dose response study of dabigatran

etexilate (BIBR 1048) in pharmacodynamics and safety in patients with non-

Acknowledgment valvular atrial ﬁbrillation in comparison to warfarin. ClinicalTrials gov; 2010

[Internet]. Available from: URL: http://clinicaltrials.gov/ct2/show/results/

NCT01136408 [cited 01.08.12]; NLM Identiﬁer: NCT01136408.

None.

[17] Lopes RD, Alexander JH, Al-Khatib SM, Ansell J, Diaz R, Easton JD, Gersh BJ,

Granger CB, Hanna M, Horowitz J, Hylek EM, McMurray JJ, Verheugt FW,

Wallentin L, ARISTOTLE Investigators. Apixaban for reduction in stroke and

other ThromboemboLic events in atrial ﬁbrillation (ARISTOTLE) trial: design

Appendix A. Supplementary data and rationale. Am Heart J 2010;159:331–9.

[18] Schulz KF, Chalmers I, Altman DG. The landscape and lexicon of blinding in

randomized trials. Ann Intern Med 2002;136:254–9.

Supplementary data associated with this article can be found, in

[19] ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct factor Xa

the online version, at doi:10.1016/j.jjcc.2015.05.018. inhibition compared with vitamin K antagonism for prevention of stroke and

Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF

study. Am Heart J 2010;159:340–7.

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