Papel de la Vitamina K en la prevención de los embolismos

Factor Xa inhibitors versus vitamin K antagonists for

preventing cerebral or systemic embolism in patients with

atrial fibrillation (Review)

Bruins Slot KMH, Berge E

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2013, Issue 8

http://www.thecochranelibrary.com

Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation

(Review)

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

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

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .

6BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

15DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 1 Stroke and other systemic embolic events. . 40

Analysis 1.2. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 2 All strokes. . . . . . . . . . . . 41

Analysis 1.3. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 3 Ischaemic stroke. . . . . . . . . . 43

Analysis 1.4. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 4 Disabling or fatal stroke. . . . . . . . 44

Analysis 1.5. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 5 Systemic embolic events (non-CNS). . . 46

Analysis 1.6. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 6 Major bleedings. . . . . . . . . . 47

Analysis 1.7. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 7 Intracranial haemorrhages. . . . . . . 49

Analysis 1.8. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 8 Non-major clinically relevant bleeds. . . 50

Analysis 1.9. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 9 Myocardial infarction. . . . . . . . 52

Analysis 1.10. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 10 Vascular deaths. . . . . . . . . . 53

Analysis 1.11. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 11 All-cause deaths. . . . . . . . . . 55

Analysis 2.1. Comparison 2 Factor Xa inhibitors versus VKA: route of administration, Outcome 1 Stroke and systemic

other embolic events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

Analysis 2.2. Comparison 2 Factor Xa inhibitors versus VKA: route of administration, Outcome 2 Major bleeding. . 57

Analysis 3.1. Comparison 3 Factor Xa inhibitor versus VKA: dose of Factor Xa inhibitor, Outcome 1 Stroke and other

systemic embolic events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Analysis 3.2. Comparison 3 Factor Xa inhibitor versus VKA: dose of Factor Xa inhibitor, Outcome 2 Major bleedings. 61

Analysis 4.1. Comparison 4 Factor Xa inhibitors versus VKA: previous stroke or TIA, Outcome 1 Stroke and other systemic

embolic events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Analysis 4.2. Comparison 4 Factor Xa inhibitors versus VKA: previous stroke or TIA, Outcome 2 Major bleedings. . 65

Analysis 5.1. Comparison 5 Factor Xa inhibitors versus VKA: quality of anticoagulation with VKA (TTR), Outcome 1

Stroke and other systemic embolic events. . . . . . . . . . . . . . . . . . . . . . . . . 66

Analysis 6.1. Comparison 6 Factor Xa inhibitors versus VKA: previous VKA use, Outcome 1 Stroke and other systemic

embolic events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Analysis 6.2. Comparison 6 Factor Xa inhibitors versus VKA: previous VKA use, Outcome 2 Major bleedings. . . 68

Analysis 7.1. Comparison 7 Factor Xa inhibitors versus VKA: concomitant antiplatelet use, Outcome 1 Stroke and other


Analysis 7.2. Comparison 7 Factor Xa inhibitors versus VKA: concomitant antiplatelet use, Outcome 2 Major bleedings. 70

Analysis 8.1. Comparison 8 Factor Xa inhibitors versus VKA: age, Outcome 1 Stroke and other systemic embolic events. 71

Analysis 9.1. Comparison 9 Factor Xa inhibitors versus VKA: race, Outcome 1 Stroke and other systemic embolic events. 72

Analysis 9.2. Comparison 9 Factor Xa inhibitors versus VKA: race, Outcome 2 Major bleedings. . . . . . . . 73

Analysis 10.1. Comparison 10 Factor Xa inhibitors versus VKA: sex, Outcome 1 Stroke and other systemic embolic

events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

Analysis 10.2. Comparison 10 Factor Xa inhibitors versus VKA: sex, Outcome 2 Major bleeding. . . . . . . . 75

Analysis 11.1. Comparison 11 Factor Xa inhibitors versus VKA: baseline CHADS2 score, Outcome 1 Stroke and other


iFactor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation

(Review)


Analysis 11.2. Comparison 11 Factor Xa inhibitors versus VKA: baseline CHADS2 score, Outcome 2 Major bleedings. 77

77APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

79FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

86SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

86DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

86INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iiFactor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation

(Review)


[Intervention Review]

Factor Xa inhibitors versus vitamin K antagonists forpreventing cerebral or systemic embolism in patients withatrial fibrillation

Karsten MH Bruins Slot1, Eivind Berge1

1Department of Internal Medicine, Oslo University Hospital, Oslo, Norway

Contact address: Karsten MH Bruins Slot, Department of Internal Medicine, Oslo University Hospital, Oslo, NO-0407, Norway.

[email protected].

Editorial group: Cochrane Stroke Group.

Publication status and date: Edited (no change to conclusions), comment added to review, published in Issue 2, 2015.

Review content assessed as up-to-date: 29 April 2013.

Citation: Bruins Slot KMH, Berge E. Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic em-

bolism in patients with atrial fibrillation. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD008980. DOI:

10.1002/14651858.CD008980.pub2.


A B S T R A C T

Background

Anticoagulant treatment with vitamin K antagonists (VKAs) is aimed at preventing thromboembolic complications and has been the

therapy of choice for most people with non-valvular atrial fibrillation (AF) for many decades. A new class of anticoagulants, the factor

Xa inhibitors, appear to have several pharmacological and practical advantages over VKAs.

Objectives

To assess the effectiveness and safety of treatment with factor Xa inhibitors versus VKAs for the prevention of cerebral or systemic

embolic events in people with AF.

Search methods

We searched the trials registers of the Cochrane Stroke Group and the Cochrane Heart Group (June 2012), the Cochrane Central

Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 10), MEDLINE (1950 to April 2013) and EMBASE

(1980 to April 2013). In an effort to identify further published, unpublished and ongoing trials we searched trials registers and

Google Scholar (July 2012). We also screened reference lists and contacted pharmaceutical companies, authors and sponsors of relevant

published trials.

Selection criteria

Randomised controlled trials that directly compared the effects of long-term treatment (more than four weeks) with factor Xa inhibitors

and VKAs for the prevention of cerebral and systemic embolism in patients with AF. We included patients with and without a previous

stroke or TIA.

Data collection and analysis

The primary efficacy outcome was the composite endpoint of all strokes and other systemic embolic events. Two authors independently

assessed trial quality and the risk of bias, and extracted data. We calculated a weighted estimate of the typical treatment effect across

trials using the odds ratio (OR) with 95% confidence interval (CI) by means of a fixed-effect model. However, in the case of moderate

or high heterogeneity of treatment effects, we used a random-effects model to compare the overall treatment effects and performed a

pre-specified sensitivity analysis excluding any fully open-label studies.

1Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation

(Review)


mailto:[email protected]

Main results

We included data from 42,084 participants randomised into 10 trials. All participants had a confirmed diagnosis of AF (or atrial flutter)

and were deemed by the randomising physician to be eligible for long-term anticoagulant treatment with a VKA (warfarin) with a target

International Normalised Ratio (INR) of 2.0 to 3.0 in most patients. The included trials directly compared dose-adjusted warfarin with

either apixaban, betrixaban, darexaban, edoxaban, idraparinux or rivaroxaban. Four trials were double-masked, five partially-masked

(that is different doses of factor Xa inhibitor administered double-masked and warfarin administered open-label) and one was open-

label. Median duration of follow-up ranged from 12 weeks to 1.9 years.

The composite primary efficacy endpoint of all strokes (both ischaemic and haemorrhagic) and non-central nervous systemic embolic

events was reported in nine of the included studies (40,777 participants). Treatment with a factor Xa inhibitor significantly decreased

the number of strokes and systemic embolic events compared with dose-adjusted warfarin (OR 0.81, 95% CI 0.72 to 0.91). We also

analysed both components of this composite endpoint separately: treatment with a factor Xa inhibitor significantly decreased both the

number of ischaemic and haemorrhagic strokes (OR 0.78, 95% CI 0.69 to 0.89) and the number of systemic embolic events (OR

0.53, 95% CI 0.32 to 0.87).

All of the included studies (42,078 participants) reported the number of major bleedings. Treatment with a factor Xa inhibitor

significantly reduced the number of major bleedings compared with warfarin (OR 0.89, 95% CI 0.81 to 0.98). There was, however,

statistically significant and high heterogeneity (I² = 81%) and an analysis using a random-effects model did not show a statistically

significant decrease in the number of major bleedings (OR 0.92, 95% CI 0.63 to 1.34). The pre-specified sensitivity analysis excluding

open-label studies showed that treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared

with warfarin (OR 0.84, 95% CI 0.76 to 0.92) but moderate heterogeneity was still observed (I² = 65%). A similar sensitivity analysis

using a random-effects model did not show a statistically significant decrease in the number of major bleedings in patients treated with

factor Xa inhibitors (OR 0.78, 95% CI 0.57 to 1.05). Part of the observed heterogeneity can thus be explained by the increased risk of

major bleedings in the factor Xa treatment arm in the single included open-label study, which studied idraparinux. Other heterogeneity

might be explained by differences in baseline bleeding risks in the two largest trials of apixaban and rivaroxaban that we included in

this review.

Data on intracranial haemorrhages (ICHs) were reported in eight studies (39,638 participants). Treatment with a factor Xa inhibitor

significantly reduced the risk of ICH compared with warfarin (OR 0.56, 95% CI 0.45 to 0.70). Again, we observed statistically

significant heterogeneity (I² = 60%). The pre-specified sensitivity analysis excluding the open-label study showed that treatment with a

factor Xa inhibitor significantly reduced the number of ICHs compared with warfarin (OR 0.51, 95% CI 0.41 to 0.64), without any

sign of statistical heterogeneity (I² = 0%).

The number of patients who died from any cause was reported in six studies (38,924 participants). Treatment with a factor Xa inhibitor

significantly reduced the number of all-cause deaths compared with warfarin (OR 0.88, 95% 0.81 to 0.97).

Authors’ conclusions

Factor Xa inhibitors significantly reduced the number of strokes and systemic embolic events compared with warfarin in patients with

AF. Factor Xa inhibitors also seem to reduce the number of major bleedings and ICHs compared with warfarin, though the evidence

for a reduction of major bleedings is somewhat less robust. There is currently no conclusive evidence to determine which factor Xa

inhibitor is more effective and safer for long-term anticoagulant treatment of patients with AF as head-to-head studies of the different

factor Xa inhibitors have not yet been performed.

P L A I N L A N G U A G E S U M M A R Y

Comparison of two types of blood thinning drugs for preventing blood clots in people with atrial fibrillation

People with atrial fibrillation, a condition that causes the heart to beat irregularly, are at an increased risk of the formation of blood clots.

Such clots can block blood vessels and cause severe organ damage (infarction), for example in the brain or lungs. Various guidelines

recommend that patients with atrial fibrillation should be treated with blood thinning drugs that can prevent the formation of blood

clots. Serious side effects of such treatment are bleedings (for example into the brain) that can cause serious disability or even death.

Until recently, the most often used blood thinning drug in people with atrial fibrillation has been warfarin, a vitamin K antagonist.

Results from several studies of a new class of blood thinners, the factor Xa inhibitors, have now become available. In this review we have


(Review)


analysed data from 10 studies that included a total of 42,084 participants with atrial fibrillation that were either treated with warfarin

or a factor Xa inhibitor. We found that the factor Xa inhibitors, when compared with warfarin, reduced the formation of blood clots

in people with atrial fibrillation. Factor Xa inhibitors also appear to reduce the number of serious bleedings (including those into the

brain) and number of people dying from any cause compared with warfarin.


(Review)


S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Factor Xa inhibitors compared with vitamin K antagonists for prevention of stroke and other systemic embolic events in patient with atrial fibrillation

Patient or population: Patients with atrial fibrillation deemed eligible for long-term anticoagulant treatment

Settings: Hospital-based setting

Intervention: Factor Xa inhibitor1

Comparison: Dose-adjusted vitamin K antagonist2

Outcomes Illustrative comparative risks* (95% CI) Relative effect

(95% CI)

No of Participants

(studies)

Quality of the evidence

(GRADE)

Comments

Assumed risk Corresponding risk

Warfarin Factor Xa inhibitors

Stroke and other sys-

temic embolic events

(Follow-up: 12 weeks to

1.9 years)

32 per 1000 25 per 1000

(0 to 38)

RR 0.82

(0.73 to 0.91)

40777

(9)

⊕⊕⊕⊕

high

Most data (84%) from

studies with apixaban and

rivaroxaban

All strokes


1.9 years)

27 per 1000 20 per 1000

(0 to 26)

RR 0.79

(0.69 to 0.89)

40749

(9)

⊕⊕⊕⊕

high



rivaroxaban

Major bleedings


1.9 years)

46 per 1000 39 per 1000

(0 to 55)

RR 0.90 (0.82 to 0.98) 42078

(10)

⊕⊕⊕©

moderate3



rivaroxaban

Intracranial

haemorrhages


1.9 years)

11 per 1000 6 per 1000

(0 to 8)

RR 0.56

(0.45 to 0.70)

39638

(8)

⊕⊕⊕⊕

high4



rivaroxaban

All-cause deaths


1.9 years)

51 per 1000 45 per 1000

(0 to 66)

RR 0.89

(0.82 to 0.97)

38924

(6)

⊕⊕⊕⊕

high



rivaroxaban

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http://www.thecochranelibrary.com/view/0/SummaryFindings.html

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the

assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; RR: risk ratio.

GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.

Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low quality: We are very uncertain about the estimate.

1T he10studiesincludedinthisreviewstudiedthef ollowingtypesof oralandparenteralf actorXainhibitors:rivaroxaban,apixaban,edoxaban,betrixaban,darexabanandidraparinux.

2Allincludedstudiesuseddose−adjustedwarf arinwithatargetINR2.0to3.0asactivecomparator.T wostudiesperf ormedinJapanhadatargetINRof 1.6to2.6,and2.0to2.6inpatientsaged>70years.

3High,statisticallysignif icantheterogeneitywasobservedintheinitialanalysisandinpre−specif iedsensitivityanalysisexcludingf ullyopen−labelstudies(i.e.prematurelyhaltedAMADEUStrial).Someotherheterogeneitymightbeexplainedbyb

4High,statisticallysignif icantheterogeneitywasobservedintheinitialanalysis.Nostatisticallysignif icantheterogeneitywasobservedinapre−specif iedsensitivityanalysisinwhichdataf romf ullyopen−labelstudieswereexcluded(i.e.prematur

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B A C K G R O U N D

Description of the condition

Atrial fibrillation (AF) is the most common type of arrhythmia in

adults and becomes more common with increased age (Go 2001).

The prevalence of AF is estimated at around 2% of the population

(Kirchhof 2007). The lifetime risk for developing AF is approxi-

mately one in four for people aged 40 years and older (Lloyd-Jones

2004; Heeringa 2006). Furthermore, with an increasing elderly

population, the incidence of AF is set to rise substantially during

the coming decades (Wattigney 2003; Miyasaki 2006).

Individuals with AF have an increased risk of thromboembolic

events (e.g. stroke, deep venous thrombosis, pulmonary em-

bolism). The mechanisms behind this increased risk that is asso-

ciated with AF are complex and seem to be related to abnormal

changes in blood flow, the vessel wall and blood constituents that

lead to a hypercoagulable or prothrombotic state (Watson 2009).

The risk of stroke is about four to five times greater than for people

of the same age who are in sinus rhythm, and it is estimated that

about 15% to 20% of all strokes are caused by AF (Wolf 1991).

Ischaemic strokes in people with AF are more often disabling and

fatal, and occur at a greater age compared with strokes in people

with sinus rhythm (Marini 2005).

Description of the intervention

Management of people with AF is aimed at reducing symptoms

and preventing severe thromboembolic complications. Prevention

of the latter relies on adequate antithrombotic therapy with a vi-

tamin K antagonist (VKA) or, in some cases, antiplatelet drugs

(ACC/AHA/ESC 2006; ESC 2010; ESC 2012). VKAs, such as

warfarin, are a class of anticoagulants that reduce blood clotting

by inhibiting the action of vitamin K. Treatment with warfarin,

generally within the International Normalised Ratio (INR) target

range of 2.0 to 3.0, has been shown to reduce the risk of stroke by

about two-thirds in patients with AF and is more effective than

antiplatelet agents (Hart 2007). Antithrombotic therapy with a

VKA was therefore, until recently, recommended in several clin-

ical guidelines for people with AF, who have an increased risk

of thromboembolic complications (ACC/AHA/ESC 2006; ESC

2010). However, it is estimated that only about 50% to 60% of

eligible people with AF actually receive treatment with a VKA,

and of those who receive treatment many are treated suboptimally

(Boulanger 2006; Connolly 2007). One important reason for this

is that patients or their physicians fear bleeding complications, es-

pecially among the elderly (Sudlow 1997; Hylek 2007). Another

reason is that VKAs exhibit a considerable variability in dose re-

sponse among patients, are subject to multiple food and drug in-

teractions, and have a narrow therapeutic window. Treatment with

VKAs thus necessitates frequent laboratory monitoring and dose

adjustments, which can be burdensome and difficult.

The under-use of VKAs for stroke prevention in people with AF

has prompted the development of new anticoagulant drugs. Re-

cently, a new class of anticoagulants, the factor Xa inhibitors, has

become available on the market. These factor Xa inhibitors have

similar mechanisms of action (binding reversibly to the active site

of factor Xa thereby inhibiting the formation of thrombin and

fibrin). At least for the orally administered agents, the pharma-

cokinetic profile appears to be more or less comparable with a rel-

atively short half-life (leading to once or twice daily dosing of the

oral agents) (Mousa 2010). Factor Xa inhibitors appear to offer

practical advantages over VKAs, with fewer food and drug inter-

actions, a fixed daily or weekly dose, and no need for monitoring

of the anticoagulant effect (Mousa 2010). There are currently no

approved antidotes to counteract the anticoagulation effect of fac-

tor Xa inhibitors.

Various oral and parenteral agents in this new class have already

been compared with VKAs in large randomised clinical trials

(RCTs) and some have recently been approved by regulatory au-

thorities in the US and Europe for use in stroke prevention in

people with AF (Eikelboom 2010; ESC 2012). Based on the data

from two large RCTs that have directly compared the novel an-

ticoagulants dabigatran (an oral direct thrombin inhibitor) and

rivaroxaban (an oral factor Xa inhibitor) with VKA, a recently up-

dated guideline by the European Society of Cardiology (ESC) now

recommends these new agents as preferable to VKA for preventing

stroke and other thromboembolic events in the vast majority of

people with AF (ESC 2012).

Why it is important to do this review

The prevalence and incidence of AF will most likely continue to

increase and will cause more strokes during the coming decades

(Wattigney 2003; Miyasaki 2006). Until very recently, most guide-

lines have recommended the use of VKAs in the majority of people

with AF for preventing stroke and other thromboembolic events

(ACC/AHA/ESC 2006; ESC 2010). Still, several limitations of

VKAs have resulted in their under-use for stroke prevention in

people with AF (Boulanger 2006; Connolly 2007). Factor Xa in-

hibitors appear to have several pharmacological and practical ad-

vantages over VKAs (Eikelboom 2010; Mousa 2010). This new

class of anticoagulants also has the potential to increase the propor-

tion of people with AF who receive effective anticoagulant therapy.

Despite the fact that a recently updated European guideline now

recommends the novel anticoagulants dabigatran and rivaroxaban,

it still begins by recommending treatment with VKAs (ESC 2012;

EHRA 2013). Many people will continue to be treated with VKAs

in the coming years, but this may vary between countries and re-

gions. A comparison of the effectiveness and safety of the factor

Xa inhibitors versus VKAs is therefore needed.


(Review)


O B J E C T I V E S

To assess the effectiveness and safety of treatment with factor Xa

inhibitors versus VKAs for the prevention of cerebral or systemic

embolic events in people with AF.

M E T H O D S

Criteria for considering studies for this review

Types of studies

We sought to identify all RCTs that directly compare the effects

of long-term treatment (more than four weeks) with factor Xa

inhibitors with that of VKAs for preventing cerebral and systemic

embolism in people with AF.

Types of participants

People with AF who were eligible for treatment with anticoagu-

lants in order to reduce the risk of cerebral and systemic embolism.

We included people with and without a previous stroke or tran-

sient ischaemic attack (TIA).

Types of interventions

Treatment with an oral or parenteral factor Xa inhibitor (e.g.

antistasin, apixaban, betrixaban, darexaban, DU176b, edoxaban,

eribaxaban, fondaparinux, idraparinux, otamixaban, razaxaban, ri-

varoxaban, yagin, YM150, LY517717, SSR126517E) versus oral

vitamin K antagonists (warfarin and congeners) with the inten-

sity of anticoagulation dose-adjusted using the International Nor-

malised Ratio (INR).

Types of outcome measures

Primary outcomes

The composite endpoint of all strokes (both ischaemic and haem-

orrhagic) and other systemic embolic events.

Secondary outcomes

1. All strokes (both ischaemic and haemorrhagic).

2. All disabling or fatal strokes (both ischaemic and

haemorrhagic). The definition of a disabling stroke depends on

the varying criteria in the included studies. Strokes are deemed

fatal when death ensues within 30 days of the onset of stroke.

3. Intracranial haemorrhages. This includes all

intraparenchymal, subdural and epidural haematomas, and

subarachnoid haemorrhages confirmed by neuroimaging or post-

mortem examination.

4. Major bleedings (defined by the International Society on

Thrombosis and Haemostasis (ISTH) criteria or modified ISTH

criteria).

5. Non-major clinically relevant bleedings (defined by ISTH-

criteria or modified ISTH-criteria).

6. Systemic embolic events (excluding embolic events in the

central nervous system).

7. Myocardial infarction. The diagnosis of myocardial

infarction was based upon electrocardiographic changes,

elevation of enzymes or confirmation during post-mortem

examination.

8. Vascular deaths (deaths due to stroke, heart disease,

haemorrhage and sudden deaths of unknown cause).

9. All-cause deaths.

10. Other adverse events (i.e. non-bleeding adverse events).

Search methods for identification of studies

See the ’Specialized register’ section in the Cochrane Stroke Group

module. We searched for trials in all languages and arranged trans-

lation of relevant papers published in languages other than En-

glish.

Electronic searches

We searched the trials registers of the Cochrane Stroke Group and

the Cochrane Heart Group (June 2012). In addition, we searched

the following electronic databases and trials registers:

1. Cochrane Central Register of Controlled Trials

(CENTRAL) (The Cochrane Library 2012, Issue 10);

2. MEDLINE (from 1950 to June 2012) (Appendix 1);

3. EMBASE (from 1980 to June 2012) (Appendix 2);

4. Stroke Trials Directory (http://www.strokecenter.org/trials)

(June 2012 and April 2013);

5. ClinicalTrials.gov (http://www.clinicaltrials.gov) (July 2012

and April 2013);

6. Current Controlled Trials (http://www.controlled-

trials.com) (July 2012 and April 2013).

We developed the MEDLINE and EMBASE search strategies with

the help of the Cochrane Stroke Group Trials Search Co-ordinator

and adapted the MEDLINE strategy for the other databases.

Searching other resources

In an effort to identify further published, unpublished, ongoing

and planned trials we:

• screened reference lists of relevant trials;

• contacted the following relevant pharmaceutical companies:


(Review)


http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/STROKE/frame.html



http://www.strokecenter.org/trials




http://www.clinicaltrials.gov/



http://www.controlled-trials.com/




i) Sanofi (July 2012), responded and additional data

were received for AMADEUS 2008,

ii) Bristol Myers Squibb (July 2012), no response,

iii) Daiichi Sankyo (July 2012), no response.

iv) Portola Pharmaceuticals (July 2012), no response.

v) Bayer (July 2012), no response,

vi) Astellas Europe (July 2012), no response;

• contacted the following authors, colleagues and researchers

active in the field:

i) HR Büller (June and July 2012), responded,

additional data subsequently provided by sponsor of AMADEUS

2008 (Sanofi Aventis),

ii) CB Granger (June and July 2012), responded, but no

additional data provided for ARISTOTLE 2011,

iii) S Ogawa (June and July 2012), no response and no

additional data provided for ARISTOTLE-J 2011,

iv) N Chung (June and July 2012), no response and no

additional data provided for Edoxaban Asia 2010,

v) JI Weitz (June and July 2012), responded, but no

additional data provided for Edoxaban US/Europe 2010,

vi) MD Ezekowitz (June and July 2012), responded, but

no additional data provided for EXPLORE-Xa 2013,

vii) M Hori (June and July 2012), responded, additional

data were provided for J-ROCKET AF 2012,

viii) M Patel (June and July 2012), no response and no

additional data provided for ROCKET AF 2011,

ix) AGG Turpie (June and July 2012), no response and

no additional data provided for OPAL-1 2010,

x) GYH. Lip (June and July 2012), no response and no

additional data provided for OPAL-2 2011;

• searched Google Scholar (http://scholar.google.co.uk/)

(July 2012);

• used Science Citation Index Cited Reference search for

forward tracking of relevant references.

Data collection and analysis

Selection of studies

One of the review authors (KBS) independently screened titles

and abstracts of references identified by the searches and excluded

obviously irrelevant citations. We obtained the full paper copies of

the remaining articles, and both authors assessed these for inclu-

sion. We resolved any uncertainties or disagreements on whether

papers were eligible for inclusion by discussion with an external

expert. If a trial was excluded, we kept a record of both the report

and the reason for exclusion.

We did not use a scoring system to assess the quality of each trial,

but for each included trial we collected information about:

1. the method of randomisation (including concealment of

allocation);

2. blinding (care provider, patient, outcome assessment);

3. the number of participants lost to follow-up;

4. whether or not the trial data were analysed according to the

’intention-to-treat’ principle.

Data extraction and management

Both review authors independently extracted data from the report

of each eligible trial and recorded the information on a specially

designed data extraction form. We were not blinded to journal or

institution and extracted the following data from each report:

• inclusion and exclusion criteria;

• method of randomisation;

• masked versus open-label intervention;

• diagnostic criteria used for the assessment of major vascular

events, stroke (both ischaemic and haemorrhagic), vascular death

(including fatal haemorrhages), myocardial infarction or

systemic embolism;

• number of participants in each treatment group with

outcome events;

• generic name and dose(s) of factor Xa inhibitor used;

• duration of anticoagulant therapy in the trial, the intensity

of anticoagulation dose-adjusted using INR, and adherence to

anticoagulant treatment;

• concomitant treatment with other anticoagulants,

antiplatelets, or both, or any non-steroidal anti-inflammatory

drugs;

• outcomes (as listed above).

One review author (KBS) entered the data into the Cochrane Re-

view Manager software, RevMan 5.2 (RevMan 2012). The other

review author (EB) checked these data against the hard-copy data

extraction forms to correct any clerical data entry errors. If any

relevant data were missing from the available publications, we di-

rectly contacted the principal investigators or sponsor concerned,

or both.

Assessment of risk of bias in included studies

We used the Cochrane Collaboration’s recommended tool for as-

sessing the risk of bias in included studies (Cochrane Handbook

2011). Both review authors scored the potential for bias of specific

features of each study as ’low’, ’unclear’ or ’high’ risk. We resolved

any disagreements by discussion with an external expert.

Measures of treatment effect

For dichotomous outcomes, we calculated a weighted estimate of

the treatment effects across trials (odds ratio (OR)).


(Review)


http://scholar.google.co.uk/



Dealing with missing data

In cases where the published information did not allow for an in-

tention-to-treat analysis, we contacted the authors to get as com-

plete follow-up data as possible on all randomised participants for

the originally proposed period of follow-up.

Assessment of heterogeneity

We tested for heterogeneity between trial results with the Cochrane

Q statistic and I² statistic (percentage of total variation across stud-

ies due to heterogeneity). We interpreted the amount of hetero-

geneity as ’low’, ’moderate’ and ’high’ for I² values of 25%, 50%

and 75%, respectively. We also assessed heterogeneity qualitatively.

Assessment of reporting biases

We used funnel plots to assess reporting bias. We also assessed

these plots qualitatively.

Data synthesis

We calculated a weighted estimate of the typical treatment effect

across trials using OR by means of a fixed-effect model. However,

in the case of moderate to high heterogeneity of treatment effects,

we used a random-effects model to enable further comparison of

the overall treatment effects.

Subgroup analysis and investigation of heterogeneity

Where possible, we performed subgroup analyses for: administra-

tion route and dose of factor Xa inhibitor; previous stroke versus

no previous stroke; participants who received VKA treatment with

time-in-therapeutic range (TTR) equal to or greater than 60%

(’good quality’) versus less than 60% (’poor quality’) (Connolly

2008; ESC 2010); VKA treatment-experienced participants ver-

sus treatment-naive participants; participants who received con-

comitant antiplatelet therapy (that is aspirin) versus those who did

not; age less than 75 years versus age 75 years or over; race; sex;

and baseline stroke risk factors (assessed by the CHADS2 score).

We used the method described by Deeks et al for performing

subgroup analyses (Deeks 2001).

Sensitivity analysis

In the case of any evidence of heterogeneity that could not be

explained by study quality, we intended to conduct a sensitivity

analysis excluding any fully open-label trials.

R E S U L T S

Description of studies

For detailed descriptions see the Characteristics of included

studies; Characteristics of excluded studies; Characteristics

of ongoing studies; and Characteristics of studies awaiting

classification tables.

Results of the search

The literature search identified a total of 231 reports (original

search performed in June 2012 and repeated in April 2013; see

Figure 1 for details). After removing duplicates and screening of

titles and abstracts, we identified 21 reports that we retrieved in

full text and evaluated for eligibility.


(Review)


Figure 1. Study flow diagram.


(Review)


Nine of these reports were either expert reviews that contained no

original data, publications of subgroup analyses of included stud-

ies, or study protocols (see Characteristics of excluded studies for

further details). The remaining reports were original publications

of randomised, controlled clinical trials enrolling a total of 42,274

participants with AF who were considered eligible for long-term

anticoagulation with a VKA (AMADEUS 2008; Edoxaban Asia

2010; Edoxaban US/Europe 2010; OPAL-1 2010; OPAL-2 2011;

ARISTOTLE 2011; ARISTOTLE-J 2011; ROCKET AF 2011;

J-ROCKET AF 2012; EXPLORE-Xa 2013).

We also identified an ongoing study of edoxaban (ENGAGE AF-

TIMI 48). Finally, we identified a study of biotinylated idraparinux

(BOREALIS AF 2007) that was terminated prematurely; outcome

data have not yet been reported for this study. When available,

data from these two studies will be included in updates of this

review.

In AMADEUS 2008 97 participants recruited by a single cen-

tre were excluded from the intention-to-treat analyses for reasons

that were not stated in the publication. In ROCKET AF 2011

93 participants, all recruited by one centre, were excluded from

the intention-to-treat analyses because of good clinical practice

violations that made the data unreliable. After exclusion of these

190 people, we had data for 42,084 randomised participants for

analysis in this systematic review.

Various types of factor Xa inhibitors were directly compared with

warfarin in the included studies. AMADEUS 2008 studied the

compound idraparinux, which was administered subcutaneously

once a week. The remaining nine trials all used oral factor Xa

inhibitors (i.e. rivaroxaban, apixaban, edoxaban, betrixaban and

darexaban) that were administered once or twice daily. All studies

randomised participants to more than one dose of the studied

factor Xa inhibitor. Studies of apixaban (ARISTOTLE 2011;

ARISTOTLE-J 2011) and rivaroxaban (ROCKET AF 2011; J-

ROCKET AF 2012) contributed to approximately 80% of all data

included in this review.

In all trials dose-adjusted warfarin was the active comparator. In

most trials the target INR was between 2.0 to 3.0. However, peo-

ple aged at least 70 years or more that were randomised into

ARISTOTLE-J 2011 had a target INR of 2.0 to 2.6, whereas peo-

ple in this age category had a target INR of 1.6 to 2.6 in OPAL-1

2010 and J-ROCKET AF 2012. The quality of the anticoagulation

with warfarin (TTR calculated using the Rosendaal method) was

reported in AMADEUS 2008, Edoxaban Asia 2010, Edoxaban

US/Europe 2010, ARISTOTLE 2011, ARISTOTLE-J 2011,

ROCKET AF 2011, J-ROCKET AF 2012 and EXPLORE-Xa

2013. Reported TTR values ranged from 45% to 65% in these

studies. TTR values were not reported in OPAL-1 2010 and

OPAL-2 2011.

The mean baseline CHADS2 score in the included studies was

2.7 (range 1.9 to 3.5). Mean baseline CHADS2 scores were not

reported in AMADEUS 2008, Edoxaban US/Europe 2010 and

OPAL-1 2010.

All participants were 18 years or older. Mean and median ages of

randomised participants ranged between 65 and 74 years, and 36%

of randomised participants were women. Mean ages and gender

were not stated in OPAL-1 2010.

The median duration of follow-up ranged from 12 weeks to

1.9 years. The larger AMADEUS 2008, ROCKET AF 2011,

J-ROCKET AF 2012 and ARISTOTLE 2011 trials were all event-

driven studies, whereas the remaining smaller studies all had pre-

defined durations of follow-up.

The included studies used different definitions of ’disabling stroke’.

ROCKET AF 2011 used the modified Rankin scale to score stroke

outcome; scores from 0 to 2 were defined as ’non-disabling’, and

scores 3 to 5 as ’disabling’. The outcome of stroke was only assessed

by the investigator in this study. Data on disabling strokes (that

is ’strokes with serious residual disability’) were also reported in

J-ROCKET AF 2012, though it was not stated which functional

outcome scale and which cut-off value, if any, were used to define

’serious residual disability’. In OPAL-1 2010 it was unclear which

scale was used for assessing functional outcome in one patient

that suffered an ischaemic stroke during the study period. In the

paper it was stated that this stroke was ’resolved’. We have therefore

chosen not to count this ischaemic stroke as a disabling stroke.

Risk of bias in included studies

For detailed information see: Characteristics of included studies.

Allocation

All 10 included trials randomly assigned participants to treat-

ment groups using either a computerised interactive voice re-

sponse system (AMADEUS 2008; Edoxaban US/Europe 2010;

ROCKET AF 2011), block randomisation schedule (Edoxaban

Asia 2010), or a non-specified randomisation method (OPAL-1

2010; ARISTOTLE 2011; ARISTOTLE-J 2011; OPAL-2 2011;

J-ROCKET AF 2012; EXPLORE-Xa 2013).

Randomisation was stratified for previous warfarin use (that is

warfarin-experienced versus naive) and clinical site in AMADEUS

2008, ARISTOTLE 2011, ARISTOTLE-J 2011 and EXPLORE-

Xa 2013. The remaining seven trials did not report stratification

for any baseline variables.

Blinding

ARISTOTLE 2011, OPAL-2 2011, ROCKET AF 2011 and

J-ROCKET AF 2012 were fully double-masked trials. Edoxaban

Asia 2010, Edoxaban US/Europe 2010, ARISTOTLE-J 2011

and EXPLORE-Xa 2013 were partially-masked trials: the differ-

ent doses of factor Xa inhibitors were administered in a double-


(Review)


masked fashion, whereas warfarin was administered open-label.

The AMADEUS 2008 trial was the only fully open-label study.

Adjudication of outcome events was performed by blinded, cen-

tralised committees in AMADEUS 2008, Edoxaban US/Europe

2010, ARISTOTLE 2011, ARISTOTLE-J 2011, ROCKET AF

2011, J-ROCKET AF 2012 and EXPLORE-Xa 2013. A cen-

tralised adjudication committee was also used in Edoxaban Asia

2010, but it was unclear whether this committee was fully blinded

or not as this was not specified in the publication. No details on

the adjudication of outcome events were provided for OPAL-1

2010 and OPAL-2 2011.

Incomplete outcome data

The reported analysis for efficacy outcomes was intention-to-treat

analysis in AMADEUS 2008, OPAL-1 2010, ARISTOTLE 2011,

ARISTOTLE-J 2011, OPAL-2 2011, ROCKET AF 2011 and

EXPLORE-Xa 2013. In J-ROCKET AF 2012 the primary effi-

cacy outcome (composite of stroke and systemic embolic events)

was reported for the intention-to-treat population; other efficacy

outcomes were analysed in the per protocol population, defined as

participants without any major study protocol violations. This def-

inition led to the exclusion of six (0.5%) of the 1280 randomised

participants from all secondary efficacy analyses in J-ROCKET

AF 2012. In Edoxaban Asia 2010 and Edoxaban US/Europe 2010

efficacy outcomes were only analysed in the ’safety population’,

defined as participants who received at least one dose of the study

drug and had at least one post-dose assessment. This led to the

exclusion of one (0.4%) of the 235 randomised participants in

Edoxaban Asia 2010, and three (0.3%) of the 1146 randomised

participants in Edoxaban US/Europe 2010.

Safety outcomes were analysed in the intention-to-treat pop-

ulation in AMADEUS 2008, OPAL-1 2010, OPAL-2 2011

and EXPLORE-Xa 2013. In Edoxaban Asia 2010, Edoxaban

US/Europe 2010, ARISTOTLE 2011, ARISTOTLE-J 2011,

ROCKET AF 2011 and J-ROCKET AF 2012 safety outcomes

were only analysed in the ’safety population’, defined as the par-

ticipants who received at least one dose of the study drug. This

led to the exclusion of one (0.4%); three (0.3%); 61 (0.3%); five

(2.3%); 28 (0.2%); and two (0.2%) randomised participants in

Edoxaban Asia 2010, Edoxaban US/Europe 2010, ARISTOTLE

2011, ARISTOTLE-J 2011, ROCKET AF 2011 and J-ROCKET

AF 2012, respectively.

Loss to follow-up in the included studies was low, ranging

from 0% (ARISTOTLE-J 2011; J-ROCKET AF 2012) to 2.7%

(AMADEUS 2008) of all randomised participants. The number

of participants lost to follow-up was not reported in OPAL-1 2010

and OPAL-2 2011.

Selective reporting

There was no indication of selective reporting in any of the in-

cluded studies. All predefined efficacy and safety outcomes stated

in the study protocols were reported in the publications or ab-

stracts, or both.

Other potential sources of bias

AMADEUS 2008 was terminated prematurely after a recommen-

dation from the trial’s data and safety monitoring board (DSMB)

because of excess bleeding complications in the idraparinux group.

None of the other included trials were stopped prematurely. En-

rolment into the darexaban 240 mg once daily treatment arm

in OPAL-1 2010 and the edoxaban 60 mg twice daily arm in

Edoxaban US/Europe 2010 was halted after recommendations by

the trials’ respective DSMBs due to an excess of bleeding compli-

cations.

Effects of interventions

See: Summary of findings for the main comparison

See the analyses. Note that all outcomes had fewer trials contribut-

ing data than the 10 studies that we included in the review. This

was because none of the included trials collected or reported data

on all outcomes examined in this review.

Primary outcome

The composite endpoint of all strokes (both ischaemic and haem-

orrhagic) and other systemic embolic events was reported in nine

of the included studies (n = 40,777). Most data (approximately

90%) were available from studies that used the agents apixa-

ban (ARISTOTLE 2011; ARISTOTLE-J 2011) and rivaroxaban

(ROCKET AF 2011; J-ROCKET AF 2012). No data were avail-

able for one of the trials that studied darexaban (OPAL-2 2011).

Treatment with a factor Xa inhibitor significantly decreased the

number of strokes and other systemic embolic events compared

with dose-adjusted warfarin in participants with AF (Analysis 1.1:

OR 0.81, 95% CI 0.72 to 0.91). We observed no statistically sig-

nificant heterogeneity (I² = 0%). Of note, the total number of

non-central nervous system (CNS) systemic embolic events was

very low (n = 66), contributing to approximately 5% of all out-

comes of the composite endpoint. The primary outcome was thus

mainly driven by the stroke component.

We also calculated the number needed to treat (NNT) for studies

with follow-up periods of one year or more (ARISTOTLE 2011;

ROCKET AF 2011; J-ROCKET AF 2012). The NNT for apix-

aban (ARISTOTLE 2011) was 304 per year (or 169 for a total

treatment period of 1.8 years), indicating that 304 people needed

to be treated with apixaban for one year to prevent one more stroke

or systemic embolic embolism compared with dose-adjusted war-

farin. The NNTs for rivaroxaban were 369 per year (194 for a total

treatment period of 1.9 years) based on data from ROCKET AF

2011, and 81 per year (58 for a total treatment period of 1.4 years)

based on data from the smaller J-ROCKET AF 2012 trial.


(Review)


http://archie.cochrane.org/sections/documents/view?version=z1307221314505956570231682179101%26format=REVMAN#STD-ARISTOTLE-2011


http://archie.cochrane.org/sections/documents/view?version=z1307221314505956570231682179101%26format=REVMAN#STD-ROCKET-AF-2011



http://archie.cochrane.org/sections/documents/view?version=z1307221314505956570231682179101%26format=REVMAN#STD-J_x002d_ROCKET-AF-2012













Secondary outcomes

All strokes (ischaemic and haemorrhagic)

The composite endpoint of all strokes was reported in nine studies

(n = 40,749). No data were available for OPAL-2 2011. Treatment

with a factor Xa inhibitor significantly decreased the number of

strokes compared with warfarin (Analysis 1.2: OR 0.78, 95% CI

0.69 to 0.89). There was no heterogeneity between the studies (I²

= 0%).

Ischaemic stroke

We calculated the effect of treatment with a factor Xa inhibitor

compared with a VKA on the number of ischaemic strokes for eight

of the included studies that randomised 39,606 participants. No

data were available for Edoxaban US/Europe 2010 and OPAL-2

2011. The analysis showed a lower number of ischaemic strokes

in participants treated with a factor Xa inhibitor compared with

warfarin, but this difference did not reach statistical significance

(Analysis 1.3: OR 0.88, 95% CI 0.76 to 1.02). There was low,

non-significant heterogeneity between the analysed studies (I² =

3%).

Disabling or fatal strokes

Four studies that included 16,099 participants reported data on

disabling or fatal strokes (Edoxaban Asia 2010; OPAL-1 2010;

ROCKET AF 2011; J-ROCKET AF 2012). Treatment with a

factor Xa inhibitor significantly reduced the number of disabling

or fatal strokes compared with warfarin (Analysis 1.4: OR 0.71,

95% CI 0.54 to 0.92). We observed no heterogeneity (I² = 0%).

Non-central nervous system (CNS) systemic embolic events

The occurrence of non-CNS systemic embolic events was sepa-

rately reported in nine of the included studies, including a to-

tal of 40,749 participants. No data were available for OPAL-2

2011. Treatment with a factor Xa inhibitor significantly reduced

the number of non-CNS systemic embolic events compared with

warfarin (Analysis 1.5: OR 0.53, 95% CI 0.32 to 0.87). There

was low, non-significant heterogeneity (I² = 17%).

Major bleedings

All of the included studies (n = 42,078) reported the number of

major bleedings defined either by the ISTH-criteria or a slight

modification of these criteria. Treatment with a factor Xa inhibitor

significantly reduced the number of major bleedings compared

with warfarin (Analysis 1.6: OR 0.89, 95% CI 0.81 to 0.98). There

was, however, statistically significant heterogeneity (I² = 81%). In

view of this high heterogeneity, we also performed an analysis using

a random-effects model. Contrary to the results from the fixed-

effect model, this analysis did not show a statistically significant

decrease in the number of major bleedings in participants treated

with factor Xa inhibitors compared with warfarin (OR 0.92, 95%

CI 0.63 to 1.34).

To explore the observed statistical heterogeneity we also performed

a pre-specified sensitivity analysis excluding open-label studies

(sensitivity analyses not shown in forest plots). The only fully open-

label trial was AMADEUS 2008, which was stopped prematurely

due to an excess of major bleeding in the idraparinux arm (OR

2.62, 95% CI 1.70 to 4.03). The sensitivity analysis excluding

AMADEUS 2008, and the use of a fixed-effect model, showed

that treatment with a factor Xa inhibitor significantly reduced the

number of major bleedings compared with warfarin (OR 0.84,

95% CI 0.76 to 0.92). We still, however, observed moderate het-

erogeneity (I² = 65%). An identical sensitivity analysis using a ran-

dom-effects model did not show a statistically significant decrease

in the number of major bleedings in participants treated with fac-

tor Xa inhibitors (OR 0.78, 95% CI 0.57 to 1.05).

Some of the remaining heterogeneity might be explained by dif-

ferences in bleeding risks between the study populations in the

two largest trials (i.e.ROCKET AF 2011 and ARISTOTLE 2011).

Participants enrolled into ROCKET AF 2011, when compared

with those enrolled into ARISTOTLE 2011, were generally older

(median age 73 years versus 70 years, respectively), had higher

CHADS2 scores (mean 3.8 versus 2.1), had more often suffered

previous stroke or TIA (55% versus 19%), were more often treated

for hypertension (90% versus 87%) and more often used aspirin

at baseline (38% versus 31%), which are all known risk factors for

(major) bleedings during anticoagulant treatment (Pisters 2010).

The observed differences between the enrolled study populations

might partly explain the increased risk of major bleeding compli-

cations that was seen in participants treated with rivaroxaban in

ROCKET AF 2011.

Intracranial haemorrhages (ICH)

Data on ICHs were reported in eight studies that randomised

39,638 participants. No data were reported for Edoxaban US/

Europe 2010 and OPAL-2 2011. Treatment with a factor Xa

inhibitor significantly reduced the risk of ICH compared with

warfarin (Analysis 1.7: OR 0.56, 95% CI 0.45 to 0.70). Still,

we observed statistically significant, moderate heterogeneity (I²

= 60%). An additional analysis using a random-effects model

showed a somewhat smaller, non-significant reduction in partic-

ipants treated with a factor Xa inhibitor compared with warfarin

(OR 0.61, 95% CI 0.36 to 1.05).

Again, we performed a pre-specified sensitivity analysis excluding

open-label studies to further explore the observed moderate het-

erogeneity (sensitivity analyses not shown in forest plots). The only

open-label study was the prematurely halted AMADEUS 2008,

in which a statistically significant increase in the risk of ICHs was


(Review)


observed (OR 11.10, 95% CI 1.43 to 86.02). The sensitivity anal-

ysis with a fixed-effect model showed that treatment with a factor

Xa inhibitor significantly reduced the number of ICHs compared

with warfarin (OR 0.51, 95% CI 0.41 to 0.64). We observed no

heterogeneity (I² = 0%).

Non-major clinically relevant bleedings

All studies reported the number of non-major clinically relevant

bleeding defined by either ISTH criteria or a modification of these

criteria. Data on 42,078 randomised participants were available

for analysis. There was no statistically significant difference in the

number of non-major clinically relevant bleedings in participants

treated with a factor Xa inhibitor compared with warfarin (Analysis

1.8: OR 1.00, 95% CI 0.93 to 1.07). We observed statistically

significant, high heterogeneity (I² = 85%). An analysis with a ran-

dom-effects model also showed no statistically significant differ-

ence in the number of non-major clinically relevant bleedings that

were observed in the two treatment groups (OR 0.97, 95% CI

0.74 to 1.27).

We performed a pre-specified sensitivity analysis excluding open-

label studies (sensitivity analysis not shown in forest plots).

This sensitivity analysis again excluded the prematurely halted

AMADEUS 2008 study, in which a statistically significant increase

in the risk of non-major clinically relevant bleedings was reported

(OR 1.48, 95% CI 1.23 to 1.79). The sensitivity analysis using

a fixed-effect model showed that treatment with a factor Xa in-

hibitor did not significantly reduce the number of non-major clin-

ically relevant bleedings compared with warfarin (OR 0.94, 95%

CI 0.87 to 1.01). However, we observed statistically significant,

high heterogeneity (I² = 80%). The same sensitivity analysis using

a random-effects model gave similar results (OR 0.89, 95% CI

0.67 to 1.18).

Some of this observed statistical heterogeneity in the analyses

for clinically relevant non-major bleedings might again be ex-

plained by baseline differences in bleeding risk between the study

populations in the two largest trials (i.e. ROCKET AF 2011

and ARISTOTLE 2011) included in this review (see also section

Effects of interventions, Major bleedings).

Myocardial infarction

The number of myocardial infarctions that occurred during the

study period was reported in eight studies that randomised 40,301

participants. No data were available for OPAL-1 2010 and OPAL-

2 2011. There was no statistically significant difference between

the number of myocardial infarctions in participants treated with

factor Xa inhibitors compared with warfarin (Analysis 1.9: OR

0.87, 95% CI 0.73 to 1.05). We observed no heterogeneity (I² =

0%).

Vascular deaths

Vascular deaths were reported in seven studies (n = 22,100). No

data were available for OPAL-1 2010, ARISTOTLE 2011 and

OPAL-2 2011. The analysis showed no statistically significant dif-

ference between the number of vascular deaths in participants

treated with factor Xa inhibitors compared with warfarin (Analysis

1.10: OR 0.87, 95% CI 0.72 to 1.05). There was no sign of any

heterogeneity (I² = 0%).

All-cause deaths

The number of participants who died from any cause was reported

in six studies (n = 38,924). No data were available for Edoxaban

Asia 2010, Edoxaban US/Europe 2010, OPAL-1 2010 and OPAL-

2 2011. Treatment with a factor Xa inhibitor significantly reduced

the number of all-cause deaths compared with warfarin (Analysis

1.11: OR 0.88, 95% 0.81 to 0.97). We observed no heterogeneity

(I² = 0%).

Other adverse events

The pre-specified secondary outcome ’Other adverse events’ was

not analysed because of a paucity of data on adverse events other

than bleedings, non-CNS systemic embolic events, and other car-

diovascular events in a large majority of the included studies. Suf-

ficient data on other adverse events were only systematically pre-

sented for apixaban and rivaroxaban and are listed in the appen-

dices of the original publications (ARISTOTLE 2011; ROCKET

AF 2011). There was no evidence for an increased risk of hepa-

totoxicity associated with apixaban or rivaroxaban compared with

warfarin in these two studies.

Subgroup analyses

We performed several pre-specified subgroup analyses for both

the primary efficacy outcome (composite of stroke and systemic

embolic events) and the main safety outcome (major bleedings).

Different factor Xa inhibitors

A subgroup analysis of the different factor Xa inhibitors showed

that only the agents apixaban (OR 0.78, 95% CI 0.65 to 0.93)

and rivaroxaban (OR 0.85, 95% CI 0.72 to 1.00) significantly de-

creased the number of strokes and systemic embolic events com-

pared with warfarin (Analysis 1.1). The agents idraparinux, edox-

aban, darexaban and betrixaban did not show a statistically sig-

nificant difference in the number of strokes and systemic embolic

events compared with warfarin, but there was no evidence of het-

erogeneity between the risk estimates of these agents and those of

apixaban or rivaroxaban (Analysis 1.1).

We also analysed the number of major bleedings by type of factor

Xa inhibitor (Analysis 1.6). Major bleedings occurred significantly


(Review)


less often in participants that were treated with apixaban (OR

0.69, 95% CI 0.60 to 0.80) and betrixaban (OR 0.19, 95%CI

0.05 to 0.82) compared with warfarin, whereas significantly more

major bleedings were observed in participants treated with idra-

parinux (OR 2.62, 95% CI 1.70 to 4.03). We saw no statistically

significant differences compared with warfarin for the compounds

rivaroxaban, edoxaban and darexaban; there was no evidence of

heterogeneity between the risk estimates (Analysis 1.6).

Quality of anticoagulation with warfarin

We intended to perform a subgroup analysis in participants who

received VKA treatment with time-in-therapeutic range (TTR)

equal to or greater than 60% versus less than 60%. Unfortu-

nately, we had only sufficient raw data from ROCKET AF 2011 to

perform this subgroup analysis for the primary efficacy endpoint

(Analysis 5.1). The number of strokes and systemic embolic events

in participants treated at centres with ’good quality’ warfarin ad-

ministration (centre TTR > 58.5%) was lower in participants that

were treated with rivaroxaban compared with warfarin, though the

difference did not reach statistical significance (OR 0.78, 95% CI

0.60 to 1.02). The number of strokes and systemic embolic events

in centres with ’poor quality’ warfarin administration (centre TTR

< 58.5%) was also lower in participants treated with rivaroxaban,

though again a statistically significant difference was not observed

(OR 0.81, 95% CI 0.62 to 1.07).

Data presented in the publication of the final results of the

J-ROCKET AF 2012 trial also indicated that there was a non-

significant decrease in the number of strokes and systemic embolic

events in participants treated with rivaroxaban regardless of the

quality of warfarin administration assessed by centre TTR.

Data from the ARISTOTLE 2011 trial also indicated a non-sig-

nificant decrease in the number of strokes and systemic embolic

events in participants treated with apixaban regardless of the qual-

ity of warfarin administration by centre TTR (Wallentin 2011).

These findings might indicate that, at least for apixaban and ri-

varoxaban, the benefits of preventing stroke and other systemic

embolic events compared with warfarin are more or less consis-

tent regardless of the quality of warfarin administration. Still, local

standards of care might well affect the benefits of treatment with

factor Xa inhibitors, as was observed with the direct thrombin in-

hibitor dabigatran when studied for a similar indication (Wallentin

2010). This important issue clearly merits further investigation.

Other pre-specified subgroup analyses

We also performed analyses for the primary efficacy and safety end-

point for the following subgroups: administration route (Analysis

2.1; Analysis 2.2); dose of factor Xa inhibitor (Analysis 3.1;

Analysis 3.2); previous stroke (Analysis 4.1; Analysis 4.2); prior

VKA treatment-experience (Analysis 6.1; Analysis 6.2); concomi-

tant antiplatelet therapy (aspirin) (Analysis 7.1; Analysis 7.2); age

less than 75 years (Analysis 8.1); race (Analysis 9.1; Analysis 9.2);

sex (Analysis 10.1; Analysis 10.2); and baseline stroke risk factors

(Analysis 11.1; Analysis 11.2).

Most of the explored subgroups contained relatively few events in

the experimental and control arms and the results of these sub-

group analyses should be interpreted with caution.

D I S C U S S I O N

Summary of main results

We analysed data from 42,084 participants with a confirmed di-

agnosis of AF, which were included in 10 trials that directly com-

pared the effectiveness and safety of long-term anticoagulation

with factor Xa inhibitors with those of VKAs. Treatment with a

factor Xa inhibitor significantly reduced the number of strokes

and other systemic embolic events compared with dose-adjusted

warfarin. Still, the absolute overall effect in the reduction of stroke

and systemic embolic events with a factor Xa inhibitor compared

with warfarin appears to be rather small, as shown by the relatively

high NNTs in the larger studies with follow-up periods of more

than one year (NNT 304 per year for apixaban and NNT 369 per

year for rivaroxaban).

Treatment with a factor Xa inhibitor significantly reduced the

number of major bleedings (including ICHs) compared with war-

farin, but there was a moderate to high degree of heterogeneity

between the included trials. A pre-specified sensitivity analysis ex-

cluding the open-label studies showed that part of the observed

heterogeneity can be explained by the increased risk of major bleed-

ings in one open-label study of subcutaneously administered idra-

parinux (AMADEUS 2008). This study was also stopped prema-

turely on the basis of increased risk of bleeding in the idraparinux

treatment arm. Because of the premature termination of the study

it is difficult to know whether this was a false positive finding or

whether there is indeed an increased risk of bleeding from idra-

parinux or from subcutaneous administration, or both. Other het-

erogeneity might be explained by baseline differences in the risk

of bleeding between the study populations enrolled into the two

largest trials (i.e.ROCKET AF 2011 and ARISTOTLE 2011).

Importantly, treatment with a factor Xa inhibitor significantly re-

duced the number of all-cause deaths compared with dose-ad-

justed warfarin. Furthermore, treatment with a factor Xa inhibitor

did not seem to be associated with an increased risk of acute my-

ocardial infarction or vascular death.

In conclusion, factor Xa inhibitors appear to be an effective treat-

ment for the prevention of stroke or other systemic embolic events

in people with AF who are eligible for long-term anticoagulation.

However, high NNTs indicate that factor Xa inhibitors are only

marginally more effective in the prevention of strokes and sys-

temic embolic events than treatment with dose-adjusted warfarin.


(Review)


Factor Xa inhibitors also appear to reduce the number of major

bleedings and intracranial haemorrhages (ICHs) compared with

warfarin, though the evidence for a statistically significant reduc-

tion in major bleedings is less robust. The effect estimates varied

for the different factor Xa inhibitors and it is not possible to deter-

mine which factor Xa inhibitor is more effective and safe as head-

to-head studies have not yet been performed.

Overall completeness and applicability ofevidence

All data that were used in this review are from studies that ran-

domised people with a confirmed diagnosis of AF and who were

deemed eligible for long-term anticoagulation with a VKA by the

randomising physician. The mean CHADS2 score of the ran-

domised participants was 2.7 (range 1.9 to 3.5), suggesting that

few, if any, people with AF who did not need anticoagulation

for preventing thromboembolic events (so called ’truly low risk

people’) were included in the trials. Reported TTR values ranged

from 45% to 65% in the included studies but varied between re-

gion and centres. In general, the observed TTRs are comparable

with those of older studies that used dose-adjusted warfarin for

preventing stroke and systemic embolic events in people with AF.

The majority of included studies did not state an upper age limit

as a contraindication and the mean or median ages of randomised

participants ranged between 65 and 74 years. Based on these ob-

servations, we can be reasonably confident that this review covers a

relevant population of people with AF eligible for anticoagulation

in a ’real world’ setting.

The CHA2DS2-VASc score was not used in any of the included

studies to assess the risk of stroke. Recent guidelines (ESC 2012)

recommend that anticoagulation with either a new oral anticoag-

ulant or VKA should be considered in people with a CHA2DS2-

VASc score ≥1. There is evidence that the CHA2DS2-VASc scale

is better at identifying people with a ’very low’ risk of stroke than

the older CHADS2 score (ESC 2012). Consequently, data from

people who are at a ’very low’ risk of stroke are probably not in-

cluded in this review. Caution is thus needed when drawing any

conclusions on the effectiveness and safety of factor Xa inhibitors

compared with warfarin in these ’very low risk’ people.

Data on participants with severe renal failure (that is creatinine

clearance < 30 ml/minute), who have a high risk of both throm-

boembolic events and bleedings, are also scarce in this review be-

cause these people were excluded from participation in most of

the included trials.

We intended to perform a subgroup analysis in participants who

received VKA treatment with time-in-therapeutic range (TTR)

equal to or greater than 60% (’good quality’) versus less than 60%

(’poor quality’). Unfortunately, we had only sufficient raw data

from one study to perform this subgroup analysis for the primary

efficacy endpoint. Although there is evidence that the efficacy and

safety of rivaroxaban and apixaban are more or less consistent re-

gardless of the quality of warfarin administration, local standards

of care might well affect the benefits of treatment with these and

other factor Xa inhibitors, as was observed with the direct throm-

bin inhibitor dabigatran when studied for a similar indication

(Wallentin 2010). This important issue clearly merits further in-

vestigation and we plan to update this subgroup analysis when

more date become available.

Finally, we have included data from six different factor Xa in-

hibitors in this review. Still, a large majority of the data (approxi-

mately 80%) is from only two types of factor Xa inhibitors: apix-

aban and rivaroxaban. Results from the analyses of the other fac-

tor Xa inhibitors are based on smaller data sets and are thus less

robust.

Quality of the evidence

The studies included in this review were generally large to very

large; the smallest study included 222 participants. Only one of the

10 included studies was conducted in an open-label fashion. The

remaining studies were either double-masked or partially-masked.

Most studies used centralised and blinded adjudication commit-

tees for the primary safety and efficacy outcomes. Furthermore,

outcome data from the (larger) studies appear generally consistent.

Based on these considerations, the overall quality of the body of

evidence assessed in this review is considered high.

Potential biases in the review process

We carried out thorough searches of several different databases to

avoid selection bias, but there is still a small possibility that we

might have missed some (smaller) studies.

We contacted lead authors and sponsors in order to gather non-re-

ported (raw) data from relevant studies. Unfortunately, such data

were only (partly) provided for two studies (AMADEUS 2008

and J-ROCKET AF 2012). When additional relevant data from

included studies become available, we will update the review. For

future updates of this review, we also plan to request access to rel-

evant study reports that were submitted to regulatory agencies by

pharmaceutical companies in applications for marketing authori-

sation.

Agreements and disagreements with otherstudies or reviews

We compared our findings with a recent meta-analysis performed

by Miller and colleagues (Miller 2012). This meta-analysis in-

cluded results from the factor Xa inhibitors apixaban and rivarox-

aban that were reported in ARISTOTLE 2011 and ROCKET AF

2011, respectively. Results from these two trials were pooled with

the results from the RE-LY trial that compared the direct thrombin

inhibitor dabigatran with dose-adjusted warfarin in people with


(Review)


AF. The raw data entered for the primary efficacy and safety out-

comes for rivaroxaban and apixaban are identical to the data used

in our review, but data from two studies of these compounds, per-

formed in Japan, were lacking (ARISTOTLE-J 2011; J-ROCKET

AF 2012).

We did not identify any other published systematic meta-analyses

of factor Xa inhibitors compared with VKA for the prevention of

thromboembolic events in people with AF.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice• Overall, there is a small net clinical benefit of treatment

with factor Xa inhibitors in people with AF as it leads to a

reduction of strokes and systemic embolic events and also seems

to lower the risk of major bleedings (including intracranial

haemorrhages) compared with dose-adjusted warfarin.

• Despite the apparent overall net clinical benefit, the

currently available efficacy and safety data do not provide

sufficient evidence to determine the optimal factor Xa inhibitor,

as head-to-head studies have not yet been performed.

• Caution is needed when drawing any conclusions about the

net clinical benefit for people with a ’very low risk’ for

thromboembolic events (i.e. low CHA2DS2-VASc scores) and

people with severe renal failure, as these people were not included

in the majority of studies that we analysed in this review.

Implications for research

Future studies could aim to:

• further determine the effectiveness and safety of long-term

anticoagulation treatment with a factor Xa inhibitor (i.e. beyond

two years) in a ’real world’ population of people with AF;

• identify means of minimising the risk of major and

clinically relevant non-major bleedings without reducing the

benefit of factor Xa inhibitors;

• further assess the efficacy and safety of factor Xa inhibitors

in people with a ’very low risk’ for thromboembolic events (i.e.

low CHA2DS2-VASc scores);

• provide more (long-term) data on quality of life and cost-

effectiveness of treatment with factor Xa inhibitors compared

with VKA for prevention of thromboembolic events in people

with AF;

• identify blood tests to monitor the effect of factor Xa

inhibitors and develop antidotes to counteract the

anticoagulation effect when needed.

A C K N O W L E D G E M E N T S

We thank Brenda Thomas for her help in developing the search

strategies, and the peer reviewers for their constructive feedback.

R E F E R E N C E S

References to studies included in this review

AMADEUS 2008 {published and unpublished data}

The Amadeus Investigators. Comparison of idraparinux

with vitamin K antagonists for prevention of

thromboembolism in patients with atrial fibrillation: a

randomised, open-label, non-inferiority trial. Lancet 2008;

371:315–21.

ARISTOTLE 2011 {published data only (unpublished sought but not

used)}

Granger CB, Alexander JH, McMurray JJ, Lopes RD,

Hylek EM, Hanna M, et al. Apixaban versus warfarin in

patients with atrial fibrillation. New England Journal of

Medicine 2011;365:981–92.

ARISTOTLE-J 2011 {published data only (unpublished sought but

not used)}

Ogawa S, Shinohara Y, Kanmuri K. Safety and efficacy of

the oral direct factor Xa inhibitor apixaban in Japanese

patients with non-valvular atrial fibrillation. Circulation

Journal 2011;75:1852–9.

Edoxaban Asia 2010 {published data only (unpublished sought but

not used)}

Chung N, Jeon H-K, Lien L-M, Lai W-T, Tse H-F, Chung

W-S, et al. Safety of edoxaban, an oral factor Xa inhibitor,

in Asian patients with non-valvular atrial fibrillation.

Thrombosis and Haemostasis 2010;105:535–45.

Edoxaban US/Europe 2010 {published data only (unpublished sought

but not used)}

Weitz JI, Connolly SJ, Patel I, Salazar D, Rohatagi S,

Mendell J, et al. Randomised, parallel-group, multicentre,

multinational phase 2 study comparing edoxaban, an oral

factor Xa inhibitor, with warfarin for stroke prevention in

patients with atrial fibrillation. Thrombosis and Haemostasis

2010;104:633–41.

EXPLORE-Xa 2013 {published data only (unpublished sought but not

used)}

Connoly SJ, Eikelboom J, Dorian P, Hohnloser SH, Gretler

DD, Sinha U, et al. Betrixaban compared with warfarin

in patients with atrial fibrillation: results of a phase 2,

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(Review)


Heart Journal 2013;34(20):1498–505. [DOI: 10.1093/

eurheartj/eht/039]

J-ROCKET AF 2012 {published and unpublished data}

Hori M, Matsumoto M, Tanahashi N, Momomura SI,

Uchiyama S, Goto S, J-ROCKET AF study investigators.

Rivaroxaban vs warfarin in Japanese patients with atrial

fibrillation. Circulation Journal 2012;76(9):2104–11. [doi:

10.1253/circj.CJ–12–0454]

OPAL-1 2010 {published and unpublished data}

Turpie AGGF, Lip GYH, Minematsu K, Goto S, Renfurm

RW, Wong KSL. Safety and tolerability of YM150 in

subjects with non-valvular atrial fibrillation: a phase II

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Lip GYH, Halperin JL, Petersen P, Rodger GM, Renfurm

RW. Safety and tolerability of the oral factor Xa inhibitor

YM150 vs warfarin in 1297 patients with non-valvular atrial

fibrillation: a dose confirmation study (OPAL-2). Journal of

Thrombosis and Haemostatis 2011;9 Suppl 2:748.

ROCKET AF 2011 {published data only (unpublished sought but not

used)}

Patel MR, Mahaffey KW, Garg Y, Pan G, Singer DE, Hacke

W, et al. Rivaroxaban versus warfarin in nonvalvular atrial

fibrillation. New England Journal of Medicine 2011;365:

883–91.

References to studies excluded from this review

Camm 2011 {published data only}

Camm AJ, Bounameaux H. Edoxaban: a new oral direct

factor xa inhibitor. Drugs 2011;71(12):1503–26.

Fox 2011 {published data only}

Fox KA, Piccini JP, Wojdyla D. Prevention of stroke

and systemic embolism with rivaroxaban compared with

warfarin in patients with non-valvular atrial fibrillation and

moderate renal impairment. European Heart Journal 2011;

32(19):2387–94.

Hankey 2012 {published data only}

Hankey GJ, Patel MR, Stevens SR, ROCKET AF Steering

Committee Investigators. Rivaroxaban compared with

warfarin in patients with atrial fibrillation and previous

stroke or transient ischaemic attack: a subgroup analysis of

ROCKET AF. Lancet Neurology 2012;11(4):315–22.

Harenberg 2010 {published data only}

Harenberg J. Idraparinux and idrabioparinux. Expert Review

of Clinical Pharmacology 2010;3(1):9–16.

Lane 2011 {published data only}

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GY. Bleeding risk in patients with atrial fibrillation: the

AMADEUS study. Chest 2011;140(1):146–55.

Lopes 2010 {published data only}

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investigators. Apixaban for reduction in stroke and other

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trial: design and rationale. American Heart Journal 2010;

159(3):331–9.

Partida 2011 {published data only}

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principles, preclinical and early-phase clinical testing.

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ROCKET investigators 2010 {published data only}

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atrial fibrillation: rationale and design of the ROCKET AF

study. American Heart Journal 2010;159(3):340–7.

References to studies awaiting assessment

BOREALIS AF 2007 {published data only}

Evaluation of weekly subcutaneous biotinylated idraparinux

versus oral adjusted-dose warfarin to prevent stroke and

systemic thromboembolic events in patients with atrial

fibrillation (BOREALIS-AF). ClinicalTrials.gov 2007. [:

http://clinicaltrials.gov/show/NCT00580216]

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ENGAGE AF-TIMI 48 {published data only}

Ruff CT, Giugliano RP, Antman EM, Crugnale SE,

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factor Xa inhibitor edoxaban compared with warfarin in

patients with atrial fibrillation: design and rationale for the

Effective aNticoaGulation with factor xA next GEneration

in Atrial Fibrillation-Thrombolysis In Myocardial Infarction

study 48 (ENGAGE AF-TIMI 48). American Heart Journal

2010;160(4):635–41.

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

AMADEUS 2008

Methods Randomised, open-label, active-controlled trial

Participants 4673 people with documented AFand an indication for long-term anticoagulation based

on the presence of at least 1 of the following risk factors: previous ischaemic stroke, TIA or

systemic embolism; hypertension requiring drug treatment; left ventricular dysfunction;

age over 75 years; age 65 to 75 years with either diabetes mellitus or symptomatic coronary

artery disease

Interventions Idraparinux (2.5 mg weekly or 1.5 mg weekly subcutaneously in patients with a calculated

creatinine clearance at baseline of 10 to 30 ml/minute), or dose-adjusted warfarin (target

INR 2.0 to 3.0)

Outcomes Primary efficacy outcome: composite of stroke or systemic embolic event

Secondary efficacy outcomes: ischaemic stroke; non-ischaemic stroke; haemorrhagic

stroke; undefined stroke; non-CNS systemic embolism; venous thromboembolic events;

myocardial infarction

Primary safety outcome: major bleeding (defined by ISTH criteria)

Secondary safety outcomes: any clinically relevant bleeding; fatal bleeding; non-fatal

bleeding; non-fatal intracranial haemorrhage; bleeding into critical organ; bleeding as-

sociated with fall in haemoglobin of more than 20 g/L or leading to transfusion of

more than 2 units of blood; intracranial haemorrhage; intracranial events (ischaemic or

haemorrhagic stroke or other intracranial haemorrhage); non-major clinically relevant

bleeding; mortality

Notes Study sponsored by Sanofi

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk Participants were randomly assigned to

treatment groups

Allocation concealment (selection bias) Low risk Participants were randomly assigned to

treatment groups with a computerised in-

teractive voice response system. Stratifica-

tion by study centre and prior use of VKA

Blinding of participants and personnel

(performance bias)

All outcomes

High risk Open-label study: both participants and

study personnel were aware of the assigned

treatment


(Review)


AMADEUS 2008 (Continued)

Blinding of outcome assessment (detection

bias)

All outcomes

Low risk All suspected outcome events were adjudi-

cated by a central adjudication committee

unaware of the treatment assignment

Incomplete outcome data (attrition bias)

All outcomes

Low risk Efficacy and safety outcomes analysed in

ITT population. Number of participants

that discontinued are reported. Reasons for

discontinuation are listed

Selective reporting (reporting bias) Low risk All predefined efficacy and safety outcomes

are reported for the ITT population

Other bias Unclear risk Study terminated prior to finalisation af-

ter recommendation by the DSMB due to

excess bleeding complications in the idra-

parinux group

ARISTOTLE 2011

Methods Randomised, double-blind, active controlled trial

Participants 18,201 people with documented AF or atrial flutter and at least 1 additional risk factor for

stroke: at least 75 years old; previous stroke, TIA or systemic embolic event; symptomatic

heart failure within previous 3 months or left ventricular ejection fraction of no more

than 40%; diabetes mellitus; hypertension requiring pharmacologic treatment

Interventions Apixaban (5 mg twice daily, or 2.5 mg twice daily in participants with at least 2 or more

of the following criteria: age at least 80 years, body weight of no more than 60 kg, or

serum creatinine level of 1.5 mg/dl or more) versus dose-adjusted warfarin (target INR

2.0 to 3.0)

Outcomes Primary efficacy outcome: composite of stroke or systemic embolic events

Secondary efficacy outcomes: death from any cause, myocardial infarction

Primary safety outcome: major bleeding (ISTH criteria)

Secondary safety outcomes: composite of major bleeding and clinically relevant non-

major bleeding; any bleeding; other adverse events; liver function abnormalities

Notes Study sponsored by Bristol-Myers Squibb and Pfizer

Risk of bias



bias)


treatment groups


(Review)


ARISTOTLE 2011 (Continued)


treatment groups. Stratification by clinical

site and prior VKA use


(performance bias)

All outcomes

Low risk Double-blind, double-dummy design


bias)

All outcomes

Low risk Efficacy and safety outcomes were adjudi-

cated by a clinical events committee whose

members were not aware of study group as-

signments


All outcomes

Low risk Efficacy and safety outcomes analysed in

ITT population. Number of participants

with missing data on vital status and rea-

sons reported. Number of participants that

discontinued during study and reasons are

reported


reported for ITT population

Other bias Low risk N/A

ARISTOTLE-J 2011

Methods Randomised, partially-blinded, active controlled trial

Participants 222 Japanese people with a history of documented non-valvular AF and 1 or more

additional risk factors for stroke: age at least 75 years; congestive heart failure with left

ventricular ejection fraction of no more than 40%; hypertension requiring medication;

diabetes mellitus deemed to require medication on physicians’ discretion; history of

cerebral infarction or TIA

Interventions Apixaban (5 mg twice daily or 2.5 mg twice daily) versus dose-adjusted warfarin (target

INR 2.0 to 3.0 or 2.0 to 2.6 if age 70 or more years) during a predefined 12-week

treatment period

Outcomes Primary safety outcome: composite of major bleeding and clinically relevant non-major

bleeding (defined by ISTH criteria)

Secondary safety and efficacy outcomes: major bleeding; clinically relevant non-major

bleeding; composite of total bleeding events (including minor bleedings); composite of

stroke or systemic embolism; composite of stroke, systemic embolism and myocardial

infarction or all-cause death

Notes Study co-sponsored by Pfizer and Bristol-Myers Squibb


(Review)


ARISTOTLE-J 2011 (Continued)

Risk of bias



bias)


treatment groups


treatment groups. Stratification by trial site

and prior use of VKA


(performance bias)

All outcomes

Unclear risk Partially blinded design: open label war-

farin and double-blind apixaban adminis-

tration


bias)

All outcomes

Low risk Reported efficacy and safety outcomes were

adjudicated by an independent committee

whose members were not aware of study

group assignments


All outcomes

Unclear risk Primary efficacy outcome analysed in ITT

population. All other efficacy and safety

outcomes analysed in ’safety population’.

Number of participants that discontinued

during study and reasons not stated


reported for safety population


Edoxaban Asia 2010


Participants 235 Asian people with documented non-valvular AF

Interventions Edoxaban (30 mg daily or 60 mg daily) versus dose-adjusted warfarin (target INR 2.0

to 3.0) during a predefined 3-month period

Outcomes Primary safety outcome: composite of major, clinically relevant non-major, and minor

bleeding (by ISTH definitions)

Secondary safety outcome: all adverse events, laboratory variables

Secondary efficacy outcome: composite of stroke, systemic embolic events, myocardial

infarction, cardiovascular death and hospitalisation for any other cardiac condition

Notes Study sponsored by Daiichi Sankyo


(Review)


Edoxaban Asia 2010 (Continued)

Risk of bias



bias)


treatment groups


treatment groups


(performance bias)

All outcomes

High risk Open-label administration of both edoxa-

ban and warfarin. Different edoxaban doses

administered in double-blind fashion


bias)

All outcomes

Unclear risk Adjudication of outcomes by investigator

and Clinical Events Committee. Unclear

whether Clinical Events Committee was

blinded to treatment assignment


All outcomes

Low risk Safety outcomes analysed in safety popu-

lation (participants who received at least 1

dose of study drug and had at least 1 post-

dose safety assessment)

Efficacy outcomes analysed in full analysis

set (all participants who received at least 1

dose of study drug and had at least 1 post-

dose efficacy assessment)


during study and reasons for discontinua-

tion stated

Selective reporting (reporting bias) Low risk All predefined safety and efficacy outcomes

reported for safety population and full anal-

ysis set, respectively


Edoxaban US/Europe 2010


Participants 1146 people aged between 18 and 65 years with documented non-valvular AF and a

CHADS2 score of at least 2

Interventions Edoxaban (30 mg once daily, 30 mg twice daily, 60 mg once daily, or 60 mg twice daily)

versus dose-adjusted warfarin (target INR 2.0 to 3.0) during a predefined 12-week period


(Review)


Edoxaban US/Europe 2010 (Continued)

Outcomes Primary safety outcome: major bleeding (defined by modified ISTH criteria)

Secondary safety outcomes: clinically relevant non-major bleeding; minor bleeding; liver

function tests

Secondary efficacy outcomes: composite of stroke (ischaemic or haemorrhagic), systemic

embolic event, myocardial infarction, cardiovascular death and hospitalisation for any

cardiac conditions

Notes Study sponsored by Daiichi Sankyo

Risk of bias



bias)


treatment groups


treatment groups


(performance bias)

All outcomes

High risk Open-label administration of both edoxa-

ban and warfarin. Different doses of edox-

aban administered in double-blind fashion


bias)

All outcomes

Unclear risk Adjudication of bleeding events by inde-

pendent central adjudication committee

that was blinded to treatment assignment.

Unclear whether efficacy outcomes were

centrally adjudicated


All outcomes

Unclear risk Safety and efficacy outcomes analysed in

’safety population’ (participants who re-

ceived at least 1 dose of study drug and

had at least 1 post-dose safety assessment).



tion not stated

Selective reporting (reporting bias) Low risk All predefined safety and efficacy outcomes

reported for safety population

Other bias Unclear risk Randomisation into edoxaban 60 mg twice

daily treatment arm prematurely termi-

nated after enrolment of 180 patients

based on recommendation of independent

DSMB due to an excess of bleedings


(Review)


EXPLORE-Xa 2013


Participants 508 people with documented non-valvular AF and an indication for anticoagulation

with VKA

Interventions Betrixaban (40 mg, 60 mg or 80 mg daily) or dose-adjusted warfarin (target INR 2.0 to

3.0) for at least 3 months

Outcomes Primary safety outcome: composite of major or clinically relevant non-major bleeding

(ISTH criteria)

Secondary safety and efficacy outcomes: stroke (fatal and non-fatal); myocardial infarc-

tion; systemic embolic events; pulmonary embolism; all-cause death; other adverse events

Notes Study sponsored by Portola Pharmaceuticals

Risk of bias



bias)


treatment groups


treatment groups with a computerised in-

teractive voice response system


(performance bias)

All outcomes

High risk Open-label administration of both betrix-

aban and warfarin. Separate dosages of

betrixaban administered in double-blind

fashion


bias)

All outcomes

Low risk Adjudication of safety and efficacy out-

comes by an independent clinical endpoint

committee that was blinded to treatment

assignment


All outcomes

Low risk Outcomes reported in ITT population.


during study stated with reason

Selective reporting (reporting bias) Low risk All predefined outcomes reported for ITT

population



(Review)


J-ROCKET AF 2012


Participants 1280 Japanese people aged ≥ 20 years with documented AF and either a risk of stroke,

TIA or systemic embolic embolism or ≥ 2 of the following risk factors for thromboem-

bolism: congestive heart failure and/or left ventricular ejection fraction < 35%, hyper-

tension, age ≥ 75 years or diabetes mellitus

Interventions Rivaroxaban (10 mg, or 15 mg daily in participants with a creatinine clearance of 30 to

49 ml/minute), or dose-adjusted warfarin (target INR 1.6 to 2.6 for patients ≥ 70 years

and 2.0 to 3.0 for patients < 70 years)

Outcomes Primary safety outcome: composite of major bleeding (defined by ISTH definition) or

non-major clinically relevant bleeding

Primary efficacy outcome: composite of stroke or non-CNS systemic embolic events

Secondary safety and efficacy outcomes: composite of stroke, non-CNS systemic embolic

events or vascular death; composite of stroke, non-CNS systemic embolic events, vascular

death or myocardial infarction; stroke; myocardial infarction; vascular death; non-CNS

systemic embolic events; disabling stroke; all-cause death; major bleeding; non-major

clinically relevant bleeding; other adverse events; liver function tests

Notes Study sponsored by Johnson & Johnson Pharmaceutical Research and Development,

and Bayer HealthCare

Risk of bias



bias)


treatment groups


treatment groups


(performance bias)

All outcomes



bias)

All outcomes

Low risk Adjudication of safety and efficacy out-

comes by an independent clinical endpoint

committee that was blinded to treatment

assignment


All outcomes

Low risk Outcomes reported in safety analysis pop-

ulation, ITT population or per protocol

analysis population. Number of partici-

pants that discontinued due to adverse

events stated


(Review)


J-ROCKET AF 2012 (Continued)


reported


OPAL-1 2010

Methods Randomised, partially blind, active controlled trial

Participants 448 people recruited in the Asian-Pacific region with documented non-valvular AF

Interventions Darexaban (30 mg, 60 mg, 120 mg or 240 mg once daily) versus dose-adjusted warfarin

(target INR 2.0 to 3.0 in patients below 70 years and 1.6 to 2.6 in patients 70 years or

more) during a predefined period of 12 weeks

Outcomes Primary safety outcome: composite of major or clinically relevant non-major bleeding

Secondary safety outcome: adverse events, liver function tests (ALT and AST) and renal

function (serum creatinine)

Primary efficacy outcome: composite of stroke, TIA, systemic embolic events and all-

cause death

Notes Study sponsored by Astellas

Risk of bias



bias)


treatment groups


treatment groups


(performance bias)

All outcomes

High risk Open-label administration of both darexa-

ban and warfarin. Different doses of darex-

aban administered in double-blind fashion


bias)

All outcomes

High risk Adjudication of outcomes not described


All outcomes




tion stated

Selective reporting (reporting bias) Low risk All predefined outcomes reported for ITT

population


(Review)


OPAL-1 2010 (Continued)

Other bias Unclear risk Randomisation into 240 mg darexa-

ban arm terminated early due to in-

creased bleeding after recommendation

from DSMB

OPAL-2 2011


Participants 1297 people with documented AF and a CHADS2 score of 1 to 6

Interventions Darexaban (15 mg twice daily, 30 mg once daily, 30 mg twice daily, 60 mg once daily,

60 mg twice daily or 120 mg once daily) versus dose adjusted warfarin (target INR 2.0

to 3.0) during a period of 24 to 52 weeks

Outcomes Primary safety endpoint: composite of major or clinically relevant non-major bleeding

(ISTH definitions)

Secondary safety endpoint: major bleeding (ISTH definition)

Primary efficacy endpoint: composite of ischaemic stroke, TIA, systemic embolic em-

bolism, vascular death

Notes Study sponsored by Astellas

Risk of bias



bias)


treatment groups


treatment groups


(performance bias)

All outcomes



bias)

All outcomes

Unclear risk Adjudication of outcomes not described


All outcomes



during study stated

Selective reporting (reporting bias) Unclear risk All predefined outcomes reported for ITT

population


(Review)


OPAL-2 2011 (Continued)


ROCKET AF 2011


Participants 14,264 people with documented AF and a CHADS2 score ≥ 2

Interventions Rivoraxaban (20 mg daily, or 15 mg daily in participants with a creatinine clearance of

30 to 49 ml/minute) versus dose-adjusted warfarin (target INR 2.0 to 3.0)

Outcomes Primary efficacy outcome: composite of stroke or systemic embolic events

Secondary efficacy outcomes: composite of stroke, systemic embolism or death from

cardiovascular cause; composite of stroke, systemic embolism, death from cardiovascular

cause or myocardial infarction; individual components of composite efficacy endpoints

Primary safety outcome: composite of major bleedings (defined by ISTH criteria) and

non-major clinically relevant bleedings

Secondary safety outcomes: major bleedings, intracranial haemorrhages, minor bleedings

Notes Study sponsored by Johnson & Johnson Pharmaceutical Research and Development,

and Bayer HealthCare

Risk of bias



bias)


treatment groups


treatment groups with the use of a central,

computerised, automated voice-response

system


(performance bias)

All outcomes



bias)

All outcomes

Low risk Efficacy and safety outcomes were adjudi-

cated by a blinded and independent clini-

cal endpoint committee


All outcomes

Unclear risk Primary efficacy outcome analysed in ITT

population. Primary and secondary efficacy

also analysed in the as treated, per protocol

population during treatment. Safety out-

comes only analysed in safety, on-treatment

population. Number of participants that


(Review)


ROCKET AF 2011 (Continued)

discontinued during study and reasons are

reported


reported, but not all for ITT population


AF = atrial fibrillation; ALT = alanine transaminase; AST = aspartate aminotransferase; CNS = central nervous system; DSMB =

Data Safety and Monitoring Board; INR = International Normalised Ratio; ISTH = International Society on Thrombosis and

Haemostasis; ITT = intention-to-treat; TIA = transient ischaemic attack; VKA = vitamin K antagonist

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Camm 2011 Expert review of edoxaban; no data

Fox 2011 Subgroup analysis of patients with moderate renal impairment randomised into ROCKET AF 2011,

which is included in the present review; no additional data

Hankey 2012 Subgroup analysis of patients with previous stroke or TIA randomised into ROCKET AF 2011,

which is included in the present review; no additional data

Harenberg 2010 Expert review of idraparinux and idrabioparinux; no data

Lane 2011 Post hoc analysis of factors that increased bleeding risk in patients enrolled into the AMADEUS

2008 trial, which is included in the present review; no additional data

Lopes 2010 Study protocol and rationale for ARISTOTLE 2011; no data

Partida 2011 Expert review of edoxaban; no data

ROCKET investigators 2010 Study protocol and rationale for ROCKET AF 2011; no data


(Review)


Characteristics of studies awaiting assessment [ordered by study ID]

BOREALIS AF 2007


Participants People with non-valvular AF with an indication for long-term VKA therapy based on the presence of previous

ischaemic stroke, TIA or systemic embolism and/or at least 2 of the following risk factors: hypertension requiring

drug treatment, moderately or severely impaired left ventricular function and/or congestive heart failure, age ≥ 75

years, diabetes mellitus

Interventions Biotinylated idraparinux (SSR126517E) administered by once-weekly subcutaneous injection versus dose-adjusted

warfarin

Outcomes Primary efficacy outcome: composite of all strokes or non-CNS systemic embolic events

Secondary efficacy/safety outcomes: separate components of the primary efficacy outcome; composite outcome of

stroke, non-CNS systemic embolic events, major bleeding or death

Notes This study was terminated prematurely. According to information available on ClinicalTrials.gov this was based on

a strategic sponsor decision and not driven by safety concerns

Data from this trial have not yet been published in any form (based on renewed literature search in April 2013)

AF = atrial fibrillation; CNS = central nervous system; TIA = transient ischaemic attack; VKA = vitamin K antagonist

Characteristics of ongoing studies [ordered by study ID]

ENGAGE AF-TIMI 48

Trial name or title Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial

Infarction study 48 (ENGAGE AF-TIMI 48)

Methods Randomised, double-blind, double-dummy, event driven study

Participants 21,107 people with electrical documentation of AF ≤ 12 months and a CHADS2 score ≥ 2

Interventions Edoxaban (30 mg daily or 60 mg daily) versus dose-adjusted warfarin with a target INR of 2.0 to 3.0

Outcomes Primary efficacy outcome: stroke and systemic embolic events

Primary safety outcome: major bleeding (defined by modified ISTH criteria)

Starting date November 2008

Contact information [email protected]

Notes Enrollment of 21,107 participants was completed in December 2010; final results are expected in 2013

AF = atrial fibrillation; INR = International Normalized Ratio; ISTH = International Society on Thrombosis and Haemostasis


(Review)


D A T A A N D A N A L Y S E S

Comparison 1. Factor Xa inhibitor versus VKA

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Stroke and other systemic

embolic events

9 40777 Odds Ratio (M-H, Fixed, 95% CI) 0.81 [0.72, 0.91]

1.1 Apixaban versus VKA 2 18423 Odds Ratio (M-H, Fixed, 95% CI) 0.78 [0.65, 0.93]

1.2 Darexaban versus VKA 1 448 Odds Ratio (M-H, Fixed, 95% CI) 1.88 [0.10, 36.75]

1.3 Edoxaban versus VKA 2 1377 Odds Ratio (M-H, Fixed, 95% CI) 0.49 [0.14, 1.67]

1.4 Idraparinux versus VKA 1 4576 Odds Ratio (M-H, Fixed, 95% CI) 0.67 [0.37, 1.21]

1.5 Rivaroxaban versus VKA 2 15445 Odds Ratio (M-H, Fixed, 95% CI) 0.85 [0.72, 1.00]

1.6 Betrixaban versus VKA 1 508 Odds Ratio (M-H, Fixed, 95% CI) 1.68 [0.08, 35.22]

2 All strokes 9 40749 Odds Ratio (M-H, Fixed, 95% CI) 0.78 [0.69, 0.89]







3 Ischaemic stroke 8 39606 Odds Ratio (M-H, Fixed, 95% CI) 0.88 [0.76, 1.02]







4 Disabling or fatal stroke 4 16099 Odds Ratio (M-H, Fixed, 95% CI) 0.71 [0.54, 0.92]




5 Systemic embolic events

(non-CNS)








6 Major bleedings 10 42078 Odds Ratio (M-H, Fixed, 95% CI) 0.89 [0.81, 0.98]








(Review)


7 Intracranial haemorrhages 8 39638 Odds Ratio (M-H, Fixed, 95% CI) 0.56 [0.45, 0.70]







8 Non-major clinically relevant

bleeds








9 Myocardial infarction 8 40301 Odds Ratio (M-H, Fixed, 95% CI) 0.87 [0.73, 1.05]






10 Vascular deaths 7 22100 Odds Ratio (M-H, Fixed, 95% CI) 0.87 [0.72, 1.05]






11 All-cause deaths 6 38924 Odds Ratio (M-H, Fixed, 95% CI) 0.88 [0.81, 0.97]





Comparison 2. Factor Xa inhibitors versus VKA: route of administration


studies

No. of


1 Stroke and systemic other

embolic events


1.1 Oral administration 8 36201 Odds Ratio (M-H, Fixed, 95% CI) 0.82 [0.72, 0.92]

1.2 Parenteral administration 1 4576 Odds Ratio (M-H, Fixed, 95% CI) 0.67 [0.37, 1.21]

2 Major bleeding 10 42078 Odds Ratio (M-H, Fixed, 95% CI) 0.89 [0.81, 0.98]

2.1 Oral administration 9 37502 Odds Ratio (M-H, Fixed, 95% CI) 0.84 [0.76, 0.92]

2.2 Parenteral administration 1 4576 Odds Ratio (M-H, Fixed, 95% CI) 2.62 [1.70, 4.03]


(Review)


Comparison 3. Factor Xa inhibitor versus VKA: dose of Factor Xa inhibitor


studies

No. of



embolic events


1.1 Apixaban 2.5mg twice

daily


1.2 Apixaban 5 mg twice daily 1 148 Odds Ratio (M-H, Fixed, 95% CI) 0.14 [0.01, 2.70]

1.3 Edoxaban 30mg once

daily



daily


1.5 Edoxaban 30mg twice

daily



daily


1.7 Rivaroxaban 10mg once

daily



daily


1.9 Darexaban 30mg once

daily



daily



daily


1.12 Darexaban 240mg 1 172 Odds Ratio (M-H, Fixed, 95% CI) 3.66 [0.15, 91.07]

1.13 Idraparinux 1,5mg once

weekly


1.14 Idraparinux 2,5mg once

weekly


1.15 Betrixaban 40 mg 1 254 Odds Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]




2.1 Apixaban 2.5mg twice

daily


2.2 Apixaban 5mg twice daily 1 146 Odds Ratio (M-H, Fixed, 95% CI) 0.35 [0.01, 8.67]


daily



daily



daily



daily


2.7 Darexaban 15mg twice

daily



(Review)



daily



daily



daily



daily



daily



daily



daily



daily





Comparison 4. Factor Xa inhibitors versus VKA: previous stroke or TIA


studies

No. of



embolic events


1.1 Previous stroke or TIA 3 5340 Odds Ratio (M-H, Fixed, 95% CI) 0.70 [0.53, 0.92]

1.2 No previous stroke or TIA 3 18710 Odds Ratio (M-H, Fixed, 95% CI) 0.81 [0.65, 1.01]


2.1 Previous stroke or TIA 1 813 Odds Ratio (M-H, Fixed, 95% CI) 0.63 [0.31, 1.29]

2.2 No previous stroke or TIA 1 465 Odds Ratio (M-H, Fixed, 95% CI) 1.34 [0.57, 3.11]

Comparison 5. Factor Xa inhibitors versus VKA: quality of anticoagulation with VKA (TTR)


studies

No. of



embolic events


1.1 Good quality 1 6977 Odds Ratio (M-H, Fixed, 95% CI) 0.78 [0.60, 1.02]

1.2 Bad quality 1 6994 Odds Ratio (M-H, Fixed, 95% CI) 0.81 [0.62, 1.07]


(Review)


Comparison 6. Factor Xa inhibitors versus VKA: previous VKA use


studies

No. of



embolic events


1.1 VKA naive 3 6545 Odds Ratio (M-H, Fixed, 95% CI) 0.71 [0.55, 0.92]

1.2 VKA experienced 3 13476 Odds Ratio (M-H, Fixed, 95% CI) 0.92 [0.76, 1.12]


2.1 VKA naive 1 128 Odds Ratio (M-H, Fixed, 95% CI) 1.45 [0.31, 6.75]

2.2 VKA experienced 1 1150 Odds Ratio (M-H, Fixed, 95% CI) 0.80 [0.45, 1.42]

Comparison 7. Factor Xa inhibitors versus VKA: concomitant antiplatelet use


studies

No. of



embolic events


1.1 Concomitant antiplatelet

use


1.2 No concomitant

antiplatelet use



2.1 Concomitant antiplatelet

use


2.2 No concomitant

antiplatelet use


Comparison 8. Factor Xa inhibitors versus VKA: age


studies

No. of



embolic events


1.1 Age < 75 years 2 10972 Odds Ratio (M-H, Fixed, 95% CI) 0.94 [0.75, 1.18]

1.2 Age ≥ 75 years 2 7775 Odds Ratio (M-H, Fixed, 95% CI) 0.78 [0.61, 0.98]


(Review)


Comparison 9. Factor Xa inhibitors versus VKA: race


studies

No. of



embolic events


1.1 Asian patients 5 3538 Odds Ratio (M-H, Fixed, 95% CI) 0.71 [0.50, 1.00]

1.2 White patients 2 16271 Odds Ratio (M-H, Fixed, 95% CI) 0.87 [0.73, 1.04]

1.3 Black patients 2 208 Odds Ratio (M-H, Fixed, 95% CI) 0.76 [0.25, 2.36]

1.4 Other races 2 465 Odds Ratio (M-H, Fixed, 95% CI) 1.88 [0.56, 6.33]


2.1 Asian patients 3 1730 Odds Ratio (M-H, Fixed, 95% CI) 0.72 [0.42, 1.24]

Comparison 10. Factor Xa inhibitors versus VKA: sex


studies

No. of



embolic events


1.1 Female 3 7386 Odds Ratio (M-H, Fixed, 95% CI) 0.81 [0.64, 1.03]

1.2 Male 3 12634 Odds Ratio (M-H, Fixed, 95% CI) 0.86 [0.69, 1.06]

2 Major bleeding 1 1278 Odds Ratio (M-H, Fixed, 95% CI) 0.85 [0.50, 1.45]

2.1 Male 1 1030 Odds Ratio (M-H, Fixed, 95% CI) 0.79 [0.44, 1.41]

2.2 Female 1 248 Odds Ratio (M-H, Fixed, 95% CI) 1.29 [0.31, 5.26]

Comparison 11. Factor Xa inhibitors versus VKA: baseline CHADS2 score


studies

No. of



embolic events


1.1 CHADS2-score 0-1 1 1878 Odds Ratio (M-H, Fixed, 95% CI) 1.41 [0.40, 5.01]

1.2 CHADS2-score 2 3 3517 Odds Ratio (M-H, Fixed, 95% CI) 0.81 [0.52, 1.24]

1.3 CHADS2-score ≥ 3 3 14622 Odds Ratio (M-H, Fixed, 95% CI) 0.83 [0.70, 0.99]


2.1 CHADS2-score 0-1 1 1878 Odds Ratio (M-H, Fixed, 95% CI) 3.69 [1.60, 8.52]

2.2 CHADS2-score 2 2 1661 Odds Ratio (M-H, Fixed, 95% CI) 1.86 [0.92, 3.73]

2.3 CHADS2-score ≥ 3 2 2315 Odds Ratio (M-H, Fixed, 95% CI) 1.34 [0.88, 2.05]


(Review)


Analysis 1.1. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 1 Stroke and other systemic embolic

events.

Review: Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation

Comparison: 1 Factor Xa inhibitor versus VKA

Outcome: 1 Stroke and other systemic embolic events

Study or subgroup Factor Xa inhibitor VKA Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Apixaban versus VKA

ARISTOTLE 2011 212/9120 265/9081 42.2 % 0.79 [ 0.66, 0.95 ]

ARISTOTLE-J 2011 0/148 3/74 0.8 % 0.07 [ 0.00, 1.35 ]

Subtotal (95% CI) 9268 9155 43.0 % 0.78 [ 0.65, 0.93 ]

Total events: 212 (Factor Xa inhibitor), 268 (VKA)

Heterogeneity: Chi2 = 2.58, df = 1 (P = 0.11); I2 =61%

Test for overall effect: Z = 2.69 (P = 0.0072)

2 Darexaban versus VKA

OPAL-1 2010 3/354 0/94 0.1 % 1.88 [ 0.10, 36.75 ]

Subtotal (95% CI) 354 94 0.1 % 1.88 [ 0.10, 36.75 ]


Heterogeneity: not applicable


3 Edoxaban versus VKA

Edoxaban Asia 2010 0/159 0/75 Not estimable

Edoxaban US/Europe 2010 7/893 4/250 1.0 % 0.49 [ 0.14, 1.67 ]

Subtotal (95% CI) 1052 325 1.0 % 0.49 [ 0.14, 1.67 ]




4 Idraparinux versus VKA

AMADEUS 2008 18/2283 27/2293 4.4 % 0.67 [ 0.37, 1.21 ]

Subtotal (95% CI) 2283 2293 4.4 % 0.67 [ 0.37, 1.21 ]




5 Rivaroxaban versus VKA

J-ROCKET AF 2012 11/637 22/637 3.5 % 0.49 [ 0.24, 1.02 ]

ROCKET AF 2011 269/7081 306/7090 47.9 % 0.88 [ 0.74, 1.03 ]

Subtotal (95% CI) 7718 7727 51.4 % 0.85 [ 0.72, 1.00 ]



0.01 0.1 1 10 100

Favours FXa inhibitor Favours VKA

(Continued . . . )


(Review)


(. . . Continued)Study or subgroup Factor Xa inhibitor VKA Odds Ratio Weight Odds Ratio



6 Betrixaban versus VKA

EXPLORE-Xa 2013 2/381 0/127 0.1 % 1.68 [ 0.08, 35.22 ]

Subtotal (95% CI) 381 127 0.1 % 1.68 [ 0.08, 35.22 ]




Total (95% CI) 21056 19721 100.0 % 0.81 [ 0.72, 0.91 ]


Heterogeneity: Chi2 = 6.91, df = 7 (P = 0.44); I2 =0.0%


Test for subgroup differences: Chi2 = 2.09, df = 5 (P = 0.84), I2 =0.0%

0.01 0.1 1 10 100


Analysis 1.2. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 2 All strokes.



Outcome: 2 All strokes




ARISTOTLE 2011 199/9120 250/9081 47.4 % 0.79 [ 0.65, 0.95 ]

ARISTOTLE-J 2011 0/148 3/74 0.9 % 0.07 [ 0.00, 1.35 ]

Subtotal (95% CI) 9268 9155 48.3 % 0.77 [ 0.64, 0.93 ]





EXPLORE-Xa 2013 2/381 0/127 0.1 % 1.68 [ 0.08, 35.22 ]

0.01 0.1 1 10 100


(Continued . . . )


(Review)




Subtotal (95% CI) 381 127 0.1 % 1.68 [ 0.08, 35.22 ]





OPAL-1 2010 2/354 0/94 0.2 % 1.34 [ 0.06, 28.16 ]

Subtotal (95% CI) 354 94 0.2 % 1.34 [ 0.06, 28.16 ]







Subtotal (95% CI) 1052 325 0.9 % 0.46 [ 0.11, 1.95 ]





AMADEUS 2008 18/2283 26/2293 5.0 % 0.69 [ 0.38, 1.27 ]

Subtotal (95% CI) 2283 2293 5.0 % 0.69 [ 0.38, 1.27 ]





J-ROCKET AF 2012 10/637 21/637 4.0 % 0.47 [ 0.22, 1.00 ]

ROCKET AF 2011 184/7061 221/7082 41.6 % 0.83 [ 0.68, 1.01 ]

Subtotal (95% CI) 7698 7719 45.5 % 0.80 [ 0.66, 0.97 ]




Total (95% CI) 21036 19713 100.0 % 0.78 [ 0.69, 0.89 ]





0.01 0.1 1 10 100



(Review)


Analysis 1.3. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 3 Ischaemic stroke.



Outcome: 3 Ischaemic stroke




ARISTOTLE 2011 162/9120 175/9081 46.4 % 0.92 [ 0.74, 1.14 ]

ARISTOTLE-J 2011 0/148 2/74 0.9 % 0.10 [ 0.00, 2.06 ]

Subtotal (95% CI) 9268 9155 47.3 % 0.90 [ 0.73, 1.12 ]





OPAL-1 2010 1/354 0/94 0.2 % 0.80 [ 0.03, 19.85 ]

Subtotal (95% CI) 354 94 0.2 % 0.80 [ 0.03, 19.85 ]






Subtotal (95% CI) 159 75 Not estimable



Test for overall effect: not applicable


AMADEUS 2008 13/2283 20/2293 5.3 % 0.65 [ 0.32, 1.31 ]

Subtotal (95% CI) 2283 2293 5.3 % 0.65 [ 0.32, 1.31 ]





J-ROCKET AF 2012 7/637 17/637 4.5 % 0.41 [ 0.17, 0.98 ]

ROCKET AF 2011 149/7061 161/7082 42.4 % 0.93 [ 0.74, 1.16 ]

Subtotal (95% CI) 7698 7719 46.9 % 0.88 [ 0.71, 1.09 ]





0.01 0.1 1 10 100


(Continued . . . )


(Review)




EXPLORE-Xa 2013 2/381 0/127 0.2 % 1.68 [ 0.08, 35.22 ]

Subtotal (95% CI) 381 127 0.2 % 1.68 [ 0.08, 35.22 ]




Total (95% CI) 20143 19463 100.0 % 0.88 [ 0.76, 1.02 ]





0.01 0.1 1 10 100


Analysis 1.4. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 4 Disabling or fatal stroke.



Outcome: 4 Disabling or fatal stroke




OPAL-1 2010 1/354 0/94 0.6 % 0.80 [ 0.03, 19.85 ]

Subtotal (95% CI) 354 94 0.6 % 0.80 [ 0.03, 19.85 ]










0.01 0.1 1 10 100


(Continued . . . )


(Review)





J-ROCKET AF 2012 5/637 10/637 7.5 % 0.50 [ 0.17, 1.46 ]

ROCKET AF 2011 90/7061 124/7082 91.9 % 0.72 [ 0.55, 0.95 ]

Subtotal (95% CI) 7698 7719 99.4 % 0.71 [ 0.54, 0.92 ]




Total (95% CI) 8211 7888 100.0 % 0.71 [ 0.54, 0.92 ]





0.01 0.1 1 10 100



(Review)


Analysis 1.5. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 5 Systemic embolic events (non-

CNS).



Outcome: 5 Systemic embolic events (non-CNS)




ARISTOTLE 2011 15/9120 17/9081 38.6 % 0.88 [ 0.44, 1.76 ]

ARISTOTLE-J 2011 0/148 0/74 Not estimable

Subtotal (95% CI) 9268 9155 38.6 % 0.88 [ 0.44, 1.76 ]





OPAL-1 2010 1/354 0/94 1.8 % 0.80 [ 0.03, 19.85 ]

Subtotal (95% CI) 354 94 1.8 % 0.80 [ 0.03, 19.85 ]







Subtotal (95% CI) 1052 325 1.8 % 1.40 [ 0.07, 29.36 ]





AMADEUS 2008 0/2283 2/2293 5.7 % 0.20 [ 0.01, 4.18 ]

Subtotal (95% CI) 2283 2293 5.7 % 0.20 [ 0.01, 4.18 ]





J-ROCKET AF 2012 1/637 1/637 2.3 % 1.00 [ 0.06, 16.02 ]

ROCKET AF 2011 5/7061 22/7082 49.9 % 0.23 [ 0.09, 0.60 ]

Subtotal (95% CI) 7698 7719 52.1 % 0.26 [ 0.11, 0.64 ]



0.01 0.1 1 10 100


(Continued . . . )


(Review)






EXPLORE-Xa 2013 0/381 0/127 Not estimable





Total (95% CI) 21036 19713 100.0 % 0.53 [ 0.32, 0.87 ]




Test for subgroup differences: Chi2 = 5.22, df = 4 (P = 0.27), I2 =23%

0.01 0.1 1 10 100


Analysis 1.6. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 6 Major bleedings.



Outcome: 6 Major bleedings




ARISTOTLE 2011 327/9088 462/9052 49.9 % 0.69 [ 0.60, 0.80 ]

ARISTOTLE-J 2011 0/143 1/75 0.2 % 0.17 [ 0.01, 4.30 ]

Subtotal (95% CI) 9231 9127 50.1 % 0.69 [ 0.60, 0.80 ]



Test for overall effect: Z = 5.00 (P < 0.00001)


OPAL-1 2010 1/354 0/94 0.1 % 0.80 [ 0.03, 19.85 ]

0.01 0.1 1 10 100


(Continued . . . )


(Review)




OPAL-2 2011 16/973 8/324 1.3 % 0.66 [ 0.28, 1.56 ]

Subtotal (95% CI) 1327 418 1.4 % 0.67 [ 0.29, 1.53 ]





Edoxaban Asia 2010 0/159 2/75 0.4 % 0.09 [ 0.00, 1.94 ]


Subtotal (95% CI) 1052 325 0.6 % 1.13 [ 0.33, 3.86 ]





AMADEUS 2008 74/2283 29/2293 3.1 % 2.62 [ 1.70, 4.03 ]

Subtotal (95% CI) 2283 2293 3.1 % 2.62 [ 1.70, 4.03 ]





J-ROCKET AF 2012 26/639 30/639 3.2 % 0.86 [ 0.50, 1.47 ]

ROCKET AF 2011 395/7111 386/7125 40.7 % 1.03 [ 0.89, 1.19 ]

Subtotal (95% CI) 7750 7764 44.0 % 1.01 [ 0.88, 1.17 ]





EXPLORE-Xa 2013 3/381 5/127 0.8 % 0.19 [ 0.05, 0.82 ]

Subtotal (95% CI) 381 127 0.8 % 0.19 [ 0.05, 0.82 ]




Total (95% CI) 22024 20054 100.0 % 0.89 [ 0.81, 0.98 ]


Heterogeneity: Chi2 = 48.42, df = 9 (P<0.00001); I2 =81%



0.01 0.1 1 10 100



(Review)


Analysis 1.7. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 7 Intracranial haemorrhages.



Outcome: 7 Intracranial haemorrhages




ARISTOTLE 2011 52/9088 122/9052 55.6 % 0.42 [ 0.30, 0.58 ]

ARISTOTLE-J 2011 0/143 1/75 0.9 % 0.17 [ 0.01, 4.30 ]

Subtotal (95% CI) 9231 9127 56.5 % 0.42 [ 0.30, 0.58 ]





OPAL-1 2010 1/354 0/94 0.4 % 0.80 [ 0.03, 19.85 ]

Subtotal (95% CI) 354 94 0.4 % 0.80 [ 0.03, 19.85 ]











AMADEUS 2008 11/2283 1/2293 0.5 % 11.10 [ 1.43, 86.02 ]

Subtotal (95% CI) 2283 2293 0.5 % 11.10 [ 1.43, 86.02 ]





J-ROCKET AF 2012 5/639 10/639 4.5 % 0.50 [ 0.17, 1.46 ]

ROCKET AF 2011 55/7111 84/7125 38.1 % 0.65 [ 0.46, 0.92 ]

Subtotal (95% CI) 7750 7764 42.7 % 0.64 [ 0.46, 0.88 ]





0.01 0.1 1 10 100


(Continued . . . )


(Review)









Total (95% CI) 20158 19480 100.0 % 0.56 [ 0.45, 0.70 ]





0.01 0.1 1 10 100


Analysis 1.8. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 8 Non-major clinically relevant

bleeds.



Outcome: 8 Non-major clinically relevant bleeds




ARISTOTLE 2011 286/9088 415/9052 23.9 % 0.68 [ 0.58, 0.79 ]

ARISTOTLE-J 2011 2/143 3/75 0.2 % 0.34 [ 0.06, 2.08 ]

Subtotal (95% CI) 9231 9127 24.1 % 0.67 [ 0.58, 0.78 ]





OPAL-1 2010 19/354 2/94 0.2 % 2.61 [ 0.60, 11.41 ]

OPAL-2 2011 38/973 27/324 2.3 % 0.45 [ 0.27, 0.74 ]

0.01 0.1 1 10 100


(Continued . . . )


(Review)




Subtotal (95% CI) 1327 418 2.5 % 0.60 [ 0.38, 0.96 ]





Edoxaban Asia 2010 42/893 7/250 0.6 % 1.71 [ 0.76, 3.86 ]


Subtotal (95% CI) 1052 325 0.9 % 1.50 [ 0.75, 3.02 ]





AMADEUS 2008 291/2283 206/2293 10.6 % 1.48 [ 1.23, 1.79 ]

Subtotal (95% CI) 2283 2293 10.6 % 1.48 [ 1.23, 1.79 ]





J-ROCKET AF 2012 115/639 97/639 4.7 % 1.23 [ 0.91, 1.65 ]

ROCKET AF 2011 1185/7111 1151/7125 56.8 % 1.04 [ 0.95, 1.13 ]

Subtotal (95% CI) 7750 7764 61.6 % 1.05 [ 0.97, 1.15 ]





EXPLORE-Xa 2013 8/381 4/127 0.3 % 0.66 [ 0.20, 2.23 ]

Subtotal (95% CI) 381 127 0.3 % 0.66 [ 0.20, 2.23 ]




Total (95% CI) 22024 20054 100.0 % 1.00 [ 0.93, 1.07 ]





0.01 0.1 1 10 100



(Review)


Analysis 1.9. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 9 Myocardial infarction.



Outcome: 9 Myocardial infarction




ARISTOTLE 2011 90/9120 102/9081 42.2 % 0.88 [ 0.66, 1.17 ]


Subtotal (95% CI) 9268 9155 42.2 % 0.88 [ 0.66, 1.17 ]







Subtotal (95% CI) 1052 325 0.3 % 3.10 [ 0.17, 56.28 ]





AMADEUS 2008 16/2283 13/2293 5.4 % 1.24 [ 0.59, 2.58 ]

Subtotal (95% CI) 2283 2293 5.4 % 1.24 [ 0.59, 2.58 ]





J-ROCKET AF 2012 3/637 1/637 0.4 % 3.01 [ 0.31, 29.01 ]

ROCKET AF 2011 101/7061 126/7082 51.7 % 0.80 [ 0.62, 1.04 ]

Subtotal (95% CI) 7698 7719 52.1 % 0.82 [ 0.63, 1.06 ]










0.01 0.1 1 10 100


(Continued . . . )


(Review)




Total (95% CI) 20682 19619 100.0 % 0.87 [ 0.73, 1.05 ]





0.01 0.1 1 10 100


Analysis 1.10. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 10 Vascular deaths.



Outcome: 10 Vascular deaths










Edoxaban Asia 2010 1/159 0/75 0.3 % 1.43 [ 0.06, 35.49 ]


Subtotal (95% CI) 1052 325 1.6 % 0.94 [ 0.22, 3.97 ]





AMADEUS 2008 25/2283 35/2293 15.0 % 0.71 [ 0.43, 1.20 ]

Subtotal (95% CI) 2283 2293 15.0 % 0.71 [ 0.43, 1.20 ]

0.01 0.1 1 10 100


(Continued . . . )


(Review)








J-ROCKET AF 2012 6/637 2/637 0.9 % 3.02 [ 0.61, 15.01 ]

ROCKET AF 2011 170/7061 193/7082 81.8 % 0.88 [ 0.71, 1.09 ]

Subtotal (95% CI) 7698 7719 82.7 % 0.90 [ 0.73, 1.11 ]





EXPLORE-Xa 2013 1/381 1/127 0.7 % 0.33 [ 0.02, 5.34 ]

Subtotal (95% CI) 381 127 0.7 % 0.33 [ 0.02, 5.34 ]




Total (95% CI) 11562 10538 100.0 % 0.87 [ 0.72, 1.05 ]





0.01 0.1 1 10 100



(Review)


Analysis 1.11. Comparison 1 Factor Xa inhibitor versus VKA, Outcome 11 All-cause deaths.



Outcome: 11 All-cause deaths




ARISTOTLE 2011 603/9120 669/9081 67.0 % 0.89 [ 0.79, 1.00 ]


Subtotal (95% CI) 9268 9155 67.0 % 0.89 [ 0.79, 1.00 ]





EXPLORE-Xa 2013 1/381 1/127 0.2 % 0.33 [ 0.02, 5.34 ]

Subtotal (95% CI) 381 127 0.2 % 0.33 [ 0.02, 5.34 ]





AMADEUS 2008 62/2283 61/2293 6.3 % 1.02 [ 0.71, 1.46 ]

Subtotal (95% CI) 2283 2293 6.3 % 1.02 [ 0.71, 1.46 ]





J-ROCKET AF 2012 7/637 5/637 0.5 % 1.40 [ 0.44, 4.45 ]

ROCKET AF 2011 208/7061 250/7082 25.9 % 0.83 [ 0.69, 1.00 ]

Subtotal (95% CI) 7698 7719 26.5 % 0.84 [ 0.70, 1.01 ]




Total (95% CI) 19630 19294 100.0 % 0.88 [ 0.81, 0.97 ]





0.01 0.1 1 10 100



(Review)


Analysis 2.1. Comparison 2 Factor Xa inhibitors versus VKA: route of administration, Outcome 1 Stroke

and systemic other embolic events.


Comparison: 2 Factor Xa inhibitors versus VKA: route of administration

Outcome: 1 Stroke and systemic other embolic events



1 Oral administration

ARISTOTLE 2011 212/9120 265/9081 42.2 % 0.79 [ 0.66, 0.95 ]

ARISTOTLE-J 2011 0/148 3/74 0.8 % 0.07 [ 0.00, 1.35 ]



EXPLORE-Xa 2013 2/381 0/127 0.1 % 1.68 [ 0.08, 35.22 ]

J-ROCKET AF 2012 11/637 22/637 3.5 % 0.49 [ 0.24, 1.02 ]

OPAL-1 2010 3/354 0/94 0.1 % 1.88 [ 0.10, 36.75 ]

ROCKET AF 2011 269/7081 306/7090 47.9 % 0.88 [ 0.74, 1.03 ]

Subtotal (95% CI) 18773 17428 95.6 % 0.82 [ 0.72, 0.92 ]




2 Parenteral administration

AMADEUS 2008 18/2283 27/2293 4.4 % 0.67 [ 0.37, 1.21 ]

Subtotal (95% CI) 2283 2293 4.4 % 0.67 [ 0.37, 1.21 ]




Total (95% CI) 21056 19721 100.0 % 0.81 [ 0.72, 0.91 ]





0.01 0.1 1 10 100



(Review)


Analysis 2.2. Comparison 2 Factor Xa inhibitors versus VKA: route of administration, Outcome 2 Major

bleeding.


Comparison: 2 Factor Xa inhibitors versus VKA: route of administration

Outcome: 2 Major bleeding



1 Oral administration

ARISTOTLE 2011 327/9088 462/9052 49.9 % 0.69 [ 0.60, 0.80 ]

ARISTOTLE-J 2011 0/143 1/75 0.2 % 0.17 [ 0.01, 4.30 ]

Edoxaban Asia 2010 0/159 2/75 0.4 % 0.09 [ 0.00, 1.94 ]


EXPLORE-Xa 2013 3/381 5/127 0.8 % 0.19 [ 0.05, 0.82 ]

J-ROCKET AF 2012 26/639 30/639 3.2 % 0.86 [ 0.50, 1.47 ]

OPAL-1 2010 1/354 0/94 0.1 % 0.80 [ 0.03, 19.85 ]

OPAL-2 2011 16/973 8/324 1.3 % 0.66 [ 0.28, 1.56 ]

ROCKET AF 2011 395/7111 386/7125 40.7 % 1.03 [ 0.89, 1.19 ]

Subtotal (95% CI) 19741 17761 96.9 % 0.84 [ 0.76, 0.92 ]




2 Parenteral administration

AMADEUS 2008 74/2283 29/2293 3.1 % 2.62 [ 1.70, 4.03 ]

Subtotal (95% CI) 2283 2293 3.1 % 2.62 [ 1.70, 4.03 ]




Total (95% CI) 22024 20054 100.0 % 0.89 [ 0.81, 0.98 ]





0.01 0.1 1 10 100



(Review)


Analysis 3.1. Comparison 3 Factor Xa inhibitor versus VKA: dose of Factor Xa inhibitor, Outcome 1 Stroke

and other systemic embolic events.


Comparison: 3 Factor Xa inhibitor versus VKA: dose of Factor Xa inhibitor




1 Apixaban 2.5mg twice daily

ARISTOTLE-J 2011 0/74 3/74 4.7 % 0.14 [ 0.01, 2.70 ]

Subtotal (95% CI) 74 74 4.7 % 0.14 [ 0.01, 2.70 ]




2 Apixaban 5 mg twice daily

ARISTOTLE-J 2011 0/74 3/74 4.7 % 0.14 [ 0.01, 2.70 ]

Subtotal (95% CI) 74 74 4.7 % 0.14 [ 0.01, 2.70 ]




3 Edoxaban 30mg once daily



Subtotal (95% CI) 314 325 3.9 % 0.71 [ 0.12, 4.27 ]







Subtotal (95% CI) 314 325 3.9 % 0.35 [ 0.04, 3.42 ]




5 Edoxaban 30mg twice daily


Subtotal (95% CI) 244 250 4.0 % 1.02 [ 0.20, 5.13 ]




0.01 0.1 1 10 100


(Continued . . . )


(Review)






Subtotal (95% CI) 180 250 3.4 % 0.46 [ 0.05, 4.46 ]




7 Rivaroxaban 10mg once daily

J-ROCKET AF 2012 5/141 22/640 10.4 % 1.03 [ 0.38, 2.78 ]

Subtotal (95% CI) 141 640 10.4 % 1.03 [ 0.38, 2.78 ]





J-ROCKET AF 2012 6/496 22/640 25.8 % 0.34 [ 0.14, 0.85 ]

Subtotal (95% CI) 496 640 25.8 % 0.34 [ 0.14, 0.85 ]




9 Darexaban 30mg once daily

OPAL-1 2010 0/90 0/94 Not estimable






OPAL-1 2010 1/93 0/94 0.7 % 3.06 [ 0.12, 76.20 ]

Subtotal (95% CI) 93 94 0.7 % 3.06 [ 0.12, 76.20 ]





OPAL-1 2010 1/93 0/94 0.7 % 3.06 [ 0.12, 76.20 ]

Subtotal (95% CI) 93 94 0.7 % 3.06 [ 0.12, 76.20 ]




12 Darexaban 240mg

OPAL-1 2010 1/78 0/94 0.6 % 3.66 [ 0.15, 91.07 ]

Subtotal (95% CI) 78 94 0.6 % 3.66 [ 0.15, 91.07 ]



0.01 0.1 1 10 100


(Continued . . . )


(Review)





13 Idraparinux 1,5mg once weekly

AMADEUS 2008 0/32 0/36 Not estimable





14 Idraparinux 2,5mg once weekly

AMADEUS 2008 18/2251 27/2257 36.4 % 0.67 [ 0.37, 1.21 ]

Subtotal (95% CI) 2251 2257 36.4 % 0.67 [ 0.37, 1.21 ]




15 Betrixaban 40 mg






16 Betrixaban 60 mg

EXPLORE-Xa 2013 1/127 0/127 0.7 % 3.02 [ 0.12, 74.93 ]

Subtotal (95% CI) 127 127 0.7 % 3.02 [ 0.12, 74.93 ]




17 Betrixaban 80 mg






Total (95% CI) 4855 5628 100.0 % 0.63 [ 0.44, 0.92 ]





0.01 0.1 1 10 100



(Review)


Analysis 3.2. Comparison 3 Factor Xa inhibitor versus VKA: dose of Factor Xa inhibitor, Outcome 2 Major

bleedings.


Comparison: 3 Factor Xa inhibitor versus VKA: dose of Factor Xa inhibitor




1 Apixaban 2.5mg twice daily

ARISTOTLE-J 2011 0/72 1/75 1.5 % 0.34 [ 0.01, 8.55 ]

Subtotal (95% CI) 72 75 1.5 % 0.34 [ 0.01, 8.55 ]




2 Apixaban 5mg twice daily

ARISTOTLE-J 2011 0/71 1/75 1.5 % 0.35 [ 0.01, 8.67 ]

Subtotal (95% CI) 71 75 1.5 % 0.35 [ 0.01, 8.67 ]





Edoxaban Asia 2010 0/79 2/75 2.7 % 0.18 [ 0.01, 3.92 ]


Subtotal (95% CI) 314 325 4.2 % 0.25 [ 0.03, 2.21 ]





Edoxaban Asia 2010 0/80 2/75 2.7 % 0.18 [ 0.01, 3.87 ]


Subtotal (95% CI) 314 325 3.7 % 0.42 [ 0.06, 2.86 ]






Subtotal (95% CI) 244 250 1.0 % 5.21 [ 0.60, 44.92 ]




0.01 0.1 1 10 100


(Continued . . . )


(Review)






Subtotal (95% CI) 180 250 0.8 % 8.59 [ 1.02, 71.95 ]




7 Darexaban 15mg twice daily

OPAL-2 2011 1/162 8/324 5.5 % 0.25 [ 0.03, 1.98 ]

Subtotal (95% CI) 162 324 5.5 % 0.25 [ 0.03, 1.98 ]






OPAL-2 2011 0/161 8/324 5.9 % 0.12 [ 0.01, 2.01 ]

Subtotal (95% CI) 251 418 5.9 % 0.12 [ 0.01, 2.01 ]





OPAL-2 2011 3/162 8/324 5.5 % 0.75 [ 0.20, 2.85 ]

Subtotal (95% CI) 162 324 5.5 % 0.75 [ 0.20, 2.85 ]






OPAL-2 2011 3/163 8/324 5.5 % 0.74 [ 0.19, 2.83 ]

Subtotal (95% CI) 256 418 5.5 % 0.74 [ 0.19, 2.83 ]





OPAL-2 2011 5/162 8/324 5.4 % 1.26 [ 0.40, 3.91 ]

Subtotal (95% CI) 162 324 5.4 % 1.26 [ 0.40, 3.91 ]






0.01 0.1 1 10 100


(Continued . . . )


(Review)




OPAL-2 2011 4/163 8/324 5.4 % 0.99 [ 0.29, 3.35 ]

Subtotal (95% CI) 256 418 5.4 % 0.99 [ 0.29, 3.35 ]





OPAL-1 2010 1/78 0/94 0.5 % 3.66 [ 0.15, 91.07 ]

Subtotal (95% CI) 78 94 0.5 % 3.66 [ 0.15, 91.07 ]





J-ROCKET AF 2012 9/141 30/639 10.6 % 1.38 [ 0.64, 2.98 ]

Subtotal (95% CI) 141 639 10.6 % 1.38 [ 0.64, 2.98 ]





J-ROCKET AF 2012 17/498 30/639 26.5 % 0.72 [ 0.39, 1.32 ]

Subtotal (95% CI) 498 639 26.5 % 0.72 [ 0.39, 1.32 ]




16 Betrixaban 40 mg

EXPLORE-Xa 2013 0/127 5/127 5.7 % 0.09 [ 0.00, 1.60 ]

Subtotal (95% CI) 127 127 5.7 % 0.09 [ 0.00, 1.60 ]




17 Betrixaban 60 mg

EXPLORE-Xa 2013 0/127 5/127 5.7 % 0.09 [ 0.00, 1.60 ]

Subtotal (95% CI) 127 127 5.7 % 0.09 [ 0.00, 1.60 ]




18 Betrixaban 80 mg

EXPLORE-Xa 2013 3/127 5/127 5.1 % 0.59 [ 0.14, 2.52 ]

Subtotal (95% CI) 127 127 5.1 % 0.59 [ 0.14, 2.52 ]


0.01 0.1 1 10 100


(Continued . . . )


(Review)






Total (95% CI) 3542 5279 100.0 % 0.78 [ 0.57, 1.06 ]





0.01 0.1 1 10 100


Analysis 4.1. Comparison 4 Factor Xa inhibitors versus VKA: previous stroke or TIA, Outcome 1 Stroke



Comparison: 4 Factor Xa inhibitors versus VKA: previous stroke or TIA




1 Previous stroke or TIA

AMADEUS 2008 7/517 15/575 4.6 % 0.51 [ 0.21, 1.27 ]

ARISTOTLE 2011 73/1694 98/1742 30.3 % 0.76 [ 0.55, 1.03 ]

J-ROCKET AF 2012 9/407 17/405 5.5 % 0.52 [ 0.23, 1.17 ]

Subtotal (95% CI) 2618 2722 40.4 % 0.70 [ 0.53, 0.92 ]




2 No previous stroke or TIA

AMADEUS 2008 11/1766 12/1717 4.0 % 0.89 [ 0.39, 2.02 ]

ARISTOTLE 2011 139/7426 167/7339 54.0 % 0.82 [ 0.65, 1.03 ]

J-ROCKET AF 2012 2/230 5/232 1.6 % 0.40 [ 0.08, 2.07 ]

0.01 0.1 1 10 100


(Continued . . . )


(Review)




Subtotal (95% CI) 9422 9288 59.6 % 0.81 [ 0.65, 1.01 ]




Total (95% CI) 12040 12010 100.0 % 0.77 [ 0.65, 0.91 ]





0.01 0.1 1 10 100


Analysis 4.2. Comparison 4 Factor Xa inhibitors versus VKA: previous stroke or TIA, Outcome 2 Major

bleedings.


Comparison: 4 Factor Xa inhibitors versus VKA: previous stroke or TIA




1 Previous stroke or TIA

J-ROCKET AF 2012 13/408 20/405 67.5 % 0.63 [ 0.31, 1.29 ]

Subtotal (95% CI) 408 405 67.5 % 0.63 [ 0.31, 1.29 ]




2 No previous stroke or TIA

J-ROCKET AF 2012 13/231 10/234 32.5 % 1.34 [ 0.57, 3.11 ]

Subtotal (95% CI) 231 234 32.5 % 1.34 [ 0.57, 3.11 ]




0.01 0.1 1 10 100


(Continued . . . )


(Review)


(. . . Continued)



Total (95% CI) 639 639 100.0 % 0.86 [ 0.50, 1.47 ]





0.01 0.1 1 10 100


Analysis 5.1. Comparison 5 Factor Xa inhibitors versus VKA: quality of anticoagulation with VKA (TTR),

Outcome 1 Stroke and other systemic embolic events.


Comparison: 5 Factor Xa inhibitors versus VKA: quality of anticoagulation with VKA (TTR)




1 Good quality

ROCKET AF 2011 98/3481 125/3496 52.2 % 0.78 [ 0.60, 1.02 ]

Subtotal (95% CI) 3481 3496 52.2 % 0.78 [ 0.60, 1.02 ]




2 Bad quality

ROCKET AF 2011 91/3410 117/3584 47.8 % 0.81 [ 0.62, 1.07 ]

Subtotal (95% CI) 3410 3584 47.8 % 0.81 [ 0.62, 1.07 ]




Total (95% CI) 6891 7080 100.0 % 0.80 [ 0.66, 0.97 ]





0.01 0.1 1 10 100



(Review)


Analysis 6.1. Comparison 6 Factor Xa inhibitors versus VKA: previous VKA use, Outcome 1 Stroke and

other systemic embolic events.


Comparison: 6 Factor Xa inhibitors versus VKA: previous VKA use




1 VKA naive

AMADEUS 2008 3/548 11/552 3.2 % 0.27 [ 0.08, 0.98 ]

J-ROCKET AF 2012 0/61 2/66 0.7 % 0.21 [ 0.01, 4.46 ]

ROCKET AF 2011 101/2668 131/2650 36.9 % 0.76 [ 0.58, 0.99 ]

Subtotal (95% CI) 3277 3268 40.7 % 0.71 [ 0.55, 0.92 ]




2 VKA experienced

AMADEUS 2008 15/1735 16/1741 4.6 % 0.94 [ 0.46, 1.91 ]

J-ROCKET AF 2012 11/576 20/571 5.7 % 0.54 [ 0.25, 1.13 ]

ROCKET AF 2011 168/4413 175/4440 48.9 % 0.96 [ 0.78, 1.20 ]

Subtotal (95% CI) 6724 6752 59.3 % 0.92 [ 0.76, 1.12 ]




Total (95% CI) 10001 10020 100.0 % 0.83 [ 0.71, 0.98 ]





0.01 0.1 1 10 100



(Review)


Analysis 6.2. Comparison 6 Factor Xa inhibitors versus VKA: previous VKA use, Outcome 2 Major

bleedings.


Comparison: 6 Factor Xa inhibitors versus VKA: previous VKA use




1 VKA naive

J-ROCKET AF 2012 4/62 3/66 9.4 % 1.45 [ 0.31, 6.75 ]

Subtotal (95% CI) 62 66 9.4 % 1.45 [ 0.31, 6.75 ]




2 VKA experienced

J-ROCKET AF 2012 22/577 27/573 90.6 % 0.80 [ 0.45, 1.42 ]

Subtotal (95% CI) 577 573 90.6 % 0.80 [ 0.45, 1.42 ]




Total (95% CI) 639 639 100.0 % 0.86 [ 0.50, 1.48 ]





0.01 0.1 1 10 100



(Review)


Analysis 7.1. Comparison 7 Factor Xa inhibitors versus VKA: concomitant antiplatelet use, Outcome 1

Stroke and other systemic embolic events.


Comparison: 7 Factor Xa inhibitors versus VKA: concomitant antiplatelet use




1 Concomitant antiplatelet use

J-ROCKET AF 2012 6/242 6/221 1.7 % 0.91 [ 0.29, 2.87 ]

ROCKET AF 2011 105/2575 121/2609 31.8 % 0.87 [ 0.67, 1.14 ]

Subtotal (95% CI) 2817 2830 33.5 % 0.88 [ 0.68, 1.14 ]




2 No concomitant antiplatelet use

J-ROCKET AF 2012 5/395 16/416 4.2 % 0.32 [ 0.12, 0.88 ]

ROCKET AF 2011 164/4506 185/2609 62.3 % 0.49 [ 0.40, 0.61 ]

Subtotal (95% CI) 4901 3025 66.5 % 0.48 [ 0.39, 0.60 ]




Total (95% CI) 7718 5855 100.0 % 0.62 [ 0.52, 0.72 ]





0.01 0.1 1 10 100



(Review)


Analysis 7.2. Comparison 7 Factor Xa inhibitors versus VKA: concomitant antiplatelet use, Outcome 2

Major bleedings.


Comparison: 7 Factor Xa inhibitors versus VKA: concomitant antiplatelet use




1 Concomitant antiplatelet use

J-ROCKET AF 2012 16/243 13/222 44.0 % 1.13 [ 0.53, 2.41 ]

Subtotal (95% CI) 243 222 44.0 % 1.13 [ 0.53, 2.41 ]




2 No concomitant antiplatelet use

J-ROCKET AF 2012 10/396 17/417 56.0 % 0.61 [ 0.28, 1.35 ]

Subtotal (95% CI) 396 417 56.0 % 0.61 [ 0.28, 1.35 ]




Total (95% CI) 639 639 100.0 % 0.84 [ 0.49, 1.44 ]





0.01 0.1 1 10 100



(Review)


Analysis 8.1. Comparison 8 Factor Xa inhibitors versus VKA: age, Outcome 1 Stroke and other systemic

embolic events.


Comparison: 8 Factor Xa inhibitors versus VKA: age




1 Age < 75 years

AMADEUS 2008 11/1496 12/1469 3.7 % 0.90 [ 0.40, 2.04 ]

ROCKET AF 2011 144/3999 152/4008 45.6 % 0.95 [ 0.75, 1.20 ]

Subtotal (95% CI) 5495 5477 49.4 % 0.94 [ 0.75, 1.18 ]




2 Age ≥ 75 years

AMADEUS 2008 7/787 15/824 4.5 % 0.48 [ 0.20, 1.19 ]

ROCKET AF 2011 125/3082 154/3082 46.1 % 0.80 [ 0.63, 1.02 ]

Subtotal (95% CI) 3869 3906 50.6 % 0.78 [ 0.61, 0.98 ]




Total (95% CI) 9364 9383 100.0 % 0.86 [ 0.73, 1.01 ]





0.01 0.1 1 10 100



(Review)


Analysis 9.1. Comparison 9 Factor Xa inhibitors versus VKA: race, Outcome 1 Stroke and other systemic

embolic events.


Comparison: 9 Factor Xa inhibitors versus VKA: race




1 Asian patients


ARISTOTLE-J 2011 0/148 3/74 1.3 % 0.07 [ 0.00, 1.35 ]


J-ROCKET AF 2012 22/640 26/640 7.2 % 0.84 [ 0.47, 1.50 ]

ROCKET AF 2011 36/897 50/889 13.8 % 0.70 [ 0.45, 1.09 ]

Subtotal (95% CI) 1852 1686 22.2 % 0.71 [ 0.50, 1.00 ]




2 White patients

AMADEUS 2008 17/2235 26/2250 7.3 % 0.66 [ 0.35, 1.21 ]

ROCKET AF 2011 220/5872 246/5914 67.3 % 0.90 [ 0.74, 1.08 ]

Subtotal (95% CI) 8107 8164 74.6 % 0.87 [ 0.73, 1.04 ]




3 Black patients

AMADEUS 2008 1/15 1/13 0.3 % 0.86 [ 0.05, 15.22 ]

ROCKET AF 2011 5/94 6/86 1.7 % 0.75 [ 0.22, 2.55 ]

Subtotal (95% CI) 109 99 2.0 % 0.76 [ 0.25, 2.36 ]




4 Other races


ROCKET AF 2011 8/218 4/201 1.1 % 1.88 [ 0.56, 6.33 ]

Subtotal (95% CI) 243 222 1.1 % 1.88 [ 0.56, 6.33 ]




0.01 0.1 1 10 100


(Continued . . . )


(Review)




Total (95% CI) 10311 10171 100.0 % 0.85 [ 0.72, 0.99 ]





0.01 0.1 1 10 100


Analysis 9.2. Comparison 9 Factor Xa inhibitors versus VKA: race, Outcome 2 Major bleedings.


Comparison: 9 Factor Xa inhibitors versus VKA: race




1 Asian patients

ARISTOTLE-J 2011 0/143 1/75 6.2 % 0.17 [ 0.01, 4.30 ]

Edoxaban Asia 2010 0/159 2/75 10.8 % 0.09 [ 0.00, 1.94 ]

J-ROCKET AF 2012 23/639 27/639 83.0 % 0.85 [ 0.48, 1.49 ]

Total (95% CI) 941 789 100.0 % 0.72 [ 0.42, 1.24 ]




Test for subgroup differences: Not applicable

0.01 0.1 1 10 100



(Review)


Analysis 10.1. Comparison 10 Factor Xa inhibitors versus VKA: sex, Outcome 1 Stroke and other systemic

embolic events.


Comparison: 10 Factor Xa inhibitors versus VKA: sex




1 Female

AMADEUS 2008 6/742 14/791 3.9 % 0.45 [ 0.17, 1.18 ]

J-ROCKET AF 2012 0/109 7/139 1.9 % 0.08 [ 0.00, 1.43 ]

ROCKET AF 2011 126/2802 142/2803 39.6 % 0.88 [ 0.69, 1.13 ]

Subtotal (95% CI) 3653 3733 45.5 % 0.81 [ 0.64, 1.03 ]




2 Male

AMADEUS 2008 12/1541 13/1501 3.8 % 0.90 [ 0.41, 1.98 ]

J-ROCKET AF 2012 11/528 15/498 4.4 % 0.69 [ 0.31, 1.51 ]

ROCKET AF 2011 143/4279 164/4287 46.3 % 0.87 [ 0.69, 1.09 ]

Subtotal (95% CI) 6348 6286 54.5 % 0.86 [ 0.69, 1.06 ]




Total (95% CI) 10001 10019 100.0 % 0.84 [ 0.71, 0.98 ]





0.01 0.1 1 10 100



(Review)


Analysis 10.2. Comparison 10 Factor Xa inhibitors versus VKA: sex, Outcome 2 Major bleeding.


Comparison: 10 Factor Xa inhibitors versus VKA: sex

Outcome: 2 Major bleeding



1 Male

J-ROCKET AF 2012 22/530 26/500 88.3 % 0.79 [ 0.44, 1.41 ]

Subtotal (95% CI) 530 500 88.3 % 0.79 [ 0.44, 1.41 ]




2 Female

J-ROCKET AF 2012 4/109 4/139 11.7 % 1.29 [ 0.31, 5.26 ]

Subtotal (95% CI) 109 139 11.7 % 1.29 [ 0.31, 5.26 ]




Total (95% CI) 639 639 100.0 % 0.85 [ 0.50, 1.45 ]





0.01 0.1 1 10 100



(Review)


Analysis 11.1. Comparison 11 Factor Xa inhibitors versus VKA: baseline CHADS2 score, Outcome 1 Stroke



Comparison: 11 Factor Xa inhibitors versus VKA: baseline CHADS2 score




1 CHADS2-score 0-1

AMADEUS 2008 6/969 4/909 1.2 % 1.41 [ 0.40, 5.01 ]

Subtotal (95% CI) 969 909 1.2 % 1.41 [ 0.40, 5.01 ]




2 CHADS2-score 2

AMADEUS 2008 6/710 7/739 2.0 % 0.89 [ 0.30, 2.66 ]

J-ROCKET AF 2012 2/97 5/114 1.3 % 0.46 [ 0.09, 2.42 ]

ROCKET AF 2011 30/924 36/933 10.1 % 0.84 [ 0.51, 1.37 ]

Subtotal (95% CI) 1731 1786 13.4 % 0.81 [ 0.52, 1.24 ]




3 CHADS2-score ≥ 3

AMADEUS 2008 6/604 16/645 4.5 % 0.39 [ 0.15, 1.01 ]

J-ROCKET AF 2012 9/540 17/522 5.0 % 0.50 [ 0.22, 1.14 ]

ROCKET AF 2011 239/6156 270/6155 75.9 % 0.88 [ 0.74, 1.05 ]

Subtotal (95% CI) 7300 7322 85.4 % 0.83 [ 0.70, 0.99 ]




Total (95% CI) 10000 10017 100.0 % 0.84 [ 0.71, 0.98 ]





0.01 0.1 1 10 100



(Review)


Analysis 11.2. Comparison 11 Factor Xa inhibitors versus VKA: baseline CHADS2 score, Outcome 2 Major

bleedings.


Comparison: 11 Factor Xa inhibitors versus VKA: baseline CHADS2 score




1 CHADS2-score 0-1

AMADEUS 2008 27/969 7/909 12.5 % 3.69 [ 1.60, 8.52 ]

Subtotal (95% CI) 969 909 12.5 % 3.69 [ 1.60, 8.52 ]




2 CHADS2-score 2

AMADEUS 2008 19/710 7/739 11.9 % 2.88 [ 1.20, 6.88 ]

J-ROCKET AF 2012 3/97 6/115 9.5 % 0.58 [ 0.14, 2.38 ]

Subtotal (95% CI) 807 854 21.3 % 1.86 [ 0.92, 3.73 ]




3 CHADS2-score ≥ 3

AMADEUS 2008 28/604 15/645 24.6 % 2.04 [ 1.08, 3.86 ]

J-ROCKET AF 2012 23/542 24/524 41.6 % 0.92 [ 0.51, 1.66 ]

Subtotal (95% CI) 1146 1169 66.2 % 1.34 [ 0.88, 2.05 ]




Total (95% CI) 2922 2932 100.0 % 1.74 [ 1.26, 2.42 ]





0.01 0.1 1 10 100



(Review)


A P P E N D I C E S

Appendix 1. MEDLINE (Ovid) search strategy

1. atrial fibrillation/ or atrial flutter/

2. ((atrial or auricular) adj5 (fibrillation$ or flutter$)).tw.

3. AF.tw.

4. 1 or 2 or 3

5. factor Xa/ai

6. ((factor Xa or factor 10a or fXa or autoprothrombin c or thrombokinase) adj5 inhib$).tw.

7. (activated adj5 (factor X or factor 10) adj5 inhib$).tw.

8. xabans.tw.

9. (antistasin or apixaban or betrixaban or du 176b or eribaxaban or fondaparinux or idraparinux or otamixaban or razaxaban or

rivaroxaban or yagin or ym 150 or ym150 or LY517717 or darexaban or edoxaban or SSR126517E).tw.


rivaroxaban or yagin or ym 150 or ym150 or LY517717 or darexaban or edoxaban or SSR126517E).nm.

11. 5 or 6 or 7 or 8 or 9 or 10

12. Warfarin/

13. (warfarin$ or adoisine or aldocumar or athrombin$ k or carfin or coumadin$ or coumafene or coumaphene or jantoven or kumatox

or lawarin or marevan or panwarfarin or panwarfin or prothromadin or sofarin or tedicumar or tintorane or waran or warfant or

warfilone or warnerin).tw.



warfilone or warnerin).nm.

15. exp Vitamin K/ai [Antagonists & Inhibitors]

16. (vitamin K antagonist$ or VKA or VKAs).tw.

17. 4-hydroxycoumarins/ or acenocoumarol/ or coumarins/ or dicumarol/ or ethyl biscoumacetate/ or phenindione/ or phenprocoumon/

18. (coumarin$ or cumarin$ or phenprocoum$ or phenprocum$ or dicoumar$ or dicumar$ or acenocoumar$ or acenocumar$ or

fluindione or phenindione or clorindione or diphenadione).tw.


fluindione or phenindione or clorindione or diphenadione).nm.

20. 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19

21. 4 and 11 and 20

Appendix 2. EMBASE (Ovid) search strategy

1. exp heart atrium fibrillation/ or heart atrium flutter/

2. ((atrial or auricular) adj5 (fibrillation$ or flutter$)).tw.

3. AF.tw.

4. 1 or 2 or 3

5. exp blood clotting factor 10a inhibitor/

6. ((factor Xa or factor 10a or fXa or autoprothrombin c or thrombokinase) adj5 inhib$).tw.

7. (activated adj5 (factor X or factor 10) adj5 inhib$).tw.

8. xabans.tw.


rivaroxaban or yagin or ym 150 or ym150 or LY517717 or darexaban or edoxaban or SSR126517E).tw.

10. 5 or 6 or 7 or 8 or 9

11. Warfarin/



warfilone or warnerin).tw.

13. antivitamin K/

14. (vitamin K antagonist$ or VKA or VKAs).tw.


(Review)


15. exp coumarin anticoagulant/


fluindione or phenindione or clorindione or diphenadione).tw.

17. 11 or 12 or 13 or 14 or 15 or 16

18. 4 and 10 and 17

F E E D B A C K

New Feedback, 20 June 2014

Summary

In reviewing “Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial

fibrillation (Review)”1 it seems to us that the choice of outcomes may have been driven in part by how they were defined within

the clinical trials, rather than via a hierarchy of outcomes pre-specified by the reviewers. For example, the “diagnosis of myocardial

infarction was based upon electrocardiographic changes, elevation of enzymes or confirmation during post-mortem examination.”

Simply choosing the outcome definition as reported in clinical trials may compel readers to draw conclusions on outcomes even if

they are not defined in a clinically meaningful way. In this particular case one could argue that biomarker or ECG defined myocardial

infarctions (MIs) are less important to patients than symptomatic MIs resulting in hospitalization and disability. In this review the

conclusion is that

MI risk is not increased with this class of drugs. However, it remains entirely possible that symptomatic MI risk is increased while

asymptomatic MI is decreased, leading to a conclusion of “no difference”. It might be preferable to collect information on all MIs and

discuss and analyze the implications for differences in the way clinical trials actually report and define MI.

While the review1 concludes that “[t]here was no indication of selective reporting in any of the included studies”, we suggest that there

is indeed selective outcome reporting in the identified trials and that this has serious implications for drug- therapy decision making.

First, it is reported that disabling or fatal strokes were only reported in four of 10 trials, i.e., for 16,099 participants. It would seem

highly unlikely that a clinical trial would not categorize strokes in this way and that it is possible that this information might be available

in sources other than the published clinical trial report. Did the review authors attempt to contact the trial authors? Have the relevant

FDA drug approval packages been searched for this data?2 Given the ARISTOTLE trial3 enrolled over 18,000 participants, but is not

counted in this outcome analysis, a more comprehensive search for this data seems warranted. Last, the addition of nine more disabling

or fatal strokes to the Factor Xa inhibitor side of the analysis renders the finding non-statistically significant and highlights that the

magnitude of the reported effect is small relative to the size of the missing data. Until this data is acquired we feel it is premature to

draw any conclusions on these types of strokes.

We have equal concern with respect to the all-cause death analysis. Only six of 10 trials reported on this outcome, yet the review authors

fail to recommend caution in the interpretation of their finding that “Factor Xa inhibitors significantly reduced the number of all-

cause deaths compared with warfarin”1. In addition, we note in the risk of bias assessment for the ARISTOTLE trial3 that a judgment

of low risk is assigned for incomplete outcome data (attrition bias). The support for judgment reads “[e]fficacy and safety outcomes

analysed in ITT population. Number of participants with missing data on vital status and reasons reported. Number of participants

that discontinued during study and reasons are reported”. It is true that in the main publication of the ARISTOTLE trial3 that the

number of participants with missing data on vital status is reported: 380 patients or 2.1% of the originally randomized population. It is

unclear to us though how this might equate a low risk of bias given that the proportion of participants with missing vital status (2.1%)

is five times greater than the difference in mortality reported between the two groups in this trial (absolute difference 0.4%). This

missingness of course was of great importance in the US FDA review of apixaban4 . One reviewer concluded that “[t]he alleged death

benefit of apixaban compared to warfarin is fragile as reported by the sponsor, i.e., p = 0.046, a change in only one death rendering

the difference significantly insignificant. Furthermore, the validity of this fragile benefit depends upon having 100% valid data. The

substantial missing vital status follow-up, the problems with data recordings, and the lack of a significant death benefit for warfarin

destroy confidence that apixaban reduces all-cause mortality” 4. Given that the ARISTOTLE trial contributes substantially to the all-

cause death analysis we feel the findings from the US FDA review should serve to temper confidence in this suggested benefit of Factor

Xa inhibitors as compared to warfarin.In the main publications of the ARISTOTLE and ROCKET- AF trials3,5 it is indicated that

major bleeds were only counted if they occurred within 48 hours of the last dose of assigned study drug. This truncated duration of


(Review)


follow up raises some concerns. First, this is not congruent with the principle of intention-to-treat analysis. A bleed occurring 60 hours

after the last dose of study drug, for example, would not be counted as a consequence of the intervention even though it could indeed

be a result of treatment with the study drug. Thus all major bleeds that happened to patients enrolled in these two large RCTs may not

have been captured. This should be addressed in the risk of bias assessment, discussion, and conclusion sections of the review.

Further, the review reports that intracranial hemorrhages “includes all intraparenchymal, subdural and epidural hematomas, subarach-

noid haemorrhages confirmed by neuroimaging or post-mortem examination”. Were the reviewers able to find this detailed level of

diagnostic criteria in each of the studies included in this outcome analysis? We could not.

Last, while the FDA reviewers performed a sensitivity analysis to hypothetically estimate the impact of dispensing errors that occurred

in the ARISTOTLE trial4 on some outcomes, this was not performed for all outcomes (i.e., it was not performed for intracranial

hemorrhages). This should be discussed given the importance of this outcome in drug-therapy decision making and it surely warrants

consideration in the risk of bias assessment of this large trial. In fact, we find no mention of the dispensing errors that occurred in

the ARISTOTLE trial in this review and we suggest referral to the “Submission Quality and Integrity” section of FDA drug approval

packages be considered an essential starting point in the systematic review of this data6.

We were extremely pleased to see attention drawn to the inability to extrapolate the results of these trials to very low risk people given

the lowering threshold for treatment occurring in current clinical practice guidelines.

Thank you for the opportunity to share our concerns.

Cait O’Sullivan (PharmD, BScPh, BA) Clinical Pharmacist Island Health Clinical Pharmacy Programs

Aaron M Tejani (BSc(Pharm), PharmD) Researcher Therapeutics Initiative, University of British Columbia

We certify that we have no affiliations with or involvement in any organisation or entity with a direct financial interest in the subject

matter of this feedback.

References

1. Bruins Slot KMH, Berge E. Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in

patients with atrial fibrillation (Review). Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.:CD008980.

2. Turner EH. How to access and process FDA drug approval packages for use in research. BMJ 2013;347:f5992.

3. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with

atrial fibrillation. New England Journal of Medicine 2011;365:981-92.

4. U.S. Food and Drug Administration. Apixaban Medical Review. NDA 202155 [Internet]. 2012 [cited 2014 May 11]. Available

from http://www.accessdata.fda.gov/drugsatfda˙docs/nda/2012/202155Orig1s000MedR.pdf.

5. Patel MR, Mahaffey KW, Garg Y, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial

fibrillation. New England Journal of Medicine 2011;365;883-91.

6. U.S. Food and Drug Administration. Drugs@FDA. FDA Approved Drug Products. [Internet]. Available from http://

www.accessdata.fda.gov/Scripts/cder/drugsatfda/index.cfm.

Reply

We thank the authors for their comprehensive and constructive feedback on our review. We have addressed their comments below.

[1] In reviewing “Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial

fibrillation (Review)” it seems to us that the choice of outcomes may have been driven in part by how they were defined within the clinical

trials, rather than via a hierarchy of outcomes pre-specified by the reviewers. For example, the “diagnosis of myocardial infarction was

based upon electrocardiographic changes, elevation of enzymes or confirmation during post-mortem examination”. Simply choosing

the outcome definition as reported in clinical trials may compel readers to draw conclusions on outcomes even if they are not defined in

a clinically meaningful way. In this particular case one could argue that biomarker or ECG defined myocardial infarctions (MIs) are less

important to patients than symptomatic MIs resulting in hospitalization and disability. In this review the conclusion is that MI risk is

not increased with this class of drugs. However, it remains entirely possible that symptomatic MI risk is increased while asymptomatic

MI is decreased, leading to a conclusion of “no difference”. It might be preferable to collect information on all MIs and discuss and

analyze the implications for differences in the way clinical trials actually report and define MI.

Reply: The outcomes that were used in our review were all pre-specified in the protocol that was published in 20111 , and the definitions

were not driven by the definitions used in the trials. Outcome definitions were based on those that were used in Cochrane reviews in the same

therapeutic area2,3. Use of similar outcome definitions might enable and facilitate a cross-review comparison of the results. Furthermore, we

used outcome definitions that are widely used in clinical practice and in other clinical trials.


(Review)


http://www.accessdata.fda.gov/Scripts/cder/drugsatfda/index.cfm







The definition of myocardial infarctions (MIs) that was used in our review is similar to the one used by the World Health Organisation (WHO)

to define MIs, i.e. a patient is diagnosed with MI if two (probable) or three (definite) of the following criteria are satisfied:

1. Clinical history of ischaemic type chest pain lasting for more than 20 minutes

2. Changes in serial ECG tracings

3. Rise and fall of serum cardiac biomarkers

This definition captures the symptomatic MIs (as pointed out by the reviewers), but also underlines that the diagnosis should not be based on

symptoms only, as these might vary considerably between patients and might even be absent in others (i.e., “silent” MI). This definition may

not capture the small proportion of patients with truly “silent” MIs, but we agree with the comment that the symptomatic MIs are what are

most relevant for patients, and are the ones that should be assessed in the review.

[2] While the review concludes that “[t]here was no indication of selective reporting in any of the included studies”, we suggest that

there is indeed selective outcome reporting in the identified trials and that this has serious implications for drug-therapy decision

making. First, it is reported that disabling or fatal strokes were only reported in four of 10 trials, i.e., for 16,099 participants. It would

seem highly unlikely that a clinical trial would not categorize strokes in this way and that it is possible that this information might be

available in sources other than the published clinical trial report. Did the review authors attempt to contact the trial authors? Have the

relevant FDA drug approval packages been searched for this data? Given the ARISTOTLE trial enrolled over 18,000 participants, but

is not counted in this outcome analysis, a more comprehensive search for this data seems warranted. Last, the addition of nine more

disabling or fatal strokes to the Factor Xa inhibitor side of the analysis renders the finding non-statistically significant and highlights

that the magnitude of the reported effect is small relative to the size of the missing data. Until this data is acquired we feel it is premature

to draw any conclusions on these types of

strokes.

Reply: We agree that it is important to identify the disabling and fatal strokes. We did contact the sponsors of the clinical trials and the principle

investigators to provide more data on disabling or fatal strokes, but in nearly all cases this was not provided. According to published protocols

this outcome was not systematically collected in some studies (e.g. the large ARISTOTLE trial), and this is not unusual for large clinical

cardiovascular prevention trials (mixed primary and secondary prevention).

We did not search the drug approval packages that have been submitted to regulatory authorities (US FDA and the European Medicines

Agency), but plan to do this when we update the review later this year. We also plan to re-contact the sponsors/principle investigators of all

studies to collect these data. Hopefully, we will then be able to draw better conclusions on this clinically relevant outcome.

[3] We have equal concern with respect to the all-cause death analysis. Only six of 10 trials reported on this outcome, yet the review

authors fail to recommend caution in the interpretation of their finding that “Factor Xa inhibitors significantly reduced the number of

all-cause deaths compared with warfarin“.

Reply: Again, we agree that this is a very important effect variable and we regret that it was not possible to get data from four of the included

studies that enrolled 3160 patients in total. As with the disabling stroke-outcome we plan to collect more data for the planned update of the

review later this year. Still, considering that we had data on 92.5% of all included patients (n = 38,924) for this outcome, we consider that

our interpretation is valid and supported by relatively robust data.

[4] In addition, we note in the risk of bias assessment for the ARISTOTLE trial that a judgment of low risk is assigned for incomplete

outcome data (attrition bias). The support for judgment reads ”[e]fficacy and safety outcomes analysed in ITT population. Number of

participants with missing data on vital status and reasons reported. Number of participants that discontinued during study and reasons

are reported“. It is true that in the main publication of the ARISTOTLE trial that the number of participants with missing data on vital

status is reported: 380 patients or 2.1% of the originally randomized population. It is unclear to us though how this might equate a low

risk of bias given that the proportion of participants with missing vital status (2.1%) is five times greater than the difference in mortality

reported between the two groups in this trial (absolute difference 0.4%). This missingness of course was of great importance in the

US FDA review of apixaban. One reviewer concluded that “[t]he alleged death benefit of apixaban compared to warfarin is fragile as

reported by the sponsor, i.e., P = 0.046, a change in only one death rendering the difference significantly insignificant. Furthermore, the

validity of this fragile benefit depends upon having 100% valid data. The substantial missing vital status follow-up, the problems with

data recordings, and the lack of a significant death benefit for warfarin destroy confidence that apixaban reduces all-cause mortality”,

Given that the ARISTOTLE trial contributes substantially to the all-cause death analysis we feel the findings from the US FDA review

should serve to temper confidence in this suggested benefit of Factor Xa inhibitors as compared to warfarin.

Reply: We thank you for pointing this out and agree that this hampers the interpretation of mortality data from the ARISTOTLE trial. We

will address this issue in the update of the review.

[5] In the main publications of the ARISTOTLE and ROCKET-AF trials it is indicated that major bleeds were only counted if they

occurred within 48 hours of the last dose of assigned study drug. This truncated duration of follow up raises some concerns. First,

this is not congruent with the principle of intention-to-treat analysis. A bleed occurring 60 hours after the last dose of study drug, for


(Review)


example, would not be counted as a consequence of the intervention even though it could indeed be a result of treatment with the

study drug. Thus all major bleeds that happened to patients enrolled in

these two large RCTs may not have been captured. This should be addressed in the risk of bias assessment, discussion, and conclusion

sections of the review.

Reply: We thank the reviewers for this comment. We will look more critically into the various definitions of (major) bleedings that were used

in the included studies and discuss this in more detail in the update of the review.

[6] Further, the review reports that intracranial hemorrhages “includes all intraparenchymal, subdural and epidural hematomas, sub-

arachnoid haemorrhages confirmed by neuroimaging or post-mortem examination”. Were the reviewers able to find this detailed level

of diagnostic criteria in each of the studies included in this outcome analysis? We could not.

Reply: Neuroimaging and/or autopsy was performed in all of the included studies to diagnose intracranial haemorrhages. According to the

study protocols and/or publications of the results that we reviewed intracranial haemorrhages were diagnosed based on the identification of

a haemorrhage in the parenchymal, subdural, epidural and subarachnoid regions. In the larger studies, which contributed the majority of

intracranial haemorrhages, blinded neuroimaging committees also adjudicated this outcome. We have no reason to doubt that the haemorrhages

were classified in accordance with the protocols, and therefore consider the available data on intracranial haemorrhages to be robust.

[7] Last, while the FDA reviewers performed a sensitivity analysis to hypothetically estimate the impact of dispensing errors that

occurred in the ARISTOTLE trial on some outcomes, this was not performed for all outcomes (i.e., it was not performed for intracranial

hemorrhages). This should be discussed given the importance of this outcome in drug-therapy decision making and it surely warrants

consideration in the risk of bias assessment of this large trial. In fact, we find no mention of the dispensing errors that occurred in

the ARISTOTLE trial in this review and we suggest referral to the “Submission Quality and Integrity” section of FDA drug approval

packages be considered an essential starting point in the systematic review of this data.

Reply: As mentioned previously, we only used published data in our review and did not have access to drug approval packages that have been

submitted to regulatory authorities or assessment reports of these data by regulatory authorities. At the time of our analysis we were thus not

aware of this issue (dispensing errors in the ARISTOTLE trial) and were not able to assess and further discuss this. We will take this issue into

account in the update of our review.

[8] We were extremely pleased to see attention drawn to the inability to extrapolate the results of these trials to very low risk people

given the lowering threshold for treatment occurring in current clinical practice guidelines.

Reply: Thanks for your feedback.

References:

1. Bruins Slot KMH, Berge E. Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients

with atrial fibrillation (Protocol). Cochrane Database of Systematic Reviews 2011, Issue 2. Art. No.: CD008980. DOI: 10.1002/

14651858.CD008980.

2. Aguilar MI, Hart R, Pearce LA. Oral anticoagulants versus antiplatelet therapy for preventing stroke in patients with non-valvular

atrial fibrillation and no history of stroke or transient ischemic attacks. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.:

CD006186. DOI: 10.1002/14651858.CD006186.pub2.

3. Saxena R, Koudstaal PJ. Anticoagulants versus antiplatelet therapy for preventing stroke in patients with nonrheumatic atrial

fibrillation and a history of stroke or transient ischemic attack. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.:

CD000187. DOI: 10.1002/14651858.CD000187.pub2.

Contributors

Feedback: Cait O’Sullivan, Aaron M Tejani

Responses: Karsten MH Bruins Slot, Eivind Berge


(Review)


Feedback, 16 February 2015

Summary

We read with interest the review on factor Xa Inhibitors versus vitamin K antagonists (VKA) for preventing cerebral or systemic

embolism in patients with atrial fibrillation (1) and there are a few points we wish to address.

[1] The majority of the outcome data for major bleeding included in the review comes from the results of single, randomized controlled

trials of apixaban (2: ARISTOTLE) and rivaroxaban (3: ROCKET-AF). For the primary outcome of stroke and systemic embolism,

the review calculates a number-needed-to-treat (NNT) for rivaroxaban of 369 per year, indicating that 369 people need to be treated

with rivaroxaban instead of dose-adjusted warfarin for one year to prevent one stroke or systemic embolism. We find the inclusion

of an NNT in this case inappropriate. In the ROCKET-AF trial, the rates of the primary efficacy outcome between rivaroxaban and

warfarin were found to be not statistically significant and met the criteria for non-inferiority, not superiority. Presenting a NNT infers

that rivaroxaban is superior to warfarin and that an estimated number of patients can be treated with rivaroxaban instead of warfarin to

prevent the primary outcome, which is misleading. If an NNT is calculated on non-statistically significant results, one of the confidence

intervals will indicate benefit and the other harm (Cochrane Handbook). We would recommend removing the NNT data presented

altogether to avoid misinterpretation. In the case you disagree, confidence intervals should be added for qualification. In addition, a

description of how the NNT was calculated would be helpful as we could not replicate the findings given the available trial data.

[2] In the conclusion of the review, it states that “factor Xa inhibitors lower the risk of major bleedings”. We disagree with this statement.

In the included ROCKET-AF trial (3), rivaroxaban was found to have similar rates of all-cause mortality and major and clinically

relevant non-major bleeding. However, the main limitation of the ROCKET-AF trial was the poor INR control in the warfarin groups,

with the mean time in therapeutic range (TTR) reported as 55%. The poor INR control in the warfarin arm biases the results in favor

of rivaroxaban and questions whether or not rivaroxaban was adequately compared to the standard of care. Efficacy of warfarin in

preventing thrombotic events and safety in terms of bleeding risk is dependent on the quality of INR control. The review planned a

subgroup analysis in patients that received VKA treatment and had data regarding TTR greater than or less than 60%, however, only

data from the ROCKET-AF trial was available and presented. An analysis of center-TTR quartile in the ROCKET-AF trial found

in the supplementary appendix, the authors state that the effect of rivaroxaban did not differ across quartiles and that at the highest

quartile with the best INR control, the hazard ratio of 0.74 (0.49-1.12) still favored rivaroxaban compared to warfarin (Table 5 in the

Supplementary Appendix). In contrast, the analysis in the FDA medical review (4) demonstrates that when warfarin administration was

associated with TTR greater than 68%, there was actually a relative increase in primary outcome events in the rivaroxaban group with

point estimates of the hazard ratio greater than 1 and wide confidence intervals. Similarly, the FDA’s United States subgroup analysis

(mean TTR 63%) showed a statistically significant increase in the number of major bleeding events in the rivaroxaban arm (4). In

addition, major bleeding events were recorded in the ROCKET-AF up until two days after the last dose which we feel would lead to

missed bleeding events. The FDA medical review also includes major bleeding events up to thirty days after the last dose which is more

likely to capture events and we are curious as to what data the authors included in their analysis. Overall, we are not convinced that

rivaroxaban decreases major bleeding risk. Given that the relatively poor INR control in the warfarin arm is a major limitation of the

ROCKET-AF trial, we recommend that it be included in the discussion when interpreting the results. The following statement, “the

benefits of rivaroxaban in preventing stroke and systemic embolic events compared to warfarin are more or less consistent regardless

of warfarin administration” should also be revised. Another consideration is that the finding of a significant benefit in major bleeding

risk with the factor Xa inhibitors in the review depended on what type of analysis was conducted; fixed-effect or random-effect. Even

with a sensitivity analysis that removed the open-label trial, there was still considerable heterogeneity. We appreciate the reviewers for

exploring the possible causes of the heterogeneity (e.g. bleeding risk was higher in ROCKET-AF given patient population), however,

given that the results were not robust or consistent with various analyses, we would avoid a blanket statement of reduced major bleeding

risk with factor Xa inhibitors in all patients as it is misleading.

[3] Even if the analyses were straightforward, the fact that both the apixaban and rivaroxaban RCTs have yet to be replicated should

caution any firm conclusions on the safety and efficacy of these agents. The inclusion of serious adverse events (SAEs) would have

been helpful to represent the overall net impact of factor Xa Inhibitors, including rivaroxaban. Unfortunately, the ROCKET-AF trial

inappropriately excluded the clinical efficacy endpoints of ischemic stroke, systemic embolism or myocardial infarction as SAEs, making

an accurate interpretation of the net benefit or harm difficult.

[4] Finally, since the data from the ROCKET-AF trial does not adequately support that rivaroxaban is as effective as warfarin used

skilfully (4), it may be more appropriate to conclude that rivaroxaban may be an alternative to those who refuse warfarin therapy or

cannot comply with warfarin monitoring.

Thank you for your attention to our concerns.


(Review)


References:

1. Bruins Slot KMH, Berge E. Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in

patients with atrial fibrillation (Review). Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.:CD008980.

2. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with

atrial fibrillation. New England Journal of Medicine 2011; 365:981-92.

3. Patel MR, Mahaffey KW, Garg Y, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in non-valvular atrial

fibrillation. New England Journal of Medicine 2011;365:883-91.

4. U.S Food and Drug Administration. Drugs@FDA. FDA Approved Drug Products. [Internet]. Available from http://

www.accessdata.fda.gov/scripts/cder/drugsatfda/

5. Patel MR, Mahaffey KW, Garg Y, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in non-valvular atrial

fibrillation. Supplementary appendix. New England Journal of Medicine 2011;365:883-91. Available at http://www.nejm.org/doi/

full/10.1056/NEJMoa1009638.

6. Therapeutics Initiative. Serious Adverse Event Analysis: Lipid-Lowering Therapy Revisited. Therapeutics Letter Issue 42, Aug-

Oct 2001.

Reply

We thank the authors for the critical review of our meta-analysis. We have addressed their comments and feedback below.

[1] The NNT for rivaroxaban was calculated with an online NNT-calculator (http://www.calctool.org/CALC/prof/medical/NNT). We

entered the following variables to calculate the NNT for the entire trial period of 1.9 years: 269 events for 7081 patients treated with

rivaroxaban, and 306 events for 7090 patients treated with warfarin. This gave a NNT for the 1.9 year period of 193.409, which then

was rounded up to 194 as is customary and recommended in the literature (e.g. Sackett et al 1996). Since the NNT of 194 is for a 1.9

year treatment period, the NNT per year is calculated by multiplying 194 with 1.9. By doing this we assumed that the event rate is

constant over time.

We agree with the comment that this NNT should be interpreted with caution, since superiority of rivaroxaban over warfarin for the

primary efficacy outcome was not shown in the ROCKET-AF trial and will add confidence intervals and a note of caution (i.e. non-

significance of the results) to the next version of the review. We feel that mentioning the NNT is of interest for the reader, as it indicates

that any differences in the number of stroke and SEEs of factor Xa inhibitors (including rivaroxaban) compared with warfarin are rather

marginal, since (well-regulated) warfarin appears to be a highly effective drug.

[2] In our review we have not concluded that “factor Xa inhibitors lower the risk of major bleedings”. Instead, we concluded in the

Summary of main results that “factor Xa inhibitors appear to reduce the number of major bleedings and intracranial haemorrhages

compared with warfarin, though the evidence for a statistically significant reduction in major bleedings is less robust.” We have also

stated in the Authors’ conclusions section that “… overall, there is a small net clinical benefit of treatment with factor Xa inhibitors in

people with AF as it leads to a reduction of strokes and systemic embolic events and also seems to lower the risk of major bleedings

(including intracranial haemorrhages) compared with dose-adjusted warfarin.” We have thus not categorically stated that factor Xa

inhibitors lower the risk of major bleedings, as is suggested in the comment, but have used more careful wordings on this important

issue in our review.

Unfortunately, we only had data from the ROCKET-AF study for the pre-specified subgroup analysis in patients who received VKA

treatment with time-in-therapeutic range (TTR) equal to or greater than 60% versus less than 60%, and have not used data from the

FDA medical review. We agree with the comments concerning the limitations of this subgroup analysis and plan to include a revised

analysis on the quality of anticoagulation with warfarin in the next version of the review. This new analysis will hopefully include data

of more factor Xa inhibitors (i.e. apixaban and edoxaban) and also non-published data that was submitted to the European Medicines

Agency (EMA). If poor INR control continues to be a limitation we will include this in the discussion when interpreting the results.

We will also carefully reconsider the reasons for heterogeneity and our statement that “the benefits of rivaroxaban in preventing stroke

and systemic embolic events compared to warfarin are more or less consistent regardless of warfarin administration”.

[3] We planned to perform an analysis of ’Other adverse events’ in our review, as stated in the review’s protocol and Methods section.

Unfortunately, there were very few studies that presented these data systematically. We therefore have chosen to focus on bleeding and

major cardiovascular adverse events and deaths in our review. Depending on the availability of more specific data on ’other’ adverse

events (e.g. hepatotoxicity) in non-published data submitted to the EMA for the compounds rivaroxaban, edoxaban and apixaban we

plan to update this analysis.

[4] In our conclusions of the review, we have given the results for all factor Xa inhibitors combined, and not for the individual

compounds, such as rivaroxaban. We conclude that factor Xa inhibitors appear to be an effective treatment for the prevention of stroke

or other systemic embolic events in people with AF who are eligible for long-term anticoagulation. This conclusion is based on the


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available data for all six included factor Xa inhibitors that showed a statistically significant reduction of the number of strokes and

SEEs compared with warfarin (OR 0.81, 95% CI 0.72 to 0.91). We have not specifically mentioned that rivaroxaban is as effective as

warfarin. We did, however, state that based on the assessed data we are currently not able to determine which of the available factor Xa

inhibitors is the most effective and safe.

Contributors

Feedback: Sarah Burgess and Aaron M Tejani

Responses: Karsten MH Bruins Slot, Eivind Berge

W H A T ’ S N E W

Last assessed as up-to-date: 29 April 2013.

Date Event Description

16 February 2015 Feedback has been incorporated New feedback has been added to the review

H I S T O R Y

Protocol first published: Issue 2, 2011

Review first published: Issue 8, 2013

Date Event Description

1 October 2014 Amended Correction to name in Feedback section

20 June 2014 Feedback has been incorporated See the Feedback section

C O N T R I B U T I O N S O F A U T H O R S

KBS: conception and design of the review; writing of the protocol and review.

EB: commenting on the protocol and reviewing drafts.


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

KBS received a small honorarium from Boehringer Ingelheim for a lecture to general practitioners (GPs) about thrombolytic stroke

treatment in 2006. KBS is employed by the Norwegian Medicines Agency and is a member of the European Medicines Agency’s

Committee for Medicinal Products for Human Use (CHMP) and the Cardiovascular Working Party. The views expressed in this review

are the personal views of KBS and should not be understood or quoted as being made on behalf of or reflecting the position of the

Norwegian Medicines Agency and the European Medicines Agency or one of its committees or working parties.

EB participated in an advisory committee meeting for Bayer Schering Pharma to discuss the results of the ROCKET AF (rivaroxaban).

He received an honorarium and reimbursement of expenses related to this meeting.

S O U R C E S O F S U P P O R T

Internal sources

• No sources of support supplied

External sources

• South-Eastern Norway Regional Health Authority, Norway.

Educational grant

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

1. In light of the available data we have chosen to modify the following two secondary outcomes that were defined in the protocol:

• we changed ’Major extracranial haemorrhages, defined as severe enough to lead to hospitalisation, blood transfusion or surgery’

into ’Major bleedings (defined by ISTH criteria or modified ISTH criteria)’, and we changed ’Minor bleeding and bruising’ to ’Non-

major clinically relevant bleeding (defined by ISTH criteria or modified ISTH criteria)’.

2. A handsearch of conference proceedings has not been performed systematically. We found it unlikely that any important trial in this

field would not be reported in full.

I N D E X T E R M S

Medical Subject Headings (MeSH)

∗Factor Xa Inhibitors; Atrial Fibrillation [∗complications]; Embolism [∗prevention & control]; Intracranial Embolism [∗prevention &

control]; Randomized Controlled Trials as Topic; Vitamin K [∗antagonists & inhibitors]

MeSH check words

Humans


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