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

  1. Karsten MH Bruins Slot*,
  2. Eivind Berge

Editorial Group: Cochrane Stroke Group

Published Online: 8 AUG 2013

Assessed as up-to-date: 29 APR 2013

DOI: 10.1002/14651858.CD008980.pub2


How to Cite

Bruins Slot KMH, Berge E. Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD008980. DOI: 10.1002/14651858.CD008980.pub2.

Author Information

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

*Karsten MH Bruins Slot, Department of Internal Medicine, Oslo University Hospital, Oslo, NO-0407, Norway. kbruinsslot@yahoo.no.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 8 AUG 2013

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Characteristics of included studies [ordered by study ID]
AMADEUS 2008

MethodsRandomised, open-label, active-controlled trial


Participants4673 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


InterventionsIdraparinux (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)


OutcomesPrimary 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 associated 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


NotesStudy sponsored by Sanofi


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were randomly assigned to treatment groups

Allocation concealment (selection bias)Low riskParticipants were randomly assigned to treatment groups with a computerised interactive voice response system. Stratification by study centre and prior use of VKA

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label study: both participants and study personnel were aware of the assigned treatment

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAll suspected outcome events were adjudicated by a central adjudication committee unaware of the treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Low riskEfficacy and safety outcomes analysed in ITT population. Number of participants that discontinued are reported. Reasons for discontinuation are listed

Selective reporting (reporting bias)Low riskAll predefined efficacy and safety outcomes are reported for the ITT population

Other biasUnclear riskStudy terminated prior to finalisation after recommendation by the DSMB due to excess bleeding complications in the idraparinux group

ARISTOTLE 2011

MethodsRandomised, double-blind, active controlled trial


Participants18,201 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


InterventionsApixaban (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)


OutcomesPrimary 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


NotesStudy sponsored by Bristol-Myers Squibb and Pfizer


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were randomly assigned to treatment groups

Allocation concealment (selection bias)Low riskParticipants were randomly assigned to treatment groups. Stratification by clinical site and prior VKA use

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind, double-dummy design

Blinding of outcome assessment (detection bias)
All outcomes
Low riskEfficacy and safety outcomes were adjudicated by a clinical events committee whose members were not aware of study group assignments

Incomplete outcome data (attrition bias)
All outcomes
Low riskEfficacy 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

Selective reporting (reporting bias)Low riskAll predefined efficacy and safety outcomes reported for ITT population

Other biasLow riskN/A

ARISTOTLE-J 2011

MethodsRandomised, partially-blinded, active controlled trial


Participants222 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


InterventionsApixaban (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


OutcomesPrimary 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


NotesStudy co-sponsored by Pfizer and Bristol-Myers Squibb


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were randomly assigned to treatment groups

Allocation concealment (selection bias)Low riskParticipants were randomly assigned to treatment groups. Stratification by trial site and prior use of VKA

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskPartially blinded design: open label warfarin and double-blind apixaban administration

Blinding of outcome assessment (detection bias)
All outcomes
Low riskReported efficacy and safety outcomes were adjudicated by an independent committee whose members were not aware of study group assignments

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskPrimary 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

Selective reporting (reporting bias)Low riskAll predefined efficacy and safety outcomes reported for safety population

Other biasLow riskN/A

Edoxaban Asia 2010

MethodsRandomised, partially-blinded, active controlled trial


Participants235 Asian people with documented non-valvular AF


InterventionsEdoxaban (30 mg daily or 60 mg daily) versus dose-adjusted warfarin (target INR 2.0 to 3.0) during a predefined 3-month period


OutcomesPrimary 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


NotesStudy sponsored by Daiichi Sankyo


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were randomly assigned to treatment groups

Allocation concealment (selection bias)Low riskParticipants were randomly assigned to treatment groups

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label administration of both edoxaban and warfarin. Different edoxaban doses administered in double-blind fashion

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskAdjudication of outcomes by investigator and Clinical Events Committee. Unclear whether Clinical Events Committee was blinded to treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Low riskSafety outcomes analysed in safety population (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)

Number of participants that discontinued during study and reasons for discontinuation stated

Selective reporting (reporting bias)Low riskAll predefined safety and efficacy outcomes reported for safety population and full analysis set, respectively

Other biasLow riskN/A

Edoxaban US/Europe 2010

MethodsRandomised, partially-blinded, active controlled trial


Participants1146 people aged between 18 and 65 years with documented non-valvular AF and a CHADS2 score of at least 2


InterventionsEdoxaban (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


OutcomesPrimary 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


NotesStudy sponsored by Daiichi Sankyo


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were randomly assigned to treatment groups

Allocation concealment (selection bias)Low riskParticipants were randomly assigned to treatment groups

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label administration of both edoxaban and warfarin. Different doses of edoxaban administered in double-blind fashion

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskAdjudication of bleeding events by independent central adjudication committee that was blinded to treatment assignment. Unclear whether efficacy outcomes were centrally adjudicated

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskSafety and efficacy outcomes analysed in 'safety population' (participants who received at least 1 dose of study drug and had at least 1 post-dose safety assessment). Number of participants that discontinued during study and reasons for discontinuation not stated

Selective reporting (reporting bias)Low riskAll predefined safety and efficacy outcomes reported for safety population

Other biasUnclear riskRandomisation into edoxaban 60 mg twice daily treatment arm prematurely terminated after enrolment of 180 patients based on recommendation of independent DSMB due to an excess of bleedings

EXPLORE-Xa 2013

MethodsRandomised, partially-blinded, active controlled trial


Participants508 people with documented non-valvular AF and an indication for anticoagulation with VKA


InterventionsBetrixaban (40 mg, 60 mg or 80 mg daily) or dose-adjusted warfarin (target INR 2.0 to 3.0) for at least 3 months


OutcomesPrimary safety outcome: composite of major or clinically relevant non-major bleeding (ISTH criteria)

Secondary safety and efficacy outcomes: stroke (fatal and non-fatal); myocardial infarction; systemic embolic events; pulmonary embolism; all-cause death; other adverse events


NotesStudy sponsored by Portola Pharmaceuticals


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were randomly assigned to treatment groups

Allocation concealment (selection bias)Low riskParticipants were randomly assigned to treatment groups with a computerised interactive voice response system

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label administration of both betrixaban and warfarin. Separate dosages of betrixaban administered in double-blind fashion

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAdjudication of safety and efficacy outcomes by an independent clinical endpoint committee that was blinded to treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes reported in ITT population. Number of participants that discontinued during study stated with reason

Selective reporting (reporting bias)Low riskAll predefined outcomes reported for ITT population

Other biasLow riskN/A

J-ROCKET AF 2012

MethodsRandomised, double-blind, active controlled trial


Participants1280 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 thromboembolism: congestive heart failure and/or left ventricular ejection fraction < 35%, hypertension, age ≥ 75 years or diabetes mellitus


InterventionsRivaroxaban (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)


OutcomesPrimary 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


NotesStudy sponsored by Johnson & Johnson Pharmaceutical Research and Development, and Bayer HealthCare


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were randomly assigned to treatment groups

Allocation concealment (selection bias)Low riskParticipants were randomly assigned to treatment groups

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind, double-dummy design

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAdjudication of safety and efficacy outcomes by an independent clinical endpoint committee that was blinded to treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes reported in safety analysis population, ITT population or per protocol analysis population. Number of participants that discontinued due to adverse events stated

Selective reporting (reporting bias)Low riskAll predefined efficacy and safety outcomes reported

Other biasLow riskN/A

OPAL-1 2010

MethodsRandomised, partially blind, active controlled trial


Participants448 people recruited in the Asian-Pacific region with documented non-valvular AF


InterventionsDarexaban (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


OutcomesPrimary 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


NotesStudy sponsored by Astellas


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were randomly assigned to treatment groups

Allocation concealment (selection bias)Low riskParticipants were randomly assigned to treatment groups

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label administration of both darexaban and warfarin. Different doses of darexaban administered in double-blind fashion

Blinding of outcome assessment (detection bias)
All outcomes
High riskAdjudication of outcomes not described

Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes reported in ITT population. Number of participants that discontinued during study and reasons for discontinuation stated

Selective reporting (reporting bias)Low riskAll predefined outcomes reported for ITT population

Other biasUnclear riskRandomisation into 240 mg darexaban arm terminated early due to increased bleeding after recommendation from DSMB

OPAL-2 2011

MethodsRandomised, double-blind, active controlled trial


Participants1297 people with documented AF and a CHADS2 score of 1 to 6


InterventionsDarexaban (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


OutcomesPrimary 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 embolism, vascular death


NotesStudy sponsored by Astellas


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were randomly assigned to treatment groups

Allocation concealment (selection bias)Low riskParticipants were randomly assigned to treatment groups

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind, double-dummy design

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskAdjudication of outcomes not described

Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes reported in ITT population. Number of participants that discontinued during study stated

Selective reporting (reporting bias)Unclear riskAll predefined outcomes reported for ITT population

Other biasLow riskN/A

ROCKET AF 2011

MethodsRandomised, double-blind, active controlled trial


Participants14,264 people with documented AF and a CHADS2 score ≥ 2


InterventionsRivoraxaban (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)


OutcomesPrimary 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


NotesStudy sponsored by Johnson & Johnson Pharmaceutical Research and Development, and Bayer HealthCare


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were randomly assigned to treatment groups

Allocation concealment (selection bias)Low riskParticipants were randomly assigned to treatment groups with the use of a central, computerised, automated voice-response system

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind, double-dummy design

Blinding of outcome assessment (detection bias)
All outcomes
Low riskEfficacy and safety outcomes were adjudicated by a blinded and independent clinical endpoint committee

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskPrimary efficacy outcome analysed in ITT population. Primary and secondary efficacy also analysed in the as treated, per protocol population during treatment. Safety outcomes only analysed in safety, on-treatment population. Number of participants that discontinued during study and reasons are reported

Selective reporting (reporting bias)Low riskAll predefined efficacy and safety outcomes reported, but not all for ITT population

Other biasLow riskN/A

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Camm 2011Expert review of edoxaban; no data

Fox 2011Subgroup analysis of patients with moderate renal impairment randomised into ROCKET AF 2011, which is included in the present review; no additional data

Hankey 2012Subgroup analysis of patients with previous stroke or TIA randomised into ROCKET AF 2011, which is included in the present review; no additional data

Harenberg 2010Expert review of idraparinux and idrabioparinux; no data

Lane 2011Post 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 2010Study protocol and rationale for ARISTOTLE 2011; no data

Partida 2011Expert review of edoxaban; no data

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

 
Characteristics of studies awaiting assessment [ordered by study ID]
BOREALIS AF 2007

MethodsRandomised, double-blind, active controlled trial

ParticipantsPeople 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

InterventionsBiotinylated idraparinux (SSR126517E) administered by once-weekly subcutaneous injection versus dose-adjusted warfarin

OutcomesPrimary 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

NotesThis 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)

 
Characteristics of ongoing studies [ordered by study ID]
ENGAGE AF-TIMI 48

Trial name or titleEffective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48)

MethodsRandomised, double-blind, double-dummy, event driven study

Participants21,107 people with electrical documentation of AF ≤ 12 months and a CHADS2 score ≥ 2

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

OutcomesPrimary efficacy outcome: stroke and systemic embolic events

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

Starting dateNovember 2008

Contact informationshirali.patel@quintiles.com

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

 
Comparison 1. Factor Xa inhibitor versus VKA

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Stroke and other systemic embolic events940777Odds Ratio (M-H, Fixed, 95% CI)0.81 [0.72, 0.91]

    1.1 Apixaban versus VKA
218423Odds Ratio (M-H, Fixed, 95% CI)0.78 [0.65, 0.93]

    1.2 Darexaban versus VKA
1448Odds Ratio (M-H, Fixed, 95% CI)1.88 [0.10, 36.75]

    1.3 Edoxaban versus VKA
21377Odds Ratio (M-H, Fixed, 95% CI)0.49 [0.14, 1.67]

    1.4 Idraparinux versus VKA
14576Odds Ratio (M-H, Fixed, 95% CI)0.67 [0.37, 1.21]

    1.5 Rivaroxaban versus VKA
215445Odds Ratio (M-H, Fixed, 95% CI)0.85 [0.72, 1.00]

    1.6 Betrixaban versus VKA
1508Odds Ratio (M-H, Fixed, 95% CI)1.68 [0.08, 35.22]

 2 All strokes940749Odds Ratio (M-H, Fixed, 95% CI)0.78 [0.69, 0.89]

    2.1 Apixaban versus VKA
218423Odds Ratio (M-H, Fixed, 95% CI)0.77 [0.64, 0.93]

    2.2 Betrixaban versus VKA
1508Odds Ratio (M-H, Fixed, 95% CI)1.68 [0.08, 35.22]

    2.3 Darexaban versus VKA
1448Odds Ratio (M-H, Fixed, 95% CI)1.34 [0.06, 28.16]

    2.4 Edoxaban versus VKA
21377Odds Ratio (M-H, Fixed, 95% CI)0.46 [0.11, 1.95]

    2.5 Idraparinux versus VKA
14576Odds Ratio (M-H, Fixed, 95% CI)0.69 [0.38, 1.27]

    2.6 Rivaroxaban versus VKA
215417Odds Ratio (M-H, Fixed, 95% CI)0.80 [0.66, 0.97]

 3 Ischaemic stroke839606Odds Ratio (M-H, Fixed, 95% CI)0.88 [0.76, 1.02]

    3.1 Apixaban versus VKA
218423Odds Ratio (M-H, Fixed, 95% CI)0.90 [0.73, 1.12]

    3.2 Darexaban versus VKA
1448Odds Ratio (M-H, Fixed, 95% CI)0.80 [0.03, 19.85]

    3.3 Edoxaban versus VKA
1234Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.4 Idraparinux versus VKA
14576Odds Ratio (M-H, Fixed, 95% CI)0.65 [0.32, 1.31]

    3.5 Rivaroxaban versus VKA
215417Odds Ratio (M-H, Fixed, 95% CI)0.88 [0.71, 1.09]

    3.6 Betrixaban versus VKA
1508Odds Ratio (M-H, Fixed, 95% CI)1.68 [0.08, 35.22]

 4 Disabling or fatal stroke416099Odds Ratio (M-H, Fixed, 95% CI)0.71 [0.54, 0.92]

    4.1 Darexaban versus VKA
1448Odds Ratio (M-H, Fixed, 95% CI)0.80 [0.03, 19.85]

    4.2 Edoxaban versus VKA
1234Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.3 Rivaroxaban versus VKA
215417Odds Ratio (M-H, Fixed, 95% CI)0.71 [0.54, 0.92]

 5 Systemic embolic events (non-CNS)940749Odds Ratio (M-H, Fixed, 95% CI)0.53 [0.32, 0.87]

    5.1 Apixaban versus VKA
218423Odds Ratio (M-H, Fixed, 95% CI)0.88 [0.44, 1.76]

    5.2 Darexaban versus VKA
1448Odds Ratio (M-H, Fixed, 95% CI)0.80 [0.03, 19.85]

    5.3 Edoxaban versus VKA
21377Odds Ratio (M-H, Fixed, 95% CI)1.40 [0.07, 29.36]

    5.4 Idraparinux versus VKA
14576Odds Ratio (M-H, Fixed, 95% CI)0.20 [0.01, 4.18]

    5.5 Rivaroxaban versus VKA
215417Odds Ratio (M-H, Fixed, 95% CI)0.26 [0.11, 0.64]

    5.6 Betrixaban versus VKA
1508Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Major bleedings1042078Odds Ratio (M-H, Fixed, 95% CI)0.89 [0.81, 0.98]

    6.1 Apixaban versus VKA
218358Odds Ratio (M-H, Fixed, 95% CI)0.69 [0.60, 0.80]

    6.2 Darexaban versus VKA
21745Odds Ratio (M-H, Fixed, 95% CI)0.67 [0.29, 1.53]

    6.3 Edoxaban versus VKA
21377Odds Ratio (M-H, Fixed, 95% CI)1.13 [0.33, 3.86]

    6.4 Idraparinux versus VKA
14576Odds Ratio (M-H, Fixed, 95% CI)2.62 [1.70, 4.03]

    6.5 Rivaroxaban versus VKA
215514Odds Ratio (M-H, Fixed, 95% CI)1.01 [0.88, 1.17]

    6.6 Betrixaban versus VKA
1508Odds Ratio (M-H, Fixed, 95% CI)0.19 [0.05, 0.82]

 7 Intracranial haemorrhages839638Odds Ratio (M-H, Fixed, 95% CI)0.56 [0.45, 0.70]

    7.1 Apixaban versus VKA
218358Odds Ratio (M-H, Fixed, 95% CI)0.42 [0.30, 0.58]

    7.2 Darexaban versus VKA
1448Odds Ratio (M-H, Fixed, 95% CI)0.80 [0.03, 19.85]

    7.3 Edoxaban versus VKA
1234Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    7.4 Idraparinux versus VKA
14576Odds Ratio (M-H, Fixed, 95% CI)11.10 [1.43, 86.02]

    7.5 Rivaroxaban versus VKA
215514Odds Ratio (M-H, Fixed, 95% CI)0.64 [0.46, 0.88]

    7.6 Betrixaban versus VKA
1508Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Non-major clinically relevant bleeds1042078Odds Ratio (M-H, Fixed, 95% CI)1.00 [0.93, 1.07]

    8.1 Apixaban versus VKA
218358Odds Ratio (M-H, Fixed, 95% CI)0.67 [0.58, 0.78]

    8.2 Darexaban versus VKA
21745Odds Ratio (M-H, Fixed, 95% CI)0.60 [0.38, 0.96]

    8.3 Edoxaban versus VKA
21377Odds Ratio (M-H, Fixed, 95% CI)1.50 [0.75, 3.02]

    8.4 Idraparinux versus VKA
14576Odds Ratio (M-H, Fixed, 95% CI)1.48 [1.23, 1.79]

    8.5 Rivaroxaban versus VKA
215514Odds Ratio (M-H, Fixed, 95% CI)1.05 [0.97, 1.15]

    8.6 Betrixaban versus VKA
1508Odds Ratio (M-H, Fixed, 95% CI)0.66 [0.20, 2.23]

 9 Myocardial infarction840301Odds Ratio (M-H, Fixed, 95% CI)0.87 [0.73, 1.05]

    9.1 Apixaban versus VKA
218423Odds Ratio (M-H, Fixed, 95% CI)0.88 [0.66, 1.17]

    9.2 Edoxaban versus VKA
21377Odds Ratio (M-H, Fixed, 95% CI)3.10 [0.17, 56.28]

    9.3 Idraparinux versus VKA
14576Odds Ratio (M-H, Fixed, 95% CI)1.24 [0.59, 2.58]

    9.4 Rivaroxaban versus VKA
215417Odds Ratio (M-H, Fixed, 95% CI)0.82 [0.63, 1.06]

    9.5 Betrixaban versus VKA
1508Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 10 Vascular deaths722100Odds Ratio (M-H, Fixed, 95% CI)0.87 [0.72, 1.05]

    10.1 Apixaban versus VKA
1222Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    10.2 Edoxaban versus VKA
21377Odds Ratio (M-H, Fixed, 95% CI)0.94 [0.22, 3.97]

    10.3 Idraparinux versus VKA
14576Odds Ratio (M-H, Fixed, 95% CI)0.71 [0.43, 1.20]

    10.4 Rivaroxaban versus VKA
215417Odds Ratio (M-H, Fixed, 95% CI)0.90 [0.73, 1.11]

    10.5 Betrixaban versus VKA
1508Odds Ratio (M-H, Fixed, 95% CI)0.33 [0.02, 5.34]

 11 All-cause deaths638924Odds Ratio (M-H, Fixed, 95% CI)0.88 [0.81, 0.97]

    11.1 Apixaban versus VKA
218423Odds Ratio (M-H, Fixed, 95% CI)0.89 [0.79, 1.00]

    11.2 Betrixaban versus VKA
1508Odds Ratio (M-H, Fixed, 95% CI)0.33 [0.02, 5.34]

    11.3 Idraparinux versus VKA
14576Odds Ratio (M-H, Fixed, 95% CI)1.02 [0.71, 1.46]

    11.4 Rivaroxaban versus VKA
215417Odds Ratio (M-H, Fixed, 95% CI)0.84 [0.70, 1.01]

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

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Stroke and systemic other embolic events940777Odds Ratio (M-H, Fixed, 95% CI)0.81 [0.72, 0.91]

    1.1 Oral administration
836201Odds Ratio (M-H, Fixed, 95% CI)0.82 [0.72, 0.92]

    1.2 Parenteral administration
14576Odds Ratio (M-H, Fixed, 95% CI)0.67 [0.37, 1.21]

 2 Major bleeding1042078Odds Ratio (M-H, Fixed, 95% CI)0.89 [0.81, 0.98]

    2.1 Oral administration
937502Odds Ratio (M-H, Fixed, 95% CI)0.84 [0.76, 0.92]

    2.2 Parenteral administration
14576Odds Ratio (M-H, Fixed, 95% CI)2.62 [1.70, 4.03]

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

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Stroke and other systemic embolic events710483Odds Ratio (M-H, Fixed, 95% CI)0.63 [0.44, 0.92]

    1.1 Apixaban 2.5mg twice daily
1148Odds Ratio (M-H, Fixed, 95% CI)0.14 [0.01, 2.70]

    1.2 Apixaban 5 mg twice daily
1148Odds Ratio (M-H, Fixed, 95% CI)0.14 [0.01, 2.70]

    1.3 Edoxaban 30mg once daily
2639Odds Ratio (M-H, Fixed, 95% CI)0.71 [0.12, 4.27]

    1.4 Edoxaban 60mg once daily
2639Odds Ratio (M-H, Fixed, 95% CI)0.35 [0.04, 3.42]

    1.5 Edoxaban 30mg twice daily
1494Odds Ratio (M-H, Fixed, 95% CI)1.02 [0.20, 5.13]

    1.6 Edoxaban 60mg twice daily
1430Odds Ratio (M-H, Fixed, 95% CI)0.46 [0.05, 4.46]

    1.7 Rivaroxaban 10mg once daily
1781Odds Ratio (M-H, Fixed, 95% CI)1.03 [0.38, 2.78]

    1.8 Rivaroxaban 15mg once daily
11136Odds Ratio (M-H, Fixed, 95% CI)0.34 [0.14, 0.85]

    1.9 Darexaban 30mg once daily
1184Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.10 Darexaban 60mg once daily
1187Odds Ratio (M-H, Fixed, 95% CI)3.06 [0.12, 76.20]

    1.11 Darexaban 120mg once daily
1187Odds Ratio (M-H, Fixed, 95% CI)3.06 [0.12, 76.20]

    1.12 Darexaban 240mg
1172Odds Ratio (M-H, Fixed, 95% CI)3.66 [0.15, 91.07]

    1.13 Idraparinux 1,5mg once weekly
168Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.14 Idraparinux 2,5mg once weekly
14508Odds Ratio (M-H, Fixed, 95% CI)0.67 [0.37, 1.21]

    1.15 Betrixaban 40 mg
1254Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.16 Betrixaban 60 mg
1254Odds Ratio (M-H, Fixed, 95% CI)3.02 [0.12, 74.93]

    1.17 Betrixaban 80 mg
1254Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Major bleedings78821Odds Ratio (M-H, Fixed, 95% CI)0.78 [0.57, 1.06]

    2.1 Apixaban 2.5mg twice daily
1147Odds Ratio (M-H, Fixed, 95% CI)0.34 [0.01, 8.55]

    2.2 Apixaban 5mg twice daily
1146Odds Ratio (M-H, Fixed, 95% CI)0.35 [0.01, 8.67]

    2.3 Edoxaban 30mg once daily
2639Odds Ratio (M-H, Fixed, 95% CI)0.25 [0.03, 2.21]

    2.4 Edoxaban 60mg once daily
2639Odds Ratio (M-H, Fixed, 95% CI)0.42 [0.06, 2.86]

    2.5 Edoxaban 30mg twice daily
1494Odds Ratio (M-H, Fixed, 95% CI)5.21 [0.60, 44.92]

    2.6 Edoxaban 60mg twice daily
1430Odds Ratio (M-H, Fixed, 95% CI)8.59 [1.02, 71.95]

    2.7 Darexaban 15mg twice daily
1486Odds Ratio (M-H, Fixed, 95% CI)0.25 [0.03, 1.98]

    2.8 Darexaban 30mg once daily
2669Odds Ratio (M-H, Fixed, 95% CI)0.12 [0.01, 2.01]

    2.9 Darexaban 30mg twice daily
1486Odds Ratio (M-H, Fixed, 95% CI)0.75 [0.20, 2.85]

    2.10 Darexaban 60mg once daily
2674Odds Ratio (M-H, Fixed, 95% CI)0.74 [0.19, 2.83]

    2.11 Darexaban 60mg twice daily
1486Odds Ratio (M-H, Fixed, 95% CI)1.26 [0.40, 3.91]

    2.12 Darexaban 120mg once daily
2674Odds Ratio (M-H, Fixed, 95% CI)0.99 [0.29, 3.35]

    2.13 Darexaban 240mg once daily
1172Odds Ratio (M-H, Fixed, 95% CI)3.66 [0.15, 91.07]

    2.14 Rivaroxaban 10mg once daily
1780Odds Ratio (M-H, Fixed, 95% CI)1.38 [0.64, 2.98]

    2.15 Rivaroxaban 15mg once daily
11137Odds Ratio (M-H, Fixed, 95% CI)0.72 [0.39, 1.32]

    2.16 Betrixaban 40 mg
1254Odds Ratio (M-H, Fixed, 95% CI)0.09 [0.00, 1.60]

    2.17 Betrixaban 60 mg
1254Odds Ratio (M-H, Fixed, 95% CI)0.09 [0.00, 1.60]

    2.18 Betrixaban 80 mg
1254Odds Ratio (M-H, Fixed, 95% CI)0.59 [0.14, 2.52]

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

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Stroke and other systemic embolic events324050Odds Ratio (M-H, Fixed, 95% CI)0.77 [0.65, 0.91]

    1.1 Previous stroke or TIA
35340Odds Ratio (M-H, Fixed, 95% CI)0.70 [0.53, 0.92]

    1.2 No previous stroke or TIA
318710Odds Ratio (M-H, Fixed, 95% CI)0.81 [0.65, 1.01]

 2 Major bleedings11278Odds Ratio (M-H, Fixed, 95% CI)0.86 [0.50, 1.47]

    2.1 Previous stroke or TIA
1813Odds Ratio (M-H, Fixed, 95% CI)0.63 [0.31, 1.29]

    2.2 No previous stroke or TIA
1465Odds 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)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Stroke and other systemic embolic events113971Odds Ratio (M-H, Fixed, 95% CI)0.80 [0.66, 0.97]

    1.1 Good quality
16977Odds Ratio (M-H, Fixed, 95% CI)0.78 [0.60, 1.02]

    1.2 Bad quality
16994Odds Ratio (M-H, Fixed, 95% CI)0.81 [0.62, 1.07]

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

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Stroke and other systemic embolic events320021Odds Ratio (M-H, Fixed, 95% CI)0.83 [0.71, 0.98]

    1.1 VKA naive
36545Odds Ratio (M-H, Fixed, 95% CI)0.71 [0.55, 0.92]

    1.2 VKA experienced
313476Odds Ratio (M-H, Fixed, 95% CI)0.92 [0.76, 1.12]

 2 Major bleedings11278Odds Ratio (M-H, Fixed, 95% CI)0.86 [0.50, 1.48]

    2.1 VKA naive
1128Odds Ratio (M-H, Fixed, 95% CI)1.45 [0.31, 6.75]

    2.2 VKA experienced
11150Odds Ratio (M-H, Fixed, 95% CI)0.80 [0.45, 1.42]

 
Comparison 7. Factor Xa inhibitors versus VKA: concomitant antiplatelet use

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Stroke and other systemic embolic events213573Odds Ratio (M-H, Fixed, 95% CI)0.62 [0.52, 0.72]

    1.1 Concomitant antiplatelet use
25647Odds Ratio (M-H, Fixed, 95% CI)0.88 [0.68, 1.14]

    1.2 No concomitant antiplatelet use
27926Odds Ratio (M-H, Fixed, 95% CI)0.48 [0.39, 0.60]

 2 Major bleedings11278Odds Ratio (M-H, Fixed, 95% CI)0.84 [0.49, 1.44]

    2.1 Concomitant antiplatelet use
1465Odds Ratio (M-H, Fixed, 95% CI)1.13 [0.53, 2.41]

    2.2 No concomitant antiplatelet use
1813Odds Ratio (M-H, Fixed, 95% CI)0.61 [0.28, 1.35]

 
Comparison 8. Factor Xa inhibitors versus VKA: age

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Stroke and other systemic embolic events218747Odds Ratio (M-H, Fixed, 95% CI)0.86 [0.73, 1.01]

    1.1 Age < 75 years
210972Odds Ratio (M-H, Fixed, 95% CI)0.94 [0.75, 1.18]

    1.2 Age ≥ 75 years
27775Odds Ratio (M-H, Fixed, 95% CI)0.78 [0.61, 0.98]

 
Comparison 9. Factor Xa inhibitors versus VKA: race

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Stroke and other systemic embolic events520482Odds Ratio (M-H, Fixed, 95% CI)0.85 [0.72, 0.99]

    1.1 Asian patients
53538Odds Ratio (M-H, Fixed, 95% CI)0.71 [0.50, 1.00]

    1.2 White patients
216271Odds Ratio (M-H, Fixed, 95% CI)0.87 [0.73, 1.04]

    1.3 Black patients
2208Odds Ratio (M-H, Fixed, 95% CI)0.76 [0.25, 2.36]

    1.4 Other races
2465Odds Ratio (M-H, Fixed, 95% CI)1.88 [0.56, 6.33]

 2 Major bleedings31730Odds Ratio (M-H, Fixed, 95% CI)0.72 [0.42, 1.24]

    2.1 Asian patients
31730Odds Ratio (M-H, Fixed, 95% CI)0.72 [0.42, 1.24]

 
Comparison 10. Factor Xa inhibitors versus VKA: sex

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Stroke and other systemic embolic events320020Odds Ratio (M-H, Fixed, 95% CI)0.84 [0.71, 0.98]

    1.1 Female
37386Odds Ratio (M-H, Fixed, 95% CI)0.81 [0.64, 1.03]

    1.2 Male
312634Odds Ratio (M-H, Fixed, 95% CI)0.86 [0.69, 1.06]

 2 Major bleeding11278Odds Ratio (M-H, Fixed, 95% CI)0.85 [0.50, 1.45]

    2.1 Male
11030Odds Ratio (M-H, Fixed, 95% CI)0.79 [0.44, 1.41]

    2.2 Female
1248Odds Ratio (M-H, Fixed, 95% CI)1.29 [0.31, 5.26]

 
Comparison 11. Factor Xa inhibitors versus VKA: baseline CHADS2 score

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Stroke and other systemic embolic events320017Odds Ratio (M-H, Fixed, 95% CI)0.84 [0.71, 0.98]

    1.1 CHADS2-score 0-1
11878Odds Ratio (M-H, Fixed, 95% CI)1.41 [0.40, 5.01]

    1.2 CHADS2-score 2
33517Odds Ratio (M-H, Fixed, 95% CI)0.81 [0.52, 1.24]

    1.3 CHADS2-score ≥ 3
314622Odds Ratio (M-H, Fixed, 95% CI)0.83 [0.70, 0.99]

 2 Major bleedings25854Odds Ratio (M-H, Fixed, 95% CI)1.74 [1.26, 2.42]

    2.1 CHADS2-score 0-1
11878Odds Ratio (M-H, Fixed, 95% CI)3.69 [1.60, 8.52]

    2.2 CHADS2-score 2
21661Odds Ratio (M-H, Fixed, 95% CI)1.86 [0.92, 3.73]

    2.3 CHADS2-score ≥ 3
22315Odds Ratio (M-H, Fixed, 95% CI)1.34 [0.88, 2.05]

 
Summary of findings for the main comparison.

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

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

WarfarinFactor Xa inhibitors

Stroke and other systemic embolic events

(Follow-up: 12 weeks to 1.9 years)
32 per 100025 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

(Follow-up: 12 weeks to 1.9 years)
27 per 100020 per 1000
(0 to 26)
RR 0.79

(0.69 to 0.89)
40749
(9)
⊕⊕⊕⊕
high
Most data (83%) from studies with apixaban and rivaroxaban

Major bleedings

(Follow-up: 12 weeks to 1.9 years)
46 per 100039 per 1000
(0 to 55)
RR 0.90 (0.82 to 0.98)42078
(10)
⊕⊕⊕⊝
moderate3
Most data (87%) from studies with apixaban and rivaroxaban

Intracranial haemorrhages

(Follow-up: 12 weeks to 1.9 years)
11 per 10006 per 1000
(0 to 8)
RR 0.56

(0.45 to 0.70)
39638
(8)
⊕⊕⊕⊕
high4
Most data (86%) from studies with apixaban and rivaroxaban

All-cause deaths

(Follow-up: 12 weeks to 1.9 years)
51 per 100045 per 1000
(0 to 66)
RR 0.89

(0.82 to 0.97)
38924
(6)
⊕⊕⊕⊕
high
Most data (87%) from studies with apixaban and rivaroxaban

*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.

 1 The 10 studies included in this review studied the following types of oral and parenteral factor Xa inhibitors: rivaroxaban, apixaban, edoxaban, betrixaban, darexaban and idraparinux.
2 All included studies used dose-adjusted warfarin with a target INR 2.0 to 3.0 as active comparator. Two studies performed in Japan had a target INR of 1.6 to 2.6, and 2.0 to 2.6 in patients aged > 70 years.
3 High, statistically significant heterogeneity was observed in the initial analysis and in pre-specified sensitivity analysis excluding fully open-label studies (i.e. prematurely halted AMADEUS trial). Some other heterogeneity might be explained by baseline differences in the included populations in the two largest trials (ROCKET AF and ARISTOTLE). See section Effects of Interventions, Major bleedings for further discussion.
4 High, statistically significant heterogeneity was observed in the initial analysis. No statistically significant heterogeneity was observed in a pre-specified sensitivity analysis in which data from fully open-label studies were excluded (i.e. prematurely halted AMADEUS trial).