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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), comment added to review
  2. Published Online: 8 AUG 2013

SEARCH

 

Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms

 
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).

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms
 

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 approximately 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 embolism). The mechanisms behind this increased risk that is associated 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 vitamin 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 clinical 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, especially among the elderly (Sudlow 1997; Hylek 2007). Another reason is that VKAs exhibit a considerable variability in dose response among patients, are subject to multiple food and drug interactions, 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. Recently, 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 pharmacokinetic profile appears to be more or less comparable with a relatively 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 interactions, 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 factor 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 authorities 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 anticoagulants dabigatran (an oral direct thrombin inhibitor) and rivaroxaban (an oral factor Xa inhibitor) with VKA, a recently updated 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 guidelines 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 inhibitors appear to have several pharmacological and practical advantages over VKAs (Eikelboom 2010; Mousa 2010). This new class of anticoagulants also has the potential to increase the proportion 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 regions. A comparison of the effectiveness and safety of the factor Xa inhibitors versus VKAs is therefore needed.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms

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.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms
 

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 anticoagulants in order to reduce the risk of cerebral and systemic embolism. We included people with and without a previous stroke or transient 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, rivaroxaban, yagin, YM150, LY517717, SSR126517E) versus oral vitamin K antagonists (warfarin and congeners) with the intensity of anticoagulation dose-adjusted using the International Normalised Ratio (INR).

 

Types of outcome measures

 

Primary outcomes

The composite endpoint of all strokes (both ischaemic and haemorrhagic) 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 translation of relevant papers published in languages other than English.

 

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:

    1. Sanofi (July 2012), responded and additional data were received for AMADEUS 2008,
    2. Bristol Myers Squibb (July 2012), no response,
    3. Daiichi Sankyo (July 2012), no response.
    4. Portola Pharmaceuticals (July 2012), no response.
    5. Bayer (July 2012), no response,
    6. Astellas Europe (July 2012), no response;

  • contacted the following authors, colleagues and researchers active in the field:

    1. HR Büller (June and July 2012), responded, additional data subsequently provided by sponsor of AMADEUS 2008 (Sanofi Aventis),
    2. CB Granger (June and July 2012), responded, but no additional data provided for ARISTOTLE 2011,
    3. S Ogawa (June and July 2012), no response and no additional data provided for ARISTOTLE-J 2011,
    4. N Chung (June and July 2012), no response and no additional data provided for Edoxaban Asia 2010,
    5. JI Weitz (June and July 2012), responded, but no additional data provided for Edoxaban US/Europe 2010,
    6. MD Ezekowitz (June and July 2012), responded, but no additional data provided for EXPLORE-Xa 2013,
    7. M Hori (June and July 2012), responded, additional data were provided for J-ROCKET AF 2012,
    8. M Patel (June and July 2012), no response and no additional data provided for ROCKET AF 2011,
    9. AGG Turpie (June and July 2012), no response and no additional data provided for OPAL-1 2010,
    10. GYH. Lip (June and July 2012), no response and no additional data provided for OPAL-2 2011;

  • 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 inclusion. 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 Review 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 directly 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 assessing 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)).

 

Dealing with missing data

In cases where the published information did not allow for an intention-to-treat analysis, we contacted the authors to get as complete 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 studies due to heterogeneity). We interpreted the amount of heterogeneity 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: administration 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 versus treatment-naive participants; participants who received concomitant 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.

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms
 

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.

 FigureFigure 1. Study flow diagram.

Nine of these reports were either expert reviews that contained no original data, publications of subgroup analyses of included studies, 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 centre 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, people 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 people 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 predefined 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 treatment groups using either a computerised interactive voice response 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 different doses of factor Xa inhibitors were administered in a double-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, centralised 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 centralised 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 efficacy 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 definition 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 population 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 participants 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 included studies. All predefined efficacy and safety outcomes stated in the study protocols were reported in the publications or abstracts, or both.

 

Other potential sources of bias

AMADEUS 2008 was terminated prematurely after a recommendation 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. Enrolment 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 complications.

 

Effects of interventions

See:  Summary of findings for the main comparison

See the analyses. Note that all outcomes had fewer trials contributing 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 haemorrhagic) 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 apixaban (ARISTOTLE 2011; ARISTOTLE-J 2011) and rivaroxaban (ROCKET AF 2011; J-ROCKET AF 2012). No data were available 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 significant 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 outcomes 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 apixaban (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 warfarin. 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.

 

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 separately reported in nine of the included studies, including a total 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 heterogeneity (I² = 65%). An identical sensitivity analysis using a random-effects model did not show a statistically significant decrease in the number of major bleedings in participants treated with factor Xa inhibitors (OR 0.78, 95% CI 0.57 to 1.05).

Some of the remaining heterogeneity might be explained by differences 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 complications 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 participants 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 heterogeneity (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 observed (OR 11.10, 95% CI 1.43 to 86.02). The sensitivity analysis 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 random-effects model also showed no statistically significant difference 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 inhibitor did not significantly reduce the number of non-major clinically 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 explained 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 difference 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 cardiovascular events in a large majority of the included studies. Sufficient data on other adverse events were only systematically presented for apixaban and rivaroxaban and are listed in the appendices of the original publications (ARISTOTLE 2011; ROCKET AF 2011). There was no evidence for an increased risk of hepatotoxicity 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 decreased the number of strokes and systemic embolic events compared with warfarin ( Analysis 1.1). The agents idraparinux, edoxaban, darexaban and betrixaban did not show a statistically significant difference in the number of strokes and systemic embolic events compared with warfarin, but there was no evidence of heterogeneity 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 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 idraparinux (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%. Unfortunately, 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 administration (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-significant decrease in the number of strokes and systemic embolic events in participants treated with apixaban regardless of the quality of warfarin administration by centre TTR (Wallentin 2011).

These findings might indicate that, at least for apixaban and rivaroxaban, the benefits of preventing stroke and other systemic embolic events compared with warfarin are more or less consistent 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 inhibitor 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 endpoint 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); concomitant 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 subgroup analyses should be interpreted with caution.

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms
 

Summary of main results

We analysed data from 42,084 participants with a confirmed diagnosis of AF, which were included in 10 trials that directly compared 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 warfarin, but there was a moderate to high degree of heterogeneity between the included trials. A pre-specified sensitivity analysis excluding the open-label studies showed that part of the observed heterogeneity can be explained by the increased risk of major bleedings in one open-label study of subcutaneously administered idraparinux (AMADEUS 2008). This study was also stopped prematurely 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 idraparinux or from subcutaneous administration, or both. Other heterogeneity 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 reduced the number of all-cause deaths compared with dose-adjusted warfarin. Furthermore, treatment with a factor Xa inhibitor did not seem to be associated with an increased risk of acute myocardial infarction or vascular death.

In conclusion, 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. However, high NNTs indicate that factor Xa inhibitors are only marginally more effective in the prevention of strokes and systemic embolic events than treatment with dose-adjusted warfarin. 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 reduction in major bleedings is less robust. The effect estimates varied for the different factor Xa inhibitors and it is not possible to determine which factor Xa inhibitor is more effective and safe as head-to-head studies have not yet been performed.

 

Overall completeness and applicability of evidence

All data that were used in this review are from studies that randomised 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 randomised 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 region 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 observations, 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 anticoagulant 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 included 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 thromboembolic events and bleedings, are also scarce in this review because 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 regardless 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 thrombin inhibitor dabigatran when studied for a similar indication (Wallentin 2010). This important issue clearly merits further investigation and we plan to update this subgroup analysis when more date become available.

Finally, we have included data from six different factor Xa inhibitors in this review. Still, a large majority of the data (approximately 80%) is from only two types of factor Xa inhibitors: apixaban and rivaroxaban. Results from the analyses of the other factor 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 committees 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-reported (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 relevant study reports that were submitted to regulatory agencies by pharmaceutical companies in applications for marketing authorisation.

 

Agreements and disagreements with other studies or reviews

We compared our findings with a recent meta-analysis performed by Miller and colleagues (Miller 2012). This meta-analysis included results from the factor Xa inhibitors apixaban and rivaroxaban 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 AF. The raw data entered for the primary efficacy and safety outcomes for rivaroxaban and apixaban are identical to the data used in our review, but data from two studies of these compounds, performed 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.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms

 

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.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms

We thank Brenda Thomas for her help in developing the search strategies, and the peer reviewers for their constructive feedback.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms
Download statistical data

 
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]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms
 

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$).tw.
8. xabans.tw.
9. (antistasin or apixaban or betrixaban or du 176b or eribaxaban or fondaparinux or idraparinux or otamixaban or razaxaban or rivaroxaban or yagin or ym 150 or ym150 or LY517717 or darexaban or edoxaban or SSR126517E).tw.
10. (antistasin or apixaban or betrixaban or du 176b or eribaxaban or fondaparinux or idraparinux or otamixaban or razaxaban or rivaroxaban or yagin or ym 150 or ym150 or LY517717 or darexaban or edoxaban or SSR126517E).nm.
11. 5 or 6 or 7 or 8 or 9 or 10
12. Warfarin/
13. (warfarin$ 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.
14. (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).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.
19. (coumarin$ or cumarin$ or phenprocoum$ or phenprocum$ or dicoumar$ or dicumar$ or acenocoumar$ or acenocumar$ or 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$).tw.
8. xabans.tw.
9. (antistasin or apixaban or betrixaban or du 176b or eribaxaban or fondaparinux or idraparinux or otamixaban or razaxaban or rivaroxaban or yagin or ym 150 or ym150 or LY517717 or darexaban or edoxaban or SSR126517E).tw.
10. 5 or 6 or 7 or 8 or 9
11. Warfarin/
12. (warfarin$ 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.
13. antivitamin K/
14. (vitamin K antagonist$ or VKA or VKAs).tw.
15. exp coumarin anticoagulant/
16. (coumarin$ or cumarin$ or phenprocoum$ or phenprocum$ or dicoumar$ or dicumar$ or acenocoumar$ or acenocumar$ or 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

 

Feedback

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms
 

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 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, subarachnoid 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.

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 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, subarachnoid 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

 

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.

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 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

 

What's new

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms

Last assessed as up-to-date: 29 April 2013.


DateEventDescription

16 February 2015Feedback has been incorporatedNew feedback has been added to the review



 

History

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms

Protocol first published: Issue 2, 2011
Review first published: Issue 8, 2013


DateEventDescription

1 October 2014AmendedCorrection to name in Feedback section

20 June 2014Feedback has been incorporatedSee the Feedback section



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms

KBS: conception and design of the review; writing of the protocol and review.
EB: commenting on the protocol and reviewing drafts.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms

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.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms
 

Internal sources

  • No sources of support supplied

 

External sources

  • South-Eastern Norway Regional Health Authority, Norway.
    Educational grant

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Index terms

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.

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Feedback
  14. What's new
  15. History
  16. Contributions of authors
  17. Declarations of interest
  18. Sources of support
  19. Differences between protocol and review
  20. Characteristics of studies
  21. References to studies included in this review
  22. References to studies excluded from this review
  23. References to studies awaiting assessment
  24. References to ongoing studies
  25. Additional references
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)}
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)}
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 study. European Heart Journal 2010;31 Suppl 1:173.
OPAL-2 2011 {published data only}
  • 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)}

References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Feedback
  14. What's new
  15. History
  16. Contributions of authors
  17. Declarations of interest
  18. Sources of support
  19. Differences between protocol and review
  20. Characteristics of studies
  21. References to studies included in this review
  22. References to studies excluded from this review
  23. References to studies awaiting assessment
  24. References to ongoing studies
  25. Additional references
Camm 2011 {published data only}
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}
Lopes 2010 {published data only}
  • Lopes RD, Alexander JH, Al-Khatib SM, the ARISTOTLE investigators. Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. American Heart Journal 2010;159(3):331-9.
Partida 2011 {published data only}
  • Partida RA, Guigliano RP. Edoxaban: pharmacological principles, preclinical and early-phase clinical testing. Future Cardiology 2011;7(4):459-70.
ROCKET investigators 2010 {published data only}
  • ROCKET AF Study Investigators. Rivaroxaban once-daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation: rationale and design of the ROCKET AF study. American Heart Journal 2010;159(3):340-7.

References to studies awaiting assessment

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Feedback
  14. What's new
  15. History
  16. Contributions of authors
  17. Declarations of interest
  18. Sources of support
  19. Differences between protocol and review
  20. Characteristics of studies
  21. References to studies included in this review
  22. References to studies excluded from this review
  23. References to studies awaiting assessment
  24. References to ongoing studies
  25. Additional references
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]

References to ongoing studies

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Feedback
  14. What's new
  15. History
  16. Contributions of authors
  17. Declarations of interest
  18. Sources of support
  19. Differences between protocol and review
  20. Characteristics of studies
  21. References to studies included in this review
  22. References to studies excluded from this review
  23. References to studies awaiting assessment
  24. References to ongoing studies
  25. Additional references
ENGAGE AF-TIMI 48 {published data only}
  • Ruff CT, Giugliano RP, Antman EM, Crugnale SE, Bocanegra T, Mercuri M, et al. Evaluation of the novel 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.

Additional references

  1. Top of page
  2. Abstract
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Feedback
  14. What's new
  15. History
  16. Contributions of authors
  17. Declarations of interest
  18. Sources of support
  19. Differences between protocol and review
  20. Characteristics of studies
  21. References to studies included in this review
  22. References to studies excluded from this review
  23. References to studies awaiting assessment
  24. References to ongoing studies
  25. Additional references
ACC/AHA/ESC 2006
  • Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al. Guidelines for the management of patients with atrial fibrillation. Circulation 2006;114:700-52. [DOI: 10.1161/CIRCULATIONAHA.106.177031]
Boulanger 2006
CHADS2
  • Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285(22):2864-70.
Cochrane Handbook 2011
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Connolly 2007
Connolly 2008
  • Connolly SJ, Pogue J, Eikelboom J, Flaker G, Commerford P, Franzosi G, the ACTIVE W Investigators. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of International Normalized Ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation 2008;118:2029-37.
Deeks 2001
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EHRA 2013
  • Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, et al. European Heart Rhythm Association practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15:625-51.
Eikelboom 2010
ESC 2010
ESC 2012
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Go 2001
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Hart 2007
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Heeringa 2006
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Hylek 2007
  • Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major haemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007;115:2689-96.
Kirchhof 2007
  • Kirchhof P, Auricchio A, Bax J, Crijns H, Camm J, Diener H-C, et al. Outcome parameters for trials in atrial fibrillation: executive summary. Recommendations from a consensus conference organized by the German Atrial Fibrillation Competence NETwork (AFNET) and the European Heart Rhythm Association (EHRA). European Heart Journal 2007;28:2803-17.
Lloyd-Jones 2004
Marini 2005
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Miller 2012
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Miyasaki 2006
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Mousa 2010
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Pisters 2010
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RevMan 2012
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Sudlow 1997
Wallentin 2010
  • Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, the RE-LY investigators. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 2010;18(9745):975-83.
Wallentin 2011
  • Wallentin L. Efficacy and safety of apixaban compared with warfarin at different levels of INR control for stroke prevention in atrial fibrillation. http://www.escardio.org/congresses/esc-2011/congress-reports/Documents/28-8-CTU/ARISTOTLE-presenter-Wallentin-slides.pdf 2011.
Watson 2009
Wattigney 2003
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Wolf 1991