Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation
Abstract
Background
Factor Xa inhibitors and vitamin K antagonists (VKAs) are now recommended in treatment guidelines for preventing stroke and systemic embolic events in people with atrial fibrillation (AF). This is an update of a Cochrane review previously published in 2013.
Objectives
To assess the effectiveness and safety of treatment with factor Xa inhibitors versus VKAs for preventing cerebral or systemic embolic events in people with AF.
Search methods
We searched the trials registers of the Cochrane Stroke Group and the Cochrane Heart Group (September 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (August 2017), MEDLINE (1950 to April 2017), and Embase (1980 to April 2017). We also contacted pharmaceutical companies, authors and sponsors of relevant published trials. We used outcome data from marketing authorisation applications of apixaban, edoxaban and rivaroxaban that were submitted to regulatory authorities in Europe and the USA.
Selection criteria
We included randomised controlled trials (RCTs) that directly compared the effects of long‐term treatment (lasting more than four weeks) with factor Xa inhibitors versus VKAs for preventing cerebral and systemic embolism in people with AF.
Data collection and analysis
The primary efficacy outcome was the composite endpoint of all strokes and systemic embolic events. Two review authors independently extracted data, and assessed the quality of the trials and the risk of bias. We calculated a weighted estimate of the typical treatment effect across trials using the odds ratio (OR) with 95% confidence interval (CI) by means of a fixed‐effect model. In case of moderate or high heterogeneity of treatment effects, we used a random‐effects model to compare the overall treatment effects. We also performed a pre‐specified sensitivity analysis excluding any open‐label studies.
Main results
We included data from 67,688 participants randomised into 13 RCTs. The included trials directly compared dose‐adjusted warfarin with either apixaban, betrixaban, darexaban, edoxaban, idraparinux, idrabiotaparinux, or rivaroxaban. The majority of the included data (approximately 90%) was from apixaban, edoxaban, and rivaroxaban.
The composite primary efficacy endpoint of all strokes (both ischaemic and haemorrhagic) and non‐central nervous systemic embolic events was reported in all of the included studies. Treatment with a factor Xa inhibitor significantly decreased the number of strokes and systemic embolic events compared with dose‐adjusted warfarin in participants with AF (OR 0.89, 95% CI 0.82 to 0.97; 13 studies; 67,477 participants; high‐quality evidence).
Treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (OR 0.78, 95% CI 0.73 to 0.84; 13 studies; 67,396 participants; moderate‐quality evidence). There was, however, statistically significant and high heterogeneity (I2 = 83%). When we repeated this analysis using a random‐effects model, it did not show a statistically significant decrease in the number of major bleedings (OR 0.88, 95% CI 0.66 to 1.17). A pre‐specified sensitivity analysis excluding all open‐label studies showed that treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (OR 0.75, 95% CI 0.69 to 0.81), but high heterogeneity was also observed in this analysis (I2 = 72%). The same sensitivity analysis using a random‐effects model also showed a statistically significant decrease in the number of major bleedings in participants treated with factor Xa inhibitors (OR 0.76, 95% CI 0.60 to 0.96).
Treatment with a factor Xa inhibitor significantly reduced the risk of intracranial haemorrhages (ICHs) compared with warfarin (OR 0.50, 95% CI 0.42 to 0.59; 12 studies; 66,259 participants; high‐quality evidence). We observed moderate, but statistically significant heterogeneity (I2 = 55%). The pre‐specified sensitivity analysis excluding open‐label studies showed that treatment with a factor Xa inhibitor significantly reduced the number of ICHs compared with warfarin (OR 0.47, 95% CI 0.40 to 0.56), with low, non‐statistically significant heterogeneity (I2 = 27%).
Treatment with a factor Xa inhibitor also significantly reduced the number of all‐cause deaths compared with warfarin (OR 0.89, 95% 0.83 to 0.95; 10 studies; 65,624 participants; moderate‐quality evidence).
Authors' conclusions
Treatment with factor Xa inhibitors significantly reduced the number of strokes and systemic embolic events compared with warfarin in people with AF. The absolute effect of factor Xa inhibitors compared with warfarin treatment was, however, rather small. Factor Xa inhibitors also reduced the number of ICHs, all‐cause deaths and major bleedings compared with warfarin, although the evidence for a reduction in the latter is less robust.
PICOs
Plain language summary
Comparing two types of blood‐thinning drugs, factor Xa inhibitors and vitamin K antagonists, to prevent blood clots in people with atrial fibrillation
Review question
We compared the benefits and harms of two types of so‐called "blood‐thinning" drugs (factor Xa inhibitors and vitamin K antagonists) in people with atrial fibrillation.
Background
People with atrial fibrillation, a condition that causes the heart to beat irregularly, are at an increased risk of getting blood clots. Such clots can block blood vessels and cause severe organ damage in the brain (stroke) or other organs. Various guidelines recommend that people with atrial fibrillation should be treated with "blood‐thinning" drugs such as factor Xa inhibitors or vitamin K antagonists (e.g. warfarin) because these drugs can prevent the formation of blood clots. Serious side effects of these drugs are bleedings (e.g. into the brain) that can cause serious disability or even death.
Study characteristics
We searched various sources up to 29 August 2017 and included 13 studies that involved 67,688 people with atrial fibrillation who received either a factor Xa inhibitor or a vitamin K antagonist. All included people were adults and on average aged between 65 and 74 years. Approximately one‐third were women.
Key results
We found that factor Xa inhibitors when compared with warfarin, which was used as comparator in all trials, reduced the number of strokes in people with atrial fibrillation. This reduction was, however, rather small. Factor Xa inhibitors also appeared to reduce the number of serious bleedings (including those into the brain) and the number of people dying from any cause compared with warfarin.
Quality of evidence
We considered the quality of evidence in our review as moderate to high. The studies that we included were generally large to very large. We found that the results from the larger studies were generally similar and this strengthened our findings. Finally, we are confident that we included all relevant studies in our review and did not miss any important studies.
Authors' conclusions
Summary of findings
| Factor Xa inhibitors compared with vitamin K antagonists for preventing stroke and other systemic embolic events in patient with atrial fibrillation | ||||||
| Patient or population: people with atrial fibrillation deemed eligible for long‐term anticoagulant treatment Settings: hospital‐based setting Intervention: factor Xa inhibitor1 Comparison: dose‐adjusted vitamin K antagonist2 | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Warfarin | Factor Xa inhibitors | |||||
| Stroke and other systemic embolic events Follow‐up: 12 weeks to 2.8 years | 34 per 1000 | 32 per 1000 (33 to 28) | OR 0.89 (0.82 to 0.97) | 67477 | ⊕⊕⊕⊕ | Most data (90%) from studies of apixaban, edoxaban and rivaroxaban |
| All strokes Follow‐up: 12 weeks to 2.8 years | 30 per 1000 | 28 per 1000 (29 to 24) | OR 0.89 (0.81 to 0.97) | 67449 | ⊕⊕⊕⊕ | Most data (90%) from studies of apixaban, edoxaban rivaroxaban |
| Major bleedings Follow‐up: 12 weeks to 2.8 years | 51 per 1000 | 41 per 1000 (43 to 38) | OR 0.78 (0.73 to 0.84) | 67396 | ⊕⊕⊕⊝ | Most data (90%) from studies of apixaban, edoxaban and rivaroxaban |
| Intracranial haemorrhages Follow‐up: 12 weeks to 2.8 years | 13 per 1000 | 7 per 1000 (8 to 6) | OR 0.50 (0.42 to 0.59) | 66259 | ⊕⊕⊕⊕ | Most data (90%) from studies of apixaban, edoxaban and rivaroxaban |
| All‐cause deaths Follow‐up: 12 weeks to 2.8 years | 67 per 1000 | 66 per 1000 (67 to 57) | OR 0.89 (0.83 to 0.95) | 65624 | ⊕⊕⊕⊝ | Most data (90%) from studies of apixaban, edoxaban 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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 The 13 studies included in this review studied the following types of oral and parenteral factor Xa inhibitors: edoxaban, rivaroxaban, apixaban, edoxaban, betrixaban, darexaban, idraparinux and idrabiotaparinux. Assumed risk calculated from pooled data from warfarin treatment arms (mean) of included studies. 2 All included studies used warfarin with a target INR 2.0‐3.0 as active comparator. Three studies performed in Japan had a target INR of 1.6‐2.6 and 2.0‐2.6 in participants aged > 70 years. 3 High, statistically significant heterogeneity was observed in the initial analysis and in pre‐specified sensitivity analysis excluding all open‐label studies (i.e. the prematurely halted AMADEUS trial). Some other heterogeneity might be explained by baseline differences in the included populations in the three largest trials (ROCKET AF, ENGAGE TIMI‐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 all open‐label studies were excluded (i.e. prematurely halted AMADEUS trial). 5 Outcome not reported in three trials and was missing/unknown for some randomised participants (up to 2.1% ) in some of the other included trials. | ||||||
Background
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% to 3% of the adult population (Kirchhof 2007; Haim 2015). 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 in most countries, the incidence of AF is set to rise substantially during the coming decades (Wattigney 2003; Miyasaki 2006; Krijthe 2013).
Individuals with AF have an increased risk of thromboembolic events (e.g. ischaemic stroke, deep venous thrombosis, pulmonary embolism). The mechanisms behind this increased risk are complex and seem to be related to abnormal changes in blood flow, vessel walls 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 30% of all strokes are caused by AF (Wolf 1991; Henriksson 2012). Ischaemic strokes in people with AF are more often disabling and fatal, and generally occur at a higher age compared with strokes in people with a normal sinus rhythm (Marini 2005).
Description of the intervention
In people with AF, prevention of thromboembolic events relies mainly on adequate antithrombotic therapy with a vitamin K antagonist (VKA), direct thrombin inhibitor or factor Xa inhibitor (ACC/AHA/HRS 2014; ESC 2016).
VKAs, such as warfarin, are a class of anticoagulants that reduce blood clotting by inhibiting the action of vitamin K. Treatment with warfarin, with an 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 people with AF and is more effective than antiplatelet agents (Hart 2007). Antithrombotic therapy with a VKA is still recommended as a treatment option in both European and American clinical guidelines for people with AF, who have an increased risk of thromboembolic complications (ACC/AHA/HRS 2014; ESC 2016). 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). Other reasons are that VKAs exhibit 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 in clinical practice.
The under‐use of VKAs for stroke prevention in people with AF has prompted the development of other types of anticoagulant drugs. In 2012 a new class of anticoagulants, the factor Xa inhibitors, became 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 even 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.
Several factor Xa inhibitors (apixaban, rivaroxaban and edoxaban) and one oral direct thrombin inhibitor (dabigatran) have already been compared with VKAs in large, phase III randomised controlled trials (RCTs). Based on the results from these large studies, recently updated guidelines now also recommend such agents as treatment options for preventing stroke and other thromboembolic events in people with AF (EHRA 2013; ACC/AHA/HRS 2014; ESC 2016).
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; Krijthe 2013). Factor Xa inhibitors appear to have several pharmacological and practical advantages over VKAs (Eikelboom 2010; Mousa 2010). They also have the potential to increase the proportion of people with AF who receive effective anticoagulant therapy. Despite the fact that recently updated European and American guidelines now also recommend apixaban, dabigatran, edoxaban and rivaroxaban, many people will continue to be treated with the relatively cheap and effective VKAs in the coming years, although this may vary considerably between countries and regions (EHRA 2013; ACC/AHA/HRS 2014; ESC 2016). A comparison of the efficacy and safety of the factor Xa inhibitors versus VKAs is therefore considered highly relevant.
Objectives
To assess the effectiveness and safety of treatment with factor Xa inhibitors versus vitamin K antagonists (VKAs) for preventing cerebral or systemic embolic events in people with AF.
Methods
Criteria for considering studies for this review
Types of studies
We sought to identify all unconfounded randomised controlled trials (RCTs) that directly compared 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, idrabiotaparinux, otamixaban, razaxaban, rivaroxaban, yagin, YM150, LY517717, SSR126517E) versus oral vitamin K antagonists (warfarin and congeners) with the intensity monitored 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
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All strokes (both ischaemic and haemorrhagic)
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Ischaemic strokes
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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
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Systemic embolic events (excluding embolic events in the central nervous system)
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Major bleedings (defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria or modified ISTH criteria)
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Intracranial haemorrhages. This includes all intraparenchymal, subdural and epidural haematomas, and subarachnoid haemorrhages confirmed by neuroimaging or post‐mortem examination
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Non‐major clinically relevant bleedings (defined by ISTH‐criteria or modified ISTH‐criteria)
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Myocardial infarction. The diagnosis of myocardial infarction was based upon electrocardiographic changes, elevation of enzymes or confirmation during post‐mortem examination
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Vascular deaths (deaths due to stroke, heart disease, haemorrhage and sudden deaths of unknown cause)
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All‐cause deaths
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Other adverse events (i.e. non‐bleeding adverse events)
Search methods for identification of studies
See the 'Specialised register' section in the Cochrane Stroke Group module. We searched for trials in all languages and arranged translation of relevant papers where required.
Electronic searches
We searched the trials registers of the Cochrane Stroke Group and the Cochrane Heart Group (September 2016). In addition, we searched the following electronic databases and trials registers:
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Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 8) in the Cochrane Library (searched August 2017) (Appendix 2);
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MEDLINE Ovid (from 1950 to April 2017) (Appendix 2);
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Embase Ovid (from 1980 to April 2017) (Appendix 3);
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Stroke Trials Directory (www.strokecenter.org/trials) (June 2012 and September 2016);
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US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; searched September 2016);
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ISRCTN Registry Current Controlled Trials (www.isrctn.com) (September 2016);
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World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch) (August 2017).
We developed the initial MEDLINE and Embase search strategies with the help of the Cochrane Stroke Group Information Specialist (2013) and updated search strategies with help from a librarian at the Norwegian Institute of Public Health (2016). We adapted the MEDLINE strategy for the searches of the other databases listed above.
Searching other resources
In an effort to identify further published, unpublished, ongoing and planned trials we:
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screened reference lists of relevant trials;
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contacted the following relevant pharmaceutical companies:
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Sanofi (July 2012), responded and additional data were received for AMADEUS 2008;
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Bristol Myers Squibb (July 2012), no response;
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Daiichi Sankyo (July 2012), no response;
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Portola Pharmaceuticals (July 2012), no response;
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Bayer (July 2012), no response;
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Astellas Europe (July 2012), no response;
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contacted the following authors, colleagues and researchers active in the field:
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HR Büller (June and July 2012), responded, additional data subsequently provided by sponsor of AMADEUS 2008 (Sanofi Aventis);
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CB Granger (June and July 2012), responded, but no additional data provided for ARISTOTLE 2011;
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S Ogawa (June and July 2012), no response and no additional data provided for ARISTOTLE‐J 2011;
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N Chung (June and July 2012), no response and no additional data provided for Edoxaban Asia 2011;
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JI Weitz (June and July 2012), responded, but no additional data provided for Edoxaban US/Europe 2010;
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MD Ezekowitz (June and July 2012), responded, but no additional data provided for EXPLORE‐Xa 2013;
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M Hori (June and July 2012), responded, additional data were provided for J‐ROCKET AF 2012;
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M Patel (June and July 2012), no response and no additional data provided for ROCKET AF 2011;
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AGG Turpie (June and July 2012), no response and no additional data provided for OPAL‐1 2010;
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GYH Lip (June and July 2012), no response and no additional data provided for OPAL‐2 2011;
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searched Google Scholar (http://scholar.google.co.uk/) (latest search September 2016);
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used Science Citation Index Cited Reference search for forward tracking of relevant references;
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used clinical outcome data from apixaban, rivaroxaban and edoxaban published in publicly available reports published on the website of the Food and Drug Administration (FDA);
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contacted the European Medicines Agency (EMA) to gain access to the clinical trials study reports that were submitted by pharmaceutical companies for the marketing authorisation approval procedures of apixaban, rivaroxaban and edoxaban. Access to clinical study data of these compounds was granted by the EMA in 2015 and relevant outcome data have been included in this update.
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 external experts. If we excluded a trial 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:
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the method of randomisation (including concealment of allocation);
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blinding (care provider, patient, outcome assessment);
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the number of participants lost to follow‐up;
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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:
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inclusion and exclusion criteria;
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method of randomisation;
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masked versus open‐label intervention;
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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;
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number of participants in each treatment group with outcome events;
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generic name and dose(s) of factor Xa inhibitor used;
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duration of anticoagulant therapy in the trial, the intensity of anticoagulation dose‐adjusted using INR, and adherence to anticoagulant treatment;
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concomitant treatment with other anticoagulants, antiplatelets, or both, or any non‐steroidal anti‐inflammatory drugs;
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outcomes (as listed above).
One review author (KBS) entered the data into the Cochrane Review Manager software, Review Manager 5 (RevMan 2014). 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 used data from clinical study reports submitted to the EMA or FDA, or both.
Assessment of risk of bias in included studies
We used Cochrane'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 external experts.
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, or used data from clinical study reports submitted to the European Medicines Agency (EMA) and Food and Drug Administration (FDA).
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 cut‐off 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 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
We performed pre‐planned subgroup analyses for:
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type of factor Xa inhibitor;
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dose of factor Xa inhibitor;
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route of administration of factor Xa inhibitor;
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previous stroke versus no previous stroke;
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participants who received VKA treatment with time‐in‐therapeutic range (TTR) equal to or greater than 60% ("high" quality) versus less than 60% ("low" quality) (Connolly 2008; ESC 2016);
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VKA treatment‐experienced participants versus treatment‐naive participants;
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participants who received concomitant antiplatelet therapy (aspirin) versus those who did not;
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age less than 75 years versus age 75 years or over;
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race;
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sex;
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baseline stroke risk factors (assessed by the CHADS2 score).
We used the method described by Deeks 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 conducted a sensitivity analysis excluding any open‐label trials.
GRADE and 'Summary of findings'
We assessed the quality of evidence by using the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias). Overall quality of the evidence was assessed as either high, moderate, low or very low (Higgins 2011).
We also included a summary of findings Table for the main comparison, comparing factor Xa inhibitors with vitamin K antagonists for the important outcomes of:
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stroke and other systemic embolic events;
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all strokes;
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major bleedings;
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intracranial haemorrhages;
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all‐cause death.
Results
Description of studies
For detailed descriptions see the Characteristics of included studies and Characteristics of excluded studies tables.
Results of the search
The literature search identified a total of 1900 reports (updated search April 2017; see Figure 1 for further details). After removing duplicates and screening titles and abstracts, we identified 21 reports that we retrieved in full text and evaluated for eligibility.
Study flow diagram.
Eight of the 21 reports were either: overviews or expert reviews that contained no new outcome data; publications of study protocols; studies with no direct comparison of the study drug to vitamin K antagonists (VKAs); or studies with a duration shorter than four weeks (see Characteristics of excluded studies for further details).
We included the remaining 13 reports, which were original publications of randomised controlled trials (RCTs) enrolling a total of 67,688 participants with atrial fibrillation (AF) who were considered eligible for long‐term (more than four weeks) anticoagulation treatment with a VKA (AMADEUS 2008; Edoxaban US/Europe 2010; OPAL‐1 2010; ARISTOTLE 2011; ARISTOTLE‐J 2011; Edoxaban Asia 2011; OPAL‐2 2011; ROCKET AF 2011; Edoxaban Japan 2012; J‐ROCKET AF 2012; ENGAGE AF‐TIMI 48 2013; EXPLORE‐Xa 2013; BOREALIS AF STUDY 2014).
In AMADEUS 2008 97 participants recruited by a single centre were excluded from the intention‐to‐treat analyses; the reason for this was not clearly 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 (GCP) violations that rendered the data unreliable. After excluding these 190 participants, we had data from 67,498 participants for further analysis.
The included studies directly compared various types of factor Xa inhibitors with VKAs. One trial studied the compound idraparinux, which was administered subcutaneously once weekly (AMADEUS 2008). One trial studied idrabiotaparinux—a biotin moiety to idraparinux—that was also administered subcutaneously once weekly (BOREALIS AF STUDY 2014) . The remaining trials all studied oral factor Xa inhibitors (i.e. apixaban, betrixaban, darexaban, edoxaban and rivaroxaban), that were administered once or twice daily.
All studies randomised participants to more than one dose of the studied factor Xa inhibitor. Studies of the compounds apixaban (ARISTOTLE 2011; ARISTOTLE‐J 2011), rivaroxaban (ROCKET AF 2011; J‐ROCKET AF 2012) and edoxaban (Edoxaban US/Europe 2010; Edoxaban Asia 2011; Edoxaban Japan 2012; ENGAGE AF‐TIMI 48 2013) contributed to approximately 90% of all data included in this review.
Dose‐adjusted warfarin was the active comparator in all included trials. In most trials the target INR for warfarin treatment was between 2.0 and 3.0. In ARISTOTLE‐J 2011, participants aged 70 years and over had a target INR of 2.0 to 2.6, whereas in OPAL‐1 2010, Edoxaban Japan 2012 and J‐ROCKET AF 2012, participants in this age category had a target INR of 1.6 to 2.6. The quality of the anticoagulation with warfarin (time in therapeutic range (TTR) calculated using the Rosendaal method) was reported in 11 trials (AMADEUS 2008; Edoxaban US/Europe 2010; ARISTOTLE 2011; ARISTOTLE‐J 2011; Edoxaban Asia 2011; ROCKET AF 2011; Edoxaban Japan 2012; J‐ROCKET AF 2012; ENGAGE AF‐TIMI 48 2013; EXPLORE‐Xa 2013; BOREALIS AF STUDY 2014). Reported (median) TTR values ranged from 45% to 83% in these studies. TTR values were not reported in two studies (OPAL‐1 2010; OPAL‐2 2011).
The mean baseline CHADS2 score in the included studies ranged from 1.9 to 3.5. Mean baseline CHADS2 scores were not reported in four studies (AMADEUS 2008; Edoxaban US/Europe 2010; OPAL‐1 2010; BOREALIS AF STUDY 2014).
All participants were aged 18 years or older. Mean and median ages of randomised participants ranged between 65 and 74 years, and approximately one‐third of all randomised participants were women. Mean ages and gender were not stated in one study (OPAL‐1 2010).
The median duration of follow‐up ranged from 12 weeks to 2.8 years. Six trials (AMADEUS 2008; ARISTOTLE 2011; ROCKET AF 2011; J‐ROCKET AF 2012; ENGAGE AF‐TIMI 48 2013; BOREALIS AF STUDY 2014) were all designed as event‐driven studies, whereas the remaining smaller studies all had predefined durations of follow‐up.
The included studies used different definitions of 'disabling stroke'. One study used the modified Rankin scale to score stroke outcome; scores from 0 to 2 were defined as 'non‐disabling', and scores from 3 to 5 as 'disabling' (ROCKET AF 2011). The outcome of stroke was only assessed by the investigator in this study. Data on disabling strokes (defined as '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 one study it was unclear which scale was used for assessing functional outcome in one participant who suffered an ischaemic stroke during the study period (OPAL‐1 2010). It was, however, stated that this stroke was 'resolved' and we have therefore chosen not to count this as a disabling stroke.
Risk of bias in included studies
For detailed information see: Characteristics of included studies, Figure 2 ('Risk of bias' graph) and Figure 3 ('Risk of bias' summary).
'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.
Allocation
All 13 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; ENGAGE AF‐TIMI 48 2013; BOREALIS AF STUDY 2014), block randomisation schedule (Edoxaban Asia 2011), or a non‐specified randomisation method (OPAL‐1 2010; ARISTOTLE 2011; ARISTOTLE‐J 2011; OPAL‐2 2011; Edoxaban Japan 2012; J‐ROCKET AF 2012; EXPLORE‐Xa 2013).
In six studies, randomisation was stratified for previous warfarin use (warfarin experienced versus warfarin naive) or clinical site, or both, (AMADEUS 2008; ARISTOTLE 2011; ARISTOTLE‐J 2011; Edoxaban Japan 2012; EXPLORE‐Xa 2013; BOREALIS AF STUDY 2014). One study stratified participants according to their baseline CHADS2 score (scores 2 to 3 versus 4 to 6) and need for a reduction in the edoxaban dose (30 mg versus 60 mg) (ENGAGE AF‐TIMI 48 2013). The remaining trials did not report stratification for any baseline variables.
Blinding
Six studies were fully double‐masked (blinded) trials (ARISTOTLE 2011; OPAL‐2 2011; ROCKET AF 2011; J‐ROCKET AF 2012; ENGAGE AF‐TIMI 48 2013; BOREALIS AF STUDY 2014): we judged these studies as having low risk of performance bias. Another six studies were partially‐masked trials, i.e. the different doses of factor Xa inhibitors were administered in a double‐masked fashion, but warfarin was administered open‐label (Edoxaban US/Europe 2010; OPAL‐1 2010; ARISTOTLE‐J 2011; Edoxaban Asia 2011; Edoxaban Japan 2012; EXPLORE‐Xa 2013): these studies were judged as having unclear or high risk of performance bias. We included only one fully open‐label study with a high risk of performance bias (AMADEUS 2008).
Adjudication of outcome events was performed by blinded, centralised committees in 11 studies (AMADEUS 2008; Edoxaban US/Europe 2010; ARISTOTLE 2011; ARISTOTLE‐J 2011; OPAL‐2 2011; ROCKET AF 2011; Edoxaban Japan 2012; J‐ROCKET AF 2012; ENGAGE AF‐TIMI 48 2013; EXPLORE‐Xa 2013; BOREALIS AF STUDY 2014). A centralised adjudication committee was also used in Edoxaban Asia 2011, but it was unclear whether this committee was blinded or not, since this was not specified in the publication. No details on the adjudication of outcome events were provided for OPAL‐1 2010.
Incomplete outcome data
The reported analysis for efficacy outcomes was a (modified) intention‐to‐treat analysis in 10 studies (AMADEUS 2008; OPAL‐1 2010; ARISTOTLE 2011; ARISTOTLE‐J 2011; OPAL‐2 2011; ROCKET AF 2011; Edoxaban Japan 2012; ENGAGE AF‐TIMI 48 2013; EXPLORE‐Xa 2013; BOREALIS AF STUDY 2014). In one study 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 (J‐ROCKET AF 2012). This definition led to the exclusion of 6/1280 randomised participants (0.5%) from all secondary efficacy analyses in J‐ROCKET AF 2012. Two studies only analysed efficacy outcomes 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 (Edoxaban US/Europe 2010; Edoxaban Asia 2011). This led to the exclusion of 1/235 participants (0.4%) in Edoxaban Asia 2011, and 3/1146 (0.3%) participants in Edoxaban US/Europe 2010.
Four studies analysed safety outcomes in the intention‐to‐treat population (AMADEUS 2008; OPAL‐1 2010; OPAL‐2 2011; EXPLORE‐Xa 2013). Nine studies only analysed safety outcomes in the 'safety population', defined as the participants who received at least one dose of the study drug (Edoxaban US/Europe 2010; ARISTOTLE 2011; ARISTOTLE‐J 2011; Edoxaban Asia 2011; ROCKET AF 2011; Edoxaban Japan 2012; J‐ROCKET AF 2012; ENGAGE AF‐TIMI 48 2013; BOREALIS AF STUDY 2014). This led to the exclusion of one (0.4%); three (0.3%); 61 (0.3%); five (2.3%); 28 (0.2%); two (0.2%); 11 (2.1%) and 79 (0.4%) participants in Edoxaban Asia 2011, Edoxaban US/Europe 2010, ARISTOTLE 2011, ARISTOTLE‐J 2011, ROCKET AF 2011, J‐ROCKET AF 2012, Edoxaban Japan 2012 and ENGAGE AF‐TIMI 48 2013, respectively.
We used data from a subgroup analysis in people with previous stroke and TIA who were randomised into the ROCKET AF trial (Hankey 2012).
Loss to follow‐up in the included studies was generally 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.
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, abstracts or clinical study reports submitted to regulatory authorities.
Other potential sources of bias
One study was terminated prematurely after a recommendation from the trial's Data and Safety Monitoring Board because of excess bleeding complications in the idraparinux group (AMADEUS 2008). Another study was also halted prematurely by the sponsor (Sanofi Aventis), but for commercial or strategic reasons (BOREALIS AF STUDY 2014). None of the other included trials were stopped prematurely.
Enrolment into the treatment arm receiving darexaban 240 mg once daily (OPAL‐1 2010) and the arm receiving edoxaban 60 mg twice daily (Edoxaban US/Europe 2010) was halted after recommendations by the trials' respective Data and Safety Monitoring Boards due to an excess of bleeding complications.
Effects of interventions
See: Summary of findings for the main comparison
Although we included 13 studies in this review, most of the following analyses include data from less than 13 studies.
Primary outcome
Composite endpoint of all strokes (both ischaemic and haemorrhagic) and other systemic embolic events
This outcome was reported in all 13 included studies (number of participants (n) = 67,477). Most data (approximately 90%) came from studies that used the agents apixaban (ARISTOTLE 2011; ARISTOTLE‐J 2011), rivaroxaban (ROCKET AF 2011; J‐ROCKET AF 2012) and edoxaban (Edoxaban US/Europe 2010; Edoxaban Asia 2011; Edoxaban Japan 2012; ENGAGE AF‐TIMI 48 2013). 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 atrial fibrillation (AF) (odds ratio (OR) 0.89, 95% confidence interval (CI) 0.82 to 0.97; 13 studies; 67,477 participants; high‐quality evidence: Analysis 1.1). We observed low, non‐statistically significant heterogeneity (I2 = 13%). The total number of non‐central nervous system systemic embolic events was very low, contributing to approximately 5% of the total outcomes of the composite endpoint, meaning that the primary outcome was largely driven by the stroke component (ischaemic and haemorrhagic strokes).
We calculated the number needed to treat (NNT), or number need to treat for an additional harmful outcome (NNTH), for studies with median follow‐up periods of one year or more (ARISTOTLE 2011; ROCKET AF 2011; ENGAGE AF‐TIMI 48 2013). We used a web‐based NNT calculator to calculate the NNTs/NNTHs with 95% CIs (graphpad.com/quickcalcs/NNT2) and entered the outcome data used in Analysis 1.1. The NNT for apixaban was 169 (95% CI 94.5 to 772.7) for a median treatment/follow‐up period of 1.8 years (ARISTOTLE 2011). Assuming that the risk of these outcome events was constant during treatment, this translates into a NNT of 304 for one year of treatment. This NNT indicates that 304 people need to be treated with apixaban for one year in order to prevent one stroke or systemic embolic event compared with warfarin. For rivaroxaban the NNT was 194 for a median treatment/follow‐up period of 1.9 years, which translates into a NNT of 376 per year. Because the 95% CI for the absolute risk reduction (0.52%) extends from a negative number (‐0.13%) to a positive number (1.17%), it is difficult to compute a 95% CI for the NNT in this case.
We could only calculate a NNTH for edoxaban, since the OR was greater than 1 in ENGAGE AF‐TIMI 48 2013 (OR 1.01, 95% CI 0.88 to 1.15). The NNTH was 2736 for a median treatment/follow‐up period of 2.8 years, which is equivalent to a NNTH of 7661 per year. This NNTH indicates that 7661 people need to be treated for one year with edoxaban to cause one more stroke or systemic embolic embolism compared with warfarin.
Secondary outcomes
All strokes (ischaemic and haemorrhagic)
The composite endpoint of 'all strokes' was reported in all 13 included studies (n = 67,449). Treatment with a factor Xa inhibitor significantly decreased the number of strokes compared with warfarin (OR 0.89, 95% CI 0.81 to 0.97; 13 studies; 67,449 participants; high‐quality evidence: Analysis 1.2). There was low, non‐statistically significant heterogeneity (I2 = 18%).
Ischaemic stroke
We were able to calculate the effect of study versus control treatment on the number of ischaemic strokes for 12 studies (n = 66,306). No data were available for Edoxaban US/Europe 2010. The analysis showed no statistically significant decrease or increase in the number of ischaemic strokes in participants treated with a factor Xa inhibitor compared with warfarin (OR 1.03, 95% CI 0.92 to 1.14: Analysis 1.3). There was moderate, non‐statistically significant heterogeneity between the analysed studies (I2 = 37%).
Disabling or fatal strokes
Seven studies that included 39,026 participants reported data on disabling or fatal strokes. Treatment with a factor Xa inhibitor was not associated with a statistically significant reduction in the number of disabling or fatal strokes compared with warfarin (OR 0.91, 95% CI 0.77 to 1.06: Analysis 1.4). We observed low, non‐statistically significant heterogeneity (I2 = 16%).
Non‐central nervous system (CNS) systemic embolic events
The occurrence of non‐CNS systemic embolic events was reported in all 13 included studies (n = 67,449). Treatment with a factor Xa inhibitor significantly reduced the number of non‐CNS systemic embolic events compared with warfarin (OR 0.68, 95% CI 0.48 to 0.96: Analysis 1.5). There was low, non‐statistically significant heterogeneity (I2 = 15%).
Major bleedings
All 13 included studies (n = 67,396) 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 (OR 0.78, 95% CI 0.73 to 0.84; moderate‐quality evidence: Analysis 1.6). There was, however, high and statistically significant heterogeneity (I2 = 83%). Because of this, we 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 people treated with factor Xa inhibitors compared with warfarin (OR 0.88, 95% CI 0.66 to 1.17).
To further explore the observed statistical heterogeneity we also performed a pre‐specified sensitivity analysis in which we excluded open‐label studies (sensitivity analyses not shown in forest plots). The only included 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, using a fixed‐effect model, showed that treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (OR 0.75, 95% CI 0.69 to 0.81). However, we still observed moderate and statistically significant heterogeneity (I2 = 72%). A sensitivity analysis excluding AMADEUS 2008, but using a random‐effects model, also showed a statistically significant decrease in the number of major bleedings in people treated with factor Xa inhibitors (OR 0.76, 95% CI 0.60 to 0.96).
Intracranial haemorrhages (ICHs)
Data on ICHs were reported in 12 studies that randomised 66,259 participants. No data were reported for Edoxaban US/Europe 2010. Treatment with a factor Xa inhibitor significantly reduced the risk of ICH compared with warfarin (OR 0.50, 95% CI 0.42 to 0.59; 12 studies; 66,259 participants; high‐quality evidence: Analysis 1.7). We observed statistically significant, moderate heterogeneity (I2 = 55%). An analysis using a random‐effects model also indicated a statistically significant reduction of ICHs in participants treated with a factor Xa inhibitor compared with warfarin (OR 0.57, 95% CI 0.40 to 0.82).
We performed a pre‐specified sensitivity analysis in which we excluded open‐label studies to further explore the observed moderate heterogeneity (sensitivity analyses not shown in forest plots). As mentioned previously, 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 0.47, 95% CI 0.40 to 0.56). We observed low, non‐statistically significant heterogeneity in this analysis (I2 = 27%).
Non‐major clinically relevant bleedings
All 13 studies reported the number of non‐major clinically relevant bleeding defined by either ISTH criteria or a modification of these criteria. Data on 67,396 randomised participants were available for analysis. We found a statistically significant difference in the number of non‐major clinically relevant bleedings, which favoured factor Xa inhibitors over warfarin (OR 0.86, 95% CI 0.82 to 0.91: Analysis 1.8). We observed statistically significant and high heterogeneity (I2 = 88%). An analysis with a random‐effects model showed no statistically significant difference in the number of non‐major clinically relevant bleedings that were observed in the two treatment groups (OR 0.87, 95% CI 0.70 to 1.07).
We performed a pre‐specified sensitivity analysis in which we excluded 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). This analysis, using a fixed‐effect model, showed that treatment with factor Xa inhibitors did significantly reduce the number of non‐major clinically relevant bleedings compared with warfarin (OR 0.83, 95% CI 0.79 to 0.87). However, we observed statistically significant, high heterogeneity (I2 = 84%). We repeated the same sensitivity analysis using a random‐effects model, and found similar results (OR 0.80, 95% CI 0.65 to 0.98).
Myocardial infarction
The number of myocardial infarctions that occurred during the study period was reported in 10 studies that randomised 62,703 participants. No data were available for OPAL‐2 2011, Edoxaban Japan 2012 and BOREALIS AF STUDY 2014. There was no statistically significant difference between the number of myocardial infarctions in participants treated with factor Xa inhibitors compared with warfarin (OR 0.96, 95% CI 0.84 to 1.10: Analysis 1.9). We observed no heterogeneity in the analysis (I2 = 0%).
Vascular deaths
Vascular deaths were reported in 10 studies (n = 45,027). No data were available for OPAL‐1 2010, ARISTOTLE 2011 and BOREALIS AF STUDY 2014. The analysis showed a statistically significant difference between the number of vascular deaths, which favoured factor Xa inhibitors over warfarin (OR 0.86, 95% CI 0.79 to 0.94: Analysis 1.10). There was no sign of any heterogeneity between the included studies (I2 = 0%).
All‐cause deaths
The number of participants who died from any cause was reported in 10 studies (n = 65,624). No data were available for Edoxaban US/Europe 2010, OPAL‐1 2010 and Edoxaban Asia 2011. Treatment with a factor Xa inhibitor significantly reduced the number of deaths compared with warfarin (OR 0.89, 95% 0.83 to 0.95; 10 studies; 65,624 participants; moderate‐quality evidence: Analysis 1.11). We observed no heterogeneity (I2 = 0%).
Other adverse events
We did not analyse this outcome because of a paucity of data on adverse events other than the ones reported above. Sufficient data on other adverse events were only systematically presented for the large phase III studies of apixaban, rivaroxaban and edoxaban (ARISTOTLE 2011; ROCKET AF 2011, ENGAGE AF‐TIMI 48 2013) and are listed in the appendices of the original publications, in the clinical study reports of these three compounds that were submitted to regulatory authorities, and in the approved product labels. Of note, there was no evidence for an increased risk of hepatotoxicity associated with apixaban, rivaroxaban or edoxaban compared with warfarin based on these data.
Subgroup analyses
We performed 22 pre‐specified subgroup analyses for the primary efficacy outcome (composite of stroke and systemic embolic events) and safety outcome (major bleedings). Results of these subgroup analyses are presented below.
Interpretation of subgroup data requires caution because the trials were not powered to detect differences in these subgroups. Furthermore, randomisation into the included studies was in most cases not stratified by the factors that were analysed in these subgroup analyses; it is therefore not possible to ensure that potential confounders were balanced across treatment arms.
Different factor Xa inhibitors
Subgroup analysis 1: stroke and systemic embolic events
An 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, idrabiotaparinux, edoxaban, darexaban and betrixaban did not show a statistically significant difference, but there was no evidence of any statistically significant differences between the risk estimates of these agents and those of apixaban or rivaroxaban (test for subgroup differences: P = 0.36; I2 = 10%).
Subgroup analysis 2: major bleedings
. Major bleedings occurred significantly less often in participants that were treated with apixaban (OR 0.69, 95% CI 0.60 to 0.80), betrixaban (OR 0.19, 95% CI 0.05 to 0.82) and edoxaban (OR 0.63, 95% CI 0.56, 0.71) compared with warfarin (Analysis 1.6). More major bleedings were observed in participants treated with idraparinux compared with warfarin (OR 2.62, 95% CI 1.70 to 4.03). We observed no statistically significant differences for idrabiotaparinux, rivaroxaban and darexaban compared with warfarin. There was evidence of high heterogeneity and statistically significant differences between the risk estimates of the various agents (test for subgroup differences: P < 0.00001; I2 = 95%).
Different doses of factor Xa inhibitors
Subgroup analysis 3: stroke and systemic embolic events
A total of 22 different doses of the included factor Xa inhibitors were assessed in the studies (Analysis 3.1). Unfortunately, we could not use data from ROCKET AF 2011, since the number of events were not reported for the different dose levels used in this study. Overall, we observed no statistically significant differences in the number of stroke or systemic embolic events between the various tested doses of the factor Xa inhibitors compared with warfarin (test for subgroup differences: P = 0.22; I2 = 19.1%). Both apixaban doses (2.5 mg and 5 mg twice daily) and the rivaroxaban dose (15 mg once‐daily) showed a statistically significant decreased number of strokes and other systemic embolic events compared with warfarin. Differences in thromboembolic events between the other doses and types of factor Xa inhibitors compared with warfarin were not statistically significant.
Subgroup analysis 4: major bleedings
We could use data about 21 different doses of factor Xa inhibitors for this subgroup analysis (Analysis 3.2). Outcome data for the two different idraparinux doses were pooled because we could not obtain data for two separate doses that were used in AMADEUS 2008. Overall, we observed statistically significant differences in the number of major bleedings between the doses of factor Xa inhibitors compared with warfarin (test for subgroup differences: P < 0.00001; I2 = 78%). For both idraparinux doses and the edoxaban dose of 60 mg twice daily, there was a statistically significant increase in the number of major bleedings compared with warfarin. We observed a statistically significant decrease in the number of major bleedings compared with warfarin for two doses of edoxaban (30 mg and 60 mg once daily) and for apixaban (5 mg twice‐daily dose).
Route of administration
Subgroup analysis 5: stroke and systemic embolic events
We compared the number of stroke and systemic embolic events in people treated with oral versus parenteral factor Xa inhibitors (Analysis 2.1). Of note, only the agents idraparinux and idrabiotaparinux were administered parenterally. We only observed a statistically significant decrease for this outcome in people treated with oral factor Xa inhibitors compared with warfarin (OR 0.87, 95% CI 0.80 to 0.96). Overall, we observed no statistically significant differences in the number of strokes and systemic embolic events between the oral and parenteral factor Xa inhibitors (test for subgroup differences: P = 0.59; I2 = 0%).
Subgroup analysis 6: major bleedings
The number of major bleedings was lower in people receiving orally administered factor Xa inhibitors compared with warfarin (OR 0.74, 95% CI 0.69 to 0.80: Analysis 2.2). For the parenterally administered factor Xa inhibitors, we observed a statistically significant increase in major bleedings when compared with warfarin (OR 1.82, 95% CI 1.30 to 2.55). We observed a statistically significant difference in the number of major bleedings between the oral and parenteral factor Xa inhibitors (test for subgroup differences: P < 0.00001; I2 = 96%).
Quality of anticoagulation with warfarin
Subgroup analysis 7: stroke and systemic embolic events
We performed a subgroup analysis in people who received warfarin treatment with median time‐in‐therapeutic range (TTR) ≤ 60% versus ≥ 60%, i.e. 'low/bad' versus 'high/good' quality treatment (Analysis 5.1). To perform this analysis for the primary efficacy endpoint, we had sufficient data from the phase III trials of apixaban, rivaroxaban and edoxaban (ARISTOTLE 2011; ROCKET AF 2011; ENGAGE AF‐TIMI 48 2013), which enrolled 52,695 participants in total. The number of strokes and systemic embolic events was lower among people treated with factor Xa inhibitors compared with warfarin in centres with TTRs ≥ 60%, although this difference did not reach statistical significance (OR 0.89, 95% CI 0.77 to 1.04). In centres with TTRs ≤ 60% the number of strokes and systemic embolic events was again lower in people treated with factor Xa inhibitors and this difference was statistically significant (OR 0.81, 95% CI 0.70 to 0.93). Overall, we did not observe any statistically significant differences between the three compounds in this subgroup analysis (test for subgroup differences: P = 0.34; I2 = 0%).
Subgroup analysis 8: major bleedings
We performed a similar subgroup analysis based on the quality of warfarin treatment for major bleedings (Analysis 5.2). Again, we could only include data for apixaban, edoxaban and rivaroxaban from their respective phase III studies (n = 52,730). We observed a lower number of major bleedings with factor Xa inhibitors compared with warfarin (OR 0.80, 95% CI 0.72 to 0.90) in centres with TTRs ≥ 60%. There was, however, high and statistically significant heterogeneity in this analysis (I2 = 90%; P < 0.0001). A sensitivity analysis using a random‐effects model did not show a statistically significant decrease (OR 0.87, 95% CI 0.60 to 1.27). In centres with TTRs ≤ 60% the risk of major bleedings was lower for the factor Xa inhibitors compared with warfarin (OR 0.69, 95% CI 0.62 to 0.77), but we observed high heterogeneity (I2 = 88%; P = 0.0002). A sensitivity analysis using a random‐effects model also showed a statistically significant lower risk for the factor Xa inhibitors compared with 'low' quality warfarin treatment (OR 0.67, 95% CI 0.49 to 0.93). Overall, there were no significant differences between the three compounds in this subgroup analysis (test for subgroup differences: P = 0.05; I2 = 73%).
Previous stroke and transient ischaemic attack (TIA)
Subgroup analysis 9: stroke and systemic embolic events
We compared the efficacy of factor Xa inhibitors in participants with or without a previous stroke or TIA (Analysis 4.1). We had data from four compounds (n = 59,247) for this for this subgroup analysis: idraparinux, apixaban, edoxaban and rivaroxaban. The risk of stroke and systemic embolic events was significantly lower in people treated with factor Xa inhibitors who had previously suffered a stroke or TIA (OR 0.87, 95% CI 0.76 to 1.00), and in people who did not have a previous stroke or TIA (OR 0.85, 95% CI 0.74 to 0.97), compared to warfarin. We observed no statistically significant differences in these analyses (test for subgroup differences: P = 0.78; I2 = 0%).
Subgroup analysis 10: major bleedings
We performed a similar subgroup analysis for the major bleedings outcome (Analysis 4.2). We were able to include data on three factor Xa inhibitors: apixaban, edoxaban and rivaroxaban (n = 54,615). The number of major bleedings was significantly lower in participants with or without a previous stroke or TIA who received treatment with factor Xa inhibitors compared with warfarin: OR 0.79 (95% CI 0.69 to 0.90) and OR 0.73 (95% CI 0.67 to 0.80), respectively. Overall, we observed no statistically significant differences in these analyses (test for subgroup differences: P = 0.35; I2 = 0%).
Prior VKA treatment
Subgroup analysis 11: stroke and systemic embolic events
We analysed the efficacy of factor Xa inhibitors in people who had received prior treatment with a VKA versus those who had not (total n = 59,247). The number of strokes and systemic embolic events was significantly lower with factor Xa inhibitors in people who had not received prior VKA treatment (OR 0.80, 95% CI 0.69 to 0.93), but not in people who had received treatment with a VKA prior to randomisation (OR 0.90, 95% CI 0.79 to 1.02) (Analysis 6.1). We found low, non‐statistically significant heterogeneity in these analyses (test for subgroup differences: P = 0.24; I2 = 26%).
Subgroup analysis 12: major bleedings
A similar analysis for the primary safety endpoint showed a statistically significant lower risk of major bleedings with factor Xa inhibitors in people who had not received prior VKA treatment (OR 0.74, 95% CI 0.66 to 0.84) and in those who had prior VKA treatment (OR 0.75, 95% CI 0.68 to 0.83) (Analysis 6.2). High and statistically significant heterogeneity was observed in the latter analysis (I2 = 89%; P < 0.00001). Overall however, we observed no statistically significant differences in the analyses (test for subgroup differences: P = 0.85; I2 = 0%).
Concomitant antiplatelet therapy
Subgroup analysis 13: stroke and systemic embolic events
We had data to explore the efficacy of the factor Xa inhibitors apixaban and rivaroxaban in people receiving concomitant antiplatelet therapy (Analysis 7.1). The number of strokes and systemic embolic events in people treated with the factor Xa inhibitors was significantly lower regardless of concomitant antiplatelet use at baseline or not: OR 0.81 (95% CI 0.66 to 0.98) and OR 0.69 (95% CI 0.61 to 0.78), respectively. We did, however, observe high and statistically significant heterogeneity in the analysis of the latter subgroup (I2 = 84%; P = 0.002). A sensitivity analysis with a random‐effects model also showed a statistically significant lower risk of strokes and systemic embolic events in this group (OR 0.58, 95% CI 0.36 to 0.93). Overall, we observed statistically significant differences in the number of stroke and systemic embolic events in this subgroup analysis (P = 0.05; I2 = 74%).
Subgroup analysis 14: major bleedings
The number of major bleedings was significantly lower in people treated with a factor Xa inhibitor who did not receive concomitant antiplatelet therapy at baseline (OR 0.80, 95% CI 0.70 to 0.91) (Analysis 7.2), however, we observed high, statistically significant heterogeneity (I2 = 75%; P = 0.0008). There was no statistically significant difference in the risk of major bleeding events in people receiving concomitant antiplatelet therapy (OR 0.93, 95% CI 0.80 to 1.09). Again, we observed high heterogeneity (I2 = 61%; P = 0.08). Sensitivity analyses with a random‐effects model did not show statistically significant differences in these two subgroups: OR 0.78 (95% CI 0.57 to 1.08) versus OR 0.94 (95% CI 0.70 to 1.26), respectively.
Age
Subgroup analysis 15: stroke and systemic embolic events
We analysed the efficacy of treatment with some factor Xa inhibitors in two age categories: age less than 75 years versus 75 years or more (Analysis 8.1). The number of strokes and systemic embolic events was significantly lower in people aged 75 years or more with factor Xa inhibitors (OR 0.76, 95% CI 0.66 to 0.88). We found no statistically significant difference in participants aged less than 75 years (OR 0.96, 95% CI 0.84 to 1.09). Overall, there was a statistically significant difference in the number of strokes and systemic embolic events in this subgroup analysis (P = 0.02; I2 = 80%).
Subgroup analysis 16: major bleedings
The number of major bleedings was significantly lower with factor Xa inhibitors in both age categories (Analysis 8.2). Still, high and statistically heterogeneity was observed in both analyses (I2 = 81% and 89%; P < 0.0001, respectively). Sensitivity analyses with a random‐effects model showed a statistically significant difference in the number of major bleedings in people aged less than 75 years (OR 0.73, 95% CI 0.57 to 0.94), but not in people aged 75 years or more (OR 0.80, 95% CI 0.57 to 1.11).
Sex
Subgroup analysis 17: stroke and systemic embolic events
We had data from four compounds to assess the efficacy of factor Xa inhibitors compared with warfarin in women and men. There was a similar and statistically significant reduction of the risk of strokes and systemic embolic events for both women (OR 0.84, 95% CI 0.73 to 0.98) and men (OR 0.87, 95% CI 0.76 to 0.98) treated with factor Xa inhibitors, and no statistically significant differences (Analysis 10.1). Overall, there was no statistically significant difference in the number of strokes and systemic embolic events in this subgroup analysis (P = 0.80; I2 = 0%).
Subgroup analysis 18: major bleedings
An analysis of major bleeding events showed a statistically significantly lower risk in both women and men in favour of factor Xa inhibitors compared with warfarin (Analysis 10.2). There was, however, high and statistically significant heterogeneity in both analyses (I2 = 80% and 78%; P < 0.001, respectively). Pre‐specified sensitivity analyses with a random‐effects model showed no statistically significant differences in the number of bleedings in both sexes (men: OR 0.79, 95% CI 0.63 to 1.01; women: OR 0.72, 95% CI 0.52 to 1.00).
Baseline stroke risk (CHADS2 score)
Subgroup analysis 19: stroke and systemic embolic events
We had data from four agents (apixaban, edoxaban, idraparinux and rivaroxaban) to assess the efficacy in people with different baseline stroke risks based on their CHADS2 scores (Analysis 11.1). The risk of stroke and systemic embolic events was significantly lower in people with baseline CHADS2 scores of 3 or more (i.e. high risk of stroke) who were treated with factor Xa inhibitors compared with warfarin (OR 0.81, 95% CI 0.72 to 0.92). No statistically significant differences were observed in people with baseline CHADS2 scores of 0 to 1 (OR 0.90, 95% CI 0.61 to 1.32) and 2 (OR 0.92, 95% CI 0.78 to 1.08). Overall, there was no statistically significant difference in the number of strokes and systemic embolic events in this subgroup analysis (P = 0.49; I2 = 0%).
Subgroup analysis 20: major bleedings
We also analysed the risk of major bleedings by baseline CHADS2 score (Analysis 11.2). In all three subcategories there were significantly lower numbers of major bleedings in participants treated with factor Xa inhibitors compared with warfarin (CHADS2 score 0 to 1: OR 0.69 (95% CI 0.53 to 0.90); CHADS2 score 2: OR 0.71 (95% CI 0.63 to 0.80); and CHADS2 score 3 or more: OR 0.88 (95% CI 0.79 to 0.98)). There was, however, high and statistically significant heterogeneity in these analyses (I2 ranging from 77% to 95%; P values < 0.001). Sensitivity analyses with a random‐effects model did not show any statistically significant differences in the number of bleedings between factor Xa inhibitors and warfarin in any of the subgroups: CHADS2 score 0 to 1: OR 1.34 (95% CI 0.20 to 9.09); CHADS2 score 2: OR 0.92 (95% CI 0.63 to 1.35); and CHADS2 score 3 or more: OR 0.91 (95% CI 0.70 to 1.19).
Race
Subgroup analysis 21: stroke and systemic embolic events
Most people included in the studies were either Asian (22%) or White (74%). We only observed a statistically significant lower number of stroke and systemic embolic events in Asian people treated with factor Xa inhibitors compared with warfarin (OR 0.73, 95% CI 0.56 to 0.94: Analysis 9.1). Overall, there was no statistically significant difference in the number of strokes and systemic embolic events in this subgroup analysis (P = 0.36; I2 = 62%).
Subgroup analysis 22: major bleedings
We observed statistically significant lower numbers of major bleedings in all races included in the studies treated with factor Xa inhibitors, but not in Black people (OR 0.91, 95% CI 0.45 to 1.87: Analysis 9.2).
Discussion
Summary of main results
Primary and secondary analyses
We analysed data from 67,688 people with a confirmed diagnosis of atrial fibrillation (AF), who were included in 13 trials that examined the efficacy and safety of long‐term anticoagulation with a factor Xa inhibitor compared with vitamin K antagonists (VKAs).
Treatment with factor Xa inhibitors significantly reduced the number of strokes and systemic embolic events compared with dose‐adjusted warfarin. Still, the absolute overall effect in the reduction of stroke and systemic embolic events with factor Xa inhibitors was rather small, as shown by the high NNTs and NNTHs observed in the phase III studies of apixaban, rivaroxaban and edoxaban. The number of ischaemic strokes only was not significantly different when comparing the various factor Xa inhibitors with warfarin, although studies were not adequately powered for this subgroup analysis.
An analysis of all factor Xa inhibitors showed a statistically significant reduced risk of major bleedings compared with warfarin. However, there was a moderate to high degree of heterogeneity between the included studies. A pre‐specified sensitivity analysis excluding all open‐label studies showed that part of the observed heterogeneity was caused by the increased risk of major bleedings in one open‐label study of subcutaneously administered idraparinux (AMADEUS 2008). This study was stopped prematurely because of an increased risk of bleeding in the idraparinux treatment arm. Due to the premature termination of this study it is difficult to assess whether this was a false positive finding, or whether there is indeed an increased risk of bleeding associated with idraparinux. Other heterogeneity might be explained by baseline differences in the risk of bleeding between the study populations enrolled into the three largest trials that accounted for approximately 90% of the data included in this review (ARISTOTLE 2011; ROCKET AF 2011; ENGAGE AF‐TIMI 48 2013). When compared with people enrolled into ARISTOTLE 2011 and ENGAGE AF‐TIMI 48 2013, people enrolled into ROCKET AF 2011 were generally older (median age 70 and 72 years, versus 73 years), had higher baseline CHADS2 scores (mean 2.1 and 2.8, versus 3.8), had more often suffered a previous stroke or transient ischaemic attack (TIA) (19% and 28%, versus 55%), and more often used aspirin at baseline (31% and 29%, versus 38%). These are all known risk factors for (major) bleedings during anticoagulant treatment (Pisters 2010). In addition, the observed heterogeneity might also be partly explained by differences in the characteristics and bleeding profiles of apixaban, edoxaban and rivaroxaban.
Importantly, the number of intracranial haemorrhages (ICHs) was significantly lower in people treated with factor Xa inhibitors compared with warfarin. We observed high and statistically significant heterogeneity in this analysis, which appeared to be mainly caused by the increased number of ICHs in the prematurely halted open‐label study of idraparinux (AMADEUS 2008). A pre‐specified sensitivity analysis, in which we excluded data from this open‐label study, showed a clinically relevant and statistically significant reduction of the number of ICHs in people treated with a factor Xa inhibitor compared with warfarin without any signs of heterogeneity.
Treatment with factor Xa inhibitors also significantly reduced the number of deaths compared with warfarin, though this outcome was not reported in three smaller trials and was missing or unknown for a small number of participants (up to 2.1% ) in some of the other trials. Treatment with factor Xa inhibitors also did not appear to be associated with an increased risk of acute myocardial infarctions or vascular deaths compared with warfarin.
Subgroup analyses
Generally, the subgroup analyses for stroke and systemic embolic events supported the results from the main analysis, though no statistically significant reduction was seen in some important subgroups (e.g. people who had previously received VKA treatment, people aged under 75 years, and people with baseline CHADS2 scores of less than 3). The difference in major bleedings in most subgroups was also in line with findings from the main analysis that showed a statistically significant reduction with factor Xa inhibitors. High heterogeneity was, however, observed in many of the subgroup analyses for this outcome. Furthermore, many of the included subgroups (i.e. different dose levels of factor Xa inhibitors) contained no, or only very few, events and should therefore be interpreted cautiously.
We also performed a subgroup analysis comparing outcomes in people treated with apixaban, edoxaban and rivaroxaban versus 'high' and 'low' quality warfarin treatment. This analysis showed that a statistically significant reduction of thromboembolic events in people receiving these factor Xa inhibitors was only observed in comparison with 'low' quality warfarin treatment, although overall there was no statistically significant difference between these two subgroups. The number of major bleedings was significantly lower with these three factor Xa inhibitors regardless of the quality of the warfarin treatment. It should, however, be noted that the evidence for a reduction in bleedings compared with 'high' quality warfarin treatment is less robust due to high and statistically significant heterogeneity between the three factor Xa inhibitors included in this subgroup analysis. Interpretation of these analyses requires further caution since none of the included studies were adequately powered to detect differences between these subgroups.
Summary
In summary, factor Xa inhibitors appear to be an effective treatment for the prevention of stroke or systemic embolic events in people with AF who are eligible for long‐term anticoagulation. The absolute effect of factor Xa inhibitors compared with warfarin treatment was, however, rather small. Treatment with factor Xa inhibitors was associated with a reduction of deaths, ICHs and major bleedings compared with warfarin, although the evidence for a statistically significant reduction in major bleedings is less robust due to high heterogeneity between the included studies. Finally, even though effect estimates varied for the different factor Xa inhibitors, it is currently not possible to accurately determine which factor Xa inhibitor is the most effective and safe as head‐to‐head studies have not been performed.
Overall completeness and applicability of evidence
All data that were used in this review are derived from studies that randomised people with a confirmed diagnosis of AF, who were all deemed eligible for long‐term anticoagulation with warfarin by the randomising physician. The mean CHADS2 score of the randomised participants was around 2.7 (range 1.9 to 3.5), suggesting that few, if any, people with AF who did not need anticoagulation for prevention of thromboembolic events (a so‐called 'truly low risk population') were included in the studies. Reported median time in therapeutic range (TTR) values ranged from 45% to 89% in the included studies, but varied between regions and study centres. In general, the observed TTRs are comparable with those seen in older studies that used dose‐adjusted warfarin for preventing stroke and systemic embolic events in people with AF, and with data from clinical practice. The majority of included studies did not state an upper age limit as a contraindication and the mean and 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 clinically relevant population of people with AF eligible for long‐term anticoagulation that also appears generalisable to 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 prefer the use of this score over the simpler CHADS2 score and recommend that anticoagulation with either an oral anticoagulant (i.e. apixaban, dabigatran, edoxaban or rivaroxaban) or a VKA should be considered in people with a CHA2DS2‐VASc score of 1 or more in men and 2 or more in women (ACC/AHA/HRS 2014; ESC 2016). There is some evidence that the CHA2DS2‐VASc scale is better at identifying people with a 'very low' risk of stroke than the older CHADS2 score (ESC 2016). Consequently, data from people who are at a 'very low' risk of stroke are most probably not included in this review. Caution is thus needed when drawing any conclusions on the effectiveness and safety of factor Xa inhibitors in people that fall into this 'very low risk' category.
Data on participants with severe renal failure (i.e. creatinine clearance < 30 ml/minute) and on haemodialysis, who are known to have a higher 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.
Finally, we have included data from seven different factor Xa inhibitors in this review. Still, the majority of the data (approximately 90%) are from only three factor Xa inhibitors: apixaban, edoxaban and rivaroxaban. Results from the presented analyses of the other factor Xa inhibitors are based on smaller data sets and therefore considered less robust.
Quality of the evidence
The studies included in this review were generally large to very large; the smallest study enrolled 222 participants. Only one of the 13 included studies was conducted in an open‐label fashion. The remaining studies were either double‐masked or partially‐masked. Most studies used centralised, blinded adjudication committees for the assessments of 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 contacted lead authors and sponsors in order to gather any non‐reported data from relevant studies. Disappointingly, such additional data were only provided for two studies (AMADEUS 2008 and J‐ROCKET AF 2012).
We also used data from licensing applications that were submitted to the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) for the compounds apixaban, edoxaban and rivaroxaban in our analyses. Data from these three compounds comprise approximately 90% of all data that were analysed in our review. The use of these unpublished data has significantly decreased the potential for publication biases in our review.
We also carried out thorough searches of several different databases to further avoid selection bias. There is, however, a small possibility that we still might have missed some (smaller) studies.
Agreements and disagreements with other studies or reviews
We compared our findings with the results from several other recently published meta‐analyses and systematic reviews that examined the efficacy and safety of factor Xa inhibitors compared with warfarin in people with AF (Biondi‐Zoccai 2013; Capodanno 2013; Dogliotti 2013; Kwong 2013; Lega 2013; Mitchell 2013; Tahir 2013; Cameron 2014; Fu 2014; Providencia 2014; Ruff 2014; Caldeira 2015; Gomez‐Outes 2015; Lin 2015; Morimoto 2015; Almutairi 2016; Garg 2016; Lip 2016; Liu 2016; Tawfik 2016; Xiang 2016). Findings from these studies are generally in agreement with the findings and conclusions from our review, notably for the primary efficacy and safety outcomes. These meta‐analyses and reviews were, however, less comprehensive than our review because they all included data from fewer studies and fewer factor Xa inhibitors, performed fewer (subgroup) analyses and also did not appear to have used unpublished data that were submitted to regulatory bodies (i.e. EMA and FDA).
'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.
Comparison 1 Factor Xa inhibitors versus VKA, Outcome 1 Stroke and other systemic embolic events.
Comparison 1 Factor Xa inhibitors versus VKA, Outcome 2 All strokes.
Comparison 1 Factor Xa inhibitors versus VKA, Outcome 3 Ischaemic stroke.
Comparison 1 Factor Xa inhibitors versus VKA, Outcome 4 Disabling or fatal stroke.
Comparison 1 Factor Xa inhibitors versus VKA, Outcome 5 Systemic embolic events (non‐CNS).
Comparison 1 Factor Xa inhibitors versus VKA, Outcome 6 Major bleedings.
Comparison 1 Factor Xa inhibitors versus VKA, Outcome 7 Intracranial haemorrhages.
Comparison 1 Factor Xa inhibitors versus VKA, Outcome 8 Non‐major clinically relevant bleeds.
Comparison 1 Factor Xa inhibitors versus VKA, Outcome 9 Myocardial infarction.
Comparison 1 Factor Xa inhibitors versus VKA, Outcome 10 Vascular deaths.
Comparison 1 Factor Xa inhibitors versus VKA, Outcome 11 All‐cause deaths.
Comparison 2 Factor Xa inhibitors versus VKA: route of administration, Outcome 1 Stroke and other systemic embolic events.
Comparison 2 Factor Xa inhibitors versus VKA: route of administration, Outcome 2 Major bleedings.
Comparison 3 Factor Xa inhibitors versus VKA: dose of Factor Xa inhibitor, Outcome 1 Stroke and other systemic embolic events.
Comparison 3 Factor Xa inhibitors versus VKA: dose of Factor Xa inhibitor, Outcome 2 Major bleedings.
Comparison 4 Factor Xa inhibitors versus VKA: previous stroke or TIA, Outcome 1 Stroke and other systemic embolic events.
Comparison 4 Factor Xa inhibitors versus VKA: previous stroke or TIA, Outcome 2 Major bleedings.
Comparison 5 Factor Xa inhibitors versus VKA: quality of anticoagulation with VKA (TTR), Outcome 1 Stroke and other systemic embolic events.
Comparison 5 Factor Xa inhibitors versus VKA: quality of anticoagulation with VKA (TTR), Outcome 2 Major bleedings.
Comparison 6 Factor Xa inhibitors versus VKA: previous VKA use, Outcome 1 Stroke and other systemic embolic events.
Comparison 6 Factor Xa inhibitors versus VKA: previous VKA use, Outcome 2 Major bleedings.
Comparison 7 Factor Xa inhibitors versus VKA: concomitant antiplatelet use, Outcome 1 Stroke and other systemic embolic events.
Comparison 7 Factor Xa inhibitors versus VKA: concomitant antiplatelet use, Outcome 2 Major bleedings.
Comparison 8 Factor Xa inhibitors versus VKA: age, Outcome 1 Stroke and other systemic embolic events.
Comparison 8 Factor Xa inhibitors versus VKA: age, Outcome 2 Major bleedings.
Comparison 9 Factor Xa inhibitors versus VKA: race, Outcome 1 Stroke and other systemic embolic events.
Comparison 9 Factor Xa inhibitors versus VKA: race, Outcome 2 Major bleedings.
Comparison 10 Factor Xa inhibitors versus VKA: sex, Outcome 1 Stroke and other systemic embolic events.
Comparison 10 Factor Xa inhibitors versus VKA: sex, Outcome 2 Major bleeding.
Comparison 11 Factor Xa inhibitors versus VKA: baseline CHADS2 score, Outcome 1 Stroke and other systemic embolic events.
Comparison 11 Factor Xa inhibitors versus VKA: baseline CHADS2 score, Outcome 2 Major bleedings.
| Factor Xa inhibitors compared with vitamin K antagonists for preventing stroke and other systemic embolic events in patient with atrial fibrillation | ||||||
| Patient or population: people with atrial fibrillation deemed eligible for long‐term anticoagulant treatment Settings: hospital‐based setting Intervention: factor Xa inhibitor1 Comparison: dose‐adjusted vitamin K antagonist2 | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Warfarin | Factor Xa inhibitors | |||||
| Stroke and other systemic embolic events Follow‐up: 12 weeks to 2.8 years | 34 per 1000 | 32 per 1000 (33 to 28) | OR 0.89 (0.82 to 0.97) | 67477 | ⊕⊕⊕⊕ | Most data (90%) from studies of apixaban, edoxaban and rivaroxaban |
| All strokes Follow‐up: 12 weeks to 2.8 years | 30 per 1000 | 28 per 1000 (29 to 24) | OR 0.89 (0.81 to 0.97) | 67449 | ⊕⊕⊕⊕ | Most data (90%) from studies of apixaban, edoxaban rivaroxaban |
| Major bleedings Follow‐up: 12 weeks to 2.8 years | 51 per 1000 | 41 per 1000 (43 to 38) | OR 0.78 (0.73 to 0.84) | 67396 | ⊕⊕⊕⊝ | Most data (90%) from studies of apixaban, edoxaban and rivaroxaban |
| Intracranial haemorrhages Follow‐up: 12 weeks to 2.8 years | 13 per 1000 | 7 per 1000 (8 to 6) | OR 0.50 (0.42 to 0.59) | 66259 | ⊕⊕⊕⊕ | Most data (90%) from studies of apixaban, edoxaban and rivaroxaban |
| All‐cause deaths Follow‐up: 12 weeks to 2.8 years | 67 per 1000 | 66 per 1000 (67 to 57) | OR 0.89 (0.83 to 0.95) | 65624 | ⊕⊕⊕⊝ | Most data (90%) from studies of apixaban, edoxaban 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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 The 13 studies included in this review studied the following types of oral and parenteral factor Xa inhibitors: edoxaban, rivaroxaban, apixaban, edoxaban, betrixaban, darexaban, idraparinux and idrabiotaparinux. Assumed risk calculated from pooled data from warfarin treatment arms (mean) of included studies. 2 All included studies used warfarin with a target INR 2.0‐3.0 as active comparator. Three studies performed in Japan had a target INR of 1.6‐2.6 and 2.0‐2.6 in participants aged > 70 years. 3 High, statistically significant heterogeneity was observed in the initial analysis and in pre‐specified sensitivity analysis excluding all open‐label studies (i.e. the prematurely halted AMADEUS trial). Some other heterogeneity might be explained by baseline differences in the included populations in the three largest trials (ROCKET AF, ENGAGE TIMI‐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 all open‐label studies were excluded (i.e. prematurely halted AMADEUS trial). 5 Outcome not reported in three trials and was missing/unknown for some randomised participants (up to 2.1% ) in some of the other included trials. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Stroke and other systemic embolic events Show forest plot | 13 | 67477 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.82, 0.97] |
| 1.1 Apixaban versus VKA | 2 | 18423 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.78 [0.65, 0.93] |
| 1.2 Darexaban versus VKA | 2 | 1745 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.18 [0.29, 4.80] |
| 1.3 Edoxaban versus VKA | 4 | 23007 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.88, 1.14] |
| 1.4 Idraparinux versus VKA | 1 | 4576 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.67 [0.37, 1.21] |
| 1.5 Rivaroxaban versus VKA | 2 | 15445 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.72, 1.00] |
| 1.6 Betrixaban versus VKA | 1 | 508 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.68 [0.08, 35.22] |
| 1.7 Idrabiotaparinux versus VKA | 1 | 3773 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.49, 1.67] |
| 2 All strokes Show forest plot | 13 | 67449 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.81, 0.97] |
| 2.1 Apixaban versus VKA | 2 | 18423 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.64, 0.93] |
| 2.2 Betrixaban versus VKA | 1 | 508 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.68 [0.08, 35.22] |
| 2.3 Darexaban versus VKA | 2 | 1745 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.78 [0.31, 10.10] |
| 2.4 Edoxaban versus VKA | 4 | 23007 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.88, 1.15] |
| 2.5 Idraparinux versus VKA | 1 | 4576 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.69 [0.38, 1.27] |
| 2.6 Rivaroxaban versus VKA | 2 | 15417 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.80 [0.66, 0.97] |
| 2.7 Idrabiotaparinux versus VKA | 1 | 3773 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.51, 1.79] |
| 3 Ischaemic stroke Show forest plot | 12 | 66306 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.92, 1.14] |
| 3.1 Apixaban versus VKA | 2 | 18423 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.73, 1.12] |
| 3.2 Darexaban versus VKA | 2 | 1745 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.55 [0.18, 13.22] |
| 3.3 Edoxaban versus VKA | 3 | 21864 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.22 [1.04, 1.42] |
| 3.4 Idraparinux versus VKA | 1 | 4576 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.65 [0.32, 1.31] |
| 3.5 Rivaroxaban versus VKA | 2 | 15417 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.71, 1.09] |
| 3.6 Betrixaban versus VKA | 1 | 508 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.68 [0.08, 35.22] |
| 3.7 Idrabiotaparinux versus VKA | 1 | 3773 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.69 [0.29, 1.62] |
| 4 Disabling or fatal stroke Show forest plot | 7 | 39026 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.77, 1.06] |
| 4.1 Darexaban versus VKA | 2 | 1745 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.23 [0.14, 10.94] |
| 4.2 Edoxaban versus VKA | 3 | 21864 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.86, 1.29] |
| 4.3 Rivaroxaban versus VKA | 2 | 15417 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.71 [0.54, 0.92] |
| 5 Systemic embolic events (non‐CNS) Show forest plot | 13 | 67449 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.48, 0.96] |
| 5.1 Apixaban versus VKA | 2 | 18423 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.44, 1.76] |
| 5.2 Darexaban versus VKA | 2 | 1745 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.29 [0.04, 2.13] |
| 5.3 Edoxaban versus VKA | 4 | 23007 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.59, 1.59] |
| 5.4 Idraparinux versus VKA | 1 | 4576 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.20 [0.01, 4.18] |
| 5.5 Rivaroxaban versus VKA | 2 | 15417 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.26 [0.11, 0.64] |
| 5.6 Betrixaban versus VKA | 1 | 508 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 5.7 Idrabiotaparinux versus VKA | 1 | 3773 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.5 [0.05, 5.52] |
| 6 Major bleedings Show forest plot | 13 | 67396 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.78 [0.73, 0.84] |
| 6.1 Apixaban versus VKA | 2 | 18358 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.69 [0.60, 0.80] |
| 6.2 Darexaban versus VKA | 2 | 1745 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.63 [0.27, 1.45] |
| 6.3 Edoxaban versus VKA | 4 | 22922 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.63 [0.56, 0.71] |
| 6.4 Idraparinux versus VKA | 1 | 4576 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.62 [1.70, 4.03] |
| 6.5 Rivaroxaban versus VKA | 2 | 15514 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.88, 1.17] |
| 6.6 Betrixaban versus VKA | 1 | 508 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.19 [0.05, 0.82] |
| 6.7 Idrabiotaparinux versus VKA | 1 | 3773 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.92 [0.52, 1.63] |
| 7 Intracranial haemorrhages Show forest plot | 12 | 66259 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.50 [0.42, 0.59] |
| 7.1 Apixaban versus VKA | 2 | 18358 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.42 [0.30, 0.58] |
| 7.2 Darexaban versus VKA | 2 | 1745 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.15, 5.93] |
| 7.3 Edoxaban versus VKA | 3 | 21785 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.38 [0.30, 0.50] |
| 7.4 Idraparinux versus VKA | 1 | 4576 | Odds Ratio (M‐H, Fixed, 95% CI) | 11.10 [1.43, 86.02] |
| 7.5 Rivaroxaban versus VKA | 2 | 15514 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.64 [0.46, 0.88] |
| 7.6 Betrixaban versus VKA | 1 | 508 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 7.7 Idrabiotaparinux versus VKA | 1 | 3773 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.45, 2.23] |
| 8 Non‐major clinically relevant bleeds Show forest plot | 13 | 67396 | Odds Ratio (M‐H, Random, 95% CI) | 0.87 [0.70, 1.07] |
| 8.1 Apixaban versus VKA | 2 | 18358 | Odds Ratio (M‐H, Random, 95% CI) | 0.67 [0.58, 0.78] |
| 8.2 Darexaban versus VKA | 2 | 1745 | Odds Ratio (M‐H, Random, 95% CI) | 0.90 [0.14, 5.70] |
| 8.3 Edoxaban versus VKA | 4 | 22922 | Odds Ratio (M‐H, Random, 95% CI) | 0.88 [0.60, 1.30] |
| 8.4 Idraparinux versus VKA | 1 | 4576 | Odds Ratio (M‐H, Random, 95% CI) | 1.48 [1.23, 1.79] |
| 8.5 Rivaroxaban versus VKA | 2 | 15514 | Odds Ratio (M‐H, Random, 95% CI) | 1.06 [0.95, 1.18] |
| 8.6 Betrixaban versus VKA | 1 | 508 | Odds Ratio (M‐H, Random, 95% CI) | 0.66 [0.20, 2.23] |
| 8.7 Idrabiotaparinux versus VKA | 1 | 3773 | Odds Ratio (M‐H, Random, 95% CI) | 0.54 [0.39, 0.75] |
| 9 Myocardial infarction Show forest plot | 10 | 62703 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.84, 1.10] |
| 9.1 Apixaban versus VKA | 2 | 18423 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.66, 1.17] |
| 9.2 Edoxaban versus VKA | 3 | 22482 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.08 [0.88, 1.32] |
| 9.3 Idraparinux versus VKA | 1 | 4576 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.24 [0.59, 2.58] |
| 9.4 Rivaroxaban versus VKA | 2 | 15417 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.63, 1.06] |
| 9.5 Betrixaban versus VKA | 1 | 508 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 9.6 Darexaban vs VKA | 1 | 1297 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.33 [0.28, 6.32] |
| 10 Vascular deaths Show forest plot | 10 | 45027 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.79, 0.94] |
| 10.1 Apixaban versus VKA | 1 | 222 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 10.2 Edoxaban versus VKA | 4 | 23007 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.77, 0.95] |
| 10.3 Idraparinux versus VKA | 1 | 4576 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.71 [0.43, 1.20] |
| 10.4 Rivaroxaban versus VKA | 2 | 15417 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.73, 1.11] |
| 10.5 Betrixaban versus VKA | 1 | 508 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.02, 5.34] |
| 10.6 Darexaban vs VKA | 1 | 1297 | Odds Ratio (M‐H, Fixed, 95% CI) | 3.01 [0.16, 56.10] |
| 11 All‐cause deaths Show forest plot | 10 | 65624 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.83, 0.95] |
| 11.1 Apixaban versus VKA | 2 | 18423 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.79, 1.00] |
| 11.2 Betrixaban versus VKA | 1 | 508 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.02, 5.34] |
| 11.3 Idraparinux versus VKA | 1 | 4576 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.71, 1.46] |
| 11.4 Rivaroxaban versus VKA | 2 | 15417 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.70, 1.01] |
| 11.5 Edoxaban versus VKA | 2 | 21630 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.81, 0.97] |
| 11.6 Darexaban vs VKA | 1 | 1297 | Odds Ratio (M‐H, Fixed, 95% CI) | 4.36 [0.24, 77.61] |
| 11.7 Idrabiotaparinux versus VKA | 1 | 3773 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.66, 1.22] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Stroke and other systemic embolic events Show forest plot | 13 | 67477 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.80, 0.95] |
| 1.1 Oral administration | 11 | 59128 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.80, 0.96] |
| 1.2 Parenteral administration | 2 | 8349 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.78 [0.51, 1.19] |
| 2 Major bleedings Show forest plot | 13 | 67396 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.78 [0.73, 0.84] |
| 2.1 Oral administration | 11 | 59047 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.69, 0.80] |
| 2.2 Parenteral administration | 2 | 8349 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.82 [1.30, 2.55] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Stroke and other systemic embolic events Show forest plot | 12 | 64283 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.85, 1.01] |
| 1.1 Apixaban 2.5mg twice daily | 2 | 979 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.45 [0.23, 0.90] |
| 1.2 Apixaban 5 mg twice daily | 2 | 17518 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.67, 0.98] |
| 1.3 Edoxaban 30mg once daily | 4 | 14964 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.14 [0.98, 1.33] |
| 1.4 Edoxaban 45mg once daily | 1 | 259 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.82 [0.11, 69.87] |
| 1.5 Edoxaban 60mg once daily | 4 | 14965 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.74, 1.02] |
| 1.6 Edoxaban 30mg twice daily | 1 | 494 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.20, 5.13] |
| 1.7 Edoxaban 60mg twice daily | 1 | 430 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.46 [0.05, 4.46] |
| 1.8 Rivaroxaban 10mg once daily | 1 | 781 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.38, 2.78] |
| 1.9 Rivaroxaban 15mg once daily | 1 | 1136 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.34 [0.14, 0.85] |
| 1.10 Darexaban 15mg twice daily | 1 | 486 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.09, 11.11] |
| 1.11 Darexaban 30mg once daily | 2 | 669 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.09, 11.18] |
| 1.12 Darexaban 30mg twice daily | 1 | 486 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.09, 11.11] |
| 1.13 Darexaban 60mg once daily | 2 | 674 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.55 [0.25, 9.59] |
| 1.14 Darexaban 60mg twice daily | 1 | 486 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.01 [0.28, 14.42] |
| 1.15 Darexaban 120mg once daily | 2 | 673 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.15, 6.62] |
| 1.16 Darexaban 240mg | 1 | 172 | Odds Ratio (M‐H, Fixed, 95% CI) | 3.66 [0.15, 91.07] |
| 1.17 Idraparinux 1,5mg once weekly | 1 | 68 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 1.18 Idraparinux 2,5mg once weekly | 1 | 4508 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.67 [0.37, 1.21] |
| 1.19 Betrixaban 40 mg | 1 | 254 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 1.20 Betrixaban 60 mg | 1 | 254 | Odds Ratio (M‐H, Fixed, 95% CI) | 3.02 [0.12, 74.93] |
| 1.21 Betrixaban 80 mg | 1 | 254 | Odds Ratio (M‐H, Fixed, 95% CI) | 3.02 [0.12, 74.93] |
| 1.22 Idrabiotaparinux 3mg once weekly | 1 | 3773 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.49, 1.67] |
| 2 Major bleedings Show forest plot | 11 | 63950 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.70 [0.65, 0.75] |
| 2.1 Apixaban 2.5mg twice daily | 2 | 973 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.67 [0.38, 1.16] |
| 2.2 Apixaban 5mg twice daily | 2 | 17460 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.70 [0.61, 0.82] |
| 2.3 Edoxaban 30mg once daily | 4 | 14741 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.46 [0.40, 0.54] |
| 2.4 Edoxaban 45mg once daily | 1 | 259 | Odds Ratio (M‐H, Fixed, 95% CI) | 6.68 [0.34, 130.64] |
| 2.5 Edoxaban 60mg once daily | 4 | 14918 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.69, 0.90] |
| 2.6 Edoxaban 30mg twice daily | 1 | 494 | Odds Ratio (M‐H, Fixed, 95% CI) | 5.21 [0.60, 44.92] |
| 2.7 Edoxaban 60mg twice daily | 1 | 430 | Odds Ratio (M‐H, Fixed, 95% CI) | 8.59 [1.02, 71.95] |
| 2.8 Darexaban 15mg twice daily | 1 | 486 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.25 [0.03, 1.98] |
| 2.9 Darexaban 30mg once daily | 2 | 669 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.12 [0.01, 2.01] |
| 2.10 Darexaban 30mg twice daily | 1 | 486 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.20, 2.85] |
| 2.11 Darexaban 60mg once daily | 2 | 674 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.49 [0.10, 2.34] |
| 2.12 Darexaban 60mg twice daily | 1 | 486 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.26 [0.40, 3.91] |
| 2.13 Darexaban 120mg once daily | 2 | 674 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.29, 3.35] |
| 2.14 Darexaban 240mg once daily | 1 | 172 | Odds Ratio (M‐H, Fixed, 95% CI) | 3.66 [0.15, 91.07] |
| 2.15 Rivaroxaban 10mg once daily | 1 | 780 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.55 [0.71, 3.36] |
| 2.16 Rivaroxaban 15mg once daily | 1 | 1137 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.80 [0.43, 1.49] |
| 2.17 Betrixaban 40 mg | 1 | 254 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.09 [0.00, 1.60] |
| 2.18 Betrixaban 60 mg | 1 | 254 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.09 [0.00, 1.60] |
| 2.19 Betrixaban 80 mg | 1 | 254 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.59 [0.14, 2.52] |
| 2.20 Idrabiotaparinux 3mg once weekly | 1 | 3773 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.92 [0.52, 1.63] |
| 2.21 Idraparinux 1.5/2.5mg once weekly | 1 | 4576 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.62 [1.70, 4.03] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Stroke and other systemic embolic events Show forest plot | 5 | 59247 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.78, 0.94] |
| 1.1 Previous stroke or TIA | 5 | 18721 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.76, 1.00] |
| 1.2 No previous stroke or TIA | 5 | 40526 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.74, 0.97] |
| 2 Major bleedings Show forest plot | 4 | 54615 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.70, 0.81] |
| 2.1 Previous stroke or TIA | 4 | 17616 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.69, 0.90] |
| 2.2 No previous stroke or TIA | 4 | 36999 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.73 [0.67, 0.80] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Stroke and other systemic embolic events Show forest plot | 3 | 52695 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.77, 0.94] |
| 1.1 Good quality | 3 | 27714 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.77, 1.04] |
| 1.2 Bad quality | 3 | 24981 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.70, 0.93] |
| 2 Major bleedings Show forest plot | 3 | 52730 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.68, 0.80] |
| 2.1 Good quality | 3 | 22288 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.80 [0.72, 0.90] |
| 2.2 Bad quality | 3 | 30442 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.69 [0.62, 0.77] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Stroke and other systemic embolic events Show forest plot | 5 | 59247 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.78, 0.94] |
| 1.1 VKA naive | 5 | 22969 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.80 [0.69, 0.93] |
| 1.2 VKA experienced | 5 | 36278 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.79, 1.02] |
| 2 Major bleedings Show forest plot | 4 | 54679 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.69, 0.81] |
| 2.1 VKA naive | 4 | 21863 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.66, 0.84] |
| 2.2 VKA experienced | 4 | 32816 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.68, 0.83] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Stroke and other systemic embolic events Show forest plot | 3 | 31774 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.69 [0.61, 0.78] |
| 1.1 Concomitant antiplatelet use | 3 | 11279 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.66, 0.98] |
| 1.2 No concomitant antiplatelet use | 3 | 20495 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.63 [0.54, 0.73] |
| 2 Major bleedings Show forest plot | 3 | 33654 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.77, 0.94] |
| 2.1 Concomitant antiplatelet use | 3 | 11267 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.80, 1.09] |
| 2.2 No concomitant antiplatelet use | 3 | 22387 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.80 [0.70, 0.91] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Stroke and other systemic embolic events Show forest plot | 4 | 57974 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.79, 0.95] |
| 1.1 Age < 75 years | 4 | 36089 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.84, 1.09] |
| 1.2 Age ≥ 75 years | 4 | 21885 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.76 [0.66, 0.88] |
| 2 Major bleedings Show forest plot | 3 | 53402 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.69, 0.81] |
| 2.1 Age < 75 years | 3 | 33100 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.72 [0.64, 0.80] |
| 2.2 Age ≥ 75 years | 3 | 20302 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.78 [0.70, 0.87] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Stroke and other systemic embolic events Show forest plot | 6 | 41449 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.79, 0.99] |
| 1.1 Asian participants | 6 | 6432 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.73 [0.56, 0.94] |
| 1.2 White participants | 3 | 33279 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.82, 1.06] |
| 1.3 Black participants | 3 | 486 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.36, 2.50] |
| 1.4 Other races | 3 | 1252 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.80 [0.41, 1.58] |
| 2 Major bleedings Show forest plot | 6 | 55056 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.69, 0.80] |
| 2.1 Asian participants | 6 | 8931 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.59 [0.49, 0.71] |
| 2.2 White participants | 3 | 44010 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.73, 0.86] |
| 2.3 Black participants | 3 | 665 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.45, 1.87] |
| 2.4 Other races | 3 | 1450 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.52 [0.34, 0.81] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Stroke and other systemic embolic events Show forest plot | 5 | 59247 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.78, 0.94] |
| 1.1 Women | 5 | 21808 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.73, 0.98] |
| 1.2 Men | 5 | 37439 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.76, 0.98] |
| 2 Major bleeding Show forest plot | 4 | 54680 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.69, 0.81] |
| 2.1 Men | 4 | 34388 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.78 [0.71, 0.85] |
| 2.2 Women | 4 | 20292 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.69 [0.61, 0.79] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Stroke and other systemic embolic events Show forest plot | 5 | 59244 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.78, 0.94] |
| 1.1 CHADS2‐score 0‐1 | 2 | 8061 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.61, 1.32] |
| 1.2 CHADS2‐score 2 | 5 | 26309 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.92 [0.78, 1.08] |
| 1.3 CHADS2‐score ≥ 3 | 5 | 24874 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.72, 0.92] |
| 2 Major bleedings Show forest plot | 5 | 59253 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.73, 0.85] |
| 2.1 CHADS2‐score 0‐1 | 2 | 8047 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.69 [0.53, 0.90] |
| 2.2 CHADS2‐score 2 | 5 | 26284 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.71 [0.63, 0.80] |
| 2.3 CHADS2‐score ≥ 3 | 5 | 24922 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.79, 0.98] |
