A review of the clinical effectiveness of direct oral anticoagulants for the prevention of stroke and systemic embolism in adult patients with

A review of the clinical effectiveness of direct oral anticoagulants for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation June 2017

Healthcare Improvement Scotland 2017 Published June 2017 This document is licensed under the Creative Commons Attribution-Noncommercial- NoDerivatives 4.0 International Licence. This allows for the copy and redistribution of this document as long as Healthcare Improvement Scotland is fully acknowledged and given credit. The material must not be remixed, transformed or built upon in any way. To view a copy of this licence, visit https://creativecommons.org/licenses/by-nc-nd/4.0/ www.healthcareimprovementscotland.org 2

Contents Contents... 3 Introduction... 4 Key points... 4 Definitions... 5 Literature search... 6 Epidemiology... 6 Health technology description... 7 Clinical effectiveness... 8 Stroke and systemic embolism... 10 Safety... 11 Major bleeding... 11 Intra-cranial haemorrhage... 12 Gastrointestinal bleeding... 12 Absolute risk... 13 SUCRA analysis... 14 Patient acceptability criteria... 15 Conclusion... 17 Appendix 1: Indirect comparisons included in this evidence review... 19 Appendix 2: Key characteristics of DOAC trials included in indirect comparisons... 22 Appendix 3: Prevention of stroke and systemic embolism... 25 Appendix 4: Major bleeding... 28 Appendix 5: Intra-cranial haemorrhage... 31 Appendix 6: Gastrointestinal bleeding... 34 References... 37 3

Introduction This review summarises the published evidence on clinical effectiveness of direct acting oral anticoagulants (DOAC) for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF). In terms of safety outcomes, the review evaluates the risk of major bleeding events, intra-cranial haemorrhaging, and gastrointestinal (GI) bleeding in adult patients with NVAF who are taking oral anticoagulants. The review included standard dose apixaban 5mg twice daily, dabigatran 150mg twice daily, edoxaban 60mg once daily, and rivaroxaban 20mg once daily. Lower dose edoxaban 30mg once daily and dabigatran 110mg twice daily were also included. The pre-specified remit of this rapid review is to present clinical effectiveness evidence from published network meta-analyses, indirect treatment comparisons and mixed treatment comparisons, in relation to the DOACs and outcomes listed above. DOACs were not compared to warfarin or other oral anticoagulants. This review is therefore based on several indirect comparisons using Bayesian statistics and has been briefly reviewed by a Bayesian statistician. The review is intended to inform clinical decision-making but not make specific recommendations. Key points No direct comparisons between DOACs were identified. Therefore this rapid review is based entirely on indirect evidence from published network meta-analyses. Efficacy: stroke and systemic embolism prevention The effects of apixaban 5mg, edoxaban 60mg and dabigatran 150mg on stroke and systemic embolism prevention were similar. Rivaroxaban 20mg was less effective than dabigatran 150mg. In analysis of absolute risks, rather than relative risks, the absolute risk of stroke and systemic embolism for NVAF patients treated with a standard dose DOAC was lowest for dabigatran 150mg. Safety: major bleeding, intra-cranial haemorrhage and gastrointestinal (GI) bleeding Apixaban 5mg resulted in fewer major bleeding events than dabigatran 150mg or rivaroxaban 20mg. Edoxaban 60mg resulted in fewer major bleeding events than rivaroxaban 20mg. The incidence of intra-cranial haemorrhage was similar for all standard dose DOACs. Apixaban 5mg resulted in fewer GI bleeding events than dabigatran 150mg or rivaroxaban 20mg. 4

In analysis of absolute risks, rather than relative risks, the absolute risk of major bleeding for NVAF patients treated with a standard dose DOAC was lowest in patients receiving apixaban 5mg. Lower doses for special populations Edoxaban 30mg was associated with more strokes and systemic embolisms than standard dose DOACs. Edoxaban 30mg was associated with fewer major bleeding events than other DOACs and doses, and fewer GI bleeding events than all DOACs except apixaban 5mg. Dabigatran 110mg and edoxaban 30mg resulted in fewer intra-cranial haemorrhages than rivaroxaban 20mg. In analysis of absolute risks, rather than relative risks, the absolute risk of stroke and systemic embolism for NVAF patients treated with any DOAC dose was highest for edoxaban 30mg. The absolute risk of major bleeding in patients treated with any DOAC dose was lowest in patients taking edoxaban 30mg. SUCRA scores In SUCRA analyses, standard dose dabigatran 150mg had the highest probability of being the most effective DOAC for the prevention of stroke and systemic embolism. Apixaban 5mg was the standard dose DOAC with the highest probability of being associated with fewer major bleeding events. Definitions Atrial fibrillation A heart condition featuring an irregular and abnormally fast heart rate due to random contraction of the atrial chambers of the heart 1. Non-valvular atrial fibrillation (NVAF) Considered to be cases of atrial fibrillation (heart rhythm disturbance) occurring in the absence of mitral valve disease, prosthetic heart valves, or mitral valve repair 2. CHADS2 A risk scoring scheme that determines long-term risk of stroke in atrial fibrillation based on clinical predictors (congestive heart failure, hypertension, age >75 years, diabetes, prior stroke) 3. International normalised ratio (INR) A measure of the length of time it takes blood to clot. The longer the blood takes to clot, the higher the INR value. The INR value for an individual determines the dose of anticoagulant therapy required 4. 5

Standard dose Standard doses of DOACs are used in this evidence review to refer to the dose of each DOAC licensed for the majority of NVAF patients. These standard doses are apixaban 5mg twice daily, dabigatran 150mg twice daily, edoxaban 60mg once daily and rivaroxaban 20mg once daily. 95% confidence interval (CI) If a study was repeated many times, and on each occasion a 95% CI calculated, then 95% of these intervals would contain the true population effect. 95% credible interval (CrI) The treatment effect of interest has a 95% probability of lying within the interval. Literature search A search of the published literature was carried out on 30 January 2017 to identify network meta-analyses, indirect treatment comparisons and mixed treatment comparisons published in English. The MEDLINE, MEDLINE in Process and EMBASE databases were searched from date of database inception to date of search. Keywords used in all searches were apixaban, edoxaban, dabigatran, rivaroxaban and the registered brand name for each DOAC. Unpublished materials and grey literature were not searched due to tight timescales for this review. The following inclusion criteria were applied to the search results: reported an indirect comparison (network meta-analysis, indirect treatment comparison or mixed treatment comparison) of randomised controlled trials (RCTs) focused on patients with non-valvular atrial fibrillation all four DOACs of interest (apixaban 5mg, dabigatran 110mg or 150mg, edoxaban 30mg or 60mg, rivaroxaban 20mg) were included in the comparison, and published in English. Seven network meta-analyses were identified in the search that met the inclusion criteria for the review (Appendix 1). One network meta-analysis was excluded as the authors combined the two doses of dabigatran (110mg and 150mg) and two doses of edoxaban (30mg and 60mg) which prevented extraction of results for each drug dose separately 5. A mixed treatment comparison was excluded as it did not include the pivotal edoxaban trial ENGAGE AF-TIMI 48 6. Epidemiology Atrial fibrillation is a condition affecting approximately 92,000 people in Scotland 1. Although a consistent definition is not available for NVAF, this evidence review and other referenced 6

publications describe it as a heart rhythm disturbance (atrial fibrillation) where there is no prosthetic heart valve, associated mitral valve disease, or mitral valve repair surgery 2, 7. NVAF is associated with increased morbidity and mortality due to an elevated risk of stroke. The average risk of stroke in patients with NVAF is 5% per year, two to seven times the risk in people without atrial fibrillation 2. A large UK cohort study reported a standardised NVAF incidence rate of 6.7 per 1000 person-years (95% CI 6.7 to 6.8) in the UK 8. This incidence rate has increased slightly in the last 10 years largely due to an increasing older population 8. ISD Scotland reports a raw prevalence for atrial fibrillation of 1.6 per 100 patients in Scotland in 2014/15 1. This represents a slight increase in prevalence in Scotland 1 and is higher than the equivalent estimate in England (1.5%) 9. It should be noted that estimating prevalence based on Quality Outcomes Framework data is thought to underestimate the true prevalence which may be closer to 2.0% in England 9. Incidence of NVAF increases with age and is higher in men than women at all ages (male to female ratio 1.2:1.0) 8, 10. Health technology description Four DOACs used for treating NVAF are included in this evidence summary: apixaban, dabigatran, edoxaban, and rivaroxaban. Dabigatran directly inhibits thrombin thereby reducing the formation of blood clots 11. Apixaban, edoxaban and rivaroxaban all inhibit factor Xa, which is a key component in the formation of blood clots, inhibiting thrombin formation and development of thrombi 11. The Scottish Medicines Consortium (SMC) has accepted apixaban, dabigatran and edoxaban for use in the prevention of stroke and systemic embolism in adult patients with NVAF in Scotland 12-14. Rivaroxaban has been accepted by SMC for restricted use in patients with NVAF who have poor INR control despite complying with previous anticoagulant regimens 15. Each DOAC is available in a standard dose that is appropriate for use in the majority of NVAF patients: 5mg apixaban twice daily, 150mg dabigatran twice daily, 60mg edoxaban once daily and 20mg rivaroxaban once daily. Both dabigatran and edoxaban are also available as a reduced dose for specific subgroups of NVAF patients: dabigatran 110mg twice daily and edoxaban 30mg once daily. The lower dose of dabigatran (110mg) is recommended for NVAF patients who have a high risk of bleeding, are aged 80 years or older, take concomitant verapamil, or who have moderate renal impairment, gastritis, esophagitis, or gastroesophageal reflux 16. Edoxaban 30mg is recommended for NVAF patients with moderate to severe renal failure, body weight of 60kg or less, or concomitant use of ciclosporin, dronedarone, erythromycin or ketoconazole 17. As the lower doses of dabigatran and edoxaban are relevant to some patients, and indirect comparisons do not analyse these lower doses separately from the standard dose DOACs, both doses of dabigatran and edoxaban were included in this evidence summary along with the standard doses of all four DOACs. 7

Clinical effectiveness Seven indirect comparisons were included in this evidence review (Appendix 1) 11, 18-23. None of the indirect comparisons identified randomised controlled trials (RCTs) that directly compared one DOAC with another. Therefore all of the comparisons included in this review provide only indirect evidence on the comparative effectiveness of DOACs, based on RCTs that compared each individual DOAC to warfarin (the common comparator). This lack of direct or head-to-head comparisons reduces the strength of the evidence on the comparative effectiveness of DOACs. The indirect comparisons each incorporated all four anticoagulants of interest: apixaban, dabigatran, edoxaban and rivaroxaban. All seven indirect comparisons reported stroke/systemic embolism and major bleeding outcomes for NVAF patients treated with DOACs. Four of the indirect comparisons provided results separately for intra-cranial haemorrhage and GI bleeding outcomes 19-21, 23. The outcomes reported in the indirect comparisons all seem to be based on similar definitions, although some indirect comparisons did not elaborate on the definitions they used. Some of the indirect comparisons included other approaches to stroke prevention in NVAF patients such as warfarin, aspirin, clopidogrel and the WATCHMAN surgical device 11, 18, 22. These interventions are beyond the scope of this review; hence the data for these interventions are not reported. Several of the indirect comparisons reported significant heterogeneity between RCTs included in their analysis 11, 18, 20, 21. This heterogeneity generally related to the severity of NVAF as measured by CHADS2 scores in RCT participants at baseline, and the duration of follow-up. The three indirect comparisons that assessed and reported quality of included RCTs concluded that the RCTs were methodologically robust 11, 18, 20. These three indirect comparisons incorporated all the RCTs used in the seven indirect comparisons included in this evidence summary and therefore the quality assessment of included RCTs is assumed to apply to all the indirect comparisons. The statistical methods used in the indirect comparisons varied, with four using a Bayesian probabilistic network meta-analysis approach 11, 20-22, two using frequentist statistical methods 18, 19 and one using Bucher indirect treatment comparison 23. The analysis by Fernandez (2015) 19, which used frequentist statistical methods, reported effect estimates as risk ratios. In this evidence review frequentist risk ratios are reported separately from odds ratios from Bayesian analyses, therefore the underlying differences in statistical methodology should not impact on the results of this review. Less emphasis is given to evidence from the Bucher indirect treatment comparison as this methodology may not be comparable with the Bayesian analyses 23. Most of the indirect comparisons applied a fixed effect model due to the small number of studies included in the analysis 11, 19-21. 8

Effect estimates were reported in the indirect comparisons as odds ratios (OR), risk ratios (RR) or hazard ratios (HR). Five indirect comparisons reported confidence intervals for each effect estimate 18-20, 22, 23 and two reported credible intervals 11, 21. In Bayesian meta-analysis, it is more appropriate to report credible intervals but only two of the four Bayesian indirect comparisons reported this interval. It is assumed that the Bayesian indirect comparisons are actually reporting credible intervals. The effect estimates and credible intervals from Bayesian analyses specifically stating they present credible intervals are preferentially reported if available for each DOAC comparison. Credible intervals and confidence intervals are often considered inter-changeable and were similar for individual DOAC comparisons; therefore they are interpreted similarly to confidence intervals in this review (Prof. Neil Hawkins, Professor of Health Technology Assessment, University of Glasgow. Personal communication, 23 Mar 2017). All seven indirect comparisons incorporated the following four RCTs: ARISTOTLE: apixaban 5mg compared with warfarin RE-LY: dabigatran 110mg and dabigatran 150mg compared with warfarin ENGAGE AF-TIMI-48: edoxaban 30mg and edoxaban 60mg compared with warfarin ROCKET-AF: rivaroxaban 20mg compared with warfarin All four studies were large, multi-centre RCTs published between 2009 and 2013. RE-LY was an open label RCT, while ARISTOTLE, ENGAGE and ROCKET-AF are all double-blind RCTs. The indirect comparison by Cameron (2014) included five additional RCTs on DOACs 11, and Morimoto (2015) included four extra DOAC RCTs in their analysis 22. Key characteristics of the DOAC RCTs included in the indirect comparisons are described in Appendix 2. The combined total number of patients included in RCTs within the indirect treatment comparisons who received each anticoagulant was as follows 11, 18-23 : 9,194 patients received apixaban 5mg (74 on 2.5mg) 12,315 patients received dabigatran (6,015 on 110mg; 6,300 on 150mg) 14,957 patients received edoxaban (7,748 on 30mg; 7,479 on 60mg) 7,771 patients received rivaroxaban 20mg, and 30,568 patients received warfarin (INR 2.0-3.0). All of the RCTs included in the indirect comparisons enrolled patients with NVAF. However, in most cases the authors did not provide a detailed definition of NVAF. Mean baseline CHADS2 score was reported for 8 out of 11 included RCTs. In five RCTs, the mean baseline CHADS2 score was 2, and in three RCTs the mean baseline CHADS2 score was 3 (Appendix 2). This suggests that patients in some RCTs had a higher baseline risk of stroke or systemic embolism compared with RCTs involving other DOACs. The mean age of participants in RCTs was approximately 70 years and the majority were male. 9

The four main RCTs included in all the indirect comparisons (ARISTOTLE, ENGAGE, RE-LY, ROCKET-AF) reported stroke and systemic embolism as the primary efficacy outcome, and major bleeding as the safety outcome. Two other RCTs reported stroke and systemic embolism as the primary efficacy outcome and bleeding events as the safety outcome (JROCKET, AF-DABIG-VKA-JAPAN) and one RCT reported thromboembolic events as the primary efficacy outcome (PETRO). Four other RCTs focused on reporting safety outcomes in the form of bleeding events (ARISTOTLE-J, AF-EDOX-VKA-ASIA, AF-EDOX-VKA-MULTI, AF- EDOX-VKA-JAPAN). All but one of the indirect comparisons reported stroke and systemic embolism as the primary efficacy outcome, and major bleeding as the safety outcome11, 19-23. The authors of two indirect comparisons declared conflicts of interest as they were paid employees or consultants for pharmaceutical companies producing one of the DOACs 19, 21. In both cases author conclusions favoured the drug manufactured by the company employing them 19, 21. Results from these analyses should be interpreted with caution. All of the indirect comparisons reported results as relative measures of effect. While most of the indirect comparisons reported results as odds ratios, one reported hazard ratios 21 and one reported risk ratios 19. Stroke and systemic embolism Four indirect comparisons reported results for stroke and systemic embolism prevention as odds ratios and provide the majority of results in this evidence summary 11, 20, 22, 23. All four indirect comparisons reported a composite of all cause stroke and systemic embolism as the primary efficacy outcome. Three indirect comparisons also reported results for different types of stroke and systemic embolism separately 20, 22, 23. Only results for the primary efficacy outcome of composite stroke and systemic embolism were extracted for this evidence summary. Odds ratios and confidence intervals/credible intervals for all DOAC comparisons for the outcome of stroke and systemic embolism are presented in Appendix 3, Table 1. For the prevention of stroke and systemic embolism in patients with NVAF, dabigatran 150mg was more effective than rivaroxaban 20mg (OR 0.75, 95% CrI 0.57 to 0.99) 11. Standard dose apixaban 5mg, dabigatran 150mg and edoxaban 60mg had equivalent effects on stroke and systemic embolism prevention. Low dose edoxaban 30mg was less effective than standard dose apixaban 5mg (OR 1.45, 95% CrI 1.15 to 1.84) 11, dabigatran 150mg (OR 1.67, 95% CI 1.26 to 2.21) 20 and edoxaban 60mg (OR 1.31, 95% CrI 1.13 to 1.54) 11 for preventing stroke and systemic embolism in patients with NVAF. There was no evidence of a difference in stroke and systemic embolism prevention between edoxaban 30mg and rivaroxaban 20mg. For the prevention of stroke and systemic embolism, standard dose dabigatran 150mg was more effective than 10

dabigatran 110mg (OR 0.72, 95% CrI 0.57 to 0.90) 11. Dabigatran 110mg had similar effects to apixaban 5mg, edoxaban 30mg, edoxaban 60mg or rivaroxaban 20mg for the prevention of stroke and systemic embolism. Generally, the risk ratios and hazard ratios reported for stroke and systemic embolism were similar to the odds ratios discussed above (Appendix 3, Table 2 and 3) 19, 21. Notable exceptions are that Lip et al (2016) found rivaroxaban 20mg was less effective than edoxaban 30mg (HR 1.30, 95% CrI 1.04 to 1.62), and dabigatran 150mg was less effective than edoxaban 60mg (HR 1.35, 95% CrI 1.03 to 1.76) 21. Safety The safety outcomes considered in this review are major bleeding, intra-cranial haemorrhage and GI bleeding. Major bleeding Four indirect comparisons reported odds ratios for the effect of DOACs on major bleeding events in NVAF patients 11, 20, 22, 23. Odds ratios and credible intervals for all DOAC comparisons for the major bleeding outcome are presented in Appendix 4, Table 1. Edoxaban 60mg was associated with fewer major bleeding events than rivaroxaban 20mg (OR 0.76, 95% CrI 0.63 to 0.92) 11. Apixaban 5mg resulted in fewer major bleeding events than dabigatran 150mg (OR 0.74, 95% CrI 0.61 to 0.91) 11 and rivaroxaban 20mg (OR 0.67, 95% CrI 0.55 to 0.83) 11. The odds of major bleeding were similar for dabigatran 150mg and rivaroxaban 20mg. The odds of major bleeding events with edoxaban 60mg was equivalent to those of apixaban 5mg or dabigatran 150mg. Lower dose edoxaban 30mg was associated with fewer major bleeding events than any of the other DOACs or doses: apixaban 5mg (OR 0.67, 95% CrI 0.54 to 0.83) 11, dabigatran 110mg (OR 0.58, 95% CrI 0.47 to 0.72) 11, dabigatran 150mg (OR 0.50, 95% CrI 0.40 to 0.61) 11, edoxaban 60mg (OR 0.59, 95% CrI 0.50 to 0.69) 11 and rivaroxaban 20mg (OR 0.45, 95% CrI 0.37 to 0.56) 11. Dabigatran 110mg was associated with fewer major bleeding events than rivaroxaban 20mg (OR 0.78, 95% CrI 0.63 to 0.96) 11. Dabigatran 110mg was no less effective than apixaban 5mg, dabigatran 150mg or edoxaban 60mg for reduction of major bleeding risk. Results from indirect comparisons reporting risk ratios and hazard ratios generally agreed with the odds ratios reported above with one exception (Appendix 4, Table 2 and 3). Fernandez et al (2015) reported significant results for two DOAC comparisons: edoxaban 60mg resulted in fewer major bleeding events than dabigatran 110mg (RR 0.83, 95% CI 0.71 to 0.98) and dabigatran 150mg (RR 0.72, 95% CI 0.61 to 0.84) 19. 11

Intra-cranial haemorrhage Intra-cranial haemorrhage is a relatively rare event affecting approximately 0.3% to 0.6% of atrial fibrillation patients on warfarin, hence RCTs and indirect comparisons may be less likely to detect an effect of DOACs on this outcome 24. Two indirect comparisons reported odds ratios for the effect of DOACs on intra-cranial haemorrhage in NVAF patients 20, 23. Odds ratios and confidence intervals for all DOAC comparisons for intra-cranial haemorrhage are presented in Appendix 5, Table 1. The risk of intra-cranial bleeding was similar for all standard dose DOACs 20. This differed from the major bleeding outcome where edoxaban 60mg and apixaban 5mg both led to fewer major bleeding events than rivaroxaban 20mg, and apixaban 5mg resulted in fewer major bleeding events than dabigatran 150mg. Both lower dose edoxaban 30mg (OR 0.48, 95% CI 0.28 to 0.75) and dabigatran 110mg (OR 0.45, 95% CI 0.26 to 0.81) resulted in significantly fewer intra-cranial bleeding events than rivaroxaban 20mg 20. There were no other significant differences between lower dose edoxaban 30mg or dabigatran 110mg and any of the standard dose DOACs. This differs from the major bleeding analysis where edoxaban 30mg resulted in fewer major bleeding events than all the other DOACs and doses. The indirect comparison which presented hazard ratios reported two results that differed from indirect comparisons reporting odds ratios for intra-cranial bleeding 21. Lip (2016) 21 reported that dabigatran 150mg resulted in fewer intra-cranial haemorrhages than rivaroxaban 20mg (HR 0.59, 95% CrI 0.35 to 0.98) 21. Apixaban 5mg also resulted in fewer intra-cranial haemorrhages than rivaroxaban 20mg in this analysis (HR 0.58, 95% CrI 0.36 to 0.93). All risk ratios and hazard ratios for the intra-cranial haemorrhage outcome are reported in Appendix 5, Tables 2 and 3. Gastrointestinal bleeding Two indirect comparisons reported odds ratios for the effect of DOACs on GI bleeding events in NVAF patients 20, 23. Odds ratios and confidence intervals for all DOAC comparisons for the GI bleeding outcome are presented in Appendix 6, Table 1. Among the standard dose DOACs, apixaban 5mg resulted in significantly fewer GI bleeding events compared to dabigatran 150mg (OR 0.59, 95% CI 0.41 to 0.82) and rivaroxaban 20mg (OR 0.59, 95% CI 0.43 to 0.86) 20. These results are in accordance with the major bleeding outcome analysis. However, analysis of GI bleeding events did not find that edoxaban 60mg was more effective than rivaroxaban 20mg, as reported for the major bleeding outcome. Lower dose edoxaban 30mg resulted in significantly fewer GI bleeding events than all of the other DOACs and doses, with the exception of apixaban 5mg 20. These results are similar to 12

those reported for the major bleeding outcome where edoxaban 30mg resulted in less bleeding than any of the other DOACs and doses. Results from indirect comparisons by Lip (2016) 21 and Fernandez (2015) 19 generally agreed with the results for GI bleeding reported above with one notable exception. Fernandez (2015) 19 reported that edoxaban 60mg resulted in significantly fewer GI bleeding events than rivaroxaban 20mg (RR 0.75, 95% CI 0.63 to 0.91). This is contrary to the results reported above for GI bleeding in indirect comparisons using odds ratios. All risk ratios and hazard ratios for the GI bleeding outcome are reported in Appendix 6, Tables 2 and 3. Absolute risk All of the indirect comparisons discussed in the previous section reported results as relative measures, in other words the effect on stroke and systemic embolism or major bleeding of each DOAC relative to another DOAC. It is also possible, and potentially clinically useful, to calculate the absolute risk of experiencing a stroke, systemic embolism or major bleeding event for each DOAC individually. Estimates of absolute risk of stroke and systemic embolism or major bleeding in NVAF patients treated with DOACs were only available from a single indirect comparison (Table 1 below) 11. The analysis did not calculate absolute risk for intra-cranial haemorrhage or GI bleeding. The authors of this analysis acknowledged that the absolute risks calculated may not be clinically significant. These absolute risk estimates were calculated based on the warfarin arm of the RE-LY RCT, the only large open label study of a DOAC, which may increase the risk of bias in the results of the absolute risk analysis. Of the standard dose DOACs, dabigatran 150mg had the lowest absolute risk of stroke and systemic embolism per 1000 patients treated 11. Edoxaban 60mg and rivaroxaban 20mg had the same absolute risk of stroke and systemic embolism per 1000 patients treated 11. Rivaroxaban 20mg had the highest absolute risk of major bleeding and apixaban 5mg the lowest absolute risk of major bleeding among the standard dose DOACs 11. Lower dose edoxaban 30mg had the highest absolute risk of stroke and systemic embolism per 1000 patients treated compared to both dabigatran 110mg and each of the standard dose DOACs 11. Dabigatran 110mg had the same absolute risk of stroke and systemic embolism per 1000 patients treated as standard dose edoxaban 60mg and rivaroxaban 20mg 11. Edoxaban 30mg had the lowest absolute risk of major bleeding compared to both dabigatran 110mg and the standard dose DOACs 11. 13

Table 1: absolute risk estimates for stroke and systemic embolism or major bleeding events per 1000 patients treated 11 Stroke & systemic embolism Major bleeding Apixaban 5mg Dabigatran 150mg Edoxaban 60mg Rivaroxaban 20mg Absolute risk per 1000 patients treated Dabigatran 110mg Edoxaban 30mg 13 11 15 15 15 19 23 31 26 34 27 16 SUCRA analysis Another analysis used in indirect comparisons allows authors to calculate a score for each intervention based on the probability that each treatment would be best, second best, and so on, for each outcome. Cameron (2014) 11 used Bayesian network meta-analysis to calculate this SUCRA score and rank treatments in order of the probability of each DOAC being most effective for preventing strokes and systemic embolisms and causing the fewest major bleeding events. The SUCRA scores provided ranking of all the anticoagulants included in this evidence summary. For prevention of stroke and systemic embolism, the top ranked DOAC was dabigatran 150mg (98.1%), followed by apixaban 5mg (85.4%), edoxaban 60mg (72.8%) and rivaroxaban 20mg (71.2%). Lower dose dabigatran 110mg (64.7%) and edoxaban 30mg (36.5%) were ranked below the standard dose DOACs for this outcome 11. For the minimisation of major bleeding events, edoxaban 30mg (92.9%) was ranked first when all doses of the DOACs were included in the analysis 11. If edoxaban 30mg was removed from the analysis, apixaban 5mg (78.1%) was ranked highest of the standard dose DOACs, followed by edoxaban 60mg (64.6%), dabigatran 150mg (41.7%) and rivaroxaban 20mg (26.3%) 11. A second indirect comparison also calculated the SUCRA statistic for stroke and systemic embolism and major bleeding outcomes 18. The authors of this indirect comparison agreed with Cameron (2014) 11 that dabigatran 150mg had the highest ranking for stroke and systemic embolism prevention, but the estimated probability was much lower (29%) 18. Bajaj (2016) concluded that apixaban 5mg had the highest ranking for minimising major bleeding events (86%) as they did not include the lower doses of edoxaban 30mg and dabigatran 110mg in their analysis 18. 14

Patient acceptability criteria Local discussions within NHS Greater Glasgow and Clyde resulted in a set of draft patient acceptability criteria for DOACs. In this section, any evidence from the indirect comparisons or a brief literature search is presented for each proposed criteria. Criterion 1: each DOAC should be licensed to be taken either once or twice daily In all of the indirect comparisons and the RCTs included within them, each DOAC was administered at the appropriate licensed dose once or twice daily 11, 18-23. Apixaban 5mg, dabigatran 110mg and dabigatran 150mg are each taken twice daily. Edoxaban 30mg, edoxaban 60mg and rivaroxaban 20mg are taken once daily. Advice from the summary product characteristics documents for each anticoagulant is to administer the DOACs as indicated above 16, 17, 25-28. Criterion 2: each DOAC should have a clear and easily adjusted dosing schedule in relation to age and/or renal impairment Apixaban can be reduced to 2.5mg twice daily in NVAF patients who are 80 years or older when the patient has concomitant renal impairment (serum creatinine 1.5mg/dl) or a body weight of 60kg or less 28. The lower dose of dabigatran (110mg twice daily) should be used in treating NVAF patients aged 80 years or older 16, 27. Edoxaban and rivaroxaban do not require dose adjustments for older patients 17, 25, 26. The dosage schedule for apixaban, dabigatran, edoxaban and rivaroxaban can be adapted for NVAF patients with renal impairment (Table 2 below). In NVAF patients with mild or moderate renal impairment, apixaban dose should be adjusted to 2.5mg twice daily if the patient is also 80 years of age or older, or has a low body weight of 60kg or less. The dose of apixaban should be reduced to 2.5mg twice daily for all NVAF patients with severe renal impairment indicated by creatinine clearance (CrC) of 15-29ml/min. Apixaban is not recommended at any dose in NVAF patients with creatinine clearance <15ml/min. No adjustment to dabigatran dose is needed in NVAF patients with mild renal impairment (CrC between 50ml/min and 80ml/min) 16, 27. Patients with moderate renal impairment (CrC 30-50ml/min) can be prescribed 150mg dabigatran twice daily unless they have an elevated risk of bleeding, in which case the dose should be reduced to 110mg twice daily. Dabigatran should not be used in NVAF patients with severe renal impairment indicated by creatinine clearance <30ml/min. Close clinical surveillance is recommended for all NVAF patients with renal impairment who are taking dabigatran. The dose of edoxaban does not need to be reduced from 60mg once daily in NVAF patients with mild renal impairment 17, 26. Patients with moderate or severe renal impairment (CrC 15

15-50ml/min) should be prescribed the lower dose of 30mg edoxaban once daily. Edoxaban is not recommended at any dose in patients with end stage renal disease or on dialysis. No adjustment in rivaroxaban dose is required for patients with mild renal impairment with creatinine clearance 50-80ml/min 25. The dose of rivaroxaban can be reduced to 15mg daily if patients have moderate to severe renal impairment (CrC 15-50ml/min). There is limited data on rivaroxaban in patients with severe renal impairment so rivaroxaban should be used with caution in these patients. Rivaroxaban is not recommended for patients with creatinine clearance <15ml/min. Table 2: summary of DOAC dosage adjustments for patients with renal impairment16, 17, 25-28 Mild (CrC 50-80ml/min) Moderate (CrC 30-50ml/min) Severe (CrC 15-29ml/min) Apixaban Dabigatran Edoxaban Rivaroxaban 2.5mg if patient also 80 years old or has bodyweight 60kg 2.5mg if patient also 80 years old or has bodyweight 60kg 2.5mg No adjustment No adjustment No adjustment 110mg if high risk of bleeding Not recommended 30mg 30mg 15mg 15mg CrC <15ml/min Not recommended - - Not recommended Criterion 3: each DOAC should remain appropriate if renal function deteriorates to severe impairment (CrC of 15 to 29ml/min) not withstanding clinical review of appropriateness for individual patients None of the indirect comparisons included in the evidence review reported results for a subgroup based on renal impairment. As described for Criterion 2, several of the DOACs provide an alternative dose for use in patients with renal impairment. Dabigatran is not recommended at any dose in patients with severe renal impairment (CrC 15-29ml/min) 16, 27. Criterion 4: each DOAC should be suitable for use in a standard compliance device The use of compliance devices was not mentioned in the indirect comparisons included in the evidence review. A UK regional patient decision aid states that there are no known issues with using apixaban, edoxaban or rivaroxaban in compliance aids and devices 29. Dabigatran should not be placed in compliance aids or devices as it is susceptible to moisture. A specialist compliance device is available for use with dabigatran 29. 16

Criterion 5: ideally each DOAC should be able to be crushed if required This criterion was not considered by NHS Greater Glasgow and Clyde to be as important as criteria one to four. No information was provided in the indirect comparisons on crushing medications for administration. A brief search indicated that rivaroxaban and apixaban can be crushed if required 30, 31. Dabigatran should not be crushed or chewed before swallowing 30. No information was available on whether edoxaban can be crushed 32. Conclusion NVAF is a heart rhythm disorder associated with an elevated risk of stroke. Apixaban, dabigatran, edoxaban and rivaroxaban are DOACs that can be used to prevent stroke and systemic embolism in patients with NVAF. No head-to-head comparisons of DOACs have been reported. However, several indirect comparisons of apixaban, dabigatran, edoxaban and rivaroxaban have been published. The seven indirect comparisons which form the basis of this review are all based on indirect evidence from RCTs that compared DOACs with warfarin which reduces the robustness of the conclusions that can be drawn from the results. Evidence from indirect comparisons showed similar effectiveness for stroke and systemic embolism prevention for standard dose DOACs, except for rivaroxaban 20mg which was less effective than dabigatran 150mg. There was a higher risk of stroke and systemic embolism in patients treated with the lower dose of edoxaban 30mg compared to patients receiving standard dose apixaban 5mg, dabigatran 150mg or edoxaban 60mg. The lower dose of dabigatran 110mg was less effective than standard dose dabigatran 150mg in preventing stroke and systemic embolism. Apixaban 5mg resulted in fewer major bleeding events than standard dose dabigatran 150mg and rivaroxaban 20mg. Occurrence of major bleeding events was similar between edoxaban 60mg and apixaban 5mg or dabigatran 150mg. Treatment with standard dose rivaroxaban 20mg resulted in more major bleeding events than any of the other standard dose DOACs, except for dabigatran 150mg. The risk of intra-cranial haemorrhage was similar between the standard dose DOACs. Apixaban 5mg resulted in fewer GI bleeding events than dabigatran 150mg and rivaroxaban 20mg. Lower dose edoxaban 30mg was associated with fewer major bleeding events than any of the other DOACs and doses. Intra-cranial bleeding occurred less frequently in patients treated with edoxaban 30mg or dabigatran 110mg compared to rivaroxaban 20mg. Edoxaban 30mg resulted in fewer GI bleeding events than dabigatran 110mg and 150mg, edoxaban 60mg and rivaroxaban 20mg. 17

In analyses using absolute risk estimates, the absolute risk of stroke and systemic embolism for NVAF patients treated with standard dose DOACs was lowest for dabigatran 150mg. The absolute risk of major bleeding on a standard dose DOAC was lowest in patients receiving apixaban 5mg. Lower dose edoxaban 30mg had the highest absolute risk of stroke and systemic embolism, and the lowest absolute risk of major bleeding, compared to other DOACs and doses. Two indirect comparisons presenting probability ranking of DOACs concluded that dabigatran 150mg had the highest probability of being the most effective treatment for the prevention of stroke and systemic embolism in NVAF patients. Apixaban 5mg had the highest probability of causing the fewest major bleeding events among the standard dose DOACs. The indirect comparison that included all DOAC doses in their SUCRA analysis concluded edoxaban 30mg had the highest probability of causing fewest major bleeding events. Overall, apixaban 5mg, standard dose dabigatran 150mg and standard dose edoxaban 60mg had similar effects on prevention of stroke and systemic embolism in NVAF patients. Apixaban 5mg had a lower risk of major bleeding than dabigatran 150mg and equivalent risk to edoxaban 60mg. Apixaban 5mg also resulted in fewer GI bleeding events than dabigatran 150mg and rivaroxaban 20mg. Lower dose edoxaban 30mg had the lowest risk of major bleeding compared to all DOAC doses but was less effective than standard dose apixaban 5mg, dabigatran 150mg, and edoxaban 60mg for preventing stroke and systemic embolism. 18

Appendix 1: Indirect comparisons included in this evidence review Study Relevant included trials Author main conclusion Bajaj NS, Kalra R, Patel N, Hashim T, Godara H, Ather S, et al. Comparison of approaches for stroke prophylaxis in patients with nonvalvular atrial fibrillation: network metaanalyses of randomized controlled trials. PLoS ONE. 2016;11(10):e0163608 18. ARISTOTLE (apixaban) ENGAGE (edoxaban) RE-LY (dabigatran) ROCKET-AF (rivaroxaban) Warfarin, DOACs and the WATCHMAN device have equal efficacy in stroke prevention but different safety profiles. Cameron C, Coyle D, Richter T, Kelly S, Gauthier K, Steiner S, et al. Systematic review and network meta-analysis comparing antithrombotic agents for the prevention of stroke and major bleeding in patients with atrial fibrillation. BMJ Open. 2014;4(6):e004301 11. ARISTOTLE (apixaban) ARISTOTLE J (apixaban) ENGAGE (edoxaban) PETRO (dabigatran) RE-LY (dabigatran) ROCKET-AF (rivaroxaban) AF-EDOX-VKA-ASIA (edoxaban) The balance of benefits and harms of DOACs is positive for stroke or systemic embolism and major bleeding compared to standard adjusted dose warfarin, and largely similar between DOACs. AF-EDOX-VKA-MULTI (edoxaban) AF-EDOX-VKA-JAPAN (edoxaban) 19

Study Relevant included trials Author main conclusion Fernandez MM, Wang J, Ye X, Kwong WJ, Sherif B, Hogue S, et al. Systematic review and network meta-analysis of the relative efficacy and safety of edoxaban versus other nonvitamin K antagonist oral anticoagulants among patients with nonvalvular atrial fibrillation and CHADS2 score2. SAGE Open Med. 2015;3:2050312115613350 19. ARISTOTLE (apixaban) ENGAGE (edoxaban) RE-LY (dabigatran) ROCKET-AF (rivaroxaban) In NVAF patients with CHADS2 score 2, high-dose edoxaban offers similar efficacy to other DOACs with significant bleeding benefit over rivaroxaban and dabigatran. Fu W, Guo H, Guo J, Lin K, Wang H, Zhang Y, et al. Relative efficacy and safety of direct oral anticoagulants in patients with atrial fibrillation by network meta-analysis. J Cardiovasc Med. 2014;15(12):873-9 20. ARISTOTLE (apixaban) ENGAGE (edoxaban) RE-LY (dabigatran) ROCKET-AF (rivaroxaban) Apixaban had an advantage over the other DOACs in terms of safety. With the exception of edoxaban 30mg, all DOACs had similar efficacy with respect to stroke prevention. Lip GYH, Mitchell SA, Liu X, Liu LZ, Phatak H, Kachroo S, et al. Relative efficacy and safety of non-vitamin K oral anticoagulants for nonvalvular atrial fibrillation: network metaanalysis comparing apixaban, dabigatran, rivaroxaban and edoxaban in three patient subgroups. Int J Cardiol. 2016;204:88-94 21. ARISTOTLE (apixaban) ENGAGE (edoxaban) RE-LY (dabigatran) ROCKET-AF (rivaroxaban) All DOACs offer efficacy and safety compared to warfarin. Apixaban offers a favourable balance between efficacy, safety and tolerability compared to other DOACs. 20

Study Relevant included trials Author main conclusion Morimoto T, Crawford B, Wada K, Ueda S. Comparative efficacy and safety of novel oral anticoagulants in patients with atrial fibrillation: A network meta-analysis with the adjustment for the possible bias from open label studies. J Cardiol 2015;66(6):466-474 22. ARISTOTLE (apixaban) ARISTOTLE J (apixaban) ENGAGE (edoxaban) JROCKET (rivaroxaban) ROCKET-AF (rivaroxaban) RE-LY (dabigatran) DOACs are nearly equivalent in efficacy apart from low dose edoxaban and dabigatran. Some differences exist in safety and risk of myocardial infarction. PETRO (dabigatran) AF-DABIG-VKA-JAPAN (dabigatran) Verdecchia P, Angeli F, Lip GYH, Reboldi G. Edoxaban in the evolving scenario of non vitamin K antagonist oral anticoagulants imputed placebo analysis and multiple treatment comparisons. PLoS ONE 2014;9(6):e100478 23. ARISTOTLE (apixaban) ENGAGE (edoxaban) RE-LY (dabigatran) ROCKET-AF (rivaroxaban) Edoxaban 30mg is associated with lower risk of major bleeding than other DOACs. Edoxaban 30mg has lower efficacy in prevention of thromboembolism although with a final benefit on all cause mortality. 21

Appendix 2: Key characteristics of DOAC trials included in indirect comparisons Study Population Intervention Comparator Outcomes ARISTOTLE N=18,201 Apixaban 5mg Warfarin (INR 2.0-3.0) Stroke or systemic embolism Mean CHADS2 score 2.1+/-1.1 Major bleeding Mean age 70 years 65% male Follow up 1.8 years ARISTOTLE-J N=222 Mean CHADS2 score 1.9 Mean age 70 years Apixaban 2.5mg Apixaban 5mg Warfarin (INR 2.0-3.0) Composite of major bleeding and clinically relevant nonmajor bleeding events 83% male Follow up 12 weeks AF-EDOX-VKA-ASIA N=234 Edoxaban 30mg Warfarin (INR 2.0-3.0) All bleeding events Mean CHADS2 score 1.9+/-1.1 Mean age 65+/-9 years Edoxaban 60mg 65% male Follow up 12 weeks 22

Study Population Intervention Comparator Outcomes ENGAGE AF-TIMI 48 N=21,105 Edoxaban 30mg Warfarin (INR 2.0-3.0) Stroke or systemic embolism Mean CHADS2 score 2.8+/-1.0 Edoxaban 60mg Mean age 72 years Major bleeding JROCKET 62% male Follow up 2.8 years N=1,278 Mean CHADS2 score 3.25 Mean age 71.1 years 80.6% male Follow up 1.3 years Rivaroxaban 15mg Warfarin (INR 2.0-3.0) Stroke or systemic embolism Major bleeding and clinically relevant non-major bleeding PETRO N=236 Mean age 70 years Dabigatran 150mg Warfarin (INR 2.0-3.0) Thromboembolic events Bleeding events 82% male Follow up 12 weeks AF-DABIG-VKA-JAPAN N=166 Dabigatran 150mg Warfarin (INR 2.0-3.0) Stroke or systemic embolism (open-label) Mean age 68.4±8.6 years 88% male Dabigatran 110mg Major bleeding and clinically relevant non-major bleeding Follow up 12 weeks 23

Study Population Intervention Comparator Outcomes RE-LY N=18,113 Dabigatran 110mg Warfarin (INR 2.0-3.0) Stroke or systemic embolism (open-label) Mean CHADS2 score 2.1 Major bleeding Mean age 71.5±8.7 years Dabigatran 150mg ROCKET-AF 64% male Follow up 2 years N=14,264 Mean CHADS2 score 3.5 Mean age 73 years 60% male Follow up 1.9 years Rivaroxaban 20mg Warfarin (INR 2.0-3.0) Composite of stroke and systemic embolism Composite of major and clinically relevant non-major bleeding AF-EDOX-VKA-MULTI N=1,143 Mean age 65+/-9 years Edoxaban 30mg Edoxaban 60mg Warfarin (INR 2.0-3.0) Bleeding and abnormalities of hepatic function 62% male Follow up 12 weeks AF-EDOX-VKA-JAPAN N=525 Edoxaban 30mg Warfarin (INR 2.0-3.0) All bleeding events Mean CHADS2 score 2.1 Edoxaban 60mg Mean age 69 years 83% male Follow up 12 weeks N=sample size; NVAF=non-valvular atrial fibrillation; VKA=vitamin K antagonist; INR=international normalised ratio 24

Appendix 3: Prevention of stroke and systemic embolism Table 1: results for prevention of stroke and systemic embolism from indirect comparisons reporting odds ratios11, 20 Comparison Odds ratio (OR) 95% Confidence interval (CI) or 95% Credible interval (CrI) Interpretation Apixaban 5mg vs. dabigatran 150mg 1.19 CrI 0.89 to 1.58 No difference Dabigatran 110mg vs. apixaban 5mg 1.17 CrI 0.88 to 1.53 No difference Dabigatran 110mg vs. dabigatran 150mg 1.38 CrI 1.11 to 1.74 Favours dabigatran 150mg over dabigatran 110mg Dabigatran 110mg vs. edoxaban 60mg 1.16 CI 0.88 to 1.56 No significant difference Dabigatran 110mg vs. rivaroxaban 20mg 1.04 CrI 0.80 to 1.36 No difference Edoxaban 30mg vs. apixaban 5mg 1.45 CrI 1.15 to 1.84 Favours apixaban 5mg over edoxaban 30mg Edoxaban 30mg vs. dabigatran 110mg 1.21 CI 0.93 to 1.57 No significant difference Edoxaban 30mg vs. dabigatran 150mg 1.67 CI 1.26 to 2.21 Edoxaban 30mg vs. edoxaban 60mg 1.31 CrI 1.13 to 1.54 Favours dabigatran 150mg over edoxaban 30mg Favours edoxaban 60mg over edoxaban 30mg Edoxaban 30mg vs. rivaroxaban 20mg 1.26 CI 0.96 to 1.60 No significant difference Edoxaban 60mg vs. apixaban 5mg 1.11 CrI 0.89 to 1.41 No difference 25

Table 1 continued Comparison Odds ratio (OR) 95% Confidence interval (CI) or 95% Credible interval (CrI) Interpretation Edoxaban 60mg vs. dabigatran 150 mg 1.19 CI 0.91 to 1.58 No significant difference Rivaroxaban 20mg vs. apixaban 5mg 1.12 CrI 0.87 to 1.43 No difference Rivaroxaban 20mg vs. dabigatran 150mg 1.33 CrI 1.01 to 1.76 Favours dabigatran 150mg (slightly) over rivaroxaban 20mg Rivaroxaban 20mg vs. edoxaban 60mg 1.23 CI 0.88 to 1.45 No significant difference Table 2: results for prevention of stroke and systemic embolism from one Bayesian indirect comparison reporting hazard ratios 21 Comparison Hazards ratio (HR) 95% Credible interval Interpretation Apixaban 5mg vs. dabigatran 110mg 0.88 0.68 to 1.15 No difference Apixaban 5mg vs. dabigatran 150mg 1.23 0.93 to 1.63 No difference Apixaban 5mg vs. edoxaban 30mg 0.70 0.55 to 0.88 Favours apixaban 5mg over edoxaban 30mg Apixaban 5mg vs. edoxaban 60mg 0.91 0.72 to 1.16 No difference Apixaban 5mg vs. rivaroxaban 20mg 0.91 0.71 to 1.16 No difference Dabigatran 110mg vs. rivaroxaban 20mg 1.03 0.79 to 1.33 No difference Dabigatran 150mg vs. dabigatran 110mg 0.72 0.57 to 0.90 Favours dabigatran 150mg over dabigatran 110mg 26

Table 2 continued Comparison Hazards ratio (HR) 95% Credible interval Interpretation Dabigatran 150mg vs. rivaroxaban 20mg 0.74 0.56 to 0.97 Favours dabigatran 150mg over rivaroxaban 20mg Edoxaban 30mg vs. dabigatran 110mg 1.26 0.99 to 1.62 No difference Edoxaban 30mg vs. dabigatran 150mg 1.75 1.35 to 2.28 Favours dabigatran 150mg over edoxaban 30mg Edoxaban 30mg vs. rivaroxaban 20mg 1.30 1.04 to 1.62 Favours rivaroxaban 20mg over edoxaban 30mg Edoxaban 60mg vs. dabigatran 110mg 0.97 0.75 to 1.25 No difference Edoxaban 60mg vs. dabigatran 150mg 1.35 1.03 to 1.76 Favours dabigatran 150mg over edoxaban 60mg Edoxaban 60mg vs. edoxaban 30mg 0.77 0.66 to 0.90 Favours edoxaban 60mg over edoxaban 30mg Edoxaban 60mg vs. rivaroxaban 20mg 1.00 0.80 to 1.25 No difference Table 3: results for prevention of stroke and systemic embolism from one frequentist indirect comparison using reporting risk ratios 19 Comparison Risk ratio (RR) 95% Confidence interval Interpretation Apixaban 5mg vs. edoxaban 30mg 0.71 0.56 to 0.89 Favours apixaban 5mg over edoxaban 30mg Apixaban 5mg vs. edoxaban 60mg 0.92 0.73 to 1.16 No significant difference Edoxaban 30mg vs. dabigatran 150mg 1.64 1.26 to 2.13 Favours dabigatran 150mg over edoxaban 30mg Edoxaban 30mg vs. rivaroxaban 20mg 1.17 0.92 to 1.50 No significant difference Edoxaban 60mg vs. dabigatran 110mg 0.95 0.74 to 1.22 No significant difference Edoxaban 60mg vs. dabigatran 150mg 1.26 0.97 to 1.64 No significant difference Edoxaban 60mg vs. rivaroxaban 20mg 0.90 0.70 to 1.16 No significant difference 27

Appendix 4: Major bleeding Table 1: results for major bleeding outcomes from indirect comparisons reporting odds ratios 11 Comparison Odds ratio (OR) 95% Credible interval (CrI) Interpretation Apixaban 5mg vs. dabigatran 150mg 0.74 0.6 to 0.91 Favours apixaban 5mg over dabigatran 150mg Dabigatran 110mg vs. apixaban 5mg 1.16 0.94 to 1.43 No difference Dabigatran 110mg vs. dabigatran 150mg 0.86 0.74 to 1.00 No difference Dabigatran 110mg vs. edoxaban 60mg 1.02 0.83 to 1.25 No difference Dabigatran 110mg vs. rivaroxaban 20mg 0.78 0.63 to 0.96 Favours dabigatran 110mg over rivaroxaban 20mg Edoxaban 30mg vs. apixaban 5mg 0.67 0.54 to 0.83 Favours edoxaban 30mg over apixaban 5mg Edoxaban 30mg vs. dabigatran 110mg 0.58 0.47 to 0.72 Edoxaban 30mg vs. dabigatran 150mg 0.5 0.4 to 0.61 Favours edoxaban 30mg over dabigatran 110mg Favours edoxaban 30mg over dabigatran 150mg Edoxaban 30mg vs. edoxaban 60mg 0.59 0.5 to 0.69 Favours edoxaban 30mg over edoxaban 60mg Edoxaban 30mg vs. rivaroxaban 20mg 0.45 0.37 to 0.56 Edoxaban 60mg vs. apixaban 5mg 1.14 0.93 to 1.38 No difference Edoxaban 60mg vs. dabigatran 150 mg 0.84 0.69 to 1.03 No difference Favours edoxaban 30mg over rivaroxaban 20mg Rivaroxaban 20mg vs. apixaban 5mg 1.49 1.21 to 1.82 Favours apixaban 5mg over rivaroxaban 20mg Rivaroxaban 20mg vs. dabigatran 150mg 1.10 0.9 to 1.35 No difference Rivaroxaban 20mg vs. edoxaban 60mg 1.31 1.08 to 1.59 Favours edoxaban 60mg over rivaroxaban 20mg 28

Table 2: results for major bleeding outcomes from one Bayesian indirect comparison reporting hazard ratios 21 Comparison Hazards ratio (HR) 95% Credible interval Interpretation Apixaban 5mg vs. dabigatran 110mg 0.86 0.70 to 1.05 No difference Apixaban 5mg vs. dabigatran 150mg 0.74 0.61 to 0.90 Favours apixaban 5mg over dabigatran 150mg Apixaban 5mg vs. edoxaban 30mg 1.47 1.20 to 1.81 Favours edoxaban 30mg over apixaban 5mg Apixaban 5mg vs. edoxaban 60mg 0.86 0.71 to 1.04 No difference Apixaban 5mg vs. rivaroxaban 20mg 0.66 0.54 to 0.81 Favours apixaban 5mg over rivaroxaban 20mg Dabigatran 110mg vs. rivaroxaban 20mg 0.77 0.63 to 0.94 Favours dabigatran 110mg over rivaroxaban 20mg Dabigatran 150mg vs. dabigatran 110mg 1.16 1.00 to 1.34 No difference Dabigatran 150mg vs. rivaroxaban 20mg 0.89 0.73 to 1.08 No difference Edoxaban 30mg vs. dabigatran 110mg 0.58 0.47 to 0.72 Favours edoxaban 30mg over dabigatran 110mg Edoxaban 30mg vs. dabigatran 150mg 0.50 0.41 to 0.62 Favours edoxaban 30mg over dabigatran 150mg Edoxaban 30mg vs. rivaroxaban 20mg 0.45 0.37 to 0.55 Favours edoxaban 30mg over rivaroxaban 20mg Edoxaban 60mg vs. dabigatran 110mg 1.00 0.82 to 1.21 No difference Edoxaban 60mg vs. dabigatran 150mg 0.86 0.71 to 1.04 No difference Edoxaban 60mg vs. edoxaban 30mg 1.71 1.46 to 2.00 Favours edoxaban 30mg over edoxaban 60mg Edoxaban 60mg vs. rivaroxaban 20mg 0.77 0.63 to 0.92 Favours edoxaban 60mg over rivaroxaban 20mg 29

Table 3: results for major bleeding outcomes from one frequentist indirect comparison reporting risk ratios 19 Comparison Risk ratio (RR) 95% Confidence interval Interpretation Apixaban 5mg vs. edoxaban 30mg 1.59 1.31 to 1.92 Favours edoxaban 30mg over apixaban 5mg Apixaban 5mg vs. edoxaban 60mg 0.92 0.78 to 1.10 No significant difference Edoxaban 30mg vs. dabigatran 110mg 0.49 0.41 to 0.59 Favours edoxaban 30mg over dabigatran 110mg Edoxaban 30mg vs. dabigatran 150mg 0.42 0.35 to 0.50 Favours edoxaban 30mg over dabigatran 150mg Edoxaban 30mg vs. rivaroxaban 20mg 0.45 0.38 to 0.53 Favours edoxaban 30mg over rivaroxaban 20mg Edoxaban 60mg vs. dabigatran 110mg 0.83 0.71 to 0.98 Favours edoxaban 60mg over dabigatran 110mg Edoxaban 60mg vs. dabigatran 150mg 0.72 0.61 to 0.84 Favours edoxaban 60mg over dabigatran 150mg Edoxaban 60mg vs. rivaroxaban 20mg 0.76 0.66 to 0.89 Favours edoxaban 60mg over rivaroxaban 20mg 30

Appendix 5: Intra-cranial haemorrhage Table 1: results for intra-cranial haemorrhage outcomes from Bayesian indirect comparisons reporting odds ratios 20 Comparison Odds ratio (OR) 95% Confidence interval Interpretation Apixaban 5mg vs. dabigatran 150mg 1.06 0.61 to 1.74 No significant difference Dabigatran 110mg vs. apixaban 5mg 0.69 0.41 to 1.22 No significant difference Dabigatran 110mg vs. dabigatran 150mg 0.71 0.40 to 1.33 No significant difference Dabigatran 110mg vs. edoxaban 60mg 0.64 0.39 to 1.09 No significant difference Dabigatran 110mg vs. rivaroxaban 20mg 0.45 0.26 to 0.81 Favours dabigatran 110mg over rivaroxaban 20mg Edoxaban 30mg vs. apixaban 5mg 0.75 0.45 to 1.16 No significant difference Edoxaban 30mg vs. dabigatran 110mg 1.05 0.59 to 1.80 No significant difference Edoxaban 30mg vs. dabigatran 150mg 0.78 0.43 to 1.29 No significant difference Edoxaban 30mg vs. edoxaban 60mg 0.65 0.43 to 1.05 No significant difference Edoxaban 30mg vs. rivaroxaban 20mg 0.48 0.28 to 0.75 Favours edoxaban 30mg over rivaroxaban 20mg Edoxaban 60mg vs. apixaban 5mg 1.12 0.68 to 1.70 No significant difference Edoxaban 60mg vs. dabigatran 150 mg 1.16 0.69 to 1.93 No significant difference Rivaroxaban 20mg vs. apixaban 5mg 1.61 0.96 to 2.48 No significant difference Rivaroxaban 20mg vs. dabigatran 150mg 1.66 0.93 to 2.68 No significant difference Rivaroxaban 20mg vs. edoxaban 60mg 1.39 0.89 to 2.22 No significant difference 31

Table 2: results for intra-cranial haemorrhage outcomes from one Bayesian indirect comparison reporting hazard ratios 21 Comparison Hazards ratio (HR) 95% Credible interval Interpretation Apixaban 5mg vs. dabigatran 110mg 1.38 0.81 to 2.38 No difference Apixaban 5mg vs. dabigatran 150mg 0.99 0.60 to 1.63 No difference Apixaban 5mg vs. edoxaban 30mg 1.35 0.84 to 2.20 No difference Apixaban 5mg vs. edoxaban 60mg 0.90 0.58 to 1.42 No difference Apixaban 5mg vs. rivaroxaban 20mg 0.58 0.36 to 0.93 Favours apixaban 5mg over rivaroxaban 20mg Dabigatran 110mg vs. rivaroxaban 20mg 0.42 0.24 to 0.72 Favours dabigatran 110mg over rivaroxaban 20mg Dabigatran 150mg vs. dabigatran 110mg 1.40 0.86 to 2.31 No difference Dabigatran 150mg vs. rivaroxaban 20mg 0.59 0.35 to 0.98 Favours dabigatran 150mg over rivaroxaban 20mg Edoxaban 30mg vs. dabigatran 110mg 1.02 0.58 to 1.79 No difference Edoxaban 30mg vs. dabigatran 150mg 0.73 0.43 to 1.23 No difference Edoxaban 30mg vs. rivaroxaban 20mg 0.43 0.26 to 0.70 Favours edoxaban 30mg over rivaroxaban 20mg Edoxaban 60mg vs. dabigatran 110mg 1.53 0.91 to 2.62 No difference Edoxaban 60mg vs. dabigatran 150mg 1.09 0.68 to 1.80 No difference Edoxaban 60mg vs. edoxaban 30mg 1.50 1.01 to 2.25 Favours edoxaban 30mg over edoxaban 60mg Edoxaban 60mg vs. rivaroxaban 20mg 0.64 0.41 to 1.02 No difference 32

Table 3: results for intra-cranial haemorrhage outcomes from one frequentist indirect comparison reporting risk ratios 19 Comparison Risk ratio (RR) 95% Confidence interval Interpretation Apixaban 5mg vs. edoxaban 30mg 1.41 0.89 to 2.22 No significant difference Apixaban 5mg vs. edoxaban 60mg 0.94 0.62 to 1.45 No significant difference Edoxaban 30mg vs. dabigatran 110mg 1.09 0.62 to 1.90 No significant difference Edoxaban 30mg vs. dabigatran 150mg 0.68 0.42 to 1.10 No significant difference Edoxaban 30mg vs. rivaroxaban 20mg 0.50 0.33 to 0.77 Favours edoxaban 30mg over rivaroxaban 20mg Edoxaban 60mg vs. dabigatran 110mg 1.63 0.96 to 2.76 No significant difference Edoxaban 60mg vs. dabigatran 150mg 1.02 0.65 to 1.59 No significant difference Edoxaban 60mg vs. rivaroxaban 20mg 0.76 0.52 to 1.10 No significant difference 33

Appendix 6: Gastrointestinal bleeding Table 1: results for gastrointestinal bleeding outcomes from Bayesian indirect comparisons reporting odds ratios 20 Comparison Odds ratio (OR) 95% Confidence interval Interpretation Apixaban 5mg vs. dabigatran 150mg 0.59 0.41 to 0.82 Favours apixaban 5mg over dabigatran 150mg Dabigatran 110mg vs. apixaban 5mg 1.25 0.88 to 1.85 No significant difference Dabigatran 110mg vs. dabigatran 150mg 0.72 0.50 to 1.03 No significant difference Dabigatran 110mg vs. edoxaban 60mg 0.89 0.64 to 1.26 No significant difference Dabigatran 110mg vs. rivaroxaban 20mg 0.75 0.53 to 1.05 No significant difference Edoxaban 30mg vs. apixaban 5mg 0.78 0.54 to 1.08 No significant difference Edoxaban 30mg vs. dabigatran 110mg 0.61 0.42 to 0.86 Favours edoxaban 30mg over dabigatran 110mg Edoxaban 30mg vs. dabigatran 150mg 0.45 0.32 to 0.60 Favours edoxaban 30mg over dabigatran 150mg Edoxaban 30mg vs. edoxaban 60mg 0.54 0.39 to 0.73 Favours edoxaban 30mg over edoxaban 60mg Edoxaban 30mg vs. rivaroxaban 20mg 0.46 0.33 to 0.61 Favours edoxaban 30mg over rivaroxaban 20mg Edoxaban 60mg vs. apixaban 5mg 1.41 0.99 to 1.95 No significant difference Edoxaban 60mg vs. dabigatran 150 mg 0.82 0.61 to 1.09 No significant difference Rivaroxaban 20mg vs. apixaban 5mg 1.70 1.16 to 2.31 Favours apixaban 5mg over rivaroxaban 20mg Rivaroxaban 20mg vs. dabigatran 150mg 0.98 0.71 to 1.29 No significant difference Rivaroxaban 20mg vs. edoxaban 60mg 1.19 0.88 to 1.61 No significant difference 34

Table 2: results for gastrointestinal bleeding outcomes from one Bayesian indirect comparison reporting hazard ratios 21 Comparison Hazards ratio (HR) 95% Credible interval Interpretation Apixaban 5mg vs. dabigatran 110mg 0.82 0.58 to 1.18 No difference Apixaban 5mg vs. dabigatran 150mg 0.61 0.43 to 0.86 Favours apixaban 5mg over dabigatran 150mg Apixaban 5mg vs. edoxaban 30mg 1.33 0.94 to 1.88 No difference Apixaban 5mg vs. edoxaban 60mg 0.72 0.52 to 1.03 No difference Apixaban 5mg vs. rivaroxaban 20mg 0.61 0.43 to 0.85 Favours apixaban 5mg over rivaroxaban 20mg Dabigatran 110mg vs. rivaroxaban 20mg 0.74 0.53 to 1.01 No difference Dabigatran 150mg vs. dabigatran 110mg 1.36 1.09 to 1.69 Favours dabigatran 110mg over dabigatran 150mg Dabigatran 150mg vs. rivaroxaban 20mg 1.00 0.73 to 1.35 No difference Edoxaban 30mg vs. dabigatran 110mg 0.62 0.45 to 0.86 Favours edoxaban 30mg over dabigatran 110mg Edoxaban 30mg vs. dabigatran 150mg 0.46 0.33 to 0.63 Favours edoxaban 30mg over dabigatran 150mg Edoxaban 30mg vs. rivaroxaban 20mg 0.46 0.34 to 0.62 Favours edoxaban 30mg over rivaroxaban 20mg Edoxaban 60mg vs. dabigatran 110mg 1.15 0.84 to 1.56 No difference Edoxaban 60mg vs. dabigatran 150mg 0.84 0.63 to 1.14 No difference Edoxaban 60mg vs. edoxaban 30mg 1.84 1.49 to 2.29 Favours edoxaban 30mg over edoxaban 60mg Edoxaban 60mg vs. rivaroxaban 20mg 0.84 0.63 to 1.12 No difference 35

Table 3: results for gastrointestinal bleeding outcomes from one indirect comparison reporting risk ratios 19 Comparison Risk ratio (RR) 95% Confidence interval Interpretation Edoxaban 30mg vs. rivaroxaban 20mg 0.41 0.33 to 0.51 Favours edoxaban 30mg over rivaroxaban 20mg Edoxaban 60mg vs. rivaroxaban 20mg 0.75 0.63 to 0.91 Favours edoxaban 60mg over rivaroxaban 20mg 36

References 1. ISD Scotland. Scottish heart disease statistics: year ending 31 March 2015. 2016 [cited 10 Oct 2016]; Available from: https://isdscotland.scot.nhs.uk/health-topics/heart- Disease/Publications/2016-01-26/2016-01-26-Heart-Disease-Report.pdf?98643130065. 2. Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. Circulation. 2006;114(7):e257-354. 3. GP Notebook. CHADS2 scoring system. c2014 [cited 11 Oct 2016]; Available from: http://www.gpnotebook.co.uk/simplepage.cfm?id=x20110126111352933383. 4. NHS Choices. Warfarin. 2016 [cited 11 Oct 2016]; Available from: http://www.nhs.uk/conditions/anticoagulants-warfarin-/pages/introduction.aspx. 5. Tereshchenko LG, Henrikson CA, Cigarroa J, Steinberg JS. Comparative effectiveness of interventions for stroke prevention in atrial fibrillation: a network meta-analysis. J Am Heart Assoc. 2016;5(5):e003206. 6. Assiri A, Al-Majzoub O, Kanaan AO, Donovan JL, Silva M. Mixed treatment comparison meta-analysis of aspirin, warfarin, and new anticoagulants for stroke prevention in patients with nonvalvular atrial fibrillation. Clin Ther. 2013;35(7):967-84. 7. Camm AJ, Lip GYH, De Caterina R, Savelieva I, Atar D, Hohnloser SH, et al. 2012 focused update of the ESC guidelines for the management of atrial fibrillation. Eur Heart J. 2012;33(21):2719-27. 8. Martinez C, Katholing A, Wallenhorst C, Granziera S, Cohen AT, Freedman SB. Increasing incidence of non-valvular atrial fibrillation in the UK from 2001 to 2013. Heart. 2015;101(21):1748-54. 9. NICE. Atrial fibrillation: the management of atrial fibrillation. 2014 [cited 10 Oct 2016]; Available from: https://www.nice.org.uk/guidance/cg180/evidence/atrial-fibrillationupdate-full-guideline-243739981. 10. Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: a European perspective. Clin Epidemiology. 2014;6:213-20. 11. Cameron C, Coyle D, Richter T, Kelly S, Gauthier K, Steiner S, et al. Systematic review and network meta-analysis comparing antithrombotic agents for the prevention of stroke and major bleeding in patients with atrial fibrillation. BMJ Open. 2014;4(6):e004301. 12. Scottish Medicines Consortium. Dabigatran etexilate 110mg and 150mg hard capsules (Pradaxa). 2011 [cited 8 Feb 2017]; Available from: https://www.scottishmedicines.org.uk/files/advice/dabigatran_pradaxa_final_august _2011_Amended_05.09.11_for_website.pdf. 13. Scottish Medicines Consortium. Apixaban 2.5mg and 5mg film-coated tablets (Eliquis). 2013 [cited 23 Feb 2017]; Available from: 37

https://www.scottishmedicines.org.uk/files/advice/apixaban_eliquis_final_january_2 013_Amended_060213_for_website.pdf. 14. Scottish Medicines Consortium. Edoxaban tosilate 15mg, 30mg and 60mg film-coated tablets (Lixiana). 2015 [cited 8 Feb 2017]; Available from: https://www.scottishmedicines.org.uk/files/advice/edoxaban Lixiana NVAF_FINAL_ October_2015_Amended_03.11.15.pdf. 15. Scottish Medicines Consortium. Rivaroxaban 15 and 20mg film-coated tablets (Xarelto). 2012 [cited 8 Feb 2017]; Available from: https://www.scottishmedicines.org.uk/files/advice/rivaroxaban_xarelto_for_af_final _Jan_2012_for_website.pdf. 16. Electronic Medicines Consortium. Pradaza 110mg hard capsules: summary of product characteristics. 2016 [cited 2 Mar 2017]; Available from: https://www.medicines.org.uk/emc/medicine/20760. 17. Electronic Medicines Consortium. Lixiana 30mg film-coated tablets: summary of product characteristics. 2016 [cited 2 March 2017]; Available from: https://www.medicines.org.uk/emc/medicine/30512. 18. Bajaj NS, Kalra R, Patel N, Hashim T, Godara H, Ather S, et al. Comparison of approaches for stroke prophylaxis in patients with non-valvular atrial fibrillation: network metaanalyses of randomized controlled trials. PLoS ONE. 2016;11(10):e0163608. 19. Fernandez MM, Wang J, Ye X, Kwong WJ, Sherif B, Hogue S, et al. Systematic review and network meta-analysis of the relative efficacy and safety of edoxaban versus other nonvitamin K antagonist oral anticoagulants among patients with nonvalvular atrial fibrillation and CHADS2 score >=2. SAGE Open Med. 2015;3:2050312115613350. 20. Fu W, Guo H, Guo J, Lin K, Wang H, Zhang Y, et al. Relative efficacy and safety of direct oral anticoagulants in patients with atrial fibrillation by network meta-analysis. J Cardiovasc Med. 2014;15(12):873-9. 21. Lip GYH, Mitchell SA, Liu X, Liu LZ, Phatak H, Kachroo S, et al. Relative efficacy and safety of non-vitamin K oral anticoagulants for non-valvular atrial fibrillation: network metaanalysis comparing apixaban, dabigatran, rivaroxaban and edoxaban in three patient subgroups. Int J Cardiol. 2016;204:88-94. 22. Morimoto, Crawford B, Wada K, Ueda S. Comparative efficacy and safety of novel oral anticoagulants in patients with atrial fibrillation: a network meta-analysis with the adjustment for the possible bias from open label studies. J Cardiol. 2015;66(6):466-74. 23. Verdecchia P, Angeli F, Lip GYH, Reboldi G. Edoxaban in the evolving scenario of non vitamin K antagonist oral anticoagulants imputed placebo analysis and multiple treatment comparisons. PLoS ONE. 2014;9(6):e100478. 24. Hart RG, Tonarelli SB, Pearce LA. Avoiding central nervous system bleeding during antithrombotic therapy: recent data and ideas. Stroke. 2005;36(7):1588-93. 25. Electronic Medicines Consortium. Xarelto 20mg film-coated tablets: summary of product characteristics. 2016 [cited 2 Mar 2017]; Available from: https://www.medicines.org.uk/emc/medicine/25586. 38

26. Electronic Medicines Consortium. Lixiana 60mg film-coated tablets: summary product characteristics. 2016 [cited 2 Mar 2017]; Available from: https://www.medicines.org.uk/emc/medicine/30506. 27. Electronic Medicines Consortium. Pradaxa 150mg hard capsules: summary of product characterstics. 2016 [cited 2 Mar 2017]; Available from: https://www.medicines.org.uk/emc/medicine/24839. 28. Electronic Medicines Consortium. Eliquis 5mg film-coated tablets: summary of product characteristics. 2017 [cited 2 Mar 2017]; Available from: https://www.medicines.org.uk/emc/medicine/27220. 29. NHS Vale of York Clinical Commissioning Group, York Teaching Hospital NHS Foundation Trust. Patients/healthcare professional decision aid: atrial fibrillation medicines to help reduce your risk of a stroke - what are the options? 2016 [cited 23 Feb 2017]; Available from: http://www.yorkandscarboroughformulary.nhs.uk/docs/bnf/02/atrial%20fibrillation% 20patient%20decision%20aid.pdf. 30. Cowell RPW. Direct oral anticoagulants: integration into clinical practice. Postgrad Med J. 2014;90:529-39. 31. Douketis J, Bell AD, Eikelboom J, Liew A. Approach to the new oral anticoagulants in family practice part 2: addressing frequently asked questions. Can Fam Physician. 2014;60:997-1001. 32. Schaefer JK, McBane RD, Wysokinski WE. How to choose appropriate direct oral anticoagulant for patients with nonvalvular atrial fibrillation. Ann Hematol. 2016;95:437-49. 39

You can read and download this document from our website. We are happy to consider requests for other languages or formats. Please contact our Equality and Diversity Officer on 0141 225 6999 or email contactpublicinvolvement.his@nhs.net www.healthcareimprovementscotland.org Edinburgh Office: Gyle Square 1 South Gyle Crescent Edinburgh EH12 9EB Telephone: 0131 623 4300 Glasgow Office: Delta House 50 West Nile Street Glasgow G1 2NP Telephone: 0141 225 6999 The Healthcare Environment Inspectorate, Improvement Hub, Scottish Health Council, Scottish Health Technologies Group, Scottish Intercollegiate Guidelines Network (SIGN) and Scottish Medicines Consortium are part of our organisation.