SUPPLEMENTARY APPENDIX:

Page 1 of 20 DETAILS OF THE BIBLIOGRAPHIC SEARCH:

1) Main bibliographic search:

1a. MEDLINE: http://www.ncbi.nlm.nih.gov/pubmed Search: “Terms: rivaroxaban and/or dabigatran and/or apixaban; “Limits Activated: Publication Date: from 2000/01/01 to 2012/12/31.” Results: 1561 articles.

1b. CENTRAL: http://onlinelibrary.wiley.com/o/cochrane/cochrane_clcentral_articles_fs.html Search: “Terms: rivaroxaban or dabigatran or apixaban (Search Text Fields).”; “Limits Activated: Data range from 2000 to 2012. Results: 138 articles (no additional clinical trials to those identified through MEDLINE were found).

2) Additional bibliographic search:

2a. Regulatory Authorities:

Food and Drug Administration (FDA): www.accessdata.fda.gov/scripts/cder/drugsatfda

European Medicines Agency (EMA): www.ema.europa.eu

2b. Clinical trials websites:

Clinicaltrials.gov Registry (“U.S. National Institute of Health”): http://www.clinicaltrials.gov/

EU Clinical Trials Register https://www.clinicaltrialsregister.eu/ctr-search/search

Boehringer-Ingelheim clinical trial register website (dabigatran studies): http://trials.boehringer-ingelheim.com/trial_results.html

Bayer Healthcare clinical trial register website (rivaroxaban studies): http://healthcare.bayer.com/scripts/pages/en/research_development/clinical_trials/trial_f inder/index.php

2c. Abstracts from international congresses:

American Society of Hematology (ASH): 2007: http://abstracts.hematologylibrary.org/content/vol110/issue11/ 2008: http://abstracts.hematologylibrary.org/content/vol112/issue11/ 2009: http://abstracts.hematologylibrary.org/content/vol114/issue22/ 2010: http://abstracts.hematologylibrary.org/content/vol116/issue21/ 2011: http://abstracts.hematologylibrary.org/content/vol118/issue21/ 2012: http://abstracts.hematologylibrary.org/content/vol120/issue21/

Page 2 of 20 American College of Cardiology (ACC) Annual Scientific Sessions: 2007-2010: http://content.onlinejacc.org/ 2011-2012: http://www.cardiosource.org/Meetings/Previous-Meetings-OLD.aspx

American Heart Association (AHA) Scientific Sessions: 2007: http://circ.ahajournals.org/content/vol116/16_MeetingAbstracts/ 2008: http://circ.ahajournals.org/content/vol118/18_MeetingAbstracts/ 2009: http://circ.ahajournals.org/content/vol120/18_MeetingAbstracts/ 2010: http://circ.ahajournals.org/content/vol122/21_MeetingAbstracts/ 2011: http://circ.ahajournals.org/content/vol124/21_MeetingAbstracts/ 2012: http://www.abstractsonline.com/Plan/start.aspx

European Society of Cardiology (ESC) 2007: http://www.escardio.org/congresses/esc2007/Pages/resources.aspx 2008: http://www.escardio.org/congresses/esc2008/Pages/welcome.aspx 2009: http://www.escardio.org/congresses/esc-2009/Pages/welcome.aspx 2010: http://www.escardio.org/congresses/esc-2010/Pages/welcome.aspx 2011: http://www.escardio.org/congresses/esc-2011/Pages/welcome.aspx 2012: http://www.escardio.org/congresses/esc-2012/Pages/welcome.aspx

Page 3 of 20 Table A1 Risk of bias for the 3 included studies

STUDY/Characteristic Judgement Support for judgement RE-LY Random sequence generation Low risk. Quote: “all trial participants were randomly assigned”. (selection bias) Allocation concealment Low risk. Quote: “central, interactive, automated telephone system”. (selection bias) Blinding of participants and Unclear Quote: “multicenter, prospective, open-label, randomized trial, with blinded adjudication of all personnel (performance bias) risk. outcomes (PROBE design)”. Comment: There were multiple measures put in place to ensure the robustness and reliability of the results: a) data management was external to the sponsor and was managed by an independent academic group with firewalls to protect the integrity of the study; b) adjudication was performed with procedures to ensure adjudicators were unaware of treatment group assignments and the selected outcomes were of clinical importance; c) stroke and bleeding questionnaires were used at every visit to decrease ascertainment bias and subjects in all treatment groups had a similar number of visits to the study centers; d) screening of free text fields on case report form (CRF) were done to identify subjects with findings that could be indicative of an outcome event.; e) the study was blinded for dabigatran doses. However, these measures cannot remove all the bias of an open-label design [FDA briefing]. Blinding of outcome Unclear Quote: “The outcome events including strokes, non-central nervous system systemic emboli, deaths, assessment (detection bias) risk. myocardial infarctions, pulmonary embolism, major bleeds, and some minor bleeds are adjudicated by a blinded adjudication committee”. “An independent data safety monitoring board reviewed the unblinded study data and performed two prespecified interim analyses of efficacy.” Comment: The potential influence of the 2 unblinded interim analyses on study conduct is unknown. Incomplete outcome data Unclear Insufficient reporting of attrition/exclusions to permit judgement of ‘Low risk’ or ‘High risk’. There addressed (attrition bias) risk. were higher withdrawal rates in patients on dabigatran and “as-treated” analysis is not publicly available. Selective reporting (reporting Unclear The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes bias) risk. that are of interest in the review have been reported in the pre-specified way. However, in an open- label study there may have been biases when it came to investigator reporting of adverse event as well as when investigators chose to discontinue study medication [FDA briefing]. Summary Unclear Unclear risk of bias for one or more key domains. risk ROCKET-AF Random sequence generation Low risk. Quote: “patients were randomly allocated.” (selection bias) Allocation concealment Low risk. Quote: “To effect concealment of randomization, treatment allocation is randomized using a blinded, (selection bias) central telephonic Interactive Voice Response System”

Blinding of participants and Low risk. Quote: “A double-blind design was chosen to minimize bias in cointerventions and interpretation of personnel (performance bias) clinical events. To maintain blinding in ROCKET AF, sham INR results were provided. Patients in each group also received a placebo tablet in order to maintain blinding”. Blinding of outcome Low risk. Quote: “The independent blinded clinical end-point committee…applied protocol definitions to assessment (detection bias) adjudicate all suspected cases of stroke, systemic embolism, myocardial infarction, death, and bleeding events that contributed to the prespecified end points” Incomplete outcome data Low risk. Reasons for missing outcome data unlikely to be related to true outcome; Missing outcome data addressed (attrition bias) balanced in numbers across intervention groups, with similar reasons for missing data across groups; The proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate. Selective reporting (reporting Low risk. The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes bias) that are of interest in the review have been reported in the pre-specified way; Summary Low risk Low risk of bias for all key domains. ARISTOTLE Random sequence generation Low risk. Quote: “patients were randomly assigned.” (selection bias) Allocation concealment Low risk. Quote: “central response system.” (selection bias) Blinding of participants and Low risk. Quote: “double-blind”. To maintain blinding, study medications are packaged using a double-dummy personnel (performance bias) design. INRs were monitored with the use of a blinded, encrypted, point-of-care INR device”. Blinding of outcome Low risk. Quote: “The primary and secondary efficacy and safety outcomes were adjudicated on the basis of assessment (detection bias) prespecified criteria by a clinical-events committee whose members were not aware of study-group assignments”. Incomplete outcome data Low risk. Reasons for missing outcome data unlikely to be related to true outcome; Missing outcome data addressed (attrition bias) balanced in numbers across intervention groups, with similar reasons for missing data across groups; The proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate. Selective reporting (reporting Low risk. The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes bias) that are of interest in the review have been reported in the pre-specified way. Summary Low risk Low risk of bias for all key domains.

Page 4 of 20 Table A2 Characteristics of the patients and events in patients with prior stroke or transient ischemic attack

Drug, trial Dabigatran Rivaroxaban Apixaban p-value* RE-LY22,29 ROCKET23,36 ARISTOTLE24,37 N=3623 N=7468 N=3436 Patients characteristics Age (years) 70.4 (mean) 71 (median) 70.1 (mean) - Male gender 2279 (63%) 4538 (61%) 2152 (63%) 0.1825

CHADS2 (mean or median) - 3 (median) 3.7 (mean) -

CHADS2 ≥3 3246 (90%) 7044 (94%) 3168 (92%) <0.0001

CHADS2 ≥2 3623 (100%) 7468 (100%) 3436 (100%) -

CHADS2 =1 0 0 0 - Congestive heart failure - 3785 (51%) 939 (27%) - Hypertension 2783 (77%) 6343 (85%) 2858 (83%) <0.0001 Age ≥75 years - - 1205 (35%) - Diabetes 816 (23%) 1806 (24%) 902 (26%) 0.0095 Prior myocardial infarction - 1131 (15%) 587 (17%) TTR prior stroke, median % (range) 63 (mean) 57 (43-70) 65 (51-76) TTR no prior stroke, median % (range) 65 (mean) 59 (44-71) 66 (53-77) p-value (TTR prior stroke versus no Not reported 0.041 0.022 prior stroke) Type of atrial fibrillation Permanent-persistent - 5924 (79%) - - Paroxysmal - 1437 (19%) - - Antithrombotic treatment at baseline VKA 2009 (55%) 4429 (59%) 2082 (61%) 0.0002 Acetylsalicylic acid 1444 (40%) 2808 (38%) 1067 (31%) <0.0001 Event rate in the control group N=1195 N=3714 N=1742 Total stroke or SEE 65 (5.44%) 187 (5.04%) 98 (5.63%) 0.9215 Ischemic stroke 41 (3.43%) 144 (3.88%) 68 (3.90%) 0.9678 Hemorrhagic stroke 18 (1.51%) 30 (0.81%) 31 (1.78%) 0.0289 Systemic embolism 6 (0.50%) 17 (0.46%) 2 (0.11%) 0.2615 Intracranial bleeding 30 (2.51%) 46 (1.24%) 41 (2.35%) 0.0099 Major bleeding 97 (8.12%) 183 (4.93%) 106 (6.08%) 0.0018 Death from any cause 107 (8.95%) 294 (7.92%) 150 (8.61%) 0.8065 Treatment discontinuation - - - - SEE = systemic embolic event; TTR = time in therapeutic range; VKA = vitamin K antagonist. *Chi-square test for categorical variables and one-way analysis of variance (ANOVA) for continuous variables

Page 5 of 20 Table A3 Sensitivity analyses depending on statistical model used and risk of bias

Outcome Base case: Sensitivity analysis 1: Sensitivity analysis 2: random effects model, fixed effects model, all random effects, studies all studies studies at low risk of bias*

Relative risk (95%CI) Relative risk (95%CI) Relative risk (95%CI) Non-hemorrhagic 0.93 (0.83 to 1.04) 0.93 (0.83 to 1.04) 0.94 (0.82 to 1.07) stroke and systemic embolic event Intracranial bleeding 0.46 (0.33 to 0.65) 0.46 (0.38 to 0.56) 0.53 (0.34 to 0.80)

All strokes and 0.82 (0.74 to 0.91) 0.82 (0.74 to 0.91) 0.84 (0.75 to 0.95) systemic embolic events Major bleeding 0.86 (0.70 to 1.05) 0.86 (0.80 to 0.93) 0.85 (0.59 to 1.22)

Deaths 0.91 (0.85 to 0.97) 0.91 (0.85 to 0.96) 0.91 (0.84 to 0.98)

*ROCKET-AF and ARISTOTLE

Page 6 of 20 Figure A1 Subgroup analyses for non-hemorrhagic stroke and systemic embolic events

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 3.1.1 PREVIOUS STROKE/TIA 01. RE-LY 101 2428 47 1195 10.2% 1.06 [0.75, 1.48] 02. ROCKET-AF 159 3754 161 3714 25.6% 0.98 [0.79, 1.21] 03. ARISTOTLE 63 1694 70 1742 10.6% 0.93 [0.66, 1.29] Subtotal (95% CI) 7876 6651 46.4% 0.98 [0.84, 1.15] Total events 323 278 Heterogeneity: Tau² = 0.00; Chi² = 0.31, df = 2 (P = 0.86); I² = 0% Test for overall effect: Z = 0.22 (P = 0.82)

3.1.2 NO PREVIOUS STROKE/TIA 01. RE-LY 193 9662 112 4827 22.2% 0.86 [0.68, 1.08] 02. ROCKET-AF 79 3377 92 3419 13.4% 0.87 [0.65, 1.17] 03. ARISTOTLE 112 7426 120 7339 18.0% 0.92 [0.71, 1.19] Subtotal (95% CI) 20465 15585 53.6% 0.88 [0.76, 1.02] Total events 384 324 Heterogeneity: Tau² = 0.00; Chi² = 0.17, df = 2 (P = 0.92); I² = 0% Test for overall effect: Z = 1.64 (P = 0.10)

Total (95% CI) 28341 22236 100.0% 0.93 [0.83, 1.03] Total events 707 602 Heterogeneity: Tau² = 0.00; Chi² = 1.39, df = 5 (P = 0.93); I² = 0% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 1.35 (P = 0.18) Favours experimental Favours control Test for subgroup differences: Chi² = 0.91, df = 1 (P = 0.34), I² = 0%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 5.1.1 TTR >65% 1.0 RE-LY 136 5954 62 2996 22.3% 1.10 [0.82, 1.49] 3. ARISTOTLE 70 4517 83 4539 20.1% 0.85 [0.62, 1.16] Subtotal (95% CI) 10471 7535 42.4% 0.97 [0.75, 1.26] Total events 206 145 Heterogeneity: Tau² = 0.01; Chi² = 1.43, df = 1 (P = 0.23); I² = 30% Test for overall effect: Z = 0.21 (P = 0.83)

5.1.2 TTR <65% 1.0 RE-LY 153 6056 95 3018 29.2% 0.80 [0.62, 1.03] 3. ARISTOTLE 101 4522 130 4518 28.4% 0.78 [0.60, 1.00] Subtotal (95% CI) 10578 7536 57.6% 0.79 [0.66, 0.95] Total events 254 225 Heterogeneity: Tau² = 0.00; Chi² = 0.03, df = 1 (P = 0.86); I² = 0% Test for overall effect: Z = 2.57 (P = 0.01)

Total (95% CI) 21049 15071 100.0% 0.86 [0.74, 1.01] Total events 460 370 Heterogeneity: Tau² = 0.00; Chi² = 3.62, df = 3 (P = 0.31); I² = 17% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 1.90 (P = 0.06) Favours experimental Favours control Test for subgroup differences: Chi² = 1.68, df = 1 (P = 0.19), I² = 40.5%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 4.1.1 CHADS =>2 02. ROCKET-AF 238 7130 251 7131 100.0% 0.95 [0.80, 1.13] Subtotal (95% CI) 7130 7131 100.0% 0.95 [0.80, 1.13] Total events 238 251 Heterogeneity: Not applicable Test for overall effect: Z = 0.60 (P = 0.55)

4.1.2 CHADS 0-1 02. ROCKET-AF 0 1 0 2 Not estimable Subtotal (95% CI) 1 2 Not estimable Total events 0 0 Heterogeneity: Not applicable Test for overall effect: Not applicable

Total (95% CI) 7131 7133 100.0% 0.95 [0.80, 1.13] Total events 238 251 Heterogeneity: Not applicable 0.5 0.7 1 1.5 2 Test for overall effect: Z = 0.60 (P = 0.55) Favours experimental Favours control Test for subgroup differences: Not applicable

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 1. RE-LY 150 MG BID 123 6076 159 6022 49.0% 0.77 [0.61, 0.97] 2. RELY 110 MG BID 171 6015 159 6022 51.0% 1.08 [0.87, 1.33]

Total (95% CI) 12091 12044 100.0% 0.91 [0.65, 1.27] Total events 294 318 Heterogeneity: Tau² = 0.04; Chi² = 4.45, df = 1 (P = 0.03); I² = 78% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 0.54 (P = 0.59) Favours experimental Favours control

Page 7 of 20 Figure A2 Subgroup analyses for intracranial bleeding

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 3.2.1 PREVIOUS STROKE/TIA 01. RE-LY 19 2428 30 1195 12.8% 0.31 [0.18, 0.55] 02. ROCKET-AF 34 3754 46 3714 18.1% 0.73 [0.47, 1.14] 03. ARISTOTLE 15 1694 41 1742 12.2% 0.38 [0.21, 0.68] Subtotal (95% CI) 7876 6651 43.1% 0.45 [0.26, 0.78] Total events 68 117 Heterogeneity: Tau² = 0.16; Chi² = 6.36, df = 2 (P = 0.04); I² = 69% Test for overall effect: Z = 2.84 (P = 0.004)

3.2.2 NO PREVIOUS STROKE/TIA 01. RE-LY 47 9662 60 4827 21.6% 0.39 [0.27, 0.57] 02. ROCKET-AF 21 3377 38 3419 14.2% 0.56 [0.33, 0.95] 03. ARISTOTLE 37 7426 81 7339 21.1% 0.45 [0.31, 0.67] Subtotal (95% CI) 20465 15585 56.9% 0.45 [0.35, 0.57] Total events 105 179 Heterogeneity: Tau² = 0.00; Chi² = 1.16, df = 2 (P = 0.56); I² = 0% Test for overall effect: Z = 6.56 (P < 0.00001)

Total (95% CI) 28341 22236 100.0% 0.46 [0.36, 0.58] Total events 173 296 Heterogeneity: Tau² = 0.03; Chi² = 7.71, df = 5 (P = 0.17); I² = 35% 0.2 0.5 1 2 5 Test for overall effect: Z = 6.41 (P < 0.00001) Favours experimental Favours control Test for subgroup differences: Chi² = 0.00, df = 1 (P = 0.96), I² = 0%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 5.2.1 TTR >65% 1.0 RE-LY 26 5954 43 2996 25.3% 0.30 [0.19, 0.49] 2. ROCKET-AF 11 1689 24 1839 17.4% 0.50 [0.25, 1.02] Subtotal (95% CI) 7643 4835 42.7% 0.36 [0.23, 0.58] Total events 37 67 Heterogeneity: Tau² = 0.03; Chi² = 1.27, df = 1 (P = 0.26); I² = 22% Test for overall effect: Z = 4.27 (P < 0.0001)

5.2.2 TTR <65% 1.0 RE-LY 40 6056 46 3018 28.0% 0.43 [0.28, 0.66] 2. ROCKET-AF 43 5252 60 5284 29.3% 0.72 [0.49, 1.06] Subtotal (95% CI) 11308 8302 57.3% 0.56 [0.34, 0.93] Total events 83 106 Heterogeneity: Tau² = 0.09; Chi² = 3.03, df = 1 (P = 0.08); I² = 67% Test for overall effect: Z = 2.26 (P = 0.02)

Total (95% CI) 18951 13137 100.0% 0.47 [0.32, 0.70] Total events 120 173 Heterogeneity: Tau² = 0.09; Chi² = 7.81, df = 3 (P = 0.05); I² = 62% 0.2 0.5 1 2 5 Test for overall effect: Z = 3.78 (P = 0.0002) Favours experimental Favours control Test for subgroup differences: Chi² = 1.58, df = 1 (P = 0.21), I² = 36.9%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 6.2.1 CHADS =>2 1.0 RE-LY 50 8174 70 4163 39.2% 0.36 [0.25, 0.52] 2. ROCKET-AF 55 7130 84 7131 0.0% 0.65 [0.47, 0.92] 3. ARISTOTLE 37 6020 89 5998 35.1% 0.41 [0.28, 0.61] Subtotal (95% CI) 14194 10161 74.3% 0.39 [0.30, 0.50] Total events 87 159 Heterogeneity: Tau² = 0.00; Chi² = 0.24, df = 1 (P = 0.63); I² = 0% Test for overall effect: Z = 7.10 (P < 0.00001)

6.2.2 CHADS 0-1 1.0 RE-LY 16 3916 20 1859 11.9% 0.38 [0.20, 0.73] 2. ROCKET-AF 0 1 0 2 Not estimable 3. ARISTOTLE 15 3100 33 3083 13.8% 0.45 [0.25, 0.83] Subtotal (95% CI) 7016 4942 25.7% 0.42 [0.27, 0.65] Total events 31 53 Heterogeneity: Tau² = 0.00; Chi² = 0.15, df = 1 (P = 0.70); I² = 0% Test for overall effect: Z = 3.85 (P = 0.0001)

Total (95% CI) 21210 15103 100.0% 0.39 [0.31, 0.49] Total events 118 212 Heterogeneity: Tau² = 0.00; Chi² = 0.46, df = 3 (P = 0.93); I² = 0% 0.2 0.5 1 2 5 Test for overall effect: Z = 8.07 (P < 0.00001) Favours experimental Favours control Test for subgroup differences: Chi² = 0.08, df = 1 (P = 0.78), I² = 0%

Page 8 of 20 NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 7.2.1 AGE =>75 01. RE-LY 37 4815 47 2423 54.6% 0.40 [0.26, 0.61] Subtotal (95% CI) 4815 2423 54.6% 0.40 [0.26, 0.61] Total events 37 47 Heterogeneity: Not applicable Test for overall effect: Z = 4.24 (P < 0.0001)

7.2.2 AGE <75 01. RE-LY 29 7276 43 3599 45.4% 0.33 [0.21, 0.53] Subtotal (95% CI) 7276 3599 45.4% 0.33 [0.21, 0.53] Total events 29 43 Heterogeneity: Not applicable Test for overall effect: Z = 4.59 (P < 0.00001)

Total (95% CI) 12091 6022 100.0% 0.37 [0.27, 0.50] Total events 66 90 Heterogeneity: Tau² = 0.00; Chi² = 0.28, df = 1 (P = 0.60); I² = 0% 0.2 0.5 1 2 5 Test for overall effect: Z = 6.22 (P < 0.00001) Favours experimental Favours control Test for subgroup differences: Chi² = 0.28, df = 1 (P = 0.60), I² = 0%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 13.2.1 VKA EXPERIENCED 01. RE-LY 36 6060 48 2929 54.1% 0.36 [0.24, 0.56] Subtotal (95% CI) 6060 2929 54.1% 0.36 [0.24, 0.56] Total events 36 48 Heterogeneity: Not applicable Test for overall effect: Z = 4.63 (P < 0.00001)

13.2.2 VKA NAIVE 01. RE-LY 30 6030 42 3093 45.9% 0.37 [0.23, 0.58] Subtotal (95% CI) 6030 3093 45.9% 0.37 [0.23, 0.58] Total events 30 42 Heterogeneity: Not applicable Test for overall effect: Z = 4.22 (P < 0.0001)

Total (95% CI) 12090 6022 100.0% 0.36 [0.27, 0.50] Total events 66 90 Heterogeneity: Tau² = 0.00; Chi² = 0.00, df = 1 (P = 0.97); I² = 0% 0.2 0.5 1 2 5 Test for overall effect: Z = 6.26 (P < 0.00001) Favours experimental Favours control Test for subgroup differences: Chi² = 0.00, df = 1 (P = 0.97), I² = 0%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 1. RE-LY 150 MG BID 39 6076 90 6022 54.4% 0.43 [0.30, 0.62] 2. RELY 110 MG BID 27 6015 90 6022 45.6% 0.30 [0.20, 0.46]

Total (95% CI) 12091 12044 100.0% 0.36 [0.26, 0.52] Total events 66 180 Heterogeneity: Tau² = 0.02; Chi² = 1.52, df = 1 (P = 0.22); I² = 34% 0.2 0.5 1 2 5 Test for overall effect: Z = 5.65 (P < 0.00001) Favours experimental Favours control

Page 9 of 20 Figure A3 Subgroup analyses for all strokes and systemic embolic events

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 6.3.1 EUROPE 01. RE-LY 109 4512 57 2258 10.5% 0.96 [0.70, 1.31] 02. ROCKET-AF 140 3747 157 3756 19.2% 0.89 [0.71, 1.12] 03. ARISTOTLE 75 3672 77 3671 10.6% 0.97 [0.71, 1.33] Subtotal (95% CI) 11931 9685 40.2% 0.93 [0.79, 1.09] Total events 324 291 Heterogeneity: Tau² = 0.00; Chi² = 0.23, df = 2 (P = 0.89); I² = 0% Test for overall effect: Z = 0.92 (P = 0.36)

6.3.2 REST OF THE WORLD 01. RE-LY 208 7579 145 3764 21.5% 0.71 [0.58, 0.88] 02. ROCKET-AF 129 3334 149 3334 18.2% 0.87 [0.69, 1.09] 03. ARISTOTLE 137 5448 188 5410 20.1% 0.72 [0.58, 0.90] Subtotal (95% CI) 16361 12508 59.8% 0.76 [0.67, 0.86] Total events 474 482 Heterogeneity: Tau² = 0.00; Chi² = 1.79, df = 2 (P = 0.41); I² = 0% Test for overall effect: Z = 4.29 (P < 0.0001)

Total (95% CI) 28292 22193 100.0% 0.82 [0.74, 0.92] Total events 798 773 Heterogeneity: Tau² = 0.00; Chi² = 5.87, df = 5 (P = 0.32); I² = 15% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 3.52 (P = 0.0004) Favours experimental Favours control Test for subgroup differences: Chi² = 3.85, df = 1 (P = 0.05), I² = 74.0%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 3.3.1 PREVIOUS STROKE/TIA 01. RE-LY 106 2428 65 1195 10.7% 0.80 [0.59, 1.08] 02. ROCKET-AF 179 3754 187 3714 24.2% 0.95 [0.78, 1.16] 03. ARISTOTLE 73 1694 98 1742 11.0% 0.77 [0.57, 1.03] Subtotal (95% CI) 7876 6651 45.9% 0.87 [0.75, 1.00] Total events 358 350 Heterogeneity: Tau² = 0.00; Chi² = 1.68, df = 2 (P = 0.43); I² = 0% Test for overall effect: Z = 1.95 (P = 0.05)

3.3.2 NO PREVIOUS STROKE/TIA 01. RE-LY 211 9662 137 4827 21.4% 0.77 [0.62, 0.95] 02. ROCKET-AF 90 3377 119 3419 13.3% 0.77 [0.58, 1.00] 03. ARISTOTLE 139 7426 167 7339 19.5% 0.82 [0.66, 1.03] Subtotal (95% CI) 20465 15585 54.1% 0.79 [0.69, 0.90] Total events 440 423 Heterogeneity: Tau² = 0.00; Chi² = 0.23, df = 2 (P = 0.89); I² = 0% Test for overall effect: Z = 3.51 (P = 0.0004)

Total (95% CI) 28341 22236 100.0% 0.82 [0.75, 0.91] Total events 798 773 Heterogeneity: Tau² = 0.00; Chi² = 2.81, df = 5 (P = 0.73); I² = 0% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 3.90 (P < 0.0001) Favours experimental Favours control Test for subgroup differences: Chi² = 0.90, df = 1 (P = 0.34), I² = 0%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 5.3.1 TTR >65% 01. RE-LY 145 5954 85 2996 15.4% 0.86 [0.66, 1.12] 02. ROCKET-AF 37 1676 55 1826 6.4% 0.73 [0.49, 1.11] 03. ARISTOTLE 87 4517 109 4529 13.9% 0.80 [0.61, 1.06] Subtotal (95% CI) 12147 9351 35.7% 0.81 [0.68, 0.97] Total events 269 249 Heterogeneity: Tau² = 0.00; Chi² = 0.42, df = 2 (P = 0.81); I² = 0% Test for overall effect: Z = 2.35 (P = 0.02)

5.3.2 TTR <65% 01. RE-LY 170 6056 116 3018 20.0% 0.73 [0.58, 0.92] 02. ROCKET-AF 152 5215 187 5254 24.3% 0.82 [0.66, 1.01] 03. ARISTOTLE 124 4522 156 4518 20.0% 0.79 [0.63, 1.00] Subtotal (95% CI) 15793 12790 64.3% 0.78 [0.69, 0.89] Total events 446 459 Heterogeneity: Tau² = 0.00; Chi² = 0.53, df = 2 (P = 0.77); I² = 0% Test for overall effect: Z = 3.71 (P = 0.0002)

Total (95% CI) 27940 22141 100.0% 0.79 [0.71, 0.88] Total events 715 708 Heterogeneity: Tau² = 0.00; Chi² = 1.06, df = 5 (P = 0.96); I² = 0% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 4.38 (P < 0.0001) Favours experimental Favours control Test for subgroup differences: Chi² = 0.11, df = 1 (P = 0.74), I² = 0%

Page 10 of 20 Figure A3 Subgroup analyses for all strokes and systemic embolic events (continued)

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 4.3.1 CHADS => 2 01. RE-LY 249 8174 162 4163 25.6% 0.78 [0.64, 0.95] 02. ROCKET-AF 269 7130 306 7131 37.5% 0.88 [0.75, 1.03] 03. ARISTOTLE 168 6020 214 5998 24.4% 0.78 [0.64, 0.95] Subtotal (95% CI) 21324 17292 87.5% 0.82 [0.74, 0.91] Total events 686 682 Heterogeneity: Tau² = 0.00; Chi² = 1.16, df = 2 (P = 0.56); I² = 0% Test for overall effect: Z = 3.64 (P = 0.0003)

4.3.2 CHADS 0-1 01. RE-LY 68 3916 40 1859 6.5% 0.81 [0.55, 1.19] 02. ROCKET-AF 0 1 0 2 Not estimable 03. ARISTOTLE 44 3100 51 3083 6.0% 0.86 [0.58, 1.28] Subtotal (95% CI) 7017 4944 12.5% 0.83 [0.63, 1.10] Total events 112 91 Heterogeneity: Tau² = 0.00; Chi² = 0.05, df = 1 (P = 0.83); I² = 0% Test for overall effect: Z = 1.30 (P = 0.19)

Total (95% CI) 28341 22236 100.0% 0.82 [0.75, 0.91] Total events 798 773 Heterogeneity: Tau² = 0.00; Chi² = 1.21, df = 4 (P = 0.88); I² = 0% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 3.87 (P = 0.0001) Favours experimental Favours control Test for subgroup differences: Chi² = 0.00, df = 1 (P = 0.94), I² = 0%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 7.3.1 AGE =>75 01. RE-LY 156 4815 101 2423 16.0% 0.78 [0.61, 0.99] 02. ROCKET-AF 125 3082 154 3082 18.2% 0.81 [0.64, 1.02] 03. ARISTOTLE 79 2850 109 2828 11.9% 0.72 [0.54, 0.96] Subtotal (95% CI) 10747 8333 46.1% 0.77 [0.67, 0.90] Total events 360 364 Heterogeneity: Tau² = 0.00; Chi² = 0.42, df = 2 (P = 0.81); I² = 0% Test for overall effect: Z = 3.45 (P = 0.0006)

7.3.2 AGE <75 01. RE-LY 161 7276 101 3599 16.0% 0.79 [0.62, 1.01] 02. ROCKET-AF 144 3999 152 4008 19.3% 0.95 [0.76, 1.19] 03. ARISTOTLE 133 6270 156 6253 18.5% 0.85 [0.68, 1.07] Subtotal (95% CI) 17545 13860 53.9% 0.86 [0.76, 0.99] Total events 438 409 Heterogeneity: Tau² = 0.00; Chi² = 1.24, df = 2 (P = 0.54); I² = 0% Test for overall effect: Z = 2.12 (P = 0.03)

Total (95% CI) 28292 22193 100.0% 0.82 [0.75, 0.91] Total events 798 773 Heterogeneity: Tau² = 0.00; Chi² = 2.85, df = 5 (P = 0.72); I² = 0% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 3.90 (P < 0.0001) Favours experimental Favours control Test for subgroup differences: Chi² = 1.19, df = 1 (P = 0.27), I² = 16.1%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 8.3.1 MALE 01. RE-LY 188 7705 114 3809 18.4% 0.82 [0.65, 1.03] 02. ROCKET-AF 143 4279 164 4287 19.9% 0.87 [0.70, 1.09] 03. ARISTOTLE 132 5886 160 5899 18.6% 0.83 [0.66, 1.04] Subtotal (95% CI) 17870 13995 56.9% 0.84 [0.74, 0.96] Total events 463 438 Heterogeneity: Tau² = 0.00; Chi² = 0.21, df = 2 (P = 0.90); I² = 0% Test for overall effect: Z = 2.64 (P = 0.008)

8.3.2 FEMALE 01. RE-LY 130 4385 88 2213 13.7% 0.75 [0.57, 0.97] 02. ROCKET-AF 126 2802 142 2803 17.6% 0.89 [0.70, 1.12] 03. ARISTOTLE 80 3234 105 3182 11.8% 0.75 [0.56, 1.00] Subtotal (95% CI) 10421 8198 43.1% 0.80 [0.69, 0.93] Total events 336 335 Heterogeneity: Tau² = 0.00; Chi² = 1.22, df = 2 (P = 0.54); I² = 0% Test for overall effect: Z = 2.89 (P = 0.004)

Total (95% CI) 28291 22193 100.0% 0.82 [0.75, 0.91] Total events 799 773 Heterogeneity: Tau² = 0.00; Chi² = 1.63, df = 5 (P = 0.90); I² = 0% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 3.89 (P = 0.0001) Favours experimental Favours control Test for subgroup differences: Chi² = 0.20, df = 1 (P = 0.65), I² = 0%

Page 11 of 20 Figure A3 Subgroup analyses for all strokes and systemic embolic events (continued)

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 9.3.1 DIABETES 02. ROCKET-AF 95 2851 114 2796 19.9% 0.82 [0.63, 1.07] 03. ARISTOTLE 57 2284 75 2263 12.3% 0.75 [0.54, 1.06] Subtotal (95% CI) 5135 5059 32.3% 0.79 [0.64, 0.98] Total events 152 189 Heterogeneity: Tau² = 0.00; Chi² = 0.14, df = 1 (P = 0.71); I² = 0% Test for overall effect: Z = 2.18 (P = 0.03)

9.3.2 NO DIABETES 02. ROCKET-AF 174 4230 192 4294 35.3% 0.92 [0.75, 1.12] 03. ARISTOTLE 155 6836 190 6818 32.4% 0.81 [0.66, 1.00] Subtotal (95% CI) 11066 11112 67.7% 0.87 [0.75, 1.00] Total events 329 382 Heterogeneity: Tau² = 0.00; Chi² = 0.69, df = 1 (P = 0.41); I² = 0% Test for overall effect: Z = 1.92 (P = 0.05)

Total (95% CI) 16201 16171 100.0% 0.84 [0.75, 0.95] Total events 481 571 Heterogeneity: Tau² = 0.00; Chi² = 1.31, df = 3 (P = 0.73); I² = 0% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 2.82 (P = 0.005) Favours experimental Favours control Test for subgroup differences: Chi² = 0.49, df = 1 (P = 0.48), I² = 0%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 10.3.1 HEART FAILURE AT RANDOMIZATION 01. RE-LY 128 3871 72 1922 12.0% 0.88 [0.66, 1.17] 02. ROCKET-AF 160 4438 172 4413 21.6% 0.92 [0.75, 1.14] 03. ARISTOTLE 70 3235 79 3216 9.5% 0.88 [0.64, 1.21] Subtotal (95% CI) 11544 9551 43.1% 0.90 [0.78, 1.05] Total events 358 323 Heterogeneity: Tau² = 0.00; Chi² = 0.10, df = 2 (P = 0.95); I² = 0% Test for overall effect: Z = 1.33 (P = 0.18)

10.3.2 NO HEART FAILURE AT RANDOMIZATION 01. RE-LY 196 8220 132 4100 20.4% 0.74 [0.60, 0.92] 02. ROCKET-AF 109 2642 134 2676 15.8% 0.82 [0.64, 1.05] 03. ARISTOTLE 142 5885 186 5865 20.8% 0.76 [0.61, 0.94] Subtotal (95% CI) 16747 12641 56.9% 0.77 [0.68, 0.88] Total events 447 452 Heterogeneity: Tau² = 0.00; Chi² = 0.42, df = 2 (P = 0.81); I² = 0% Test for overall effect: Z = 3.93 (P < 0.0001)

Total (95% CI) 28291 22192 100.0% 0.83 [0.75, 0.91] Total events 805 775 Heterogeneity: Tau² = 0.00; Chi² = 3.00, df = 5 (P = 0.70); I² = 0% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 3.84 (P = 0.0001) Favours experimental Favours control Test for subgroup differences: Chi² = 2.48, df = 1 (P = 0.12), I² = 59.6%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 11.3.1 CrCl <50 ml/min 01. RE-LY 83 2292 55 1051 8.8% 0.69 [0.50, 0.97] 02. ROCKET-AF 77 1490 86 1459 11.0% 0.88 [0.65, 1.18] 03. ARISTOTLE 54 1502 69 1515 8.1% 0.79 [0.56, 1.12] Subtotal (95% CI) 5284 4025 27.9% 0.79 [0.65, 0.95] Total events 214 210 Heterogeneity: Tau² = 0.00; Chi² = 1.07, df = 2 (P = 0.58); I² = 0% Test for overall effect: Z = 2.48 (P = 0.01)

11.3.2 CrCl =>50 ml/min 01. RE-LY 217 9272 141 4683 22.4% 0.78 [0.63, 0.96] 02. ROCKET-AF 191 5583 219 5622 27.0% 0.88 [0.73, 1.06] 03. ARISTOTLE 157 7578 195 7527 22.7% 0.80 [0.65, 0.98] Subtotal (95% CI) 22433 17832 72.1% 0.82 [0.73, 0.92] Total events 565 555 Heterogeneity: Tau² = 0.00; Chi² = 0.81, df = 2 (P = 0.67); I² = 0% Test for overall effect: Z = 3.32 (P = 0.0009)

Total (95% CI) 27717 21857 100.0% 0.81 [0.74, 0.90] Total events 779 765 Heterogeneity: Tau² = 0.00; Chi² = 2.00, df = 5 (P = 0.85); I² = 0% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 4.12 (P < 0.0001) Favours experimental Favours control Test for subgroup differences: Chi² = 0.12, df = 1 (P = 0.72), I² = 0%

Page 12 of 20 Figure A3 Subgroup analyses for all strokes and systemic embolic events (continued)

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 12.3.1 PERMANENT/PERSISTENT 01. RE-LY 232 8179 132 3985 22.1% 0.86 [0.69, 1.06] 02. ROCKET-AF 225 5754 255 5731 31.4% 0.88 [0.74, 1.05] 03. ARISTOTLE 191 7744 235 7668 27.4% 0.80 [0.67, 0.97] Subtotal (95% CI) 21677 17384 80.8% 0.85 [0.76, 0.95] Total events 648 622 Heterogeneity: Tau² = 0.00; Chi² = 0.46, df = 2 (P = 0.79); I² = 0% Test for overall effect: Z = 2.97 (P = 0.003)

12.3.2 PAROXSYSMAL 01. RE-LY 84 3907 71 2036 10.2% 0.62 [0.45, 0.84] 02. ROCKET-AF 42 1231 43 1259 5.7% 1.00 [0.66, 1.52] 03. ARISTOTLE 21 1374 30 1412 3.3% 0.72 [0.41, 1.25] Subtotal (95% CI) 6512 4707 19.2% 0.75 [0.55, 1.02] Total events 147 144 Heterogeneity: Tau² = 0.03; Chi² = 3.30, df = 2 (P = 0.19); I² = 39% Test for overall effect: Z = 1.86 (P = 0.06)

Total (95% CI) 28189 22091 100.0% 0.82 [0.74, 0.91] Total events 795 766 Heterogeneity: Tau² = 0.00; Chi² = 5.09, df = 5 (P = 0.41); I² = 2% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 3.81 (P = 0.0001) Favours experimental Favours control Test for subgroup differences: Chi² = 0.57, df = 1 (P = 0.45), I² = 0%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 13.3.1 VKA EXPERIENCED 01. RE-LY 167 6060 105 2929 16.8% 0.77 [0.60, 0.98] 02. ROCKET-AF 168 4413 175 4440 22.5% 0.97 [0.78, 1.19] 03. ARISTOTLE 102 5208 138 5193 15.1% 0.74 [0.57, 0.95] Subtotal (95% CI) 15681 12562 54.4% 0.83 [0.70, 0.98] Total events 437 418 Heterogeneity: Tau² = 0.01; Chi² = 3.28, df = 2 (P = 0.19); I² = 39% Test for overall effect: Z = 2.15 (P = 0.03)

13.3.2 VKA NAIVE 01. RE-LY 150 6030 97 3093 15.3% 0.79 [0.62, 1.02] 02. ROCKET-AF 101 2668 131 2650 15.0% 0.77 [0.59, 0.99] 03. ARISTOTLE 110 3912 127 3888 15.3% 0.86 [0.67, 1.11] Subtotal (95% CI) 12610 9631 45.6% 0.81 [0.70, 0.93] Total events 361 355 Heterogeneity: Tau² = 0.00; Chi² = 0.43, df = 2 (P = 0.80); I² = 0% Test for overall effect: Z = 2.90 (P = 0.004)

Total (95% CI) 28291 22193 100.0% 0.82 [0.74, 0.91] Total events 798 773 Heterogeneity: Tau² = 0.00; Chi² = 3.84, df = 5 (P = 0.57); I² = 0% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 3.92 (P < 0.0001) Favours experimental Favours control Test for subgroup differences: Chi² = 0.05, df = 1 (P = 0.81), I² = 0%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 14.3.1 ASPIRIN AT RANDOMIZATION 01. RE-LY 139 4756 92 2442 14.4% 0.78 [0.60, 1.00] 02. ROCKET-AF 105 2586 121 2619 14.8% 0.88 [0.68, 1.13] 03. ARISTOTLE 70 2859 94 2773 10.4% 0.72 [0.53, 0.98] Subtotal (95% CI) 10201 7834 39.6% 0.80 [0.68, 0.93] Total events 314 307 Heterogeneity: Tau² = 0.00; Chi² = 1.00, df = 2 (P = 0.61); I² = 0% Test for overall effect: Z = 2.84 (P = 0.005)

14.3.2 NO ASPIRIN AT RANDOMIZATION 01. RE-LY 178 7332 110 3575 17.6% 0.79 [0.62, 1.00] 02. ROCKET-AF 164 4545 185 4514 22.8% 0.88 [0.72, 1.08] 03. ARISTOTLE 142 6261 171 6308 20.0% 0.84 [0.67, 1.04] Subtotal (95% CI) 18138 14397 60.4% 0.84 [0.74, 0.95] Total events 484 466 Heterogeneity: Tau² = 0.00; Chi² = 0.47, df = 2 (P = 0.79); I² = 0% Test for overall effect: Z = 2.73 (P = 0.006)

Total (95% CI) 28339 22231 100.0% 0.82 [0.75, 0.91] Total events 798 773 Heterogeneity: Tau² = 0.00; Chi² = 1.71, df = 5 (P = 0.89); I² = 0% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 3.91 (P < 0.0001) Favours experimental Favours control Test for subgroup differences: Chi² = 0.24, df = 1 (P = 0.63), I² = 0%

Page 13 of 20 Figure A3 Subgroup analyses for all strokes and systemic embolic events (continued)

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 1. RE-LY 150 MG BID 134 6076 202 6022 49.0% 0.66 [0.53, 0.82] 2. RELY 110 MG BID 183 6015 202 6022 51.0% 0.91 [0.74, 1.10]

Total (95% CI) 12091 12044 100.0% 0.77 [0.57, 1.06] Total events 317 404 Heterogeneity: Tau² = 0.04; Chi² = 4.67, df = 1 (P = 0.03); I² = 79% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 1.59 (P = 0.11) Favours experimental Favours control

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 21.3.1 EUROPE 1.1. RE-LY 150 MG BID 47 2261 57 2258 20.6% 0.82 [0.56, 1.21] 1.2. RELY 110 MG BID 62 2251 57 2258 22.1% 1.09 [0.77, 1.56] Subtotal (95% CI) 4512 4516 42.7% 0.96 [0.73, 1.26] Total events 109 114 Heterogeneity: Tau² = 0.00; Chi² = 1.12, df = 1 (P = 0.29); I² = 11% Test for overall effect: Z = 0.32 (P = 0.75)

21.3.2 REST OF THE WORLD 1.1. RE-LY 150 MG BID 87 3815 145 3764 27.8% 0.59 [0.46, 0.77] 1.2. RELY 110 MG BID 121 3764 145 3764 29.5% 0.83 [0.66, 1.06] Subtotal (95% CI) 7579 7528 57.3% 0.71 [0.50, 0.99] Total events 208 290 Heterogeneity: Tau² = 0.04; Chi² = 3.63, df = 1 (P = 0.06); I² = 72% Test for overall effect: Z = 2.03 (P = 0.04)

Total (95% CI) 12091 12044 100.0% 0.80 [0.63, 1.03] Total events 317 404 Heterogeneity: Tau² = 0.04; Chi² = 8.08, df = 3 (P = 0.04); I² = 63% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 1.74 (P = 0.08) Favours experimental Favours control Test for subgroup differences: Chi² = 1.87, df = 1 (P = 0.17), I² = 46.6%

Page 14 of 20 Figure A4 Subgroup analyses for major bleeding

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 6.5.1 EUROPE 01. RE-LY 180 4512 104 2258 14.8% 0.87 [0.68, 1.10] 02. ROCKET-AF 137 3786 153 3796 15.2% 0.90 [0.72, 1.13] 03. ARISTOTLE 110 3672 135 3671 14.2% 0.81 [0.64, 1.04] Subtotal (95% CI) 11970 9725 44.2% 0.86 [0.75, 0.99] Total events 427 392 Heterogeneity: Tau² = 0.00; Chi² = 0.33, df = 2 (P = 0.85); I² = 0% Test for overall effect: Z = 2.15 (P = 0.03)

6.5.2 REST OF THE WORLD 01. RE-LY 561 7579 317 3764 19.8% 0.88 [0.77, 1.00] 02. ROCKET-AF 258 3325 233 3329 17.9% 1.11 [0.93, 1.31] 03. ARISTOTLE 217 5448 327 5410 18.1% 0.66 [0.56, 0.78] Subtotal (95% CI) 16352 12503 55.8% 0.86 [0.66, 1.13] Total events 1036 877 Heterogeneity: Tau² = 0.05; Chi² = 18.34, df = 2 (P = 0.0001); I² = 89% Test for overall effect: Z = 1.06 (P = 0.29)

Total (95% CI) 28322 22228 100.0% 0.86 [0.74, 1.00] Total events 1463 1269 Heterogeneity: Tau² = 0.02; Chi² = 18.67, df = 5 (P = 0.002); I² = 73% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 1.96 (P = 0.05) Favours experimental Favours control Test for subgroup differences: Chi² = 0.00, df = 1 (P = 0.99), I² = 0%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 3.15.1 PREVIOUS STROKE/TIA 1.0 RE-LY 167 2428 97 1195 14.3% 0.85 [0.67, 1.08] 2. ROCKET-AF 178 3754 183 3714 16.5% 0.96 [0.79, 1.18] 3. ARISTOTLE 77 1694 106 1742 12.0% 0.75 [0.56, 0.99] Subtotal (95% CI) 7876 6651 42.8% 0.87 [0.76, 1.00] Total events 422 386 Heterogeneity: Tau² = 0.00; Chi² = 2.10, df = 2 (P = 0.35); I² = 5% Test for overall effect: Z = 1.93 (P = 0.05)

3.15.2 NO PREVIOUS STROKE/TIA 1.0 RE-LY 574 9662 324 4827 20.7% 0.89 [0.78, 1.01] 2. ROCKET-AF 217 3377 203 3419 17.4% 1.08 [0.90, 1.30] 3. ARISTOTLE 250 7426 356 7339 19.1% 0.69 [0.59, 0.81] Subtotal (95% CI) 20465 15585 57.2% 0.87 [0.69, 1.10] Total events 1041 883 Heterogeneity: Tau² = 0.04; Chi² = 13.13, df = 2 (P = 0.001); I² = 85% Test for overall effect: Z = 1.18 (P = 0.24)

Total (95% CI) 28341 22236 100.0% 0.86 [0.75, 0.99] Total events 1463 1269 Heterogeneity: Tau² = 0.02; Chi² = 15.26, df = 5 (P = 0.009); I² = 67% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 2.11 (P = 0.03) Favours experimental Favours control Test for subgroup differences: Chi² = 0.00, df = 1 (P = 0.99), I² = 0%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 5.4.1 TTR >65% 01. RE-LY 387 5954 194 2996 17.4% 1.00 [0.85, 1.19] 02. ROCKET-AF 135 1689 115 1839 15.1% 1.28 [1.01, 1.62] 03. ARISTOTLE 201 4517 245 4529 16.9% 0.82 [0.69, 0.99] Subtotal (95% CI) 12160 9364 49.3% 1.01 [0.80, 1.27] Total events 723 554 Heterogeneity: Tau² = 0.03; Chi² = 8.35, df = 2 (P = 0.02); I² = 76% Test for overall effect: Z = 0.06 (P = 0.95)

5.4.2 TTR <65% 01. RE-LY 347 6056 225 3018 17.5% 0.77 [0.65, 0.90] 02. ROCKET-AF 249 5252 271 5284 17.3% 0.92 [0.78, 1.09] 03. ARISTOTLE 125 4522 217 4518 15.8% 0.58 [0.46, 0.71] Subtotal (95% CI) 15830 12820 50.7% 0.75 [0.58, 0.96] Total events 721 713 Heterogeneity: Tau² = 0.04; Chi² = 11.53, df = 2 (P = 0.003); I² = 83% Test for overall effect: Z = 2.27 (P = 0.02)

Total (95% CI) 27990 22184 100.0% 0.87 [0.72, 1.04] Total events 1444 1267 Heterogeneity: Tau² = 0.04; Chi² = 29.84, df = 5 (P < 0.0001); I² = 83% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 1.51 (P = 0.13) Favours experimental Favours control Test for subgroup differences: Chi² = 2.94, df = 1 (P = 0.09), I² = 66.0%

Page 15 of 20 Figure A4 Subgroup analyses for major bleeding (continued)

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 4.4.1 CHADS =>2 01. RE-LY 583 8174 316 4163 22.8% 0.94 [0.82, 1.07] 02. ROCKET-AF 395 7130 386 7131 22.6% 1.02 [0.89, 1.17] 03. ARISTOTLE 251 6020 336 5998 21.5% 0.74 [0.63, 0.87] Subtotal (95% CI) 21324 17292 66.9% 0.90 [0.75, 1.07] Total events 1229 1038 Heterogeneity: Tau² = 0.02; Chi² = 9.17, df = 2 (P = 0.01); I² = 78% Test for overall effect: Z = 1.19 (P = 0.23)

4.4.2 CHADS 0-1 01. RE-LY 158 3916 105 1859 17.5% 0.71 [0.56, 0.91] 02. ROCKET-AF 0 1 0 2 Not estimable 03. ARISTOTLE 76 3100 126 3083 15.6% 0.60 [0.45, 0.79] Subtotal (95% CI) 7017 4944 33.1% 0.66 [0.55, 0.80] Total events 234 231 Heterogeneity: Tau² = 0.00; Chi² = 0.86, df = 1 (P = 0.35); I² = 0% Test for overall effect: Z = 4.41 (P < 0.0001)

Total (95% CI) 28341 22236 100.0% 0.81 [0.68, 0.96] Total events 1463 1269 Heterogeneity: Tau² = 0.03; Chi² = 19.76, df = 4 (P = 0.0006); I² = 80% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 2.37 (P = 0.02) Favours experimental Favours control Test for subgroup differences: Chi² = 5.52, df = 1 (P = 0.02), I² = 81.9%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 7.5.1 AGE =>75 01. RE-LY 450 4815 206 2423 17.4% 1.10 [0.94, 1.29] 02. ROCKET-AF 203 2688 179 2702 16.4% 1.14 [0.94, 1.38] 03. ARISTOTLE 151 2850 224 2828 16.3% 0.67 [0.55, 0.82] Subtotal (95% CI) 10353 7953 50.0% 0.95 [0.69, 1.30] Total events 804 609 Heterogeneity: Tau² = 0.07; Chi² = 18.40, df = 2 (P = 0.0001); I² = 89% Test for overall effect: Z = 0.34 (P = 0.73)

7.5.2 AGE <75 01. RE-LY 291 7276 215 3599 17.0% 0.67 [0.56, 0.79] 02. ROCKET-AF 192 4423 207 4423 16.5% 0.93 [0.77, 1.12] 03. ARISTOTLE 176 6270 238 6253 16.5% 0.74 [0.61, 0.89] Subtotal (95% CI) 17969 14275 50.0% 0.77 [0.64, 0.93] Total events 659 660 Heterogeneity: Tau² = 0.02; Chi² = 6.33, df = 2 (P = 0.04); I² = 68% Test for overall effect: Z = 2.72 (P = 0.007)

Total (95% CI) 28322 22228 100.0% 0.85 [0.70, 1.04] Total events 1463 1269 Heterogeneity: Tau² = 0.05; Chi² = 34.78, df = 5 (P < 0.00001); I² = 86% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 1.57 (P = 0.12) Favours experimental Favours control Test for subgroup differences: Chi² = 1.20, df = 1 (P = 0.27), I² = 16.3%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 8.5.1 MALE 01. RE-LY 483 7705 273 3809 19.3% 0.87 [0.76, 1.01] 02. ROCKET-AF 260 4292 253 4299 17.9% 1.03 [0.87, 1.22] 03. ARISTOTLE 225 5886 294 5899 17.8% 0.77 [0.65, 0.91] Subtotal (95% CI) 17883 14007 55.0% 0.88 [0.75, 1.04] Total events 968 820 Heterogeneity: Tau² = 0.01; Chi² = 5.87, df = 2 (P = 0.05); I² = 66% Test for overall effect: Z = 1.53 (P = 0.13)

8.5.2 FEMALE 01. RE-LY 258 4385 148 2213 16.4% 0.88 [0.72, 1.07] 02. ROCKET-AF 135 2819 133 2826 14.5% 1.02 [0.81, 1.29] 03. ARISTOTLE 102 3234 168 3182 14.1% 0.60 [0.47, 0.76] Subtotal (95% CI) 10438 8221 45.0% 0.81 [0.61, 1.09] Total events 495 449 Heterogeneity: Tau² = 0.05; Chi² = 10.40, df = 2 (P = 0.006); I² = 81% Test for overall effect: Z = 1.37 (P = 0.17)

Total (95% CI) 28321 22228 100.0% 0.85 [0.74, 0.98] Total events 1463 1269 Heterogeneity: Tau² = 0.02; Chi² = 17.02, df = 5 (P = 0.004); I² = 71% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 2.22 (P = 0.03) Favours experimental Favours control Test for subgroup differences: Chi² = 0.23, df = 1 (P = 0.63), I² = 0%

Page 16 of 20 Figure A4 Subgroup analyses for major bleeding (continued)

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 9.5.1 DIABETES 02. ROCKET-AF 165 2869 169 2814 24.8% 0.96 [0.78, 1.18] 03. ARISTOTLE 112 2284 114 2263 23.2% 0.97 [0.75, 1.26] Subtotal (95% CI) 5153 5077 48.1% 0.96 [0.82, 1.13] Total events 277 283 Heterogeneity: Tau² = 0.00; Chi² = 0.01, df = 1 (P = 0.92); I² = 0% Test for overall effect: Z = 0.45 (P = 0.65)

9.5.2 NO DIABETES 02. ROCKET-AF 230 4242 217 4311 25.7% 1.08 [0.90, 1.29] 03. ARISTOTLE 215 6836 348 6818 26.2% 0.62 [0.52, 0.73] Subtotal (95% CI) 11078 11129 51.9% 0.81 [0.47, 1.41] Total events 445 565 Heterogeneity: Tau² = 0.15; Chi² = 19.85, df = 1 (P < 0.00001); I² = 95% Test for overall effect: Z = 0.74 (P = 0.46)

Total (95% CI) 16231 16206 100.0% 0.88 [0.67, 1.16] Total events 722 848 Heterogeneity: Tau² = 0.07; Chi² = 23.27, df = 3 (P < 0.0001); I² = 87% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 0.88 (P = 0.38) Favours experimental Favours control Test for subgroup differences: Chi² = 0.34, df = 1 (P = 0.56), I² = 0%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 10.5.1 HEART FAILURE AT RANDOMIZATION 01. RE-LY 200 3281 120 1623 15.3% 0.82 [0.66, 1.03] 02. ROCKET-AF 233 4457 233 4437 17.7% 1.00 [0.83, 1.19] 03. ARISTOTLE 87 3235 137 3216 13.0% 0.63 [0.48, 0.82] Subtotal (95% CI) 10973 9276 46.0% 0.82 [0.63, 1.05] Total events 520 490 Heterogeneity: Tau² = 0.04; Chi² = 8.01, df = 2 (P = 0.02); I² = 75% Test for overall effect: Z = 1.59 (P = 0.11)

10.5.2 NO HEART FAILURE AT RANDOMIZATION 01. RE-LY 540 8806 301 4397 20.0% 0.90 [0.78, 1.03] 02. ROCKET-AF 162 2653 153 2687 15.5% 1.07 [0.87, 1.33] 03. ARISTOTLE 240 5885 325 5865 18.5% 0.74 [0.63, 0.87] Subtotal (95% CI) 17344 12949 54.0% 0.88 [0.73, 1.07] Total events 942 779 Heterogeneity: Tau² = 0.02; Chi² = 7.89, df = 2 (P = 0.02); I² = 75% Test for overall effect: Z = 1.27 (P = 0.21)

Total (95% CI) 28317 22225 100.0% 0.85 [0.74, 0.98] Total events 1462 1269 Heterogeneity: Tau² = 0.02; Chi² = 15.96, df = 5 (P = 0.007); I² = 69% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 2.25 (P = 0.02) Favours experimental Favours control Test for subgroup differences: Chi² = 0.24, df = 1 (P = 0.63), I² = 0%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 11.5.1 CrCl <50 ml/min 01. RE-LY 243 2292 112 1051 16.3% 0.99 [0.81, 1.23] 02. ROCKET-AF 99 1502 100 1476 14.1% 0.97 [0.74, 1.27] 03. ARISTOTLE 73 1502 142 1515 13.9% 0.52 [0.39, 0.68] Subtotal (95% CI) 5296 4042 44.3% 0.80 [0.53, 1.20] Total events 415 354 Heterogeneity: Tau² = 0.11; Chi² = 15.59, df = 2 (P = 0.0004); I² = 87% Test for overall effect: Z = 1.09 (P = 0.27)

11.5.2 CrCl =>50 ml/min 01. RE-LY 473 9272 300 4683 19.0% 0.80 [0.69, 0.92] 02. ROCKET-AF 295 5601 286 5640 18.4% 1.04 [0.89, 1.22] 03. ARISTOTLE 253 7578 318 7527 18.2% 0.79 [0.67, 0.93] Subtotal (95% CI) 22451 17850 55.7% 0.87 [0.73, 1.03] Total events 1021 904 Heterogeneity: Tau² = 0.02; Chi² = 7.65, df = 2 (P = 0.02); I² = 74% Test for overall effect: Z = 1.62 (P = 0.11)

Total (95% CI) 27747 21892 100.0% 0.84 [0.71, 0.99] Total events 1436 1258 Heterogeneity: Tau² = 0.03; Chi² = 23.43, df = 5 (P = 0.0003); I² = 79% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 2.04 (P = 0.04) Favours experimental Favours control Test for subgroup differences: Chi² = 0.13, df = 1 (P = 0.72), I² = 0%

Page 17 of 20 Figure A4 Subgroup analyses for major bleeding (continued)

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 12.5.1 PERMANENT/PERSISTENT 01. RE-LY 480 8179 265 3985 21.1% 0.88 [0.76, 1.02] 02. ROCKET-AF 323 5771 315 5754 20.7% 1.02 [0.88, 1.19] 03. ARISTOTLE 283 7744 402 7668 20.9% 0.70 [0.60, 0.81] Subtotal (95% CI) 21694 17407 62.7% 0.86 [0.69, 1.06] Total events 1086 982 Heterogeneity: Tau² = 0.03; Chi² = 12.82, df = 2 (P = 0.002); I² = 84% Test for overall effect: Z = 1.40 (P = 0.16)

12.5.2 PAROXSYSMAL 01. RE-LY 263 3907 156 2036 18.0% 0.88 [0.73, 1.06] 02. ROCKET-AF 66 1242 65 1269 10.5% 1.04 [0.74, 1.45] 03. ARISTOTLE 44 1374 60 1412 8.8% 0.75 [0.51, 1.10] Subtotal (95% CI) 6523 4717 37.3% 0.89 [0.76, 1.03] Total events 373 281 Heterogeneity: Tau² = 0.00; Chi² = 1.56, df = 2 (P = 0.46); I² = 0% Test for overall effect: Z = 1.54 (P = 0.12)

Total (95% CI) 28217 22124 100.0% 0.87 [0.76, 1.00] Total events 1459 1263 Heterogeneity: Tau² = 0.02; Chi² = 14.54, df = 5 (P = 0.01); I² = 66% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 2.02 (P = 0.04) Favours experimental Favours control Test for subgroup differences: Chi² = 0.07, df = 1 (P = 0.79), I² = 0%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 13.5.1 VKA EXPERIENCED 01. RE-LY 375 6060 216 2929 18.1% 0.84 [0.71, 0.99] 02. ROCKET-AF 270 4431 249 4458 17.8% 1.09 [0.92, 1.29] 03. ARISTOTLE 185 5208 274 5193 16.9% 0.67 [0.56, 0.81] Subtotal (95% CI) 15699 12580 52.7% 0.85 [0.65, 1.11] Total events 830 739 Heterogeneity: Tau² = 0.05; Chi² = 14.79, df = 2 (P = 0.0006); I² = 86% Test for overall effect: Z = 1.17 (P = 0.24)

13.5.2 VKA NAIVE 01. RE-LY 366 6030 205 3093 17.8% 0.92 [0.78, 1.08] 02. ROCKET-AF 125 2680 137 2667 14.1% 0.91 [0.72, 1.15] 03. ARISTOTLE 142 3912 188 3888 15.3% 0.75 [0.61, 0.93] Subtotal (95% CI) 12622 9648 47.3% 0.86 [0.76, 0.98] Total events 633 530 Heterogeneity: Tau² = 0.00; Chi² = 2.31, df = 2 (P = 0.31); I² = 14% Test for overall effect: Z = 2.35 (P = 0.02)

Total (95% CI) 28321 22228 100.0% 0.86 [0.74, 0.98] Total events 1463 1269 Heterogeneity: Tau² = 0.02; Chi² = 17.10, df = 5 (P = 0.004); I² = 71% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 2.20 (P = 0.03) Favours experimental Favours control Test for subgroup differences: Chi² = 0.00, df = 1 (P = 0.95), I² = 0%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 14.5.1 ASPIRIN AT RANDOMIZATION 01. RE-LY 365 4756 207 2442 17.9% 0.91 [0.77, 1.07] 02. ROCKET-AF 171 2586 159 2619 15.4% 1.09 [0.88, 1.34] 03. ARISTOTLE 129 2859 164 2773 14.5% 0.76 [0.61, 0.96] Subtotal (95% CI) 10201 7834 47.8% 0.91 [0.76, 1.10] Total events 665 530 Heterogeneity: Tau² = 0.02; Chi² = 5.20, df = 2 (P = 0.07); I² = 62% Test for overall effect: Z = 0.98 (P = 0.33)

14.5.2 NO ASPIRIN AT RANDOMIZATION 01. RE-LY 381 7332 216 3575 18.0% 0.86 [0.73, 1.01] 02. ROCKET-AF 224 4545 227 4514 17.0% 0.98 [0.82, 1.17] 03. ARISTOTLE 198 6261 298 6308 17.2% 0.67 [0.56, 0.80] Subtotal (95% CI) 18138 14397 52.2% 0.83 [0.67, 1.02] Total events 803 741 Heterogeneity: Tau² = 0.03; Chi² = 9.17, df = 2 (P = 0.01); I² = 78% Test for overall effect: Z = 1.75 (P = 0.08)

Total (95% CI) 28339 22231 100.0% 0.87 [0.76, 0.99] Total events 1468 1271 Heterogeneity: Tau² = 0.02; Chi² = 16.15, df = 5 (P = 0.006); I² = 69% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 2.09 (P = 0.04) Favours experimental Favours control Test for subgroup differences: Chi² = 0.47, df = 1 (P = 0.49), I² = 0%

Page 18 of 20 Figure A4 Subgroup analyses for major bleeding (continued)

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 1. RE-LY 150 MG BID 399 6076 421 6022 51.0% 0.94 [0.82, 1.07] 2. RELY 110 MG BID 342 6015 421 6022 49.0% 0.81 [0.71, 0.93]

Total (95% CI) 12091 12044 100.0% 0.88 [0.76, 1.01] Total events 741 842 Heterogeneity: Tau² = 0.01; Chi² = 2.18, df = 1 (P = 0.14); I² = 54% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 1.85 (P = 0.06) Favours experimental Favours control

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 21.5.1 EUROPE 1.1. RE-LY 150 MG BID 98 2261 104 2258 12.5% 0.94 [0.72, 1.23] 1.2. RELY 110 MG BID 82 2251 104 2258 11.3% 0.79 [0.60, 1.05] Subtotal (95% CI) 4512 4516 23.8% 0.87 [0.71, 1.05] Total events 180 208 Heterogeneity: Tau² = 0.00; Chi² = 0.76, df = 1 (P = 0.38); I² = 0% Test for overall effect: Z = 1.44 (P = 0.15)

21.5.2 REST OF THE WORLD 1.1. RE-LY 150 MG BID 301 3815 317 3764 39.7% 0.94 [0.81, 1.09] 1.2. RELY 110 MG BID 260 3764 317 3764 36.5% 0.82 [0.70, 0.96] Subtotal (95% CI) 7579 7528 76.2% 0.88 [0.77, 1.00] Total events 561 634 Heterogeneity: Tau² = 0.00; Chi² = 1.42, df = 1 (P = 0.23); I² = 30% Test for overall effect: Z = 1.95 (P = 0.05)

Total (95% CI) 12091 12044 100.0% 0.88 [0.80, 0.96] Total events 741 842 Heterogeneity: Tau² = 0.00; Chi² = 2.20, df = 3 (P = 0.53); I² = 0% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 2.72 (P = 0.006) Favours experimental Favours control Test for subgroup differences: Chi² = 0.01, df = 1 (P = 0.91), I² = 0%

Page 19 of 20 Figure A5 Subgroup analyses for deaths

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 3.8.1 PREVIOUS STROKE/TIA 01. RE-LY 185 2428 107 1195 7.3% 0.85 [0.68, 1.07] 02. ROCKET-AF 288 3754 294 3714 15.6% 0.97 [0.83, 1.13] 03. ARISTOTLE 129 1694 150 1742 7.5% 0.88 [0.71, 1.11] Subtotal (95% CI) 7876 6651 30.3% 0.92 [0.82, 1.03] Total events 602 551 Heterogeneity: Tau² = 0.00; Chi² = 1.00, df = 2 (P = 0.61); I² = 0% Test for overall effect: Z = 1.49 (P = 0.14)

3.8.2 NO PREVIOUS STROKE/TIA 01. RE-LY 699 9662 380 4827 26.3% 0.92 [0.82, 1.04] 02. ROCKET-AF 294 3377 338 3419 17.1% 0.88 [0.76, 1.02] 03. ARISTOTLE 474 7426 519 7339 26.2% 0.90 [0.80, 1.02] Subtotal (95% CI) 20465 15585 69.7% 0.90 [0.84, 0.97] Total events 1467 1237 Heterogeneity: Tau² = 0.00; Chi² = 0.19, df = 2 (P = 0.91); I² = 0% Test for overall effect: Z = 2.70 (P = 0.007)

Total (95% CI) 28341 22236 100.0% 0.91 [0.85, 0.97] Total events 2069 1788 Heterogeneity: Tau² = 0.00; Chi² = 1.24, df = 5 (P = 0.94); I² = 0% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 3.08 (P = 0.002) Favours experimental Favours control Test for subgroup differences: Chi² = 0.06, df = 1 (P = 0.81), I² = 0%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 5.6.1 TTR >65% 01. RE-LY 407 5954 201 2996 22.3% 1.02 [0.87, 1.20] 03. ARISTOTLE 280 4517 301 4529 23.5% 0.93 [0.80, 1.09] Subtotal (95% CI) 10471 7525 45.8% 0.97 [0.87, 1.09] Total events 687 502 Heterogeneity: Tau² = 0.00; Chi² = 0.58, df = 1 (P = 0.44); I² = 0% Test for overall effect: Z = 0.47 (P = 0.64)

5.6.2 TTR <65% 01. RE-LY 468 6056 284 3018 27.5% 0.82 [0.71, 0.95] 03. ARISTOTLE 321 4522 368 4518 26.7% 0.87 [0.75, 1.01] Subtotal (95% CI) 10578 7536 54.2% 0.85 [0.76, 0.93] Total events 789 652 Heterogeneity: Tau² = 0.00; Chi² = 0.33, df = 1 (P = 0.56); I² = 0% Test for overall effect: Z = 3.27 (P = 0.001)

Total (95% CI) 21049 15061 100.0% 0.90 [0.82, 0.99] Total events 1476 1154 Heterogeneity: Tau² = 0.00; Chi² = 4.24, df = 3 (P = 0.24); I² = 29% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 2.25 (P = 0.02) Favours experimental Favours control Test for subgroup differences: Chi² = 3.32, df = 1 (P = 0.07), I² = 69.9%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 4.6.1 CHADS =>2 01. RE-LY 714 8174 389 4163 27.3% 0.93 [0.83, 1.05] 02. ROCKET-AF 582 7130 632 7131 32.6% 0.92 [0.83, 1.03] 03. ARISTOTLE 465 6020 527 5998 26.5% 0.88 [0.78, 0.99] Subtotal (95% CI) 21324 17292 86.4% 0.91 [0.85, 0.97] Total events 1761 1548 Heterogeneity: Tau² = 0.00; Chi² = 0.56, df = 2 (P = 0.75); I² = 0% Test for overall effect: Z = 2.72 (P = 0.007)

4.6.2 CHADS 0-1 01. RE-LY 170 3916 98 1859 6.4% 0.82 [0.65, 1.05] 02. ROCKET-AF 0 1 0 2 Not estimable 03. ARISTOTLE 138 3100 142 3083 7.2% 0.97 [0.77, 1.22] Subtotal (95% CI) 7017 4944 13.6% 0.90 [0.76, 1.06] Total events 308 240 Heterogeneity: Tau² = 0.00; Chi² = 0.89, df = 1 (P = 0.35); I² = 0% Test for overall effect: Z = 1.29 (P = 0.20)

Total (95% CI) 28341 22236 100.0% 0.91 [0.86, 0.97] Total events 2069 1788 Heterogeneity: Tau² = 0.00; Chi² = 1.49, df = 4 (P = 0.83); I² = 0% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 3.01 (P = 0.003) Favours experimental Favours control Test for subgroup differences: Chi² = 0.04, df = 1 (P = 0.85), I² = 0%

NEW ANTICOAGULANT WARFARIN Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI 1. RE-LY 150 MG BID 438 6076 487 6022 49.7% 0.89 [0.79, 1.01] 2. RELY 110 MG BID 446 6015 487 6022 50.3% 0.92 [0.81, 1.04]

Total (95% CI) 12091 12044 100.0% 0.90 [0.83, 0.99] Total events 884 974 Heterogeneity: Tau² = 0.00; Chi² = 0.10, df = 1 (P = 0.75); I² = 0% 0.5 0.7 1 1.5 2 Test for overall effect: Z = 2.26 (P = 0.02) Favours experimental Favours control

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