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
RE-LY
Random sequence generation
(selection bias)
Allocation concealment
(selection bias)
Blinding of participants and
personnel (performance bias)
Judgement
Low risk.
Quote: “all trial participants were randomly assigned”.
Low risk.
Quote: “central, interactive, automated telephone system”.
Unclear
risk.
Blinding of outcome
assessment (detection bias)
Unclear
risk.
Incomplete outcome data
addressed (attrition bias)
Unclear
risk.
Selective reporting (reporting
bias)
Unclear
risk.
Summary
Unclear
risk
ROCKET-AF
Random sequence generation
(selection bias)
Allocation concealment
(selection bias)
Support for judgement
Quote: “multicenter, prospective, open-label, randomized trial, with blinded adjudication of all
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].
Quote: “The outcome events including strokes, non-central nervous system systemic emboli, deaths,
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.
Insufficient reporting of attrition/exclusions to permit judgement of ‘Low risk’ or ‘High risk’. There
were higher withdrawal rates in patients on dabigatran and “as-treated” analysis is not publicly
available.
The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes
that are of interest in the review have been reported in the pre-specified way. However, in an openlabel 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].
Unclear risk of bias for one or more key domains.
Low risk.
Quote: “patients were randomly allocated.”
Low risk.
Quote: “To effect concealment of randomization, treatment allocation is randomized using a blinded,
central telephonic Interactive Voice Response System”
Blinding of participants and
personnel (performance bias)
Low risk.
Blinding of outcome
assessment (detection bias)
Low risk.
Incomplete outcome data
addressed (attrition bias)
Low risk.
Selective reporting (reporting
bias)
Summary
ARISTOTLE
Random sequence generation
(selection bias)
Allocation concealment
(selection bias)
Blinding of participants and
personnel (performance bias)
Blinding of outcome
assessment (detection bias)
Low risk.
Low risk
Quote: “A double-blind design was chosen to minimize bias in cointerventions and interpretation of
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”.
Quote: “The independent blinded clinical end-point committee…applied protocol definitions to
adjudicate all suspected cases of stroke, systemic embolism, myocardial infarction, death, and bleeding
events that contributed to the prespecified end points”
Reasons for missing outcome data unlikely to be related to true outcome; Missing outcome data
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.
The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes
that are of interest in the review have been reported in the pre-specified way;
Low risk of bias for all key domains.
Low risk.
Quote: “patients were randomly assigned.”
Low risk.
Quote: “central response system.”
Low risk.
Incomplete outcome data
addressed (attrition bias)
Low risk.
Selective reporting (reporting
bias)
Summary
Low risk.
Quote: “double-blind”. To maintain blinding, study medications are packaged using a double-dummy
design. INRs were monitored with the use of a blinded, encrypted, point-of-care INR device”.
Quote: “The primary and secondary efficacy and safety outcomes were adjudicated on the basis of
prespecified criteria by a clinical-events committee whose members were not aware of study-group
assignments”.
Reasons for missing outcome data unlikely to be related to true outcome; Missing outcome data
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.
The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes
that are of interest in the review have been reported in the pre-specified way.
Low risk of bias for all key domains.
Low risk.
Low risk
Page 4 of 20
Table A2 Characteristics of the patients and events in patients with prior stroke or
transient ischemic attack
Drug, trial
Dabigatran
RE-LY22,29
N=3623
Rivaroxaban
ROCKET23,36
N=7468
Apixaban
ARISTOTLE24,37
N=3436
p-value*
70.4 (mean)
71 (median)
70.1 (mean)
-
2279 (63%)
-
4538 (61%)
3 (median)
2152 (63%)
3.7 (mean)
0.1825
-
CHADS2 ≥3
3246 (90%)
7044 (94%)
3168 (92%)
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%)
Age ≥75 years
1205 (35%)
Diabetes
816 (23%)
1806 (24%)
902 (26%)
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%)
Acetylsalicylic acid
1444 (40%)
2808 (38%)
1067 (31%)
N=1195
N=3714
N=1742
Event rate in the control group
Total stroke or SEE
65 (5.44%)
187 (5.04%)
98 (5.63%)
Ischemic stroke
41 (3.43%)
144 (3.88%)
68 (3.90%)
Hemorrhagic stroke
18 (1.51%)
30 (0.81%)
31 (1.78%)
Systemic embolism
6 (0.50%)
17 (0.46%)
2 (0.11%)
Intracranial bleeding
30 (2.51%)
46 (1.24%)
41 (2.35%)
Major bleeding
97 (8.12%)
183 (4.93%)
106 (6.08%)
Death from any cause
107 (8.95%)
294 (7.92%)
150 (8.61%)
Treatment discontinuation
SEE = systemic embolic event; TTR = time in therapeutic range; VKA = vitamin K antagonist.
<0.0001
<0.0001
0.0095
Patients characteristics
Age (years)
Male gender
CHADS2 (mean or median)
0.0002
<0.0001
0.9215
0.9678
0.0289
0.2615
0.0099
0.0018
0.8065
-
*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:
random effects model,
all studies
Sensitivity analysis 1:
fixed effects model, all
studies
Sensitivity analysis 2:
random effects, studies
at low risk of bias*
Relative risk (95%CI)
Relative risk (95%CI)
Relative risk (95%CI)
Non-hemorrhagic
stroke and systemic
embolic event
Intracranial bleeding
0.93 (0.83 to 1.04)
0.93 (0.83 to 1.04)
0.94 (0.82 to 1.07)
0.46 (0.33 to 0.65)
0.46 (0.38 to 0.56)
0.53 (0.34 to 0.80)
All strokes and
systemic embolic
events
Major bleeding
0.82 (0.74 to 0.91)
0.82 (0.74 to 0.91)
0.84 (0.75 to 0.95)
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
Study or Subgroup
Events
Total
WARFARIN
Risk Ratio
Events
Total
Weight
Risk Ratio
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]
63
1694
70
1742
10.6%
0.93 [0.66, 1.29]
6651
46.4%
0.98 [0.84, 1.15]
03. ARISTOTLE
Subtotal (95% CI)
7876
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
02. ROCKET-AF
03. ARISTOTLE
193
9662
112
4827
22.2%
0.86 [0.68, 1.08]
79
3377
92
3419
13.4%
0.87 [0.65, 1.17]
112
7426
120
7339
18.0%
0.92 [0.71, 1.19]
15585
53.6%
0.88 [0.76, 1.02]
100.0%
0.93 [0.83, 1.03]
Subtotal (95% CI)
20465
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
Total events
707
22236
602
Heterogeneity: Tau² = 0.00; Chi² = 1.39, df = 5 (P = 0.93); I² = 0%
0.5
Test for overall effect: Z = 1.35 (P = 0.18)
0.7
1
Favours experimental
1.5
2
Favours control
Test for subgroup differences: Chi² = 0.91, df = 1 (P = 0.34), I² = 0%
NEW ANTICOAGULANT
WARFARIN
Study or Subgroup
Events
Total Events Total Weight
5.1.1 TTR >65%
1.0 RE-LY
136
5954
62 2996 22.3%
3. ARISTOTLE
70
4517
83 4539 20.1%
Subtotal (95% CI)
10471
7535
42.4%
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
3. ARISTOTLE
101
4522
130 4518
Subtotal (95% CI)
10578
7536
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)
Risk Ratio
M-H, Random, 95% CI
1.10 [0.82, 1.49]
0.85 [0.62, 1.16]
0.97 [0.75, 1.26]
29.2%
28.4%
57.6%
0.80 [0.62, 1.03]
0.78 [0.60, 1.00]
0.79 [0.66, 0.95]
Total (95% CI)
21049
15071 100.0%
Total events
460
370
Heterogeneity: Tau² = 0.00; Chi² = 3.62, df = 3 (P = 0.31); I² = 17%
Test for overall effect: Z = 1.90 (P = 0.06)
Test for subgroup differences: Chi² = 1.68, df = 1 (P = 0.19), I² = 40.5%
0.86 [0.74, 1.01]
NEW ANTICOAGULANT
Study or Subgroup
Events
0.5
0.7
1
1.5
2
Favours experimental Favours control
WARFARIN
Total
Events
7130
251
Risk Ratio
M-H, Random, 95% CI
Risk Ratio
Risk Ratio
Total
Weight
M-H, Random, 95% CI
7131
100.0%
0.95 [0.80, 1.13]
7131
100.0%
0.95 [0.80, 1.13]
M-H, Random, 95% CI
4.1.1 CHADS =>2
02. ROCKET-AF
238
Subtotal (95% CI)
7130
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
Subtotal (95% CI)
1
0
1
Total events
0
2
Not estimable
2
Not estimable
0
Heterogeneity: Not applicable
Test for overall effect: Not applicable
Total (95% CI)
7131
Total events
238
7133
100.0%
0.95 [0.80, 1.13]
251
Heterogeneity: Not applicable
0.5
Test for overall effect: Z = 0.60 (P = 0.55)
0.7
1
Favours experimental
1.5
2
Favours control
Test for subgroup differences: Not applicable
NEW ANTICOAGULANT
Study or Subgroup
WARFARIN
Risk Ratio
Risk Ratio
Events
Total
Events
Total
Weight
1. RE-LY 150 MG BID
123
6076
159
6022
49.0%
2. RELY 110 MG BID
171
6015
159
6022
51.0%
1.08 [0.87, 1.33]
12044
100.0%
0.91 [0.65, 1.27]
Total (95% CI)
Total events
12091
294
M-H, Random, 95% CI
M-H, Random, 95% CI
0.77 [0.61, 0.97]
318
Heterogeneity: Tau² = 0.04; Chi² = 4.45, df = 1 (P = 0.03); I² = 78%
0.5
Test for overall effect: Z = 0.54 (P = 0.59)
0.7
Favours experimental
Page 7 of 20
1
1.5
2
Favours control
Figure A2 Subgroup analyses for intracranial bleeding
NEW ANTICOAGULANT
Study or Subgroup
Events
WARFARIN
Risk Ratio
Total
Events
Total
Weight
Risk Ratio
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%
02. ROCKET-AF
34
3754
46
3714
18.1%
03. ARISTOTLE
15
1694
41
1742
12.2%
0.38 [0.21, 0.68]
6651
43.1%
0.45 [0.26, 0.78]
Subtotal (95% CI)
Total events
7876
68
0.31 [0.18, 0.55]
0.73 [0.47, 1.14]
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]
15585
56.9%
0.45 [0.35, 0.57]
100.0%
0.46 [0.36, 0.58]
Subtotal (95% CI)
Total events
20465
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)
Total events
28341
173
22236
296
Heterogeneity: Tau² = 0.03; Chi² = 7.71, df = 5 (P = 0.17); I² = 35%
0.2
Test for overall effect: Z = 6.41 (P < 0.00001)
0.5
Favours experimental
1
2
Favours control
Test for subgroup differences: Chi² = 0.00, df = 1 (P = 0.96), I² = 0%
NEW ANTICOAGULANT
WARFARIN
Study or Subgroup
Events
Total Events Total Weight
5.2.1 TTR >65%
1.0 RE-LY
26
5954
43 2996 25.3%
2. ROCKET-AF
11
1689
24 1839 17.4%
Subtotal (95% CI)
7643
4835
42.7%
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
2. ROCKET-AF
43
5252
60 5284
Subtotal (95% CI)
11308
8302
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)
Risk Ratio
M-H, Random, 95% CI
0.30 [0.19, 0.49]
0.50 [0.25, 1.02]
0.36 [0.23, 0.58]
28.0%
29.3%
57.3%
0.43 [0.28, 0.66]
0.72 [0.49, 1.06]
0.56 [0.34, 0.93]
Total (95% CI)
18951
13137 100.0%
Total events
120
173
Heterogeneity: Tau² = 0.09; Chi² = 7.81, df = 3 (P = 0.05); I² = 62%
Test for overall effect: Z = 3.78 (P = 0.0002)
Test for subgroup differences: Chi² = 1.58, df = 1 (P = 0.21), I² = 36.9%
0.47 [0.32, 0.70]
NEW ANTICOAGULANT
WARFARIN
Study or Subgroup
Events
Total Events Total Weight
6.2.1 CHADS =>2
1.0 RE-LY
50
8174
70 4163 39.2%
2. ROCKET-AF
55
7130
84 7131
0.0%
3. ARISTOTLE
37
6020
89 5998 35.1%
Subtotal (95% CI)
14194
10161
74.3%
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
2. ROCKET-AF
0
1
0
2
3. ARISTOTLE
15
3100
33 3083
Subtotal (95% CI)
7016
4942
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)
Risk Ratio
M-H, Random, 95% CI
0.2
0.5
1
2
5
Favours experimental Favours control
Risk Ratio
M-H, Random, 95% CI
11.9%
13.8%
25.7%
Total (95% CI)
21210
15103 100.0%
Total events
118
212
Heterogeneity: Tau² = 0.00; Chi² = 0.46, df = 3 (P = 0.93); I² = 0%
Test for overall effect: Z = 8.07 (P < 0.00001)
Test for subgroup differences: Chi² = 0.08, df = 1 (P = 0.78), I² = 0%
Page 8 of 20
Risk Ratio
M-H, Random, 95% CI
0.36 [0.25, 0.52]
0.65 [0.47, 0.92]
0.41 [0.28, 0.61]
0.39 [0.30, 0.50]
0.38 [0.20, 0.73]
Not estimable
0.45 [0.25, 0.83]
0.42 [0.27, 0.65]
0.39 [0.31, 0.49]
0.2
0.5
1
2
5
Favours experimental Favours control
5
NEW ANTICOAGULANT
Study or Subgroup
Events
WARFARIN
Total
Events
4815
47
Risk Ratio
Total
Weight
Risk Ratio
M-H, Random, 95% CI
M-H, Random, 95% CI
7.2.1 AGE =>75
01. RE-LY
37
Subtotal (95% CI)
4815
Total events
37
2423
54.6%
0.40 [0.26, 0.61]
2423
54.6%
0.40 [0.26, 0.61]
47
Heterogeneity: Not applicable
Test for overall effect: Z = 4.24 (P < 0.0001)
7.2.2 AGE <75
01. RE-LY
29
7276
Subtotal (95% CI)
43
7276
Total events
29
3599
45.4%
0.33 [0.21, 0.53]
3599
45.4%
0.33 [0.21, 0.53]
6022
100.0%
0.37 [0.27, 0.50]
43
Heterogeneity: Not applicable
Test for overall effect: Z = 4.59 (P < 0.00001)
Total (95% CI)
12091
Total events
66
90
Heterogeneity: Tau² = 0.00; Chi² = 0.28, df = 1 (P = 0.60); I² = 0%
0.2
Test for overall effect: Z = 6.22 (P < 0.00001)
0.5
1
Favours experimental
2
5
Favours control
Test for subgroup differences: Chi² = 0.28, df = 1 (P = 0.60), I² = 0%
NEW ANTICOAGULANT
Study or Subgroup
Events
WARFARIN
Total
Events
6060
48
Risk Ratio
Total
Weight
Risk Ratio
M-H, Random, 95% CI
M-H, Random, 95% CI
13.2.1 VKA EXPERIENCED
01. RE-LY
36
Subtotal (95% CI)
6060
Total events
36
2929
54.1%
0.36 [0.24, 0.56]
2929
54.1%
0.36 [0.24, 0.56]
48
Heterogeneity: Not applicable
Test for overall effect: Z = 4.63 (P < 0.00001)
13.2.2 VKA NAIVE
01. RE-LY
30
6030
Subtotal (95% CI)
42
6030
Total events
30
3093
45.9%
0.37 [0.23, 0.58]
3093
45.9%
0.37 [0.23, 0.58]
6022
100.0%
0.36 [0.27, 0.50]
42
Heterogeneity: Not applicable
Test for overall effect: Z = 4.22 (P < 0.0001)
Total (95% CI)
Total events
12090
66
90
Heterogeneity: Tau² = 0.00; Chi² = 0.00, df = 1 (P = 0.97); I² = 0%
0.2
Test for overall effect: Z = 6.26 (P < 0.00001)
0.5
1
Favours experimental
2
5
Favours control
Test for subgroup differences: Chi² = 0.00, df = 1 (P = 0.97), I² = 0%
NEW ANTICOAGULANT
Study or Subgroup
WARFARIN
Risk Ratio
Risk Ratio
Events
Total
Events
Total
Weight
1. RE-LY 150 MG BID
39
6076
90
6022
54.4%
2. RELY 110 MG BID
27
6015
90
6022
45.6%
0.30 [0.20, 0.46]
12044
100.0%
0.36 [0.26, 0.52]
Total (95% CI)
Total events
12091
66
M-H, Random, 95% CI
M-H, Random, 95% CI
0.43 [0.30, 0.62]
180
Heterogeneity: Tau² = 0.02; Chi² = 1.52, df = 1 (P = 0.22); I² = 34%
0.2
Test for overall effect: Z = 5.65 (P < 0.00001)
0.5
Favours experimental
Page 9 of 20
1
2
5
Favours control
Figure A3 Subgroup analyses for all strokes and systemic embolic events
NEW ANTICOAGULANT
Study or Subgroup
Events
Total
01. RE-LY
109
02. ROCKET-AF
140
75
WARFARIN
Risk Ratio
Risk Ratio
Events
Total
Weight
M-H, Random, 95% CI
4512
57
2258
10.5%
0.96 [0.70, 1.31]
3747
157
3756
19.2%
0.89 [0.71, 1.12]
3672
77
3671
10.6%
0.97 [0.71, 1.33]
9685
40.2%
0.93 [0.79, 1.09]
M-H, Random, 95% CI
6.3.1 EUROPE
03. ARISTOTLE
Subtotal (95% CI)
11931
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]
12508
59.8%
0.76 [0.67, 0.86]
100.0%
0.82 [0.74, 0.92]
Subtotal (95% CI)
16361
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
Total events
798
22193
773
Heterogeneity: Tau² = 0.00; Chi² = 5.87, df = 5 (P = 0.32); I² = 15%
0.5
Test for overall effect: Z = 3.52 (P = 0.0004)
0.7
1
Favours experimental
1.5
2
Favours control
Test for subgroup differences: Chi² = 3.85, df = 1 (P = 0.05), I² = 74.0%
NEW ANTICOAGULANT
Study or Subgroup
Events
Total
WARFARIN
Risk Ratio
Events
Total
Weight
Risk Ratio
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%
02. ROCKET-AF
179
3754
187
3714
24.2%
1694
98
1742
11.0%
0.77 [0.57, 1.03]
6651
45.9%
0.87 [0.75, 1.00]
03. ARISTOTLE
73
Subtotal (95% CI)
Total events
7876
358
0.80 [0.59, 1.08]
0.95 [0.78, 1.16]
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
02. ROCKET-AF
03. ARISTOTLE
211
9662
137
4827
21.4%
0.77 [0.62, 0.95]
90
3377
119
3419
13.3%
0.77 [0.58, 1.00]
139
7426
167
7339
19.5%
0.82 [0.66, 1.03]
15585
54.1%
0.79 [0.69, 0.90]
100.0%
0.82 [0.75, 0.91]
Subtotal (95% CI)
Total events
20465
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)
Total events
28341
798
22236
773
Heterogeneity: Tau² = 0.00; Chi² = 2.81, df = 5 (P = 0.73); I² = 0%
0.5
Test for overall effect: Z = 3.90 (P < 0.0001)
0.7
1
Favours experimental
1.5
2
Favours control
Test for subgroup differences: Chi² = 0.90, df = 1 (P = 0.34), I² = 0%
NEW ANTICOAGULANT
Study or Subgroup
WARFARIN
Risk Ratio
Events
Total
Events
Total
Weight
Risk Ratio
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]
9351
35.7%
0.81 [0.68, 0.97]
0.73 [0.58, 0.92]
Subtotal (95% CI)
Total events
12147
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%
02. ROCKET-AF
152
5215
187
5254
24.3%
03. ARISTOTLE
124
4522
156
4518
20.0%
0.79 [0.63, 1.00]
12790
64.3%
0.78 [0.69, 0.89]
100.0%
0.79 [0.71, 0.88]
Subtotal (95% CI)
Total events
15793
446
0.82 [0.66, 1.01]
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)
Total events
27940
715
22141
708
Heterogeneity: Tau² = 0.00; Chi² = 1.06, df = 5 (P = 0.96); I² = 0%
0.5
Test for overall effect: Z = 4.38 (P < 0.0001)
0.7
Favours experimental
Test for subgroup differences: Chi² = 0.11, df = 1 (P = 0.74), I² = 0%
Page 10 of 20
1
1.5
Favours control
2
Figure A3
Subgroup analyses for all strokes and systemic embolic events (continued)
NEW ANTICOAGULANT
Study or Subgroup
WARFARIN
Risk Ratio
Risk Ratio
Events
Total
Events
Total
Weight
M-H, Random, 95% CI
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]
17292
87.5%
0.82 [0.74, 0.91]
6.5%
0.81 [0.55, 1.19]
M-H, Random, 95% CI
4.3.1 CHADS => 2
Subtotal (95% CI)
Total events
21324
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
02. ROCKET-AF
03. ARISTOTLE
68
3916
40
1859
0
1
0
2
44
3100
51
3083
6.0%
0.86 [0.58, 1.28]
4944
12.5%
0.83 [0.63, 1.10]
100.0%
0.82 [0.75, 0.91]
Subtotal (95% CI)
Total events
7017
112
Not estimable
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)
Total events
28341
798
22236
773
Heterogeneity: Tau² = 0.00; Chi² = 1.21, df = 4 (P = 0.88); I² = 0%
0.5
Test for overall effect: Z = 3.87 (P = 0.0001)
0.7
1
Favours experimental
1.5
2
Favours control
Test for subgroup differences: Chi² = 0.00, df = 1 (P = 0.94), I² = 0%
NEW ANTICOAGULANT
Study or Subgroup
WARFARIN
Risk Ratio
Risk Ratio
Events
Total
Events
Total
Weight
M-H, Random, 95% CI
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]
79
2850
109
2828
11.9%
0.72 [0.54, 0.96]
8333
46.1%
0.77 [0.67, 0.90]
M-H, Random, 95% CI
7.3.1 AGE =>75
03. ARISTOTLE
Subtotal (95% CI)
Total events
10747
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]
13860
53.9%
0.86 [0.76, 0.99]
100.0%
0.82 [0.75, 0.91]
Subtotal (95% CI)
Total events
17545
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)
Total events
28292
798
22193
773
Heterogeneity: Tau² = 0.00; Chi² = 2.85, df = 5 (P = 0.72); I² = 0%
0.5
Test for overall effect: Z = 3.90 (P < 0.0001)
0.7
1
Favours experimental
1.5
2
Favours control
Test for subgroup differences: Chi² = 1.19, df = 1 (P = 0.27), I² = 16.1%
NEW ANTICOAGULANT
Study or Subgroup
WARFARIN
Risk Ratio
Risk Ratio
Events
Total
Events
Total
Weight
M-H, Random, 95% CI
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]
13995
56.9%
0.84 [0.74, 0.96]
0.75 [0.57, 0.97]
M-H, Random, 95% CI
8.3.1 MALE
Subtotal (95% CI)
Total events
17870
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%
02. ROCKET-AF
126
2802
142
2803
17.6%
03. ARISTOTLE
80
3234
105
3182
11.8%
0.75 [0.56, 1.00]
8198
43.1%
0.80 [0.69, 0.93]
100.0%
0.82 [0.75, 0.91]
Subtotal (95% CI)
Total events
10421
336
0.89 [0.70, 1.12]
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)
Total events
28291
799
22193
773
Heterogeneity: Tau² = 0.00; Chi² = 1.63, df = 5 (P = 0.90); I² = 0%
0.5
Test for overall effect: Z = 3.89 (P = 0.0001)
0.7
Favours experimental
Test for subgroup differences: Chi² = 0.20, df = 1 (P = 0.65), I² = 0%
Page 11 of 20
1
1.5
Favours control
2
Figure A3
Subgroup analyses for all strokes and systemic embolic events (continued)
NEW ANTICOAGULANT
Study or Subgroup
WARFARIN
Risk Ratio
Risk Ratio
Events
Total
Events
Total
Weight
M-H, Random, 95% CI
02. ROCKET-AF
95
2851
114
2796
19.9%
03. ARISTOTLE
57
2284
75
2263
12.3%
0.75 [0.54, 1.06]
5059
32.3%
0.79 [0.64, 0.98]
0.92 [0.75, 1.12]
M-H, Random, 95% CI
9.3.1 DIABETES
Subtotal (95% CI)
5135
Total events
152
0.82 [0.63, 1.07]
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%
03. ARISTOTLE
155
6836
190
6818
32.4%
0.81 [0.66, 1.00]
11112
67.7%
0.87 [0.75, 1.00]
100.0%
0.84 [0.75, 0.95]
Subtotal (95% CI)
11066
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
Total events
481
16171
571
Heterogeneity: Tau² = 0.00; Chi² = 1.31, df = 3 (P = 0.73); I² = 0%
0.5
Test for overall effect: Z = 2.82 (P = 0.005)
0.7
1
Favours experimental
1.5
2
Favours control
Test for subgroup differences: Chi² = 0.49, df = 1 (P = 0.48), I² = 0%
NEW ANTICOAGULANT
Study or Subgroup
Events
Total
WARFARIN
Risk Ratio
Events
Total
Weight
Risk Ratio
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]
9551
43.1%
0.90 [0.78, 1.05]
Subtotal (95% CI)
11544
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]
12641
56.9%
0.77 [0.68, 0.88]
100.0%
0.83 [0.75, 0.91]
Subtotal (95% CI)
16747
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
Total events
805
22192
775
Heterogeneity: Tau² = 0.00; Chi² = 3.00, df = 5 (P = 0.70); I² = 0%
0.5
Test for overall effect: Z = 3.84 (P = 0.0001)
0.7
1
Favours experimental
1.5
2
Favours control
Test for subgroup differences: Chi² = 2.48, df = 1 (P = 0.12), I² = 59.6%
NEW ANTICOAGULANT
Study or Subgroup
WARFARIN
Risk Ratio
Weight
Risk Ratio
Events
Total
Events
Total
M-H, Random, 95% CI
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]
4025
27.9%
0.79 [0.65, 0.95]
M-H, Random, 95% CI
11.3.1 CrCl <50 ml/min
Subtotal (95% CI)
Total events
5284
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]
17832
72.1%
0.82 [0.73, 0.92]
100.0%
0.81 [0.74, 0.90]
Subtotal (95% CI)
Total events
22433
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)
Total events
27717
779
21857
765
Heterogeneity: Tau² = 0.00; Chi² = 2.00, df = 5 (P = 0.85); I² = 0%
0.5
Test for overall effect: Z = 4.12 (P < 0.0001)
0.7
Favours experimental
Test for subgroup differences: Chi² = 0.12, df = 1 (P = 0.72), I² = 0%
Page 12 of 20
1
1.5
Favours control
2
Figure A3
Subgroup analyses for all strokes and systemic embolic events (continued)
NEW ANTICOAGULANT
Study or Subgroup
Events
WARFARIN
Risk Ratio
Total
Events
Total
Weight
Risk Ratio
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]
17384
80.8%
0.85 [0.76, 0.95]
Subtotal (95% CI)
21677
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]
4707
19.2%
0.75 [0.55, 1.02]
100.0%
0.82 [0.74, 0.91]
Subtotal (95% CI)
6512
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
Total events
795
22091
766
Heterogeneity: Tau² = 0.00; Chi² = 5.09, df = 5 (P = 0.41); I² = 2%
0.5
Test for overall effect: Z = 3.81 (P = 0.0001)
0.7
1
Favours experimental
1.5
2
Favours control
Test for subgroup differences: Chi² = 0.57, df = 1 (P = 0.45), I² = 0%
NEW ANTICOAGULANT
Study or Subgroup
WARFARIN
Risk Ratio
Risk Ratio
Events
Total
Events
Total
Weight
M-H, Random, 95% CI
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]
12562
54.4%
0.83 [0.70, 0.98]
0.79 [0.62, 1.02]
M-H, Random, 95% CI
13.3.1 VKA EXPERIENCED
Subtotal (95% CI)
Total events
15681
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%
02. ROCKET-AF
101
2668
131
2650
15.0%
03. ARISTOTLE
110
3912
127
3888
15.3%
0.86 [0.67, 1.11]
9631
45.6%
0.81 [0.70, 0.93]
100.0%
0.82 [0.74, 0.91]
Subtotal (95% CI)
Total events
12610
361
0.77 [0.59, 0.99]
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)
Total events
28291
798
22193
773
Heterogeneity: Tau² = 0.00; Chi² = 3.84, df = 5 (P = 0.57); I² = 0%
0.5
Test for overall effect: Z = 3.92 (P < 0.0001)
0.7
1
Favours experimental
1.5
2
Favours control
Test for subgroup differences: Chi² = 0.05, df = 1 (P = 0.81), I² = 0%
NEW ANTICOAGULANT
Study or Subgroup
Events
Total
WARFARIN
Risk Ratio
Events
Total
Weight
Risk Ratio
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]
7834
39.6%
0.80 [0.68, 0.93]
0.79 [0.62, 1.00]
Subtotal (95% CI)
Total events
10201
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%
02. ROCKET-AF
164
4545
185
4514
22.8%
03. ARISTOTLE
142
6261
171
6308
20.0%
0.84 [0.67, 1.04]
14397
60.4%
0.84 [0.74, 0.95]
100.0%
0.82 [0.75, 0.91]
Subtotal (95% CI)
Total events
18138
484
0.88 [0.72, 1.08]
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)
Total events
28339
798
22231
773
Heterogeneity: Tau² = 0.00; Chi² = 1.71, df = 5 (P = 0.89); I² = 0%
0.5
Test for overall effect: Z = 3.91 (P < 0.0001)
0.7
Favours experimental
Test for subgroup differences: Chi² = 0.24, df = 1 (P = 0.63), I² = 0%
Page 13 of 20
1
1.5
Favours control
2
Figure A3
Subgroup analyses for all strokes and systemic embolic events (continued)
NEW ANTICOAGULANT
Study or Subgroup
Events
WARFARIN
Risk Ratio
Total Events
Total Weight
Risk Ratio
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]
12044
100.0%
0.77 [0.57, 1.06]
Total (95% CI)
12091
Total events
317
404
Heterogeneity: Tau² = 0.04; Chi² = 4.67, df = 1 (P = 0.03); I² = 79%
0.5
Test for overall effect: Z = 1.59 (P = 0.11)
0.7
1
Favours experimental
NEW ANTICOAGULANT
Study or Subgroup
M-H, Random, 95% CI
WARFARIN
Risk Ratio
Total Weight
1.5
2
Favours control
Risk Ratio
Events
Total
Events
M-H, Random, 95% CI
1.1. RE-LY 150 MG BID
47
2261
57
2258
20.6%
1.2. RELY 110 MG BID
62
2251
57
2258
22.1%
1.09 [0.77, 1.56]
4516
42.7%
0.96 [0.73, 1.26]
0.59 [0.46, 0.77]
M-H, Random, 95% CI
21.3.1 EUROPE
Subtotal (95% CI)
Total events
4512
109
0.82 [0.56, 1.21]
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
1.2. RELY 110 MG BID
87
3815
145
3764
27.8%
121
3764
145
3764
29.5%
0.83 [0.66, 1.06]
7528
57.3%
0.71 [0.50, 0.99]
12044
100.0%
0.80 [0.63, 1.03]
Subtotal (95% CI)
Total events
7579
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)
Total events
12091
317
404
Heterogeneity: Tau² = 0.04; Chi² = 8.08, df = 3 (P = 0.04); I² = 63%
0.5
Test for overall effect: Z = 1.74 (P = 0.08)
0.7
Favours experimental
Test for subgroup differences: Chi² = 1.87, df = 1 (P = 0.17), I² = 46.6%
Page 14 of 20
1
1.5
Favours control
2
Figure A4 Subgroup analyses for major bleeding
NEW ANTICOAGULANT
Study or Subgroup
WARFARIN
Risk Ratio
Risk Ratio
Events
Total
Events
Total
Weight
M-H, Random, 95% CI
01. RE-LY
180
4512
104
2258
14.8%
02. ROCKET-AF
137
3786
153
3796
15.2%
03. ARISTOTLE
110
3672
135
3671
14.2%
0.81 [0.64, 1.04]
9725
44.2%
0.86 [0.75, 0.99]
0.88 [0.77, 1.00]
M-H, Random, 95% CI
6.5.1 EUROPE
Subtotal (95% CI)
11970
Total events
427
0.87 [0.68, 1.10]
0.90 [0.72, 1.13]
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%
02. ROCKET-AF
258
3325
233
3329
17.9%
03. ARISTOTLE
217
5448
327
5410
18.1%
0.66 [0.56, 0.78]
12503
55.8%
0.86 [0.66, 1.13]
100.0%
0.86 [0.74, 1.00]
Subtotal (95% CI)
Total events
16352
1036
1.11 [0.93, 1.31]
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)
Total events
28322
1463
22228
1269
Heterogeneity: Tau² = 0.02; Chi² = 18.67, df = 5 (P = 0.002); I² = 73%
0.5
Test for overall effect: Z = 1.96 (P = 0.05)
0.7
1
Favours experimental
1.5
2
Favours control
Test for subgroup differences: Chi² = 0.00, df = 1 (P = 0.99), I² = 0%
NEW ANTICOAGULANT
Study or Subgroup
Events
Total
WARFARIN
Risk Ratio
Events
Total
Weight
Risk Ratio
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%
2. ROCKET-AF
178
3754
183
3714
16.5%
3. ARISTOTLE
77
1694
106
1742
12.0%
0.75 [0.56, 0.99]
6651
42.8%
0.87 [0.76, 1.00]
Subtotal (95% CI)
Total events
7876
422
0.85 [0.67, 1.08]
0.96 [0.79, 1.18]
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]
15585
57.2%
0.87 [0.69, 1.10]
100.0%
0.86 [0.75, 0.99]
Subtotal (95% CI)
Total events
20465
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)
Total events
28341
1463
22236
1269
Heterogeneity: Tau² = 0.02; Chi² = 15.26, df = 5 (P = 0.009); I² = 67%
0.5
Test for overall effect: Z = 2.11 (P = 0.03)
0.7
1
Favours experimental
1.5
2
Favours control
Test for subgroup differences: Chi² = 0.00, df = 1 (P = 0.99), I² = 0%
NEW ANTICOAGULANT
Study or Subgroup
WARFARIN
Risk Ratio
Risk Ratio
Events
Total
Events
Total
Weight
M-H, Random, 95% CI
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]
9364
49.3%
1.01 [0.80, 1.27]
M-H, Random, 95% CI
5.4.1 TTR >65%
Subtotal (95% CI)
Total events
12160
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]
12820
50.7%
0.75 [0.58, 0.96]
100.0%
0.87 [0.72, 1.04]
Subtotal (95% CI)
Total events
15830
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)
Total events
27990
1444
22184
1267
Heterogeneity: Tau² = 0.04; Chi² = 29.84, df = 5 (P < 0.0001); I² = 83%
Test for overall effect: Z = 1.51 (P = 0.13)
0.5
0.7
Favours experimental
Test for subgroup differences: Chi² = 2.94, df = 1 (P = 0.09), I² = 66.0%
Page 15 of 20
1
1.5
Favours control
2
Figure A4 Subgroup analyses for major bleeding (continued)
NEW ANTICOAGULANT
Study or Subgroup
WARFARIN
Risk Ratio
Risk Ratio
Events
Total
Events
Total
Weight
M-H, Random, 95% CI
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]
17292
66.9%
0.90 [0.75, 1.07]
17.5%
0.71 [0.56, 0.91]
M-H, Random, 95% CI
4.4.1 CHADS =>2
Subtotal (95% CI)
Total events
21324
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
02. ROCKET-AF
03. ARISTOTLE
158
3916
105
1859
0
1
0
2
76
3100
126
3083
15.6%
0.60 [0.45, 0.79]
4944
33.1%
0.66 [0.55, 0.80]
100.0%
0.81 [0.68, 0.96]
Subtotal (95% CI)
Total events
7017
234
Not estimable
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)
Total events
28341
1463
22236
1269
Heterogeneity: Tau² = 0.03; Chi² = 19.76, df = 4 (P = 0.0006); I² = 80%
0.5
Test for overall effect: Z = 2.37 (P = 0.02)
0.7
1
Favours experimental
1.5
2
Favours control
Test for subgroup differences: Chi² = 5.52, df = 1 (P = 0.02), I² = 81.9%
NEW ANTICOAGULANT
Study or Subgroup
WARFARIN
Risk Ratio
Risk Ratio
Events
Total
Events
Total
Weight
M-H, Random, 95% CI
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]
7953
50.0%
0.95 [0.69, 1.30]
M-H, Random, 95% CI
7.5.1 AGE =>75
Subtotal (95% CI)
Total events
10353
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]
14275
50.0%
0.77 [0.64, 0.93]
100.0%
0.85 [0.70, 1.04]
Subtotal (95% CI)
Total events
17969
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)
Total events
28322
1463
22228
1269
Heterogeneity: Tau² = 0.05; Chi² = 34.78, df = 5 (P < 0.00001); I² = 86%
0.5
Test for overall effect: Z = 1.57 (P = 0.12)
0.7
1
Favours experimental
1.5
2
Favours control
Test for subgroup differences: Chi² = 1.20, df = 1 (P = 0.27), I² = 16.3%
NEW ANTICOAGULANT
Study or Subgroup
WARFARIN
Risk Ratio
Risk Ratio
Events
Total
Events
Total
Weight
M-H, Random, 95% CI
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]
14007
55.0%
0.88 [0.75, 1.04]
0.88 [0.72, 1.07]
M-H, Random, 95% CI
8.5.1 MALE
Subtotal (95% CI)
Total events
17883
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%
02. ROCKET-AF
135
2819
133
2826
14.5%
03. ARISTOTLE
102
3234
168
3182
14.1%
0.60 [0.47, 0.76]
8221
45.0%
0.81 [0.61, 1.09]
100.0%
0.85 [0.74, 0.98]
Subtotal (95% CI)
Total events
10438
495
1.02 [0.81, 1.29]
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)
Total events
28321
1463
22228
1269
Heterogeneity: Tau² = 0.02; Chi² = 17.02, df = 5 (P = 0.004); I² = 71%
Test for overall effect: Z = 2.22 (P = 0.03)
0.5
0.7
Favours experimental
Test for subgroup differences: Chi² = 0.23, df = 1 (P = 0.63), I² = 0%
Page 16 of 20
1
1.5
2
Favours control
Figure A4 Subgroup analyses for major bleeding (continued)
NEW ANTICOAGULANT
Study or Subgroup
WARFARIN
Risk Ratio
Risk Ratio
Events
Total
Events
Total
Weight
M-H, Random, 95% CI
02. ROCKET-AF
165
2869
169
2814
24.8%
03. ARISTOTLE
112
2284
114
2263
23.2%
0.97 [0.75, 1.26]
5077
48.1%
0.96 [0.82, 1.13]
1.08 [0.90, 1.29]
M-H, Random, 95% CI
9.5.1 DIABETES
Subtotal (95% CI)
5153
Total events
277
0.96 [0.78, 1.18]
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%
03. ARISTOTLE
215
6836
348
6818
26.2%
0.62 [0.52, 0.73]
11129
51.9%
0.81 [0.47, 1.41]
100.0%
0.88 [0.67, 1.16]
Subtotal (95% CI)
11078
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
Total events
722
16206
848
Heterogeneity: Tau² = 0.07; Chi² = 23.27, df = 3 (P < 0.0001); I² = 87%
0.5
Test for overall effect: Z = 0.88 (P = 0.38)
0.7
1
Favours experimental
1.5
2
Favours control
Test for subgroup differences: Chi² = 0.34, df = 1 (P = 0.56), I² = 0%
NEW ANTICOAGULANT
Study or Subgroup
Events
Total
WARFARIN
Risk Ratio
Events
Total
Weight
Risk Ratio
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]
87
3235
137
3216
13.0%
0.63 [0.48, 0.82]
9276
46.0%
0.82 [0.63, 1.05]
0.90 [0.78, 1.03]
03. ARISTOTLE
Subtotal (95% CI)
10973
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%
02. ROCKET-AF
162
2653
153
2687
15.5%
03. ARISTOTLE
240
5885
325
5865
18.5%
0.74 [0.63, 0.87]
12949
54.0%
0.88 [0.73, 1.07]
100.0%
0.85 [0.74, 0.98]
Subtotal (95% CI)
17344
Total events
942
1.07 [0.87, 1.33]
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
Total events
1462
22225
1269
Heterogeneity: Tau² = 0.02; Chi² = 15.96, df = 5 (P = 0.007); I² = 69%
0.5
Test for overall effect: Z = 2.25 (P = 0.02)
0.7
1
Favours experimental
1.5
Favours control
Test for subgroup differences: Chi² = 0.24, df = 1 (P = 0.63), I² = 0%
NEW ANTICOAGULANT
Study or Subgroup
WARFARIN
Risk Ratio
Events
Total
Events
Total
Weight
Risk Ratio
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]
4042
44.3%
0.80 [0.53, 1.20]
Subtotal (95% CI)
Total events
5296
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]
17850
55.7%
0.87 [0.73, 1.03]
100.0%
0.84 [0.71, 0.99]
Subtotal (95% CI)
Total events
22451
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)
Total events
27747
1436
21892
1258
Heterogeneity: Tau² = 0.03; Chi² = 23.43, df = 5 (P = 0.0003); I² = 79%
Test for overall effect: Z = 2.04 (P = 0.04)
0.5 0.7
Favours experimental
Test for subgroup differences: Chi² = 0.13, df = 1 (P = 0.72), I² = 0%
Page 17 of 20
1
1.5 2
Favours control
2
Figure A4 Subgroup analyses for major bleeding (continued)
NEW ANTICOAGULANT
Study or Subgroup
Events
WARFARIN
Risk Ratio
Total
Events
Total
Weight
Risk Ratio
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]
17407
62.7%
0.86 [0.69, 1.06]
Subtotal (95% CI)
21694
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]
4717
37.3%
0.89 [0.76, 1.03]
100.0%
0.87 [0.76, 1.00]
Subtotal (95% CI)
6523
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
Total events
1459
22124
1263
Heterogeneity: Tau² = 0.02; Chi² = 14.54, df = 5 (P = 0.01); I² = 66%
0.5
Test for overall effect: Z = 2.02 (P = 0.04)
0.7
1
Favours experimental
1.5
2
Favours control
Test for subgroup differences: Chi² = 0.07, df = 1 (P = 0.79), I² = 0%
NEW ANTICOAGULANT
Study or Subgroup
WARFARIN
Risk Ratio
Risk Ratio
Events
Total
Events
Total
Weight
M-H, Random, 95% CI
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]
12580
52.7%
0.85 [0.65, 1.11]
M-H, Random, 95% CI
13.5.1 VKA EXPERIENCED
Subtotal (95% CI)
Total events
15699
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]
9648
47.3%
0.86 [0.76, 0.98]
100.0%
0.86 [0.74, 0.98]
Subtotal (95% CI)
Total events
12622
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)
Total events
28321
1463
22228
1269
Heterogeneity: Tau² = 0.02; Chi² = 17.10, df = 5 (P = 0.004); I² = 71%
0.5
Test for overall effect: Z = 2.20 (P = 0.03)
0.7
1
Favours experimental
1.5
2
Favours control
Test for subgroup differences: Chi² = 0.00, df = 1 (P = 0.95), I² = 0%
NEW ANTICOAGULANT
Study or Subgroup
Events
WARFARIN
Risk Ratio
Total
Events
Total
Weight
Risk Ratio
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%
02. ROCKET-AF
171
2586
159
2619
15.4%
03. ARISTOTLE
129
2859
164
2773
14.5%
0.76 [0.61, 0.96]
7834
47.8%
0.91 [0.76, 1.10]
Subtotal (95% CI)
Total events
10201
665
0.91 [0.77, 1.07]
1.09 [0.88, 1.34]
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]
14397
52.2%
0.83 [0.67, 1.02]
100.0%
0.87 [0.76, 0.99]
Subtotal (95% CI)
Total events
18138
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)
Total events
28339
1468
22231
1271
Heterogeneity: Tau² = 0.02; Chi² = 16.15, df = 5 (P = 0.006); I² = 69%
Test for overall effect: Z = 2.09 (P = 0.04)
0.5
0.7
Favours experimental
Test for subgroup differences: Chi² = 0.47, df = 1 (P = 0.49), I² = 0%
Page 18 of 20
1
1.5
Favours control
2
Figure A4 Subgroup analyses for major bleeding (continued)
NEW ANTICOAGULANT
Study or Subgroup
WARFARIN
Risk Ratio
Risk Ratio
Events
Total
Events
Total
Weight
1. RE-LY 150 MG BID
399
6076
421
6022
51.0%
2. RELY 110 MG BID
342
6015
421
6022
49.0%
0.81 [0.71, 0.93]
12044
100.0%
0.88 [0.76, 1.01]
Total (95% CI)
12091
Total events
741
M-H, Random, 95% CI
0.94 [0.82, 1.07]
842
Heterogeneity: Tau² = 0.01; Chi² = 2.18, df = 1 (P = 0.14); I² = 54%
0.5
Test for overall effect: Z = 1.85 (P = 0.06)
0.7
1
Favours experimental
NEW ANTICOAGULANT
Study or Subgroup
M-H, Random, 95% CI
WARFARIN
Risk Ratio
1.5
2
Favours control
Risk Ratio
Events
Total
Events
Total
Weight
M-H, Random, 95% CI
1.1. RE-LY 150 MG BID
98
2261
104
2258
12.5%
1.2. RELY 110 MG BID
82
2251
104
2258
11.3%
0.79 [0.60, 1.05]
4516
23.8%
0.87 [0.71, 1.05]
0.94 [0.81, 1.09]
M-H, Random, 95% CI
21.5.1 EUROPE
Subtotal (95% CI)
Total events
4512
180
0.94 [0.72, 1.23]
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%
1.2. RELY 110 MG BID
260
3764
317
3764
36.5%
0.82 [0.70, 0.96]
7528
76.2%
0.88 [0.77, 1.00]
12044
100.0%
0.88 [0.80, 0.96]
Subtotal (95% CI)
Total events
7579
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)
Total events
12091
741
842
Heterogeneity: Tau² = 0.00; Chi² = 2.20, df = 3 (P = 0.53); I² = 0%
0.5
Test for overall effect: Z = 2.72 (P = 0.006)
0.7
Favours experimental
Test for subgroup differences: Chi² = 0.01, df = 1 (P = 0.91), I² = 0%
Page 19 of 20
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Favours control
2
Figure A5 Subgroup analyses for deaths
NEW ANTICOAGULANT
Study or Subgroup
Events
WARFARIN
Risk Ratio
Total
Events
Total
Weight
Risk Ratio
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]
6651
30.3%
0.92 [0.82, 1.03]
Subtotal (95% CI)
Total events
7876
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]
15585
69.7%
0.90 [0.84, 0.97]
100.0%
0.91 [0.85, 0.97]
Subtotal (95% CI)
Total events
20465
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)
Total events
28341
2069
22236
1788
Heterogeneity: Tau² = 0.00; Chi² = 1.24, df = 5 (P = 0.94); I² = 0%
0.5
Test for overall effect: Z = 3.08 (P = 0.002)
0.7
1
Favours experimental
1.5
2
Favours control
Test for subgroup differences: Chi² = 0.06, df = 1 (P = 0.81), I² = 0%
NEW ANTICOAGULANT
Study or Subgroup
WARFARIN
Risk Ratio
Risk Ratio
Events
Total
Events
Total
Weight
M-H, Random, 95% CI
01. RE-LY
407
5954
201
2996
22.3%
03. ARISTOTLE
280
4517
301
4529
23.5%
0.93 [0.80, 1.09]
7525
45.8%
0.97 [0.87, 1.09]
0.82 [0.71, 0.95]
M-H, Random, 95% CI
5.6.1 TTR >65%
Subtotal (95% CI)
Total events
10471
687
1.02 [0.87, 1.20]
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%
03. ARISTOTLE
321
4522
368
4518
26.7%
0.87 [0.75, 1.01]
7536
54.2%
0.85 [0.76, 0.93]
100.0%
0.90 [0.82, 0.99]
Subtotal (95% CI)
Total events
10578
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)
Total events
21049
1476
15061
1154
Heterogeneity: Tau² = 0.00; Chi² = 4.24, df = 3 (P = 0.24); I² = 29%
0.5
Test for overall effect: Z = 2.25 (P = 0.02)
0.7
1
Favours experimental
1.5
2
Favours control
Test for subgroup differences: Chi² = 3.32, df = 1 (P = 0.07), I² = 69.9%
NEW ANTICOAGULANT
Study or Subgroup
WARFARIN
Risk Ratio
Risk Ratio
Events
Total
Events
Total
Weight
M-H, Random, 95% CI
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]
17292
86.4%
0.91 [0.85, 0.97]
6.4%
0.82 [0.65, 1.05]
M-H, Random, 95% CI
4.6.1 CHADS =>2
Subtotal (95% CI)
Total events
21324
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
02. ROCKET-AF
03. ARISTOTLE
170
3916
98
1859
0
1
0
2
3100
142
138
Subtotal (95% CI)
Total events
7017
308
Not estimable
3083
7.2%
0.97 [0.77, 1.22]
4944
13.6%
0.90 [0.76, 1.06]
100.0%
0.91 [0.86, 0.97]
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)
Total events
28341
2069
22236
1788
Heterogeneity: Tau² = 0.00; Chi² = 1.49, df = 4 (P = 0.83); I² = 0%
0.5
Test for overall effect: Z = 3.01 (P = 0.003)
0.7
1
Favours experimental
1.5
2
Favours control
Test for subgroup differences: Chi² = 0.04, df = 1 (P = 0.85), I² = 0%
NEW ANTICOAGULANT
Study or Subgroup
WARFARIN
Risk Ratio
Risk Ratio
Events
Total
Events
Total
Weight
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]
12044
100.0%
0.90 [0.83, 0.99]
Total (95% CI)
Total events
12091
884
M-H, Random, 95% CI
M-H, Random, 95% CI
974
Heterogeneity: Tau² = 0.00; Chi² = 0.10, df = 1 (P = 0.75); I² = 0%
0.5
Test for overall effect: Z = 2.26 (P = 0.02)
0.7
Favours experimental
Page 20 of 20
1
1.5
Favours control
2