Mechanism

treatment

comparator

All cause death (0)

All cause death (1)

Coronary death (2)

Coronary event (3)

Coronary event (4)

Coronary event (5)

Adverse events (6)

Bleeding (7)

Cardiovascular death (8)

Cardiovascular death (9)

Major bleeding (10)

Major bleeding (11)

Minor bleeding (12)

Haemmorhagic stroke (13)

Haemmorhagic stroke (14)

Fatal stroke (15)

Fatal stroke (16)

Non fatal stroke (17)

Non fatal MI (18)

Fatal bleeding (19)

thrombo-embolic event (cerebral or systemic) (20)

ischemic stroke (21)

hypertransaminasemia (22)

intracranial hemorrhage (23)

TE event or ischemic stroke or systemic embolism (24)

stroke (fatal and non fatal) (25)

stroke (fatal and non fatal) (26)

myocardial infarction (fatal and non fatal) (27)

myocardial infarction (fatal and non fatal) (28)

Deep vein thrombosis (29)

cardiovascular events (30)

cardiac event (fatal and non fatal ) (31)

proximal DVT (32)

distal DVT (33)

non-fatal pulmonary embolism (34)

asymptomatic DVT (35)

total VTE and all-cause mortality (36)

fatal pulmonary embolism (37)

Symptomatic venous thromboembolism (DVT, PE) (38)

major VTE (fatal and non fatal DVT,PE) (39)

recurrent DVT (40)

Gastrointestinal major bleeding (41)

Non-lifethreatening major bleeding (42)

Lifethreatening major bleeding (43)

Acute coronary syndrome (44)

Symptomatic deep-vein thrombosis (45)

major or clinically relevant non-major bleeding (46)

any bleedings (47)

stent thrombosis (48)

systemic thrombo-embolic complication (49)

major or minor bleeding (50)

VTE (51)

Edit

Edoxaban

atrial fibrillation, in all type of patients

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	0.92 [0.83 1.01]	p=1.00	0	14071	1	ENGAGE-AF TIMI 48 High dose,
All cause death	0.92 [0.83 1.01]	p=1.00	0	14071	1	ENGAGE-AF TIMI 48 High dose,
Coronary death	no data
Coronary event	no data
Coronary event	no data
Coronary event	no data
Adverse events	no data
Bleeding	0.87 [0.82 0.92]	p=0.04	0	14071	1	ENGAGE-AF TIMI 48 High dose,
Cardiovascular death	0.86 [0.77 0.97]	p=0.04	0	14071	1	ENGAGE-AF TIMI 48 High dose,
Cardiovascular death	0.86 [0.77 0.97]	p=0.04	0	14071	1	ENGAGE-AF TIMI 48 High dose,
Major bleeding	0.80 [0.71 0.91]	p=0.04	0	14071	1	ENGAGE-AF TIMI 48 High dose,
Major bleeding	0.80 [0.71 0.91]	p=0.04	0	14071	1	ENGAGE-AF TIMI 48 High dose,
Minor bleeding	0.84 [0.76 0.93]	p=0.04	0	14071	1	ENGAGE-AF TIMI 48 High dose,
Haemmorhagic stroke	0.47 [0.35 0.64]	p=0.04	0	14071	1	ENGAGE-AF TIMI 48 High dose,
Haemmorhagic stroke	0.47 [0.35 0.64]	p=0.04	0	14071	1	ENGAGE-AF TIMI 48 High dose,
Fatal stroke	0.92 [0.68 1.25]	p=1.00	0	14071	1	ENGAGE-AF TIMI 48 High dose,
Fatal stroke	0.92 [0.68 1.25]	p=1.00	0	14071	1	ENGAGE-AF TIMI 48 High dose,
Non fatal stroke	no data
Non fatal MI	no data
Fatal bleeding	0.55 [0.36 0.84]	p=0.04	0	14071	1	ENGAGE-AF TIMI 48 High dose,
thrombo-embolic event (cerebral or systemic)	0.87 [0.73 1.04]	p=1.00	0	14071	1	ENGAGE-AF TIMI 48 High dose,
ischemic stroke	1.00 [0.84 1.20]	p=1.00	0	14071	1	ENGAGE-AF TIMI 48 High dose,
hypertransaminasemia	no data
intracranial hemorrhage	0.47 [0.35 0.64]	p=0.04	0	14071	1	ENGAGE-AF TIMI 48 High dose,
TE event or ischemic stroke or systemic embolism	no data
stroke (fatal and non fatal)	0.88 [0.75 1.03]	p=1.00	0	14071	1	ENGAGE-AF TIMI 48 High dose,
stroke (fatal and non fatal)	0.88 [0.75 1.03]	p=1.00	0	14071	1	ENGAGE-AF TIMI 48 High dose,
myocardial infarction (fatal and non fatal)	0.94 [0.74 1.19]	p=1.00	0	14071	1	ENGAGE-AF TIMI 48 High dose,
myocardial infarction (fatal and non fatal)	0.94 [0.74 1.19]	p=1.00	0	14071	1	ENGAGE-AF TIMI 48 High dose,
Deep vein thrombosis	no data
cardiovascular events	no data
cardiac event (fatal and non fatal )	no data
proximal DVT	no data
distal DVT	no data
non-fatal pulmonary embolism	no data
asymptomatic DVT	no data
total VTE and all-cause mortality	no data
fatal pulmonary embolism	no data
Symptomatic venous thromboembolism (DVT, PE)	no data
major VTE (fatal and non fatal DVT,PE)	no data
recurrent DVT	no data
Gastrointestinal major bleeding	1.23 [1.01 1.49]	p=0.04	0	14071	1	ENGAGE-AF TIMI 48 High dose,
Non-lifethreatening major bleeding	no data
Lifethreatening major bleeding	0.51 [0.38 0.69]	p=0.04	0	14071	1	ENGAGE-AF TIMI 48 High dose,
Acute coronary syndrome	no data
Symptomatic deep-vein thrombosis	no data
major or clinically relevant non-major bleeding	0.86 [0.80 0.92]	p=0.04	0	14071	1	ENGAGE-AF TIMI 48 High dose,
any bleedings	no data
stent thrombosis	no data
systemic thrombo-embolic complication	0.65 [0.34 1.24]	p=1.00	0	14071	1	ENGAGE-AF TIMI 48 High dose,
major or minor bleeding	no data
VTE	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
Weitz (edoxaban phase 2), 0	Four Fixed Dose Regimens of edoxaban (DU-176b)	warfarin	Subjects With Non- Valvular Atrial Fibrillation
ENGAGE-AF TIMI 48 High dose, 2013	edoxaban 60mg once daily	warfarin (INR 2-3)	AF patients (CHADS2 >=2)
phase 2 edoxaban, 0	edoxaban (DU-176b)	warfarin	male and female subjects aged 18 to 80 years, inclusive, with non-valvular AF and a CHADS2 Score of at least 1

Edoxaban

thrombosis prevention, in all type of patients

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	no data
All cause death	no data
Coronary death	no data
Coronary event	no data
Coronary event	no data
Coronary event	no data
Adverse events	no data
Bleeding	no data
Cardiovascular death	no data
Cardiovascular death	no data
Major bleeding	no data
Major bleeding	no data
Minor bleeding	no data
Haemmorhagic stroke	no data
Haemmorhagic stroke	no data
Fatal stroke	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
Fatal bleeding	no data
thrombo-embolic event (cerebral or systemic)	no data
ischemic stroke	no data
hypertransaminasemia	no data
intracranial hemorrhage	no data
TE event or ischemic stroke or systemic embolism	no data
stroke (fatal and non fatal)	no data
stroke (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	no data
Deep vein thrombosis	no data
cardiovascular events	no data
cardiac event (fatal and non fatal )	no data
proximal DVT	0.49 [0.04 5.40]	p=1.00	0	503	1	STARS J-V,
distal DVT	0.36 [0.14 0.95]	p=0.04	0	503	1	STARS J-V,
non-fatal pulmonary embolism	no data
asymptomatic DVT	0.38 [0.16 0.92]	p=0.04	0	503	1	STARS J-V,
total VTE and all-cause mortality	no data
fatal pulmonary embolism	no data
Symptomatic venous thromboembolism (DVT, PE)	no data
major VTE (fatal and non fatal DVT,PE)	0.34 [0.13 0.89]	p=0.04	0	503	1	STARS J-V,
recurrent DVT	no data
Gastrointestinal major bleeding	no data
Non-lifethreatening major bleeding	no data
Lifethreatening major bleeding	no data
Acute coronary syndrome	no data
Symptomatic deep-vein thrombosis	0.97 [0.02 49.21]	p=1.00	0	503	1	STARS J-V,
major or clinically relevant non-major bleeding	no data
any bleedings	no data
stent thrombosis	no data
systemic thrombo-embolic complication	no data
major or minor bleeding	no data
VTE	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
STARS J-V, 0	edoxaban 30 mg once daily for 11 to 14 days	subcutaneous enoxaparin 2,000 IU, equivalent to 20 mg, twice daily (BID) for 11 to 14 days	total hip arthroplasty

Dabigatran

acute coronary syndrome, in all type of patients

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	no data
All cause death	no data
Coronary death	no data
Coronary event	1.99 [0.70 5.67]	p=1.00	0	1861	1	REDEEM,
Coronary event	1.99 [0.70 5.67]	p=1.00	0	1861	1	REDEEM,
Coronary event	1.99 [0.70 5.67]	p=1.00	0	1861	1	REDEEM,
Adverse events	no data
Bleeding	no data
Cardiovascular death	no data
Cardiovascular death	no data
Major bleeding	no data
Major bleeding	no data
Minor bleeding	no data
Haemmorhagic stroke	no data
Haemmorhagic stroke	no data
Fatal stroke	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
Fatal bleeding	no data
thrombo-embolic event (cerebral or systemic)	no data
ischemic stroke	no data
hypertransaminasemia	no data
intracranial hemorrhage	no data
TE event or ischemic stroke or systemic embolism	no data
stroke (fatal and non fatal)	no data
stroke (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	no data
Deep vein thrombosis	no data
cardiovascular events	no data
cardiac event (fatal and non fatal )	no data
proximal DVT	no data
distal DVT	no data
non-fatal pulmonary embolism	no data
asymptomatic DVT	no data
total VTE and all-cause mortality	no data
fatal pulmonary embolism	no data
Symptomatic venous thromboembolism (DVT, PE)	no data
major VTE (fatal and non fatal DVT,PE)	no data
recurrent DVT	no data
Gastrointestinal major bleeding	no data
Non-lifethreatening major bleeding	no data
Lifethreatening major bleeding	no data
Acute coronary syndrome	no data
Symptomatic deep-vein thrombosis	no data
major or clinically relevant non-major bleeding	no data
any bleedings	no data
stent thrombosis	no data
systemic thrombo-embolic complication	no data
major or minor bleeding	no data
VTE	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
REDEEM, 2009	dabigatran 4 dosages (50mg twice daily, 75mg twice daily, 110mg twice daily, 150mg twice daily)	placebo	patients with recent acute coronary syndromes (ST- or non-ST-elevation myocardical infarction)

Apixaban

acute coronary syndrome, in all type of patients

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	1.08 [0.86 1.36]	p=1.00	0	7392	1	APPRAISE 2,
All cause death	1.08 [0.86 1.36]	p=1.00	0	7392	1	APPRAISE 2,
Coronary death	no data
Coronary event	0.96 [0.83 1.12]	p=1.00	0	8638	2	APPRAISE-1 (10mg od), APPRAISE 2,
Coronary event	0.96 [0.83 1.12]	p=1.00	0	8638	2	APPRAISE-1 (10mg od), APPRAISE 2,
Coronary event	0.96 [0.83 1.12]	p=1.00	0	8638	2	APPRAISE-1 (10mg od), APPRAISE 2,
Adverse events	no data
Bleeding	no data
Cardiovascular death	0.96 [0.73 1.26]	p=1.00	0	7392	1	APPRAISE 2,
Cardiovascular death	0.96 [0.73 1.26]	p=1.00	0	7392	1	APPRAISE 2,
Major bleeding	2.53 [1.47 4.38]	p=0.04	0	7315	1	APPRAISE 2,
Major bleeding	2.53 [1.47 4.38]	p=0.04	0	7315	1	APPRAISE 2,
Minor bleeding	no data
Haemmorhagic stroke	no data
Haemmorhagic stroke	no data
Fatal stroke	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
Fatal bleeding	10.91 [0.60 197.33]	p=1.00	0	7315	1	APPRAISE 2,
thrombo-embolic event (cerebral or systemic)	no data
ischemic stroke	0.67 [0.40 1.14]	p=1.00	0	7392	1	APPRAISE 2,
hypertransaminasemia	no data
intracranial hemorrhage	no data
TE event or ischemic stroke or systemic embolism	no data
stroke (fatal and non fatal)	no data
stroke (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	0.93 [0.76 1.15]	p=1.00	0	7392	1	APPRAISE 2,
myocardial infarction (fatal and non fatal)	0.93 [0.76 1.15]	p=1.00	0	7392	1	APPRAISE 2,
Deep vein thrombosis	no data
cardiovascular events	0.93 [0.80 1.08]	p=1.00	0	8923	3	APPRAISE-1 (10mg od), APPRAISE-1 (2.5 mg bid), APPRAISE 2,
cardiac event (fatal and non fatal )	0.95 [0.81 1.10]	p=1.00	0	7392	1	APPRAISE 2,
proximal DVT	no data
distal DVT	no data
non-fatal pulmonary embolism	no data
asymptomatic DVT	no data
total VTE and all-cause mortality	no data
fatal pulmonary embolism	no data
Symptomatic venous thromboembolism (DVT, PE)	no data
major VTE (fatal and non fatal DVT,PE)	no data
recurrent DVT	no data
Gastrointestinal major bleeding	no data
Non-lifethreatening major bleeding	no data
Lifethreatening major bleeding	no data
Acute coronary syndrome	no data
Symptomatic deep-vein thrombosis	no data
major or clinically relevant non-major bleeding	2.39 [1.82 3.14]	p=0.04	0	8846	3	APPRAISE-1 (10mg od), APPRAISE-1 (2.5 mg bid), APPRAISE 2,
any bleedings	2.21 [1.91 2.55]	p=0.04	0	7315	1	APPRAISE 2,
stent thrombosis	0.73 [0.47 1.12]	p=1.00	0	7392	1	APPRAISE 2,
systemic thrombo-embolic complication	no data
major or minor bleeding	2.74 [1.78 4.19]	p=0.04	0	7315	1	APPRAISE 2,
VTE	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
APPRAISE-1 (10mg od), 2009	apixaban 10 mg once daily	placebo	patients with a recent ST-elevation or non–ST-elevation acute coronary syndrome(<7 days)
APPRAISE-1 (2.5 mg bid), 2009	Apixaban 2.5mg twice daily	placebo	patients with a recent ST-elevation or non–ST-elevation acute coronary syndrome(<7 days)
APPRAISE 2, 2011	apixaban 5mg twice daily	placebo	patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events

Apixaban

atrial fibrillation, in all type of patients

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	0.89 [0.81 0.98]	p=0.04	0	18201	1	ARISTOTLE,
All cause death	0.89 [0.81 0.98]	p=0.04	0	18201	1	ARISTOTLE,
Coronary death	no data
Coronary event	0.88 [0.66 1.17]	p=1.00	0	18140	1	ARISTOTLE,
Coronary event	0.88 [0.66 1.17]	p=1.00	0	18140	1	ARISTOTLE,
Coronary event	0.88 [0.66 1.17]	p=1.00	0	18140	1	ARISTOTLE,
Adverse events	no data
Bleeding	0.77 [0.72 0.82]	p=0.04	0	18201	1	ARISTOTLE,
Cardiovascular death	no data
Cardiovascular death	no data
Major bleeding	0.70 [0.61 0.81]	p=0.04	0	18201	1	ARISTOTLE,
Major bleeding	0.70 [0.61 0.81]	p=0.04	0	18201	1	ARISTOTLE,
Minor bleeding	no data
Haemmorhagic stroke	0.51 [0.35 0.75]	p=0.04	0	18201	1	ARISTOTLE,
Haemmorhagic stroke	0.51 [0.35 0.75]	p=0.04	0	18201	1	ARISTOTLE,
Fatal stroke	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
Fatal bleeding	no data
thrombo-embolic event (cerebral or systemic)	0.80 [0.66 0.96]	p=0.04	0	18201	1	ARISTOTLE,
ischemic stroke	0.92 [0.74 1.14]	p=1.00	0	18201	1	ARISTOTLE,
hypertransaminasemia	no data
intracranial hemorrhage	0.42 [0.31 0.59]	p=0.04	0	18201	1	ARISTOTLE,
TE event or ischemic stroke or systemic embolism	no data
stroke (fatal and non fatal)	0.79 [0.66 0.96]	p=0.04	0	18201	1	ARISTOTLE,
stroke (fatal and non fatal)	0.79 [0.66 0.96]	p=0.04	0	18201	1	ARISTOTLE,
myocardial infarction (fatal and non fatal)	0.88 [0.66 1.17]	p=1.00	0	18201	1	ARISTOTLE,
myocardial infarction (fatal and non fatal)	0.88 [0.66 1.17]	p=1.00	0	18201	1	ARISTOTLE,
Deep vein thrombosis	no data
cardiovascular events	no data
cardiac event (fatal and non fatal )	no data
proximal DVT	no data
distal DVT	no data
non-fatal pulmonary embolism	no data
asymptomatic DVT	no data
total VTE and all-cause mortality	no data
fatal pulmonary embolism	no data
Symptomatic venous thromboembolism (DVT, PE)	no data
major VTE (fatal and non fatal DVT,PE)	no data
recurrent DVT	no data
Gastrointestinal major bleeding	0.88 [0.67 1.14]	p=1.00	0	18201	1	ARISTOTLE,
Non-lifethreatening major bleeding	no data
Lifethreatening major bleeding	no data
Acute coronary syndrome	no data
Symptomatic deep-vein thrombosis	no data
major or clinically relevant non-major bleeding	0.70 [0.63 0.78]	p=0.04	0	18201	1	ARISTOTLE,
any bleedings	no data
stent thrombosis	no data
systemic thrombo-embolic complication	0.88 [0.44 1.76]	p=1.00	0	18201	1	ARISTOTLE,
major or minor bleeding	no data
VTE	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
ARISTOTLE, 2011	apixaban 5mg twice daily	warfarin adjusted for an INR between 2 and 3	subjects with atrial fibrillation and risk factors for stroke
phase 2 apixaban, 0	apixaban 5 or 2.5 mg twice daily	warfarin	patient with non valvular AF

Apixaban

atrial fibrillation, in all type of patients

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	0.79 [0.62 1.01]	p=1.00	0	5599	1	AVERROES,
All cause death	0.79 [0.62 1.01]	p=1.00	0	5599	1	AVERROES,
Coronary death	no data
Coronary event	0.85 [0.49 1.47]	p=1.00	0	5599	1	AVERROES,
Coronary event	0.85 [0.49 1.47]	p=1.00	0	5599	1	AVERROES,
Coronary event	0.85 [0.49 1.47]	p=1.00	0	5599	1	AVERROES,
Adverse events	no data
Bleeding	no data
Cardiovascular death	0.86 [0.64 1.16]	p=1.00	0	5599	1	AVERROES,
Cardiovascular death	0.86 [0.64 1.16]	p=1.00	0	5599	1	AVERROES,
Major bleeding	1.14 [0.74 1.75]	p=1.00	0	5599	1	AVERROES,
Major bleeding	1.14 [0.74 1.75]	p=1.00	0	5599	1	AVERROES,
Minor bleeding	1.27 [1.01 1.60]	p=0.04	0	5599	1	AVERROES,
Haemmorhagic stroke	0.66 [0.24 1.86]	p=1.00	0	5599	1	AVERROES,
Haemmorhagic stroke	0.66 [0.24 1.86]	p=1.00	0	5599	1	AVERROES,
Fatal stroke	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
Fatal bleeding	0.84 [0.26 2.72]	p=1.00	0	5599	1	AVERROES,
thrombo-embolic event (cerebral or systemic)	0.46 [0.33 0.64]	p=0.04	0	5599	1	AVERROES,
ischemic stroke	0.37 [0.25 0.55]	p=0.04	0	5599	1	AVERROES,
hypertransaminasemia	no data
intracranial hemorrhage	1.09 [0.50 2.38]	p=1.00	0	5599	1	AVERROES,
TE event or ischemic stroke or systemic embolism	no data
stroke (fatal and non fatal)	0.46 [0.33 0.65]	p=0.04	0	5599	1	AVERROES,
stroke (fatal and non fatal)	0.46 [0.33 0.65]	p=0.04	0	5599	1	AVERROES,
myocardial infarction (fatal and non fatal)	0.85 [0.49 1.47]	p=1.00	0	5599	1	AVERROES,
myocardial infarction (fatal and non fatal)	0.85 [0.49 1.47]	p=1.00	0	5599	1	AVERROES,
Deep vein thrombosis	no data
cardiovascular events	no data
cardiac event (fatal and non fatal )	no data
proximal DVT	no data
distal DVT	no data
non-fatal pulmonary embolism	no data
asymptomatic DVT	no data
total VTE and all-cause mortality	no data
fatal pulmonary embolism	no data
Symptomatic venous thromboembolism (DVT, PE)	no data
major VTE (fatal and non fatal DVT,PE)	no data
recurrent DVT	no data
Gastrointestinal major bleeding	0.85 [0.39 1.85]	p=1.00	0	5599	1	AVERROES,
Non-lifethreatening major bleeding	no data
Lifethreatening major bleeding	no data
Acute coronary syndrome	no data
Symptomatic deep-vein thrombosis	no data
major or clinically relevant non-major bleeding	no data
any bleedings	no data
stent thrombosis	no data
systemic thrombo-embolic complication	no data
major or minor bleeding	no data
VTE	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
AVERROES, 2011	apixaban 5 mg (or 2.5 mg) twice daily	aspirin 81-324 md daily	patients with atrial fibrillation who have failed or are unsuitable for vitamin K antagonist treatment

Apixaban

thrombosis prevention, in all type of patients

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	2.99 [0.31 28.76]	p=1.00	0	5407	1	ADVANCE 3,
All cause death	2.99 [0.31 28.76]	p=1.00	0	5407	1	ADVANCE 3,
Coronary death	no data
Coronary event	1.66 [0.40 6.94]	p=1.00	0	5332	1	ADVANCE 3,
Coronary event	1.66 [0.40 6.94]	p=1.00	0	5332	1	ADVANCE 3,
Coronary event	1.66 [0.40 6.94]	p=1.00	0	5332	1	ADVANCE 3,
Adverse events	no data
Bleeding	no data
Cardiovascular death	no data
Cardiovascular death	no data
Major bleeding	1.22 [0.65 2.27]	p=1.00	0	5332	1	ADVANCE 3,
Major bleeding	1.22 [0.65 2.27]	p=1.00	0	5332	1	ADVANCE 3,
Minor bleeding	no data
Haemmorhagic stroke	no data
Haemmorhagic stroke	no data
Fatal stroke	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
Fatal bleeding	no data
thrombo-embolic event (cerebral or systemic)	no data
ischemic stroke	no data
hypertransaminasemia	no data
intracranial hemorrhage	no data
TE event or ischemic stroke or systemic embolism	no data
stroke (fatal and non fatal)	no data
stroke (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	2.24 [0.69 7.29]	p=1.00	0	5407	1	ADVANCE 3,
myocardial infarction (fatal and non fatal)	2.24 [0.69 7.29]	p=1.00	0	5407	1	ADVANCE 3,
Deep vein thrombosis	0.32 [0.20 0.52]	p=0.04	0	3855	1	ADVANCE 3,
cardiovascular events	no data
cardiac event (fatal and non fatal )	no data
proximal DVT	0.35 [0.15 0.83]	p=0.04	0	4386	1	ADVANCE 3,
distal DVT	no data
non-fatal pulmonary embolism	0.40 [0.08 2.06]	p=1.00	0	5407	1	ADVANCE 3,
asymptomatic DVT	0.33 [0.20 0.55]	p=0.04	0	5407	1	ADVANCE 3,
total VTE and all-cause mortality	0.36 [0.23 0.56]	p=0.04	0	3866	1	ADVANCE 3,
fatal pulmonary embolism	no data
Symptomatic venous thromboembolism (DVT, PE)	0.40 [0.04 4.00]	p=1.00	0	5407	1	ADVANCE 3,
major VTE (fatal and non fatal DVT,PE)	0.40 [0.17 0.94]	p=0.04	0	4394	1	ADVANCE 3,
recurrent DVT	no data
Gastrointestinal major bleeding	no data
Non-lifethreatening major bleeding	no data
Lifethreatening major bleeding	no data
Acute coronary syndrome	no data
Symptomatic deep-vein thrombosis	0.20 [0.02 1.71]	p=1.00	0	5407	1	ADVANCE 3,
major or clinically relevant non-major bleeding	0.96 [0.75 1.23]	p=1.00	0	5332	1	ADVANCE 3,
any bleedings	no data
stent thrombosis	no data
systemic thrombo-embolic complication	no data
major or minor bleeding	no data
VTE	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
ADVANCE 3, 2010	apixaban 2.5mg twice daily for 35 days	enoxaparin 40mg once daily for 35 days	patients undergoing elective total hip replacement surgery

Apixaban

thrombosis prevention, in all type of patients

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	5.00 [0.24 104.31]	p=1.00	0	3057	1	ADVANCE 2,
All cause death	5.00 [0.24 104.31]	p=1.00	0	3057	1	ADVANCE 2,
Coronary death	no data
Coronary event	1.00 [0.06 16.08]	p=1.00	0	3009	1	ADVANCE 2,
Coronary event	1.00 [0.06 16.08]	p=1.00	0	3009	1	ADVANCE 2,
Coronary event	1.00 [0.06 16.08]	p=1.00	0	3009	1	ADVANCE 2,
Adverse events	no data
Bleeding	no data
Cardiovascular death	no data
Cardiovascular death	no data
Major bleeding	0.65 [0.28 1.50]	p=1.00	0	3009	1	ADVANCE 2,
Major bleeding	0.65 [0.28 1.50]	p=1.00	0	3009	1	ADVANCE 2,
Minor bleeding	no data
Haemmorhagic stroke	no data
Haemmorhagic stroke	no data
Fatal stroke	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
Fatal bleeding	no data
thrombo-embolic event (cerebral or systemic)	no data
ischemic stroke	no data
hypertransaminasemia	no data
intracranial hemorrhage	no data
TE event or ischemic stroke or systemic embolism	no data
stroke (fatal and non fatal)	no data
stroke (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	1.00 [0.06 16.01]	p=1.00	0	3057	1	ADVANCE 2,
myocardial infarction (fatal and non fatal)	1.00 [0.06 16.01]	p=1.00	0	3057	1	ADVANCE 2,
Deep vein thrombosis	0.60 [0.48 0.75]	p=0.04	0	1968	1	ADVANCE 2,
cardiovascular events	no data
cardiac event (fatal and non fatal )	no data
proximal DVT	0.35 [0.16 0.75]	p=0.04	0	2391	1	ADVANCE 2,
distal DVT	no data
non-fatal pulmonary embolism	no data
asymptomatic DVT	no data
total VTE and all-cause mortality	0.62 [0.49 0.78]	p=0.04	0	1973	1	ADVANCE 2,
fatal pulmonary embolism	no data
Symptomatic venous thromboembolism (DVT, PE)	1.00 [0.35 2.86]	p=1.00	0	3057	1	ADVANCE 2,
major VTE (fatal and non fatal DVT,PE)	0.50 [0.26 0.98]	p=0.04	0	2394	1	ADVANCE 2,
recurrent DVT	no data
Gastrointestinal major bleeding	no data
Non-lifethreatening major bleeding	no data
Lifethreatening major bleeding	no data
Acute coronary syndrome	no data
Symptomatic deep-vein thrombosis	0.43 [0.11 1.66]	p=1.00	0	3057	1	ADVANCE 2,
major or clinically relevant non-major bleeding	0.74 [0.51 1.06]	p=1.00	0	3009	1	ADVANCE 2,
any bleedings	no data
stent thrombosis	no data
systemic thrombo-embolic complication	no data
major or minor bleeding	no data
VTE	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
ADVANCE 2, 2010	apixaban 2.5mg twice daily during 12 days	enoxaparin 40mg once daily 12 days	patients undergoing elective unilateral or bilateral total knee replacement

Apixaban

thrombosis prevention, in all type of patients

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	1.24 [0.30 5.19]	p=1.00	0	3415	2	APROPOS 2.5mg, ADVANCE-1,
All cause death	1.24 [0.30 5.19]	p=1.00	0	3415	2	APROPOS 2.5mg, ADVANCE-1,
Coronary death	no data
Coronary event	0.50 [0.05 5.50]	p=1.00	0	3183	1	ADVANCE-1,
Coronary event	0.50 [0.05 5.50]	p=1.00	0	3183	1	ADVANCE-1,
Coronary event	0.50 [0.05 5.50]	p=1.00	0	3183	1	ADVANCE-1,
Adverse events	no data
Bleeding	no data
Cardiovascular death	no data
Cardiovascular death	no data
Major bleeding	0.51 [0.25 1.04]	p=1.00	0	3487	2	APROPOS 2.5mg, ADVANCE-1,
Major bleeding	0.51 [0.25 1.04]	p=1.00	0	3487	2	APROPOS 2.5mg, ADVANCE-1,
Minor bleeding	no data
Haemmorhagic stroke	no data
Haemmorhagic stroke	no data
Fatal stroke	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
Fatal bleeding	no data
thrombo-embolic event (cerebral or systemic)	no data
ischemic stroke	no data
hypertransaminasemia	no data
intracranial hemorrhage	no data
TE event or ischemic stroke or systemic embolism	no data
stroke (fatal and non fatal)	no data
stroke (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	0.40 [0.08 2.06]	p=1.00	0	3195	1	ADVANCE-1,
myocardial infarction (fatal and non fatal)	0.40 [0.08 2.06]	p=1.00	0	3195	1	ADVANCE-1,
Deep vein thrombosis	0.95 [0.70 1.29]	p=1.00	0	2264	1	ADVANCE-1,
cardiovascular events	no data
cardiac event (fatal and non fatal )	no data
proximal DVT	0.70 [0.31 1.60]	p=1.00	0	2681	2	APROPOS 2.5mg, ADVANCE-1,
distal DVT	no data
non-fatal pulmonary embolism	no data
asymptomatic DVT	0.63 [0.26 1.53]	p=1.00	0	220	1	APROPOS 2.5mg,
total VTE and all-cause mortality	0.99 [0.74 1.31]	p=1.00	0	2507	2	APROPOS 2.5mg, ADVANCE-1,
fatal pulmonary embolism	no data
Symptomatic venous thromboembolism (DVT, PE)	1.46 [0.72 2.96]	p=1.00	0	3195	1	ADVANCE-1,
major VTE (fatal and non fatal DVT,PE)	0.58 [0.25 1.33]	p=1.00	0	220	1	APROPOS 2.5mg,
recurrent DVT	no data
Gastrointestinal major bleeding	no data
Non-lifethreatening major bleeding	no data
Lifethreatening major bleeding	no data
Acute coronary syndrome	no data
Symptomatic deep-vein thrombosis	0.98 [0.06 15.90]	p=1.00	0	220	1	APROPOS 2.5mg,
major or clinically relevant non-major bleeding	0.67 [0.46 0.99]	p=0.04	0	3184	1	ADVANCE-1,
any bleedings	0.73 [0.25 2.14]	p=1.00	0	303	1	APROPOS 2.5mg,
stent thrombosis	no data
systemic thrombo-embolic complication	no data
major or minor bleeding	no data
VTE	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
APROPOS 2.5mg, 2007	apixaban 2.5mg BID for 12 days	enoxaparin 30mg twice daily for 12 days	patients undergoing elective total knee replacement surgery
ADVANCE-1, 2008	apixaban 2.5 mg orally twice daily for 10 to 14 days	enoxaparin 30mg subcutaneously every 12 hours for 10-14 days	patients undergoing knee-replacement surgery

Otamixaban

acute coronary syndrome, in all type of patients

Rivaroxaban

acute coronary syndrome, in all type of patients

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	0.52 [0.44 0.62]	p=0.04	0	20455	2	ATLAS ACS 2 - TIMI 51 (2.5mg), ATLAS ACS 2 - TIMI 51 (5mg),
All cause death	0.52 [0.44 0.62]	p=0.04	0	20455	2	ATLAS ACS 2 - TIMI 51 (2.5mg), ATLAS ACS 2 - TIMI 51 (5mg),
Coronary death	no data
Coronary event	0.91 [0.57 1.45]	p=1.00	0	10564	1	ATLAS ACS 2 - TIMI 51 (5mg),
Coronary event	0.91 [0.57 1.45]	p=1.00	0	10564	1	ATLAS ACS 2 - TIMI 51 (5mg),
Coronary event	0.91 [0.57 1.45]	p=1.00	0	10564	1	ATLAS ACS 2 - TIMI 51 (5mg),
Adverse events	no data
Bleeding	no data
Cardiovascular death	0.51 [0.43 0.61]	p=0.04	0	20455	2	ATLAS ACS 2 - TIMI 51 (2.5mg), ATLAS ACS 2 - TIMI 51 (5mg),
Cardiovascular death	0.51 [0.43 0.61]	p=0.04	0	20455	2	ATLAS ACS 2 - TIMI 51 (2.5mg), ATLAS ACS 2 - TIMI 51 (5mg),
Major bleeding	4.04 [2.85 5.73]	p=0.04	0	24134	4	ATLAS ACS 2 - TIMI 51 (2.5mg), ATLAS ACS 2 - TIMI 51 (5mg), ATLAS ACS-TIMI 46 (5mg), ATLAS ACS-TIMI 46 (2.5mg),
Major bleeding	4.04 [2.85 5.73]	p=0.04	0	24134	4	ATLAS ACS 2 - TIMI 51 (2.5mg), ATLAS ACS 2 - TIMI 51 (5mg), ATLAS ACS-TIMI 46 (5mg), ATLAS ACS-TIMI 46 (2.5mg),
Minor bleeding	no data
Haemmorhagic stroke	no data
Haemmorhagic stroke	no data
Fatal stroke	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
Fatal bleeding	1.17 [0.61 2.23]	p=1.00	0	20475	2	ATLAS ACS 2 - TIMI 51 (2.5mg), ATLAS ACS 2 - TIMI 51 (5mg),
thrombo-embolic event (cerebral or systemic)	no data
ischemic stroke	no data
hypertransaminasemia	no data
intracranial hemorrhage	no data
TE event or ischemic stroke or systemic embolism	no data
stroke (fatal and non fatal)	no data
stroke (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	0.67 [0.59 0.77]	p=0.04	0	20455	2	ATLAS ACS 2 - TIMI 51 (2.5mg), ATLAS ACS 2 - TIMI 51 (5mg),
myocardial infarction (fatal and non fatal)	0.67 [0.59 0.77]	p=0.04	0	20455	2	ATLAS ACS 2 - TIMI 51 (2.5mg), ATLAS ACS 2 - TIMI 51 (5mg),
Deep vein thrombosis	no data
cardiovascular events	0.63 [0.57 0.70]	p=0.04	0	22757	4	ATLAS ACS 2 - TIMI 51 (2.5mg), ATLAS ACS 2 - TIMI 51 (5mg), ATLAS ACS-TIMI 46 (5mg), ATLAS ACS-TIMI 46 (2.5mg),
cardiac event (fatal and non fatal )	0.60 [0.29 1.25]	p=1.00	0	1151	1	ATLAS ACS-TIMI 46 (2.5mg),
proximal DVT	no data
distal DVT	no data
non-fatal pulmonary embolism	no data
asymptomatic DVT	no data
total VTE and all-cause mortality	no data
fatal pulmonary embolism	no data
Symptomatic venous thromboembolism (DVT, PE)	no data
major VTE (fatal and non fatal DVT,PE)	no data
recurrent DVT	no data
Gastrointestinal major bleeding	no data
Non-lifethreatening major bleeding	no data
Lifethreatening major bleeding	no data
Acute coronary syndrome	no data
Symptomatic deep-vein thrombosis	no data
major or clinically relevant non-major bleeding	2.06 [1.86 2.28]	p=0.04	0	22777	4	ATLAS ACS 2 - TIMI 51 (2.5mg), ATLAS ACS 2 - TIMI 51 (5mg), ATLAS ACS-TIMI 46 (5mg), ATLAS ACS-TIMI 46 (2.5mg),
any bleedings	2.00 [1.80 2.22]	p=0.04	0	20475	2	ATLAS ACS 2 - TIMI 51 (2.5mg), ATLAS ACS 2 - TIMI 51 (5mg),
stent thrombosis	no data
systemic thrombo-embolic complication	no data
major or minor bleeding	1.75 [1.50 2.03]	p=0.04	0	10240	1	ATLAS ACS 2 - TIMI 51 (2.5mg),
VTE	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
ATLAS ACS 2 - TIMI 51 (2.5mg), 2011	rivaroxaban 2.5 mg twice daily in addition to standard care	placebo	patients with a recent ACS
ATLAS ACS 2 - TIMI 51 (5mg), 2011	rivaroxaban 5 mg twice daily in addition to standard care	placebo	patients with a recent ACS
ATLAS ACS-TIMI 46 (5mg), 2009	rivaroxaban 5 mg twice daily	placebo	recent ACS patients treated with aspirin alone (n=761) or aspirin plus clopidogrel (n=2730)
ATLAS ACS-TIMI 46 (2.5mg), 2009	rivaroxaban 2.5 mg twice daily	placebo	recent ACS patients treated with aspirin alone (n=761) or aspirin plus clopidogrel (n=2730)

Rivaroxaban

atrial fibrillation, in all type of patients

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	0.92 [0.82 1.03]	p=1.00	0	14143	1	ROCKET-AF,
All cause death	0.92 [0.82 1.03]	p=1.00	0	14143	1	ROCKET-AF,
Coronary death	no data
Coronary event	0.80 [0.62 1.05]	p=1.00	0	14236	1	ROCKET-AF,
Coronary event	0.80 [0.62 1.05]	p=1.00	0	14236	1	ROCKET-AF,
Coronary event	0.80 [0.62 1.05]	p=1.00	0	14236	1	ROCKET-AF,
Adverse events	no data
Bleeding	no data
Cardiovascular death	0.94 [0.81 1.09]	p=1.00	0	14143	1	ROCKET-AF,
Cardiovascular death	0.94 [0.81 1.09]	p=1.00	0	14143	1	ROCKET-AF,
Major bleeding	1.04 [0.90 1.20]	p=1.00	0	14236	1	ROCKET-AF,
Major bleeding	1.04 [0.90 1.20]	p=1.00	0	14236	1	ROCKET-AF,
Minor bleeding	no data
Haemmorhagic stroke	0.58 [0.38 0.89]	p=0.04	0	14143	1	ROCKET-AF,
Haemmorhagic stroke	0.58 [0.38 0.89]	p=0.04	0	14143	1	ROCKET-AF,
Fatal stroke	0.70 [0.48 1.02]	p=1.00	0	14143	1	ROCKET-AF,
Fatal stroke	0.70 [0.48 1.02]	p=1.00	0	14143	1	ROCKET-AF,
Non fatal stroke	no data
Non fatal MI	no data
Fatal bleeding	0.50 [0.31 0.80]	p=0.04	0	14236	1	ROCKET-AF,
thrombo-embolic event (cerebral or systemic)	0.88 [0.75 1.04]	p=1.00	0	14171	1	ROCKET-AF,
ischemic stroke	0.99 [0.82 1.20]	p=1.00	0	14143	1	ROCKET-AF,
hypertransaminasemia	no data
intracranial hemorrhage	0.67 [0.47 0.95]	p=0.04	0	14236	1	ROCKET-AF,
TE event or ischemic stroke or systemic embolism	no data
stroke (fatal and non fatal)	0.84 [0.68 1.02]	p=1.00	0	14143	1	ROCKET-AF,
stroke (fatal and non fatal)	0.84 [0.68 1.02]	p=1.00	0	14143	1	ROCKET-AF,
myocardial infarction (fatal and non fatal)	0.91 [0.72 1.16]	p=1.00	0	14143	1	ROCKET-AF,
myocardial infarction (fatal and non fatal)	0.91 [0.72 1.16]	p=1.00	0	14143	1	ROCKET-AF,
Deep vein thrombosis	no data
cardiovascular events	no data
cardiac event (fatal and non fatal )	no data
proximal DVT	no data
distal DVT	no data
non-fatal pulmonary embolism	no data
asymptomatic DVT	no data
total VTE and all-cause mortality	no data
fatal pulmonary embolism	no data
Symptomatic venous thromboembolism (DVT, PE)	no data
major VTE (fatal and non fatal DVT,PE)	no data
recurrent DVT	no data
Gastrointestinal major bleeding	1.46 [1.18 1.79]	p=0.04	0	14236	1	ROCKET-AF,
Non-lifethreatening major bleeding	no data
Lifethreatening major bleeding	0.69 [0.52 0.90]	p=0.04	0	14236	1	ROCKET-AF,
Acute coronary syndrome	no data
Symptomatic deep-vein thrombosis	no data
major or clinically relevant non-major bleeding	1.03 [0.96 1.11]	p=1.00	0	14236	1	ROCKET-AF,
any bleedings	no data
stent thrombosis	no data
systemic thrombo-embolic complication	0.74 [0.42 1.31]	p=1.00	0	14264	1	ROCKET-AF,
major or minor bleeding	no data
VTE	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
ROCKET-AF, 2010	Rivaroxaban 20mg p.o. once daily	Warfarin p.o. once daily titrated to a target INR of 2.5 (range 2.0 to 3.0, inclusive)	Subjects With Non-Valvular Atrial Fibrillation

Rivaroxaban

cardiovascular prevention, in secondary prevention

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	82.00 [70.52 95.35]	p=0.04	0	18278	1	COMPASS (rivaroxaban + aspirin),
All cause death	82.00 [70.52 95.35]	p=0.04	0	18278	1	COMPASS (rivaroxaban + aspirin),
Coronary death	no data
Coronary event	no data
Coronary event	no data
Coronary event	no data
Adverse events	no data
Bleeding	no data
Cardiovascular death	78.00 [63.69 95.53]	p=0.04	0	18278	1	COMPASS (rivaroxaban + aspirin),
Cardiovascular death	78.00 [63.69 95.53]	p=0.04	0	18278	1	COMPASS (rivaroxaban + aspirin),
Major bleeding	no data
Major bleeding	no data
Minor bleeding	no data
Haemmorhagic stroke	no data
Haemmorhagic stroke	no data
Fatal stroke	78.00 [63.69 95.53]	p=0.04	0	18278	1	COMPASS (rivaroxaban + aspirin),
Fatal stroke	78.00 [63.69 95.53]	p=0.04	0	18278	1	COMPASS (rivaroxaban + aspirin),
Non fatal stroke	no data
Non fatal MI	no data
Fatal bleeding	no data
thrombo-embolic event (cerebral or systemic)	no data
ischemic stroke	51.00 [38.12 68.22]	p=0.04	0	18278	1	COMPASS (rivaroxaban + aspirin),
hypertransaminasemia	no data
intracranial hemorrhage	no data
TE event or ischemic stroke or systemic embolism	no data
stroke (fatal and non fatal)	58.00 [44.13 76.23]	p=0.04	0	18278	1	COMPASS (rivaroxaban + aspirin),
stroke (fatal and non fatal)	58.00 [44.13 76.23]	p=0.04	0	18278	1	COMPASS (rivaroxaban + aspirin),
myocardial infarction (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	no data
Deep vein thrombosis	no data
cardiovascular events	no data
cardiac event (fatal and non fatal )	no data
proximal DVT	no data
distal DVT	no data
non-fatal pulmonary embolism	no data
asymptomatic DVT	no data
total VTE and all-cause mortality	no data
fatal pulmonary embolism	no data
Symptomatic venous thromboembolism (DVT, PE)	no data
major VTE (fatal and non fatal DVT,PE)	no data
recurrent DVT	no data
Gastrointestinal major bleeding	no data
Non-lifethreatening major bleeding	no data
Lifethreatening major bleeding	no data
Acute coronary syndrome	no data
Symptomatic deep-vein thrombosis	no data
major or clinically relevant non-major bleeding	no data
any bleedings	no data
stent thrombosis	no data
systemic thrombo-embolic complication	no data
major or minor bleeding	no data
VTE	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
COMPASS (rivaroxaban alone), 2017	Rivaroxaban 2.5 mg twice daily alone	aspirin 100 mg once daily	Patients With Coronary or Peripheral Artery Disease
COMPASS (rivaroxaban + aspirin), 2017	rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily)	aspirin 100 mg once daily	Patients With Coronary or Peripheral Artery Disease

Rivaroxaban

thrombosis prevention, in all type of patients

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	0.98 [0.24 3.91]	p=1.00	0	3153	1	RECORD 1,
All cause death	0.98 [0.24 3.91]	p=1.00	0	3153	1	RECORD 1,
Coronary death	no data
Coronary event	0.49 [0.12 1.96]	p=1.00	0	3153	1	RECORD 1,
Coronary event	0.49 [0.12 1.96]	p=1.00	0	3153	1	RECORD 1,
Coronary event	0.49 [0.12 1.96]	p=1.00	0	3153	1	RECORD 1,
Adverse events	no data
Bleeding	no data
Cardiovascular death	no data
Cardiovascular death	no data
Major bleeding	3.02 [0.61 14.98]	p=1.00	0	4433	1	RECORD 1,
Major bleeding	3.02 [0.61 14.98]	p=1.00	0	4433	1	RECORD 1,
Minor bleeding	no data
Haemmorhagic stroke	no data
Haemmorhagic stroke	no data
Fatal stroke	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
Fatal bleeding	no data
thrombo-embolic event (cerebral or systemic)	no data
ischemic stroke	no data
hypertransaminasemia	no data
intracranial hemorrhage	no data
TE event or ischemic stroke or systemic embolism	no data
stroke (fatal and non fatal)	no data
stroke (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	no data
Deep vein thrombosis	0.23 [0.12 0.43]	p=0.04	0	4433	1	RECORD 1,
cardiovascular events	no data
cardiac event (fatal and non fatal )	no data
proximal DVT	0.03 [0.00 0.23]	p=0.04	0	3153	1	RECORD 1,
distal DVT	0.49 [0.24 1.01]	p=1.00	0	3153	1	RECORD 1,
non-fatal pulmonary embolism	3.91 [0.44 35.00]	p=1.00	0	3153	1	RECORD 1,
asymptomatic DVT	no data
total VTE and all-cause mortality	0.30 [0.18 0.52]	p=0.04	0	3153	1	RECORD 1,
fatal pulmonary embolism	no data
Symptomatic venous thromboembolism (DVT, PE)	0.55 [0.20 1.49]	p=1.00	0	4399	1	RECORD 1,
major VTE (fatal and non fatal DVT,PE)	0.12 [0.04 0.34]	p=0.04	0	3364	1	RECORD 1,
recurrent DVT	no data
Gastrointestinal major bleeding	no data
Non-lifethreatening major bleeding	no data
Lifethreatening major bleeding	no data
Acute coronary syndrome	no data
Symptomatic deep-vein thrombosis	no data
major or clinically relevant non-major bleeding	no data
any bleedings	no data
stent thrombosis	no data
systemic thrombo-embolic complication	no data
major or minor bleeding	no data
VTE	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
RECORD 1, 2008	rivaroxaban 10mg once daily for 35 days	enoxaparin 40mg subcutaneous once daily for 31-39 days	patients undergoing total hip arthroplasty

Rivaroxaban

thrombosis prevention, in all type of patients

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	0.08 [0.00 1.39]	p=1.00	0	2418	1	RECORD 3,
All cause death	0.08 [0.00 1.39]	p=1.00	0	2418	1	RECORD 3,
Coronary death	no data
Coronary event	0.51 [0.05 5.61]	p=1.00	0	2459	1	RECORD 3,
Coronary event	0.51 [0.05 5.61]	p=1.00	0	2459	1	RECORD 3,
Coronary event	0.51 [0.05 5.61]	p=1.00	0	2459	1	RECORD 3,
Adverse events	no data
Bleeding	no data
Cardiovascular death	no data
Cardiovascular death	no data
Major bleeding	1.19 [0.40 3.55]	p=1.00	0	2531	1	RECORD 3,
Major bleeding	1.19 [0.40 3.55]	p=1.00	0	2531	1	RECORD 3,
Minor bleeding	no data
Haemmorhagic stroke	no data
Haemmorhagic stroke	no data
Fatal stroke	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
Fatal bleeding	no data
thrombo-embolic event (cerebral or systemic)	no data
ischemic stroke	no data
hypertransaminasemia	no data
intracranial hemorrhage	no data
TE event or ischemic stroke or systemic embolism	no data
stroke (fatal and non fatal)	no data
stroke (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	0.51 [0.05 5.62]	p=1.00	0	2531	1	RECORD 3,
myocardial infarction (fatal and non fatal)	0.51 [0.05 5.62]	p=1.00	0	2531	1	RECORD 3,
Deep vein thrombosis	0.53 [0.39 0.70]	p=0.04	0	1702	1	RECORD 3,
cardiovascular events	no data
cardiac event (fatal and non fatal )	no data
proximal DVT	0.48 [0.22 1.06]	p=1.00	0	1702	1	RECORD 3,
distal DVT	0.53 [0.39 0.72]	p=0.04	0	1702	1	RECORD 3,
non-fatal pulmonary embolism	0.21 [0.01 4.45]	p=1.00	0	1702	1	RECORD 3,
asymptomatic DVT	no data
total VTE and all-cause mortality	0.51 [0.38 0.68]	p=0.04	0	1702	1	RECORD 3,
fatal pulmonary embolism	no data
Symptomatic venous thromboembolism (DVT, PE)	0.34 [0.15 0.75]	p=0.04	0	2418	1	RECORD 3,
major VTE (fatal and non fatal DVT,PE)	0.38 [0.18 0.83]	p=0.04	0	1833	1	RECORD 3,
recurrent DVT	no data
Gastrointestinal major bleeding	no data
Non-lifethreatening major bleeding	no data
Lifethreatening major bleeding	no data
Acute coronary syndrome	no data
Symptomatic deep-vein thrombosis	no data
major or clinically relevant non-major bleeding	no data
any bleedings	no data
stent thrombosis	no data
systemic thrombo-embolic complication	no data
major or minor bleeding	no data
VTE	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
RECORD 3, 2008	rivaroxaban 10 mg once daily for 10- 14 days	enoxaparin 40 mg subcutaneous once daily for 10-14 days	patients undergoing total knee arthroplasty

Rivaroxaban

thrombosis prevention, in all type of patients

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	0.34 [0.07 1.67]	p=1.00	0	1733	1	RECORD 2,
All cause death	0.34 [0.07 1.67]	p=1.00	0	1733	1	RECORD 2,
Coronary death	no data
Coronary event	1.33 [0.30 5.97]	p=1.00	0	2457	1	RECORD 2,
Coronary event	1.33 [0.30 5.97]	p=1.00	0	2457	1	RECORD 2,
Coronary event	1.33 [0.30 5.97]	p=1.00	0	2457	1	RECORD 2,
Adverse events	no data
Bleeding	no data
Cardiovascular death	no data
Cardiovascular death	no data
Major bleeding	1.00 [0.06 16.02]	p=1.00	0	2457	1	RECORD 2,
Major bleeding	1.00 [0.06 16.02]	p=1.00	0	2457	1	RECORD 2,
Minor bleeding	no data
Haemmorhagic stroke	no data
Haemmorhagic stroke	no data
Fatal stroke	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
Fatal bleeding	no data
thrombo-embolic event (cerebral or systemic)	no data
ischemic stroke	no data
hypertransaminasemia	no data
intracranial hemorrhage	no data
TE event or ischemic stroke or systemic embolism	no data
stroke (fatal and non fatal)	no data
stroke (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	no data
Deep vein thrombosis	0.26 [0.17 0.42]	p=0.04	0	1953	2	ODIXa-HIP 10mg, RECORD 2,
cardiovascular events	no data
cardiac event (fatal and non fatal )	no data
proximal DVT	0.19 [0.09 0.43]	p=0.04	0	1953	2	ODIXa-HIP 10mg, RECORD 2,
distal DVT	0.34 [0.20 0.60]	p=0.04	0	1953	2	ODIXa-HIP 10mg, RECORD 2,
non-fatal pulmonary embolism	0.34 [0.05 2.34]	p=1.00	0	1953	2	ODIXa-HIP 10mg, RECORD 2,
asymptomatic DVT	no data
total VTE and all-cause mortality	0.27 [0.17 0.41]	p=0.04	0	1953	2	ODIXa-HIP 10mg, RECORD 2,
fatal pulmonary embolism	no data
Symptomatic venous thromboembolism (DVT, PE)	0.20 [0.06 0.69]	p=0.04	0	2419	1	RECORD 2,
major VTE (fatal and non fatal DVT,PE)	0.12 [0.05 0.29]	p=0.04	0	1923	1	RECORD 2,
recurrent DVT	no data
Gastrointestinal major bleeding	no data
Non-lifethreatening major bleeding	no data
Lifethreatening major bleeding	no data
Acute coronary syndrome	no data
Symptomatic deep-vein thrombosis	no data
major or clinically relevant non-major bleeding	1.20 [0.91 1.58]	p=1.00	0	2457	1	RECORD 2,
any bleedings	no data
stent thrombosis	no data
systemic thrombo-embolic complication	no data
major or minor bleeding	no data
VTE	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
ODIXa-HIP 10mg, 2006	rivaroxaban 10mg daily for 5–9 days	once-daily subcutaneous enoxaparin dose of 40 mg for 5–9 days	patients undergoing elective total hip replacement
RECORD 2, 2008	extended thromboprophylaxis with rivaroxaban 10mg once daily for 31-39 days	enoxaparin 40mg subcutaneous once daily for 10-14 days	patients undergoing elective total hip replacement

Rivaroxaban

thrombosis prevention, in all type of patients

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	0.66 [0.11 3.95]	p=1.00	0	3034	1	RECORD 4,
All cause death	0.66 [0.11 3.95]	p=1.00	0	3034	1	RECORD 4,
Coronary death	no data
Coronary event	0.33 [0.03 3.17]	p=1.00	0	3034	1	RECORD 4,
Coronary event	0.33 [0.03 3.17]	p=1.00	0	3034	1	RECORD 4,
Coronary event	0.33 [0.03 3.17]	p=1.00	0	3034	1	RECORD 4,
Adverse events	no data
Bleeding	no data
Cardiovascular death	no data
Cardiovascular death	no data
Major bleeding	1.80 [0.61 5.33]	p=1.00	0	3240	2	ODIXa-KNEE, RECORD 4,
Major bleeding	1.80 [0.61 5.33]	p=1.00	0	3240	2	ODIXa-KNEE, RECORD 4,
Minor bleeding	no data
Haemmorhagic stroke	no data
Haemmorhagic stroke	no data
Fatal stroke	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
Fatal bleeding	no data
thrombo-embolic event (cerebral or systemic)	no data
ischemic stroke	no data
hypertransaminasemia	no data
intracranial hemorrhage	no data
TE event or ischemic stroke or systemic embolism	no data
stroke (fatal and non fatal)	no data
stroke (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	0.20 [0.02 1.69]	p=1.00	0	3148	1	RECORD 4,
myocardial infarction (fatal and non fatal)	0.20 [0.02 1.69]	p=1.00	0	3148	1	RECORD 4,
Deep vein thrombosis	no data
cardiovascular events	no data
cardiac event (fatal and non fatal )	no data
proximal DVT	0.23 [0.07 0.81]	p=0.04	0	1924	1	RECORD 4,
distal DVT	0.82 [0.56 1.20]	p=1.00	0	1924	1	RECORD 4,
non-fatal pulmonary embolism	0.49 [0.15 1.64]	p=1.00	0	3034	1	RECORD 4,
asymptomatic DVT	0.72 [0.50 1.03]	p=1.00	0	1924	1	RECORD 4,
total VTE and all-cause mortality	0.69 [0.50 0.95]	p=0.04	0	1924	1	RECORD 4,
fatal pulmonary embolism	no data
Symptomatic venous thromboembolism (DVT, PE)	0.60 [0.28 1.28]	p=1.00	0	3034	1	RECORD 4,
major VTE (fatal and non fatal DVT,PE)	0.59 [0.29 1.17]	p=1.00	0	2234	1	RECORD 4,
recurrent DVT	no data
Gastrointestinal major bleeding	no data
Non-lifethreatening major bleeding	no data
Lifethreatening major bleeding	no data
Acute coronary syndrome	no data
Symptomatic deep-vein thrombosis	0.60 [0.22 1.65]	p=1.00	0	1924	1	RECORD 4,
major or clinically relevant non-major bleeding	1.34 [0.85 2.09]	p=1.00	0	3034	1	RECORD 4,
any bleedings	no data
stent thrombosis	no data
systemic thrombo-embolic complication	no data
major or minor bleeding	no data
VTE	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
ODIXa-KNEE, 2005	BAY 59-7939 5mg b.i.d. for 5–9 days	enoxaparin 30 mg b.i.d. for 5–9 days	patients undergoing elective total knee replacement
RECORD 4, 2009	rivaroxaban 10mg once daily for 10 to 14 days	enoxaparin 30 mg twice daily by subcutaneous injection for 10-14 days	patients who had undergone total-knee-replacement surgery

Ximelagatran

acute coronary syndrome, in all type of patients

Ximelagatran

venous thrombosis, in all type of patients

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	0.86 [0.29 2.56]	p=1.00	0	1223	1	THRIVE III,
All cause death	0.86 [0.29 2.56]	p=1.00	0	1223	1	THRIVE III,
Coronary death	no data
Coronary event	no data
Coronary event	no data
Coronary event	no data
Adverse events	no data
Bleeding	no data
Cardiovascular death	no data
Cardiovascular death	no data
Major bleeding	1.20 [0.36 3.95]	p=1.00	0	1223	1	THRIVE III,
Major bleeding	1.20 [0.36 3.95]	p=1.00	0	1223	1	THRIVE III,
Minor bleeding	no data
Haemmorhagic stroke	no data
Haemmorhagic stroke	no data
Fatal stroke	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
Fatal bleeding	no data
thrombo-embolic event (cerebral or systemic)	no data
ischemic stroke	no data
hypertransaminasemia	no data
intracranial hemorrhage	no data
TE event or ischemic stroke or systemic embolism	no data
stroke (fatal and non fatal)	no data
stroke (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	no data
Deep vein thrombosis	no data
cardiovascular events	no data
cardiac event (fatal and non fatal )	no data
proximal DVT	no data
distal DVT	no data
non-fatal pulmonary embolism	no data
asymptomatic DVT	no data
total VTE and all-cause mortality	no data
fatal pulmonary embolism	no data
Symptomatic venous thromboembolism (DVT, PE)	no data
major VTE (fatal and non fatal DVT,PE)	no data
recurrent DVT	no data
Gastrointestinal major bleeding	no data
Non-lifethreatening major bleeding	no data
Lifethreatening major bleeding	no data
Acute coronary syndrome	no data
Symptomatic deep-vein thrombosis	no data
major or clinically relevant non-major bleeding	no data
any bleedings	1.21 [0.91 1.60]	p=1.00	0	1223	1	THRIVE III,
stent thrombosis	no data
systemic thrombo-embolic complication	no data
major or minor bleeding	no data
VTE	0.24 [0.14 0.41]	p=0.04	0	1223	1	THRIVE III,

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
THRIVE III, 2003	ximelagatran 24 mg twice daily for 18 months	placebo for 18 months	patients with venous thromboembolism who had undergone six months of anticoagulant therapy

direct factor Xa inhibitors