direct factor Xa inhibitors

Description Results NMA

ISTH major or clinically relevant nonmajor bleeding 2.45 [1.32; 4.55]

Cardiovascular death, MI, or stroke 0.61 [0.35; 1.06]

Cardiovascular death, MI, or stroke 0.73 [0.45; 1.18]

ISTH major or clinically relevant nonmajor bleeding 1.78 [0.93; 3.41]

TIMI major or minor bleeding not related to CABG 2.74 [1.79; 4.17]

major bleeding 2.53 [1.47; 4.36]

ISTH major or clinically relevant nonmajor bleeding 2.58 [1.83; 3.62]

any bleeding 2.21 [1.94; 2.51]

major or minor bleeding 2.74 [1.79; 4.17]

net clinical benefit 0.98 [0.84; 1.15]

death 1.08 [0.86; 1.35]

cardiovascular death 0.96 [0.74; 1.25]

fatal bleeding ∞ [NaN; ∞]

ischemic stroke 0.67 [0.40; 1.14]

MI 0.93 [0.77; 1.14]

Cardiovascular death, MI, or stroke 0.99 [0.86; 1.15]

death, MI, stroke, recurrent ischaemia 0.95 [0.82; 1.09]

Thrombotic complication during PCI 0.73 [0.47; 1.12]

apixaban 10 mg once daily (n=318)

vs.

placebo (n=611)

4 arms: 20mg daily, 10mg twice daily, 10mg daily and 2.5mg twice daily. 10mg twice daily and 20mg once daily were discontinued due to an excess of major and minor bleeding

double blind

Parallel groups

Sample size: 318/611

Primary endpoint: major or clinically relevant nonmajor bleeding

FU duration: 6 months

dose-finding study

Apixaban 2.5mg twice daily (n=-9)

vs.

placebo (n=611)

4 arms: 20mg daily, 10mg twice daily, 10mg daily and 2.5mg twice daily. 10mg twice daily and 20mg once daily were discontinued due to an excess of major and minor bleeding

double blind

Sample size: -9/611

Primary endpoint: major or clinically relevant nonmajor bleeding

FU duration: 6 months

dose-finding study

apixaban 5mg twice daily (n=3705)

vs.

placebo (n=3687)

double blind

Parallel groups

Sample size: 3705/3687

Primary endpoint: Cv death, MI, ischemic stroke

FU duration: 8 months

dabigatran 4 dosages (50mg twice daily, 75mg twice daily, 110mg twice daily, 150mg twice daily) (n=1501)

vs.

placebo (n=373)

5 arms: dabigatran 50 mg twice daily (n=372), 75 mg twice daily (n=371), 110 mg twice daily (n=411), 150 mg twice daily (n=351), or placebo (n=373)

double blind

Parallel groups

Sample size: 1501/373

Primary endpoint: Major and minor bleeding

FU duration: 6 months

death, MI, recurrent ischaemia, use of Gp2b3a inhibitor 0.58 [0.34; 0.99]

death, MI 0.56 [0.30; 1.04]

TIMI major or minor bleeding not related to CABG 1.26 [0.63; 2.52]

Thrombotic complication during PCI 1.44 [0.59; 3.52]

otamixaban 5 doses (0·08 mg/kg bolus followed by 0.035, 0.070, 0.105, 0.140, 0.175 mg/kg/h) (n=2792)

vs.

Heparin+eptifibatide (n=449)

6 arms phase 2: otamixaban 5 doses (0·08 mg/kg bolus followed by 0.035, 0.070, 0.105, 0.140, 0.175 mg/kg/h) and unfractionated heparin + eptifi batide

double blind

Parallel groups

Sample size: 2792/449

Primary endpoint: death, MI, recurrent ischaemia, use of Gp2b3a

FU duration: 7 days

dose finding study

death 0.67 [0.53; 0.86]

cardiovascular death 0.66 [0.51; 0.85]

Cardiovascular death, MI, or stroke 0.83 [0.72; 0.96]

major bleeding 3.43 [2.06; 5.71]

ISTH major or clinically relevant nonmajor bleeding 1.75 [1.52; 2.01]

any bleeding 1.75 [1.52; 2.01]

major or minor bleeding 1.75 [1.52; 2.01]

fatal bleeding 0.67 [0.24; 1.88]

MI 0.90 [0.74; 1.08]

death 0.42 [0.33; 0.53]

cardiovascular death 0.42 [0.33; 0.53]

MI 0.53 [0.45; 0.63]

Cardiovascular death, MI, or stroke 0.50 [0.44; 0.57]

major bleeding 4.33 [2.63; 7.12]

ISTH major or clinically relevant nonmajor bleeding 2.27 [1.98; 2.59]

any bleeding 2.27 [1.98; 2.59]

fatal bleeding 1.67 [0.73; 3.82]

major bleeding 17.64 [2.34; 132.76]

ISTH major or clinically relevant nonmajor bleeding 3.36 [2.21; 5.10]

Cardiovascular death, MI, or stroke 0.63 [0.39; 1.01]

major bleeding 3.76 [0.24; 59.88]

Cardiovascular death, MI, or stroke 0.52 [0.23; 1.19]

death, MI, stroke, recurrent ischaemia 0.60 [0.29; 1.25]

ISTH major or clinically relevant nonmajor bleeding 1.71 [0.76; 3.85]

rivaroxaban 2.5 mg twice daily in addition to standard care (n=5174)

vs.

placebo (n=5176)

3 arms: rivaroxaban (2.5 mg twice daily or 5 mg twice daily) in addition to standard care and placebo

double blind

Parallel groups

Sample size: 5174/5176

Primary endpoint: CV death, MI, stroke

FU duration: 13 months

rivaroxaban 5 mg twice daily in addition to standard care (n=5176)

vs.

placebo (n=5176)

3 arms: rivaroxaban (2.5 mg twice daily or 5 mg twice daily) in addition to standard care and placebo

double blind

Sample size: 5176/5176

Primary endpoint: CV death, MI, stroke

FU duration: 13 months

rivaroxaban 5 mg twice daily (n=519)

vs.

placebo (n=1160)

dose finding study: rivaroxaban 5 mg, 10 mg, or 20 mg once daily, 2.5 mg, 5 mg, or 10 mg twice daily and placebo

double blind

Parallel groups

Sample size: 519/1160

Primary endpoint: clinically significant bleeding

FU duration: 6 months

dose-finding study

rivaroxaban 2.5 mg twice daily (n=152)

vs.

placebo (n=1160)

dose finding study: rivaroxaban 5 mg, 10 mg, or 20 mg once daily, 2.5 mg, 5 mg, or 10 mg twice daily and placebo

double blind

Sample size: 152/1160

Primary endpoint: clinically significant bleeding

FU duration: 6 months

dose-finding study

oral ximelagatran at doses of 24 mg, 36 mg, 48 mg, or 60 mg twice daily (n=1245)

vs.

placebo (n=638)

double-blind

Parallel groups

Sample size: 1245/638

Primary endpoint: death, MI, severe recurrent ischaemia

FU duration: 6 months

dose ranging

all death 0.89 [0.81; 0.98] Demonstrated

major bleeding 0.70 [0.61; 0.81] Demonstrated

thrombo-embolic event (cerebral or systemic) 0.80 [0.67; 0.95] Demonstrated

thrombo-embolic event (central or systemic)and fatal or intracranial hemorrhage 0.78 [0.70; 0.87]

haemorragic stroke(or intracerebral hemorrhage) 0.51 [0.35; 0.75]

All stroke(ischemic+hemorrhagic/fatal+non fatal) 0.79 [0.66; 0.95]

major and clinically relevant non-major bleeding 0.70 [0.63; 0.77]

coronary events 0.88 [0.66; 1.17]

ischemic stroke 0.92 [0.75; 1.14]

Gastrointestinal major bleeding 0.88 [0.68; 1.14]

systemic thrombo-embolic complication 0.88 [0.44; 1.76]

apixaban 5mg twice daily (n=9120)

vs.

warfarin adjusted for an INR between 2 and 3 (n=9081)

double blind

Parallel groups

Sample size: 9120/9081

Primary endpoint: stroke or systemic embolism

FU duration: 1.8 yrs (median)

apixaban 5 or 2.5 mg twice daily (n=222)

vs.

warfarin (n=0)

double blind

Parallel groups

Sample size: 222/0

Primary endpoint: major or clinically relevant non-major bleeding

FU duration: 12 weeks

phase 2

vascular death,TIA,nonfatal stroke or systemic embolism 0.66 [0.53; 0.83]

thrombo-embolic event (cerebral or systemic) 0.46 [0.33; 0.64]

ischemic stroke 0.37 [0.25; 0.55]

All stroke(ischemic+hemorrhagic/fatal+non fatal) 0.46 [0.33; 0.65]

all death 0.79 [0.62; 1.01]

coronary events 0.85 [0.50; 1.47]

vascular death 0.86 [0.64; 1.16]

major bleeding 1.14 [0.74; 1.75]

haemorragic stroke(or intracerebral hemorrhage) 0.66 [0.24; 1.86]

fatal bleeding 0.84 [0.26; 2.72]

Gastrointestinal major bleeding 0.85 [0.39; 1.84]

apixaban 5 mg (or 2.5 mg) twice daily (n=2808)

vs.

aspirin 81-324 md daily (n=2791)

double blind

Parallel groups

Sample size: 2808/2791

Primary endpoint: stroke or systemic embolism

FU duration: maximum 21 months

vascular death 0.86 [0.77; 0.97]

major bleeding 0.80 [0.71; 0.91]

haemorragic stroke(or intracerebral hemorrhage) 0.47 [0.35; 0.64]

fatal bleeding 0.55 [0.36; 0.84]

Life threatening major bleeding 0.51 [0.38; 0.69]

major and clinically relevant non-major bleeding 0.86 [0.80; 0.92]

Gastrointestinal major bleeding 1.23 [1.01; 1.49]

all death 0.92 [0.83; 1.01]

fatal stroke(ischemic+hemorrhagic) 0.92 [0.68; 1.25]

thrombo-embolic event (cerebral or systemic) 0.87 [0.73; 1.04]

ischemic stroke 1.00 [0.84; 1.20]

All stroke(ischemic+hemorrhagic/fatal+non fatal) 0.88 [0.75; 1.03]

systemic thrombo-embolic complication 0.65 [0.34; 1.24]

Four Fixed Dose Regimens of edoxaban (DU-176b) (n=1146)

vs.

warfarin (n=0)

double-blind

Parallel groups

Sample size: 1146/0

Primary endpoint: clinically relevant bleeding, •Laboratory marked abnormalities

FU duration: 3 months

phase 2

edoxaban 60mg once daily (n=7035)

vs.

warfarin (INR 2-3) (n=7036)

a third arm received a low dose of edoxaban, 30mg. The allocated dose was halved if any of the following characteristics were present at the time of randomization or during the study: estimated creatinine clearance of 30 to 50 ml per minute, a body weight of 60 kg or less, or the concomitant use of verapamil or quinidine (potent P-glycoprotein inhibitors)

double blind

Parallel groups

Sample size: 7035/7036

Primary endpoint: stroke, systemic embolic events and all-cause mortality

FU duration: 2.8 years

edoxaban (DU-176b) (n=-9)

vs.

warfarin (n=-9)

double-blind

Parallel groups

Sample size: -9/-9

Primary endpoint: all bleeding

FU duration:

haemorragic stroke(or intracerebral hemorrhage) 0.58 [0.38; 0.89]

fatal bleeding 0.50 [0.31; 0.80]

Life threatening major bleeding 0.69 [0.53; 0.89]

Gastrointestinal major bleeding 1.46 [1.19; 1.78]

vascular death,TIA,nonfatal stroke or systemic embolism 0.94 [0.84; 1.05]

all death 0.92 [0.82; 1.03]

coronary events 0.80 [0.62; 1.04]

vascular death 0.94 [0.81; 1.09]

major bleeding 1.04 [0.90; 1.20]

fatal stroke(ischemic+hemorrhagic) 0.70 [0.49; 1.02]

thrombo-embolic event (cerebral or systemic) 0.88 [0.75; 1.04]

ischemic stroke 0.99 [0.82; 1.20]

All stroke(ischemic+hemorrhagic/fatal+non fatal) 0.84 [0.69; 1.01]

major and clinically relevant non-major bleeding 1.03 [0.96; 1.11]

systemic thrombo-embolic complication 0.74 [0.42; 1.31]

Rivaroxaban 20mg p.o. once daily (n=7131)

vs.

Warfarin p.o. once daily titrated to a target INR of 2.5 (range 2.0 to 3.0, inclusive) (n=7133)

double blind

Parallel groups

Sample size: 7131/7133

Primary endpoint: stroke or non-CNS systemic embolism

FU duration: median 1.94 y

major bleeding 17.00 [6.50; 44.44]

CV events 76.00 [66.58; 86.75]

all causes deaths 82.00 [70.52; 95.35]

CV death (IHD+stroke) 78.00 [63.69; 95.53]

fatal stroke 78.00 [63.69; 95.53]

ischemic stroke 51.00 [38.12; 68.22]

all stroke 58.00 [44.13; 76.23]

Rivaroxaban 2.5 mg twice daily alone (n=27400)

vs.

aspirin 100 mg once daily (n=0)

3 arms rivaroxaban and aspirin, rivaroxaban alone, aspirin alone

Sample size: 27400/0

Primary endpoint:

FU duration:

rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily) (n=9152)

vs.

aspirin 100 mg once daily (n=9126)

3 arms rivaroxaban and aspirin, rivaroxaban alone, aspirin alone

double-blind

Parallel groups

Sample size: 9152/9126

Primary endpoint: cardiovascular death, stroke, MI

FU duration: 23 months

DVT (asymptomatic or symptomatic) 0.32 [0.20; 0.51]

proximal DVT 0.35 [0.15; 0.82]

asymptomatic DVT 0.33 [0.20; 0.54]

total VTE and all-cause mortality 0.36 [0.23; 0.56]

major VTE (fatal and non fatal DVT,PE) 0.40 [0.17; 0.94]

death 2.99 [0.31; 28.73]

coronary events 1.66 [0.40; 6.93]

major bleeding 1.22 [0.65; 2.26]

myocardial infarction 2.24 [0.69; 7.27]

non-fatal PE 0.40 [0.08; 2.05]

Symptomatic venous thromboembolism 0.40 [0.04; 4.00]

symptomatic DVT 0.20 [0.02; 1.71]

major or clinically relevant non-major bleeding 0.96 [0.76; 1.21]

apixaban 2.5mg twice daily for 35 days (n=2708)

vs.

enoxaparin 40mg once daily for 35 days (n=2699)

double blind

Parallel groups

Sample size: 2708/2699

Primary endpoint: asymptomatic and symptomatic DVT, PE,all-cause death

FU duration: 35 days (+60)

death ∞ [NaN; ∞]

major bleeding NaN [NaN; NaN]

proximal DVT 0.33 [0.03; 3.10]

asymptomatic DVT 0.63 [0.29; 1.40]

total VTE and all-cause mortality 0.39 [0.08; 1.98]

major VTE (fatal and non fatal DVT,PE) 0.58 [0.28; 1.20]

symptomatic DVT 0.98 [0.06; 15.50]

all bleeding 0.73 [0.26; 2.04]

major or clinically relevant non-major bleeding 0.67 [0.47; 0.97]

death 1.00 [0.20; 4.94]

coronary events 0.50 [0.05; 5.48]

major bleeding 0.50 [0.24; 1.02]

myocardial infarction 0.40 [0.08; 2.05]

DVT (asymptomatic or symptomatic) 0.95 [0.72; 1.26]

proximal DVT 0.79 [0.33; 1.89]

total VTE and all-cause mortality 1.02 [0.78; 1.32]

Symptomatic venous thromboembolism 1.46 [0.72; 2.94]

DVT (asymptomatic or symptomatic) 0.60 [0.50; 0.72]

proximal DVT 0.35 [0.16; 0.74]

total VTE and all-cause mortality 0.62 [0.51; 0.74]

major VTE (fatal and non fatal DVT,PE) 0.50 [0.26; 0.97]

death ∞ [NaN; ∞]

coronary events 1.00 [0.06; 16.05]

major bleeding 0.65 [0.28; 1.49]

myocardial infarction 1.00 [0.06; 15.98]

Symptomatic venous thromboembolism 1.00 [0.35; 2.85]

symptomatic DVT 0.43 [0.11; 1.66]

major or clinically relevant non-major bleeding 0.74 [0.52; 1.05]

apixaban 2.5mg BID for 12 days (n=153)

vs.

enoxaparin 30mg twice daily for 12 days (n=152)

8 arms: apixaban 2.5mg BID, 5mg BID, 10mg BID, 5mgQD, 20mg QD for 12 days, enoxaparin 30mg twice daily, warfarin INR 1.8-3.0

double blind

Parallel groups

Sample size: 153/152

Primary endpoint: VTE events and all-cause death

FU duration: 12 days

phase 2 dose ranging study

apixaban 2.5 mg orally twice daily for 10 to 14 days (n=1599)

vs.

enoxaparin 30mg subcutaneously every 12 hours for 10-14 days (n=1596)

double blind

Parallel groups

Sample size: 1599/1596

Primary endpoint: a- and symptomatic DVT, non fatal PE, death

FU duration: 10-14 days

apixaban 2.5mg twice daily during 12 days (n=1528)

vs.

enoxaparin 40mg once daily 12 days (n=1529)

"European" enoxaprin regimen

double blind

Parallel groups

Sample size: 1528/1529

Primary endpoint: asymptomatic and symptomatic proximal DVT, PE, VTE-related death

FU duration: 12 days

distal DVT 0.36 [0.15; 0.92]

asymptomatic DVT 0.38 [0.16; 0.89]

major VTE (fatal and non fatal DVT,PE) 0.34 [0.14; 0.86]

proximal DVT 0.49 [0.04; 5.33]

symptomatic DVT NaN [NaN; NaN]

edoxaban 30 mg once daily for 11 to 14 days (n=255)

vs.

subcutaneous enoxaparin 2,000 IU, equivalent to 20 mg, twice daily (BID) for 11 to 14 days (n=248)

double-blind

Parallel groups

Sample size: 255/248

Primary endpoint: all DVT,PE

FU duration:

DVT (asymptomatic or symptomatic) 0.42 [0.22; 0.79]

distal DVT 0.36 [0.17; 0.73]

total VTE and all-cause mortality 0.42 [0.22; 0.79]

proximal DVT 0.95 [0.20; 4.59]

non-fatal PE NaN [NaN; NaN]

DVT (asymptomatic or symptomatic) 0.23 [0.12; 0.43]

proximal DVT 0.03 [0.00; 0.23]

total VTE and all-cause mortality 0.30 [0.18; 0.51]

major VTE (fatal and non fatal DVT,PE) 0.12 [0.04; 0.34]

death 0.98 [0.24; 3.90]

coronary events 0.49 [0.12; 1.95]

major bleeding 3.02 [0.61; 14.95]

distal DVT 0.49 [0.24; 1.00]

non-fatal PE 3.91 [0.44; 34.92]

Symptomatic venous thromboembolism 0.55 [0.20; 1.48]

DVT (asymptomatic or symptomatic) 0.20 [0.11; 0.35]

proximal DVT 0.11 [0.05; 0.29]

distal DVT 0.34 [0.16; 0.71]

total VTE and all-cause mortality 0.21 [0.13; 0.35]

Symptomatic venous thromboembolism 0.20 [0.06; 0.69]

major VTE (fatal and non fatal DVT,PE) 0.12 [0.05; 0.28]

death 0.34 [0.07; 1.66]

coronary events 1.33 [0.30; 5.95]

major bleeding 1.00 [0.06; 15.98]

non-fatal PE 0.25 [0.03; 2.25]

major or clinically relevant non-major bleeding 1.20 [0.93; 1.54]

rivaroxaban 10mg daily for 5–9 days (n=142)

vs.

once-daily subcutaneous enoxaparin dose of 40 mg for 5–9 days (n=157)

dose finding study (doses of 5, 10, 20, 30, or 40 mg)

double blind

Parallel groups

Sample size: 142/157

Primary endpoint: any DVT, PE, all cause death

FU duration: 5-9 days

rivaroxaban 10mg once daily for 35 days (n=2266)

vs.

enoxaparin 40mg subcutaneous once daily for 31-39 days (n=2275)

double blind

Parallel groups

Sample size: 2266/2275

Primary endpoint: DVT, PE, death

FU duration: 36 days (range 30-42)

extended thromboprophylaxis with rivaroxaban 10mg once daily for 31-39 days (n=1252)

vs.

enoxaparin 40mg subcutaneous once daily for 10-14 days (n=1257)

double blind

Parallel groups

Sample size: 1252/1257

Primary endpoint: DVT, PE , all cause death

FU duration: 30-42 days

major bleeding 0.00 [0.00; NaN]

DVT (asymptomatic or symptomatic) 0.53 [0.41; 0.68]

distal DVT 0.53 [0.41; 0.70]

total VTE and all-cause mortality 0.51 [0.39; 0.65]

Symptomatic venous thromboembolism 0.34 [0.15; 0.75]

major VTE (fatal and non fatal DVT,PE) 0.38 [0.18; 0.82]

death 0.00 [0.00; NaN]

coronary events 0.51 [0.05; 5.59]

major bleeding 1.19 [0.40; 3.53]

myocardial infarction 0.51 [0.05; 5.61]

proximal DVT 0.48 [0.22; 1.05]

non-fatal PE 0.00 [0.00; NaN]

proximal DVT 0.23 [0.07; 0.80]

total VTE and all-cause mortality 0.69 [0.51; 0.92]

death 0.66 [0.11; 3.94]

coronary events 0.33 [0.03; 3.16]

major bleeding 2.47 [0.78; 7.86]

myocardial infarction 0.20 [0.02; 1.69]

distal DVT 0.82 [0.57; 1.17]

non-fatal PE 0.49 [0.15; 1.64]

asymptomatic DVT 0.72 [0.51; 1.01]

Symptomatic venous thromboembolism 0.60 [0.29; 1.27]

major VTE (fatal and non fatal DVT,PE) 0.59 [0.30; 1.16]

symptomatic DVT 0.60 [0.22; 1.63]

major or clinically relevant non-major bleeding 1.34 [0.86; 2.07]

BAY 59-7939 5mg b.i.d. for 5–9 days (n=102)

vs.

enoxaparin 30 mg b.i.d. for 5–9 days (n=105)

dose ranging study with doses 2.5, 5, 10, 20, and 30 mg

double blind

Parallel groups

Sample size: 102/105

Primary endpoint:

FU duration: 5-9 days

rivaroxaban 10 mg once daily for 10- 14 days (n=1254)

vs.

enoxaparin 40 mg subcutaneous once daily for 10-14 days (n=1277)

double blind

Parallel groups

Sample size: 1254/1277

Primary endpoint: DVT, PE all cause mortality

FU duration: 13-17 days

rivaroxaban 10mg once daily for 10 to 14 days (n=1584)

vs.

enoxaparin 30 mg twice daily by subcutaneous injection for 10-14 days (n=1564)

double blind

Parallel groups

Sample size: 1584/1564

Primary endpoint: total VTE events

FU duration: 40 days

Recurrent DVT/DVT extension (symptomatic) 0.17 [0.09; 0.31]

VTA 0.24 [0.15; 0.40]

All-cause mortality 0.86 [0.29; 2.53]

Major hemorrhage 1.20 [0.37; 3.90]

any bleedings 1.21 [0.96; 1.51]

ximelagatran 24 mg twice daily for 18 months (n=612)

vs.

placebo for 18 months (n=611)

double blind

Parallel groups

Sample size: 612/611

Primary endpoint: symptomatic recurrent venous

FU duration: 18 months