direct antithrombins

Description Results NMA

haemorragic stroke(or intracerebral hemorrhage) 0.26 [0.14; 0.49]

fatal stroke(ischemic+hemorrhagic) 0.67 [0.51; 0.89]

non fatal stroke 0.63 [0.43; 0.92]

fatal bleeding 0.82 [0.67; 1.00]

thrombo-embolic event (cerebral or systemic) 0.66 [0.53; 0.82]

ischemic stroke 0.76 [0.59; 0.97]

All stroke(ischemic+hemorrhagic/fatal+non fatal) 0.64 [0.51; 0.81]

Life threatening major bleeding 0.82 [0.67; 1.00]

Gastrointestinal major bleeding 1.50 [1.20; 1.89]

all death 0.88 [0.77; 1.00]

coronary events 1.29 [0.99; 1.69]

vascular death 0.85 [0.72; 1.00]

major bleeding 0.93 [0.81; 1.07]

Non–life threatening Major bleeding 1.08 [0.90; 1.30]

systemic thrombo-embolic complication 0.85 [0.39; 1.84]

major bleeding 0.80 [0.69; 0.93]

haemorragic stroke(or intracerebral hemorrhage) 0.31 [0.17; 0.56]

Life threatening major bleeding 0.68 [0.56; 0.84]

all death 0.91 [0.80; 1.03]

vascular death 0.90 [0.77; 1.06]

fatal stroke(ischemic+hemorrhagic) 0.95 [0.74; 1.23]

non fatal stroke 0.87 [0.62; 1.23]

thrombo-embolic event (cerebral or systemic) 0.91 [0.74; 1.11]

ischemic stroke 1.11 [0.89; 1.39]

thromboembolic event likes(TE event or ischemic stroke or systemic embolism) 0.92 [0.75; 1.12]

All stroke(ischemic+hemorrhagic/fatal+non fatal) 0.92 [0.74; 1.14]

Gastrointestinal major bleeding 1.11 [0.87; 1.42]

Non–life threatening Major bleeding 0.95 [0.79; 1.15]

systemic thrombo-embolic complication 0.79 [0.36; 1.73]

dabigatran 150 mg twice daily (alone or combined with 81- or 325-mg aspirin) (n=166)

vs.

warfarin administered to achieve an international normalized ratio of 2 to 3 for (n=70)

factorial design: Three doses of dabigatran etexilate (50, 150, and 300 mg twice daily) were combined in a 3 3 factorial fashion with no aspirin or 81- or 325-mg aspirin once daily.

double blind

Factorial plan

Sample size: 166/70

Primary endpoint: bleedings

FU duration: 12 weeks

dabigatran 150 mg twice a day (n=6076)

vs.

warfarin adjusted-dose to a 2.0 to 3.0 INR (n=6022)

3 arms: dabigatran 110 mg, 150mg and warfarin

open (blind assessment)

Parallel groups

Sample size: 6076/6022

Primary endpoint: stroke or systemic embolism

FU duration: 2 y (median)

dabigatran 110 mg twice a day (n=6015)

vs.

warfarin adjusted dose to a 2-3 INR (n=6022)

3 arms: dabigatran 110 mg, 150mg and warfarin

open (blind assessment)

Parallel groups

Sample size: 6015/6022

Primary endpoint: stroke or systemic embolism

FU duration: 2 y (median)

non fatal TE events,bleedings and vascular death* 0.71 [0.48; 1.07]

all death 0.99 [0.73; 1.34]

coronary events 1.85 [0.94; 3.61]

vascular death 1.21 [0.77; 1.91]

major bleeding 0.71 [0.44; 1.13]

haemorragic stroke(or intracerebral hemorrhage) 0.44 [0.14; 1.44]

fatal stroke(ischemic+hemorrhagic) 1.11 [0.45; 2.73]

thrombo-embolic event (cerebral or systemic) 0.71 [0.48; 1.07]

ischemic stroke 0.70 [0.45; 1.09]

thromboembolic event likes(TE event or ischemic stroke or systemic embolism) 0.70 [0.45; 1.09]

All stroke(ischemic+hemorrhagic/fatal+non fatal) 0.67 [0.44; 1.01]

systemic thrombo-embolic complication 2.00 [0.37; 10.90]

hypertransaminasemia 7.81 [4.58; 13.32]

non fatal TE events,bleedings and vascular death* 1.38 [0.91; 2.10]

all death 0.94 [0.74; 1.21]

coronary events 0.70 [0.43; 1.16]

major bleeding 0.75 [0.54; 1.03]

haemorragic stroke(or intracerebral hemorrhage) 1.00 [0.14; 7.10]

fatal stroke(ischemic+hemorrhagic) 3.34 [0.92; 12.11]

thrombo-embolic event (cerebral or systemic) 1.38 [0.91; 2.10]

ischemic stroke 1.25 [0.81; 1.93]

thromboembolic event likes(TE event or ischemic stroke or systemic embolism) 1.25 [0.81; 1.93]

All stroke(ischemic+hemorrhagic/fatal+non fatal) 1.24 [0.81; 1.89]

systemic thrombo-embolic complication 6.01 [0.72; 49.84]

ximelegatran 20,40,60 mg twice daily (n=187)

vs.

warfarin standard dose(target INR 2-3) (n=67)

-treatment with either NSAI agents or fibrinolytic agents within the week before the start was prohibited -patient previously receiving warfarin were given ximelegatran once INR value was 1.5 or under/after the end of the study patients who stopped ximelegatran began warfarin 12 to 24 h after last intake.

-SPORTIF II is a dose guiding study -66 patient received 20mg,62 received 40mg,59 received 60 mg

Open

Parallel groups

Sample size: 187/67

Primary endpoint: Thrombo-embolic events and bleedings

FU duration: 16 weeks

it is a dose guiding study

ximelagatran 36 mg twice daily (n=1704)

vs.

warfarin standard dose (target INR 2-3) (n=1703)

Aspirin was used concurrently for at least half the period on study drug by 13% patients assigned to ximelagatran and 10% on warfarin(p=0.01).

Open

Parallel groups

Sample size: 1704/1703

Primary endpoint: All stroke or systemic embolism

FU duration: 17.4 months

Premature termination of study treatment was the result of study endpoint (4% warfarin group,3% ximelegatran) and adverse effects(4% warfarin group,8% ximelegatran group:this difference is related to elevation of liver enzymes in some patients treated with ximelegatran). The trial was a non inferiority trial but the primary analysis was only by intention to treat.

ximelegatran 36 mg twice daily (n=1960)

vs.

warfarin standard dose(target INR 2-3) (n=1962)

Double blind

Parallel groups

Sample size: 1960/1962

Primary endpoint: All stroke and systemic embolism

FU duration: 20 months

death ∞ [NaN; ∞]

major bleeding 1.29 [0.70; 2.37]

proximal DVT 0.57 [0.32; 1.00]

distal DVT 0.94 [0.53; 1.66]

non-fatal PE 1.70 [0.41; 7.09]

asymptomatic DVT 0.73 [0.49; 1.08]

total VTE and all-cause mortality 0.90 [0.63; 1.29]

major VTE (fatal and non fatal DVT,PE) 0.78 [0.48; 1.27]

symptomatic DVT 6.03 [0.73; 49.98]

symptomatic DVT 8.89 [1.13; 70.07]

death NaN [NaN; NaN]

coronary events 0.72 [0.31; 1.68]

major bleeding 0.83 [0.42; 1.63]

proximal DVT 0.90 [0.55; 1.49]

distal DVT 1.50 [0.90; 2.50]

non-fatal PE 0.33 [0.03; 3.16]

asymptomatic DVT 1.15 [0.82; 1.63]

total VTE and all-cause mortality 1.28 [0.93; 1.78]

major VTE (fatal and non fatal DVT,PE) 1.09 [0.70; 1.70]

coronary events 0.99 [0.06; 15.86]

dabigatran etexilate 220 mg q.d. for 28-35 days (n=1157)

vs.

Enoxaparin 40 mg q.d. for 23-35 days (n=1162)

3 arms dabigatran 220mg, 150mg and placebo

double blind

Parallel groups

Sample size: 1157/1162

Primary endpoint: total VTE and all-cause mortality

FU duration: 28-35 days, median 33d

dabigatran etexilate 150 mg q.d. 28-35 days (n=1174)

vs.

Enoxaparin 40 mg q.d. for 28-25 days (n=1162)

3 arms dabigatran 220mg, 150mg and placebo

double blind

Sample size: 1174/1162

Primary endpoint: total VTE and all-cause mortality

FU duration: 28-35 days, median 33d

dabigatran 220mg once daily for 28-35 Days (n=1010)

vs.

enoxaparin 40mg subcutaneous once daily for 28-35 Days (n=1003)

double-blind

Parallel groups

Sample size: 1010/1003

Primary endpoint: venous thromboembolism or death

FU duration: 28-35 days (mean 32d)

total VTE and all-cause mortality 1.23 [1.03; 1.47]

coronary events 1.05 [0.48; 2.31]

major bleeding 0.42 [0.15; 1.19]

proximal DVT 1.49 [0.67; 3.33]

distal DVT 1.20 [0.99; 1.45]

major VTE (fatal and non fatal DVT,PE) 1.51 [0.79; 2.91]

major or clinically relevant non-major bleeding 0.86 [0.52; 1.41]

death 1.01 [0.06; 16.19]

coronary events 1.26 [0.40; 3.99]

major bleeding 1.14 [0.46; 2.78]

proximal DVT 0.82 [0.40; 1.69]

distal DVT 1.02 [0.85; 1.21]

asymptomatic DVT 1.00 [0.85; 1.18]

total VTE and all-cause mortality 0.97 [0.82; 1.13]

major VTE (fatal and non fatal DVT,PE) 0.73 [0.36; 1.47]

symptomatic DVT 0.13 [0.02; 1.01]

major or clinically relevant non-major bleeding 1.11 [0.76; 1.63]

death 0.98 [0.06; 15.70]

major bleeding 0.99 [0.39; 2.47]

proximal DVT 1.03 [0.54; 1.98]

distal DVT 1.07 [0.91; 1.27]

non-fatal PE ∞ [NaN; ∞]

asymptomatic DVT 1.10 [0.94; 1.29]

total VTE and all-cause mortality 1.07 [0.92; 1.25]

major VTE (fatal and non fatal DVT,PE) 1.08 [0.58; 2.01]

symptomatic DVT 0.37 [0.10; 1.37]

major or clinically relevant non-major bleeding 1.22 [0.84; 1.78]

distal DVT 1.33 [1.10; 1.59]

total VTE and all-cause mortality 1.33 [1.12; 1.58]

death ∞ [NaN; ∞]

major bleeding 0.42 [0.15; 1.17]

non-fatal PE 0.00 [0.00; NaN]

major VTE (fatal and non fatal DVT,PE) 1.36 [0.70; 2.63]

major or clinically relevant non-major bleeding 0.82 [0.49; 1.34]

dabigatran etexilate 220 mg for 12-15 days (n=862)

vs.

Enoxaparin 30mg SC BID after surgery for 12-15 days (n=876)

double blind

Parallel groups

Sample size: 862/876

Primary endpoint: total VTE and all-cause mortality

FU duration: 12-15 days, median 14d

dabigatran etexilate 220 mg q.d. 6-10 days (n=694)

vs.

Enoxaparin 40 mg q.d. for 6-10 days (n=699)

double blind

Sample size: 694/699

Primary endpoint: total VTE and all-cause mortality

FU duration: 6-10 days, mean 8 days

dabigatran etexilate 150 mg q.d. for 6-10 days (n=708)

vs.

Enoxaparin 40 mg q.d. for 6-10 days (n=699)

double blind

Parallel groups

Sample size: 708/699

Primary endpoint: total VTE and all-cause mortality

FU duration: 6-10 days, mean 8 days

dabigatran etexilate 150 mg q.d. for 12-15 days (n=877)

vs.

enoxaparin 30 mg SC BID after surgery for 12-15 days (n=876)

double blind

Sample size: 877/876

Primary endpoint: total VTE and all-cause mortality

FU duration: 12-15 days, median 14d

serious bleeding 0.00 [0.00; NaN]

DVT+PE 0.70 [0.39; 1.26]

DVT+PE 1.71 [1.15; 2.54]

serious bleeding 0.88 [0.32; 2.41]

serious bleeding NaN [NaN; NaN]

DVT+PE 0.83 [0.25; 2.76]

DVT+PE 0.53 [0.38; 0.74]

serious bleeding 2.01 [0.91; 4.42]

serious bleeding 0.86 [0.48; 1.56]

DVT+PE 1.14 [1.00; 1.29]

DVT+PE 0.76 [0.66; 0.88]

serious bleeding 2.89 [1.65; 5.09]

Ximelagatran 8, 12, 18 or 24 mgorally b.d., at least 12 h after surgery for 6–12 days (n=600)

vs.

Enoxaparin 30 mg s.c. b.d.,starting at least 12 h after surgery for 6–12 days (n=0)

double-blind

parallel group

Sample size: 600/0

Primary endpoint:

FU duration: 6–12 days

Ximelagatran 24 mg orally b.d., starting at least 12 h after surgery for 7–12 days (n=906)

vs.

Enoxaparin 30 mg s.c. b.d.,starting at least 12 h after surgery for 7–12 days (n=910)

double-blind

parallel group

Sample size: 906/910

Primary endpoint:

FU duration: 7–12 days

Melagatran 1–4 mg s.c. immediately before surgery, melagatran at 20.00 hours, then ximelagatran 6–24 mg orally b.d. for 6–9 days (n=103)

vs.

Dalteparin 5000 IU o.d., started evening before surgery for 6–9 days (n=0)

open

parallel group

Sample size: 103/0

Primary endpoint:

FU duration: 6–9 days

Melagatran 1–3 mg s.c. immediately before surgery,melagatran same day, then ximelagatran 8–24 mg orally b.d. for 7–10 days (n=1495)

vs.

Dalteparin 5000 IU o.d., started evening before surgery for 7–10 days (n=381)

double-blind

Parallel groups

Sample size: 1495/381

Primary endpoint: deep-vein thrombosis and pulmonary embolism

FU duration: 7–10 days

Melagatran 3 mg s.c. 4–12h after surgery, then ximelagatran24 mg orally b.d. for 7–10 days (n=2788)

vs.

Enoxaparin 40 mg s.c. o.d. 12 h before surgery for 7–10 days (n=0)

double-blind

Sample size: 2788/0

Primary endpoint: venous thromboembolism

FU duration: 8–11 days

Melagatran 2 mg s.c. up to 30 min before surgery, then melagatran 3 mg at least 8 hafter surgery, then ximelagatran 24 mg orally b.d. for 8–11 days (n=2835)

vs.

Enoxaparin 40 mg s.c. o.d.,starting 12 h before surgery for 8–11 days (n=0)

double-blind

parallel group

Sample size: 2835/0

Primary endpoint: venous thromboembolism

FU duration: 8–11 days