antithrombotics

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

Argatroban 60–20 mg/kg bolus; 2–4 µg /kg/min infusion for 72h (n=-9)

vs.

UFH 5000 IU bolus; 1000 IU/h infusion (n=-9)

Sample size: -9/-9

Primary endpoint:

FU duration: 30 days

Vasc events 0.23 [0.03; 1.92]

Major bleeds NaN [NaN; NaN]

Vasc deaths 0.31 [0.03; 2.76]

Non-fatal stroke NaN [NaN; NaN]

Non-fatal MI 0.00 [0.00; NaN]

Non vasc deaths NaN [NaN; NaN]

cardiovascular events 0.23 [0.03; 1.92]

Vasc events 0.61 [0.43; 0.88]

Non-fatal MI 0.56 [0.36; 0.89]

cardiovascular events 0.61 [0.43; 0.88]

Major bleeds NaN [NaN; NaN]

Vasc deaths 0.64 [0.34; 1.21]

Non-fatal stroke 1.54 [0.26; 9.17]

Non vasc deaths NaN [NaN; NaN]

Vasc events 0.90 [0.56; 1.45]

Major bleeds NaN [NaN; NaN]

Vasc deaths 0.72 [0.38; 1.35]

Non-fatal stroke ∞ [NaN; ∞]

Non-fatal MI 1.15 [0.50; 2.60]

Non vasc deaths ∞ [NaN; ∞]

cardiovascular events 0.90 [0.56; 1.45]

Vasc events 0.53 [0.38; 0.74]

Non-fatal MI 0.52 [0.35; 0.76]

cardiovascular events 0.53 [0.38; 0.74]

Major bleeds NaN [NaN; NaN]

Vasc deaths 0.56 [0.25; 1.25]

Non-fatal stroke NaN [NaN; NaN]

Non vasc deaths 0.99 [0.14; 7.03]

Vasc events 3.50 [0.45; 27.07]

Major bleeds NaN [NaN; NaN]

Vasc deaths 0.50 [0.03; 7.70]

Non-fatal stroke ∞ [NaN; ∞]

Non-fatal MI ∞ [NaN; ∞]

Non vasc deaths NaN [NaN; NaN]

cardiovascular events 3.50 [0.45; 27.07]

Non-fatal MI 0.28 [0.09; 0.82]

fatal and non fatal MI 0.28 [0.09; 0.82]

Vasc events 0.63 [0.38; 1.04]

cardiovascular events 0.63 [0.38; 1.04]

refractory ischemia 0.72 [0.43; 1.21]

Vasc events 0.00 [0.00; NaN]

Major bleeds NaN [NaN; NaN]

Vasc deaths 0.00 [0.00; NaN]

Non-fatal MI 0.00 [0.00; NaN]

Non vasc deaths NaN [NaN; NaN]

cardiovascular events 0.00 [0.00; NaN]

Aspirin 324 mg/d (n=26)

vs.

(n=24)

Sample size: 26/24

Primary endpoint:

FU duration: 3m

Aspirin 324mg/d (n=661)

vs.

placebo (n=677)

double blind

Sample size: 661/677

Primary endpoint:

FU duration: 3m

Aspirin 1300mg/d + sulfinpyrazone 800mg/d (n=416)

vs.

placebo (n=139)

double blind

Sample size: 416/139

Primary endpoint:

FU duration: 18m

Aspirin 75mg/d (n=474)

vs.

placebo (n=471)

half of the patients received heparin in a 2x2 factorial design

double blind

Factorial plan

Sample size: 474/471

Primary endpoint:

FU duration: 12m

Aspirin 325mg/d, Aspirin 40mg/d (n=56)

vs.

(n=28)

Sample size: 56/28

Primary endpoint:

FU duration: 12m

Aspirin 325 mg twice daily (n=121)

vs.

placebo (n=118)

double blind

Sample size: 121/118

Primary endpoint:

FU duration: 6d (3m)

Aspirin 80mg/d (Heparin + Warfarin) (n=37)

vs.

full-dose heparin followed by warfarin (n=24)

Sample size: 37/24

Primary endpoint:

FU duration: 3m

Aspirin 1300mg/d (n=-9)

vs.

placebo (n=139)

double blind

Sample size: -9/139

Primary endpoint:

FU duration: 18m

400-mg loading dose of atopaxar followed by a daily dose of 50 mg, 100 mg, or 200 mg for 12 weeks (n=603)

vs.

placebo (n=0)

Parallel groups

Sample size: 603/0

Primary endpoint:

FU duration:

pahse 2

atopaxar at a loading dose of 400 mg followed by 50 mg per day, 100 mg per day, or 200 mg per day for 12 weeks (n=-9)

vs.

atopaxar at a loading dose of 400 mg followed by placebo (n=-9)

Parallel groups

Sample size: -9/-9

Primary endpoint: bleeding events

FU duration:

phase 2 study

major bleeding 0.77 [0.69; 0.87]

major bleeding not related to CABG 0.53 [0.43; 0.65]

ischemic events + bleeding 0.86 [0.77; 0.97]

major bleeding TIMI 0.50 [0.35; 0.72]

all cause death 1.19 [0.85; 1.67]

MI 1.09 [0.92; 1.30]

death, MI, unplanned revascularization 1.08 [0.93; 1.24]

1 yer MI 1.12 [0.97; 1.30]

1 year death from any cause 0.98 [0.80; 1.21]

I year Unplanned revascularization for ischemia 1.04 [0.91; 1.20]

1 year composite ischemia 1.05 [0.96; 1.16]

all cause death 1.13 [0.80; 1.58]

major bleeding 0.94 [0.84; 1.06]

MI 1.01 [0.84; 1.21]

death, MI, unplanned revascularization 1.07 [0.92; 1.23]

major bleeding not related to CABG 0.93 [0.78; 1.10]

ischemic events + bleeding 1.01 [0.90; 1.12]

major bleeding TIMI 0.88 [0.65; 1.20]

1 yer MI 1.03 [0.89; 1.20]

1 year death from any cause 1.01 [0.82; 1.24]

I year Unplanned revascularization for ischemia 1.09 [0.95; 1.24]

1 year composite ischemia 1.04 [0.95; 1.15]

bivalirudin alone (n=4612)

vs.

unfractionated heparin or enoxaparin plus a glycoprotein IIb/IIIa inhibitor (n=4603)

3 arms: unfractionated heparin or enoxaparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin alone

double blind

Parallel groups

Sample size: 4612/4603

Primary endpoint: hierarchical endpoint testing

FU duration: 30 days

bivalirudin plus a glycoprotein IIb/IIIa inhibitor (n=4604)

vs.

unfractionated heparin or enoxaparin plus a glycoprotein IIb/IIIa inhibitor (n=4603)

3 arms: unfractionated heparin or enoxaparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin alone

double blind

Sample size: 4604/4603

Primary endpoint: hierarchical endpoint testing

FU duration: 30 days

bivalirudin alone (n=284)

vs.

eptifibatide plus either unfractionated heparin or enoxaparin (n=573)

3 arms trial: eptifibatide reduced dose unfractionated heparin (n=298), eptifibatide reduced-dose enoxaparin (n=275), or bivalirudin monotherapy (n=284)

open

Parallel groups

Sample size: 284/573

Primary endpoint: Coronary flow reserve

FU duration: hospital stay

Major bleeding 0.61 [0.42; 0.89]

transfusion 0.51 [0.31; 0.85]

Death 0.80 [0.36; 1.80]

MI 0.60 [0.29; 1.26]

coronary event 0.74 [0.46; 1.18]

Minor bleeding 1.02 [0.84; 1.23]

hemorrhagic stroke ∞ [NaN; ∞]

Major bleeding 0.39 [0.30; 0.50]

Death 2.23 [0.69; 7.22]

MI 0.80 [0.58; 1.11]

coronary event 0.89 [0.68; 1.16]

long term death 1.62 [0.96; 2.74]

long term CV event 0.98 [0.88; 1.09]

Bivalirudin 0.125–0.250 mg/kg bolus; 0.125–0.500 mg /kg/min infusion for 72h (n=272)

vs.

UFH 5000 IU bolus; 1000–1200 IU/h infusion (n=140)

3 arms: low-dose, high dose hirulog and heparin

double blind

Parallel groups

Sample size: 272/140

Primary endpoint: TIMI3 of the infarct-related artery at 90 to 120 minutes

FU duration: 35 days

dose-finding study

Bivalirudin 1.0 mg/kg bolus; 2.5 mg /kg/h for 4 h, then 0.2 mg /kg/h infusion for 24h (n=2059)

vs.

UFH 175 IU/kg bolus; 15 IU mg /kg/h infusion (n=2039)

double blind

Parallel groups

Sample size: 2059/2039

Primary endpoint: death, MI, abrupt vessel closure, clinical deterioration

FU duration: 6 months

all cause death 1.28 [0.75; 2.20]

Major bleeding (non-CABG related) 1.11 [0.91; 1.35]

Myocardial infarction 1.17 [0.94; 1.45]

Death, MI, urgent revascularization 1.14 [0.95; 1.36]

ischemic event + bleeding 1.12 [0.98; 1.28]

TIMI major bleeding 1.07 [0.75; 1.52]

TIMI minor bleeding 1.08 [0.90; 1.31]

Major bleeding (non-CABG related) 0.52 [0.40; 0.66]

TIMI major bleeding 0.55 [0.44; 0.69]

TIMI minor bleeding 0.37 [0.23; 0.60]

all cause death 1.19 [0.69; 2.06]

Myocardial infarction 1.15 [0.93; 1.43]

Death, MI, urgent revascularization 1.07 [0.90; 1.28]

ischemic event + bleeding 0.87 [0.75; 1.00]

bivalirudin + (n=2609)

vs.

heparin (either unfractionated or enoxaparin) plus glycoprotein IIb/IIIa inhibitors (n=2561)

2×2 factorial design with upstream glycoprotein IIb/IIIa inhibitor initiation immediately after randomisation versus deferred glycoprotein IIb/IIIa inhibitor initiation for selective use in the catheterisation laboratory starting immediately before percutaneous coronary intervention

open

Sample size: 2609/2561

Primary endpoint:

FU duration: 30 days

bivalirudin alone (n=2619)

vs.

heparin (either unfractionated or enoxaparin) plus glycoprotein IIb/IIIa inhibitors (n=2561)

2×2 factorial design with upstream glycoprotein IIb/IIIa inhibitor initiation immediately after randomisation versus deferred glycoprotein IIb/IIIa inhibitor initiation for selective use in the catheterisation laboratory starting immediately before percutaneous coronary intervention

open

Factorial plan

Sample size: 2619/2561

Primary endpoint:

FU duration: 30 days

pretreatment with clopidogrel -+aspirin 75–325 mg) (n=1313)

vs.

placebo (+ aspirin 75–325 mg) (n=1345)

double blind

Parallel groups

Sample size: 1313/1345

Primary endpoint: ardiovascular death, MI, or urgent TVR

FU duration:

Vasc events 0.82 [0.73; 0.90]

fatal and non fatal MI 0.78 [0.68; 0.90]

cardiovascular events 0.82 [0.73; 0.90]

Major bleeds 1.38 [1.13; 1.67]

Vasc deaths 0.93 [0.80; 1.08]

Non vasc deaths 0.92 [0.60; 1.40]

fatala and non fatal stroke 0.87 [0.64; 1.18]

refractory ischemia 0.93 [0.83; 1.04]

fatal bleeding 0.74 [0.34; 1.61]

clopidogrel 300 mg immediately, followed by 75 mg once daily + aspirin for 3 to 12 months (n=6259)

vs.

aspirin (+placebo) (n=6303)

double blind

Parallel groups

Sample size: 6259/6303

Primary endpoint: CV death, MI, stroke

FU duration: NA (median <9 months)

Major bleeds 1.24 [1.05; 1.46]

vascular death, MI, stroke 0.94 [0.83; 1.06]

Severe recurrent ischemia 0.93 [0.64; 1.36]

Hemorrhagic stoke 0.67 [0.19; 2.37]

Vasc events 0.94 [0.84; 1.06]

all cause death 0.96 [0.82; 1.13]

Vasc deaths 0.95 [0.81; 1.13]

fatala and non fatal stroke 0.99 [0.70; 1.39]

fatal and non fatal MI 0.86 [0.72; 1.02]

cardiovascular events 0.94 [0.84; 1.06]

fatal bleeding 1.07 [0.53; 2.16]

Double-dose clopidogrel (n=12520)

vs.

Standard-dose clopidogrel (n=12566)

patients were also assigned in an open-label manner to 300 to 325 mg of aspirin once daily or 75- to 100-mg aspirin once daily

about two thirds eventually underwent PCI (although PCI was planned for everyone who was randomized, about a third of the patients did not undergo the procedure because they were not considered suitable based on angiography findings)

open

Factorial plan

Sample size: 12520/12566

Primary endpoint: CV death/MI/stroke

FU duration: 30 days

all cause death, non-fatal MI, thrombo-embolic stroke 0.56 [0.33; 0.97]

major bleeding 2.35 [0.61; 9.03]

intracranial major bleeding ∞ [NaN; ∞]

extracranial major bleeding 2.02 [0.51; 8.00]

coumadin(INR mean 2.4) +aspirin (n=333)

vs.

aspirin (n=336)

open

Sample size: 333/336

Primary endpoint: death, MI or stroke

FU duration: 1 year

all cause death 0.28 [0.09; 0.82]

vascular death 0.34 [0.11; 1.06]

MI 0.96 [0.46; 2.01]

Revascularization 0.90 [0.58; 1.39]

minor bleeding 1.68 [0.92; 3.07]

cardiovascular events 0.57 [0.32; 1.00]

major bleeding 1.03 [0.21; 5.09]

intracranial major bleeding NaN [NaN; NaN]

all cause death, non-fatal MI, thrombo-embolic stroke 0.57 [0.32; 1.00]

coumadin (phenprocoumon or acenocoumarol) target INR 3-4) (n=325)

vs.

aspirin 80mg daily (n=336)

open

Parallel groups

Sample size: 325/336

Primary endpoint: death, MI or stroke

FU duration: 1 year (range 0-26 months)

myocardial infarction 0.70 [0.49; 0.99]

long term MI or death 0.91 [0.71; 1.16]

death 0.85 [0.46; 1.54]

all revascularisations 0.78 [0.60; 1.01]

myocardial infarction or death 0.75 [0.54; 1.03]

long term MI or death 1.05 [0.72; 1.51]

death 1.61 [0.83; 3.13]

all revascularisations 1.00 [0.79; 1.27]

myocardial infarction 0.86 [0.56; 1.32]

recurrent angina 1.12 [0.87; 1.45]

myocardial infarction or death 1.05 [0.72; 1.51]

dalteparin SC 120 IU per kg bodyweight [maximum 10 000 IU] twice daily for 6 days with 7500 IU once daily for 34-45 days +aspirin (n=746)

vs.

matched placebo + aspirin (n=760)

the primary aims was to compare the difference during the first 6 days between dalteparin and placebo

double blind

Parallel groups

Sample size: 746/760

Primary endpoint: death or new myocardial infarction

FU duration: 40 days

dalteparin SC 120 i.u./kg twice-daily for 6 days followed by dalteparin 7500UI daily up to day 45 (+aspirin) (n=731)

vs.

unfractionated heparin dose-adjusted intravenous infusion (for at least 48h) then by subcutaneous injection up to day 6 (then placebo) (+aspirin) (n=751)

double blind

Parallel groups

Sample size: 731/751

Primary endpoint: death MI recurrence of angina

FU duration: 45 days

the second phase is bliding but the first one is open. Perfommence biais is not discarded

dalteparin SC 120 IU per kg bodyweight [maximum 10 000 IU] twice daily for 6 days with 7500 IU once daily for 34-45 days +aspirin (n=746)

vs.

matched placebo + aspirin (n=760)

double blind

Sample size: 746/760

Primary endpoint: death or new myocardial infarction

FU duration: 6 days

death 3.57 [1.00; 12.74]

all revascularisations 0.90 [0.58; 1.40]

myocardial infarction 0.80 [0.44; 1.46]

myocardial infarction or death 1.09 [0.65; 1.83]

twice-daily weight-adjusted subcutaneous injections of dalteparin (120 i.u./kg) (+aspirin) (n=751)

vs.

dose-adjusted intravenous infusion of unfractionated heparin (+aspirin) (n=731)

open

Sample size: 751/731

Primary endpoint:

FU duration: 6 days

Vasc events 0.55 [0.22; 1.35]

Major bleeds NaN [NaN; NaN]

Vasc deaths ∞ [NaN; ∞]

Non-fatal stroke NaN [NaN; NaN]

Non-fatal MI 0.45 [0.17; 1.20]

Non vasc deaths ∞ [NaN; ∞]

cardiovascular events 0.55 [0.22; 1.35]

Aspirin 50mg/d + Dipyridamol 400mg/d (n=44)

vs.

placebo (n=44)

double blind

Sample size: 44/44

Primary endpoint:

FU duration: 12m

Efegatran 0.1–0.3 mg/kg bolus; 0.105–1.200 mg /kg/h infusion for 48h (n=432)

vs.

UFH 5000 IU bolus; 1000 IU/h infusion (n=0)

open

Parallel groups

Sample size: 432/0

Primary endpoint: none defined

FU duration: 30 days

Enoxaparin (n=-9)

vs.

unfractionated heparin (n=-9)

open

Parallel groups

Sample size: -9/-9

Primary endpoint: death, MI, recurrent angina requiring revasc

FU duration: 30 days

recurrent angina 0.61 [0.39; 0.96]

death, myocardial infarction, or recurrent at 30 days 0.63 [0.44; 0.90]

death 0.50 [0.05; 5.42]

myocardial infarction 0.25 [0.03; 2.20]

death at 30 days 0.50 [0.05; 5.42]

myocardial infarction at 30 days 0.17 [0.02; 1.36]

enoxaparin, 100 IU/kg subcutaneously twice daily +aspirin for 7 days (n=220)

vs.

tinzaparin, 175 IU/kg subcutaneously once daily +aspirin for 7 days (n=218)

open

Parallel groups

Sample size: 220/218

Primary endpoint:

FU duration: 30 days

death, MI and recurrence 0.84 [0.72; 0.97]

all revascularisations 0.84 [0.75; 0.93]

recurrent angina 0.83 [0.70; 0.98]

death, myocardial infarction, or recurrent at 14 days 0.84 [0.72; 0.97]

death, myocardial infarction, or recurrent at 30 days 0.85 [0.74; 0.97]

minor bleeding 1.66 [1.33; 2.08]

recurrent angina at 14 days 0.87 [0.75; 1.02]

death 0.97 [0.62; 1.54]

major bleeding 0.93 [0.71; 1.21]

stroke at 30 days 0.97 [0.34; 2.77]

myocardial infarction 0.71 [0.50; 1.01]

Drop in platelet count of 50% 0.68 [0.45; 1.01]

myocardial infarction or death 0.83 [0.43; 1.57]

death at 30 days 0.79 [0.54; 1.15]

myocardial infarction at 30 days 0.74 [0.54; 1.03]

myocardial infarction 0.71 [0.52; 0.97]

minor bleeding 3.66 [2.68; 5.01]

death, MI and revascularization 0.85 [0.73; 1.00]

death 0.83 [0.53; 1.30]

all revascularisations 0.88 [0.72; 1.07]

major bleeding 1.52 [0.86; 2.71]

myocardial infarction or death 0.78 [0.60; 1.03]

major bleeding 1.19 [1.05; 1.36]

long term MI or death 0.96 [0.87; 1.06]

death 1.04 [0.84; 1.30]

minor bleeding 1.01 [0.91; 1.12]

myocardial infarction 0.94 [0.85; 1.05]

myocardial infarction or death 0.96 [0.87; 1.06]

death at 30 days 1.04 [0.84; 1.30]

myocardial infarction at 30 days 0.92 [0.83; 1.03]

long term MI or death 0.55 [0.32; 0.96]

major bleeding 0.40 [0.17; 0.95]

myocardial infarction or death 0.55 [0.32; 0.96]

minor bleeding 1.31 [1.04; 1.65]

death, MI and revascularization 0.87 [0.61; 1.22]

death, MI and recurrence 1.30 [0.86; 1.98]

death 0.58 [0.26; 1.30]

all revascularisations 1.35 [0.77; 2.35]

myocardial infarction 0.69 [0.36; 1.31]

recurrent angina 0.45 [0.19; 1.09]

death, myocardial infarction, or recurrent at 30 days 0.71 [0.47; 1.08]

death at 30 days 0.58 [0.26; 1.30]

myocardial infarction at 30 days 0.69 [0.36; 1.31]

major bleeding 1.90 [1.08; 3.34]

minor bleeding 3.68 [2.81; 4.82]

long term MI or death 0.89 [0.73; 1.10]

death, MI and revascularization 0.88 [0.77; 1.00]

death 0.96 [0.71; 1.31]

all revascularisations 0.84 [0.71; 1.00]

myocardial infarction 0.83 [0.65; 1.07]

myocardial infarction or death 0.89 [0.73; 1.10]

enoxaparin 1mg/kg, twice daily during 48h-8days (n=1607)

vs.

continuous intravenous unfractionated heparin (n=1564)

Double blind

Parallel groups

Sample size: 1607/1564

Primary endpoint:

FU duration: 14 days (30 days)

enoxaprin during both the acute phase and outpatient phase (n=1953)

vs.

intravenous UFH for >=3 days (followed by subcutaneous placebo injections) (n=1957)

double blind

Parallel groups

Sample size: 1953/1957

Primary endpoint: death, myocardial infarction, or urgent revascularization

FU duration: 8 days (43 days)

Enoxaparin 1 mg/kg twice daily (n=4993)

vs.

unfractionated heparin (n=4985)

open

Parallel groups

Sample size: 4993/4985

Primary endpoint: death/MI

FU duration: 30 days

enoxaparin (1 mg/kg subcutaneously twice daily) for 48 hours (+eptifibatide and aspirin) (n=380)

vs.

intravenous UFH (70 U/kg bolus followed by 15 U/kg per hour adjusted to an activated partial thromboplastin time of 1.5-2 times control) for 48 hours (+eptifibatide and aspirin) (n=366)

open

Parallel groups

Sample size: 380/366

Primary endpoint: 96-hour non–CABG related major bleeding

FU duration: 30 days (2.5y)

enoxaprin during both the acute phase (IV) and outpatient phase (SC) (n=1953)

vs.

intravenous UFH for >=3 days (followed by subcutaneous placebo injections) (n=1957)

double blind

Sample size: 1953/1957

Primary endpoint: death, MI or urgent revascularization

FU duration: 43 days

Four doses fondaparinux (2.5, 4, 8, or 12 mg once daily) for three to seven days (n=908)

vs.

enoxaparin (1 mg/kg twice daily) for three to seven days (n=230)

Sample size: 908/230

Primary endpoint:

FU duration: 9 days

fondaparinux 2.5 mg daily until hospital discharge or for up to eight days (n=10057)

vs.

enoxaparin 1 mg per kilogram of body weight twice daily for two to eight days or until the patient was in clinically stable condition (n=10021)

double blind

Parallel groups

Sample size: 10057/10021

Primary endpoint: death, myocardial infarction, or refractory ischemia

FU duration: 9 days (180 days)

Hirudin 0.2 mg/kg bolus; 0.5 mg/kg twice daily 0.1 mg/kg 0.1 mg /kg/h infusion for 5-7 days (n=447)

vs.

Placebo bolus, UFH 12 500 IU twice daily (n=0)

double blind

Parallel groups

Sample size: 447/0

Primary endpoint: TIMI 3 flow at 90 min

FU duration: 30 days

Hirudin 0.1 mg/kg bolus; 0.1 mg /kg/h infusion for 96h (n=3002)

vs.

UFH 5000 IU bolus; 1000 IU/h infusion (n=0)

open

Parallel groups

Sample size: 3002/0

Primary endpoint: death,MI, HF, cardiogenic shock

FU duration: 30 days

Hirudin 0.1 mg/kg bolus; 0.1 mg /kg/h infusion for 72h (n=12142)

vs.

UFH 5000 IU bolus; 1000 IU/h infusion for 72H (n=0)

open

Parallel groups

Sample size: 12142/0

Primary endpoint: death, MI

FU duration: 30days (1 year)

Hirudin 0.2–0.4 mg/kg bolus; 0.10–0.15 mg /kg/h infusion for 72h (n=909)

vs.

UFH 5000 IU bolus; 1000–1200 IU/h infusion (n=0)

open

Parallel groups

Sample size: 909/0

Primary endpoint: death, MI, refrectory angina

FU duration: 6 months

Hirudin 40 mg intravenous bolus; 0.2 mg /kg/h infusion for 24 h, then 40 mg or placebo twice daily for 72h (n=1141)

vs.

UFH 10 000 IU bolus; 15 IU /kg/h infusion for 24 h, then placebo twice daily (n=0)

double blind

Parallel groups

Sample size: 1141/0

Primary endpoint: MACE

FU duration: 6 months

Hirudin 0.4 mg/kg bolus; 0.15 mg /kg/h infusion for 72h (n=5083)

vs.

UFH 5000 IU bolus; 15 IU /kg/h infusion (n=5058)

double blind

Parallel groups

Sample size: 5083/5058

Primary endpoint: death, MI at 7 days

FU duration: 7 days (6 months)

low-dose hirudin (0.2 mg/kg bolus+0.10 mg/kg/h infusion) or medium-dose hirudin (0.4 mg/kg bolus+0.15 mg/kg/h infusion) for 72h (n=538)

vs.

heparin 5000 IU bolus+1000 to 1200 U/h (n=371)

3 arms trial; high, medium dose of hirudin and heparin

open

Parallel groups

Sample size: 538/371

Primary endpoint: death, MI, refractory angina

FU duration: 7 days

Inogatran 0.1–5.5 mg bolus; 2.0–10.0 mg/h infusion for 72h (n=1209)

vs.

UFH 5000 IU bolus; 1200 IU/h infusion (n=0)

double blind

Parallel groups

Sample size: 1209/0

Primary endpoint: death, MI, refractory angina, recurrent angina

FU duration: 30 days

recurrent angina at 14 days 0.93 [0.76; 1.14]

long term MI or death 1.10 [0.83; 1.44]

death 1.06 [0.51; 2.18]

all revascularisations 0.95 [0.67; 1.36]

myocardial infarction 1.09 [0.66; 1.79]

recurrent angina 0.84 [0.67; 1.06]

death, myocardial infarction, or recurrent at 14 days 0.99 [0.83; 1.18]

myocardial infarction or death 0.99 [0.63; 1.56]

death at 30 days 1.18 [0.79; 1.77]

myocardial infarction at 30 days 1.10 [0.79; 1.52]

recurrent angina at 14 days 1.11 [0.92; 1.35]

long term MI or death 1.15 [0.87; 1.50]

death 1.26 [0.70; 2.29]

all revascularisations 0.95 [0.78; 1.14]

myocardial infarction 0.98 [0.64; 1.49]

recurrent angina 1.11 [0.92; 1.35]

myocardial infarction or death 1.08 [0.74; 1.56]

nadroparin for 6 days (+aspirin) (n=1166)

vs.

unfractionated heparin for 6 days (+aspirin) (n=1151)

Double blind

Parallel groups

Sample size: 1166/1151

Primary endpoint: death, MI, recurent or refractory angina

FU duration: 14 days

nadroparin for 14 days (n=1151)

vs.

unfractionated heparin for 14 days (n=1151)

double blind

Sample size: 1151/1151

Primary endpoint: death, MI, recurent or refractory angina

FU duration: 14 days

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

all cause death 0.94 [0.82; 1.08]

all bleeding (major and minor) 1.26 [0.94; 1.69]

Major bleeds 1.21 [0.83; 1.77]

Vasc deaths 0.93 [0.80; 1.08]

fatala and non fatal stroke 0.90 [0.64; 1.26]

fatal and non fatal MI 0.96 [0.84; 1.10]

fatal bleeding 0.78 [0.29; 2.09]

death, MI, stroke 0.96 [0.87; 1.06]

Vasc events 0.82 [0.74; 0.91]

revascularization 0.67 [0.55; 0.82]

Non-fatal MI 0.76 [0.68; 0.86]

all bleeding (major and minor) 1.31 [1.11; 1.55]

Major bleeds 1.31 [1.03; 1.68]

fatal bleeding 4.19 [1.58; 11.10]

all cause death 0.95 [0.78; 1.16]

Vasc deaths 0.88 [0.70; 1.11]

Non-fatal stroke 1.01 [0.71; 1.45]

prasugrel 10 mg daily (n=4663)

vs.

clopidogrel 75 mg daily (n=4663)

double-blind

Parallel groups

Sample size: 4663/4663

Primary endpoint: cardiovascular events

FU duration: 17 months (median)

prasugrel 60-mg loading dose and 10-mg daily maintenance dose, for 6 to 15 months (n=6813)

vs.

clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose) for 6 to 15 months (n=6795)

double blind

Parallel groups

Sample size: 6813/6795

Primary endpoint: cardiovascular death, nonfatal MI, or nonfatal

FU duration:

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]

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

sulfinpyrazone 800mg/d (n=-9)

vs.

placebo (n=139)

double blind

Sample size: -9/139

Primary endpoint:

FU duration: 18m

vascular death, MI, stroke 0.85 [0.78; 0.92]

Vasc events 0.88 [0.82; 0.95]

all cause death 0.78 [0.69; 0.89]

Vasc deaths 0.80 [0.69; 0.91]

fatal and non fatal MI 0.85 [0.75; 0.95]

cardiovascular events 0.85 [0.78; 0.92]

death, MI, stroke 0.84 [0.77; 0.92]

Severe recurrent ischemia 0.87 [0.75; 1.01]

Hemorrhagic stoke 1.76 [0.89; 3.47]

all bleeding (major and minor) 1.04 [0.95; 1.13]

Major bleeds 1.03 [0.92; 1.14]

Ischemic stroke 1.05 [0.79; 1.40]

Non vasc deaths 0.72 [0.49; 1.04]

fatala and non fatal stroke 1.17 [0.91; 1.52]

fatal bleeding 0.87 [0.48; 1.58]

Vasc events 1.09 [0.58; 2.07]

all cause death 1.37 [0.44; 4.27]

all bleeding (major and minor) 1.11 [0.70; 1.77]

Major bleeds 0.98 [0.58; 1.65]

Vasc deaths 1.47 [0.42; 5.16]

fatala and non fatal stroke 1.96 [0.18; 21.49]

fatal and non fatal MI 0.78 [0.37; 1.65]

cardiovascular events 1.09 [0.58; 2.07]

ticagrelor 90mg twice daily (n=9333)

vs.

clopidogrel 75mg once daily (n=9291)

Patients undergoing PCI after randomization received, in a blind fashion, an additional dose of their study drug at the time of PCI

double blind

Parallel groups

Sample size: 9333/9291

Primary endpoint: Cv death, MI, stroke

FU duration: 1 y

ticagrelor 90 mg twice daily (n=334)

vs.

clopidogrel (n=327)

3 arms trial: AZD6140 90 mg and 180mg twice daily, Clopidogrel 75 mg daily

double blind

Parallel groups

Sample size: 334/327

Primary endpoint: major or minor bleeding through 4 weeks

FU duration: 12 weeks

Vasc events 0.52 [0.32; 0.83]

Non-fatal MI 0.54 [0.30; 0.98]

cardiovascular events 0.52 [0.32; 0.83]

Major bleeds NaN [NaN; NaN]

Vasc deaths 0.54 [0.23; 1.24]

Non-fatal stroke 0.00 [0.00; NaN]

Non vasc deaths NaN [NaN; NaN]

Vasc events 1.00 [0.17; 5.98]

Major bleeds NaN [NaN; NaN]

Vasc deaths NaN [NaN; NaN]

Non-fatal stroke NaN [NaN; NaN]

Non-fatal MI 1.00 [0.17; 5.98]

Non vasc deaths NaN [NaN; NaN]

cardiovascular events 1.00 [0.17; 5.98]

ticlopidine 250 mg b.i.d (n=314)

vs.

untreated control (n=338)

single blind

Sample size: 314/338

Primary endpoint:

FU duration: 6m

Ticlopidine 500mg/d (n=12)

vs.

(n=12)

Sample size: 12/12

Primary endpoint:

FU duration: 14d

Vasc events 0.21 [0.05; 0.91]

cardiovascular events 0.21 [0.05; 0.91]

Vasc deaths 0.21 [0.02; 1.72]

Non-fatal MI 0.21 [0.02; 1.72]

trapidil (n=71)

vs.

(n=73)

Sample size: 71/73

Primary endpoint:

FU duration: 6m

triflusal 600 mg daily (n=1135)

vs.

aspirine 300 mg daily (n=1140)

double blind

Parallel groups

Sample size: 1135/1140

Primary endpoint: cardiovascular events

FU duration: 35 days

Non-fatal MI 0.34 [0.14; 0.84]

Vasc events 0.45 [0.20; 1.02]

revascularization 0.83 [0.51; 1.35]

Major bleeds NaN [NaN; NaN]

Vasc deaths ∞ [NaN; ∞]

Non vasc deaths NaN [NaN; NaN]

cardiovascular events 0.45 [0.20; 1.02]

triflusal 300 mg three times daily (n=143)

vs.

placebo (n=138)

double blind

Parallel groups

Sample size: 143/138

Primary endpoint:

FU duration: 6m

death 1.04 [0.15; 7.24]

major bleeding 7.06 [0.41; 120.87]

myocardial infarction 0.69 [0.26; 1.88]

recurrent angina 0.62 [0.32; 1.21]

myocardial infarction or death 0.46 [0.15; 1.45]

major bleeding 0.85 [0.08; 8.71]

myocardial infarction or death 0.89 [0.62; 1.29]

death NaN [NaN; NaN]

all revascularisations 1.59 [0.94; 2.67]

major bleeding NaN [NaN; NaN]

minor bleeding 0.86 [0.06; 13.28]

myocardial infarction 0.00 [0.00; NaN]

recurrent angina 1.24 [0.81; 1.91]

myocardial infarction or death 0.80 [0.32; 2.03]

myocardial infarction 0.14 [0.03; 0.59]

recurrent angina 0.47 [0.25; 0.86]

myocardial infarction or death 0.14 [0.03; 0.60]

death 0.00 [0.00; NaN]

death NaN [NaN; NaN]

all revascularisations 0.81 [0.32; 2.06]

major bleeding 5.21 [0.29; 92.25]

minor bleeding ∞ [NaN; ∞]

myocardial infarction 0.60 [0.18; 1.95]

recurrent angina 1.20 [0.80; 1.78]

myocardial infarction or death 0.60 [0.18; 1.95]

death, MI and recurrence 0.35 [0.19; 0.67]

myocardial infarction 0.07 [0.01; 0.53]

recurrent angina 0.37 [0.19; 0.73]

myocardial infarction or death 0.07 [0.01; 0.53]

death 0.00 [0.00; NaN]

major bleeding 1.00 [0.14; 6.98]

minor bleeding 2.00 [0.62; 6.46]

myocardial infarction or death 0.90 [0.54; 1.48]

death, MI and recurrence 0.45 [0.25; 0.80]

myocardial infarction or death 0.24 [0.07; 0.83]

aspirin 162.5 mg daily plus heparin (activated partial thromboplastin time, two times control) followed by aspirin 162.5 mg daily plus warfarin (international normalized ratio, 2 to 3) for 12 weeks. (n=105)

vs.

aspirin alone (162.5 mg daily) for 12 weeks. (n=109)

single blind

Parallel groups

Sample size: 105/109

Primary endpoint:

FU duration: 12 weeks

intravenous heparin plus oral aspirin (150 mg once daily) (n=154)

vs.

aspirin alone 150 mg/d (n=131)

single blind

Parallel groups

Sample size: 154/131

Primary endpoint:

FU duration: hospital stay

aspirin (80 mg/day) plus heparin and then warfarin (n=37)

vs.

aspirin (325 mg/day) (n=32)

open

Parallel groups

Sample size: 37/32

Primary endpoint:

FU duration: 12 weeks

5 days of intermittent intravenous heparin + oral aspirin 75 mg/day (n=210)

vs.

oral aspirin 75 mg/day (n=189)

open

Parallel groups

Sample size: 210/189

Primary endpoint:

FU duration: 90 days

heparin (1000 units per hour by intravenous infusion)+ aspirin (325 mg twice daily) (n=122)

vs.

aspirin (325 mg twice daily) (n=118)

double blind

Sample size: 122/118

Primary endpoint:

FU duration: 3-9 days

aspirin plus UFH 5000 IU iv then 400 IU/kg body weight per day intravenously and titered by activated partial thromboplastin time (n=70)

vs.

aspirin 200 mg/day (n=73)

double blind

Parallel groups

Sample size: 70/73

Primary endpoint:

FU duration: 5-7 days

heparin (1000 units per hour by intravenous infusion) (n=118)

vs.

placebo (n=118)

double blind

Sample size: 118/118

Primary endpoint:

FU duration: 3-9 days

5 days of intermittent intravenous heparin (n=198)

vs.

placebo (n=199)

Factorial plan

Sample size: 198/199

Primary endpoint:

FU duration: 1y (5,30 and 90 days)

aspirin 325 mg/d + heparin 1000 UI/hr IV (n=122)

vs.

aspirin 325 mg/d (n=121)

double blind

Sample size: 122/121

Primary endpoint:

FU duration: 3-9 days

oral apsirin 75mg/d + intermittent IV heparin 10000UI/d followed by 7500 UI 6-hourly for 4 days (n=210)

vs.

placebo (n=199)

Sample size: 210/199

Primary endpoint:

FU duration: 1y (5,30 and 90 days)

death NaN [NaN; NaN]

all revascularisations 1.33 [0.73; 2.43]

major bleeding NaN [NaN; NaN]

minor bleeding 0.00 [0.00; NaN]

recurrent angina 0.83 [0.46; 1.50]

myocardial infarction or death 4.00 [0.44; 36.12]

heparin followed by warfarin (without aspirin) (n=24)

vs.

aspirin 325 mg/day (n=32)

open

Parallel groups

Sample size: 24/32

Primary endpoint:

FU duration: 12 weeks

vorapaxar (SCH 530348) oral tablets; 40-mg loading dose on first day, followed by 2.5 mg once daily for at least 1 year (n=-9)

vs.

Placebo (added to the existing standard of care (eg, aspirin, clopidogrel) (n=-9)

double-blind

Parallel groups

Sample size: -9/-9

Primary endpoint: CV death, MI, stroke, recurrent ischaemia, urgent revasc

FU duration:

all cause death NaN [NaN; NaN]

MI 0.00 [0.00; NaN]

Revascularization 1.59 [0.94; 2.67]

minor bleeding 0.86 [0.06; 13.28]

major bleeding 0.86 [0.19; 3.99]

intracranial major bleeding NaN [NaN; NaN]

extracranial major bleeding 0.86 [0.19; 3.99]

all cause death, non-fatal MI, thrombo-embolic stroke 0.00 [0.00; NaN]

major bleeding ∞ [NaN; ∞]

all cause death, non-fatal MI, thrombo-embolic stroke 0.75 [0.32; 1.80]

major bleeding ∞ [NaN; ∞]

intracranial major bleeding NaN [NaN; NaN]

extracranial major bleeding ∞ [NaN; ∞]

all cause death, non-fatal MI, thrombo-embolic stroke 0.16 [0.02; 1.25]

major bleeding 1.29 [0.94; 1.76]

all cause death, non-fatal MI, thrombo-embolic stroke 1.12 [0.99; 1.27]

major bleeding ∞ [NaN; ∞]

intracranial major bleeding NaN [NaN; NaN]

extracranial major bleeding 2.98 [0.31; 28.34]

all cause death, non-fatal MI, thrombo-embolic stroke 2.48 [0.80; 7.75]

major bleeding 2.02 [0.19; 21.92]

intracranial major bleeding ∞ [NaN; ∞]

extracranial major bleeding 1.01 [0.06; 15.93]

all cause death, non-fatal MI, thrombo-embolic stroke 0.39 [0.14; 1.05]

major bleeding ∞ [NaN; ∞]

all cause death, non-fatal MI, thrombo-embolic stroke 2.09 [0.20; 22.25]

major bleeding 1.98 [1.23; 3.19]

all cause death, non-fatal MI, thrombo-embolic stroke 0.91 [0.73; 1.13]

major bleeding 1.03 [0.15; 7.21]

intracranial major bleeding NaN [NaN; NaN]

extracranial major bleeding 1.03 [0.15; 7.21]

all cause death, non-fatal MI, thrombo-embolic stroke 0.37 [0.12; 1.15]

major bleeding 1.75 [1.24; 2.47]

extracranial major bleeding 2.10 [1.41; 3.13]

intracranial major bleeding 0.94 [0.45; 1.94]

all cause death, non-fatal MI, thrombo-embolic stroke 1.01 [0.94; 1.10]

all cause death, non-fatal MI, thrombo-embolic stroke 0.75 [0.63; 0.89]

major bleeding 3.49 [1.60; 7.64]

extracranial major bleeding 3.57 [1.55; 8.21]

intracranial major bleeding 3.00 [0.31; 28.75]

major bleeding 2.04 [1.13; 3.69]

extracranial major bleeding 2.07 [1.01; 4.23]

intracranial major bleeding 1.98 [0.68; 5.78]

all cause death, non-fatal MI, thrombo-embolic stroke 0.97 [0.87; 1.09]

major bleeding 2.50 [0.50; 12.46]

intracranial major bleeding NaN [NaN; NaN]

extracranial major bleeding 2.50 [0.50; 12.46]

all cause death, non-fatal MI, thrombo-embolic stroke 0.50 [0.20; 1.26]

all cause death ∞ [NaN; ∞]

MI ∞ [NaN; ∞]

Revascularization 1.33 [0.73; 2.43]

minor bleeding 0.00 [0.00; NaN]

major bleeding NaN [NaN; NaN]

heparin/warfarin target INR 3-4.5 + aspirin (n=37)

vs.

aspirin alone (n=32)

open

Sample size: 37/32

Primary endpoint:

FU duration: 3 months

heparin/warfarin (INR median 2.3) + aspirin (n=105)

vs.

aspirin (n=109)

open

Sample size: 105/109

Primary endpoint:

FU duration: 3 months

warfarin target INR 2–2.5 +aspirin (n=29)

vs.

placebo +aspirin (n=28)

double blind

Sample size: 29/28

Primary endpoint: quantitative angiography

FU duration: 2.5 months

warfarin (INR mean 1.5) (3 mg warfarin or 1 mg warfarin with 80 mg aspirin) (n=5410)

vs.

aspirin 160 mg/d (n=3393)

Sample size: 5410/3393

Primary endpoint:

FU duration: 14 months

warfarin 3mg/d for 6 months (INR mean 1.5) (n=155)

vs.

control (n=154)

open

Sample size: 155/154

Primary endpoint:

FU duration: 6 months

warfarin adjusted dose (INR mean 2.3) for 3 months (n=98)

vs.

standard treatment (n=99)

open

Sample size: 98/99

Primary endpoint:

FU duration: 3 months

warfarin adjusted dose for INR 2–2.5 +aspirin (n=44)

vs.

placebo +aspirin (n=46)

double blind

Sample size: 44/46

Primary endpoint:

FU duration: 1 year

warfarin target INR 2–2.5 for 5 months +aspirin (n=1848)

vs.

control (n=1864)

open

Sample size: 1848/1864

Primary endpoint:

FU duration: 5 months

moderate-intensity coumarin target INR 2-3 (+aspirin) (n=135)

vs.

aspirin (n=139)

Sample size: 135/139

Primary endpoint:

FU duration: 3 months

warfarin (INR median 1.8) (n=2522)

vs.

(n=2537)

Sample size: 2522/2537

Primary endpoint:

FU duration: 2.7 years

warfarin (INR 2.2 (mean) (n=1208)

vs.

(n=1206)

Sample size: 1208/1206

Primary endpoint:

FU duration: 4 years

warfarin (prothrombin complex activity mean 95.5) (n=1659)

vs.

(n=1641)

Sample size: 1659/1641

Primary endpoint:

FU duration: 5 years

Warfarin target INR 2–3 (n=70)

vs.

(n=70)

Sample size: 70/70

Primary endpoint:

FU duration: 1 year

heparin/warfarin target INR 3-4 (n=24)

vs.

aspirin 325 mg daily (n=32)

open

Sample size: 24/32

Primary endpoint:

FU duration: 3 months

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

Argatroban 60–20 mg/kg bolus; 2–4 µg /kg/min infusion for 72h (n=-9)

vs.

UFH 5000 IU bolus; 1000 IU/h infusion (n=-9)

Sample size: -9/-9

Primary endpoint:

FU duration: 30 days

Major bleeding 0.61 [0.42; 0.89]

transfusion 0.51 [0.31; 0.85]

Death 0.80 [0.36; 1.80]

MI 0.60 [0.29; 1.26]

coronary event 0.74 [0.46; 1.18]

Minor bleeding 1.02 [0.84; 1.23]

hemorrhagic stroke ∞ [NaN; ∞]

Bivalirudin 0.125–0.250 mg/kg bolus; 0.125–0.500 mg /kg/min infusion for 72h (n=272)

vs.

UFH 5000 IU bolus; 1000–1200 IU/h infusion (n=140)

3 arms: low-dose, high dose hirulog and heparin

double blind

Parallel groups

Sample size: 272/140

Primary endpoint: TIMI3 of the infarct-related artery at 90 to 120 minutes

FU duration: 35 days

dose-finding study

Thrombotic Stroke 0.60 [0.40; 0.89]

myocardial infarction 0.47 [0.38; 0.58]

Major Bleeding 3.85 [2.34; 6.35]

Death 0.90 [0.74; 1.10]

Minor Bleeding 3.03 [1.77; 5.20]

Death 0.58 [0.26; 1.31]

Revascularization 0.80 [0.51; 1.23]

Major Bleeding 2.26 [0.59; 8.67]

Thrombotic Stroke 0.00 [0.00; NaN]

myocardial infarction 0.69 [0.31; 1.53]

nicoumalone or phenprocoumon, target INR 2.8–4.8 (n=1700)

vs.

placebo (n=1704)

double blind

Parallel groups

Sample size: 1700/1704

Primary endpoint:

FU duration: 37 months (range 6-76)

coumadin(INR mean 2.4) +aspirin (n=298)

vs.

aspirin (n=289)

open

Parallel groups

Sample size: 298/289

Primary endpoint: death, MI or stroke

FU duration: 1 year

Death 0.28 [0.09; 0.82]

Revascularization 0.90 [0.58; 1.39]

Major Bleeding 1.03 [0.21; 5.09]

Minor Bleeding 1.68 [0.92; 3.07]

intrcranial major bleeding NaN [NaN; NaN]

myocardial infarction 0.96 [0.46; 2.01]

all cause death, MI, thrombo-embolic stroke 0.57 [0.32; 1.00]

coumadin (phenprocoumon or acenocoumarol) target INR 3-4 (n=325)

vs.

aspirin 80mg daily (n=336)

open

Parallel groups

Sample size: 325/336

Primary endpoint: death, MI or stroke

FU duration: 1 year (range 0-26 months)

Dalteparin 150 mg/kg BID for 7–11 d (n=388)

vs.

placebo (n=388)

Double-blind

Parallel groups

Sample size: 388/388

Primary endpoint: Echocardiographic LV thrombus, arterial embolism

FU duration: in hospital

Dalteparin 100 mg/kg, 2 doses (n=54)

vs.

placebo (n=47)

Double-blind

Parallel groups

Sample size: 54/47

Primary endpoint: Angiographic TIMI flow in infarct-related vessel

FU duration: 14–21 d

reinfarction at 30 days 0.96 [0.47; 1.97]

death at 30 dayas 0.79 [0.33; 1.86]

Dalteparin first dose 90 IU/kg, then 120 IU/kg BID, 4–7 d (n=221)

vs.

UFH 4000–5000 IU bolus, then 800–1000 IU/h for 48 h (n=213)

open

Parallel groups

Sample size: 221/213

Primary endpoint: Angiographic 60-min TIMI flow

FU duration: 30 d

Enoxaparin 30 mg IV bolus, 1 mg/kg for 3–8 d (n=253)

vs.

placebo (n=243)

Double-blind

Parallel groups

Sample size: 253/243

Primary endpoint: Angiographic TIMI flow in infarct-related vessel

FU duration: 30 d

reinfarction at 30 days 0.64 [0.46; 0.88]

death at 30 dayas 0.89 [0.69; 1.15]

reinfarction at 30 days 1.00 [0.38; 2.61]

death at 30 dayas 0.90 [0.37; 2.17]

reinfarction at 30 days 0.74 [0.45; 1.23]

death at 30 dayas 0.57 [0.26; 1.25]

reinfarction at 30 days 0.15 [0.04; 0.54]

death at 30 dayas 0.68 [0.16; 2.98]

death at 30 dayas 1.25 [0.87; 1.80]

Enoxaparin 1 mg/kg BID, <=7d (n=2040)

vs.

UFH 60 U/kg bolus, then 12 IU/kg per h for 48 h (n=2038)

open

Parallel groups

Sample size: 2040/2038

Primary endpoint: In-hospital MI or RI

FU duration: 30 d

Enoxaparin 1 mg/kg BID, <=3d (n=200)

vs.

UFH 4000–5000 IU bolus, then 15 IU/kg per hour for >=3d (n=200)

open

Parallel groups

Sample size: 200/200

Primary endpoint: infarct-related artery patency

FU duration: 5–7 d

Enoxaparin 40 mg TID, 4 d (n=149)

vs.

UFH 5000 IU bolus, then 30 000 IU over 24 h for 4d (n=151)

90-min TIMI flow

Parallel groups

Sample size: 149/151

Primary endpoint: death, non-fatal reinfarction, or readmission with unstable angina

FU duration: 90 d

Enoxaparin 1 mg/kg BID, <=8d (n=160)

vs.

UFH 60 IU/kg, then 12 IU/kg per h for >=3d (n=82)

open

Parallel groups

Sample size: 160/82

Primary endpoint: MI, death, readmit for UA

FU duration: 30 d

Enoxaparin 1 mg/kg BID, <=7d (n=818)

vs.

UFH 60 IU/kg, then 12 IU/kg per h for >=3d (n=821)

open

Parallel groups

Sample size: 818/821

Primary endpoint: Angiographic TIMI flow

FU duration: 30 d

death in hospital 0.87 [0.76; 0.99]

death or reinfarction 0.87 [0.78; 0.96]

reinfarction during hospitalization 0.68 [0.52; 0.88]

death at 30 dayas 0.87 [0.78; 0.98]

Major bleeding 0.83 [0.64; 1.06]

reinfarction at 30 days 0.81 [0.65; 1.01]

fondaparinux 2.5 mg once daily up to 8 days (n=6036)

vs.

control (UFH or placebo) (n=6056)

from day 3 through day 9, all patients received either fondaparinux or placebo

double-blind

Factorial plan

Sample size: 6036/6056

Primary endpoint: death or reinfarction

FU duration: 30 days

Hirudin 0.2 mg/kg bolus; 0.5 mg/kg twice daily 0.1 mg/kg 0.1 mg /kg/h infusion for 5-7 days (n=447)

vs.

Placebo bolus, UFH 12 500 IU twice daily (n=0)

double blind

Parallel groups

Sample size: 447/0

Primary endpoint: TIMI 3 flow at 90 min

FU duration: 30 days

Hirudin 0.1 mg/kg bolus; 0.1 mg /kg/h infusion for 96h (n=3002)

vs.

UFH 5000 IU bolus; 1000 IU/h infusion (n=0)

open

Parallel groups

Sample size: 3002/0

Primary endpoint: death,MI, HF, cardiogenic shock

FU duration: 30 days

Reviparin 3436–6871 IU BID for 7 d (weight adjusted) (n=7780)

vs.

placebo (n=7790)

Double-blind

Parallel groups

Sample size: 7780/7790

Primary endpoint: Death, MI, or stroke; death, MI, stroke, or recurrent ischemia

FU duration: 30 d

death in hospital 1.30 [0.47; 3.60]

reinfarction during hospitalization 0.19 [0.02; 1.64]

death in hospital 0.81 [0.34; 1.92]

reinfarction during hospitalization 0.99 [0.42; 2.34]

death in hospital 0.33 [0.04; 3.12]

reinfarction during hospitalization 2.00 [0.19; 21.51]

death in hospital 1.43 [0.61; 3.38]

reinfarction during hospitalization 2.14 [0.68; 6.78]

UFH nNo bolus, 1000 IU/h for 48 h (n=106)

vs.

No heparin (n=103)

open

Parallel groups

Sample size: 106/103

Primary endpoint: New MI, death

FU duration: In-hospital, 1 y (deat

UFH 5000 IU bolus, UFH 1000 IU/h for 48–120 h (n=324)

vs.

Placebo (n=320)

Double-blind

Parallel groups

Sample size: 324/320

Primary endpoint: Angiographic patency

FU duration: In-hospital

UFH 10 000 IU bolus, 1000 IU/h for 24 h (n=64)

vs.

Placebo (n=64)

Double-blind

Parallel groups

Sample size: 64/64

Primary endpoint: Reperfusion, angiographic patency, LVEF

FU duration: In-hospital

UFH no bolus, 15 IU/kg per h for 4 d; target aPTT 50–90 s (n=128)

vs.

No heparin (n=122)

open

Parallel groups

Sample size: 128/122

Primary endpoint: Death, recurrent MI, recurrent ischemia, angiographic patency

FU duration: 14 d

Revascularization 0.33 [0.19; 0.57]

myocardial infarction 0.28 [0.08; 0.98]

Death ∞ [NaN; ∞]

Major Bleeding 1.03 [0.15; 7.21]

Minor Bleeding 2.57 [0.51; 13.04]

myocardial infarction 0.17 [0.03; 1.00]

Death 0.00 [0.00; NaN]

Revascularization 1.11 [0.45; 2.77]

Major Bleeding ∞ [NaN; ∞]

Minor Bleeding ∞ [NaN; ∞]

Thrombotic Stroke NaN [NaN; NaN]

Minor Bleeding 6.50 [1.52; 27.75]

Death 0.33 [0.07; 1.60]

Major Bleeding 2.50 [0.50; 12.46]

Thrombotic Stroke NaN [NaN; NaN]

myocardial infarction 0.67 [0.20; 2.26]

Major Bleeding 1.75 [1.24; 2.47]

Minor Bleeding 4.56 [3.58; 5.80]

Death 1.02 [0.90; 1.15]

Thrombotic Stroke 0.89 [0.66; 1.20]

intrcranial major bleeding 0.94 [0.45; 1.94]

myocardial infarction 1.02 [0.88; 1.17]

cardiovascular event 0.60 [0.52; 0.70]

non fatal MI 0.57 [0.48; 0.69]

cardiovascular death 0.69 [0.52; 0.92]

Death 0.73 [0.56; 0.94]

Major Bleeding 1.09 [0.70; 1.70]

Thrombotic Stroke 0.93 [0.53; 1.61]

Thrombotic Stroke 0.68 [0.48; 0.94]

stroke 0.67 [0.50; 0.88]

Major Bleeding 2.23 [1.24; 3.99]

Minor Bleeding 2.21 [1.55; 3.14]

cardiovascular event 0.97 [0.87; 1.09]

cardiovascular death 0.91 [0.77; 1.07]

Death 0.95 [0.83; 1.10]

intrcranial major bleeding 1.98 [0.68; 5.78]

myocardial infarction 1.04 [0.90; 1.22]

cardiovascular event 1.29 [1.10; 1.51]

non fatal MI 1.31 [1.09; 1.58]

Thrombotic Stroke 2.23 [1.27; 3.92]

cardiovascular death 1.07 [0.77; 1.49]

Death 1.03 [0.76; 1.41]

Major Bleeding 1.45 [0.86; 2.44]

cardiovascular event 0.71 [0.59; 0.86]

non fatal MI 0.56 [0.42; 0.75]

Thrombotic Stroke 0.50 [0.28; 0.91]

myocardial infarction 0.56 [0.42; 0.75]

all cause death, MI, thrombo-embolic stroke 0.71 [0.59; 0.86]

Major Bleeding 3.32 [1.51; 7.27]

Minor Bleeding 3.23 [2.27; 4.61]

Death 0.98 [0.74; 1.30]

Revascularization 0.90 [0.79; 1.02]

intrcranial major bleeding 2.84 [0.30; 27.32]

moderate-intensity coumarin target INR 2-3 (+aspirin) (n=135)

vs.

aspirin (n=139)

open

Parallel groups

Sample size: 135/139

Primary endpoint: reocclusion of the infarct-related artery

FU duration: 3 months

warfarin target INR 2–2.5 +aspirin (n=6)

vs.

placebo +aspirin (n=5)

double blind

Parallel groups

Sample size: 6/5

Primary endpoint: quantitative angiography

FU duration: 2.5 months

Warfarin target INR 2–3 +aspirin (n=70)

vs.

aspirin 100 mg/day (n=70)

open

Parallel groups

Sample size: 70/70

Primary endpoint:

FU duration: 1 year

warfarin 2.8–4.8 (n=1208)

vs.

placebo (n=1206)

double blind

Parallel groups

Sample size: 1208/1206

Primary endpoint:

FU duration: 37 months

warfarin target INR 1.5-2.5 + aspirin 81 mg daily (n=2522)

vs.

aspirin 162 mg/d (n=2537)

open

Parallel groups

Sample size: 2522/2537

Primary endpoint: all cause mortality

FU duration: 2.7 years

warfarin fixed dose 3mg/d + 80 mg ASA (n=5410)

vs.

aspirin 160 mg/d (n=3393)

double blind

Parallel groups

Sample size: 5410/3393

Primary endpoint: reinfarction, non-fatal ischaemic stroke, or cardiovascular death

FU duration: 14 months

warfarin fixed dose 1.25mg/d + ASA 75mg/d (n=1659)

vs.

aspirin alone (n=1641)

open

Parallel groups

Sample size: 1659/1641

Primary endpoint: Cardiovascular event and CV death

FU duration: 5 years

warfarin 1mg/d + aspirin 80mg/d (n=2028)

vs.

aspirin 160 mg/d (n=3393)

double blind

Parallel groups

Sample size: 2028/3393

Primary endpoint: reinfarction, non-fatal ischaemic stroke, or cardiovascular death

FU duration: 14 months

warfarin target INR 2-2.5 +ASA 75mg/d (n=4927)

vs.

ASA 160mg/d (n=4669)

open

Parallel groups

Sample size: 4927/4669

Primary endpoint: death, MI, ischaemic stroke

FU duration: 4 years

cardiovascular event 0.84 [0.71; 0.99]

non fatal MI 0.76 [0.59; 0.99]

Thrombotic Stroke 0.53 [0.29; 0.94]

all cause death, MI, thrombo-embolic stroke 0.81 [0.69; 0.95]

Major Bleeding 4.09 [1.90; 8.82]

Minor Bleeding 2.62 [1.83; 3.75]

Death 1.03 [0.79; 1.36]

intrcranial major bleeding 4.96 [0.58; 42.38]

warfarin target INR 2.8-4.2 (n=1216)

vs.

ASA 160mg/d (n=1206)

NA

Parallel groups

Sample size: 1216/1206

Primary endpoint: death, MI, ischaemic stroke

FU duration: 48 months

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 0.80 [0.38; 1.68]

major bleeding ∞ [NaN; ∞]

haemorragic stroke(or intracerebral hemorrhage) NaN [NaN; NaN]

thrombo-embolic event (cerebral or systemic) 0.84 [0.48; 1.47]

thromboembolic event likes(TE event or ischemic stroke or systemic embolism) 0.84 [0.48; 1.47]

All stroke(ischemic+hemorrhagic/fatal+non fatal) 0.84 [0.44; 1.61]

stroke*(all stroke or ischemic stroke) 0.91 [0.71; 1.18]

Non fatal TE event,bleedings and vascular death 0.89 [0.74; 1.09]

thromboembolic event*(TE event or ischemic stroke or systemic thromboembolic event) 0.82 [0.60; 1.11]

stroke,myocardial infarction,systemic arterial emboli or vascular death 2.66 [0.53; 13.33]

Non fatal TE event,bleedings and vascular death 2.66 [0.53; 13.33]

fatal bleeding 2.13 [0.20; 23.03]

thromboembolic event*(TE event or ischemic stroke or systemic thromboembolic event) 2.13 [0.20; 23.03]

thromboembolic event likes(TE event or ischemic stroke or systemic embolism) 0.06 [0.01; 0.42]

aspirin 75 mg/d (n=336)

vs.

placebo (n=336)

The AFASAK study compared 3 different treatments:aspirin, warfarin and placebo.

Double aveugle

Parallel groups

Sample size: 336/336

Primary endpoint: thrombo-embolic complication

FU duration: 2 years

The number of lost to follow up is not given.

aspirin:125mg/day(group A1);125mg on alternate days(group A2) (n=-9)

vs.

no control treatment(group C) (n=-9)

Open

Sample size: -9/-9

Primary endpoint:

FU duration:

aspirin 300 mg/d (n=404)

vs.

placebo (n=378)

There were 2 groups in the study: -patients eligible for anticoagulation(g1) who were randomly assigned to receive either open label oral anticoagulants or double blind treatment with aspirin or placebo -patients ineligible for anticoagulation (g2) who were randomised to double blind treatment with aspirin 300 mg or matching placebo.

Double blind

Parallel groups

Sample size: 404/378

Primary endpoint: death from vascular disease,stroke,myocardial infarction or sytemic embolism

FU duration: 2.3 years

fluidione standard dose (target INR: 2-2.6) + aspirin low dose 100 mg (n=76)

vs.

fluidione standard dose(target INR:2-2.6) + placebo (n=81)

Double blind

Parallel groups

Sample size: 76/81

Primary endpoint: stroke,myocardial infarction,systemic arterial emboli or vascular death

FU duration: 0.84 y

aspirin 325mg/d (n=206)

vs.

placebo (n=211)

The SPAF study compared 3 treatments :warfarin,aspirin and placebo. 2 groups were considered: -G1: in which patients received either warfarin,aspirin or placebo -G2: in which patients received either aspirin or placebo(these patients were uneligible to take warfarin) No analysis was made between warfarin and aspirin. All patients under aspirin were compared to all patients under placebo(G1+G2)

Patients with history of stroke or TIA more than 2 years before entry were eligible(7% of patients).So,it is mostly a primary prevention trial but not only.

Double blind

Parallel groups

Sample size: 206/211

Primary endpoint: ischemic stroke and systemic embolism

FU duration: 1.3 years

non fatal TE events,bleedings and vascular death* 1.03 [0.72; 1.48]

thromboembolic event likes(TE event or ischemic stroke or systemic embolism) 1.26 [0.68; 2.33]

non fatal TE events,bleedings and vascular death* 0.71 [0.32; 1.54]

all death 2.31 [0.91; 5.86]

vascular death 1.32 [0.30; 5.80]

major bleeding 1.65 [0.40; 6.78]

haemorragic stroke(or intracerebral hemorrhage) ∞ [NaN; ∞]

fatal stroke(ischemic+hemorrhagic) 0.99 [0.14; 6.93]

thrombo-embolic event (cerebral or systemic) 0.82 [0.26; 2.65]

ischemic stroke 0.82 [0.26; 2.65]

thromboembolic event likes(TE event or ischemic stroke or systemic embolism) 0.82 [0.26; 2.65]

All stroke(ischemic+hemorrhagic/fatal+non fatal) 0.64 [0.28; 1.43]

systemic thrombo-embolic complication 0.99 [0.06; 15.67]

non fatal TE events,bleedings and vascular death* 1.25 [0.81; 1.95]

fatal stroke(ischemic+hemorrhagic) ∞ [NaN; ∞]

non fatal stroke 1.31 [0.65; 2.66]

thromboembolic event likes(TE event or ischemic stroke or systemic embolism) 1.50 [0.78; 2.91]

non fatal TE events,bleedings and vascular death* 0.84 [0.37; 1.89]

fatal stroke(ischemic+hemorrhagic) ∞ [NaN; ∞]

thromboembolic event likes(TE event or ischemic stroke or systemic embolism) 1.26 [0.34; 4.60]

non fatal TE events,bleedings and vascular death* 1.11 [0.50; 2.49]

fatal stroke(ischemic+hemorrhagic) ∞ [NaN; ∞]

thromboembolic event likes(TE event or ischemic stroke or systemic embolism) 1.55 [0.38; 6.35]

non fatal TE events,bleedings and vascular death* 0.98 [0.60; 1.58]

non fatal stroke 1.40 [0.68; 2.87]

thromboembolic event likes(TE event or ischemic stroke or systemic embolism) 1.35 [0.69; 2.63]

thromboembolic event likes(TE event or ischemic stroke or systemic embolism) 1.90 [0.93; 3.89]

aspirin 300mg/d (n=319)

vs.

coumarin low dose(target INR 1.1-1.6 ) (n=279)

The PATAF trial includes 2 strata: -patients eligible for standard intensity coumarin:randomly assigned to standard anticoagulation(INR 2.5-3.5),very low intensity anticoagulation(INR 1.1-1.6) or aspirin(150mg/d). -patients ineligible for standard anticoagulation:randomly assigned to very low intensity anticoagulation(INR 1.1-1.6) or aspirin(150mg/d).

We took all patients who were given aspirin (strate 1+2) and all patients on low dose anticoagulation(strate 1+2).

Simple aveugle

Parallel groups

Sample size: 319/279

Primary endpoint: stroke,systemic embolism,major haemorrhage and vascular death

FU duration: 2.7 years

The study was carried out to show that aspirin is equivalent to warfarin, but the methodology used was inappropriate.The study team conducted an intention to treat analysis and assumed they could conclude to equivalence if no significant difference was found between treatments at the end of the study.But this hypothesis is wrong :if no difference has been found,no conclusion is possible,and particularly, equivalence can't be proven.

aspirin 300 mg/d (n=169)

vs.

warfarin low dose (1.25mg/d) (n=167)

The trial includes 4 arms: fixed low dose warfarin (1.25mg/d),fixed low dose warfarin (1.25mg/d)+ aspirin 300mg,aspirin 300 mg and conventional warfarin therapy(target INR 2-3). The protocol allows 4 weeks per year without study treatment.

Open

Parallel groups

Sample size: 169/167

Primary endpoint: all stroke or systemic thromboembolic event

FU duration: 3.5 years

Mean follow-up duration was not reported. The discontinuation of study treatment was reported globally(25.1% for reasons other than primary or secondary adverse events). Though the primary analysis of the study was made according to an "on treatment" approach ,an "intention to treat" analysis was performed for thrombo-embolic events to allow comparison with other studies.

aspirin 325 mg/d (n=357)

vs.

warfarin standard dose(target INR 2.0-4.5) (n=358)

Open

Parallel groups

Sample size: 357/358

Primary endpoint: ischemic stroke and systemic embolism

FU duration: 3.1 years

Randomisation was not centralized. 61.9%(681) patients of this study are stemming from the SPAF I study:416 had been assigned to warfarin or aspirin in the warfarin eligible group and have been included without rerandomization in SPAF II(patients aged 75 and less' strate);265 had been assigned mostly to placebo and have been rerandomized to get either aspirin or warfarin. The withdrawals from trial are not reported.

aspirin 300 mg/d (n=169)

vs.

warfarin standard dose(target INR 2-3) (n=170)

The trial includes 4 arms:fixed low dose warfarin (1.25mg/d),fixed low dose warfarin (1.25mg/d)+ aspirin 300mg,aspirin 300 mg and conventional warfarin therapy(target INR 2-3). The protocol allows 4 weeks per year without study treatment.

Open

Parallel groups

Sample size: 169/170

Primary endpoint: stroke or systemic thromboembolic event

FU duration: 3.5 years

Mean follow-up duration was not reported. The discontinuation of study treatment was reported globally(25.1% for reasons other than primary or secondary adverse events).Though the primary analysis of the study was made according to an "on treatment" approach ,an "intention to treat" analysis was performed for thrombo-embolic events to allow comparison with other studies.

aspirin 150mg/d (n=141)

vs.

coumarin standard dose(target INR 2.5-3.5) (n=131)

The PATAF trial includes 2 strata: -patients eligible for standard intensity coumarin:randomly assigned to standard anticoagulation(INR 2.5-3.5),very low intensity anticoagulation(INR 1.1-1.6) or aspirin(150mg/d). -patients ineligible for standard anticoagulation:randomly assigned to very low intensity anticoagulation(INR 1.1-1.6) or aspirin(150mg/d).

Simple aveugle

Parallel groups

Sample size: 141/131

Primary endpoint: stroke,systemic embolism,major haemorrhage and vascular death

FU duration: 2.7 years

The study was carried out to show that aspirin is equivalent to warfarin, but the methodology used was inappropriate.The study team conducted an intention to treat analysis and assumed they could conclude to equivalence if no significant difference was found between treatments at the end of the study.But this hypothesis is wrong :if no difference has been found,no conclusion is possible,and particularly, equivalence can't be proven.

aspirin 325 mg/d (n=188)

vs.

warfarin standard dose (target INR 2.0-4.5) (n=197)

Open

Parallel groups

Sample size: 188/197

Primary endpoint: ischemic stroke and systemic embolism

FU duration: 2.0 years

Randomization was not centralized. 61.9%(681) patients of this study are stemming from the SPAF I study:416 had been assigned to warfarin or aspirin in the warfarin eligible group and have been included without rerandomization in SPAF II(patients aged 75 and less' strate);265 had been assigned mostly to placebo and have been rerandomized to get either aspirin or warfarin. The withdrawals from trial are not reported.

aspirin (low dose 75 mg) (n=336)

vs.

warfarin standard dose(target INR 2.8-4.2) (n=335)

The AFASAK study compared 3 different treatments:aspirin, warfarin and placebo.

Open

Parallel groups

Sample size: 336/335

Primary endpoint: thrombo-embolic complication

FU duration: 2 years

The number of lost to follow up is not given. There is a high number of withdrawn patients, even higher in the warfarin arm(38% for warfarin,13% for aspirin,15% for placebo)).

thromboembolic event likes(TE event or ischemic stroke or systemic embolism) 0.92 [0.55; 1.55]

aspirin 325mg/d (n=346)

vs.

placebo (n=357)

The SPAF study compared 3 treatments :warfarin,aspirin and placebo. 2 groups were considered: -G1: in which patients received either warfarin,aspirin or placebo -G2: in which patients received either aspirin or placebo(these patients were uneligible to take warfarin) No analysis was made between warfarin and aspirin. All patients under aspirin were compared to all patients under placebo(G1+G2)

Patients with history of stroke or TIA more than 2 years before entry were eligible(7% of patients).So,it is mainly a primary prevention trial.

Double blind

Parallel groups

Sample size: 346/357

Primary endpoint: ischemic stroke and systemic embolism

FU duration: 1.3 years

haemorragic stroke(or intracerebral hemorrhage) 0.34 [0.12; 0.93]

non fatal TE events,bleedings and vascular death* 1.39 [1.18; 1.64]

thrombo-embolic event (cerebral or systemic) 1.43 [1.18; 1.74]

ischemic stroke 2.17 [1.51; 3.11]

All stroke(ischemic+hemorrhagic/fatal+non fatal) 1.71 [1.25; 2.36]

all death 1.02 [0.82; 1.26]

vascular death 1.14 [0.89; 1.48]

major bleeding 1.10 [0.83; 1.45]

fatal stroke(ischemic+hemorrhagic) 0.94 [0.46; 1.95]

fatal bleeding 0.64 [0.25; 1.66]

clopidogrel (75 mg per day) plus aspirin (75–100 mg per day) (n=3335)

vs.

oral anticoagulation therapy (target international normalised ratio of 2·0–3·0) (n=3371)

open

Parallel groups

Sample size: 3335/3371

Primary endpoint: stroke, non-CNS systemic embolus

FU duration: 1.28 y (median)

fatal stroke(ischemic+hemorrhagic) 0.72 [0.59; 0.88]

thrombo-embolic event (cerebral or systemic) 0.90 [0.83; 0.98]

ischemic stroke 0.69 [0.59; 0.81]

thromboembolic event likes(TE event or ischemic stroke or systemic embolism) 0.89 [0.89; 0.89]

All stroke(ischemic+hemorrhagic/fatal+non fatal) 0.73 [0.63; 0.84]

major bleeding 1.57 [1.29; 1.91]

all death 0.98 [0.90; 1.07]

vascular death 1.00 [0.91; 1.11]

haemorragic stroke(or intracerebral hemorrhage) 1.37 [0.79; 2.37]

fatal bleeding 1.56 [0.96; 2.52]

clopidogrel 75 mg daily + aspirin 75-100 mg daily (n=3772)

vs.

aspirin 75-100 mg daily alone (n=3782)

double blind

Parallel groups

Sample size: 3772/3782

Primary endpoint: stroke, MI, systemic embolus, or vascular death

FU duration: 3.7 y

non fatal TE events,bleedings and vascular death* 0.86 [0.35; 2.11]

thromboembolic event likes(TE event or ischemic stroke or systemic embolism) 1.07 [0.22; 5.22]

coumarin low dose(target INR 1.1-1.6) (n=122)

vs.

coumarin standard dose(target INR 2.5-3.5) (n=131)

The PATAF trial includes 2 strata: -patients eligible for standard intensity coumarin:randomly assigned to standard anticoagulation(INR 2.5-3.5),very low intensity anticoagulation(INR 1.1-1.6) or aspirin(150mg/d). -patients ineligible for standard anticoagulation:randomly assigned to very low intensity anticoagulation(INR 1.1-1.6) or aspirin(150mg/d).

Simple aveugle

Parallel groups

Sample size: 122/131

Primary endpoint: stroke,systemic embolism,major haemorrhage and vascular death

FU duration: 2.7 years

The study was carried out to show that aspirin is equivalent to warfarin, but the methodology used was inappropriate.The study team conducted an intention to treat analysis and assumed they could conclude to equivalence if no significant difference was found between treatments at the end of the study.But this hypothesis is wrong :if no difference has been found,no conclusion is possible,and particularly, equivalence can't be proven.

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]

haemorragic stroke(intracerebral hemorrhage) 0.27 [0.10; 0.72]

intra cranial hemorrhage(intracerebral hemorrhage + hematomas) 0.41 [0.21; 0.80]

thromboembolic event(cerebral or systemic) 0.76 [0.53; 1.09]

thromboembolic event*(TE event or ischemic stroke or systemic thromboembolic event) 0.76 [0.53; 1.09]

haemorragic stroke(intracerebral hemorrhage) 0.11 [0.03; 0.44]

intra cranial hemorrhage(intracerebral hemorrhage + hematomas) 0.20 [0.08; 0.48]

thromboembolic event(cerebral or systemic) 0.85 [0.59; 1.22]

thromboembolic event*(TE event or ischemic stroke or systemic thromboembolic event) 0.85 [0.59; 1.22]

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