| pathology | Benefit (demonstrated or suggested) and harm | | | |
|---|
| acute coronary syndrome | All results are NS for efficacy | meta-analysis | | | Trial | control | p<0.05 | harm | NS |
|---|
| ESTEEM, 2003 | vs placebo | | | |
| Trial | Treatments | Patients | Method |
|---|
| ESTEEM, 2003 | oral ximelagatran at doses of
24 mg, 36 mg, 48 mg, or 60 mg twice daily (n=1245) vs. placebo (n=638) | patients who had had recent ST-elevation or non-STelevation
myocardial infarction | double-blind Parallel groups Sample size: 1245/638 Primary endpoint: death, MI, severe recurrent ischaemia FU duration: 6 months dose ranging |
|
| atrial fibrillation | All results are NS for efficacy inferior to warfarin standard dose in terms of hypertransaminasemia in SPORTIF V, 2005 | meta-analysis | | | Trial | control | p<0.05 | harm | NS |
|---|
| SPORTIF II (ximelagatran vs warfarin standard dose), 2002 | vs warfarin standard dose | | | | | SPORTIF III, 2003 | vs warfarin standard dose | all bleeding 0.87 [0.79; 0.97] minor bleeding 0.89 [0.80; 0.99] | | all stroke or systemic embolism or death 0.83 [0.64; 1.07] TIA 1.00 [0.56; 1.77] all stroke or systemic embolism 0.71 [0.48; 1.07] 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] myocardial infarction 1.85 [0.94; 3.61] systemic thrombo-embolic complication 2.00 [0.37; 10.90] | | SPORTIF V, 2005 | vs warfarin standard dose | all bleeding 0.82 [0.76; 0.88] | hypertransaminasemia 7.81 [4.58; 13.32] | all stroke or systemic embolism or death 1.01 [0.82; 1.26] all stroke or systemic embolism 1.38 [0.91; 2.10] 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] other side effects 1.00 [0.98; 1.01] 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] myocardial infarction 0.70 [0.43; 1.16] systemic thrombo-embolic complication 6.01 [0.72; 49.84] |
| Trial | Treatments | Patients | Method |
|---|
| SPORTIF II (ximelagatran vs warfarin standard dose), 2002 | 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. | Medium to high risk patients with chronic non valvular atrial fibrillation. -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 | | SPORTIF III, 2003 | 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). | One or more stroke risk factor in addition to AF.High risk patients with non valvular atrial fibrillation. | 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. | | SPORTIF V, 2005 | ximelegatran 36 mg twice daily (n=1960) vs. warfarin standard dose(target INR 2-3) (n=1962) | One or more stroke risk factor in addition to atrial fibrillation.High risk patients with non valvular atrial fibrillation.
| Double blind Parallel groups Sample size: 1960/1962 Primary endpoint: All stroke and systemic embolism FU duration: 20 months |
|
| thrombosis prevention | All results are NS for efficacy inferior to Enoxaparin in terms of DVT+PE in Platinum (Colwell), 2003 inferior to Enoxaparin in terms of serious bleeding in EXPRESS, 2003 | meta-analysis | | | Trial | control | p<0.05 | harm | NS |
|---|
| Phase II (Heit), 2001 | vs Enoxaparin | | | serious bleeding 0.00 [0.00; NaN] DVT+PE 0.70 [0.39; 1.26] | | Platinum (Colwell), 2003 | vs Enoxaparin | | DVT+PE 1.71 [1.15; 2.54] | serious bleeding 0.88 [0.32; 2.41] | | METHRO I, 2002 | vs Enoxaparin | | | serious bleeding NaN [NaN; NaN] DVT+PE 0.83 [0.25; 2.76] | | METHRO II, 2002 | vs Enoxaparin | DVT+PE 0.53 [0.38; 0.74] | | serious bleeding 2.01 [0.91; 4.42] | | METHRO III, 2002 | vs Enoxaparin | | | serious bleeding 0.86 [0.48; 1.56] DVT+PE 1.14 [1.00; 1.29] | | EXPRESS, 2003 | vs Enoxaparin | DVT+PE 0.76 [0.66; 0.88] | serious bleeding 2.89 [1.65; 5.09] | |
| Trial | Treatments | Patients | Method |
|---|
| Phase II (Heit), 2001 | 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) | adults (age>18 years and weight at least 40 kg) undergoing knee replacements | double-blind parallel group Sample size: 600/0 Primary endpoint: FU duration: 6–12 days | | Platinum (Colwell), 2003 | 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) | adults undergoing hip replacement | double-blind parallel group Sample size: 906/910 Primary endpoint: FU duration: 7–12 days | | METHRO I, 2002 | 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) | adults undergoing hip or knee replacement | open parallel group Sample size: 103/0 Primary endpoint: FU duration: 6–9 days | | METHRO II, 2002 | 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) | undergoing hip or knee replacement | double-blind Parallel groups Sample size: 1495/381 Primary endpoint: deep-vein thrombosis and pulmonary embolism FU duration: 7–10 days | | METHRO III, 2002 | 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) | hip or knee replacement | double-blind Sample size: 2788/0 Primary endpoint: venous thromboembolism FU duration: 8–11 days | | EXPRESS, 2003 | 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) | hip or knee replacement | double-blind parallel group Sample size: 2835/0 Primary endpoint: venous thromboembolism FU duration: 8–11 days |
|
| venous thrombosis | All results are NS for efficacy | meta-analysis | | | Trial | control | p<0.05 | harm | NS |
|---|
| Schulman (subgroup), 2003 | vs discontinuation | | | | | THRIVE III, 2003 | vs discontinuation | 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] | | THRIVE I, 2003 | vs discontinuation | | | | | Fiessinger , 2005 | vs discontinuation | | | |
| Trial | Treatments | Patients | Method |
|---|
| Schulman (subgroup), 2003 | extended treatment with Ximelagatran 24mg twice daily after initial anticoagulant treatment for 6 months (n=-9) vs. placebo (initial anticoagulant treatment for 6 months) (n=-9) | study subgroup of patients with active cancer in the previous 5 years treated for DVT or pulmonary
embolism for 6 months without recurrence | single blind and outcome ass. Parallel groups Sample size: -9/-9 Primary endpoint: FU duration: 18 months | | THRIVE III, 2003 | ximelagatran 24 mg twice daily for 18 months (n=612) vs. placebo for 18 months (n=611) | patients with venous thromboembolism who had undergone six months of anticoagulant therapy | double blind Parallel groups Sample size: 612/611 Primary endpoint: symptomatic recurrent venous FU duration: 18 months | | THRIVE I, 2003 | oral ximelagatran (24, 36, 48 or 60 mg twice daily) for 2 weeks (n=-9) vs. dalteparin and warfarin for 2 weeks (n=-9) | Patients with acute DVT | Sample size: -9/-9 Primary endpoint: FU duration: | | Fiessinger , 2005 | ximelagatran 36 mg twice daily (n=-9) vs. subcutaneous enoxaparin, 1 mg/kg twice daily, for 5 to 20 days followed by warfarin adjusted to maintain an international normalized ratio of 2.0 to 3.0. (n=-9) | patients with acute deep vein thrombosis | double blind Sample size: -9/-9 Primary endpoint: 28 countries FU duration: |
|
