| pathology | Benefit (demonstrated or suggested) and harm | | | |
|---|
| acute coronary syndrome | All results are NS for efficacy inferior to placebo in terms of ISTH major or clinically relevant nonmajor bleeding in APPRAISE-1 (10mg od), 2009 inferior to placebo in terms of TIMI major or minor bleeding not related to CABG in APPRAISE 2, 2011 inferior to placebo in terms of major bleeding in APPRAISE 2, 2011 inferior to placebo in terms of ISTH major or clinically relevant nonmajor bleeding in APPRAISE 2, 2011 inferior to placebo in terms of any bleeding in APPRAISE 2, 2011 inferior to placebo in terms of major or minor bleeding in APPRAISE 2, 2011 | meta-analysis | | | Trial | control | p<0.05 | harm | NS |
|---|
| APPRAISE-1 (10mg od), 2009 | vs placebo | | ISTH major or clinically relevant nonmajor bleeding 2.45 [1.32; 4.55] | coronary events 0.83 [0.50; 1.39] Cardiovascular death, MI, or stroke
0.61 [0.35; 1.06] | | APPRAISE-1 (2.5 mg bid), 2009 | vs placebo | | | Cardiovascular death, MI, or stroke
0.73 [0.45; 1.18] ISTH major or clinically relevant nonmajor bleeding 1.78 [0.93; 3.41] | | APPRAISE 2, 2011 | vs placebo | | 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] coronary events 0.97 [0.84; 1.13] 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] |
| Trial | Treatments | Patients | Method |
|---|
| APPRAISE-1 (10mg od), 2009 | 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 | patients with a recent ST-elevation or non–ST-elevation
acute coronary syndrome(<7 days) | double blind Parallel groups Sample size: 318/611 Primary endpoint: major or clinically relevant nonmajor bleeding FU duration: 6 months dose-finding study | | APPRAISE-1 (2.5 mg bid), 2009 | 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
| patients with a recent ST-elevation or non–ST-elevation
acute coronary syndrome(<7 days)
| double blind Sample size: -9/611 Primary endpoint: major or clinically relevant nonmajor bleeding FU duration: 6 months dose-finding study
| | APPRAISE 2, 2011 | apixaban 5mg twice daily (n=3705) vs. placebo (n=3687) | patients with a recent acute coronary syndrome and at least two
additional risk factors for recurrent ischemic events | double blind Parallel groups Sample size: 3705/3687 Primary endpoint: Cv death, MI, ischemic stroke FU duration: 8 months |
|
| atrial fibrillation | superior to warfarin standard dose in terms of all death in ARISTOTLE, 2011 superior to warfarin standard dose in terms of major bleeding in ARISTOTLE, 2011 superior to warfarin standard dose in terms of thrombo-embolic event (cerebral or systemic) in ARISTOTLE, 2011 inferior to warfarin standard dose in terms of minor bleeding in AVERROES, 2011 (ineligible for VKA patients) | meta-analysis | | | Trial | control | p<0.05 | harm | NS |
|---|
| ARISTOTLE, 2011 | vs warfarin standard dose | 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 all stroke or systemic embolism or death 0.89 [0.81; 0.98] thrombo-embolic event (central or systemic)and fatal or intracranial hemorrhage 0.78 [0.70; 0.87] all bleeding 0.77 [0.73; 0.80] haemorragic stroke(or intracerebral hemorrhage) 0.51 [0.35; 0.75] intracranial hemorrhage(hemorrhagic stroke+hematomas) 0.42 [0.31; 0.59] 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] myocardial infarction 0.88 [0.66; 1.16] Gastrointestinal major bleeding 0.88 [0.68; 1.14] systemic thrombo-embolic complication 0.88 [0.44; 1.76] | | AVERROES, 2011 | vs warfarin standard dose | all stroke or systemic embolism or death 0.64 [0.52; 0.78] all stroke or systemic embolism 0.45 [0.32; 0.62] stroke,systemic embolism,major haemorrhage and vascular death 0.67 [0.54; 0.83] thromboembolic event,cerebral or fatal bleeding and vascular death 0.74 [0.61; 0.90] 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] | minor bleeding 1.27 [1.01; 1.60] | 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] intracranial hemorrhage(hemorrhagic stroke+hematomas) 1.09 [0.50; 2.38] myocardial infarction 0.85 [0.50; 1.47] Gastrointestinal major bleeding 0.85 [0.39; 1.84] | | phase 2 apixaban | vs warfarin standard dose | | | |
| Trial | Treatments | Patients | Method |
|---|
| ARISTOTLE, 2011 | apixaban 5mg twice daily
(n=9120) vs. warfarin adjusted for an INR between 2 and 3
(n=9081)
| subjects with atrial fibrillation and risk factors for stroke
| double blind Parallel groups Sample size: 9120/9081 Primary endpoint: stroke or systemic embolism FU duration: 1.8 yrs (median)
| | AVERROES, 2011 | apixaban 5 mg (or 2.5 mg) twice daily (n=2808) vs. aspirin 81-324 md daily (n=2791) | patients with atrial fibrillation who have failed or are unsuitable for vitamin K antagonist treatment | double blind Parallel groups Sample size: 2808/2791 Primary endpoint: stroke or systemic embolism FU duration: maximum 21 months | | phase 2 apixaban | apixaban 5 or 2.5 mg twice daily (n=222) vs. warfarin (n=0) | patient with non valvular AF | double blind Parallel groups Sample size: 222/0 Primary endpoint: major or clinically relevant non-major bleeding FU duration: 12 weeks phase 2 |
|
| pulmonary embolism | All results are NS for efficacy | meta-analysis | | | Trial | control | p<0.05 | harm | NS |
|---|
| AMPLIFY, 2013 | vs LMWH/VKA | Major bleeding 0.31 [0.17; 0.55] | | recurrent DVT only 0.61 [0.35; 1.06] death 0.79 [0.53; 1.19] All deaths 0.79 [0.53; 1.19] non fatal PE 1.19 [0.68; 2.06] fatal PE 0.50 [0.05; 5.57] Symptomatic nonfatal pulmonary embolism 1.19 [0.68; 2.06] recurrent VTE during treatment 0.84 [0.60; 1.18] Symptomatic deep-vein thrombosis 0.61 [0.35; 1.06] Death related to venous thromboembolism 0.85 [0.38; 1.90] recurrent VTE 0.84 [0.60; 1.18] | | AMPLIFY-EXT 2.5mg, 2012 | vs LMWH/VKA | recurrent VTE 0.33 [0.22; 0.49] | | Major bleeding 0.49 [0.09; 2.69] major or clinically
relevant nonmajor bleeding 1.21 [0.70; 2.11] | | AMPLIFY-EXT 5mg, 2012 | vs LMWH/VKA | recurrent VTE 0.36 [0.25; 0.53] | | Major bleeding 0.25 [0.03; 2.28] major or clinically
relevant nonmajor bleeding 1.62 [0.96; 2.74] |
| Trial | Treatments | Patients | Method |
|---|
| AMPLIFY, 2013 | apixaban 10 mg twice daily for 7 days then 5 mg, twice daily, 6 months (n=2691) vs. conventional
therapy: enoxaparin 1mg/kg twice daily until INR>=2 then warfarin for an INR between 2-4, once daikly, 6 months (n=2704) | patients with deep vein thrombosis or pulmonary embolism | double blind Parallel groups Sample size: 2691/2704 Primary endpoint: Venous thromboembolic recurrence or death FU duration: 6 mo | | AMPLIFY-EXT 2.5mg, 2012 | Extended Treatment with apixaban 2.5 mg twice daily 12 months (n=842) vs. placebo (n=829) 3 arms: apixaban 2.5mg, 5mg twice daily, placebo | patients who have completed their intended treatment for deep vein thrombosis or pulmonary embolism | double blind Parallel groups Sample size: 842/829 Primary endpoint: FU duration: 12 mo | | AMPLIFY-EXT 5mg, 2012 | Extended Treatment with apixaban 5 mg twice daily 12 months
(n=815) vs. placebo
(n=829) 3 arms: apixaban 2.5mg, 5mg twice daily, placebo
| patients who have completed their intended treatment for deep vein thrombosis or pulmonary embolism
| double blind Sample size: 815/829 Primary endpoint: FU duration: 12 mo
|
|
| thrombosis prevention | All results are NS for efficacy | meta-analysis | | | Trial | control | p<0.05 | harm | NS |
|---|
| APROPOS 2.5mg, 2007 | vs enoxaparin (US regimen) | | | 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] | | ADVANCE-1, 2008 | vs enoxaparin (US regimen) | 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] | | ADVANCE 3, 2010 | vs enoxaparin (US regimen) | 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] | | ADVANCE 2, 2010 | vs enoxaparin (US regimen) | 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] | | ADOPT, 2011 | vs enoxaparin (US regimen) | Symptomatic deep vein thrombosis during follow-up 0.31 [0.12; 0.86] | | Major bleeding during follow-up 2.53 [0.98; 6.50] Asymptomatic deep vein thrombosis during follow-up. 1.11 [0.76; 1.64] VTE 0.89 [0.63; 1.24] fatal PE NaN [NaN; NaN] PE 0.88 [0.32; 2.42] Venous thromboembolism or death 0.89 [0.63; 1.24] proximal deep-vein thrombosis 0.96 [0.66; 1.39] |
| Trial | Treatments | Patients | Method |
|---|
| APROPOS 2.5mg, 2007 | 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 | patients undergoing elective total knee replacement surgery | 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 | | ADVANCE-1, 2008 | 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) | patients undergoing knee-replacement surgery | double blind Parallel groups Sample size: 1599/1596 Primary endpoint: a- and symptomatic DVT, non fatal PE, death FU duration: 10-14 days | | ADVANCE 3, 2010 | apixaban 2.5mg twice daily for 35 days (n=2708) vs. enoxaparin 40mg once daily for 35 days (n=2699) | patients undergoing elective total hip replacement surgery | double blind Parallel groups Sample size: 2708/2699 Primary endpoint: asymptomatic and symptomatic DVT, PE,all-cause death FU duration: 35 days (+60) | | ADVANCE 2, 2010 | apixaban 2.5mg twice daily during 12 days (n=1528) vs. enoxaparin 40mg once daily 12 days (n=1529) "European" enoxaprin regimen | patients undergoing elective unilateral or bilateral total knee replacement | double blind Parallel groups Sample size: 1528/1529 Primary endpoint: asymptomatic and symptomatic proximal DVT, PE, VTE-related death FU duration: 12 days | | ADOPT, 2011 | apixaban, administered orally at a dose of 2.5 mg twice daily for 30 days (n=3255) vs. enoxaparin,
administered subcutaneously at a dose of 40 mg once daily for 6 to 14 days (n=3273) | acutely ill patients who had congestive heart failure or respiratory failure or other
medical disorders and at least one additional risk factor for venous thromboembolism
and who were hospitalized with an expected stay of at least 3 days | double-blind Sample size: 3255/3273 Primary endpoint: FU duration: 30 days |
|
| venous thrombosis | All results are NS for efficacy | meta-analysis | | | Trial | control | p<0.05 | harm | NS |
|---|
| Botticelli DVT, 2008 | vs LMWH/VKA | | | | | AMPLIFY, 2013 | vs LMWH/VKA | Major bleeding 0.31 [0.17; 0.55] | | recurrent DVT only 0.61 [0.35; 1.06] death 0.79 [0.53; 1.19] All deaths 0.79 [0.53; 1.19] non fatal PE 1.19 [0.68; 2.06] fatal PE 0.50 [0.05; 5.57] Symptomatic nonfatal pulmonary embolism 1.19 [0.68; 2.06] recurrent VTE during treatment 0.84 [0.60; 1.18] Symptomatic deep-vein thrombosis 0.61 [0.35; 1.06] Death related to venous thromboembolism 0.85 [0.38; 1.90] recurrent VTE 0.84 [0.60; 1.18] | | AMPLIFY-EXT 2.5mg, 2012 | vs LMWH/VKA | recurrent VTE 0.33 [0.22; 0.49] | | Major bleeding 0.49 [0.09; 2.69] major or clinically
relevant nonmajor bleeding 1.21 [0.70; 2.11] | | AMPLIFY-EXT 5mg, 2012 | vs LMWH/VKA | recurrent VTE 0.36 [0.25; 0.53] | | Major bleeding 0.25 [0.03; 2.28] major or clinically
relevant nonmajor bleeding 1.62 [0.96; 2.74] |
| Trial | Treatments | Patients | Method |
|---|
| Botticelli DVT, 2008 | apixaban 5 mg twice-daily, 10 mg twice-daily, or 20 mg once-daily for 84-91 days (n=358) vs. low molecular weight heparin followed by vitamin K antagonists (n=118) | patients with symptomatic deep vein thrombosis | open Parallel groups Sample size: 358/118 Primary endpoint: recurrent VTE or asymptomatic deterioration in the FU duration: dose-ranging study;
the primary efficacy endpoint was the composite of symptomatic recurrent venous thromboembolism and asymptomatic deterioration of bilateral compression ultrasound or perfusion lung scan | | AMPLIFY, 2013 | apixaban 10 mg twice daily for 7 days then 5 mg, twice daily, 6 months (n=2691) vs. conventional
therapy: enoxaparin 1mg/kg twice daily until INR>=2 then warfarin for an INR between 2-4, once daikly, 6 months (n=2704) | patients with deep vein thrombosis or pulmonary embolism | double blind Parallel groups Sample size: 2691/2704 Primary endpoint: Venous thromboembolic recurrence or death FU duration: 6 mo | | AMPLIFY-EXT 2.5mg, 2012 | Extended Treatment with apixaban 2.5 mg twice daily 12 months (n=842) vs. placebo (n=829) 3 arms: apixaban 2.5mg, 5mg twice daily, placebo | patients who have completed their intended treatment for deep vein thrombosis or pulmonary embolism | double blind Parallel groups Sample size: 842/829 Primary endpoint: FU duration: 12 mo | | AMPLIFY-EXT 5mg, 2012 | Extended Treatment with apixaban 5 mg twice daily 12 months
(n=815) vs. placebo
(n=829) 3 arms: apixaban 2.5mg, 5mg twice daily, placebo
| patients who have completed their intended treatment for deep vein thrombosis or pulmonary embolism
| double blind Sample size: 815/829 Primary endpoint: FU duration: 12 mo
|
|
