Clinical trials in thrombosis prevention

mechanism

treatment

Demonstrated benefit and harm

antithrombotics

acenocoumarol

versus Low molecular weight heparin

No demonstrated result for efficacy

meta-analysis

antithrombotics

acenocoumarol

versus unfractionated heparin

No demonstrated result for efficacy

meta-analysis

antithrombotics

apixaban

versus

No demonstrated result for efficacy

meta-analysis

antithrombotics

apixaban

versus Low molecular weight heparin

No demonstrated result for efficacy

meta-analysis

Trial	control	p<0.05	NS
APROPOS 2.5mg, 2007	apixaban 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	apixaban 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	apixaban vs enoxaparin	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	apixaban vs enoxaparin (europe 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]

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

antithrombotics

ardeparin

versus placebo or no treatment

No demonstrated result for efficacy

meta-analysis

antithrombotics

ardeparin

versus

No demonstrated result for efficacy

meta-analysis

antithrombotics

aspirin

versus placebo or control

No demonstrated result for efficacy

aspirin inferior to placebo in terms of major bleeding in PEP hip-fracture, 2000

meta-analysis

Trial	control	p<0.05	harm	NS
PEP hip-fracture, 2000	aspirin vs placebo	Deep venous thrombosis 0.71 [0.52; 0.97] Fatal pulmonary embolism 0.42 [0.24; 0.72]	major bleeding 1.25 [1.02; 1.54]	non fatal pulmonary embolism 0.74 [0.45; 1.20] non pulmonary embolism death 1.01 [0.84; 1.22]
MRC, 1972	aspirin vs placebo			Deep venous thrombosis 1.25 [0.84; 1.85] non fatal pulmonary embolism NaN [NaN; NaN] Fatal pulmonary embolism NaN [NaN; NaN] non pulmonary embolism death NaN [NaN; NaN]
	aspirin vs placebo
	aspirin vs control
	aspirin vs placebo
	aspirin vs placebo
	aspirin vs placebo
	aspirin vs placebo
	aspirin vs control
	aspirin vs placebo

Trial	Treatments	Patients	Method
PEP hip-fracture, 2000	aspirin 160mg/d started preoperatively and continued for 35 days (n=6679) vs. placebo (n=6677)	patients undergoing surgery for hip fracture	Double blind Parallel groups Sample size: 6679/6677 Primary endpoint: FU duration: 35 days
MRC, 1972	A600 (n=153) vs. placebo (n=150)	general surgery	double-blind Sample size: 153/150 Primary endpoint: FU duration:
Loew DVT, 1974	A600 (n=702) vs. Placebo (n=679)		double-blind Sample size: 702/679 Primary endpoint: FU duration:
Clagett, 1975	A1300 (n=56) vs. control (n=49)		open Sample size: 56/49 Primary endpoint: FU duration:
Erfurt-A, 1979	A1500 (n=357) vs. Placebo (n=357)		double-blind Sample size: 357/357 Primary endpoint: FU duration:
Zekert V, 1980	A1500+Hep??? (n=50) vs. Placebo (n=49)		double-blind Sample size: 50/49 Primary endpoint: FU duration:
Vinazzer I, 1980	A1500+Hep v Hep (n=402) vs. Placebo (n=404)		double-blind Sample size: 402/404 Primary endpoint: FU duration:
Vinazzer II, 1977	A1000+Hepv Hep (n=62) vs. Placebo (n=62)		double-blind Sample size: 62/62 Primary endpoint: FU duration:
Zekert VI, 1982	A1500 (n=50) vs. control (n=50)		open Sample size: 50/50 Primary endpoint: FU duration:
PEP elective arthroplasty, 2000	aspirin 160mg/d started preoperatively and continued for 35 daysA (n=2047) vs. placebo (n=2041)	Patients undergoing elective hip or knee arthroplasty	Double blind Parallel groups Sample size: 2047/2041 Primary endpoint: FU duration: 35 days

antithrombotics

aspirin

versus placebo or no treatment

No demonstrated result for efficacy

meta-analysis

Trial	control	p<0.05	NS
Stockholm-I, 1975	Aspirin vs placebo		non PE related death NaN [NaN; NaN] major bleeding NaN [NaN; NaN] DVT 1.68 [0.56; 5.05] non fatal PE NaN [NaN; NaN] fatal PE NaN [NaN; NaN]
Pasteyer, 1977	Aspirin vs no treatment		non PE related death NaN [NaN; NaN] major bleeding ∞ [NaN; ∞] DVT 1.00 [0.29; 3.45] proximal DVT 0.00 [0.00; NaN] non fatal PE 0.00 [0.00; NaN] wound haematoma / infection 0.50 [0.05; 5.08] fatal PE NaN [NaN; NaN]
Harris-I, 1977	Aspirin vs placebo	DVT 0.49 [0.26; 0.90] proximal DVT 0.36 [0.14; 0.94]	non PE related death NaN [NaN; NaN] major bleeding NaN [NaN; NaN] non fatal PE 0.00 [0.00; NaN] wound haematoma / infection 3.05 [0.33; 28.49] fatal PE NaN [NaN; NaN]
McKenna-I, 1980	Aspirin vs placebo	DVT 0.44 [0.23; 0.85]	non PE related death NaN [NaN; NaN] major bleeding ∞ [NaN; ∞] proximal DVT 0.33 [0.06; 1.73] non fatal PE 0.38 [0.10; 1.41] fatal PE NaN [NaN; NaN]
Sautter, 1983	Aspirin vs placebo	DVT 0.72 [0.54; 0.96] proximal DVT 0.51 [0.29; 0.89]	non PE related death NaN [NaN; NaN] major bleeding NaN [NaN; NaN] non fatal PE 0.45 [0.09; 2.26] wound haematoma / infection 0.91 [0.25; 3.24] fatal PE NaN [NaN; NaN]
Rocha, 1986	Aspirin vs no treatment	DVT 0.14 [0.04; 0.45]	non PE related death NaN [NaN; NaN] major bleeding NaN [NaN; NaN] non fatal PE 0.00 [0.00; NaN] wound haematoma / infection 1.00 [0.09; 10.59] fatal PE NaN [NaN; NaN]
McBride, 1983	Aspirin vs placebo		non PE related death NaN [NaN; NaN] DVT 1.05 [0.48; 2.28] non fatal PE NaN [NaN; NaN] fatal PE NaN [NaN; NaN]

Trial	Treatments	Patients	Method
Stockholm-I, 1975	Aspirin 2000mg daily (n=26) vs. placebo (n=25)	elective surgery of the hip	double blind Sample size: 26/25 Primary endpoint: FU duration: 2 weeks
Pasteyer, 1977	Aspirin 1000mg daily + Hep (n=20) vs. control (Hep alone) (n=20)	Elective orthopaedic surgery	Parallel groups Sample size: 20/20 Primary endpoint: FU duration: 2 weeks
Harris-I, 1977	Aspirin 1200mg daily (n=58) vs. placebo (n=59)	patients over 40 years of age, who had undergone total hip replacement	double-blind Parallel groups Sample size: 58/59 Primary endpoint: Radiographic phlebography FU duration: 1 weeks
McKenna-I, 1980	Aspirin 975mg or 3900mg daily (n=24) vs. placebo (n=12)	total knee replacement	double-blind Parallel groups Sample size: 24/12 Primary endpoint: FU duration: 2 weeks
Sautter, 1983	Aspirin 900mg daily + sulfinpyrazone (n=68) vs. placebo (n=77)	patient with total hip replacement	Parallel groups Sample size: 68/77 Primary endpoint: FU duration: 3 weeks
Rocha, 1986	Aspirin 250mg or 1000mg daily (n=60) vs. control (combination of heparin plus dihydroergotamine) (n=30)	total hip replacement	open Parallel groups Sample size: 60/30 Primary endpoint: FU duration: 1 weeks
McBride, 1983	A1800+Dipyridamole (n=21) vs. placebo (n=22)	Elective orthopaedic surgery	Sample size: 21/22 Primary endpoint: FU duration: 1 weeks

antithrombotics

betrixaban

versus

No demonstrated result for efficacy

meta-analysis

antithrombotics

candesartan

versus

No demonstrated result for efficacy

meta-analysis

antithrombotics

Certoparin

versus placebo or control

No demonstrated result for efficacy

meta-analysis

antithrombotics

Certoparin

versus

No demonstrated result for efficacy

meta-analysis

Trial	control	p<0.05	NS
Schmitz-Huebner, 1984	certoparin vs unfractionated heparin		major haemorrhage ∞ [NaN; ∞] clinical PE NaN [NaN; NaN] asymptomatic DVT ∞ [NaN; ∞] wound hematoma 2.13 [0.61; 7.41] symptomatic thromboembolism NaN [NaN; NaN]
Sasahara, 1986	certoparin vs unfractionated heparin	transfusion 0.59 [0.35; 0.99]	death 0.39 [0.08; 1.95] clinical PE 0.00 [0.00; NaN] asymptomatic DVT 1.01 [0.50; 2.07] wound hematoma 1.33 [0.23; 7.74]
Voigt, 1986	certoparin vs unfractionated heparin		death 0.63 [0.18; 2.16] total haemorrhage 0.51 [0.20; 1.34] major haemorrhage 2.83 [0.30; 26.70] clinical PE 0.00 [0.00; NaN] asymptomatic DVT 0.94 [0.06; 14.85] wound hematoma 0.30 [0.06; 1.47] symptomatic thromboembolism 0.00 [0.00; NaN] transfusion 0.91 [0.71; 1.16]
Welzel, 1988	certoparin vs unfractionated heparin	asymptomatic DVT 0.30 [0.10; 0.88]	wound hematoma 1.50 [0.31; 7.19]
Kakkar, 1989	certoparin vs unfractionated heparin		total haemorrhage 2.07 [0.53; 8.01] major haemorrhage ∞ [NaN; ∞] clinical PE ∞ [NaN; ∞] asymptomatic DVT 0.83 [0.34; 2.00] wound hematoma 2.00 [0.15; 26.19]
Adolf, 1989	certoparin vs unfractionated heparin		clinical PE 3.00 [0.26; 34.58] asymptomatic DVT 1.50 [0.54; 4.14] wound hematoma 0.74 [0.23; 2.33] transfusion 1.31 [0.95; 1.81]
Heilmann, 1989	certoparin vs unfractionated heparin		major haemorrhage 0.67 [0.11; 3.93] clinical PE NaN [NaN; NaN] asymptomatic DVT 0.33 [0.07; 1.63] wound hematoma 0.70 [0.24; 2.10]
Baumgartner, 1989	certoparin vs unfractionated heparin		death 0.52 [0.05; 5.59] major haemorrhage NaN [NaN; NaN] clinical PE 1.00 [0.05; 18.57] asymptomatic DVT 0.88 [0.31; 2.50] wound hematoma ∞ [NaN; ∞]
Hoffmann and Largiade, 1990	certoparin vs unfractionated heparin		major haemorrhage 0.97 [0.44; 2.15] clinical PE ∞ [NaN; ∞]
	certoparin vs unfractionated heparin
	certoparin vs unfractionated heparin
	certoparin vs unfractionated heparin
	certoparin vs unfractionated heparin
	certoparin vs unfractionated heparin
	certoparin vs unfractionated heparin

Trial	Treatments	Patients	Method
Schmitz-Huebner, 1984	Certoparin (dose 1 and dose 2) b.i.d. (n=84) vs. UFH 10 000 units (n=42)	Abdominal surgery	Blind Sample size: 84/42 Primary endpoint: FU duration: 1 month
Sasahara, 1986	Certoparin 3000 + DHE (n=137) vs. UFH 10 000 units +DHE (n=132)	Abdominal surgery	Blind Sample size: 137/132 Primary endpoint: FU duration: 7 days
Voigt, 1986	Certoparin 3000 + DHE (n=103) vs. UFH 10 000 units (n=97)	Abdominal surgery	Blind Sample size: 103/97 Primary endpoint: FU duration: 10 days
Welzel, 1988	Certoparin 2500 + DHE (n=98) vs. UFH 10 000 units+DHE (n=103)	Abdominal surgery	Open Sample size: 98/103 Primary endpoint: FU duration: 7 days
Kakkar, 1989	Certoparin 3000 + DHE (n=88) vs. UFH 10 000 units+DHE (n=91)	Abdominal surgery	Blind Sample size: 88/91 Primary endpoint: FU duration:
Adolf, 1989	Certoparin 3000 (n=205) vs. UFH 15 000 units (n=205)	Abdominal surgery	Blind Sample size: 205/205 Primary endpoint: FU duration: 1 month
Heilmann, 1989	Certoparin 3000 (n=150) vs. UFH 15 000 units (n=150)	Gynaecological surgery	Blind Sample size: 150/150 Primary endpoint: FU duration: 10 days
Baumgartner, 1989	Certoparin 3000 + DHE (n=99) vs. UFH 5 000 units+DHE (n=102)	Abdominal surgery	Blind Sample size: 99/102 Primary endpoint: FU duration: 10 days
Hoffmann and Largiade, 1990	Certoparin 3000 + DHE (n=464) vs. UFH 10 000 units (n=452)	Abdominal surgery	NA Sample size: 464/452 Primary endpoint: FU duration:
Koppenhagen, 1990	Certoparin 3000 anti Xa units (n=51) vs. UFH 15 000 units (n=53)	Abdominal surgery	Blind Sample size: 51/53 Primary endpoint: FU duration:
Schielke, 1991	Certoparin 3000 anti Xa units + DHE (n=47) vs. UFH 10 000 units + DHE (n=51)	Abdominal surgery	Open Sample size: 47/51 Primary endpoint: FU duration:
Koppenhagen, 1992	Certoparin 3000 anti Xa units (n=336) vs. UFH 15 000 units (n=337)	Abdominal surgery	Blind Sample size: 336/337 Primary endpoint: FU duration:
Hoffmann and Largiader, 1992	Certoparin 3000 anti Xa units (n=298) vs. UFH 10 000 units (n=296)	Abdominothoracic surgery	Blind Sample size: 298/296 Primary endpoint: FU duration:
Heilmann, 1997	Certoparin 3000 anti Xa units (n=179) vs. UFH 15 000 units (n=179)	Gynaecological and breast surgery	Blind Sample size: 179/179 Primary endpoint: FU duration:
Haas, 1999	Certoparin 3000 anti Xa units (n=11542) vs. UFH 15 000 units (n=11536)	General surgery	Blind Sample size: 11542/11536 Primary endpoint: FU duration:

antithrombotics

Certoparin

versus UFH

No demonstrated result for efficacy

meta-analysis

antithrombotics

Certoparin

versus Unfractionated heparin

No demonstrated result for efficacy

meta-analysis

antithrombotics

dabigatran

versus Low molecular weight heparin

No demonstrated result for efficacy

dabigatran 220mg inferior to enoxaparin (US regimen) in terms of total VTE and all-cause mortality in RE-MOBILIZE (220mg), 2008 (knee surgery patients)

dabigatran 150mg inferior to enoxaparin in terms of symptomatic DVT in RE-NOVATE (150mg), 2007 (hip surgery patients)

dabigatran 150mg inferior to enoxaparin (US regimen) in terms of distal DVT in RE-MOBILIZE (150mg), 2008 (knee surgery patients)

dabigatran 150mg inferior to enoxaparin (US regimen) in terms of total VTE and all-cause mortality in RE-MOBILIZE (150mg), 2008 (knee surgery patients)

meta-analysis

Trial	control	harm	NS
RE-MOBILIZE (220mg), 2008	dabigatran 220mg vs enoxaparin (US regimen)	total VTE and all-cause mortality 1.23 [1.03; 1.47]	coronary events 1.05 [0.48; 2.31] major bleeding 0.42 [0.15; 1.19] proximal DVT 1.49 [0.67; 3.33] distal DVT 1.20 [0.99; 1.45] major VTE (fatal and non fatal DVT,PE) 1.51 [0.79; 2.91] major or clinically relevant non-major bleeding 0.86 [0.52; 1.41]
RE-MODEL (220mg), 2007	dabigatran 220mg vs enoxaparin (europe regimen)		death 1.01 [0.06; 16.19] coronary events 1.26 [0.40; 3.99] major bleeding 1.14 [0.46; 2.78] proximal DVT 0.82 [0.40; 1.69] distal DVT 1.02 [0.85; 1.21] asymptomatic DVT 1.00 [0.85; 1.18] total VTE and all-cause mortality 0.97 [0.82; 1.13] major VTE (fatal and non fatal DVT,PE) 0.73 [0.36; 1.47] symptomatic DVT 0.13 [0.02; 1.01] major or clinically relevant non-major bleeding 1.11 [0.76; 1.63]
RE-NOVATE (220mg), 2007	dabigatran 220mg vs enoxaparin		death ∞ [NaN; ∞] major bleeding 1.29 [0.70; 2.37] proximal DVT 0.57 [0.32; 1.00] distal DVT 0.94 [0.53; 1.66] non-fatal PE 1.70 [0.41; 7.09] asymptomatic DVT 0.73 [0.49; 1.08] total VTE and all-cause mortality 0.90 [0.63; 1.29] major VTE (fatal and non fatal DVT,PE) 0.78 [0.48; 1.27] symptomatic DVT 6.03 [0.73; 49.98]
RE-MODEL (150mg), 2007	dabigatran 150mg vs enoxaparin (europe regimen)		death 0.98 [0.06; 15.70] major bleeding 0.99 [0.39; 2.47] proximal DVT 1.03 [0.54; 1.98] distal DVT 1.07 [0.91; 1.27] non-fatal PE ∞ [NaN; ∞] asymptomatic DVT 1.10 [0.94; 1.29] total VTE and all-cause mortality 1.07 [0.92; 1.25] major VTE (fatal and non fatal DVT,PE) 1.08 [0.58; 2.01] symptomatic DVT 0.37 [0.10; 1.37] major or clinically relevant non-major bleeding 1.22 [0.84; 1.78]
RE-NOVATE (150mg), 2007	dabigatran 150mg vs enoxaparin	symptomatic DVT 8.89 [1.13; 70.07]	death NaN [NaN; NaN] coronary events 0.72 [0.31; 1.68] major bleeding 0.83 [0.42; 1.63] proximal DVT 0.90 [0.55; 1.49] distal DVT 1.50 [0.90; 2.50] non-fatal PE 0.33 [0.03; 3.16] asymptomatic DVT 1.15 [0.82; 1.63] total VTE and all-cause mortality 1.28 [0.93; 1.78] major VTE (fatal and non fatal DVT,PE) 1.09 [0.70; 1.70]
RE-MOBILIZE (150mg), 2008	dabigatran 150mg vs enoxaparin (US regimen)	distal DVT 1.33 [1.10; 1.59] total VTE and all-cause mortality 1.33 [1.12; 1.58]	death ∞ [NaN; ∞] major bleeding 0.42 [0.15; 1.17] non-fatal PE 0.00 [0.00; NaN] major VTE (fatal and non fatal DVT,PE) 1.36 [0.70; 2.63] major or clinically relevant non-major bleeding 0.82 [0.49; 1.34]
RE-NOVATE 2	dabigatran 220mg vs enoxaparin		coronary events 0.99 [0.06; 15.86]

Trial	Treatments	Patients	Method
RE-MOBILIZE (220mg), 2008	dabigatran etexilate 220 mg for 12-15 days (n=862) vs. Enoxaparin 30mg SC BID after surgery for 12-15 days (n=876)	Total knee replacement	double blind Parallel groups Sample size: 862/876 Primary endpoint: total VTE and all-cause mortality FU duration: 12-15 days, median 14d
RE-MODEL (220mg), 2007	dabigatran etexilate 220 mg q.d. 6-10 days (n=694) vs. Enoxaparin 40 mg q.d. for 6-10 days (n=699)	patients undergoing total knee replacement	double blind Sample size: 694/699 Primary endpoint: total VTE and all-cause mortality FU duration: 6-10 days, mean 8 days
RE-NOVATE (220mg), 2007	dabigatran etexilate 220 mg q.d. for 28-35 days (n=1157) vs. Enoxaparin 40 mg q.d. for 23-35 days (n=1162) 3 arms dabigatran 220mg, 150mg and placebo	Total hip replacement	double blind Parallel groups Sample size: 1157/1162 Primary endpoint: total VTE and all-cause mortality FU duration: 28-35 days, median 33d
RE-MODEL (150mg), 2007	dabigatran etexilate 150 mg q.d. for 6-10 days (n=708) vs. Enoxaparin 40 mg q.d. for 6-10 days (n=699)	Total knee replacement	double blind Parallel groups Sample size: 708/699 Primary endpoint: total VTE and all-cause mortality FU duration: 6-10 days, mean 8 days
RE-NOVATE (150mg), 2007	dabigatran etexilate 150 mg q.d. 28-35 days (n=1174) vs. Enoxaparin 40 mg q.d. for 28-25 days (n=1162) 3 arms dabigatran 220mg, 150mg and placebo	Total hip replacement	double blind Sample size: 1174/1162 Primary endpoint: total VTE and all-cause mortality FU duration: 28-35 days, median 33d
RE-MOBILIZE (150mg), 2008	dabigatran etexilate 150 mg q.d. for 12-15 days (n=877) vs. enoxaparin 30 mg SC BID after surgery for 12-15 days (n=876)	Total knee replacement	double blind Sample size: 877/876 Primary endpoint: total VTE and all-cause mortality FU duration: 12-15 days, median 14d
RE-NOVATE 2	dabigatran 220mg once daily for 28-35 Days (n=1010) vs. enoxaparin 40mg subcutaneous once daily for 28-35 Days (n=1003)	patients undergoing total hip-replacement surgery	double-blind Parallel groups Sample size: 1010/1003 Primary endpoint: venous thromboembolism or death FU duration: 28-35 days (mean 32d)

antithrombotics

dalteparin

versus placebo or control

No demonstrated result for efficacy

meta-analysis

antithrombotics

dalteparin

versus placebo or no treatment

No demonstrated result for efficacy

meta-analysis

antithrombotics

dalteparin

versus

No demonstrated result for efficacy

dalteparin inferior to unfractionated heparin in terms of total haemorrhage in Bergqvist, 1986 (abdominal surgery patients)

dalteparin inferior to unfractionated heparin in terms of transfusion in Bergqvist, 1986 (abdominal surgery patients)

dalteparin inferior to unfractionated heparin in terms of total haemorrhage in Koller, 1986 (abdominal surgery patients)

dalteparin inferior to unfractionated heparin in terms of total haemorrhage in Bergqvist, 1988 (abdominal surgery patients)

meta-analysis

Trial	control	p<0.05	harm	NS
Bergqvist, 1986	dalteparin vs unfractionated heparin		total haemorrhage 2.52 [1.24; 5.13] transfusion 1.38 [1.03; 1.84]	major haemorrhage 3.36 [0.94; 12.06] clinical PE 0.00 [0.00; NaN] asymptomatic DVT 1.46 [0.64; 3.34] wound hematoma 1.86 [0.50; 6.84]
Onarheim, 1986	dalteparin vs unfractionated heparin			death NaN [NaN; NaN] total haemorrhage 0.54 [0.05; 5.59] major haemorrhage 1.08 [0.07; 16.36] clinical PE NaN [NaN; NaN] asymptomatic DVT ∞ [NaN; ∞] wound hematoma 0.00 [0.00; NaN]
Koller, 1986	dalteparin vs unfractionated heparin		total haemorrhage 4.78 [1.20; 19.06]	death NaN [NaN; NaN] major haemorrhage 2.61 [0.59; 11.50] wound hematoma 3.50 [0.57; 21.67] transfusion 4.35 [0.55; 34.17]
Koller, 1986	dalteparin vs unfractionated heparin			death NaN [NaN; NaN] total haemorrhage 1.00 [0.46; 2.16] major haemorrhage ∞ [NaN; ∞] clinical PE 0.00 [0.00; NaN] asymptomatic DVT 1.94 [0.18; 20.93] wound hematoma 1.50 [0.20; 11.24] transfusion 0.80 [0.22; 2.86]
Fricker, 1988	dalteparin vs unfractionated heparin			total haemorrhage 0.62 [0.29; 1.32] major haemorrhage 2.00 [0.19; 21.19] clinical PE 0.00 [0.00; NaN] asymptomatic DVT NaN [NaN; NaN] symptomatic thromboembolism 0.20 [0.02; 1.64]
Bergqvist, 1988	dalteparin vs unfractionated heparin		total haemorrhage 1.97 [1.07; 3.61]	death 0.98 [0.41; 2.34] clinical PE 0.00 [0.00; NaN] asymptomatic DVT 0.67 [0.42; 1.07] wound hematoma 2.50 [0.77; 8.13] transfusion 1.02 [0.89; 1.17]
Caen, 1988	dalteparin vs unfractionated heparin			death 0.65 [0.11; 3.84] total haemorrhage 0.97 [0.25; 3.84] major haemorrhage 0.00 [0.00; NaN] clinical PE 0.00 [0.00; NaN] asymptomatic DVT 0.84 [0.29; 2.44] wound hematoma 1.33 [0.23; 7.74] transfusion 1.34 [0.55; 3.26]
Borstad, 1988	dalteparin vs unfractionated heparin			total haemorrhage 1.16 [0.91; 1.49] major haemorrhage 1.05 [0.07; 16.53] clinical PE NaN [NaN; NaN] asymptomatic DVT NaN [NaN; NaN] wound hematoma 1.73 [0.56; 5.32] symptomatic thromboembolism NaN [NaN; NaN]
Briel, 1988	dalteparin vs unfractionated heparin			asymptomatic DVT 1.03 [0.07; 16.26] wound hematoma 1.50 [0.20; 11.24]
Creperio, 1990	dalteparin vs unfractionated heparin			clinical PE NaN [NaN; NaN] asymptomatic DVT 1.67 [0.46; 6.06] symptomatic thromboembolism NaN [NaN; NaN]
Hartl, 1990	dalteparin vs unfractionated heparin	transfusion 0.22 [0.05; 0.99]		death 1.48 [0.43; 5.10] total haemorrhage 0.98 [0.25; 3.85] major haemorrhage 0.66 [0.11; 3.86] clinical PE 1.00 [0.05; 18.57] asymptomatic DVT 1.03 [0.31; 3.45] wound hematoma 1.00 [0.05; 18.57]
	dalteparin vs unfractionated heparin
	dalteparin vs unfractionated heparin
Dahl, 1997	out of hospital Dalteparin vs standard prophylaxis	Symptomless venous thromboembolism 0.46 [0.24; 0.88]		Death 0.98 [0.06; 15.47] Major bleeding NaN [NaN; NaN] Minor bleeding 0.98 [0.14; 6.84] Pulmonary embolism 0.00 [0.00; NaN] Proximal deep vein thrombosis 0.43 [0.14; 1.33] Distal deep vein thrombosis 0.48 [0.20; 1.13] Symptomatic venous thromboembolism 0.62 [0.18; 2.14] symptomatic deep vein thrombosis 1.22 [0.28; 5.31]
Lassen, 1998	out of hospital Dalteparin vs standard prophylaxis			Death NaN [NaN; NaN] Major bleeding 0.00 [0.00; NaN] Minor bleeding 1.65 [0.81; 3.36] Pulmonary embolism NaN [NaN; NaN] Proximal deep vein thrombosis 0.00 [0.00; NaN] Distal deep vein thrombosis 0.54 [0.13; 2.21] Symptomless venous thromboembolism 0.30 [0.08; 1.08] Symptomatic venous thromboembolism 0.60 [0.10; 3.53] symptomatic deep vein thrombosis 0.60 [0.10; 3.53]
Hull, 2000	out of hospital Dalteparin vs standard prophylaxis	Proximal deep vein thrombosis 0.41 [0.21; 0.78] Symptomless venous thromboembolism 0.42 [0.18; 0.95]		Death 0.00 [0.00; NaN] Major bleeding NaN [NaN; NaN] Minor bleeding 0.65 [0.21; 2.01] Pulmonary embolism NaN [NaN; NaN] Distal deep vein thrombosis 0.61 [0.22; 1.72] Symptomatic venous thromboembolism 0.61 [0.14; 2.68] symptomatic deep vein thrombosis 0.61 [0.14; 2.68]
D-KAf (Selby), 2007	dalteparin vs placebo			DVT 0.65 [0.11; 3.84]

Trial	Treatments	Patients	Method
Bergqvist, 1986	Dalteparin 5000 (n=215) vs. UFH 10 000 units (n=217)	Abdominal surgery	Blind Sample size: 215/217 Primary endpoint: FU duration: 1 month
Onarheim, 1986	Dalteparin 5000 (n=25) vs. UFH 10 000 units (n=27)	Abdominal surgery	Blind Sample size: 25/27 Primary endpoint: FU duration: 1 month
Koller, 1986	Dalteparin 7500 (n=23) vs. UFH 10 000 units (n=20)	Abdominal surgery	Blind Sample size: 23/20 Primary endpoint: FU duration: 30 days
Koller, 1986	Dalteparin 2500 (n=75) vs. UFH 10 000 units (n=75)	Abdominal surgery	Blind Sample size: 75/75 Primary endpoint: FU duration: 30 days
Fricker, 1988	Dalteparin 5000 (n=40) vs. UFH 15 000 units (n=40)	Abdominopelvic surgery	Open Sample size: 40/40 Primary endpoint: FU duration: 1-2 months
Bergqvist, 1988	Dalteparin 5000 (n=505) vs. UFH 10 000 units (n=497)	Abdominal surgery	Blind Sample size: 505/497 Primary endpoint: FU duration: 1 month
Caen, 1988	Dalteparin 2500 (n=195) vs. UFH 10 000 units (n=190)	Abdominal surgery	Blind Sample size: 195/190 Primary endpoint: FU duration: 1 month
Borstad, 1988	Dalteparin 5000 (n=105) vs. UFH 10 000 units (n=110)	Gynaecological surgery	Blind Sample size: 105/110 Primary endpoint: FU duration:
Briel, 1988	Dalteparin 5000 (n=95) vs. UFH 10 000 units+DHE (n=98)	Gynaecological surgery	NA Sample size: 95/98 Primary endpoint: FU duration:
Creperio, 1990	Dalteparin 2500 (n=20) vs. UFH 10 000 units (n=20)	General surgery	Blind Sample size: 20/20 Primary endpoint: FU duration:
Hartl, 1990	Dalteparin 2500 (n=126) vs. UFH 10 000 units (n=124)	Abdominal surgery	Blind Sample size: 126/124 Primary endpoint: FU duration: > 7 days
Borstad, 1992	Dalteparin 2500 anti Xa units (n=77) vs. UFH 10 000 units (n=75)	Gynaecological surgery	Blind Sample size: 77/75 Primary endpoint: FU duration:
Kakkar, 1993	Dalteparin 2500 anti Xa units (n=1894) vs. UFH 10 000 units (n=1915)	Abdominal surgery	Blind Sample size: 1894/1915 Primary endpoint: FU duration:
Dahl, 1997	in hospital thromboprophylaxis followed by out of hospital Dalteparin 5000 IU once a day for a total duration of 35 days (n=134) vs. Dalteparin 5000 IU once a day for 7 days (dextran day 0 and day 1) (n=131)	THR	Sample size: 134/131 Primary endpoint: FU duration:
Lassen, 1998	in hospital thromboprophylaxis followed by out of hospital Dalteparin 5000 IU once a day for a total duration of 35 days (n=140) vs. Dalteparin 5000 IU once a day for 7 days (n=141)	THR	Sample size: 140/141 Primary endpoint: FU duration:
Hull, 2000	in hospital thromboprophylaxis followed by out of hospital Dalteparin 5000 IU once a day for a total duration of 35 days (n=389) vs. Dalteparin 5000 IU once a day or warfarin for 6 days (n=180)	THR	Sample size: 389/180 Primary endpoint: FU duration:
D-KAf (Selby), 2007	dalteparin 5000U daily (n=134) vs. placebo (n=131)	below-knee fractures repaired surgically	Sample size: 134/131 Primary endpoint: FU duration:

antithrombotics

dalteparin

versus Dextran

No demonstrated result for efficacy

meta-analysis

antithrombotics

dalteparin

versus UFH

No demonstrated result for efficacy

meta-analysis

antithrombotics

dalteparin

versus Unfractionated heparin

No demonstrated result for efficacy

meta-analysis

antithrombotics

deltaparin

versus placebo or control

No demonstrated result for efficacy

meta-analysis

antithrombotics

dipyridamol

versus

No demonstrated result for efficacy

meta-analysis

antithrombotics

dipyridamol

versus placebo or control

No demonstrated result for efficacy

meta-analysis

antithrombotics

dipyridamol

versus placebo or no treatment

No demonstrated result for efficacy

meta-analysis

antithrombotics

edoxaban

versus

No demonstrated result for efficacy

meta-analysis

antithrombotics

enoxaparin

versus placebo or control

No demonstrated result for efficacy

enoxaparin inferior to no treatment in terms of total bleeding in Ho [43]

meta-analysis

Trial	control	p<0.05	harm	NS
LeGagneux , 1987	enoxaparin vs placebo			major Bleeding 1.36 [0.52; 3.61] Pulmonary embolism NaN [NaN; NaN] Asymptomatic Deep vein thrombosis NaN [NaN; NaN] symptomatic thromboembolism event NaN [NaN; NaN] transfusin 1.36 [0.52; 3.61]
MEDENOX, 1999	Enoxaparin vs placebo	Asymptomatic deep vein thrombosis during follow-up. 0.39 [0.22; 0.67]		All-cause death during follow-up 0.74 [0.36; 1.54] Major bleeding during follow-up 1.48 [0.42; 5.21] Symptomatic pulmonary embolism during follow-up 0.00 [0.00; NaN] DVT 0.72 [0.49; 1.05] PE 0.17 [0.02; 1.52] Symptomatic deep vein thrombosis during follow-up 0.49 [0.05; 5.43]
Lederle, 2006	Enoxaparin vs placebo			Major bleeding during follow-up 0.40 [0.08; 2.03] Symptomatic pulmonary embolism during follow-up 0.33 [0.04; 3.17] PE 0.33 [0.04; 3.17] Symptomatic deep vein thrombosis during follow-up 0.63 [0.21; 1.86]
Ho [43]	enoxaparin vs no treatment		total bleeding 3.78 [1.04; 13.70]	wound hematoma ∞ [NaN; ∞] symptomatic thromboembolism event 0.00 [0.00; NaN] transfusin 1.43 [0.85; 2.43]
Agnelli, 1998	enoxaparin vs placebo	thromboembolic events (symptomatic or asymptomatic) 0.51 [0.33; 0.80] proxymal DVT 0.39 [0.17; 0.90]
Melon, 1987	enoxaparin vs placebo			thromboembolic events (symptomatic or asymptomatic) 0.65 [0.31; 1.34]
Canata, 2003	enoxaparin vs control			minor bleeding 1.50 [0.28; 7.93] VTE (symptomatic or asymptomatic) NaN [NaN; NaN]

Trial	Treatments	Patients	Method
LeGagneux , 1987	Enoxaparin 6000 anti-Xa units (n=44) vs. Placebo (n=45)	prostatectomy surgery	Blind Sample size: 44/45 Primary endpoint: FU duration:
MEDENOX, 1999	Enoxaparin 20 mg or 40 mg once daily, 6–14 days (n=291) vs. placebo (n=288) 3 arms: 40 mg of enoxaparin, 20 mg of enoxaparin, or placebo subcutaneously once daily for 6 to 14 days	Acute decompensated chronic obstructive pulmonary disease with mechanical ventilation	double blind Parallel groups Sample size: 291/288 Primary endpoint: FU duration: 6-14 days
Lederle, 2006	Enoxaparin 40 mg once daily, until hospital discharge (n=140) vs. placebo (n=140)	Hospitalization in general medical unit	double blind Parallel groups Sample size: 140/140 Primary endpoint: FU duration: 90 days
Ho [43]	Enoxaparin 4000 anti-Xa units (n=134) vs. No treatment (n=169)		Open Sample size: 134/169 Primary endpoint: FU duration:
Agnelli, 1998	Enoxaparin, 40 mg/d subcutaneously within 24 hours postoperatively plus compression stockings for >=7 days (n=153) vs. compression stockings + placebo (n=154)	Elective neurosurgery, 18 years or older, without excess bleeding risk	Sample size: 153/154 Primary endpoint: FU duration: 30 days
Melon, 1987	Enoxaparin, 20 mg/d subcutaneously 18-24 hours postoperatively for 10 days (n=67) vs. placebo (n=63)	Neurosurgery, adult, 45-90 kg of weight, without excess bleeding risk	Sample size: 67/63 Primary endpoint: FU duration: NA
Canata, 2003	enoxaparin sc daily (dose not specified) (n=18) vs. no treatment (n=18)	ACL reconstruction for symptomatic ACL-deficient knees	Parallel groups Sample size: 18/18 Primary endpoint: FU duration: 6 days

antithrombotics

enoxaparin

versus placebo or no treatment

No demonstrated result for efficacy

meta-analysis

antithrombotics

enoxaparin

versus

No demonstrated result for efficacy

meta-analysis

Trial	control	p<0.05	NS
Samama 1, 1988	enoxaparin vs unfractionated heparin		death ∞ [NaN; ∞] total haemorrhage 0.50 [0.15; 1.62] major haemorrhage 0.99 [0.06; 15.76] clinical PE NaN [NaN; NaN] asymptomatic DVT 0.50 [0.19; 1.29] wound hematoma 0.25 [0.02; 2.70] symptomatic thromboembolism ∞ [NaN; ∞] transfusion 1.21 [0.93; 1.57]
Samama 2, 1988	enoxaparin vs unfractionated heparin		death ∞ [NaN; ∞] total haemorrhage 0.68 [0.34; 1.37] major haemorrhage ∞ [NaN; ∞] clinical PE NaN [NaN; NaN] asymptomatic DVT 1.04 [0.21; 5.03] wound hematoma 0.67 [0.20; 2.26] symptomatic thromboembolism 0.00 [0.00; NaN] transfusion 0.97 [0.73; 1.29]
Samama 3, 1988	enoxaparin vs unfractionated heparin		death ∞ [NaN; ∞] total haemorrhage 0.92 [0.51; 1.67] major haemorrhage 0.92 [0.06; 14.56] clinical PE 0.00 [0.00; NaN] asymptomatic DVT 0.78 [0.21; 2.83] wound hematoma 0.94 [0.29; 3.00] symptomatic thromboembolism 0.46 [0.04; 5.01] transfusion 1.05 [0.84; 1.31]
	enoxaparin vs unfractionated heparin
	enoxaparin vs unfractionated heparin
	enoxaparin vs unfractionated heparin
	enoxaparin vs unfractionated heparin
	enoxaparin vs unfractionated heparin
	enoxaparin vs unfractionated heparin
Bergqvist, 1996	out of hospital Enoxaparin vs standard prophylaxis	Proximal deep vein thrombosis 0.28 [0.13; 0.60] Symptomless venous thromboembolism 0.48 [0.31; 0.76] Symptomatic venous thromboembolism 0.20 [0.04; 0.89]	Death NaN [NaN; NaN] Major bleeding NaN [NaN; NaN] Minor bleeding 5.95 [0.73; 48.65] Pulmonary embolism 0.00 [0.00; NaN] Distal deep vein thrombosis 0.86 [0.43; 1.72] symptomatic deep vein thrombosis 0.25 [0.05; 1.14]
Planes, 1996	out of hospital Enoxaparin vs standard prophylaxis		Death NaN [NaN; NaN] Major bleeding NaN [NaN; NaN] Minor bleeding 2.97 [0.31; 27.98] Pulmonary embolism NaN [NaN; NaN] Proximal deep vein thrombosis 1.04 [0.21; 4.99] Distal deep vein thrombosis 0.00 [0.00; NaN] Symptomless venous thromboembolism 0.31 [0.09; 1.09] Symptomatic venous thromboembolism 0.44 [0.12; 1.66] symptomatic deep vein thrombosis 0.44 [0.12; 1.66]
Comp, 2001	out of hospital Enoxaparin vs standard prophylaxis	Proximal deep vein thrombosis 0.31 [0.21; 0.47] Symptomless venous thromboembolism 0.67 [0.48; 0.93] Symptomatic venous thromboembolism 0.20 [0.04; 0.89]	Death 0.00 [0.00; NaN] Major bleeding 0.00 [0.00; NaN] Minor bleeding 0.98 [0.41; 2.33] Pulmonary embolism 0.00 [0.00; NaN] Distal deep vein thrombosis 0.85 [0.56; 1.29] symptomatic deep vein thrombosis 0.24 [0.05; 1.15]
LIFENOX, 2011	enoxaparin vs placebo		All-cause death during follow-up 1.00 [0.82; 1.22] Major bleeding during follow-up 1.40 [0.67; 2.94]

Trial	Treatments	Patients	Method
Samama 1, 1988	Enoxaparin 2000 (n=168) vs. UFH 15 000 units (n=167)	General surgery	Open Sample size: 168/167 Primary endpoint: FU duration: 7 days
Samama 2, 1988	Enoxaparin 4000 (n=127) vs. UFH 15 000 units (n=123)	General surgery	Open Sample size: 127/123 Primary endpoint: FU duration: 7 days
Samama 3, 1988	Enoxaparin 6000 (n=160) vs. UFH 15 000 units (n=147)	General surgery	Open Sample size: 160/147 Primary endpoint: FU duration: 7 days
Kaaja, 1992	Enoxaparin 2000 anti Xa units (n=37) vs. UFH 10 000 units (n=31)	Gynaecological surgery	Blind Sample size: 37/31 Primary endpoint: FU duration:
Gazzaniga (ISG), 1993	Enoxaparin 2000 anti Xa units (n=561) vs. UFH 10 000 units (n=561)	General and vascular surgery	Open Sample size: 561/561 Primary endpoint: FU duration:
Nurmohamed, 1995	Enoxaparin 2000 anti Xa units (n=737) vs. UFH 15 000 units (n=734)	General surgery	Blind Sample size: 737/734 Primary endpoint: FU duration:
McLeod (Canadian), 1995	Enoxaparin 4000 anti Xa units (n=674) vs. UFH 15 000 units (n=675)	Colorectal surgery	Blind Sample size: 674/675 Primary endpoint: FU duration:
Gonzalez, 1996	Bemiparin 2500 anti Xa units (n=84) vs. UFH 10 000 units (n=82)	Abdominal surgery	Blind Sample size: 84/82 Primary endpoint: FU duration:
ENOXACAN, 1997	Enoxaparin 4000 anti Xa units (n=555) vs. UFH 15 000 units (n=560)	Abdominopelvic surgery	Blind Sample size: 555/560 Primary endpoint: FU duration:
Bergqvist, 1996	in hospital thromboprophylaxis followed by out of hospital Enoxaparin 40 mg once a day for a total duration of 30 days (n=117) vs. Enoxaparin 40 mg once a day for 10-11 days (n=116)	THR	Sample size: 117/116 Primary endpoint: FU duration:
Planes, 1996	in hospital thromboprophylaxis followed by out of hospital Enoxaparin 40 mg once a day for a total duration of 35 days (n=90) vs. Enoxaparin 40 mg once a day for 13-15 days (n=89)	THR	Sample size: 90/89 Primary endpoint: FU duration:
Comp, 2001	in hospital thromboprophylaxis followed by out of hospital Enoxaparin 40 mg once a day for a total duration of 27-29 days (n=441) vs. Enoxaparin 30 mg twice a day for 7-10 days (n=432)	THR or TKR	Sample size: 441/432 Primary endpoint: FU duration:
LIFENOX, 2011	subcutaneous enoxaparin 40 mg daily for 10±4 days (n=4171) vs. placebo (n=4136)	hospitalized, acutely ill medical patients	double-blind Parallel groups Sample size: 4171/4136 Primary endpoint: death from any cause FU duration: 30 days

antithrombotics

enoxaparin

versus Dextran

No demonstrated result for efficacy

meta-analysis

antithrombotics

enoxaparin

versus UFH

No demonstrated result for efficacy

meta-analysis

antithrombotics

enoxaparin

versus Unfractionated heparin

No demonstrated result for efficacy

meta-analysis

antithrombotics

fondaparinux

versus placebo or control

No demonstrated result for efficacy

fondaparinux inferior to placebo (on top intermittent pneumatic comp.) in terms of Major bleeding in APOLLO (Turpie), 2007 (abdominal surgery patients)

meta-analysis

antithrombotics

fondaparinux

versus LMWH

No demonstrated result for efficacy

meta-analysis

antithrombotics

fondaparinux

versus Low molecular weight heparin

No demonstrated result for efficacy

fondaparinux inferior to enoxaparin in terms of Major bleeding in PENTAMAKS (Bauer), 2001 (knee surgery patients)

fondaparinux inferior to enoxaparin in terms of Symptomatic venous thromboembolism in PENTATHLON (Turpie), 2002 (hip surgery patients)

fondaparinux inferior to enoxaparin in terms of Symptomatic deep-vein thrombosis in PENTATHLON (Turpie), 2002 (hip surgery patients)

meta-analysis

Trial	control	p<0.05	harm	NS
PENTAMAKS (Bauer), 2001	fondaparinux vs enoxaparin	DVT 0.46 [0.33; 0.63] proximal DVT 0.45 [0.21; 0.99] VTE 0.45 [0.33; 0.62]	Major bleeding 11.00 [1.43; 84.90]	Death 0.67 [0.11; 3.97] PE 0.25 [0.03; 2.23] Nonfatal pulmonary embolism 0.25 [0.03; 2.23] Fatal pulmonary embolism NaN [NaN; NaN] Symptomatic venous thromboembolism 0.43 [0.11; 1.65] Symptomatic deep-vein thrombosis 0.75 [0.17; 3.33]
PENTHIFRA (Eriksson), 2001	fondaparinux vs enoxaparin	DVT 0.42 [0.31; 0.57] proximal DVT 0.21 [0.09; 0.51] VTE 0.44 [0.32; 0.59]		Death 0.70 [0.33; 1.49] Major bleeding 0.96 [0.51; 1.82] PE 2.20 [0.45; 10.87] Nonfatal pulmonary embolism 1.01 [0.06; 16.13] Fatal pulmonary embolism 1.01 [0.14; 7.16] Symptomatic venous thromboembolism 1.01 [0.25; 4.03] Symptomatic deep-vein thrombosis 1.01 [0.06; 16.13]
PENTATHLON (Turpie), 2002	fondaparinux vs enoxaparin	DVT 0.69 [0.48; 1.00]	Symptomatic venous thromboembolism 10.02 [1.28; 78.13] Symptomatic deep-vein thrombosis 10.02 [1.28; 78.13]	Death 3.00 [0.31; 28.82] Major bleeding 1.82 [0.88; 3.78] PE 5.01 [0.59; 42.81] proximal DVT 1.42 [0.64; 3.19] Nonfatal pulmonary embolism ∞ [NaN; ∞] VTE 0.74 [0.51; 1.05] Fatal pulmonary embolism 0.00 [0.00; NaN]
EPHESUS (Lassen), 2002	fondaparinux vs enoxaparin	DVT 0.44 [0.30; 0.64] proximal DVT 0.26 [0.11; 0.64] VTE 0.44 [0.30; 0.64]		Death 0.00 [0.00; NaN] Major bleeding 1.51 [0.96; 2.35] PE 0.99 [0.14; 7.05] Nonfatal pulmonary embolism 0.66 [0.11; 3.96] Fatal pulmonary embolism NaN [NaN; NaN] Symptomatic venous thromboembolism 1.66 [0.40; 6.92] Symptomatic deep-vein thrombosis 2.98 [0.31; 28.65]
Turpie, 2001	fondaparinux vs enoxaparin
PEGASUS, 2005	fondaparinux vs enoxaparin			Death 0.75 [0.38; 1.45] Major bleeding 1.39 [0.91; 2.13] PE 1.66 [0.40; 6.95] DVT 0.72 [0.49; 1.06] proximal DVT 1.00 [0.29; 3.45] Nonfatal pulmonary embolism ∞ [NaN; ∞] VTE 0.75 [0.52; 1.09] Fatal pulmonary embolism 1.00 [0.20; 4.94] Symptomatic venous thromboembolism 1.20 [0.37; 3.92] Symptomatic deep-vein thrombosis 1.00 [0.14; 7.08]
L8541	fondaparinux vs enoxaparin			Major bleeding 0.92 [0.41; 2.07] DVT 0.25 [0.03; 2.22]
L8635	fondaparinux vs enoxaparin			Major bleeding NaN [NaN; NaN] VTE 0.78 [0.05; 11.67]

Trial	Treatments	Patients	Method
PENTAMAKS (Bauer), 2001	fondaparinux 2.5-mg once-daily subcutaneous, starting 6 hours after surgery (n=517) vs. enoxaparin 30mg twice daily (North america recommendation) (n=517)	elective major knee surgery	double blind Parallel groups Sample size: 517/517 Primary endpoint: venous thromboembolism FU duration: 11 days
PENTHIFRA (Eriksson), 2001	fondaparinux 2.5-mg once-daily subcutaneous, starting 6 hours after surgery (n=831) vs. enoxaprin 40mg once daily (n=840)	hip fracture surgery	double blind Parallel groups Sample size: 831/840 Primary endpoint: venous thromboembolism FU duration: 11 days
PENTATHLON (Turpie), 2002	fondaparinux 2.5-mg once-daily subcutaneous, starting 6 hours after surgery (n=1138) vs. enoxaparin 30mg twice daily (North america recommendation) (n=1137)	elective hip replacement surgery	double blind Parallel groups Sample size: 1138/1137 Primary endpoint: venous thromboembolism FU duration: 11 days
EPHESUS (Lassen), 2002	fondaparinux 2.5-mg once-daily subcutaneous, starting 6 hours after surgery (n=1155) vs. enoxaprin 40mg once daily (n=1154)	elective hip replacement surgery	double blind Parallel groups Sample size: 1155/1154 Primary endpoint: venous thromboembolism FU duration: 11 days (6 weeks)
Turpie, 2001	pentasaccharide Org31540/SR90107A subcutaneous once daily at doses 0.75 mg, 1.5 mg, 3.0 mg, 6.0 mg, and 8.0 mg (n=673) vs. enoxaparin 30mg once daily subcutaneous (n=260) dose-ranging study	patients undergoing total hip replacement	double blind Parallel groups Sample size: 673/260 Primary endpoint: venous thromboembolism FU duration: >15 days dose finding study
PEGASUS, 2005	once-daily subcutaneous injections of fondaparinux 2·5 mg started 6 h after surgery for 5–9 days (n=1465) vs. once-daily subcutaneous injections of dalteparin 5000 units for 5–9 days (2500 units each, given 2 h before surgery and 12 h after the preoperative administration) (n=1462)	patients undergoing major abdominal surgery	double blind Parallel groups Sample size: 1465/1462 Primary endpoint: venous thromboembolism FU duration: 10 days (30 days)
L8541	fondaparinux 2.5mg subcutaneous once-daily for 7+/-2 days (n=119) vs. enoxaparin 40mg s.c. once-daily (n=118)	chinese patients undergoing major orthopaedic surgery of the lower limbs	single-blind Parallel groups Sample size: 119/118 Primary endpoint: overall deep vein thrombosis FU duration: 9 days (49d)
L8635	Fondaparinux 2.5mg once daily subcutaneously for 7 days (n=28) vs. enoxaparin 40mg once daily SC for 7 days (n=23)	Taiwanese patients undergoing elective knee replacement	open, blind assessment Parallel groups Sample size: 28/23 Primary endpoint: VTE events FU duration: 10 days

antithrombotics

fraxiparin

versus placebo or control

No demonstrated result for efficacy

nadroparin inferior to placebo in terms of total bleeding in Pezzuoli, 1989

nadroparin inferior to placebo in terms of major Bleeding in Pezzuoli, 1989

nadroparin inferior to placebo in terms of wound hematoma in Pezzuoli, 1989

nadroparin inferior to placebo in terms of transfusin in Pezzuoli, 1989

meta-analysis

antithrombotics

fraxiparin

versus Unfractionated heparin

No demonstrated result for efficacy

meta-analysis

antithrombotics

LMWH

versus UFH

No demonstrated result for efficacy

LMWH inferior to UFH in terms of All-cause death during follow-up in Harenberg, 1996 (medical patients patients)

meta-analysis

antithrombotics

nadroparin

versus placebo or control

No demonstrated result for efficacy

meta-analysis

Trial	control	p<0.05	NS
Fraisse, 2000	Nadroparin vs placebo		All-cause death during follow-up 1.05 [0.41; 2.69] Major bleeding during follow-up 2.09 [0.54; 8.16] Symptomatic pulmonary embolism during follow-up NaN [NaN; NaN] DVT 0.55 [0.30; 1.00] Asymptomatic deep vein thrombosis during follow-up. 0.57 [0.30; 1.06] Symptomatic deep vein thrombosis during follow-up NaN [NaN; NaN]
Mahe, 2005	Nadroparin vs placebo		All-cause death during follow-up 0.98 [0.78; 1.24] Major bleeding during follow-up 0.34 [0.04; 3.24] Symptomatic pulmonary embolism during follow-up 0.59 [0.27; 1.29] fatal PE 0.59 [0.27; 1.29] PE 0.59 [0.27; 1.29]
Balas [40]	nadroparin vs placebo		total bleeding 0.58 [0.17; 1.91]
Marassi [41]	nadroparin vs no treatment		total bleeding 0.00 [0.00; NaN] wound hematoma 0.00 [0.00; NaN] transfusin 1.15 [0.65; 2.04]
Nurmohamed, 1996	nadroparin vs placebo		thromboembolic events (symptomatic or asymptomatic) 0.71 [0.48; 1.06] proxymal DVT 0.60 [0.30; 1.18]
KANT (7 days), 2008	nadroparin vs control	asymptomatic proximal DVT, symptomatic VTE, all death 0.29 [0.12; 0.71]	major or clinically relevant bleeding 3.01 [0.61; 14.88]
KANT (14 days), 2008	nadroparin 14d vs control	asymptomatic proximal DVT, symptomatic VTE, all death 0.28 [0.10; 0.82]	major or clinically relevant bleeding 1.49 [0.21; 10.51]
Kujath, 1993	nadroparin vs control	VTE (symptomatic or asymptomatic) 0.29 [0.12; 0.69]	PE NaN [NaN; NaN]
Bergmann, 1996	nadroparin vs placebo		All-cause death during follow-up 0.98 [0.78; 1.24]

Trial	Treatments	Patients	Method
Fraisse, 2000	Nadroparin 3800–5700E once daily, Until no longer mechanical ventilation, <=21 days (n=109) vs. placebo (n=114)	Acute decompensated chronic obstructive pulmonary diseasewith mechanical ventilation	double blind Parallel groups Sample size: 109/114 Primary endpoint: FU duration: <=21 days
Mahe, 2005	nadroparin 7500E once daily, Until hospital discharge, <=21 days (n=1230) vs. placebo (n=1244)	Congestive heart failure (NYHA III–IV), acute or respiratory disease, nonpulmonary sepsis, cancer	double blind Parallel groups Sample size: 1230/1244 Primary endpoint: FU duration: <=21 days
Balas [40]	Nadroparin 2850 anti-Xa units (n=94) vs. Placebo (n=95)		Blind Sample size: 94/95 Primary endpoint: FU duration:
Marassi [41]	Nadroparin 2850 anti-Xa units (n=31) vs. No treatment (n=33)		Open Sample size: 31/33 Primary endpoint: FU duration:
Nurmohamed, 1996	Nadroparin, 7500 Institute Choay anti-Xa units per day subcutaneously 18-24 hours postoperatively plus compression for 10 days (n=241) vs. compression stockings + placebo (n=244)	Craniotomy or spinal surgery for tumor or injury, 18 years or older, without excess bleeding risk	Sample size: 241/244 Primary endpoint: FU duration: 56 days
KANT (7 days), 2008	once-daily subcutaneous injection of LMWH (nadroparin, 3800 anti-Xa IU) for 7 days (n=657) vs. full-length graduated compression stocking for 7 days (n=660) 3 arms: elastic stockings for 7 days; nadroparin 0.4 ml sc once daily for 7 days; nadroparin 0.4 ml sc once daily for 14 days	patients undergoing knee arthroscopy	open (blinded assessment) Parallel groups Sample size: 657/660 Primary endpoint: prox DVT, VTE, death FU duration: 3 months
KANT (14 days), 2008	once-daily subcutaneous injection of LMWH (nadroparin, 3800 anti-Xa IU) for 14 days (n=444) vs. full-length graduated compression stocking for 7 days (n=660) 3 arms: elastic stockings for 7 days; nadroparin 0.4 ml sc once daily for 7 days; nadroparin 0.4 ml sc once daily for 14 days	patients undergoing knee arthroscopy	open (blinded assessment) Parallel groups Sample size: 444/660 Primary endpoint: prox DVT, VTE, death FU duration: 3 months
Kujath, 1993	Nadroparin 2850 IU (n=126) vs. no prophylaxis (n=126)	patients with injuries of the lower limb immobilized by a plaster cast	open Parallel groups Sample size: 126/126 Primary endpoint: FU duration: 16 days
Bergmann, 1996	nadroparin 7500 u anti-Xa once daily (n=-9) vs. placebo (n=-9)	hospitalized medical	Parallel groups Sample size: -9/-9 Primary endpoint: FU duration: up to 21

antithrombotics

nadroparin

versus placebo or no treatment

No demonstrated result for efficacy

meta-analysis

antithrombotics

nadroparin

versus

No demonstrated result for efficacy

meta-analysis

Trial	control	p<0.05	NS
Kakkar and Murray, 1985	nadroparin vs unfractionated heparin	asymptomatic DVT 0.36 [0.13; 0.99]	death 0.83 [0.26; 2.69] clinical PE 0.00 [0.00; NaN] wound hematoma 0.79 [0.23; 2.65] symptomatic thromboembolism 0.00 [0.00; NaN] transfusion 1.14 [0.85; 1.53]
EFS, 1988	nadroparin vs unfractionated heparin	symptomatic thromboembolism 0.27 [0.07; 0.95]	death 0.89 [0.40; 2.01] total haemorrhage 0.99 [0.82; 1.19] clinical PE 0.20 [0.02; 2.07] asymptomatic DVT 0.63 [0.39; 1.01] wound hematoma 0.97 [0.37; 2.55] transfusion 1.01 [0.82; 1.25]
Dahan, 1989	nadroparin vs unfractionated heparin		clinical PE NaN [NaN; NaN] asymptomatic DVT NaN [NaN; NaN] wound hematoma 0.00 [0.00; NaN]
	nadroparin vs unfractionated heparin
	nadroparin vs unfractionated heparin
NPHDO, 1998	out of hospital Nadroparin vs standard prophylaxis		Death NaN [NaN; NaN] Major bleeding NaN [NaN; NaN] Minor bleeding ∞ [NaN; ∞] Pulmonary embolism NaN [NaN; NaN] Symptomatic venous thromboembolism 0.41 [0.04; 3.88] symptomatic deep vein thrombosis 0.30 [0.03; 2.88]

Trial	Treatments	Patients	Method
Kakkar and Murray, 1985	Nadroparin 2850 (n=200) vs. UFH 10 000 units (n=200)	General surgery	Blind Sample size: 200/200 Primary endpoint: FU duration: 10 days
EFS, 1988	Nadroparin 2850 (n=968) vs. UFH 15 000 units (n=941)	Abdominal surgery	Open Sample size: 968/941 Primary endpoint: FU duration: 1 month
Dahan, 1989	Nadroparin 2850 (n=46) vs. UFH 15 000 units (n=41)	Thoracic surgery	Open Sample size: 46/41 Primary endpoint: FU duration:
Barbui, 1990	Nadroparin 2850 anti Xa units (n=171) vs. UFH 10 000 units (n=173)	General surgery	Open Sample size: 171/173 Primary endpoint: FU duration:
Eurin, 1994	Nadroparin 2850 anti Xa units (n=241) vs. UFH 15 000 units (n=239)	Abdominopelvic surgery	Open Sample size: 241/239 Primary endpoint: FU duration:
NPHDO, 1998	in hospital thromboprophylaxis followed by out of hospital Nadroparin weight-adjusted for a total duration of 37-38 days (n=173) vs. Nadroparin weight-adjusted for 16-17 days (n=173)	THR	Sample size: 173/173 Primary endpoint: FU duration:

antithrombotics

phenindione

versus placebo or no treatment

No demonstrated result for efficacy

meta-analysis

antithrombotics

reviparin

versus placebo or control

No demonstrated result for efficacy

meta-analysis

antithrombotics

reviparin

versus

No demonstrated result for efficacy

meta-analysis

antithrombotics

rivaroxaban

versus

No demonstrated result for efficacy

rivaroxaban inferior to placebo in terms of Clinically relevant bleeding in MARINER, 2018 (medical patients patients)

meta-analysis

antithrombotics

rivaroxaban

versus Low molecular weight heparin

No demonstrated result for efficacy

meta-analysis

Trial	control	p<0.05	NS
ODIXa-HIP 10mg, 2006	rivaroxaban vs enoxaparin (short duration)	DVT (asymptomatic or symptomatic) 0.42 [0.22; 0.79] distal DVT 0.36 [0.17; 0.73] total VTE and all-cause mortality 0.42 [0.22; 0.79]	proximal DVT 0.95 [0.20; 4.59] non-fatal PE NaN [NaN; NaN]
ODIXa-KNEE, 2005	rivaroxaban vs enoxaparin (US regimen)		major bleeding 0.00 [0.00; NaN]
RECORD 1, 2008	rivaroxaban vs enoxaparin	DVT (asymptomatic or symptomatic) 0.23 [0.12; 0.43] proximal DVT 0.03 [0.00; 0.23] total VTE and all-cause mortality 0.30 [0.18; 0.51] major VTE (fatal and non fatal DVT,PE) 0.12 [0.04; 0.34]	death 0.98 [0.24; 3.90] coronary events 0.49 [0.12; 1.95] major bleeding 3.02 [0.61; 14.95] distal DVT 0.49 [0.24; 1.00] non-fatal PE 3.91 [0.44; 34.92] Symptomatic venous thromboembolism 0.55 [0.20; 1.48]
RECORD 2, 2008	rivaroxaban (long duration) vs enoxaparin (short duration)	DVT (asymptomatic or symptomatic) 0.20 [0.11; 0.35] proximal DVT 0.11 [0.05; 0.29] distal DVT 0.34 [0.16; 0.71] total VTE and all-cause mortality 0.21 [0.13; 0.35] Symptomatic venous thromboembolism 0.20 [0.06; 0.69] major VTE (fatal and non fatal DVT,PE) 0.12 [0.05; 0.28]	death 0.34 [0.07; 1.66] coronary events 1.33 [0.30; 5.95] major bleeding 1.00 [0.06; 15.98] non-fatal PE 0.25 [0.03; 2.25] major or clinically relevant non-major bleeding 1.20 [0.93; 1.54]
RECORD 3, 2008	rivaroxaban vs enoxaparin (europe regimen)	DVT (asymptomatic or symptomatic) 0.53 [0.41; 0.68] distal DVT 0.53 [0.41; 0.70] total VTE and all-cause mortality 0.51 [0.39; 0.65] Symptomatic venous thromboembolism 0.34 [0.15; 0.75] major VTE (fatal and non fatal DVT,PE) 0.38 [0.18; 0.82]	death 0.00 [0.00; NaN] coronary events 0.51 [0.05; 5.59] major bleeding 1.19 [0.40; 3.53] myocardial infarction 0.51 [0.05; 5.61] proximal DVT 0.48 [0.22; 1.05] non-fatal PE 0.00 [0.00; NaN]
RECORD 4, 2009	rivaroxaban vs enoxaparin (US regimen)	proximal DVT 0.23 [0.07; 0.80] total VTE and all-cause mortality 0.69 [0.51; 0.92]	death 0.66 [0.11; 3.94] coronary events 0.33 [0.03; 3.16] major bleeding 2.47 [0.78; 7.86] myocardial infarction 0.20 [0.02; 1.69] distal DVT 0.82 [0.57; 1.17] non-fatal PE 0.49 [0.15; 1.64] asymptomatic DVT 0.72 [0.51; 1.01] Symptomatic venous thromboembolism 0.60 [0.29; 1.27] major VTE (fatal and non fatal DVT,PE) 0.59 [0.30; 1.16] symptomatic DVT 0.60 [0.22; 1.63] major or clinically relevant non-major bleeding 1.34 [0.86; 2.07]

Trial	Treatments	Patients	Method
ODIXa-HIP 10mg, 2006	rivaroxaban 10mg daily for 5–9 days (n=142) vs. once-daily subcutaneous enoxaparin dose of 40 mg for 5–9 days (n=157) dose finding study (doses of 5, 10, 20, 30, or 40 mg)	patients undergoing elective total hip replacement	double blind Parallel groups Sample size: 142/157 Primary endpoint: any DVT, PE, all cause death FU duration: 5-9 days
ODIXa-KNEE, 2005	BAY 59-7939 5mg b.i.d. for 5–9 days (n=102) vs. enoxaparin 30 mg b.i.d. for 5–9 days (n=105) dose ranging study with doses 2.5, 5, 10, 20, and 30 mg	patients undergoing elective total knee replacement	double blind Parallel groups Sample size: 102/105 Primary endpoint: FU duration: 5-9 days
RECORD 1, 2008	rivaroxaban 10mg once daily for 35 days (n=2266) vs. enoxaparin 40mg subcutaneous once daily for 31-39 days (n=2275)	patients undergoing total hip arthroplasty	double blind Parallel groups Sample size: 2266/2275 Primary endpoint: DVT, PE, death FU duration: 36 days (range 30-42)
RECORD 2, 2008	extended thromboprophylaxis with rivaroxaban 10mg once daily for 31-39 days (n=1252) vs. enoxaparin 40mg subcutaneous once daily for 10-14 days (n=1257)	patients undergoing elective total hip replacement	double blind Parallel groups Sample size: 1252/1257 Primary endpoint: DVT, PE , all cause death FU duration: 30-42 days
RECORD 3, 2008	rivaroxaban 10 mg once daily for 10- 14 days (n=1254) vs. enoxaparin 40 mg subcutaneous once daily for 10-14 days (n=1277)	patients undergoing total knee arthroplasty	double blind Parallel groups Sample size: 1254/1277 Primary endpoint: DVT, PE all cause mortality FU duration: 13-17 days
RECORD 4, 2009	rivaroxaban 10mg once daily for 10 to 14 days (n=1584) vs. enoxaparin 30 mg twice daily by subcutaneous injection for 10-14 days (n=1564)	patients who had undergone total-knee-replacement surgery	double blind Parallel groups Sample size: 1584/1564 Primary endpoint: total VTE events FU duration: 40 days

antithrombotics

suloctidil

versus placebo or control

No demonstrated result for efficacy

meta-analysis

antithrombotics

ticlopidine

versus

No demonstrated result for efficacy

meta-analysis

antithrombotics

ticlopidine

versus placebo or control

No demonstrated result for efficacy

meta-analysis

antithrombotics

ticlopidine

versus placebo or no treatment

No demonstrated result for efficacy

meta-analysis

antithrombotics

tinzaparin

versus placebo or control

No demonstrated result for efficacy

meta-analysis

antithrombotics

tinzaparin

versus placebo or no treatment

No demonstrated result for efficacy

meta-analysis

antithrombotics

tinzaparin

versus

No demonstrated result for efficacy

meta-analysis

antithrombotics

UFH

versus control or placebo

No demonstrated result for efficacy

meta-analysis

Trial	control	p<0.05	NS
Handley (low dose), 1972	UFH vs control		DVT 0.00 [0.00; NaN] proximal DVT NaN [NaN; NaN] pulmonary embolism 0.92 [0.06; 13.95]
Handley, 1972	UFH vs control		deaths 1.00 [0.15; 6.64] proximal DVT 0.92 [0.06; 13.95] pulmonary embolism 0.00 [0.00; NaN]
Gallus, 1973	UFH vs control		proximal DVT 0.35 [0.04; 3.23]
Emerson, 1973	UFH vs control	DVT 0.16 [0.04; 0.65]	deaths 0.00 [0.00; NaN] pulmonary embolism 0.00 [0.00; NaN]
Zawilska, 1989	UFH vs control	DVT 0.21 [0.05; 0.92]	deaths 0.88 [0.29; 2.71] pulmonary embolism 0.00 [0.00; NaN]
Warlow, 1973	UFH vs control	DVT 0.16 [0.04; 0.68]	deaths 1.20 [0.38; 3.76] pulmonary embolism 0.00 [0.00; NaN]
Pitt, 1980	UFH vs placebo		DVT 0.47 [0.18; 1.21] proximal DVT NaN [NaN; NaN] pulmonary embolism NaN [NaN; NaN]

Trial	Treatments	Patients	Method
Handley (low dose), 1972	Heparin 5000 U IV and 7500 U SC as soon as possible, then 7500 U SC twice daily (n=26) vs. no heparin (n=24)	Myocardial infarction	Parallel groups Sample size: 26/24 Primary endpoint: FU duration: 7 d
Handley, 1972	Heparin 5000 U IV (loading dose) followed by 20 000 U IV twice daily (n=30) vs. no heparin (n=30)	Myocardial infarction	Parallel groups Sample size: 30/30 Primary endpoint: FU duration: 14 d
Gallus, 1973	heparin 5000 U SC 3 times daily (n=38) vs. no heparin (n=40)	Myocardial infarction	Parallel groups Sample size: 38/40 Primary endpoint: FU duration: until mobile
Emerson, 1973	Heparin Low dose SCium9 (n=37) vs. no heparin (n=41)	Myocardial infarction	Parallel groups Sample size: 37/41 Primary endpoint: FU duration: NA
Zawilska, 1989	Heparin sodium 5000 IU SC twice dailyy for 14 to 21 days (n=50) vs. no heparin (n=53)	patients with acute myocardial infarction, disqualified for thrombolytic treatment	Parallel groups Sample size: 50/53 Primary endpoint: FU duration: 14-21 d
Warlow, 1973	Heparin sodium 5000 U SC twice dailyly (n=73) vs. no heparin (n=73)	Myocardial infarction	double blind Parallel groups Sample size: 73/73 Primary endpoint: FU duration: 10 d
Pitt, 1980	Heparin 500 U IV twice daily (n=36) vs. placebo (n=37)	patients with acute myocardial infarction of less than 48 hours duration	open Parallel groups Sample size: 36/37 Primary endpoint: FU duration: 2-3 d

antithrombotics

UFH

versus placebo or control

No demonstrated result for efficacy

UFH inferior to placebo in terms of non fatala PE in Williams , 1978

meta-analysis

Trial	control	p<0.05	harm	NS
Williams , 1978	UFH vs placebo		non fatala PE 3.80 [1.47; 9.80]	fatal PE 0.00 [0.00; NaN]
Abraham-Inpijn , 1975	UFH vs placebo			non fatal bleeding NaN [NaN; NaN] fatal bleeding NaN [NaN; NaN] deep vein thrombosis 0.22 [0.03; 1.60] non fatala PE 0.00 [0.00; NaN] fatal PE NaN [NaN; NaN]
Lowe , 1981	UFH vs placebo	deep vein thrombosis 0.42 [0.19; 0.93]		non fatal bleeding 0.96 [0.14; 6.56] fatal bleeding NaN [NaN; NaN] non fatala PE 0.38 [0.08; 1.89] fatal PE NaN [NaN; NaN]
Morris, 1974	UFH vs no treatment	deep vein thrombosis 0.19 [0.06; 0.59]		non fatal bleeding 0.50 [0.05; 5.27] fatal bleeding NaN [NaN; NaN] non fatala PE NaN [NaN; NaN] fatal PE 0.00 [0.00; NaN]
Welin-Berger, 1982	UFH vs no treatment			non fatal bleeding ∞ [NaN; ∞] fatal bleeding NaN [NaN; NaN] deep vein thrombosis 1.33 [0.57; 3.14] non fatala PE NaN [NaN; NaN] fatal PE NaN [NaN; NaN]
Bergqvist , 1979	UFH vs no treatment	deep vein thrombosis 0.71 [0.52; 0.98]		non fatal bleeding NaN [NaN; NaN] fatal bleeding NaN [NaN; NaN] non fatala PE 1.38 [0.71; 2.67] fatal PE 0.00 [0.00; NaN]
Hampson, 1974	UFH vs placebo			non fatal bleeding NaN [NaN; NaN] fatal bleeding NaN [NaN; NaN] deep vein thrombosis 0.65 [0.39; 1.08] fatal PE NaN [NaN; NaN]
Moskovitz, 1978	UFH vs placebo	deep vein thrombosis 0.38 [0.20; 0.75]		non fatal bleeding ∞ [NaN; ∞] fatal bleeding NaN [NaN; NaN] non fatala PE 2.74 [0.30; 25.05] fatal PE NaN [NaN; NaN]
Gallus , 1973	UFH vs no treatment			deep vein thrombosis 0.38 [0.05; 2.92]
VTCSG, 1975	UFH vs no treatment			non fatal bleeding ∞ [NaN; ∞] fatal bleeding NaN [NaN; NaN] non fatala PE NaN [NaN; NaN] fatal PE NaN [NaN; NaN]
Mannucci , 1976	UFH vs no treatment	deep vein thrombosis 0.31 [0.10; 1.00]		non fatal bleeding 2.09 [0.42; 10.32] fatal bleeding NaN [NaN; NaN] non fatala PE NaN [NaN; NaN] fatal PE NaN [NaN; NaN]
Dechavanne, 1974	UFH vs no treatment	deep vein thrombosis 0.15 [0.04; 0.62]		non fatal bleeding 1.50 [0.27; 8.32] fatal bleeding NaN [NaN; NaN] non fatala PE ∞ [NaN; ∞] fatal PE 0.00 [0.00; NaN]
Dechavanne, 1975	UFH vs no treatment	deep vein thrombosis 0.13 [0.02; 0.96]		non fatal bleeding 0.00 [0.00; NaN] fatal bleeding NaN [NaN; NaN] non fatala PE NaN [NaN; NaN] fatal PE 0.00 [0.00; NaN]
Lahnborg, 1980	UFH vs placebo	deep vein thrombosis 0.53 [0.31; 0.90]		fatal bleeding NaN [NaN; NaN] non fatala PE ∞ [NaN; ∞] fatal PE NaN [NaN; NaN]
Xabregas , 1977	UFH vs placebo			non fatal bleeding 0.77 [0.23; 2.56] fatal bleeding NaN [NaN; NaN] deep vein thrombosis 0.00 [0.00; NaN] non fatala PE NaN [NaN; NaN] fatal PE NaN [NaN; NaN]
Bergqvist, 1979	UFH vs no treatment	deep vein thrombosis 0.65 [0.46; 0.91]		non fatal bleeding NaN [NaN; NaN] fatal bleeding NaN [NaN; NaN] non fatala PE NaN [NaN; NaN] fatal PE ∞ [NaN; ∞]
Galasko , 1976	UFH vs no treatment	deep vein thrombosis 0.36 [0.19; 0.69]		non fatal bleeding 0.00 [0.00; NaN] fatal bleeding NaN [NaN; NaN] non fatala PE NaN [NaN; NaN] fatal PE 0.40 [0.08; 1.97]
Moskovitz, 1978	UFH vs placebo			non fatal bleeding NaN [NaN; NaN] fatal bleeding NaN [NaN; NaN] deep vein thrombosis 0.99 [0.47; 2.10] non fatala PE ∞ [NaN; ∞] fatal PE 0.00 [0.00; NaN]
Svend-Hansen, 1981	UFH vs placebo	deep vein thrombosis 0.54 [0.32; 0.91]		fatal bleeding NaN [NaN; NaN] non fatala PE NaN [NaN; NaN] fatal PE 1.00 [0.06; 15.65]
Gallus , 1973	UFH vs no treatment	deep vein thrombosis 0.27 [0.09; 0.85]		fatal bleeding 0.50 [0.04; 6.55]
Morris , 1977	UFH vs no treatment			non fatal bleeding NaN [NaN; NaN] fatal bleeding NaN [NaN; NaN] deep vein thrombosis 0.75 [0.46; 1.22] non fatala PE NaN [NaN; NaN] fatal PE NaN [NaN; NaN]
Blech, 1981	UFH vs control	DVT 0.15 [0.04; 0.60]		PE 0.20 [0.01; 4.03]
Cade	UFH vs control
Gardlund, 1996	UFH vs control	fatal PE 0.26 [0.07; 0.91]		DVT 1.34 [0.55; 3.26] PE 1.30 [0.78; 2.17]
	UFH vs no treatment
	UFH vs no treatment
	UFH vs placebo
	UFH vs placebo
	UFH vs placebo
	UFH vs placebo
	UFH vs placebo
	UFH vs placebo
	UFH vs placebo
	UFH vs placebo
	UFH vs placebo
	UFH vs placebo
	UFH vs placebo
	UFH vs placebo
	UFH vs placebo
	UFH vs placebo
	UFH vs placebo
	UFH vs placebo
	UFH vs no treatment
	UFH vs no treatment
	UFH vs no treatment
	UFH vs no treatment
	UFH vs no treatment
	UFH vs no treatment
	UFH vs no treatment
	UFH vs no treatment
	UFH vs no treatment
	UFH vs no treatment
	UFH vs no treatment
	UFH vs placebo
	UFH vs placebo
	UFH vs placebo
	UFH vs placebo
	UFH vs no treatment
	UFH vs no treatment
	UFH vs no treatment
	UFH vs no treatment
	UFH vs no treatment
	UFH vs no treatment
	UFH vs no treatment
	UFH vs no treatment
	UFH vs no treatment
	UFH vs placebo
	UFH vs no treatment
	UFH vs no treatment
	UFH vs no treatment
	UFH vs placebo
	UFH vs placebo
	UFH vs placebo
Cerrato, 1978	UFH vs no treatment	thromboembolic events (symptomatic or asymptomatic) 0.18 [0.06; 0.56]

Trial	Treatments	Patients	Method
Williams , 1978	UFH twice daily for 14 days (n=106) vs. placebo (n=106)	elective orthopedic surgery	Sample size: 106/106 Primary endpoint: FU duration:
Abraham-Inpijn , 1975	UFH twice daily for 8 days (n=12) vs. placebo (n=13)	elective orthopedic surgery	Sample size: 12/13 Primary endpoint: FU duration:
Lowe , 1981	UFH twice daily for 16 days (n=51) vs. placebo (n=49)	elective orthopedic surgery	Sample size: 51/49 Primary endpoint: FU duration:
Morris, 1974	UFH twice daily for 10 days (n=36) vs. no treatment (n=36)	elective orthopedic surgery	Sample size: 36/36 Primary endpoint: FU duration:
Welin-Berger, 1982	UFH twice daily for 7 days (n=20) vs. no treatment (n=20)	elective orthopedic surgery	Sample size: 20/20 Primary endpoint: FU duration:
Bergqvist , 1979	UFH twice daily for 5 days (n=84) vs. no treatment (n=77)	elective orthopedic surgery	Sample size: 84/77 Primary endpoint: FU duration:
Hampson, 1974	UFH 3 times daily for 7- 10 days (n=48) vs. placebo (n=52)	elective orthopedic surgery	Sample size: 48/52 Primary endpoint: FU duration:
Moskovitz, 1978	UFH 3 times daily for 7 days (n=35) vs. placebo (n=32)	elective orthopedic surgery	Sample size: 35/32 Primary endpoint: FU duration:
Gallus , 1973	UFH twice daily for A days (n=8) vs. no treatment (n=9)	elective orthopedic surgery	Sample size: 8/9 Primary endpoint: FU duration:
VTCSG, 1975	UFH twice daily for 10 days (n=34) vs. no treatment (n=30)	elective orthopedic surgery	Sample size: 34/30 Primary endpoint: FU duration:
Mannucci , 1976	UFH 3 times daily for 7 days (n=23) vs. no treatment (n=24)	elective orthopedic surgery	Sample size: 23/24 Primary endpoint: FU duration:
Dechavanne, 1974	UFH 3 times daily for 10 days (n=29) vs. no treatment (n=29)	elective orthopedic surgery	Sample size: 29/29 Primary endpoint: FU duration:
Dechavanne, 1975	UFH 3 times daily for 10 days (n=20) vs. no treatment (n=21)	elective orthopedic surgery	Sample size: 20/21 Primary endpoint: FU duration:
Lahnborg, 1980	UFH twice daily for 10 days (n=70) vs. placebo (n=69)	traumatic orthopedic surgery	Sample size: 70/69 Primary endpoint: FU duration:
Xabregas , 1977	UFH twice daily for 14 days (n=27) vs. placebo (n=26)	traumatic orthopedic surgery	Sample size: 27/26 Primary endpoint: FU duration:
Bergqvist, 1979	UFH twice daily for 5 days (n=32) vs. no treatment (n=23)	traumatic orthopedic surgery	Sample size: 32/23 Primary endpoint: FU duration:
Galasko , 1976	UFH twice daily (duration unknown) (n=50) vs. no treatment (n=50)	traumatic orthopedic surgery	Sample size: 50/50 Primary endpoint: FU duration:
Moskovitz, 1978	UFH 3 times daily for 7 days (n=29) vs. placebo (n=23)	traumatic orthopedic surgery	Sample size: 29/23 Primary endpoint: FU duration:
Svend-Hansen, 1981	UFH 3 times daily for 14 days (n=65) vs. placebo (n=65)	traumatic orthopedic surgery	Sample size: 65/65 Primary endpoint: FU duration:
Gallus , 1973	UFH 3 times daily for A (n=23) vs. no treatment (n=23)	traumatic orthopedic surgery	Sample size: 23/23 Primary endpoint: FU duration:
Morris , 1977	UFH 3 times daily for 10 days (n=24) vs. no treatment (n=24)	traumatic orthopedic surgery	Sample size: 24/24 Primary endpoint: FU duration:
Blech, 1981	Unfractionated heparin, 5000 U trice daily, until mobilized (n=50) vs. control (n=50)	Heart failure, chest infection	open Parallel groups Sample size: 50/50 Primary endpoint: FU duration: <=14 days
Cade	Unfractionated heparin, 5000 U twice daily, until mobilized or <=10 days (n=-9) vs. (n=-9)	Age >40, complete bed rest, cardiac failure, obesity, previous VTE, cancer or recent surgery	Parallel groups Sample size: -9/-9 Primary endpoint: FU duration: <=10 days
Gardlund, 1996	Unfractionated heparin, 5000 U twice daily, until hospital discharge, <=21 days (n=5776) vs. control (n=5917)	Age >55, infectious disease Immobilization	open Parallel groups Sample size: 5776/5917 Primary endpoint: FU duration: <=60 days
Kakkar (IMT)	UFH 3 times daily for 7 days (n=2111) vs. no treatment (n=2137)	All other general surgery	Sample size: 2111/2137 Primary endpoint: FU duration:
Gruber	UFH 3 times daily for 7 days (n=119) vs. no treatment (n=113)	All other general surgery	Sample size: 119/113 Primary endpoint: FU duration:
Kakkar, 1972	UFH twice daily for 7 days (n=39) vs. placebo (n=39)	All other general surgery	Sample size: 39/39 Primary endpoint: FU duration:
Kiil, 1978	UFH twice daily for 7 days (n=650) vs. placebo (n=663)	All other general surgery	Sample size: 650/663 Primary endpoint: FU duration:
Torngren, 1978	UFH twice daily for 6-8 days (n=66) vs. placebo (n=62)	all other general surgery	Sample size: 66/62 Primary endpoint: FU duration:
Torngren	UFH twice daily for 6-8 days (n=47) vs. placebo (n=62)	all other general surgery	Sample size: 47/62 Primary endpoint: FU duration:
Lahnborg, 1975	UFH twice daily for 5 days (n=58) vs. placebo (n=54)	all other general surgery	Sample size: 58/54 Primary endpoint: FU duration:
Lahnborg, 1976	UFH twice daily for 5 days (n=24) vs. placebo (n=24)	all other general surgery	Sample size: 24/24 Primary endpoint: FU duration:
Covey, 1975	UFH twice daily for 8 days (n=53) vs. placebo (n=52)	all other general surgery	Sample size: 53/52 Primary endpoint: FU duration:
Belch, 1980	UFH twice daily for 7 days (n=24) vs. placebo (n=25)	all other general surgery	Sample size: 24/25 Primary endpoint: FU duration:
Taberner, 1978	UFH twice daily for 7 days (n=50) vs. placebo (n=50)	all other general surgery	Sample size: 50/50 Primary endpoint: FU duration:
Strand, 1975	UFH twice daily for 7 days (n=55) vs. placebo (n=55)	all other general surgery	Sample size: 55/55 Primary endpoint: FU duration:
Roberts, 1975	UFH twice daily for 7 days (n=39) vs. placebo (n=45)	all other general surgery	Sample size: 39/45 Primary endpoint: FU duration:
Ribaudo, 1975	UFH twice daily for A days (n=75) vs. placebo (n=75)	all other general surgery	Sample size: 75/75 Primary endpoint: FU duration:
Wu, 1977	UFH twice daily for 7 days (n=44) vs. placebo (n=44)	all other general surgery	Sample size: 44/44 Primary endpoint: FU duration:
Lawrence, 1977	UFH twice daily for 5 days (n=133) vs. placebo (n=129)	all other general surgery	Sample size: 133/129 Primary endpoint: FU duration:
Muiticentre, 1984	UFH twice daily for 5-7 days (n=222) vs. placebo (n=108)	all other general surgery	Sample size: 222/108 Primary endpoint: FU duration:
Jourdan, 1984	UFH twice daily for 5 days (n=21) vs. placebo (n=21)	all other general surgery	Sample size: 21/21 Primary endpoint: FU duration:
Gordon-Smith, 1972	UFH twice daily for 5 days (n=-9) vs. no treatment (n=51)	all other general surgery	Sample size: -9/51 Primary endpoint: FU duration:
Nicolaides, 1972	UFH twice daily for 7 days (n=128) vs. no treatment (n=122)	all other general surgery	Sample size: 128/122 Primary endpoint: FU duration:
Multiunit, 1974	UFH twice daily for 7 days (n=128) vs. no treatment (n=128)	all other general surgery	Sample size: 128/128 Primary endpoint: FU duration:
Abernethy, 1974	UFH twice daily for 7 days (n=63) vs. no treatment (n=62)	all other general surgery	Sample size: 63/62 Primary endpoint: FU duration:
Clarke-Pearson, 1983	UFH twice daily for 7 days (n=95) vs. no treatment (n=105)	all other general surgery	Sample size: 95/105 Primary endpoint: FU duration:
Plante, 1979	UFH twice daily for 8 days (n=42) vs. no treatment (n=66)	all other general surgery	Sample size: 42/66 Primary endpoint: FU duration:
Abraham-Inpijn, 1979	UFH twice daily for 7 days (n=20) vs. no treatment (n=20)	all other general surgery	Sample size: 20/20 Primary endpoint: FU duration:
Spebar, 1981	UFH twice daily for 5-7 days (n=24) vs. no treatment (n=19)	all other general surgery	Sample size: 24/19 Primary endpoint: FU duration:
Sagar, 1974	UFH twice daily for 5 days (n=264) vs. no treatment (n=236)	all other general surgery	Sample size: 264/236 Primary endpoint: FU duration:
Koppenhagen, 1982	UFH twice daily (n=162) vs. no treatment (n=50)	all other general surgery	Sample size: 162/50 Primary endpoint: FU duration:
Bergqvist, 1980	UFH twice daily for 5 days (n=53) vs. no treatment (n=58)	all other general surgery	Sample size: 53/58 Primary endpoint: FU duration:
Torngren, 1978	UFH 3 times daily for 6-8 days (n=10) vs. placebo (n=10)	all other general surgery	Sample size: 10/10 Primary endpoint: FU duration:
Kruse-Blinkenberg, 1980	UFH 3 times daily for 8 days (n=29) vs. placebo (n=33)	all other general surgery	Sample size: 29/33 Primary endpoint: FU duration:
Kraytman, 1977	UFH 3 times daily for 6 days (n=25) vs. placebo (n=22)	all other general surgery	Sample size: 25/22 Primary endpoint: FU duration:
Marchetti, 1982	UFH 3 times daily (n=16) vs. placebo (n=13)	all other general surgery	Sample size: 16/13 Primary endpoint: FU duration:
Gallus, 1973	UFH 3 times daily for A (n=100) vs. no treatment (n=109)	all other general surgery	Sample size: 100/109 Primary endpoint: FU duration:
Gallus, 1976	UFH 3 times daily for 7 days (n=408) vs. no treatment (n=412)	all other general surgery	Sample size: 408/412 Primary endpoint: FU duration:
Groote Schuur, 1979	UFH 3 times daily for 6 days (n=323) vs. no treatment (n=323)	all other general surgery	Sample size: 323/323 Primary endpoint: FU duration:
Kraytman, 1976	UFH 3 times daily for 6 days (n=21) vs. no treatment (n=28)	all other general surgery	Sample size: 21/28 Primary endpoint: FU duration:
Kraytman, 1977	UFH 3 times daily for 6 days (n=23) vs. no treatment (n=27)	all other general surgery	Sample size: 23/27 Primary endpoint: FU duration:
Kettunen, 1974	UFH 3 times daily for 7 days (n=83) vs. no treatment (n=117)	all other general surgery	Sample size: 83/117 Primary endpoint: FU duration:
Caloghera, 1984	UFH 3 times daily for 7 days (n=40) vs. no treatment (n=40)	all other general surgery	Sample size: 40/40 Primary endpoint: FU duration:
Marchelli, 1983	UFH 3 times daily for ? (n=30) vs. no treatment (n=30)	all other general surgery	Sample size: 30/30 Primary endpoint: FU duration:
Ziemski, 1979	UFH 3 times daily for 2 days (n=30) vs. no treatment (n=20)	all other general surgery	Sample size: 30/20 Primary endpoint: FU duration:
Bejjani, 1983	UFH twice daily for 2 days (n=17) vs. placebo (n=17)	urologic surgery	Sample size: 17/17 Primary endpoint: FU duration:
Coe, 1978	UFH twice daily for D (n=28) vs. no treatment (n=24)	urologic surgery	Sample size: 28/24 Primary endpoint: FU duration:
Sebeseri, 1975	UFH twice daily for D (n=34) vs. no treatment (n=31)	urologic surgery	Sample size: 34/31 Primary endpoint: FU duration:
Allen, 1978	UFH twice daily for D (n=30) vs. no treatment (n=30)	urologic surgery	Sample size: 30/30 Primary endpoint: FU duration:
Hedlund, 1979	UFH 3 times daily for 5 days (n=30) vs. placebo (n=29)	urologic surgery	Sample size: 30/29 Primary endpoint: FU duration:
Kutnowski, 1977	UFH 3 times daily for 6 days (n=6) vs. placebo (n=13)	urologic surgery	Sample size: 6/13 Primary endpoint: FU duration:
Vandendris, 1980	UFH 3 times daily for 6 days (n=32) vs. placebo (n=33)	urologic surgery	Sample size: 32/33 Primary endpoint: FU duration:
Cerrato, 1978	Unfractionated heparin, 5000 IU subcutaneously 3 times a day, starting 2 hours preoperatively for +7 days (n=50) vs. no treatment (n=50)	Elective neurosurgery for tumors, 40 years or older	Sample size: 50/50 Primary endpoint: FU duration: NA

antithrombotics

UFH

versus

No demonstrated result for efficacy

meta-analysis

antithrombotics

UFH

versus aspirin

No demonstrated result for efficacy

meta-analysis

antithrombotics

UFH

versus DHE

No demonstrated result for efficacy

meta-analysis

antithrombotics

UFH

versus oral anticoagulant

No demonstrated result for efficacy

meta-analysis

antithrombotics

warfarin

versus placebo or no treatment

No demonstrated result for efficacy

meta-analysis

antithrombotics

warfarin

versus antiplatelet drugs

No demonstrated result for efficacy

meta-analysis

antithrombotics

warfarin

versus Danaparoid

No demonstrated result for efficacy

meta-analysis

antithrombotics

warfarin

versus Dextran

No demonstrated result for efficacy

meta-analysis

antithrombotics

warfarin

versus intermittent pneumatic compression

No demonstrated result for efficacy

meta-analysis

antithrombotics

warfarin

versus Low molecular weight heparin

No demonstrated result for efficacy

meta-analysis

antithrombotics

warfarin

versus unfractionated heparin

No demonstrated result for efficacy

meta-analysis

antithrombotics

ximelagatran

versus Low molecular weight heparin

No demonstrated result for efficacy

ximelagatran inferior to Enoxaparin in terms of DVT+PE in Platinum (Colwell), 2003

ximelagatran inferior to Enoxaparin in terms of serious bleeding in EXPRESS, 2003

meta-analysis

Trial	control	p<0.05	harm	NS
Phase II (Heit), 2001	ximelagatran vs Enoxaparin			serious bleeding 0.00 [0.00; NaN] DVT+PE 0.70 [0.39; 1.26]
Platinum (Colwell), 2003	ximelagatran vs Enoxaparin		DVT+PE 1.71 [1.15; 2.54]	serious bleeding 0.88 [0.32; 2.41]
METHRO I, 2002	ximelagatran vs Dalteparin			serious bleeding NaN [NaN; NaN] DVT+PE 0.83 [0.25; 2.76]
METHRO II, 2002	ximelagatran vs Dalteparin	DVT+PE 0.53 [0.38; 0.74]		serious bleeding 2.01 [0.91; 4.42]
METHRO III, 2002	ximelagatran vs Enoxaparin			serious bleeding 0.86 [0.48; 1.56] DVT+PE 1.14 [1.00; 1.29]
EXPRESS, 2003	ximelagatran 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