Methods

Multi‐centre, randomised, open‐label, dose‐finding study

Participants

Total number of participants: 243

Number of participants allocated to each group: fondaparinux (FX) 4 mg group: 86, FX 2 mg group: 78, enoxaparin (EN) 40 mg group: 79

Number of participants excluded and/or lost to follow‐up: FX 4 mg group: 4 (1 adverse event, 1 lack of efficacy, 2 other reasons), FX 2 mg group: 3 (1 adverse event, 0 lack of efficacy, 2 other reasons), EN 40 mg group: 3 (1 adverse event, 1 lack of efficacy, 1 other reasons)

Inclusion: Men and postmenopausal women aged > 40 years with body weight 50 to 100 kg inclusive who were undergoing first single non‐revision total hip replacement (subsequently amended to non‐revision total hip replacement), with no contraindication to undergo phlebography on day 8 ± 1

Exclusion: Patients were excluded from study participation on the basis of their bleeding risk at the time of randomisation (e.g. known bleeding tendency, thrombocytes < 150 × 10⁹/L, prothrombin time < 65%, APTT/control > 1.2 or other medical conditions associated with a bleeding risk), other significant conditions (e.g. history of PE or DVT, serum creatinine > 2.3 mg% (200 µmol/L), severe hepatic disease or uncontrolled severe high blood pressure (systolic blood pressure/diastolic blood pressure > 200/120 mmHg) or use of anticoagulant or fibrinolytic therapy within 1 week before randomisation.

Interventions

FX: Phase I: 4 mg FX once daily. Phase II: 2 mg FX once daily; FX was administered for 7 days from day 2 (first injection planned 6 hours after surgery) to day 8.

EN: Phase I: 40 mg EN once daily (first control group (CG). Phase II: 40 mg EN once daily (second CG). EN was administered for 8 days, from day 1 to day 8 (first injection planned 12 hours before surgery and first postoperative injection planned 6 hours after surgery).

Outcomes

Primary efficacy outcome: incidence of any DVT; DVT was assessed on day 8 ± 1 by phlebography

Primary safety outcome: major bleeding; major bleeding was defined as a clinically overt haemorrhage (except drain < 500 mL/d) in addition to 1 of the following criteria: haemoglobin (Hb) reduction to < 8 g/dL or Hb decrease > 2 g/dL over any 48‐hour period between day 3 and day 9 inclusive, or reoperation or intracranial bleeding or retroperitoneal or withdrawal

Notes

Use of adjunctive prophylaxis methods: No adjunctive method was used in this study.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Multicentre, randomised, open‐label, dose finding study"

Comment: probably done, as earlier reports from the same company clearly describe use of random sequences

Allocation concealment (selection bias)

Low risk

Quote: "Multicentre, randomised, open‐label, dose finding study"

Comment: probably done, as most earlier multi‐centre RCT reports clearly mention that studies of the same medicine organised by the same company were centrally randomised

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Without clear description

Comment: unclear

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "A central evaluation was performed blindly by two independent experts"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

95.3%, 96.2%, 96.2% of participants in the 3 study groups finished treatment.

Comment: low risk of bias

Selective reporting (reporting bias)

Low risk

All primary efficacy and safety outcomes listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Unclear risk

Company sponsored

Methods

Multi‐centre, randomised, double‐blind, parallel‐group trial

Participants

Total number of participants: 1309

Number of participants allocated to each group: fondaparinux (FX) group: 650, placebo group: 659

Number of participants excluded and/or lost to follow‐up: FX group: 57 (23 adverse events, 1 lack of efficacy, 33 other reasons), placebo group: 58 (17 adverse events, 2 lack of efficacy, 39 other reasons)

Inclusion: Patients were eligible if they were undergoing abdominal surgery (defined as surgery between the diaphragm and the pelvic floor), lasting longer than 45 minutes (from anaesthesia induction to incision closure); over 40 years old
Exclusion: Exclusion criteria were based on the labelling of LMWH in force at the time study was conducted (e.g. active clinically significant bleeding, presence or history of low platelet count (< 100 x 10⁹/L), medical condition associated with a bleeding risk), criteria related to contrast dyes during venography (e.g. serum creatinine > 2 mg/dL (180 μmol/L) or hypersensitivity to contrast media) or criteria related to trial methods (e.g. current or recent DVT, contraindication to heparin or oral anticoagulant, use of anticoagulant or fibrinolytic therapy during screening period).

Interventions

FX: 2.5 mg FX sodium given sc starting 6 to 8 hours postoperatively, then once daily for 7 ± 2 days (day 1 was the day of surgery) or until the mandatory venography was obtained, whichever came first. Mandatory venography had to be performed between day 5 and day 10, but not more than 1 calendar day after the last study treatment administration. All participants were to receive IPC therapy concomitantly.

Placebo: Placebo was given sc starting 6 to 8 hours postoperatively, then once daily for 7 ± 2 days (day 1 was the day of surgery) or until mandatory venography was performed, whichever came first. Mandatory venography had to be performed between day 5 and day 10, but not more than 1 calendar day after the last study treatment administration. All participants were to receive IPC therapy concomitantly.

Outcomes

Primary efficacy outcome: cluster of 1 or more of the following VTE outcomes, evaluated (by an independent adjudicating committee) up to the first venography or up to day 10, whichever came first: venogram positive for DVT between day 5 and day 10, symptomatic DVT and/or non‐fatal PE, fatal PE

Primary safety outcome: incidence of major bleeding (any investigator‐reported unusual bleeding) recorded during treatment period (between first injection of study drug and 2 calendar days after last injection) and adjudicated as a major bleeding event by the Central Adjudication Committee (CAC). Major bleeding was defined as: fatal bleeding, surgical bleeding leading to intervention; non‐surgical site bleeding: retroperitoneal or intracranial bleeding, or bleeding into a critical organ (eye, adrenal gland, pericardium, spine) or leading to intervention, and/or a bleeding index ≥ 2.

Notes

Use of adjunctive prophylaxis methods: Both groups received background mechanical prophylaxis with IPC.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Multicenter, randomised, double‐blind, placebo‐controlled, parallel‐group study"

Comment: probably done, as earlier reports from the same company clearly describe use of random sequences

Allocation concealment (selection bias)

Low risk

Quote: "Multicenter, randomised, double‐blind, placebo‐controlled, parallel‐group study"

Comment: probably done, as earlier reports from the same company clearly describe use of random sequences

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Multicenter, randomised, double‐blind, placebo‐controlled, parallel‐group study……2.5 mg FX sodium (or FX placebo) given subcutaneously (s.c.)"

Comment: probably done

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "evaluated (by an independent adjudicating committee)"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Less than 10% (9% and 8.9% of the 2 study groups) of participants withdrawn

Comment: low risk of bias

Selective reporting (reporting bias)

Low risk

All primary efficacy and safety outcomes listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Unclear risk

Company sponsored

Methods

Multi‐centre, randomised, open‐label study

Participants

Total number of participants: 127

Number of participants allocated to each group: fondaparinux (FX) group: 83, intermittent pneumatic compression (IPC) group: 44

Number of participants excluded and/or lost to follow‐up: FX group: 7 (2 adverse events, 0 lack of efficacy, 5 other reasons), IPC group: 1 (0 adverse events, 0 lack of efficacy, 1 other reasons)

Inclusion: patients aged 40 years undergoing the following abdominal (area between diaphragm and pelvic floor) surgery under general anaesthesia lasting longer than 45 minutes: general or urological surgery, cancer surgery, gynaecological surgery, radical surgery for pelvic malignancy

Exlcusion: Patients were excluded if any of the exclusion criteria based on contraindications and precautions for use of anticoagulants currently approved in Japan (e.g. active, clinically significant bleeding, bleeding tendency) or exclusion criteria related to venography (e.g. severe renal disorder, hypersensitivity to contrast media) were applied, or if any of the prohibited medications were used within 1 week before first study drug administration, or use of IPC was contraindicated or inappropriate.

Interventions

FX: 2.5 mg FX was administered once daily by sc injection for 4 to 8 days. First injection of study drug was given 24 ± 2 hours after surgical closure. Second and subsequent injections of study drug were given at approximately the same time every day as far as possible (but longer than 12 hours after the first dose). IPC was prohibited during surgical and treatment periods.

IPC: IPC was initiated before or after surgery and was continued until an appropriate time point. Procedures and methods usually employed at each individual study centre were followed as a rule.

Outcomes

Primary efficacy outcome: rate of VTE (symptomatic PE and any DVT) during main efficacy period

Primary safety outcomes: major bleeding

Major bleeding defined as:

• Clinically unusual bleeding meeting any of the following criteria:

  • Fatal bleeding

  • Bleeding including retroperitoneal and intracranial bleeding, or bleeding into a critical organ (eye, adrenal gland, pericardium, spine)

  • Reoperation due to bleeding/haematoma at the operative site

  • Bleeding leading to Hb fall of 2 g/dL (1.6 mmol/L) within 48 hours of the bleed

  • Bleeding that required a transfusion of red blood cells or whole blood derived from 900 mL of whole blood within 48 hours of the bleed (excluding the autologous transfusion except for treatment of a bleeding adverse event (AE)

  • Bleeding leading to the bleeding index (BI)

BI calculated as "number of units* transfused" within 48 hours of the bleed + prebleed Hb (g/dL) – postbleed Hb within 48 hours of the bleed (g/dL)

* 450 mL of whole blood or red blood cells derived from 450 mL of whole blood is considered as 1 unit.

Notes

Use of adjunctive prophylaxis methods: No adjunctive prophylaxis method was used in this study.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "A multicenter, randomised, open‐label study"

Comment: probably done, as earlier reports from the same company clearly describe use of random sequences

Allocation concealment (selection bias)

Low risk

Quote: "A multicenter, randomised, open‐label study"

Comment: probably done, as most earlier multi‐centre RCT reports clearly mention that studies of the same medicine organised by the same company were centrally randomised

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Without clear description

Comment: unclear

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Rate of VTE (symptomatic PE and any DVT) during main efficacy period, adjudicated by Central Independent Adjudication Committee of Efficacy (CIACE)"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

85.5% and 93.2% of randomised participants in the 2 study groups respectively finished their treatment.

Comment: low risk of bias; most participants finished the study

Selective reporting (reporting bias)

Low risk

All primary efficacy and safety outcomes listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Unclear risk

Company sponsored

Methods

Multi‐centre, multi‐national, randomised, double‐blind, placebo‐controlled study

Participants

Total number of participants: 849

Number of participants allocated to each group: fondaparinux group: 429; placebo group: 420

Number of participants excluded and/or lost to follow up: fondaparinux group: 4; placebo group: 6

Inclusion: Participants were acutely ill medical patients, aged ≥ 60 years and expected to require bed rest for at least 4 days at the moment of inclusion; hospitalised for congestive heart failure New York Heart Association (NYHA) class III/IV, and/or acute respiratory illness in the presence of chronic lung disease, and/or acute infectious or inflammatory disease

Exclusion: Patients were excluded from study participation on the basis of their bleeding risk at the time of randomisation (e.g. active clinically significant bleeding or medical conditions associated with a bleeding risk) criteria related to contrast dyes during venography (e.g. serum creatinine > 2 mg/dL (180 µmol/L) or hypersensitivity to contrast media) or use of anticoagulant or fibrinolytic therapy within 48 hours before randomisation.

Interventions

Fondaparinux (FX): Administration of 2.5 mg FX (2.5 mg once daily as sc injection) started 2 hours after randomisation. Study treatment was to be given at least up to and including day 6 but not after day 14. Venography had to be performed within 1 day after cessation of treatment on days 6 to 15, or earlier in case of symptomatic VTE.

Placebo: Placebo was started 2 hours after randomisation. Study treatment was to be given at least up to and including day 6 but not after day 14. Venography had to be performed within 1 day after cessation of treatment on days 6 to 15, or earlier in case of symptomatic VTE.

Outcomes

Primary efficacy outcome: composite of the following VTE events recorded up to day 15 or up to the first venography, whichever came first: venogram positive for DVT, symptomatic DVT, non‐fatal PE or fatal PE. Venography and all other available diagnostic tests (ultrasonography, ventilation/perfusion lung scan, pulmonary angiography or spiral computed tomography scan, autopsy report, etc) were blindly adjudicated by experts of the Central Independent Adjudication Committee (CIAC).

Primary safety outcome: major bleeding during treatment and 2 days thereafter, defined as fatal bleeding, bleeding in a critical location, bleeding leading to surgical intervention or overt bleeding associated with a drop in haemoglobin (Hb) concentration ≥ 20 g/L or leading to transfusion of 2 or more units of red blood cells

Efficacy and safety outcomes were adjudicated by a central independent committee (CIAC), whose members were unaware of the treatment assignment. Accumulated safety data were regularly reviewed by an independent committee.

Notes

Use of adjunctive prophylaxis methods: Use of aspirin or non‐steroidal anti‐inflammatory drugs
was discouraged. Graduated compression stockings and physiotherapy were allowed.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomisation was carried out using a predefined central randomisation list, balanced in blocks of four"

Comment: probably done

Allocation concealment (selection bias)

Low risk

Multi‐centre, multi‐national, randomised, double‐blind, placebo‐controlled study

Comment: probably done

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Study drugs were provided in identical boxes"

Comment: probably done

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "All venograms ……were blindly adjudicated by experts of the Central Independent Adjudication Committee (CIAC)"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

89.4% and 88.7% of randomised participants in the 2 study groups, respectively, finished their treatment

Comment: low risk of bias; most participants finished the study

Selective reporting (reporting bias)

Low risk

All primary efficacy and safety outcomes listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Unclear risk

Company sponsored

Methods

Prospective, randomised, 3‐arm study

Participants

Total number of participants: 355

Number of participants allocated to each group: variable‐dose warfarin group: 118, fondaparinux group: 118, 1 mg daily warfarin group: 119

Number of participants excluded and/or lost to follow‐up: 2 in variable‐dose warfarin group did not receive allocated intervention, 1 was not analysed; 10 in fondaparinux group did not receive allocated intervention, 6 were not analysed; 7 in 1 mg daily warfarin group did not receive allocated intervention, 6 were not analysed

Inclusion criteria: Participants were recruited from among patients over 20 years of age planning elective primary unilateral total hip or knee replacement surgery at an orthopaedic specialty hospital.

Exclusion criteria

• Abnormal platelet count, prothrombin time (PT) or partial thromboplastin time (PTT)

• Surgery for acute fracture (< 4 weeks), septic joint or extraction arthroplasty

• History of VTE or documented hypercoagulation syndrome

• Increased risk of haemorrhage, as from active gastric ulcer or urinary tract bleed within the past year

• Haemorrhagic stroke; brain, spinal or ophthalmologic surgery in previous 6 months

• Liver enzymes or bilirubin greater than 2 x normal

• Decreased renal function with GFR < 30 mL/min

• Cancer in past year, other than localised cancers of the skin

• Need for chronic anticoagulation

• Need for long‐term platelet function suppressive therapy

• Prior adverse reaction to any of the study drugs

• Uncontrolled hypertension

• BMI > 42

• Pregnancy

Interventions

ARM A
Variable‐dose warfarin: 5.0 mg beginning the night before surgery, followed by 5.0 mg the night of surgery, then variable daily dose (target INR 2.0 to 2.5) until day 28 ± 2 of follow‐up
ARM B
Fondaparinux: 2.5 mg daily starting 6 or more hours after surgery, but no later than 6 AM the next day, or 6 to 8 hours after epidural catheter removal; continued until day 28 ± 2 of follow‐up
ARM C

Fixed low‐dose warfarin 1.0 mg daily, beginning 7 days preoperatively, and continued at 1.0 mg daily until day 28 ± 2 of follow‐up

Outcomes

Primary endpoint was composite DVT, PE or death due to VTE. Secondary endpoints included frequency of proximal vs distal DVT, estimated blood loss (EBL) at surgery and haemorrhagic complications.

Notes

Use of adjunctive anticoagulative methods: Patients had early postoperative ambulation. All patients wore pneumatic compression stockings while in‐patients. Elastic compression stockings were prescribed to be used after discharge until follow‐up ultrasonography. Hydroxyethyl starch (HES) 6% was allowed intraoperatively for case‐specific reasons. Use of platelet function suppressive drugs, such as non‐steroidal anti‐inflammatory drugs (NSAIDs), was discouraged but was not prohibited by the protocol.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "A member of the pharmacy department pulled randomized cards as prepared by the statisticians"

Comment: probably done

Allocation concealment (selection bias)

Low risk

Quote: "A member of the pharmacy department pulled randomized cards as prepared by the statisticians"

Comment: probably done

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not mentioned

Comment: probably not done

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Radiology technicians and the radiologists were blinded to patient randomization"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

99.1%, 94.9% and 94.9% of participants in 3 groups completed the study.

Comment: probably done

Selective reporting (reporting bias)

Low risk

All endpoints listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Low risk

No risk of other bias identified

Methods

Multi‐centre, randomised, double‐blind, placebo‐controlled, 2‐parallel‐group study

Participants

Total number of participants: 3002

Number of participants allocated to each group: fondaparinux (FX) group: 1502, placebo group: 1500

Number of participants excluded and/or lost to follow‐up: FX group: 21 (2 adverse events, 0 lack of efficacy, 19 other reasons), placebo group: 33 (1 adverse event, 0 lack of efficacy, 32 other reasons)

Inclusion: Hospitalised and non‐hospitalised male and female patients 18 years of age or older with acute symptomatic isolated superficial venous thrombosis (SVT) of the lower limbs at least 5 cm long, documented by standard compression ultrasonography (CUS) were eligible to enter the study.

Exclusion: Patients at high risk of VTE were excluded (e.g. those with DVT on the qualifying ultrasound exam and/or documented PE at inclusion, with SVT within 3 cm from the sapheno‐femoral junction (SFJ) requiring ligation of the SFJ or thrombectomy, with active cancer, or with documented DVT or PE within the previous 6 months).

Interventions

FX: 2.5 mg FX sc once daily (self‐administered or not self‐administered). Treatment was presented as prefilled (0.5 mL) syringes. Duration of treatment was 45 days with 30‐day follow‐up.

Placebo: matching placebo administered sc once daily (self‐administered or not self‐administered). Treatment was presented as prefilled (0.5 mL) syringes. Duration of treatment was 45 days with 30‐day follow‐up.

Outcomes

Primary efficacy outcome: incidence of VTE and/or death from any cause recorded up to day 47. VTE was defined as a composite of symptomatic DVT, symptomatic PE, symptomatic extension of SVT or symptomatic recurrence of SVT. All VTEs were confirmed by objective tests and were then adjudicated by an independent central adjudication committee (CAC), whose members were blinded to treatment assignment.

Primary safety outcome: major bleeding

Notes

Use of adjunctive methods: Participants were encouraged to use graduated compression stockings and were allowed to take acetaminophen or topical non‐steroidal anti‐inflammatory drugs as needed. Use of oral antiplatelet agents or aspirin at a low dose (≤ 325 mg per day) was discouraged. In total, 1131 participants in FX group used graduated stockings, and 347 participants used antiplatelet agents of all 1502 participants; 1147 participants in placebo group used graduated stockings, and 364 used antiplatelet agents of all 1500 participants, as adjunctive anticoagulative methods

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "With the use of a central telephone system and a computer‐generated randomisation list"

Comment: probably done

Allocation concealment (selection bias)

Low risk

Quote: "With the use of a central telephone system and a computer‐generated randomisation list"

Comment: probably done

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "to fondaparinux at a dose of 2.5 mg or matching placebo"

Comment: probably done

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "adjudicated by an independent central adjudication committee (CAC)"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

1481 (98.6%) and 1467 (97.8%) participants in the 2 study groups finished the study.

Comment: low risk of bias

Selective reporting (reporting bias)

Low risk

All primary efficacy and safety outcomes listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Unclear risk

Company sponsored

Methods

Double‐blind, prospective, randomised, controlled trial

Participants

Total number of participants: 148

Number of participants allocated to each group: fondaparinux group: 74, placebo group: 74

Number of participants excluded and/or lost to follow‐up: FX group: 0, placebo group: 0

Inclusion: All adult patients with a diagnosis of primary osteoarthritis of the knee and undergoing elective unilateral primary TKA were considered for inclusion in the study.

Exclusion: patients undergoing bilateral knee replacements; patients with diagnosed chronic or acute DVT preoperatively; patients with active bleeding or documented congenital or acquired bleeding disorders such as haemophilia, current ulcerative or angiodysplastic gastrointestinal disease; hemorrhagic stroke or brain, spinal or ophthalmologic surgery within the previous 3 months. Additional exclusion criteria were contraindication to anticoagulant therapy, serum creatinine concentration > 2 mg/dL in a well‐hydrated patient and platelet count < 100,000 per cubic millimetre.

Interventions

FX: subcutaneous doses of 2.5 mg of fondaparinux (Arixtra; GlaxoSmith‐Kline, UK) once daily

Placebo: 0.25 mL of isotonic saline once daily

The first postoperative injection was administered 6 to 8 hours after surgery, and the second injection was given 24 hours after the first. The day of surgery was defined as day 1. Treatment was scheduled to continue with a daily single dose until day 5.

Outcomes

Primary efficacy outcome: prevalence of DVT ‐ total, proximal and distal ‐ and symptomatic PE up to day 7

Primary safety outcome: incidence of major bleeding. Major bleeding included clinically overt bleeding requiring transfusion of ≥ 2 units of blood products (considering 450 mL of reinfused shed blood as 1 U), bleeding with a serious or life‐threatening clinical event or requiring surgical intervention, bleeding in retroperitoneal, intracranial or intraocular locations or bleeding resulting in death.

Notes

Use of adjunctive anticoagulative methods: Graduated compression stockings were applied in all participants. All were managed by the same rehabilitation protocol, which included range of motion, quadriceps, hamstring and
calf pump exercises and straight leg raising on postoperative day 1, and bedside continuous passive mobilization on day 2. Participants were made to stand on day 1 and were allowed partial weight bearing on the operated leg from day 2.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quotes: "a double‐blind, prospective randomised controlled trial" and "Eligible patients were randomly assigned prior to the surgery through a computer‐derived randomisation table with block sizes of four to receive……"

Comment: probably done

Allocation concealment (selection bias)

Low risk

Quote: "The randomisation schedule was known to the research pharmacist who prepared the study medication but was not involved in any way with the care of the patients. The patients, surgeon, health care providers, and outcome assessors were blinded to the randomisation till the end of the study"

Comment: probably done

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The patients, surgeon, health care providers, and outcome assessors were blinded to the randomisation till the end of the study"

Comment: probably done

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "The radiologist was blinded to the treatment assignment"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants in the 2 groups finished treatment, and primary efficacy and safety results were assessed.

Selective reporting (reporting bias)

Low risk

All results planned in the study design section were assessed.

Other bias

Low risk

No risk of other bias was identified.

Methods

Multi‐centre, randomised, double‐blind, placebo‐controlled, parallel‐group, dose‐response study

Participants

Total number of participants: 411

Number of participants allocated to each group: fondaparinux (FX) 0.75 mg group: 82, FX 1.5 mg group: 82, FX 2.5 mg group: 82, FX 3.0 mg group: 83, placebo group: 82

Number of participants excluded and/or lost to follow‐up: FX 0.75 mg group: 8 (6 adverse events, 0 lack of efficacy, 2 other reasons), FX 1.5 mg group: 6 (5 adverse events, 0 lack of efficacy, 1 other reasons), FX 2.5 mg group: 3 (3 adverse events, 0 lack of efficacy, 0 other reasons), FX 3.0 mg group: 5 (5 adverse events, 0 lack of efficacy, 0 other reasons), placebo group: 3 (2 adverse event, 0 lack of efficacy, 1 other reasons)

Inclusion: Patients undergoing primary elective THR surgery or revision of a THR; ≥ 20 years of age

Exclusion: Exclusion criteria were based on the Japanese labelling for anticoagulants in force at the time study was conducted (e.g. active, clinically significant bleeding; documented congenital or acquired bleeding tendency/disorders, other medical condition associated with a bleeding risk), or criteria related to use of contrast dyes during venography (e.g. serum creatinine > 2 mg/dL (180 μmol/L) or hypersensitivity to contrast media) or use of anticoagulant or fibrinolytic therapy within 1 week before first dose of study medication.

Interventions

FX: once daily sc dosing of FX 0.75, 1.5, 2.5 or 3.0 mg for at least 10 calendar days (maximum 14 days) from day 2 to day 11 or 15. The first dose of study drug was administered 24 ± 2 hours after surgical closure (day 1 was the day of surgery). Mandatory venography had to be performed between day 11 and day 17 but not later than 2 calendar days after the last study drug administration

Placebo: once daily sc placebo for at least 10 calendar days (maximum 14 days) from day 2 to day 11 or 15. First dose of study drug was administered 24 ± 2 hours after surgical closure (day 1 was the day of surgery). Mandatory venography had to be performed between day 11 and day 17 but not later than 2 calendar days after the last study drug administration.

Outcomes

Primary efficacy outcome: cluster of the following VTE outcomes recorded up to day 17 or to first venography, whichever occurred first: adjudicated mandatory venogram positive for DVT between day 11 and day 17; adjudicated symptomatic DVT; adjudicated positive fatal or non‐fatal PE. All venography sessions, scheduled or unscheduled, and other available diagnostic tests (ultrasonography, ventilation/perfusion lung scan, pulmonary angiography or spiral computed tomography scan, autopsy report, etc.) were adjudicated blindly by independent experts of the Central Independent Adjudication Committee of Efficacy (CIACE).

Primary safety outcome: incidence of major bleeding (any investigator‐reported bleeding adjudicated as a major bleeding event by the Central Independent Adjudication Committee of Safety (CIACS)) recorded during \treatment period (i.e. from first injection of study drug to 2 days after last dose). Major bleeding was defined as fatal bleeding, or clinically overt bleeding including retroperitoneal or intracranial bleeding or bleeding into a critical organ (eye, adrenal gland, pericardium, spine); reoperation due to bleeding/hematoma at the operative site; clinically overt bleeding leading to Hb fall > 2 g/dL (1.6 mmol/L) within 48 hours of the bleed; clinically overt bleeding that required a transfusion of red blood cell or whole blood derived from > 900 mL of whole blood within 48 hours of the bleed (excluding autologous transfusion except for treatment of bleeding adverse event (AE)); clinically overt bleeding leading to bleeding index > 2 (within 48 hours of the bleed, calculated as "number of units transfused" + prebleed Hb (g/dL) – postbleed Hb (g/dL)

Notes

Use of adjunctive anticoagulative methods: no mention of use of any adjunctive anticoagulative method

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Multicentre, randomised, double‐blind, placebo controlled, parallel group, dose response study"

Comment: probably done, as earlier reports from the same company clearly describe use of random sequences

Allocation concealment (selection bias)

Low risk

Quote: "Multicentre, randomised, double‐blind, placebo controlled, parallel group, dose response study"

Comment: probably done, as most earlier multi‐centre RCT reports clearly mentioned that studies of the same medicine organised by the same company were centrally randomised

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Without clear description

Comment: unclear

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "were adjudicated blindly by independent experts of the Central Independent Adjudication Committee of Efficacy (CIACE)"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

56 of 71 randomised participants, 62 of 82 randomised participants, 63 of 82 randomised participants, 67 of 82 randomised participants, 68 of 83 randomised participants in the 5 study groups, respectively, finished their treatment and were involved in the efficacy analysis.

Comment: low risk of bias; most participants finished the study

Selective reporting (reporting bias)

Low risk

All primary efficacy and safety outcomes listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Unclear risk

Company sponsored

Methods

Multi‐centre, randomised, double‐blind, placebo‐controlled, parallel‐group, dose‐response study

Participants

Total number of participants: 432

Number of participants allocated to each group: fondaparinux (FX) 0.75 mg group: 86, FX 1.5 mg group: 87, FX 2.5 mg group: 86, FX 3.0 mg group: 86, placebo group: 87

Number of participants excluded and/or lost to follow‐up: FX 0.75 mg group: 4 (4 adverse events, 0 lack of efficacy, 0 withdrawn consent, 0 other reasons), FX 1.5 mg group: 7 (3 adverse events, 0 lack of efficacy, 4 withdrawn consents, 0 other reasons), FX 2.5 mg group: 6 (2 adverse events, 0 lack of efficacy, 4 withdrawn consents, 0 other reasons), FX 3.0 mg group: 5 (4 adverse events, 0 lack of efficacy, 0 withdrawn consent, 1 other reasons), placebo group: 7 (4 adverse events, 0 lack of efficacy, 1 withdrawn consent, 2 other reasons)

Inclusion: patients who were undergoing elective primary TKR surgery or revision surgery of a TKR; ≥ 20 years of age

Exclusion: Exclusion criteria were based on the Japanese labelling for anticoagulants in force at the time study was conducted (e.g. active, clinically significant bleeding; documented congenital or acquired bleeding tendency/disorders or other medical conditions associated with a bleeding risk), criteria related to use of contrast dyes during venography (e.g. serum creatinine > 2 mg/dL (180 μmol/L) or hypersensitivity to contrast media) or use of anticoagulant or fibrinolytic therapy within 1 week before first dose of study medication.

Interventions

FX: once daily sc dosing of FX 0.75, 1.5, 2.5 or 3.0 mg for at least 10 calendar days (maximum 14 days) from day 2 to day 11 or 15. First dose of study drug was administered 24 ± 2 hours after surgical closure (day 1 was the day of surgery). Mandatory venography had to be performed between day 11 and day 17 but not later than 2 calendar days after the last study drug administration.

Placebo: once daily sc placebo for at least 10 calendar days (maximum 14 days) from day 2 to day 11 or 15. First dose of study drug was administered 24 ± 2 hours after surgical closure (day 1 was the day of surgery). Mandatory venography had to be performed between day 11 and day 17 but no later than 2 calendar days after last study drug administration.

Outcomes

Primary efficacy outcome: cluster of the following VTE outcomes recorded up to day 17 or to first venography, whichever occurred first: adjudicated mandatory venogram positive for DVT between day 11 and day 17; adjudicated symptomatic DVT; adjudicated positive fatal or non‐fatal PE. All venography procedures, scheduled or unscheduled, and other available diagnostic tests (ultrasonography, ventilation/perfusion lung scan, pulmonary angiography or spiral computed tomography scan, autopsy report, etc.) were adjudicated blindly by independent experts of the Central Independent Adjudication Committee of Efficacy (CIACE).

Primary safety outcome: incidence of major bleeding (any investigator‐reported bleeding adjudicated as a major bleeding event by the Central Independent Adjudication Committee of Safety (CIACS)). This was recorded during treatment period (i.e. from first injection of study drug to 2 days after the last dose). Major bleeding was defined as fatal bleeding, clinically overt bleeding including retroperitoneal or intracranial bleeding or bleeding into a critical organ (eye, adrenal gland, pericardium, spine); reoperation due to bleeding/haematoma at the operative site; clinically overt bleeding leading to Hb fall > 2 g/dL (1.6 mmol/L) within 48 hours of the bleed; clinically overt bleeding that required a transfusion of red blood cell or whole blood derived from > 900 mL of whole blood within 48 hours of the bleed (excluding autologous transfusion, except for treatment of bleeding adverse event (AE)); clinically overt bleeding leading to bleeding index > 2 (within 48 hours of the bleed, calculated as "number of units* transfused" + prebleed Hb (g/dL) – postbleed Hb (g/dL)). Other safety variables were minor bleeding (defined as clinically overt bleeding not meeting the criteria for major bleeding and considered more than expected in the clinical context), transfusion requirements, AEs/serious AEs (SAEs) and deaths.
*450 mL of whole blood or red blood cell derived from 450 mL of whole blood is considered as 1 unit.

Notes

Use of adjunctive anticoagulative methods: no mention of use of any adjunctive anticoagulative method

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Multicentre, randomised, double‐blind, PBO controlled, parallel group, dose response study"

Comment: probably done, as earlier reports from the same company clearly describe use of random sequences

Allocation concealment (selection bias)

Low risk

Quote: "Multicentre, randomised, double‐blind, PBO controlled, parallel group, dose response study"

Comment: probably done, as most earlier multi‐centre RCT reports clearly mentioned that studies of the same medicine organised by the same company were centrally randomised

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Without clear description

Comment: unclear

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "A central, independent adjudication committee reviewed both safety and efficacy outcomes"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

74 of 85 randomised participants, 74 of 85 randomised participants, 74 of 85 randomised participants, 74 of 85 randomised participants and 74 of 85 randomised participants in the 5 study groups, respectively, finished treatment and were involved in the efficacy analysis.

Comment: low risk of bias; most participants finished the study

Selective reporting (reporting bias)

Low risk

All primary efficacy and safety outcomes listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Unclear risk

Company sponsored

Methods

Randomised, double‐blind, pilot trial

Participants

Total number of participants: 198

Number of participants allocated to each group: fondaparinux group: 100, enoxaparin group: 98

Number of participants excluded and/or lost to follow‐up: Of the 198 randomised participants, 7 in the fondaparinux group and 7 in the enoxaparin group did not receive treatment according to protocol, but all randomised participants were analysed.

Inclusion: Patients were eligible for the study if they were 18 years of age or older with a body mass index (BMI) of 35 to 59 kg/m², and were undergoing laparoscopic vertical sleeve gastrectomy (VSG) or laparoscopic Roux‐en Y gastric bypass (LRYGB)

Exclusion: Patients with BMI > 60 were excluded, as they may have required extended DVT prophylaxis. Patients with contraindications to low molecular weight heparin or selective antithrombin III agonists, previous history of DVT or PE, documented clotting/coagulation disorders, history of treatment for cancer within the past year, history of venous stasis or superficial thrombophlebitis, vein stripping or ligation, obesity hypoventilation syndrome or recent history of smoking (within the past year) were excluded. Patients with severe hepatic impairment, creatinine clearance < 30 mL per minute or platelet count < 100,000 per cubic millimetre were also excluded, as were women of childbearing age if they were pregnant or were taking oestrogen‐based birth control medication within 1 month of surgery

Interventions

FX: The fondaparinux group received a placebo on call to the operating room. Six hours after surgery stop time, participants were given 5 mg fondaparinux subcutaneously. Beginning on postoperative day 1, participants received 5 mg of fondaparinux subcutaneously once daily in the morning and placebo (saline) injections subcutaneously once daily in the evening for the duration of their hospital stay.

Enoxaparin: In accordance with current practice, the enoxaparin group received a dose of enoxaparin 40 mg subcutaneously on call to the operating room. To maintain blinding, participants randomised to enoxaparin received placebo (saline) injection 6 hours after surgery stop time. Beginning on postoperative day 1, 40 mg of enoxaparin was administered subcutaneously twice daily for the duration of the participant's hospital stay.

Outcomes

Primary outcome was the effect of preoperative enoxaparin vs postoperative fondaparinux prophylaxis on antifactor Xa concentrations in participants undergoing bariatric surgery. Attainment of a target antifactor Xa level was determined on the basis of blood samples drawn 3 hours after the drug was received on postoperative day 1. This cutoff was the standard for adequate prophylaxis used by our in‐patient haematology lab (Z 0.20 IU/mL for enoxaparin and Z 0.39 mg/L for fondaparinux).

Secondary outcomes were asymptomatic DVT, defined as a positive MRV within 2 weeks after surgery, and symptomatic DVT. Safety outcomes included perioperative bleeding, perioperative complications and death.

Notes

Use of adjunctive anticoagulative methods: All participants had sequential compression devices and antiembolic stockings placed before induction of anaesthesia; 4 to 6 hours after surgery stop time, participants were ambulated in the hallways. Sequential compression devices were removed during ambulation. Use of aspirin, non‐steroidal anti‐inflammatory drugs and other antiplatelet agents was prohibited during participants' hospital stay.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "using a computer‐generated randomization scheme (Microsoft Excel 2007 data analysis tool pack)"

Comment: probably done

Allocation concealment (selection bias)

Low risk

Quote: "Allocation was performed by the pharmacy and was concealed from patients and study personnel"

Comment: probably done

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "placebo doses were prepared to maintain the blind. Active and placebo syringes were prepared by our inpatient pharmacy and were not identifiable by external appearance"

Comment: probably done

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "asymptomatic DVT, defined as a positive MRV within 2 weeks following surgery, and symptomatic DVT"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

83 of 98 in the enoxaparin group, 94 of 100 in the fondaparinux group had MRV results.

Comment: low risk of bias; most participants finished the study

Selective reporting (reporting bias)

Low risk

All primary efficacy and safety outcomes listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Unclear risk

Company provided study material and additional financial support but was not involved in the design and procedure of the study.

Methods

Multi‐national, multi‐centre, randomised, double‐blind, double‐dummy, parallel‐group study

Participants

Total number of participants: 2309

Number of participants allocated to each group: fondaparinux (FX) group: 1155, enoxaparin (EN) group: 1154

Number of participants excluded and/or lost to follow‐up: FX group: 70 (18 adverse events, 7 lack of efficacy, 45 other reasons), EN group: 58 (15 adverse events, 5 lack of efficacy, 38 other reasons)

Inclusion: Patients were eligible if they were undergoing an elective, primary THR surgery or a revision of at least 1 component of a THR; ≥ 18 years of age; men and women of non‐childbearing potential or of childbearing potential and having a negative pregnancy test within 48 hours before surgery or first study drug administration, whichever came first; written informed consent

Exclusion: Exclusion criteria were based on the labelling of LMWH in force at the time of study conduct (e.g. active clinically significant bleeding, presence or history of low platelet count (< 100 x 10⁹/L), medical condition associated with a bleeding risk), criteria related to contrast dyes during venography (e.g. serum creatinine > 2 mg/dL (180 µmol/L) or hypersensitivity to contrast media) or use of anticoagulant or fibrinolytic therapy within 2 days before first dose of study medication.

Interventions

FX: administration of FX (2.5 mg once daily sc injection) started postoperatively at 6 ± 2 hours after surgery closure

EN: administration of EN (40 mg once daily as sc injection) started preoperatively at 12 ± 2 hours before the start of surgery, then postoperatively at least 12 hours after the preoperative dose but not longer than 24 hours after surgery

Placebo: Respective placebo to each drug was administered to protect the double‐blind (double‐dummy method).

Study treatment was given up to day 7 ± 2 (day 1 was the day of surgery) or until mandatory venography was performed, whichever came first. Mandatory venography had to be performed between day 5 and day 11, but not more than 2 calendar days after last study treatment administration.

Outcomes

Primary efficacy outcome: cluster of the following VTE outcome results recorded up to day 11: adjudicated venogram positive for DVT or adjudicated symptomatic/asymptomatic DVT; adjudicated PE. All venography procedures, scheduled or unscheduled, and other available diagnostic tests (ultrasonography, ventilation/perfusion lung scan, pulmonary angiography or spiral computed tomography scan, autopsy report, etc) were adjudicated blindly by independent experts of the Central Independent Adjudication Committee (CIAC).

Primary safety endpoint: incidence of major bleeding (any investigator‐reported unusual bleeding adjudicated as a major bleeding event by the CIAC) recorded between first injection of study drug (active drug or placebo) and day 11. Major bleeding was defined as fatal bleeding; clinically overt bleeding including retroperitoneal or intracranial bleeding, or bleeding into a critical organ (eye, spine, pericardium, adrenal gland); reoperation due to bleeding/haematoma at the operative site; clinically overt bleeding leading to a fall in Hb ≥ 2 g/dL (1.6 mmol/L) and/or transfusion of ≥ 2 units of packed red blood cells or whole blood AND for which the combined calculated index was ≥ 2. Other safety variables were minor bleeding (defined as clinically overt bleeding not meeting the criteria for major bleeding and considered more than expected in the clinical context), transfusion requirements, adverse events (AEs)/serious AEs (SAEs), deaths and changes in laboratory parameters recorded between first injection of study drug and day 11. In addition, all safety parameters were recorded between first injection and day 49.

Notes

Use of adjunctive anticoagulative methods: In FX group, 29 participants received prohibited treatment (intermittent pneumatic compression, dextran, thrombolytic treatment and any other anticoagulant agents), 483 received discouraged treatment (aspirin or non‐steroidal anti‐inflammatory drugs) and 649 wore graduated compression stockings; in EN group, 30 participants received prohibited treatment (intermittent pneumatic compression, dextran, thrombolytic treatment and any other anticoagulant agents), 493 received discouraged treatment (aspirin or non‐steroidal anti‐inflammatory drugs) and 654 wore graduated compression stockings.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Multinational, multicenter, randomised, double‐blind, double‐dummy, parallel‐group study"

Comment: probably done, as earlier reports from the same company clearly described use of random sequences

Allocation concealment (selection bias)

Low risk

Quote: "Multinational, multicenter, randomised, double‐blind, double‐dummy, parallel‐group study"

Comment: probably done, as most earlier multi‐centre RCT reports clearly mentioned that studies of the same medicine organised by the same company were centrally randomised

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Respective placebo to each drug was administered to protect the double‐blind (double‐dummy method)"

Comment: probably done

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "were adjudicated blindly by independent experts of the Central Independent Adjudication Committee (CIAC)"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

93.9% and 94.9% of participants in the 2 study groups, respectively, finished treatment.

Comment: low risk of bias; most participants finished the study

Selective reporting (reporting bias)

Low risk

All primary efficacy and safety outcomes listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Unclear risk

Company sponsored

Methods

Multi‐centre, randomised, open‐label, controlled, 2‐parallel‐group, Phase III study

Participants

Total number of participants: 1243

Number of participants allocated to each group: fondaparinux (FX) group: 621, nadroparin (NA) group: 622

Number of participants excluded and/or lost to follow‐up: FX group: 14 (3 adverse events, 4 withdrawals by participant, 4 lost to follow‐up, 0 immobilisation, 1 investigator/orthopaedic surgeon decision, 2 orthopaedic surgery, 0 visits not performed, 0 deep vein thrombosis), NA group: 8 (0 due to adverse events, 0 due to lack of efficacy, 8 due to other reasons)

Inclusion: requiring rigid or semirigid immobilisation (e.g. with a plaster cast or brace) for at least 21 days and up to 45 days because of isolated non‐surgical below‐knee injury, with a no weight‐bearing recommendation at the time of inclusion (partial weight bearing is permitted, e.g. crutches, walking cast, relief shoes); presenting at least 1 of the following risk factors for venous thromboembolism: below‐knee fracture or Achilles tendon rupture, age ≥ 40 years, body mass index > 30 kg/m², oestrogen‐containing hormonal replacement therapy or oral contraception, active cancer (treatment ongoing or stopped for less than 1 year), history of VTE, congenital or acquired hypercoagulable stat; requiring thromboprophylaxis according to the investigator's judgement up to complete mobilisation (corresponding to cast or brace removal; able and willing to provide written informed consent)

Exclusion: delay between injury and randomisation greater than 2 days; treatment with antithrombotic or anticoagulant therapy, including low‐dose anticoagulation, for longer than 2 days before randomisation; anticoagulant therapy required or likely to be required during the study period for another reason (e.g. planned surgery justifying pharmacological thromboprophylaxis, curative dose for treatment of VTE); shown hypersensitivity to fondaparinux or nadroparin or their excipient; known history of heparin‐induced thrombocytopenia; women of childbearing potential not using a reliable contraceptive method throughout the study period; women pregnant or breast‐feeding during the study period; active, clinically significant bleeding; clinically significant bleeding within past 6 months; major surgery within previous 3 months; intraocular (other than cataract), spinal and/or brain surgery within previous 12 months; haemorrhagic stroke within previous 12 months; severe head injury within previous 3 months; documented congenital or acquired bleeding tendency/disorder(s); previous (within 12 months) or active or currently treated peptic ulcer disease; uncontrolled arterial hypertension (systolic blood pressure over 180 mmHg or diastolic blood pressure over 110 mm Hg); treatment with more than 1 antiplatelet agent (e.g. clopidogrel and aspirin) at any dose; need for long‐term aspirin at doses ≥ 325 mg or long‐term NSAIDs; bacterial endocarditis; severe hepatic impairment; calculated creatinine clearance < 30 mL/min; thrombocytopenia (< 100 x 10⁹/L); body weight < 50 kg; any condition that could prevent the patient from providing written informed consent or from adhering to study treatment; life expectancy < 6 months; participation in any study using an investigational drug during previous 3 months; patient in whom V3 is unlikely to be feasible (e.g. patient moving house);

In France, a patient was not be eligible for inclusion in this study if not affiliated with or a beneficiary of a social security system. This is an additional exclusion criterion that applies only to individuals enrolled in France.

Interventions

FX: 2.5 mg in 0.5 mL or 1.5 mg in 0.3 mL for at least 21 days and up to 45 days

NA: 2850 anti‐Xa IU in 0.3 mL administered sc once daily. Treatments were presented as prefilled syringes for at least 21 days and up to 45 days

Outcomes

Primary efficacy outcome: composite of VTE and death up to complete mobilisation, corresponding to cast or brace removal (plus 2 days). VTE was defined in this study as asymptomatic DVT detected by systematic compression ultrasonography, symptomatic DVT or symptomatic fatal or non‐fatal PE.

Primary safety outcome: major bleeding, non‐major clinically relevant bleeding and minor bleeding up to complete mobilisation (V3) plus 4 days, and up to the final visit or contact

Notes

Use of adjunctive anticoagulative methods: No adjunctive anticoagulative method was used in this study.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "multicenter, randomised, open‐label, controlled, two‐parallel‐group, phase III study"

Comment: probably done, as earlier reports from the same company clearly describe use of random sequences

Allocation concealment (selection bias)

Low risk

Quote: "multicenter, randomised, open‐label, controlled, two‐parallel‐group, phase III study"

Comment: probably done, as most earlier multi‐centre RCT reports clearly mentioned that studies of the same medicine organised by the same company were centrally randomised

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Multi‐centre, randomised, open‐label, controlled, 2‐parallel‐group, phase III study

Comment: probably not done

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "All events were blindly adjudicated by an independent committee"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

97.7% and 98.7% of participants in the 2 study groups, respectively, finished treatment.

Comment: low risk of bias; most participants finished the study

Selective reporting (reporting bias)

Low risk

All primary efficacy and safety outcomes listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Unclear risk

Company sponsored

Methods

Randomised, open‐label, controlled study

Participants

Total number of participants: 43

Number of participants allocated to each group: fondaparinux (FX) group: 21, edoxaban group: 22

Number of participants excluded and/or lost to follow‐up: FX group: 3 participants discontinued, edoxaban group: 2 participants discontinued

Inclusion: patients ≥ 20 years of age, with serious renal injury (creatinine clearance ≥ 20 mL/min to < 30 mL/min) who were undergoing unilateral TKA or THA (excluding revision surgeries) or hip fracture surgery for medial or lateral femoral neck fracture (trochanteric or subtrochanteric section of the femur) within 10 days of presurgical examination. Informed consent was obtained from all participants.

Exclusion: Presurgical exclusion criteria included, but were not limited to, patients undergoing or possibly undergoing haemodialysis; risk of bleeding; risk of thromboembolism; and hepatic dysfunction. Postsurgical exclusion criteria included, but were not limited to, creatinine clearance < 15 mL/min; abnormal bleeding at the site of spinal anaesthesia; abnormal or excessive bleeding during or immediately after surgery; and inability to take oral medication.

Interventions

Fondaparinux: subcutaneous fondaparinux 1.5 mg sc once daily

Edoxaban: oral edoxaban 15 mg once daily

Outcomes

Primary efficacy outcome: incidence of symptomatic VTE (composite of symptomatic DVT or PE) during treatment period

Primary safety outcome: major bleeding defined as fatal bleeding; clinically overt bleeding accompanied by a decrease in haemoglobin > 2 g/dL or requiring a transfusion of > 4 units of blood (1 unit = ˜200 mL); retroperitoneal, intracranial, intraocular or intrathecal bleeding; or bleeding requiring repeat surgery

Notes

Use of adjunctive anticoagulative methods: Concomitant physiotherapy (intermittent pneumatic compression devices or elastic stockings) was permitted throughout the treatment period.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomised, controlled study applied permuted block method with SAS software to generate random sequence.

Comment: probably done

Allocation concealment (selection bias)

Low risk

Randomised, controlled study applied permuted block method with SAS software to generate random sequence.

Comment: probably done

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Open‐label study

Comment: probably not done

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

All thromboembolic events were assessed by a thromboembolic event assessor, who was blinded to treatment group, on the basis of imaging results.

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

18/21 and 20/22 participants in the fondaparinux and edoxaban groups, respectively finished their treatment.

Comment: probably done

Selective reporting (reporting bias)

Low risk

All primary efficacy and safety outcomes listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Unclear risk

This study was supported by a pharmaceutical company that was involved in the study design and analysis of the data and provided writing and editorial support.

Methods

Randomised, placebo‐controlled, double‐blind study

Participants

Total number of participants: 78

Number of participants allocated to each group: fondaparinux group: 41, placebo group: 37

Number of participants excluded and/or lost to follow‐up: 2 participants in the fondaparinux group and no participants in the placebo group withdrew; all randomised participants were analysed.

Inclusion criteria: All patients scheduled to undergo a first or a repeat isolated CABG operation were considered for enrolment in the study.

Exclusion criteria

• Long‐term anticoagulation with unfractionated or low molecular weight heparin, coumadin or heparinoids

• Contraindications to anticoagulation

• Creatinine clearance < 30 mL/min

• Body weight < 50 kg

• Presence of indwelling epidural catheter

• Hepatic failure

• Pregnant state

• Life expectancy < 6 months

• Platelet count < 100,000/mm³

• Whole blood haemoglobin concentration < 9 g/dL

• Venous thromboembolism documented within past 3 months

• Acute bacterial endocarditis

• Cerebral metastasis or abscess

• History of heparin‐induced thrombocytopaenia

• Presence of acute deep venous thrombosis on preoperative duplex ultrasonography of lower extremities

• Inability to undergo venous duplex of lower extremities

• Inability to consent

• Refusal by treating physician

Interventions

Fondaparinux (FX): Intervention group received 2.5 mg subcutaneous injections of fondaparinux sodium daily, starting at a mean of 12 ± 2 hours after wound closure or on the morning of the first postoperative day. Second dose was administered at a mean of 24 ± 2 hours after the first dose, and subsequent injections were administered once daily for 9 days or until the patient was discharged from the hospital, whichever happened first.

Placebo: Control group received similar amounts of subcutaneous isotonic saline on the same schedule as the intervention group.

Outcomes

Primary study endpoint: composite, up to day 11, of cumulative incidence of all VTE events, defined as symptomatic and asymptomatic DVT, and fatal and non‐fatal pulmonary embolisms

Primary safety endpoint: cumulative incidence of major haemorrhages

Notes

Use of adjunctive anticoagulative methods: Both groups routinely received graduated compression stockings and/or intermittent pneumatic compression (mechanical antithrombotic prophylaxis).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "This study was conducted in compliance with the Good Clinical Practice guidelines"

Comment: probably done

Allocation concealment (selection bias)

Low risk

Quote: "This study was conducted in compliance with the Good Clinical Practice guidelines"

Comment: probably done

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The control group received similar amounts of subcutaneous isotonic saline on the same schedule as the interventional group"

Comment: probably done

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "Patients who developed symptomatic DVT or VTE underwent DUS scan of the lower extremities. An independent Data and Safety Monitoring Board monitored the safety of the study."

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "Two patients in the fondaparinux group, who withdrew their consent at 3 and 8 days
post enrollment, respectively, did not undergo DUS and were removed from the study. Clinical follow‐ups were complete in 76 patients (97.4%)"

Comment: probably done

Selective reporting (reporting bias)

Low risk

All primary efficacy and safety outcomes listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Low risk

No other bias noted

Methods

Multi‐centre, randomised, single‐blind, parallel‐group control study

Participants

Total number of participants: 237

Number of participants allocated to each group: fondaparinux (FX) group: 119, enoxaparin (EN) group: 118

Number of participants excluded and/or lost to follow‐up: FX group: 6 (5 adverse events, 0 lack of efficacy, 1 other reasons), EN group: 3 (2 adverse events, 0 lack of efficacy, 1 other reasons)

Inclusion: Male/female patients (aged 18 to 75 years) who were to undergo an elective hip or knee replacement or revision, and who gave written informed consent, were included in the study.
Exclusion: Exclusion criteria included the following: history of serious active bleeding in past 3 months; concurrent or history of thrombocytopenia (platelet count < 100 x 10⁹/L); concurrent haemorrhagic cerebrovascular disease or surgical history in brain, spine or eye; abnormality in hepatic (> 1.5 x ULN), renal (CrCl < 30 mL/min) or cardiac function, uncontrolled hypertension or tumour; and concurrent need for hip and knee replacement or double hip or knee replacement.

Interventions

FX: 2.5 mg for 7 ± 2 days (once daily sc injection)

EN: 40 mg for 7 ± 2 days

First treatment injection (placebo or enoxaparin) was administered at 12 ± 2 hours before surgery, then was continued for 7 ± 2 days post surgery, via daily sc injection.

Outcomes

Primary efficacy outcome: overall DVT events as confirmed by colour ultrasound imaging conducted within 2 days after the last dose following orthopaedic surgery

Primary safety outcome: major bleeding recorded between day 1 and day 9 post surgery

Notes

Use of adjunctive anticoagulative methods: no mention of use of any adjunctive anticoagulative method

Used for sensitivity analysis

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Multi‐centre, randomised, single‐blind, parallel control study"

Comment: probably done, as earlier reports from the same company clearly describe use of random sequences

Allocation concealment (selection bias)

Low risk

Quote: "Multi‐centre, randomised, single‐ blind, parallel control study"

Comment: probably done, as most earlier multi‐centre RCT reports clearly mentioned that studies of the same medicine organised by the same company were centrally randomised

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "Multi‐centre, randomised, single‐blind, parallel control study"

Comment: probably not done

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not clearly described

Comment: unclear

Incomplete outcome data (attrition bias)
All outcomes

Low risk

94.96% and 97.46% of participants in both groups completed the study.

Comment: probably done

Selective reporting (reporting bias)

Low risk

All primary efficacy and safety outcomes listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Unclear risk

Company sponsored

Methods

Randomised, open label, evaluator‐blinded

Participants

Total number of participants: 51

Number of participants allocated to each group: fondaparinux (FX) group: 28, enoxaparin (EN) group: 23

Number of participants excluded and/or lost to follow‐up: FX group: 4 (0 adverse events, 0 lack of efficacy, 4 other reasons), EN group: 1 (1 adverse event, 0 lack of efficacy, 0 other reasons)

Inclusion: Patients ≥ 20 years of age scheduled for primary elective total knee replacement surgery were included in the study.

Exclusion: Patients were excluded if they had leg oedema, peripheral vascular disease, diabetes with peripheral neuropathy or any condition likely to increase the risk of bleeding.

Interventions

FX: 2.5 mg FX 2.5 sc once daily for 7 days. First postoperative dose was given ≥ 6 hours after closure of the surgical wound, and the second dose 18 to 24 hours after the first dose. Thereafter, daily at 8 PM ± 2 hours for 5 days.
EN: 40 mg EN sc once daily for 7 days. First dose was given 12 hours before surgery, and thereafter daily for 7 days.

Outcomes

Primary efficacy outcome: incidence of occurrence of VTE events (DVT, as determined by clinical assessment and compression Doppler) up to day 10

Primary safety outcome: Major bleeding, minor bleeding, no bleeding, adverse events (AEs) and serious adverse events (SAEs) were monitored from day 0 up to day 37.

Notes

Use of adjunctive anticoagulative methods: no mention of use of any adjunctive anticoagulative method

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomized, open label"

Comment: probably done, as earlier reports from the same company clearly describe use of random sequences

Allocation concealment (selection bias)

Low risk

Quote: "Multicentre, randomised, open‐label study"

Comment: probably done, as most earlier multi‐centre RCT reports clearly mentioned that studies of the same medicine organised by the same company were centrally randomised

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "open‐label" study

Comment: probably not done

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "evaluator‐blind"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

85.7% and 95.7% of participants in the 2 study groups completed medication.

Comment: low risk of bias

Selective reporting (reporting bias)

Low risk

All primary efficacy and safety outcomes listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Unclear risk

Company sponsored

Methods

Randomised controlled study

Participants

Total number of participants: 36

Number of participants allocated to each group: fondaparinux group: 18, low molecular weight heparin (LMWH) group: 18

Number of participants excluded and/or lost to follow‐up: 0

Inclusion criteria: confirmed infection in trauma patients; hypercoagulopathy: prothrombin time (PT) < 3 seconds or longer than normal, abnormal international normalised ratio (INR) or activated partial prothrombin time (APTT) < 10 seconds or longer than normal; > 18 and < 70 years old; without haematological disorders; an informed consent

Exclusion criteria: anticoagulation therapy before enrolment; haematological or bleeding disorders; active or recent‐stroked peptic ulcer; malignant disease; diluting coagulopathy and low platelets counts; hepatic and renal failure

Interventions

Fondaparinux (FX): Participants in group F were given fondaparinux sodium (2.5 mg, 1/d for 11 d).

Low molecular weight heparin (LMWH): Participants in group L were given the standard LMWH (4100 U, 1/12 hours for 11 days) recipe and served as controls.

Outcomes

Endpoints of clinical observation were discharge and death. All participants were followed up for 3 months. Clinical parameters included deep vein thrombosis (DVT), bleeding events, occurrence of multiple organ dysfunction syndrome (MODS) and mortality. Laboratory parameters included serum fibrinogen, D‐dimer and antithrombin III. Observations were made on days 1, 3, 5, 7 and 11 after admission.
Major or minor bleeding events were monitored and recorded. Major bleeding events were defined as lethal or life‐threatening bleeding and intracranial or abdominal bleeding; minor ones consisted of occasional small bleeding that did not require further treatment.

Notes

Use of adjunctive prophylaxis methods: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Investigators used the randomisation sequence list to generate the random sequence.

This information was obtained by contacting the study authors.

Comment: probably done

Allocation concealment (selection bias)

Low risk

Investigators used the randomisation sequence list to generate the random sequence.

This information was obtained by contacting the study authors.

Comment: probably done

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Blinded to participants but not to healthcare staff

This information was obtained by contacting the study authors.

Comment: may affect participants' treatment and outcomes

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Blinded to outcome evaluator

This information was obtained by contacting the study authors.

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

100% of enrolled participants received responsive treatment, and data were analysed.

Selective reporting (reporting bias)

Low risk

All endpoints listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Low risk

No risk of other bias was identified.

Methods

Multi‐centre, multi‐national, randomised, double‐blind study

Participants

Total number of participants: 2927

Number of participants allocated to each group: fondaparinux (FX) group: 1465, dalteparin (DA) group: 1462

Number of participants excluded and/or lost to follow‐up: FX group: 127 (62 adverse events, 9 lack of efficacy, 56 other reasons), DA group: 119 (57 adverse events, 2 lack of efficacy, 60 other reasons)

Inclusion: Patients undergoing abdominal surgery under general anaesthesia, planned to last longer than 45 minutes (from incision to incision closure), and > 60 years of age with or without any other risk factor for VTE, or > 40 years of age and at risk for thromboembolic complications, were eligible. Patients at risk included those who were obese (body mass index (BMI) > 30 kg/m² for men and 28.6 kg/m² for women), undergoing cancer surgery, with a history of DVT or PE, with congestive heart failure (CHF) (grade III or IV of the New York Heart Association (NYHA) classification), with chronic obstructive pulmonary disease or with inflammatory bowel disease

Exclusion: Exclusion criteria were based on the labelling of LMWH in force at the time study was conducted (e.g. active clinically significant bleeding, presence or history of low platelet count (< 100 x 10⁹/L), medical condition associated with a bleeding risk, hypersensitivity to heparin or LMWH), or criteria related to contrast dyes during venography (e.g. serum creatinine > 2 mg/dL (180 μmol/L) or hypersensitivity to contrast media) or criteria related to trial methods (e.g. use of anticoagulant or fibrinolytic therapy within 2 days before first drug administration).

Interventions

FX: 2.5 mg once daily given by sc injection up to day 7 ± 2, with the first injection between 6 and 7 hours after incision closure, provided haemostasis had been established
DA: 2500 IU sc 2 hours preoperatively and 12 hours after the preoperative injection (and at least 6 hours after incision closure), then DA 5000 IU (once daily sc) up to day 7 ± 2

Outcomes

Primary efficacy outcome: VTE (asymptomatic and/or symptomatic DVT or PE or both) recorded until the time of screening venography or day 10, whichever occurred first. Secondary efficacy outcomes included individual events of total DVT, proximal DVT, distal DVT, symptomatic VTE up to day 10 and symptomatic VTE up to day 30 ± 2. Venography was considered positive if an intraluminal filling defect was seen on 2 different views, or after repeated injection of contrast medium; thrombi in the popliteal vein or above were considered proximal. A venogram was considered adequate if the entire deep venous system was visualised
from the calf veins to the common iliac vein in both legs.
Primary safety outcome: major bleeding detected between first injection of study drug (dalteparin or placebo) and 2 calendar days after last injection. Major bleeding was defined as fatal bleeding; bleeding that was retroperitoneal, intracranial or intraspinal or involved any other critical organ; bleeding leading to reoperation or intervention; and a bleeding index ≥ 2.0. The bleeding index was derived by adding the number of transfused units of packed red blood cells or whole blood to the difference in Hb level measured in grams per decilitre before and after a bleeding event. Secondary safety outcomes were death, other reported bleeding, thrombocytopenia and any other adverse events.

Notes

Use of adjunctive anticoagulative methods: The use of graded‐pressure elastic stockings was permitted.

Eleven (0.4 %) of 2858 participants were given a diagnosis of CHF at baseline. Results were not stratified by baseline illness, but owing to the small numbers, we decided to include this study.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "A multicenter, multinational, randomised, double‐blind study"

Comment: probably done, as earlier reports from the same company clearly describe use of random sequences

Allocation concealment (selection bias)

Low risk

Quote: "A multicenter, multinational, randomised, double‐blind study"

Comment: probably done, as most earlier multi‐centre RCT reports clearly mentioned that studies of the same medicine organised by the same company were centrally randomised

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Patients given fondaparinux received a placebo injection 2 h before surgery ……received a placebo injection 6 h after surgery to correspond with the fondaparinux injection schedule"

Comment: probably done

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote:"VTE outcomes evaluated (by an independent adjudicating committee)"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

91.1% and 91.6% of patients in 2 study groups finished treatment.

Comment: low risk of bias

Selective reporting (reporting bias)

Low risk

All primary efficacy and safety outcomes listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Unclear risk

Company sponsored

Methods

Multi‐national, multi‐centre, randomised, double‐blind, parallel‐group study

Participants

Total number of participants: 1049

Number of participants allocated to each group: fondaparinux (FX) group: 526, enoxaparin (EN) group: 523

Number of participants excluded and/or lost to follow‐up: FX group: 36 (20 adverse events, 2 lack of efficacy, 7 withdrawn consent, 7 other reasons ), EN group: 36 (13 adverse events, 6 lack of efficacy, 11 withdrawn consent, 6 other reasons).

Inclusion: Study population had to conform to the following criteria: men or women (of non‐childbearing potential, i.e. postmenopausal or with hysterectomy or bilateral tubal ligation), or women of childbearing potential using highly effective birth control and having a negative pregnancy test within 48 hours before randomisation; aged ≥ 18 years; undergoing elective major knee surgery or revision of at least 1 component (enrolment of participants with surgery limited to an osteotomy was not permitted); and haemostasis established on the calendar day of surgery, no later than 8 hours after closure of the incision.

Exclusion: Exclusion criteria were based on the labelling of LMWH in force at the time study was conducted (e.g. active clinically significant bleeding, presence or history of low platelet count (< 100 x 10⁹/L), medical condition associated with a bleeding risk), or criteria related to contrast dyes during venography (e.g. serum creatinine > 2 mg/dL (180 µmol/L) or hypersensitivity to contrast media).

Interventions

FX: Administration of FX (2.5 mg once daily as sc injection) started 6 ± 2 hours after surgical closure on day 1 (day of surgery).

EN: EN (30 mg twice daily as sc injection) at least 12 hours but less than 24 hours after surgical closure

To protect blinding (double‐dummy method), all participants received placebo to the active treatment they were not receiving. Study treatment was given up to 7 ± 2 days after surgical closure, or until the final venogram (positive unscheduled or mandatory) was obtained, whichever came first. Mandatory venography had to be performed between day 5 and day 11, but not more than 2 calendar days after the last study treatment administration.

Outcomes

Primary efficacy outcome: cluster of the following VTE outcomes recorded up to day 11: adjudicated venogram positive for DVT or adjudicated symptomatic or asymptomatic DVT; adjudicated non‐fatal PE or fatal PE. All venography procedures, scheduled and unscheduled, were adjudicated by a blinded Central Independent Adjudication Committee (CIAC).

Primary safety outcome: incidence of major bleeding, which included fatal bleeding; bleeding that was retroperitoneal, intracranial or intraspinal or that involved any other critical organ; bleeding leading to reoperation; and overt bleeding with a bleeding index ≥ 2. The bleeding index was calculated as the number of units of packed red cells or whole blood transfused plus Hb values before the bleeding episode minus Hb values after the episode (in grams per decilitre). Secondary safety outcomes were death, other bleeding, need for transfusion, thrombocytopenia and any other adverse event.

Efficacy and safety outcomes were adjudicated by a central independent committee, whose members were unaware of treatment assignments, and included reviews of all venograms and reports of bleeding and death.

Notes

Use of adjunctive anticoagulative methods: In the FX group, 4 participants received prohibited treatment (anticoagulant or antiplatelet agents other than aspirin or thrombolytic therapy), 44 received discouraged treatment (non‐steroidal anti‐inflammatory agents or aspirin) and 298 wore graduated compression stockings; in the EN group, 11 participants received prohibited treatment (anticoagulant or antiplatelet agents other than aspirin or thrombolytic therapy), 60 received discouraged treatment (non‐steroidal anti‐inflammatory agents or aspirin) and 294 wore graduated compression stockings.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Immediately after surgery, patients were randomly assigned (in a ratio of 1:1 in blocks of four, stratified according to centre), through a central computer‐derived randomisation scheme"

Comment: probably done

Allocation concealment (selection bias)

Low risk

Quote: "Immediately after surgery, patients were randomly assigned (in a ratio of 1:1 in blocks of four, stratified according to centre), through a central computer‐derived randomisation scheme"

Comment: probably done

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "To protect the blind (double‐dummy method) all subjects received placebo (PBO) to the active treatment they were not receiving"

Comment: probably done

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "were adjudicated by a blinded Central Independent Adjudication Committee (CIAC)"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

93% participants completed the study.

Comment: low risk of bias

Selective reporting (reporting bias)

Low risk

All primary efficacy and safety outcomes listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Unclear risk

Company sponsored

Methods

Multi‐centre, randomised, parallel, dose‐ranging study of FX with an assessor‐blind, comparative control group of EN

Participants

Total number of participants: 950

Number of participants allocated to each group: fondaparinux (FX) 0.75 mg group: 185, FX 1.5 mg group: 190, FX 3.0 mg group: 181, FX 6.0 mg group: 73, FX 8.0 mg group: 52; enoxaparin (EN) 60 mg group: 269

Number of participants excluded and/or lost to follow‐up: FX 0.75 mg group: 14 (8 adverse events, 0 lack of efficacy, 6 other reasons), FX 1.5 mg group: 15 (8 adverse events, 0 lack of efficacy, 7 other reasons), FX 3.0 mg group: 13 (7 adverse events, 0 lack of efficacy, 6 other reasons), FX 6.0 mg group: 12 (10 adverse events, 0 lack of efficacy, 2 other reasons), FX 8.0 mg group: 13 (9 adverse events, 0 lack of efficacy, 4 for other reasons); EN group: 27 (18 adverse events, 1 lack of efficacy, 8 other reasons).

Inclusion: males and females of non‐childbearing potential ≥ 18 years of age undergoing elective primary hip replacement or revision of a primary procedure

Exclusion: Exclusion criteria were based on the labelling of LMWH in force at the time study was conducted (such as active clinically significant bleeding, presence or history of low platelet count (< 100 x 10⁹/L) or known bleeding disorder), criteria related to venogram (such as creatinine clearance > 1.6 mg/dL; or hypersensitivity to contrast media) or use of anticoagulant or thrombolytic therapy 1 week before the start of the study.

Interventions

FX: Participants received a once daily sc injection of FX 0.75, 1.5, 3.0, 6.0 or 8.0 mg, starting 6 ± 2 hours postoperatively on day 1 (day of surgery).

EN: twice daily sc injection of EN 30 mg that started within 12 to 24 hours postoperatively (day 1 or day 2)

Participants were treated for a minimum of 5 days from day 1 until the final venogram was obtained, up to a maximum of 10 days.

Outcomes

Primary efficacy outcome: incidence of participants with adjudicated mandatory venogram positive for DVT and/or symptomatic adjudicated PE. Independent experts of the Central Independent Adjudication Committee (CIAC) evaluated blindly all venograms and lung scans performed during the study.

Primary safety outcome: major bleeding; bleeding was defined as major if it was clinically overt and fatal, intracranial or retroperitoneal; involved a critical organ; or led to reoperation for bleeding or hematoma at the operative site. Overt bleeding was also defined as major if Hb levels declined by more than 2 grams per decilitre, if more than 2 units of packed red cells or whole blood was transfused or if the number of units transfused plus the decline in Hb level in grams per decilitre was greater than 2.

Notes

Use of adjunctive anticoagulative methods: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Multicentre, randomised, parallel, dose ranging study of FX with an assessor‐blind, comparative control group of EN"

Comment: probably done, as earlier reports from the same company clearly describe use of random sequences

Allocation concealment (selection bias)

Low risk

Quote: "Multicentre, randomised, parallel, dose ranging study of FX with an assessor‐blind, comparative control group of EN"

Comment: probably done, as most earlier multi‐centre RCT reports clearly mentioned that studies of the same medicine organised by the same company were centrally randomised

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Without clear description

Comment: unclear

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Independent experts of the Central Independent Adjudication Committee (CIAC) evaluated blindly all venograms and lung scans performed during the study"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

92.4%, 92%, 92.7%, 83.3%, 75% and 89.6% of participants in the 6 different treatment groups finished their treatment.

Comment: low risk of bias

Selective reporting (reporting bias)

Low risk

All primary efficacy and safety outcomes listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Unclear risk

Company sponsored

Methods

Multi‐centre, randomised, double‐blind study

Participants

Total number of participants: 2275

Number of participants allocated to each group: fondaparinux (FX) group: 1138, enoxaparin (EN) group: 1137

Number of participants excluded and/or lost to follow‐up: FX group: 61 (33 adverse events, 4 lack of efficacy, 19 withdrawn consent, 5 other reasons ), EN group: 66 (35 adverse events, 2 lack of efficacy, 15 withdrawn consent, 14 other reasons)

Inclusion: Patients were eligible if they were undergoing an elective, primary, THR surgery or a revision of at least 1 component of a THR; > 18 years of age; men and women of non‐childbearing potential or women of childbearing potential using effective birth control with a negative pregnancy test within 48 hours before randomisation; haemostasis established on the calendar day of surgery, no later than 8 hours after incision closure; written informed consent

Exclusion: Exclusion criteria were based on the labelling of LMWH in force at the time study was conducted (e.g. active clinically significant bleeding, presence or history of low platelet count (< 100 x10⁹/L), medical condition associated with a bleeding risk) or criteria related to contrast dyes during venography (e.g. serum creatinine > 2 mg/dL (180 µmol/L) or hypersensitivity to contrast media).

Interventions

FX: administration of FX (2.5 mg once daily as sc injection) started postoperatively at 6 ± 2 hours after surgical closure

EN: administration of EN (30 mg twice daily as sc injection) started postoperatively at least 12 hours but no more than 24 hours post surgical closure

Respective placebo to each drug was administered to protect the double‐blind (double‐dummy) method. Study treatment was given up to day 7 ± 2 (day 1 was the day of surgery) or until the final venogram (positive unscheduled or mandatory) was obtained, whichever came first. Mandatory venography had to be performed between day 5 and day 11, but not more than 2 calendar days after the last study treatment administration.

Outcomes

Primary efficacy outcome: cluster of the following VTE outcome results recorded up to day 11: adjudicated venogram positive for DVT or adjudicated symptomatic/asymptomatic DVT; and adjudicated PE. All venograms, scheduled and unscheduled, and other diagnostic tests (ultrasonography, ventilation/perfusion, lung scan, pulmonary angiography, spiral computed tomography scan, autopsy report, etc.) were adjudicated blindly by independent experts of the Central Independent Adjudication Committee (CIAC).

Primary safety outcome: incidence of major bleeding (any Investigator‐reported unusual bleeding adjudicated as major or minor bleeding by the CIAC) recorded between first injection of study drug (active drug or placebo) and day 11. Major bleeding was defined as fatal bleeding; clinically overt bleeding including retroperitoneal or intracranial bleeding, or bleeding into a critical organ (eye, adrenal gland, pericardium, spine); reoperation due to bleeding/haematoma at the operative site; and clinically overt bleeding leading to a fall in Hb > 2 g/dL (1.6 mmol/L) and/or transfusion ≥ 2 units of packed red blood cells or whole blood AND for which the combined calculated index was > 2.

Notes

Use of adjunctive anticoagulative methods: use of graduated compression stockings and physiotherapy

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "a central computer‐derived randomisation scheme"

Comment: probably done

Allocation concealment (selection bias)

Low risk

Quote: "a central computer‐derived randomisation scheme"

Comment: probably done

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Respective placebo to each drug was administered to protect the double‐blind (double‐dummy method)"

Comment: probably done

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "were adjudicated blindly by independent experts of the Central Independent Adjudication Committee (CIAC)"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

94.6% and 94.2% of participants in the 2 study groups finished their relative treatments.

Comment: low risk of bias

Selective reporting (reporting bias)

Low risk

All primary efficacy and safety outcomes listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Unclear risk

Company sponsored

Methods

Multi‐national, multi‐centre, randomised, double‐blind, double‐dummy, parallel‐group study

Participants

Total number of participants: 1711

Number of participants allocated to each group: fondaparinux (FX) group: 849, enoxaparin (EN) group: 862

Number of participants excluded and/or lost to follow‐up: FX group: 55 (29 adverse events, 1 lack of efficacy, 25 other reasons), EN group: 67 (32 adverse events, 2 lack of efficacy, 33 other reasons)

Inclusion: patients undergoing standard surgery for fracture of the upper third of the femur, including femoral head and neck, not more than 48 hours after admission; ≥ 18 years of age; men and women of non‐childbearing potential or women with a negative pregnancy test

Exclusion: Exclusion criteria were based on the labelling of LMWH in force at the time study was conducted (such as active clinically significant bleeding, presence or history of low platelet count (< 100 x 10⁹/L) or known bleeding disorder), criteria related to venogram (such as creatinine clearance > 2.0 mg/dL; or hypersensitivity to contrast media) or use of anticoagulant or thrombolytic therapy during the screening period.

Interventions

FX: administration of FX (2.5 mg once daily as sc injection) started postoperatively (6 ± 2 hours after end of surgery)

EN: EN (40 mg once daily as sc injection) preoperatively (12 ± 2 hours before surgery) when surgery was planned within 24 hours after hospital admission

If surgery was delayed to 24 to 48 hours after admission, both study treatments were administered 12 ± 2 hours before the start of surgery. Study treatment was given up to day 7 ± 2 (day 1 was the day of surgery) or until the mandatory venogram was obtained, whichever came first. Mandatory venography had to be performed between days 5 and 11, but not more than 2 calendar days after the last study treatment administration.

Outcomes

Primary efficacy outcome: cluster of the following VTE outcome results recorded up to day 11: adjudicated venogram positive for DVT or adjudicated symptomatic/asymptomatic DVT; adjudicated non‐fatal and fatal PE. All venograms, scheduled and unscheduled, and other available diagnostic tests (ultrasonography, ventilation/perfusion lung scan, pulmonary angiography, spiral computed tomography scan, autopsy report, etc) were adjudicated blindly by independent experts of the CIAC.

Primary safety outcome: incidence of major bleeding, which included fatal bleeding; bleeding that was retroperitoneal, intracranial or intraspinal or that involved any other critical organ; bleeding leading to reoperation; and overt bleeding with a bleeding index ≥ 2. The bleeding index was calculated as the number of units of packed red cells or whole blood transfused plus Hb values before the bleeding episode minus Hb values after the episode (in g/dL).

Notes

Use of adjunctive anticoagulative methods: Use of graduated compression stockings and physiotherapy was recommended.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "patients were randomly assigned to treatment groups in blocks of four, with stratification according to centre, with the use of a computer‐generated randomisation list"

Comment: probably done

Allocation concealment (selection bias)

Low risk

Multi‐national, multi‐centre, randomised, double‐blind, double‐dummy, parallel‐group study

Comment: probably done

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Study medications were packaged in boxes of identical appearance"

Comment: probably done

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "were adjudicated blindly by independent experts of the CIAC"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

93.4% and 92% of participants in the 2 study groups finished the study.

Comment: low risk of bias

Selective reporting (reporting bias)

Low risk

All primary efficacy and safety outcomes listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Unclear risk

Company sponsored

Methods

Multi‐national, multi‐centre, randomised, double‐blind, placebo‐controlled, parallel‐group study

Participants

Total number of participants: 656

Number of participants allocated to each group: fondaparinux (FX) group: 326, placebo group: 330

Number of participants excluded and/or lost to follow‐up: FX group: 40 (20 adverse events, 2 lack of efficacy, 18 other reasons), placebo group: 46 (14 adverse events, 12 lack of efficacy, 20 for other reasons)

Inclusion: patients undergoing standard surgery for fracture of the upper third of the femur, including femoral head and neck, not more than 48 hours after admission; ≥ 18 years of age; men and women of non‐childbearing potential or women with a negative pregnancy test

Exclusion: Exclusion criteria included active clinically significant bleeding, or known bleeding disorder, criteria related to venography (such as creatinine clearance > 2.0 mg/dL; or hypersensitivity to contrast media) or use of anticoagulant or thrombolytic therapy during the screening period.

Interventions

Before randomisation, participants received open‐label fondaparinux 2.5 mg once daily, sc postoperatively for 7 ± 1 days (day 1 = day of surgery). They then were randomised to receive double‐blind fondaparinux 2.5 mg once daily sc for 21 ± 2 days or placebo.

Outcomes

Primary efficacy outcome: cluster of the following adjudicated VTE outcomes, evaluated from day 1 (first day of double‐blind treatment) to day 24 of postrandomisation period: mandatory venogram positive for DVT; symptomatic DVTs and/or adjudicated non‐fatal and fatal PE. During the study, the investigator had to perform appropriate evaluations in case of clinical suspicion of VTE. In the absence of previous confirmation of VTE, a mandatory venogram had to be performed between day 19 and day 24, but not more than 1 calendar day after the last study treatment administration. A Central Independent Adjudication Committee (CIAC) adjudicated any diagnostic tests performed during the double‐blind period, and all reported bleedings and deaths.

Primary safety outcome: incidence of major bleeding rate

Notes

Use of adjunctive anticoagulative methods: The use of graduated elastic stockings was permitted.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Multinational, multicenter, randomised, double‐blind, placebo‐controlled, parallel‐group study"

Comment: probably done, as earlier reports from the same company clearly describe use of random sequences

Allocation concealment (selection bias)

Low risk

Double‐blind study with effective method to confirm blindness

Comment: probably done, as most earlier multi‐centre RCT reports clearly mentioned that studies of the same medicine organised by the same company were centrally randomised

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "For the double blind period, study medications were packaged in the boxes"

Comment: probably done

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "A Central Independent Adjudication Committee (CIAC) adjudicated any diagnostic tests performed during the double‐blind period, and all reported bleedings and deaths"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

87.7% and 86.1% of participants in 2 study groups finished treatment.

Comment: low risk of bias

Selective reporting (reporting bias)

Low risk

All primary efficacy and safety outcomes listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Unclear risk

Company sponsored

Methods

Randomised controlled study

Participants

Total number of participants enrolled: 121

Number of participants allocated to each group: fondaparinux (FX) group: 59, nadroparin calcium (NA) group: 57

Number of participants excluded and/or lost to follow‐up: not mentioned

Inclusion: clinical diagnosis of oesophageal carcinoma and planned for oesophagectomy; clinical diagnosis of lung carcinoma and planned for lung resection; general anaesthesia combined with epidural anaesthesia

Exclusion: blood clotting dysfunction before surgery; anticoagulating or antiplatelet history before surgery; low blood platelet count; haemorrhagic disease; cerebral haemorrhage; cerebral, spinal or ophthalmologic operation history; peptic ulcer; bleeding > 400 mL during operation; bleeding > 100 mL/h after operation; blood transfusion during or after operation; severe renal or liver dysfunction; severe hypertension

Interventions

FX: 2.5 mg IH once daily after operation

NA: nadroparin calcium 4100 AxaIU IH once daily after operation

Outcomes

Primary efficacy outcomes: VTE events and drainage volume

Notes

Use of adjunctive anticoagulative methods: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Study authors confirmed that they used the computer‐derived randomisation table.
Comment: low risk of bias

Allocation concealment (selection bias)

Low risk

Study authors confirmed that they used the computer‐derived randomisation table.
Comment: low risk of bias

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

The study publication did not clearly describe methods of blinding, and communication with study authors did not provide further information.

Comment: unclear

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Study authors confirmed that outcome assessors did not know the group information.
Comment: low risk of bias

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "A total of 121 patients were enrolled in this study, and 116 eligible patients were randomly assigned (Group H: 57 patients; Group F: 59 patients)"

Comment: low risk of bias

Selective reporting (reporting bias)

Unclear risk

Results of VTE rates were reported, but the number of events was not clearly reported. Drainage volumes of study participants were reported.

Other bias

Low risk

No risk of other bias was identified.

Methods

Randomised controlled trial

Participants

Total number of participants: 250

Number of participants allocated to each group: fondaparinux (FX) group: 85, enoxaparin (EN): 86, placebo group: 85

Number of participants excluded and/or lost to follow‐up: FX group: 1, EN group: 2, placebo group: 2

Inclusion: patients older than 20 years of age undergoing elective primary unilateral THR

Exclusion: patients who had undergone bilateral and revision THR. Other exclusion criteria included long‐term anticoagulation treatment such as unfractionated heparin, LMWH, vitamin K antagonists and antiplatelet agents for pre‐existing cardiac or cerebrovascular disease; history of VTE; coagulation disorder including antiphospholipid syndrome; presence of a solid malignant tumour or a peptic ulcer; and major surgery in the preceding 3 months. The study also excluded Caucasian patients.

Interventions

FX: postoperative sc injections of fondaparinux (2.5 mg once daily) for 10 consecutive days

EN: postoperative sc injections of enoxaparin (40 mg or 20 mg twice daily) for 10 consecutive days

Placebo: placebo (0.5 mL of isotonic saline) for 10 consecutive days

The first postoperative injections of fondaparinux, enoxaparin and saline took place at an average of 18 hours (SD 2), 17 hours (SD 2) and 18 hours (SD 2), respectively, after the operation.

Outcomes

Primary efficacy outcome: incidence of DVT or VTE assessed by bilateral ultrasonographic studies from the external iliac vein to proximal portions of the calf veins at postoperative day 11. All scans were performed by experienced vascular technicians and were read by experienced radiologists who were blinded to participants' randomisation. Those with a negative scan were followed clinically for 12 weeks (until postoperative day 84) for signs or symptoms of DVT, pulmonary emboli or readmission to hospital because of a complication related to the chemical prophylaxis, a bleeding complication, a wound problem or any other clinical event. Participants who were found to have a distal (calf) DVT did not receive any chemical treatment. Those with proximal DVT received anticoagulant therapy, with initial administration of unfractionated heparin along with initiation of warfarin therapy.

Primary safety outcome: incidence of any bleeding, major or minor. This was assessed daily during the treatment period of 10 days and within 24 hours after completion or discontinuation of treatment. An episode of bleeding was classified as major if it was retroperitoneal, intracranial or intraocular, or if it was associated with death, transfusion of more than 2 units of packed red blood cells or whole blood (except autologous), a reduction in level of Hb > 2 g/dL or a serious or life‐threatening clinical event requiring medical intervention. Suspected intra‐abdominal or intracranial bleeding was confirmed by ultrasonography, CT or MRI. Minor episodes of bleeding were defined as those with at least 1 of the following features: epistaxis lasting longer than 5 minutes or requiring intervention, ecchymosis or haematoma with maximum size of > 5 cm, haematuria not associated with trauma from the urinary catheter, gastrointestinal haemorrhage not related to intubation or to passage of a nasogastric tube, wound haematoma or haemorrhagic wound complications not associated with major haemorrhage or subconjunctival haemorrhage, requiring cessation of medication.

Notes

Use of adjunctive anticoagulative methods: All participants received the same routine mechanical prophylaxis (intermittent pneumatic compression device and a thigh‐high elastic compression bandage) during and after operation.

Used for sensitivity analysis

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

The study did not clearly describe what randomisation method was used.

Comment: unclear

Allocation concealment (selection bias)

Unclear risk

The study did not clearly describe what randomisation method was used and whether a strategy was used to confirm allocation concealment.

Comment: unclear

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

The study did not clearly describe blinding

Comment: unclear

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "All the scans were performed by experienced vascular technicians and were read by experienced radiologists who were blinded to the patient’s randomisation"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

250 of 267 participants finished the study.

Comment: low risk of bias

Selective reporting (reporting bias)

Low risk

All primary efficacy and safety outcomes listed in the Methods section were reported.

Comment: low risk of bias

Other bias

Low risk

No risk of other bias was identified.