Table 3. Quality and characteristics of randomized controlled trials in major orthopedic surgery

Study, year / Trial characteristics / Population and interventions / Followup* and Outcomes of interest (Timing) / Quality assessment
Yokote, 2011 / Publication type:
Full text
Geographic location:
Japan
Funding:
Unknown
Number of centers:
1
Randomization and allocation concealment:
Randomly assigned to either of the three groups
Outcome assessment:
Ultrasonographic scans performed by experienced vascular technicians and were read by experienced radiologists who were blinded to the patient’s randomization
Total number randomized:
255 (255) / Inclusion criteria:
Primary, unilateral THR
Exclusion criteria:
Bilateral and revision THR; <20 years; long term anticoagulant treatment such as UFH, LMWH, VKA, antiplatelet agents; pre-existing cardiac or cerebrovascular disease; history of VTE, coagulation disorder including ant-phospholipids syndrome; presence of a solid malignancy tumor or peptic ulcer; major surgery in the preceding 3m; Caucasian patients
Intervention 1:
Fondaparinux 2.5mg SQ starting at a mean of 18h post-operatively the daily for 10 consecutive days
Intervention 2:
Enoxaparin 20mg BD or 40mg SQ starting at a mean of 17h post-operatively then daily for 10 consecutive days
Comparator:
Placebo (saline injections) / Duration of followup:
84 days post-operative
Followup:
Fondaparinux 98.8%
Enoxaparin 97.6%
Placebo 97.6%
Final:
Symptomatic VTE, PE, fatal PE, nonfatal PE (11d); mortality, mortality due to bleeding (84d)
Intermediate:
DVT, symptomatic DVT, proximal DVT, distal DVT (11d)
Adverse events:
Major bleeding, minor bleeding (11d) / 1. Were the groups similar at baseline in terms of baseline characteristics and prognostic factors? Yes
2. Were outcomes assessed using a valid methodology and criteria? Yes
3. Were subjects and providers blind to the intervention status of participants? Partially
4. Were outcome assessors blind to exposure/intervention status? Partially
5. Were the methods used for randomization adequate? Can’t tell
6. Were methods for allocation concealment adequate? Can’t tell
7. Were incomplete outcome data adequately addressed? Yes
8. Was intention to treat analysis used? Yes
9. Was the differential loss to followup between the compared groups low (< 10%)? Yes
10. Was the overall loss to followup low (< 20%)? Yes
11. Conflict of interest reported and insignificant? Yes
Overall quality rating: Fair
Fuji, 2010 / Publication type:
Full text
Geographic location:
Japan
Funding:
Industry
Number of centers:
38
Randomization and allocation concealment:
Randomized into 4 treatment groups using a computer-generated scheme stratified by study center in block of 4
Outcome assessment:
Diagnostic tests for VTE were evaluated centrally by an independent adjudication committee blinded to treatment allocation, two medical experts reviewed all cases of bleeding
Total number randomized:
512 (379) / Inclusion criteria:
Age ≥20y; weight ≥40kg; primary, unilateral elective TKA; signed, informed consent
Exclusion criteria:
Any bleeding diathesis; major surgery, trauma, uncontrolled HTN, MI in last 3m; clinically relevant bleeding, gastric/duodenal ulcer in last 6m; hx hemorrhagic stroke or acute intracranial bleeding; hx VTE or preexisting condition requiring anticoagulant therapy; severe liver disease or elevated AST or ALT >2xULN; significant renal disease; treatment with anticoagulants, antiplatelet agents, or NSAIDs with a half-life of >12h within 7d before TKA; anticipated requirement for IPC of lower limb; pregnancy, women of child-bearing potential; hx TCP; previous leg amputation; active malignant disease
Intervention 1:
Dabigatran 150mg po at least 2h after removing indwelling catheter + confirming absence of abnormal bleeding at drainage site, 150mg 8h+ after first dose then QD at 8AM for 11-14d postoperatively
Intervention 2:
Dabigatran 220mgpo at least 2h after removing indwelling catheter and confirming absence of abnormal bleeding at drainage site, 220mg 8h or more after the first dose, then QD at 8AM for 11-14d postoperatively
Comparator:
Placebo capsules / Duration of followup:
post-operative
Followup:
Dabigatran 150mg 82.54%; 220mg 74.42%; placebo 81.45%
Final:
Major VTE, PE, fatal PE, nonfatal PE, mortality, mortality due to bleeding (post-operative)
Intermediate:
DVT, asymptomatic DVT, symptomatic DVT, proximal DVT (post-operative)
Adverse events:
Major bleeding, minor bleeding, major bleeding leading to reoperation, bleeding leading to transfusion (post-operative) / 1. Were the groups similar at baseline in terms of baseline characteristics and prognostic factors? Yes
2. Were outcomes assessed using a valid methodology and criteria? Yes
3. Were subjects and providers blind to the intervention status of participants? Yes
4. Were outcome assessors blind to exposure/intervention status? Partially
5. Were the methods used for randomization adequate? Yes
6. Were methods for allocation concealment adequate? Yes
7. Were incomplete outcome data adequately addressed? Yes
8. Was intention to treat analysis used? Yes
9. Was the differential loss to followup between the compared groups low (< 10%)? Yes
10. Was the overall loss to followup low (< 20%)? No
11. Conflict of interest reported and insignificant? Yes
Overall quality rating: Good
Chin, 2009 / Publication type:
Full text
Geographic location:
Singapore
Funding:
NR
Number of centers:
1
Randomization and allocation concealment:
NR
Outcome assessment:
Bilateral DUS was carried out by ultrasonographers blinded to the prophylactic method used
Total number randomized:
440 (220) / Inclusion criteria:
Elective TKA; low-risk patients and those without predisposition to thromboembolism
Exclusion criteria:
Use of anticoagulants or aspirin; history of PE or DVT in the previous year; obesity; pre-operative prolonged immobilization or wheelchair bound; bleeding tendency or a history of GI bleeding; surgery in the previous 6m; CVA in the previous 3m; uncontrolled HTN; CHF; renal or liver impairment; allergy to heparin or HIT; varicose veins or CVI; PVD; skin ulcers; dermatitis or wounds; malignancy
Intervention:
Enoxaparin 40mg/d SQ started postoperativelyuntil 5-7d or if DVT or PE suspected
Comparator:
Control / Duration of followup:
Post-operative
Followup:
100% in all arms
Final:
PE (post-operative)
Intermediate:
DVT, proximal DVT, distal DVT (post–operative)
Adverse events:
Bleeding complications (post-operative) / 1. Were the groups similar at baseline in terms of baseline characteristics and prognostic factors? Yes
2. Were outcomes assessed using a valid methodology and criteria? Yes
3. Were subjects and providers blind to the intervention status of participants? Partially
4. Were outcome assessors blind to exposure/intervention status? Yes
5. Were the methods used for randomization adequate? Can’t tell
6. Were methods for allocation concealment adequate? Can’t tell
7. Were incomplete outcome data adequately addressed? Yes
8. Was intention to treat analysis used? Yes
9. Was the differential loss to followup between the compared groups low (< 10%)? Yes
10. Was the overall loss to followup low (< 20%)? Yes
11. Conflict of interest reported and insignificant? No
Overall quality rating: Fair
Ginsberg, 2009
RE-MOBILIZE / Publication type:
Full text
Geographic location:
Canada, Mexico, USA, UK
Funding:
Industry
Number of centers:
97
Randomization and allocation concealment:
Randomly assigned to 1 of 3 treatmentgroups after surgery using an Interactive VoiceResponse System in blocks of 6 based on an independently generated scheme
Outcome assessment:
Diagnostic tests for VTE events were initially evaluated locally, subsequently reviewed by an independent central adjudication committee blinded to treatment allocation. An independent expert adjudication committee classified all bleeding events
Total number randomized (number randomized in arms of interest):
2615 (2615) / Inclusion criteria:
≥18y and >40 kg, scheduled for primary
elective unilateral TKA
Exclusion criteria:
Known inherited or acquired clinically significant bleeding disorder; major surgery, trauma, uncontrolled HTN or MI < 3m; hx of acute intracranial disease or hemorrhagic stroke; GI or urogenital bleeding or ulcer disease < 6m;severe liver disease; ALT or AST > 2X ULN range < last m; severe renal insufficiency; concomitant long acting NSAID therapy or anticoagulant during study drug treatment; active malignant disease; platelet count< 100 × 109/L; pregnant; nursing,or premenopausal women of child-bearingpotential who were not practicing effective birth control; failure to provide informed consent
Intervention 1:
Dabigatran 75mg PO starting 6-12h post-operative followed by 150mg PO QD for a total duration of 12-15d post-operative
Intervention 2:
Dabigatran 110mg PO starting 6-12h post-operative followed by 220mg PO QD for a total duration of 12-15d post-operative
Intervention 3:
Enoxaparin 30mg SQ BID starting 12-24h post-operative for a total duration of 12-15d post-operative / Duration of followup:
90d
Followup:
100% in all arms
Final:
Mortality due to bleeding, mortality (post-operative)
Intermediate:
Symptomatic DVT, proximal DVT, distal DVT (post-operative)
Adverse events:
Major bleeding, minor bleeding (post-operative during study period, post study period-90d); major bleeding leading to re-operation, surgical site bleeding (post-operative during study period) / 1. Were the groups similar at baseline in terms of baseline characteristics and prognostic factors? Yes
2. Were outcomes assessed using a valid methodology and criteria? Yes
3. Were subjects and providers blind to the intervention status of participants? Yes
4. Were outcome assessors blind to exposure/intervention status? Yes
5. Were the methods used for randomization adequate? Yes
6. Were methods for allocation concealment adequate? Yes
7. Were incomplete outcome data adequately addressed? Yes
8. Was intention to treat analysis used? Yes
9. Was the differential loss to followup between the compared groups low (< 10%)? Yes
10. Was the overall loss to followup low (< 20%)? Yes
11. Conflict of interest reported and insignificant? Yes
Overall quality rating: Good
Edwards, 2008 / Publication type:
Full text
Geographic location:
USA
Funding:
Industry
Number of centers:
NR
Randomization and allocation concealment:
NR
Outcome assessment:
Diagnosis of PE was adjudicated by a separate committee
Total number randomized:
277 (277) / Inclusion criteria:
Patients undergoing THA or TKA
Exclusion criteria:
Protocol violations such as missed ultrasound; surgery other than THA or TKA; previous history of thrombosis; prophylaxis other than LMWH
Intervention:
Enoxaparin 30 mg Q12h SQ from the morning after surgery until 7-8th post-operative day + IPC (ActiveCare DVT) on the calves of the patients in the operation room and worn until discharge
Comparator:
Enoxaparin 30 mg Q12h SQ from the morning after surgery until 7-8th post-operative day / Duration of followup:
90d
Followup:
100% in all arms
Final:
PE, fatal PE, nonfatal PE (90d); mortality, mortality due to bleeding (post-operative)
Intermediate:
DVT, proximal DVT, distal DVT (post-operative)
Adverse events:
NR / 1. Were the groups similar at baseline in terms of baseline characteristics and prognostic factors? Yes
2. Were outcomes assessed using a valid methodology and criteria? Yes
3. Were subjects and providers blind to the intervention status of participants? No
4. Were outcome assessors blind to exposure/intervention status? Partially
5. Were the methods used for randomization adequate? Can’t tell
6. Were methods for allocation concealment adequate? Can’t tell
7. Were incomplete outcome data adequately addressed? Yes
8. Was intention to treat analysis used? Yes
9. Was the differential loss to followup between the compared groups low (< 10%)? Yes
10. Was the overall loss to followup low (< 20%)? Yes
11. Conflict of interest reported and insignificant? Yes
Overall quality rating: Fair
Fuji, 2008
THA / Publication type:
Full text
Geographic location:
Japan
Funding:
Industry
Number of centers:
51
Randomization and allocation concealment:
1:1 ratio
Outcome assessment:
Objective tests for DVT and PE were centrally adjudicated by an independent expert panel blinded to treatment group; intra-abdominal or intracranial bleeding confirmed by US, CT, or MRI
Total number randomized:
421 (421) / Inclusion criteria:
Primary elective THA; ≥20y
Exclusion criteria:
Revision THA; CI to heparin therapy; positive clinical evidence of chronic postphlebitic syndrome or acute DVT within 12m of study drug treatment; allergy to iodine or contrast medium; CrCl <30 mL/min or plasma Cr level >1.5mg/dl; severe hepatic disease; uncontrolled HTN; illicit drug use of alcohol abuse; treatment with other investigation agents within 3m of surgery; failure to achieve post-operative hemostasis; females if pregnant or breastfeeding
Intervention 1:
Enoxaparin 40mg SQ daily starting 24-36h postoperatively for 14d
Intervention 2:
Enoxaparin 20mg SQ BID starting 24-36h postoperatively for 14d
Comparator:
Placebo (saline) injections / Duration of followup:
Post-operative
Followup:
Enoxaparin 40mg 74.8%; enoxaparin 20mg 85.7%; placebo 81.9%
Final:
PE (postoperative)
Intermediate:
DVT, proximal DVT (post-operative)
Adverse events:
Major bleeding, minor bleeding (post-operative) / 1. Were the groups similar at baseline in terms of baseline characteristics and prognostic factors? Yes
2. Were outcomes assessed using a valid methodology and criteria? Yes
3. Were subjects and providers blind to the intervention status of participants? Yes
4. Were outcome assessors blind to exposure/intervention status? Partially
5. Were the methods used for randomization adequate? Can’t tell
6. Were methods for allocation concealment adequate? Can’t tell
7. Were incomplete outcome data adequately addressed? Yes
8. Was intention to treat analysis used? Yes
9. Was the differential loss to followup between the compared groups low (< 10%)? Yes
10. Was the overall loss to followup low (< 20%)? Yes
11. Conflict of interest reported and insignificant? Yes
Overall quality rating: Good
Fuji, 2008
TKA / Publication type:
Full text
Geographic location:
Japan
Funding:
Industry
Number of centers:
51
Randomization and allocation concealment:
1:1 ratio
Outcome assessment:
Objective tests for DVT and PE were centrally adjudicated by an independent expert panel blinded to treatment group; intra-abdominal or intracranial bleeding confirmed by US, CT, or MRI
Total number randomized:
382 (382) / Inclusion criteria:
Primary TKA; ≥20y
Exclusion criteria:
Revision TKA; CI to heparin therapy; positive clinical evidence of chronic postphlebitic syndrome or acute DVT within 12m of study drug treatment; allergy to iodine or contrast medium; CrCL <30 mL/min or plasma Cr >1.5 mg/dL; severe hepatic disease; uncontrolled HTN; illicit drug use of alcohol abuse; treatment with other investigation agents within 3m of surgery; failure to achieve post-operative hemostasis; females if pregnant or breastfeeding
Intervention 1:
Enoxaparin 40mg SQ daily starting 24-36h postoperatively for 14d
Intervention 2:
Enoxaparin 20mg SQ BID starting 24-36h postoperatively for 14d
Comparator:
Placebo (saline) injections / Duration of followup:
Post-operative
Followup:
Enoxaparin 40mg 78.7%; enoxaparin 20mg 84.8%; placebo 82.3%
Final:
PE (post-operative)
Intermediate:
DVT, proximal DVT (post-operative)
Adverse events:
Major bleeding, minor bleeding (post-operative) / 1. Were the groups similar at baseline in terms of baseline characteristics and prognostic factors? Yes
2. Were outcomes assessed using a valid methodology and criteria? Yes
3. Were subjects and providers blind to the intervention status of participants? Yes
4. Were outcome assessors blind to exposure/intervention status? Partially
5. Were the methods used for randomization adequate? Can’t tell
6. Were methods for allocation concealment adequate? Can’t tell
7. Were incomplete outcome data adequately addressed? Yes
8. Was intention to treat analysis used?
9. Was the differential loss to followup between the compared groups low (< 10%)? Yes
10. Was the overall loss to followup low (< 20%)? Yes
11. Conflict of interest reported and insignificant? Yes
Overall quality rating: Good
Thorey, 2008
/ Publication type:
Full text
Geographic location:
Germany
Funding:
Unknown
Number of centers:
1
Randomization and allocation concealment:
NR
Outcome assessment:
NR
Total number randomized (number randomized in arms of interest):
20 (20) / Inclusion criteria
Patients undergoing simultaneous bilateral cemented TKA
Exclusion criteria
History of DVT; musculoskeletal infection in the lower extremities; bleeding diathesis; neurological problems; PVD
Intervention 1:
Tourniquet release and hemostasis before wound closure
Intervention 2:
Tourniquet release after wound closure and pressure dressing / Duration of followup:
180d
Followup:
100%
Final:
NR
Intermediate:
DVT, asymptomatic DVT, symptomatic DVT, proximal DVT, distal DVT (180d)
Adverse events:
NR / 1. Were the groups similar at baseline in terms of baseline characteristics and prognostic factors? Yes
2. Were outcomes assessed using a valid methodology and criteria? Can’t tell
3. Were subjects and providers blind to the intervention status of participants? No
4. Were outcome assessors blind to exposure/intervention status? Can’t tell
5. Were the methods used for randomization adequate? Can’t tell
6. Were methods for allocation concealment adequate? Can’t tell
7. Were incomplete outcome data adequately addressed? Yes
8. Was intention to treat analysis used? Yes
9. Was the differential loss to followup between the compared groups low (< 10%)? Yes
10. Was the overall loss to followup low (< 20%)? Yes
11. Conflict of interest reported and insignificant? No
Overall quality rating: Poor
Eriksson, 2007a
RE-MODEL / Publication type:
Full text
Geographic location:
Australia, Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Hungary, Italy, Poland, Netherlands, South Africa, Spain, Sweden
Funding:
Industry
Number of centers:
105
Randomization and allocation concealment:
Randomly assigned using a computer-generated central scheme stratified by study center in blocks of 6
Outcome assessment:
All VTE and bleeding events reviewed by an independent central adjudication committee blinded to treatment allocation
Total number randomized (number randomized in arms of interest):
2101 (2101) / Inclusion criteria
≥18y and >40 kg, scheduled for primary
elective unilateral TKA
Exclusion criteria
Any bleeding diathesis; hx of acute
intracranial disease or hemorrhagic stroke; major surgery,trauma, uncontrolled HTN or MI within the past 3m; GI or urogenital
bleeding or ulcer disease within the past 6m; severeliver disease; AST or ALT levels >2 X ULN range within the past m; severerenal insufficiency; concomitant long-acting NSAID therapy; active malignant disease; and being female and of childbearing potential
Intervention 1:
Dabigatran 75mg PO starting 1-4h post-operative followed by 150mg PO QD for 6-10d post-operative
Intervention 2:
Dabigatran 110mg PO starting 1-4h post-operative followed by 220mg PO QD for 6-10d post-operative
Intervention 3:
Enoxaparin 40mg SQ QD starting evening before surgery (post-operative in some countries) for 6-10d post-operative / Duration of followup:
90d
Followup:
Dabigatran 150mg 88.90%
Dabigatran 220mg 89.4%
Enoxaparin 88.76%
Final:
Major VTE, fatal PE, nonfatal PE, PE, mortality due to bleeding, mortality (post-operative)
Intermediate:
Asymptomatic DVT, symptomatic DVT (post-operative)
Adverse events:
Major bleeding, minor bleeding, major bleeding leading to re-operation, bleeding leading to transfusion (post-operative) / 1. Were the groups similar at baseline in terms of baseline characteristics and prognostic factors? Yes
2. Were outcomes assessed using a valid methodology and criteria? Yes
3. Were subjects and providers blind to the intervention status of participants? Yes
4. Were outcome assessors blind to exposure/intervention status? Yes
5. Were the methods used for randomization adequate? Yes