Lubenow 2010a.

Methods	Randomised and double‐blind clinical trial Country: Germany
Participants	Patients admitted to the Trauma Surgery Department at the University Hospital Grifswald, Germany 696 participants randomised and 614 participants received the intended treatment (13.36% loss to follow‐up) Mean age of the group of participants was 49.0 years (range: 18‐98) for UFH arm and 50.0 years (range: 18‐94) for the LMWH arm (P = 0.99) From the total participants who received the intended treatment, 561 were postoperative patients (39.9% major surgery; 60.1% minor surgery) Major surgery consisted of people undergoing fracture of humerus, hip/pelvis, femur, head of tibia, tibia, or knee endoprosthesis Platelet counts: all participants had daily platelet counts measured in capillary blood (SE 9000; Sysmex) The HIPA test was used to demonstrate platelet‐activating antibodies and an in‐house platelet factor 4/heparin. ELISA for IgG, IgM and IgA was used to screen patients for HIT antibody seroconversion defined as negative HIPA test and immunoassay on admission and positive tests from day 5 onwards of heparin. The HIT antibody testing was planned to be performed on admission, at discharge (if before day 10) and between days 10 and 14. Participants undergoing major surgery had blood samples for HIT testing obtained on day 11.0 (± 3.3 days) Participants undergoing minor surgery had blood samples for HIT testing obtained on day 10.6 (± 3.3 days); P = 0.18 Participant characteristics did not differ between the heparin groups.
Interventions	316 participants received UFH (B, Braun) and 298 received the LMWH Certoparin (Certoparin, Monoembolex, Novartis). Postoperative participants comprised a number of 289 participants who received UFH and 272 participants who received LMWH. Participants were followed until end point (HIT or new thrombosis) or until discharge. Study drugs were given for a median of 10 days (range: 5‐20 days) in participants undergoing major surgery and for a median of seven days (range: 5‐19 days) in participants undergoing minor procedures.
Outcomes	Primary outcome: HIT defined as a participant with a 4Ts score of 4 or more points as agreed by 2 independent investigators, and tested positive for anti‐platelet factor 4/heparin immunoglobulin IgG antibodies, and showing platelet‐activating antibodies in the HIPA test. Secondary outcomes: venous thromboembolism diagnosed through compression ultrasonography performed as screening at discharge, or in case of clinical suspicion of DVT.
Notes	Of note, the report states in its 'Methods Section' that all participants received LMWH after day 10. However, the results presented do not appear to be in accordance with this statement. Although investigators state that the sponsor Novartis had no role in the study design, collection analysis and interpretation of data, the study was supported by an unrestricted grant from Novartis (Nürnberg, Germany).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Investigators did not state the method of randomisation neither in the protocol of the study (ClinicalTrials.gov ID NCT00196417) nor in the trial report
Allocation concealment (selection bias)	Low risk	Investigators used sealed envelopes to conceal allocation of treatment groups
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of participants and personnel to the assigned treatment group was assured by a special coding of the medications and by the use of placebo injections when necessary
Blinding of outcome assessment (detection bias) heparin‐induced thrombocytopenia	High risk	Blinding of investigators who assessed the primary outcome (HIT) was probably not done since participants were assessed by the investigators using the 4T's score and after they were known to be positive in at least one of the HIT tests used
Blinding of outcome assessment (detection bias) venous thromboembolism	Low risk	The study report states that abnormal findings were adjudicated by an investigator blinded to treatment assignment to the participant during the evaluation of venous thrombosis
Incomplete outcome data (attrition bias) HIT	High risk	Analyses were conducted 'per protocol'. Attrition accounted for 12% of the randomised participants. Numbers of exclusions and reasons for exclusions were described, but not detailed according to treatment arm. The high ratio of participants with missing data to participants' events might have affected the results
Selective reporting (reporting bias)	Low risk	The study protocol is available and all of the study’s prespecified (primary and secondary) outcomes that are of interest for this review have been reported in the pre‐specified way
Adequacy of HIT monitoring	Low risk	Assessment of HIT antibodies occurred independently of clinical suspicion of HIT