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

Methods

• RCT performed in 67 ICUs in academic and community hospitals

• Countries: Canada, Australia, Brazil, Saudi Arabia, USA, and UK

Participants

• Patients at least 18 years old, weighed at least 45 kg, and expected to remain in the ICU for at least 3 days

• 3746 participants were randomised to receive the LMWH, dalteparin, or UFH

• Mean age (SD) of participants in the UFH group was 61.7 (16.4) and equal to 61.1 (16.5) in the group of participants receiving LMWH

• From the total participants who received the intended treatment, 475 had a surgical admitting diagnosis and received heparin for at least 5 consecutive days.

• Participant characteristics did not differ between the heparin groups.

Interventions

• 238 surgical participants received UFH for prophylaxis, catheter patency or therapeutic anticoagulation.

• 237 participants received open label LMWH for treatment of prophylaxis

• Median duration of exposure to a study drug in both groups was 7 days.

Outcomes

• Clinical diagnosis of HIT: platelet count less than 50 x 10⁹/L or less than 50% of the baseline value, or if HIT was otherwise suspected

• Laboratory diagnosis of HIT: ¹⁴C‐SRA, which, if positive, defined HIT

• Secondary outcomes: DVT, PE, venous thromboembolism, death, and a composite of either venous thromboembolism or death

Notes

Funding was provided by the Canadian Institutes of Health Research, the Australian and New Zealand College of Anesthetists Research Foundation, and the Heart and Stroke Foundation of Canada. Study drugs were provided by Pfizer and by Eisai. Neither the funders nor the drug manufacturers played any role in the design or conduct of the trial or in the analysis or interpretation of the data.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

A pharmacist used a centralised electronic system to randomise participants to either intervention group

Allocation concealment (selection bias)

Low risk

Allocation concealment was detailed in the study protocol report: "Allocation concealment is ensured by access via a password‐protected Web site or voice‐activated telephone system. Research pharmacists prepare identical syringes for twice‐daily subcutaneous injection of UFH 5000 IU or dalteparin 5000 IU once daily plus once‐daily placebo injection, which are administered by bedside nurses for the duration of ICU stay."

Blinding of participants and personnel (performance bias)
All outcomes

High risk

According to correspondence with study authors, the study drugs were given in an open label fashion

Blinding of outcome assessment (detection bias)
heparin‐induced thrombocytopenia

Unclear risk

The study report did not describe any procedure to blind adjudicators for HIT diagnosis

Blinding of outcome assessment (detection bias)
venous thromboembolism

Low risk

Diagnosis of venous thromboembolism was done by two adjudicators who were unaware of study‐group assignments and of one another’s assessments

Incomplete outcome data (attrition bias)
HIT

Low risk

Losses of follow‐up of the original trial were minor and adequately reported

Selective reporting (reporting bias)

Low risk

The trial reports appeared to include all expected outcomes. Therefore, it was probably free of attrition bias. In addition, complementary data were sought from the study authors and used in the analysis.

Adequacy of HIT monitoring

Low risk

HIT was diagnosis based on clinical suspicion and appropriate confirmation through laboratory tests

Methods

• Multicentre, randomised clinical trial

• Country: Germany and Canada

Participants

• The LMWH, enoxaparin (Lovenox, Rhône–Poulenc Rorer, Montreal), was compared with a standard heparin (Calciparine, Laboratoires Anglo‐French, Dorval, Quebec, Canada; prepared from porcine intestinal mucosa) for the prevention of thrombosis after elective hip surgery.

• 665 participants were randomised in the original trial (Levine 1991) and Warkentin 2003 intended to determine the presence of platelet‐activating HIT‐IgG antibodies in a subgroup consisting of 362 participants in whom serial plasma samples were available, with at least 1 sample that was obtained on postoperative day 7 or later. These participants were tested for HIT by SRA and by an ELISA to confirm the presence of antibodies of IgG class in the samples which tested positive for HIT in the SRA.

• Mean age of participants was equal to 66.8 years (UFH group) and 66.2 years (LMWH group). Participant characteristics did not differ between the heparin groups.

• Participants enrolled were undergoing hip arthroplasty.

Interventions

• 333 participants were randomised to receive LMWH and 332 participants to UFH.

• The subgroup analysis consisted of 192 participants receiving UFH and 170 participants receiving LMWH.

• The study drugs were given for a mean (± SD) period of 10 ± 3 days (maximum: 14).

Outcomes

• The primary outcome assessed was HIT defined as a 50% or greater fall in the platelet count from the postoperative peak (up to postoperative day 14). The HIT was assured by demonstration of functional IgG antibodies through positive SRA and an immunoassay specific to IgG immunoglobulin class.

• Secondary outcomes were reported in participants in whom developed HIT were DVT and venous thromboembolism.

Notes

• This study represents a secondary analysis using participants enrolled in a major clinical trial (Levine 1991).

• Funding for the clinical trial was provided by Aventis Pharma, Laval, Quebec.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

The trial report stated the accomplishment of a randomisation process but no information regarding the method used was available

Allocation concealment (selection bias)

Unclear risk

Study authors did not report any allocation concealment approach

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Study authors did not report the method assuring blinding of participants. Indeed, they describe the study merely as a randomised trial

Blinding of outcome assessment (detection bias)
heparin‐induced thrombocytopenia

High risk

Blinding of HIT assessment was probably not done since this event was analysed only in secondary analysis years after the original trial

Blinding of outcome assessment (detection bias)
venous thromboembolism

Low risk

Clinical events and radiologic studies for the diagnosis of DVT, PE and haemorrhage were interpreted by a committee that was unaware of the assigned treatments

Incomplete outcome data (attrition bias)
HIT

High risk

Losses of follow‐up of the original trial were minor and adequately reported. However, the selection process for the subgroup of participants used in the secondary analysis to determine the incidence of HIT was conducted according to researchers' convenience. Therefore, one cannot assure that comparativeness allowed by the randomisation process was not missed

Selective reporting (reporting bias)

Low risk

Trial report appears to include all expected outcomes and it is probably free of any suggestion of selective reporting

Adequacy of HIT monitoring

Low risk

Assessment of HIT antibodies occurred independently of clinical suspicion of HIT