The authors concluded that apixaban was non-inferior to subcutaneous enoxaparin when used for the same duration, with considerable advantage regarding the safety profile of major bleeding after total knee arthroplasty. The authors' conclusions reflected the evidence presented, but caution should be taken when interpreting these findings as the review included only a small number of studies from the same author.

To compare the effects of apixaban versus enoxaparin in patients following total knee arthroplasty.

MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science were searched for studies in any language between 1966 and July 2010; search terms were reported. Reference lists of retrieved articles were searched manually.

Prospective randomised controlled trials (RCTs) in adults aged at least 18 years who were scheduled for elective total knee arthroplasty for one or both knees, including revision, were eligible for inclusion where participants were assigned to oral apixaban treatment or subcutaneous enoxaparin group. Studies could be either open label or blinded and needed to report sample sizes. Eligible studies also reported efficacy and safety outcomes.

In the included studies the primary efficacy outcome was major venous thromboembolism (asymptomatic or symptomatic proximal deep-vein thrombosis (DVT) and objectively confirmed pulmonary embolism). The primary safety endpoint of the analysis was the frequency of major bleeding events during the treatment period or within two days after the last dose of study medication. Secondary safety outcomes were assessed.

Two RCTs compared apixaban (2.5mg twice daily) versus enoxaparin: one used a 40mg dose of enoxaparin and initiated treatment preoperatively and the other used a 30mg twice-daily dose of enoxaparin and initiated treatment postoperatively; both trials followed patients for 60 days. A third study initiated treatment postoperatively and had multiple arms that assessed differing daily doses of apixaban (5mg, 10mg and 20 mg) given either once or twice daily compared with enoxaparin (30mg twice daily). The duration of drug treatment ranged from 10 to 14 days. Mean age of patients ranged from 65.6 to 67.2 years. Duration of hospital stay ranged from six to 38 days. Most patients were female. All studies were conducted in Denmark

The authors did not state how the studies were selected for the review.

Two reviewers independently assessed study quality using a critical review checklist of the Dutch Cochrane Centre. Criteria included adequate sequence generation, allocation concealment, blinding, selective outcome reporting and other sources of bias.

Two reviewers independently extracted intention-to-treat data to calculate odds ratios (OR) and 95% confidence intervals (CI) for the efficacy and safety outcomes of interest. Study authors were contacted, where necessary, for clarification or additional information. Discrepancies were resolved by consensus.

Odds ratios and 95% CI were pooled using a fixed-effects model weighted by the inverse of the variance; DerSimonian and Laird random-effects models were used where significant heterogeneity was present (I²>50%). Heterogeneity was assessed using I² and X². Heterogeneity was explored through subgroup (stratified by the different regimens of enoxaparin administration) and sensitivity analyses (omitting single studies to assess the impact of doing so). The Egger regression test, Begg adjusted rank correlation test and visual inspection of funnel plots were used to assess publication bias.

Three RCTs with 7,337 participants (4,057 were treated with apixaban and 3,280 treated with subcutaneous enoxaparin) were included. Duration of drug treatment ranged from 10 to 14 days. All studies were considered to be at low risk of bias: randomised treatment allocation sequences were generated in all trials, blinding was conducted across all trials, outcome measurements were unlikely to be influenced by lack of blinding and the numbers and reasons for withdrawal/drop-out were reported.

Compared with enoxaparin, proximal deep-vein thrombosis was significantly less prominent among participants who received apixaban (OR 0.47, 95% CI 0.27 to 0.82, I²=10.6%). There was no significant reduction in the risk of pulmonary embolism (I²=40.8%).

Apixaban was associated with lower major bleeding rates than enoxaparin (OR 0.55, 95% CI 0.32 to 0.96, I²=0). There were no significant differences between treatments for other safety outcomes (clinically relevant non-major bleeding, raised hepatic transaminase enzyme or bilirubin concentrations and arterial thromboembolic events).

There was no evidence for publication bias.

Apixaban was non-inferior to subcutaneous enoxaparin when used for the same duration and had considerable advantage regarding the safety profile of major bleeding after total knee arthroplasty.

The review question was clear and supported by potentially reproducible inclusion criteria. The search strategy appeared to include a number of relevant sources and was not restricted by language, which reduced the possibility of language bias. It appeared that no specific searches were made for unpublished studies, so some potentially relevant data may have been missed. Publication bias was assessed, but the small number of included trials meant that the findings may not have been reliable. Quality assessment and data extraction were conducted in duplicate; it was unclear whether similar methods to reduce error and bias were used for study selection. Study quality was assessed using an appropriate tool and results were reported. Adequate details of primary studies were provided. The meta-analyses used were reasonable. Heterogeneity was assessed and attempts were made to explore its sources.

The authors' conclusions reflected the results of the review, but should be interpreted with caution due to the small number of studies. The authors assessment that more high-quality RCTs were required seems reasonable.

Practice: The authors stated that for elective total knee arthroplasty patients undergoing, apixaban could be considered an alternative to conventional thromboprophylaxis regimens taking into consideration the patient’s clinical circumstances.

Research: The authors stated that larger high-quality RCTs that compared apixaban to enoxaparin at differing doses were required.

Not stated.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.