Chest
Volume 144, Issue 2, August 2013, Pages 593-600
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Original Research
Antithrombotic Therapy
Relative Effects of Two Different Enoxaparin Regimens as Comparators Against Newer Oral Anticoagulants: Meta-analysis and Adjusted Indirect Comparison

https://doi.org/10.1378/chest.12-2634Get rights and content

Background

Two different regimens of enoxaparin (40 mg once daily or 30 mg bid) have been used as control arms in trials of new oral anticoagulants. The choice of enoxaparin comparator may influence the perceived relative efficacy and safety of the newer agents, and we aimed to identify any significant differences between the two enoxaparin regimens.

Methods

We searched MEDLINE, EMBASE, and Cochrane Library for randomized controlled trials that compared enoxaparin to oral anticoagulant (apixaban, dabigatran, rivaroxaban) thromboprophylaxis in elective total knee or hip arthroplasty. Total VTE and bleeding events were pooled using fixed-effects meta-analysis and heterogeneity assessed with the I2 statistic. We conducted adjusted indirect comparisons of bid vs once-daily enoxaparin regimes based on new oral anticoagulants as common comparators.

Results

Fourteen randomized controlled trials in hip and knee replacement surgery met the inclusion criteria. Adjusted indirect comparison showed that bid enoxaparin was significantly more effective in preventing VTE than enoxaparin once daily (relative risk [RR], 0.71; 95% CI, 0.61-0.83; P < .00001). For major and clinically relevant hemorrhage, adjusted indirect comparison showed that enoxaparin bid was nonsignificantly associated with increased risk of bleeding (RR 1.27; 95% CI, 0.97-1.65; P = .08) above that of enoxaparin once daily. Subgroup analysis limited to total knee arthroplasty trials showed similar results.

Conclusions

The use of once-daily enoxaparin regimen as control in clinical trials will lead to more favorable estimates of relative efficacy for the new oral anticoagulants than if enoxaparin 30 mg bid had been chosen as a comparator.

Section snippets

Search Strategy

We conducted a systematic review of the literature to identify knee or hip surgery trials involving the oral anticoagulants dabigatran, rivaroxaban, or apixaban compared with once-daily or bid enoxaparin. A search was conducted of MEDLINE, EMBASE, and Cochrane library. The exact search strategy is shown in e-Appendix 1. We also checked the bibliographies of included trials for any relevant studies.

Eligibility Criteria

The specific inclusion criteria for randomized controlled trials (RCTs) were (1) double-blind

Study Selection, Design, and Methodology

Fourteen double-blind randomized trials met the inclusion criteria (four dabigatran,11, 12, 13, 14 six rivaroxaban,15, 16, 17, 18, 19, 20 and four apixaban21, 22, 23, 24 trials); the study selection process is shown in Figure 1. Five of the 14 trials used enoxaparin 30 mg bid as the control arm while the remaining nine used once-daily enoxaparin 40 mg. Study methods are shown in Table 1.

Quality Assessment

The quality of studies is shown in e-Table 1. Randomization methods were adequate and sufficiently described

Discussion

Our adjusted indirect comparison indicates that once-daily 40-mg enoxaparin is associated with a significantly inferior effect (about 30% less benefit) for prevention of total VTE and 45% less benefit for symptomatic VTE as compared with bid 30-mg enoxaparin. The direction of effect is consistent, irrespective of whether the adjusted indirect comparison was performed through the apixaban or dabigatran or rivaroxaban trials dataset, or whether we used total VTE or symptomatic VTE as the outcome

Acknowledgments

Author contributions: Dr Loke is the guarantor for the manuscript.

Dr Kwok: contributed to the study by performing the search, screening search results and reviewing abstracts for study selection, extracting the data, performing the data analysis, and writing the manuscript.

Dr Pradhan: contributed to the study by screening search results and reviewing abstracts for study selection, extracting the data, and writing the manuscript.

Dr Yeong: contributed to the study by screening search results and

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  • Cited by (0)

    Funding/Support: The authors have reported to CHEST that no funding was received for this study.

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