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Efficacy and safety of low molecular weight heparin, unfractionated heparin and warfarin for thrombo-embolism prophylaxis in orthopaedic surgery: a meta-analysis of randomised clinical trials |
Palmer A J, Koppenhagen K, Kirchhof B, Weber U, Bergemann R |
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Authors' objectives To compare the efficacy and safety of low molecular weight heparin (LMWH), unfractionated heparin (UHF) and warfarin for prophylaxis of thromboembolism in orthopaedic surgery.
Searching MEDLINE was searched from 1966 to June 1994 for clinical trials assessing LMWH, UFH and warfarin derivatives as prophylaxis in orthopaedic surgery patients. In addition, a manual search of the reference lists of retrieved articles, other reviews and meta-analyses was carried out. Articles written in any language were considered.
Study selection Study designs of evaluations included in the reviewTrials were included if they were randomised, open or controlled with dextran, UFH (alone or with dihydroergotamine), warfarin, placebo or other LMWH.
Specific interventions included in the reviewLMWH versus dextran, UFH (alone or with dihydroergotamine), warfarin, saline or placebo. The LMWH studied were enoxaparin, parvoparin, ORG10172, Embolex NM, heparin NM, dihydergot, fraxiparin, logiparin, Kabi 2165, sandoparin, alfa LMWH, clivarine, and RD heparin.
Participants included in the reviewPatients who underwent orthopaedic surgery and deep vein thrombosis (DVT) prophylaxis with LMWH, UFH or warfarin.
Outcomes assessed in the reviewThe outcomes assessed were DVT, pulmonary embolism (PE) and safety effects. DVT was diagnosed by phlebography, whilst PE was diagnosed by pulmonary angiography, ventilation or perfusion lung scan, or at autopsy. Safety effects were assessed by major or minor bleeding.
How were decisions on the relevance of primary studies made?The trials were assessed independently by two physicians.
Assessment of study quality The authors do not state that they assessed validity.
Data extraction The authors do not state how the data were extracted for the review, or how many of the authors performed the data extraction.
Methods of synthesis How were the studies combined?Efficacy was assessed on the basis of a standard analysis where only those who completed the trial were included in the final analysis. Safety effects were assessed on an intention to treat basis.
The relative risks (RRs) calculated from each trial were combined using both fixed-effect (Bayes) and random-effects (DerSimonian and Laird) methods with the Fast*Pro software.
How were differences between studies investigated?Homogeneity was tested using the chi-squared test.
Results of the review Twenty randomised controlled trials (24 relevant treatment arms), with 3,807 participants in the active treatment group and 3,093 in the control group, were included.
The mean probabilities to develop DVT, PE and major and minor bleeding using UFH as prophylaxis were 0.21 (95% confidence interval, CI: 0.18, 0.24), 0.01 (95% CI: 0.00, 0.02), 0.05 (95% CI: 0.03, 0.07), and 0.19 (95% CI: 0.17, 0.22), respectively.
The RR of DVT for LMWH versus UFH was 0.76 (95% CI: 0.60, 0.91) when using the fixed-effect model, which was significant (p<0.05). The RR of DVT for LMWH versus warfarin was 0.78 (95% CI: 0.69, 0.87, p<0.05).
The RR of major bleeding for LMWH versus UFH was 1.72 (95% CI: 1.00, 2.88) when using the fixed-effect model. The RR of major bleeding for LMWH versus warfarin was 1.75 (95% CI: 0.92, 3.07).
The RR of minor bleeding for LMWH versus UFH was 0.76 (95% CI: 0.64, 0.92) when using the fixed-effect model, which was significant (p<0.05). The RR of minor bleeding for LMWH versus warfarin was 3.28 (95% CI: 2.21, 4.70, p<0.05). The RR of PE for LMWH versus UFH was 0.50 (95% CI: 0.03, 2.43). The RR of PE for LMWH versus warfarin was 1.00 (95% CI: 0.10, 9.94).
The chi-squared test indicated there was no significant heterogeneity in the RR of DVT, PE, and major and minor bleeding calculated from each individual study.
Authors' conclusions In orthopaedic surgery, LMWH was significantly superior to both UFH and warfarin in the prevention of DVT> The use of LMWH resulted in significantly less minor bleeding complications when compared with UFH, but significantly more minor bleeding when compared with warfarin.
CRD commentary The authors searched MEDLINE and scanned the bibliographies of identified articles for additional studies. It is unclear how many relevant studies may have been missed by restricting the search to one electronic database.
The inclusion and exclusion criteria were listed. One table cited the characteristics of the included studies, while a second listed the excluded studies and the reasons for their exclusion. No information was given on whether the included studies were assessed for validity.
Although the authors found no significant heterogeneity between the studies, the results of this analysis should be treated with caution because there were several treatment variations and differences in group sizes between the trials, especially in the grouping of LMWH versus warfarin. Also, when the results from the random-effects and fixed-effect models were compared, differences were found. For example, the random-effects model indicated a non significant trend towards a decreased risk of DVT when using LMWH compared with UFH, whilst the fixed-effect method showed a significant difference.
Implications of the review for practice and research The authors state that there is a preference for use of LMWH over UFH in orthopaedic surgery.
The authors suggest that there is a need for a large-scale randomised controlled trial comparing LMWH, UFH and warfarin to resolve the issue of bleeding risks, and to provide sufficient statistical power to determine differences in the risks of developing PE.
Funding Knoll AG, Germany; Immuno GmbH, Germany.
Bibliographic details Palmer A J, Koppenhagen K, Kirchhof B, Weber U, Bergemann R. Efficacy and safety of low molecular weight heparin, unfractionated heparin and warfarin for thrombo-embolism prophylaxis in orthopaedic surgery: a meta-analysis of randomised clinical trials. Haemostasis 1997; 27(2): 75-84 Other publications of related interest Palmer AJ, Schramm W, Kirchhof B, Bergemann R. Low molecular weight heparin and unfractionated heparin for prevention of thrombo-embolism in general surgery: a meta-analysis of randomised clinical trials. Haemostasis 1997;27:65-74.
This additional published commentary may also be of interest. Low molecular weight heparin and knee replacement. Bandolier 1999;63:7-8.
Indexing Status Subject indexing assigned by NLM MeSH Anticoagulants /adverse effects /therapeutic use; Hemorrhage /chemically induced; Heparin /adverse effects /therapeutic use; Heparin, Low-Molecular-Weight /adverse effects /therapeutic use; Humans; Orthopedics; Postoperative Complications /prevention & Randomized Controlled Trials as Topic; Thromboembolism /prevention & Warfarin /adverse effects /therapeutic use; control; control AccessionNumber 11997003598 Date bibliographic record published 30/06/1999 Date abstract record published 30/06/1999 Record Status 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. |
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