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Low-molecular weight heparins in venous and arterial thrombotic disease |
Bijsterveld N R, Hettiarachchi R, Peters R, Prins M H, Levi M, Buller H R |
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Authors' objectives To investigate the efficacy and safety of low molecular weight heparins (LMWHs), compared with unfractionated heparin (UFH) or placebo, in the initial treatment of venous thromboembolisms, myocardial infarction, unstable coronary syndromes and ischaemic stroke.
Searching MEDLINE and EMBASE were searched from 1966 until June 1999, and the reference lists from all relevant articles were manually checked for additional publications. The principal investigators of relevant studies that were only published in abstract form were contacted. Only publications in the English language were included.
Study selection Study designs of evaluations included in the reviewRandomised controlled trials (RCTs) were included.
Specific interventions included in the reviewStudies comparing fixed-dose subcutaneous LMWH with dose-adjusted UFH or placebo were eligible for inclusion. Dose-finding studies and studies evaluating non-therapeutic doses of UFH or LMWH were excluded. The LMWHs included were CY222 (15 aXa U/kg), nadroparin (90 to 95 aXa U/kg), tinazeparin (175 aXa U/kg), enoxaparin (100 aXa U/kg), dalteparin (200 aXa U/kg) and reviparin (8.75 aXa U/kg). These were compared with UFH.
Participants included in the reviewStudies of patients with acute venous thromboembolism, acute myocardial infarction, unstable angina, non Q-wave infarction or ischaemic stroke were eligible for inclusion.
Outcomes assessed in the reviewThe studies had to report clinical outcomes to be eligible for inclusion. The outcomes reported were recurrent venous thromboembolism and total mortality after 3 months' follow-up, major bleeding, reinfarction, death, unstable angina and non Q-wave infarction, recurrent angina, myocardial infarction, death, urgent revascularisation, recurrent stroke, death due to stroke, and disability.
How were decisions on the relevance of primary studies made?The authors do not state how the papers were selected for the review, or how many of the reviewers performed the selection.
Assessment of study quality The authors do not report the criteria used to assess validity, or how the validity assessment was performed.
Data extraction The authors do not state how the data were extracted for the review, or how many of the reviewers performed the data extraction.
The data extracted included: year of study, the number of participants, diagnosis type, dose and frequency of LMWH and UFH adjunctive therapies, length of follow-up, and incidence of relevant outcomes. Odds ratios (ORs) for the efficacy and safety outcomes were calculated for each study.
Methods of synthesis How were the studies combined?When a sufficient number of studies with adequate methodology and similar design were available, the pooled ORs and 95% confidence intervals (CIs) comparing the incidences of the efficacy and safety outcomes between the treatment groups were calculated using the Mantel-Haenszel method (see Other Publications of Related Interest).
How were differences between studies investigated?Heterogeneity was not formally assessed.
Results of the review Twenty-five RCTs (21,283) were included. There were 13 RCTs (n=4,509) of venous thromboembolism, 2 RCTs (n=1,076) of acute myocardial infarction, 7 RCTs (n=13,715) of unstable angina and 3 RCTs (n=1,983) of ischaemic stroke..
Acute venous thromboembolism (13 RCTs): the pooled OR was 0.77 (95% CI: 0.57, 1.04) for the 3-month recurrent thromboembolism rates, and 0.61 (95% CI: 0.39, 0.95) for bleeding complications during exposure.
Acute myocardial infarction: one RCT suggested a reduction in the incidence of reinfarction and cardiac death in LMWH recipients compared to UFH, while a placebo-controlled study revealed no beneficial effect of LMWH on these outcomes.
Acute coronary syndromes (6 RCTs): the OR was 0.88 (95% CI: 0.76, 1.01) for recurrent angina, 0.84 (95% CI: 0.69, 1.01) for myocardial infarction, 0.83 (95% CI: 0.70, 0.99) for urgent revascularisation, 1.09 (95% CI: 0.70, 1.70) for major bleeding, and 0.98 (95% CI: 0.75, 1.75) for death.
Acute ischaemic stroke (3 RCTs): the OR was 0.68 (95% CI: 0.41, 1.13) for 10-day recurrent stroke, 0.94 (95% CI: 0.78, 1.15) for death or disability after 3 months, and 2.92 (95% CI: 1.88, 4.55) for major bleeding complications.
Authors' conclusions Fixed-dose subcutaneous LMWH appeared to be a safe and effective alternative for dose-adjusted intravenous heparin in the treatment of patients with acute venous thrombotic disease, as well as patients with acute unstable coronary syndromes. The effectiveness of LMWH in patients with acute myocardial infarction remains unclear. There seemed to be no beneficial effect of LMWH, compared with placebo, for the treatment of patients with acute ischaemic stroke, while the risk of major bleeding was clearly increased.
CRD commentary This review was presented clearly. The question to be addressed was clearly defined and the inclusion criteria were reported. The search strategy appeared adequate, although the search terms were not listed. Only trials reported in the English language were included; trials were omitted if the data were not present in the papers and no attempt to contact the authors was made. It is therefore possible that trials were missed. The 'Methods' section lacked details of the criteria used to assess validity, and of how decisions on the relevance of the studies were made and how the data were extracted from the primary studies. This review used a meta-analysis to pool the study results. Heterogeneity was not formally assessed and so it is not possible to tell whether it was appropriate to pool the results. The authors acknowledged that no attempt was made to assess the differences in different LMWH preparations. The results should therefore be treated with some caution.
Implications of the review for practice and research Practice: The authors did not state any implications for practice.
Research: The authors imply that further research is needed, although this may be supplied by ongoing large trials.
Bibliographic details Bijsterveld N R, Hettiarachchi R, Peters R, Prins M H, Levi M, Buller H R. Low-molecular weight heparins in venous and arterial thrombotic disease. Thrombosis and Haemostasis 1999; 82(Supplement 1): 139-147 Other publications of related interest Mantel N. Haenszel W. Statistical aspects of the analysis from retrospective studies of disease. J Natl Cancer Inst 1959; 22:719-48.
Indexing Status Subject indexing assigned by NLM MeSH Fibrinolytic Agents /administration & Heparin, Low-Molecular-Weight /administration & Humans; Injections, Subcutaneous; Randomized Controlled Trials as Topic; Thrombosis /drug therapy; Treatment Outcome; Venous Thrombosis /drug therapy; dosage; dosage AccessionNumber 12000003371 Date bibliographic record published 31/05/2003 Date abstract record published 31/05/2003 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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