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A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism: examining some unanswered questions regarding location of treatment, product type, and dosing frequency |
Dolovich L R, Ginsberg J S, Douketis J D, Holbrook A M, Cheah G |
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Authors' objectives To compare the efficacy and safety of unfractionated heparin (UFH) and low molecular weight heparins (LMWHs) and to examine current controversies in the treatment of venous thromboembolism (VTE) (i.e. setting, product type, and frequency of administration).
Searching MEDLINE (1986 to 1996), HEALTH (1975 to 1996) and the Cochrane Library (Issue 1, 1997) were searched using a comprehensive search strategy along with MeSH terms and textwords, including 'anticoagulant therapy', 'heparin', and 'LMWHs' in their various formulations, 'thromboembolism' and 'pulmonary embolism'. In addition the references of previous reviews, files of local thromboembolism experts, and abstracts from recent meetings were reviewed. A study was excluded if it was not in English or French, or if data could not be extracted, or if there was no patient follow-up beyond the initial heparin administration.
Study selection Study designs of evaluations included in the reviewOnly randomised controlled trials (RCTs) were included in the review.
Specific interventions included in the reviewUFH and LMWHs (Dalteparin 120 every 12 hours or 200 IU/kg once daily, nadroparin 12500 -17500 IU according to weight, tinzaparin 175 IU/kg once daily, enoxaparin 100 IU/kg twice daily, and reviparin 3500 - 6300 IU according to weight twice daily).
Participants included in the reviewPatients diagnosed with acute VTE. The diagnosis had to have been confirmed by the presence of an intraluminal filling defect on contrast venography films, venous non-compressibility on Duplex ultrasonography films taken for acute DVT, the results of a high-probability ventilation-perfusion lung scan, or the presence of an intraluminal filling defect on pulmonary angiography films taken for pulmonary embolism (PE). Twenty percent of the patients included in the review presented initially with PE. The mean age of patients in the studies included in the review ranged from 57 to 67 years and the percentage of males ranged from 43.8 to 61.2%
Outcomes assessed in the reviewThe main outcomes variables were the incidence of recurrent VTE, major bleeding and total mortality. The incidence of PE, minor bleeding and thrombocytopaena were also recorded. Major bleeding, minor bleeding, total mortality, or thrombocytopaenia were identified according to a blinded outcome assessment that was confirmed by an independent assessor or adjudication committee.
How were decisions on the relevance of primary studies made?Studies for were selected inclusion in the review according to a predetermined process and set of criteria. Selection was performed by two reviewers independently, with disagreements resolved by consensus. Agreement scores were calculated and evaluated at different stages of the process. Revisions in coding definitions and procedures at each stage were made if necessary.
Assessment of study quality The methodological quality of the studies included in the review was assessed using criteria adapted from Kahn et al. and Oxman et al. (see Other Publications of Related Interest no.1-2). The quality assessment was performed independently and in duplicate, with discrepancies resolved by review of the original study.
Data extraction The data were extracted from the original studies independently and in duplicate, with discrepancies resolved by review of the original study. The categories of data extracted were: details of treatment regimen, duration of treatment, duration of follow-up, absolute event rates for outcome variables,
Methods of synthesis How were the studies combined?The studies were combined in a quantitative synthesis. The primary analysis was the comparison of therapy with UFH versus LWMHs. A random-effects model was used to calculate a combined relative risk (RR) for LMWHs and UFH. 2-sided p values and 95% CI were calculated. The model of random effects was used. Data were analysed according to the principle of intention-to-treat. Three subgroup analyses were performed: once-daily versus twice daily treatment; in- versus out-patient treatment; and comparisons between individual LMWHs. Weighted least-squares regression linear regression was used to determine statistically significant differences between subgroups. The dependant variable was the individual study RR. Weights were the components of variance owing to interstudy variation in effect size as determined using the random-effects model. The coefficient slope of the heparin type X sub-group factor was examined to detect a significant difference in the linear relationship formed by the data generated from one subgroup compared with another.
How were differences between studies investigated?Chi-squared tests for heterogeneity were calculated.
Results of the review Thirteen studies were included in the meta-analysis (n=4447).
Of the studies included, six reported an acceptable method of randomisation and only one reported a double-blind method. All but one study re-examined over 90% of the patients who were enrolled. Eight of the 13 studies enrolled only patients with proximal DVT or PE, whilst the other five enrolled only patients with distal DVT.
No significant heterogeneity was found for any of the primary or secondary analyses.
The comparison of LMWH with UFH yielded the following results:
Incidence of recurrent VTE (n=13): pooled RR 0.85 (95% CI: 0.65,1.12) (p>0.05).
Incidence of PE (n=12): pooled RR 1.02 (95% CI:0.64, 1.62) (p>0.05).
Incidence of major bleeding (n=13): pooled RR 0.63 (95% CI: 0.37, 1.05) (p>0.05).
Incidence of minor bleeding (n=12): pooled RR 1.18 (95% CI:0.87,1.61) (p>0.05).
Total mortality (n=10): pooled RR 0.76 (95% CI: 0.59, 0.98) p< 0.05 in favour of LMWH.
Incidence of thrombocytopaenia (n=9): pooled RR 0.85 (95% CI: 0.45, 1.62) (p>0.05).
In-patient LMWH was associated with fewer major bleeding events than was out-patient LMWH and all other indirect comparisons produced differences that were not statistically significant.
Authors' conclusions LMWHs are at least as effective as UFH in preventing recurrent VTE. It is unlikely that LMWHs are superior in the treatment of VTE, but they do show a statistically significant decrease in total mortality. No differences were seen in the development of recurrent VTE dependent on treatment setting. There were no apparent differences between once-daily and twice daily therapy or among products. Inpatient therapy may be associated with less major bleeding; therefore, if LMWHs are given in the outpatient setting, patients should be rigorously monitored.
CRD commentary This was a well structured, thorough review, with well defined inclusion/exclusion criteria. The literature search was comprehensive with electronic databases supplemented by handsearches. There may be some publication bias as no attempt was made to identify unpublished studies and only English and French language articles were included. The quality of the studies included in the review was assessed according to accepted, published criteria and all selection of articles, study validation and data extraction was conducted independently in duplicate. All 13 papers included are tabulated in the review, with sufficient details regarding LMWH regimens, treatment duration, period of follow-up and outcomes. However, no information is presented regarding the regimens of UFH. The quantitative synthesis utilised was appropriate and the data are summarised with RR and displayed in forest plots. The authors' conclusion are justified by the results of the review with the exception of the statement "No differences were seen in the development of recurrent VTE dependent on treatment setting", supporting findings for which do not appear to be in the review.
Implications of the review for practice and research Practice: The author states 'LMWHs are at least as effective as UFH in preventing recurrent VTE, but that LMWHs are unlikely to be superior'.
Research: The author states 'Further studies should be done to determine whether different LMWHs have different safety and efficacy profiles and to directly compare once-daily with twice-daily dosing'.
Bibliographic details Dolovich L R, Ginsberg J S, Douketis J D, Holbrook A M, Cheah G. A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism: examining some unanswered questions regarding location of treatment, product type, and dosing frequency. Archives of Internal Medicine 2000; 160(2): 181-188 Other publications of related interest 1. Kahn KS, Daya S, Jada AR. The importance of quality of primary studies in producing unbiased systematic reviews. Arch Intern Med 1996;156:661-6. 2. Oxman AD, Cook DJ, Guyatt GH. Users' guide to the medical literature. VI. How to use an overview. Evidence-Based Medicine Working Group. JAMA 1994;272:1367-71.
Indexing Status Subject indexing assigned by NLM MeSH Anticoagulants /therapeutic use; Heparin /therapeutic use; Heparin, Low-Molecular-Weight /therapeutic use; Humans; Randomized Controlled Trials as Topic; Thromboembolism /drug therapy AccessionNumber 12000008103 Date bibliographic record published 31/03/2001 Date abstract record published 31/03/2001 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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