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The effects of unfractionated heparin on survival in patients with malignancy: a systematic review |
Smorenburg S M, Hettiarachchi R J, Vink R, Buller H R |
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Authors' objectives To perform a critical review of all the available clinical studies that reported the effects of unfractionated heparin on mortality in cancer patients, in relation to placebo or no treatment.
Searching MEDLINE, EMBASE and Current Contents were searched from 1966 to 1998. The reference lists of all articles were examined in order to identify additional papers.
Study selection Study designs of evaluations included in the reviewRandomised trials were included. Studies that were non-randomised, or which used a post-hoc analysis for the long-term effects of unfractionated heparin in cancer patients, were included if the outcome of total mortality was specified, follow-up was complete, and the dose, duration and mode of administration of unfractionated heparin was specified.
Specific interventions included in the reviewStudies that used prophylactic or therapeutic doses of unfractionated heparin were included. The included studies used unfractionated heparin either alone or in combination with chemotherapy, compared with placebo, no treatment or chemotherapy alone.
Participants included in the reviewThe included studies were conducted in patients with gastrointestinal cancers or small cell lung cancer.
Outcomes assessed in the reviewMortality was the only outcome reported. The duration of follow-up in the included studies ranged from 3 to 9 years.
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 Study quality was assessed, and the studies were classified as level 1 if they fulfilled the following criteria.
1. The study was properly randomised.
2. The study used an a priori-specified hypothesis.
3. The outcome of total mortality was specified.
4. The follow-up was completed.
5. The dose, duration and mode of administration of unfractionated heparin was specified.
Studies were grouped as level 2 if they fulfilled criteria 3, 4 and 5 only. Potentially eligible studies were evaluated for methodological strength (classified as level 1 or level 2) by two independent authors.
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 categories of data extracted were study design, type of cancer, number of patients, intervention, control and follow-up; mortality rates at 3 years were also extracted or calculated.
Methods of synthesis How were the studies combined?The odds ratio (OR) of 3-year mortality among patients treated with unfractionated heparin or placebo/no treatment was calculated separately for each study, and these were then pooled, where appropriate, using the Mantel-Haenszel method. Publication bias was not investigated.
How were differences between studies investigated?A statistical test for homogeneity was used. No details of the test were reported, other than it considered whether differences in the treatment effect across individual trials were consistent with natural variation around a constant effect. The findings from 1evel 1 studies were presented separately from level 2 studies, and within these divisions, studies using therapeutic doses of unfractionated heparin were grouped separately from those using prophylactic doses.
Results of the review The review included 3 randomised controlled trials (RCTs; n=695), 4 retrospective cohort analyses (n=1,435), and one unified study of 2 prospective non-randomised trials (n=53).
One RCT (n=277) of a therapeutic dose of unfractionated heparin in small cell lung cancer, versus chemotherapy, showed a trend towards improved survival at 3 years that did not reach statistical significance (OR 0.64, 95% confidence interval, CI: 0.25, 1.62). The median survival and complete response rates were significantly better in the unfractionated heparin group: 37 versus 23% (P=0.004) and 317 versus 261 days (P=0.01), respectively. Prophylactic doses of unfractionated heparin following surgery for colorectal cancer were tested against no further treatment in 2 RCTs (n=418). These showed a significant detrimental effect of unfractionated heparin on 3-year mortality (OR 1.66, 95% CI: 1.02, 2.71). The test for homogeneity was not significant (P=0.28).
A small level 2 study (n=53) that investigated pre-operative chemotherapy with and without a therapeutic dose of unfractionated heparin in colon cancer showed no difference in 3-year mortality (OR 0.52, 95% CI: 0.10, 2.75). Four retrospective cohort studies (n=1,435) of prophylactic doses of unfractionated heparin, versus placebo or no treatment, in patients undergoing major abdominal surgery for malignant disease, showed an overall benefit on mortality after 3 years (OR 0.65, 95% CI: 0.51, 0.84). The test for homogeneity was not significant (P=0.58).
Authors' conclusions There is no convincing evidence of either a positive or negative effect of unfractionated heparin on survival of patients with malignancy.
CRD commentary The review question was broad with respect to participants (any patients with malignancy), intervention (any dose, duration, route or timing), and study design (randomised and non-randomised). Consequently, it was not unexpected that a clear conclusion was not reached. The search to identify published studies was adequate, although publication bias may have influenced the findings. Details of how the review was conducted were not well reported. The included studies were presented adequately in the tables and text. The findings were grouped separately according to study design, and data were pooled appropriately with attention to heterogeneity. The authors discussed several possible reasons why the included studies gave conflicting results, which reflect the broad inclusion criteria, but were unable to reach any conclusions. The recommendation for an RCT of low molecular weight heparin versus placebo, on the basis of results from clinical studies that suggest a potential clinically relevant effect of low molecular weight heparin compared with unfractionated heparin, does not follow clearly from the findings of this review.
Implications of the review for practice and research Practice: The authors did not state any implications for practice.
Research: The authors state that a clinical randomised study is warranted to evaluate the effects of low molecular weight heparin, compared with placebo, on the survival of cancer patients. It is probably appropriate to include a wide spectrum of cancer types in such a trial.
Bibliographic details Smorenburg S M, Hettiarachchi R J, Vink R, Buller H R. The effects of unfractionated heparin on survival in patients with malignancy: a systematic review. Thrombosis and Haemostasis 1999; 82(6): 1600-1604 Indexing Status Subject indexing assigned by NLM MeSH Anticoagulants /adverse effects /therapeutic use; Heparin /adverse effects /therapeutic use; Humans; Meta-Analysis as Topic; Neoplasms /drug therapy /mortality; Randomized Controlled Trials as Topic; Survival Analysis AccessionNumber 11999009938 Date bibliographic record published 28/02/2002 Date abstract record published 28/02/2002 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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