A direct comparison of prophylactic low-molecular-weight heparin versus unfractionated heparin in neurosurgery: A meta-analysis
- Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan, USA.
DOI:10.25259/SNI_428_2019Copyright: © 2019 Surgical Neurology International This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
How to cite this article: Mohamed Macki, Mohamed Fakih, Sharath Kumar Anand, Raviteja Suryadevara, Jaafar Elmenini, Victor Chang. A direct comparison of prophylactic low-molecular-weight heparin versus unfractionated heparin in neurosurgery: A meta-analysis. 18-Oct-2019;10:202
How to cite this URL: Mohamed Macki, Mohamed Fakih, Sharath Kumar Anand, Raviteja Suryadevara, Jaafar Elmenini, Victor Chang. A direct comparison of prophylactic low-molecular-weight heparin versus unfractionated heparin in neurosurgery: A meta-analysis. 18-Oct-2019;10:202. Available from: http://surgicalneurologyint.com/surgicalint-articles/9711/
Background: Several studies have confirmed the role of prophylactic low-molecular-weight heparin (LMWH) for venous thromboembolism (VTE) in neurosurgery; however, a paucity of literature has assessed its safety and efficacy versus prophylactic unfractionated heparin (UFH). The objective is to present a meta-analysis directly comparing prophylactic LMWH to UFH for the prevention of VTE in neurosurgery.
Materials and Methods: Relevant studies that directly compared LMWH to UFH for prophylaxis of VTE in neurosurgery and/or spine surgery were identified by MEDLINE and EMBASE searches plus a scrutiny of references from the original articles and reviews. Three randomized trials were included in the meta-analysis. Efficacy and safety were ascertained per three primary outcome measures: VTE, minor complications (decline in hemoglobin/hematocrit), and major complications. Forest plot analysis provided odds ratio (OR), 95% confidence intervals (CIs), and P-values.
Results: Of the 429 patients in the pooled analysis, the postoperative VTE rate of 5.6% (12/213) after LMWH chemoprophylaxis was equivalent to 3.7% (8/216) after UFH chemoprophylaxis (OR = 1.42, 95% CI 0.62–3.75, P = 0.308). Minor complications of 4.7% versus 4.6%, respectively, were nearly equal (OR = 1.01, 95% CI 0.41– 2.50, P = 0.929). All four major complications included intracranial hemorrhages: three after LMWH (1.4%) and one after UFH (0.5%) (OR = 2.32, 95% CI 0.34–16.01, P = 0.831). Tests for heterogeneity were nonsignificant in all three outcome measures.
Conclusion: Rates of VTE, minor complications, and major complications were equivalent between prophylactic LMWH and UFH in neurosurgery. Further, randomized clinical trials comparing the two heparin products are required to elucidate superior safety and efficacy in neurosurgical patients.
Keywords: Chemoprophylaxis, Heparin, Low-molecular-weight heparin, Meta-analysis, Neurosurgery, Prophylaxis, Unfractionated heparin
In 1983, the pharmaceutical company (now known as) Sanofi™ created a low-molecular-weight heparin (LMWH) drug – an abbreviated formulation from the traditional unfractionated heparin (UFH). The short-chain polysaccharide, called enoxaparin (Lovenox, enoxaparin sodium; Sanofi-Aventis, Bridgewater, New Jersey, USA), promised less frequent subcutaneous dosing without the need to monitor activated partial thromboplastin time. Beginning, in 1993, the Food and Drug Administration approved LMWH for prophylaxis of deep vein thrombosis (DVT) and prophylaxis for ischemic complications of unstable angina/non-Q wave myocardial infarction. Nevertheless, neurosurgeons remained perturbed by the new chemoprophylactic agent in a postoperative regimen. This manuscript presents the first meta-analyses of studies that directly compare prophylactic LMWH to prophylactic UFH in neurosurgery with the primary outcome measures: venous thromboembolism (VTE) and complications.
This study was registered à priori in our institution’s Library Protocol for Systematic Reviews. Per this protocol, all citations were collected by a trained reference analyst with a Master of Library and Information Science and a designation by the Academy of Health Information Professionals. The analyst must follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in the Enhancing the QUAlity and Transparency Of health Research resources, in which a systematic review identified relevant studies through a computer-aided search of American articles (MEDLINE from 1946 to July 17, 2017) and European articles (EMBASE 1947–July 17, 2017) [
The following key words provided sensitivity inclusive of all types of neurosurgical procedures with postoperative chemoprophylaxis: “neurosurgery” and any of its possible endings, “spine” and any of its possible endings, “brain neoplasm” in addition to “prophylaxis” and any of its possible endings, as well as heparin, dalteparin, enoxaparin, Lovenox, and nadroparin. This technique also ensured that citations in the spine subspecialty were not overlooked in orthopedic literature. The references within literature reviews and systematic reviews generated by the computer-aided search were also scrutinized for relevant studies. Only publications that directly compared the efficacy of prophylactic doses of LMWH versus UFH were included in the study. Due to the abundance of literature comparing prophylactic heparin to placebo, studies that did not complete a head-to-head comparison of the two heparin derivatives were excluded from this review. Resources on therapeutic doses of heparin products address topics outside the scope of this analysis and were, thus, excluded from the study. Manuscripts on nonhuman subjects and in languages other than English were similarly excluded from the study. The primary outcomes measure includes incidence of VTE on prophylactic doses of LMWH versus UFH. Secondary outcome measures explored suspected adverse events secondary to chemoprophylaxis. Minor complications were limited to active, noncranial bleeding diathesis, as evidenced by an unexpected decline in hemoglobin/hematocrit. Major complications were defined as other hemorrhagic complications. Data were extracted from the articles by two independent reviewers.
Three articles met the inclusion and exclusion criteria [
Where, n equals the number of patients treated, d equals the number of patients with the event, and N equals the total number of patients in the trial. Two-tailed P values were calculated from the 95% confidence intervals (CIs) from the individual studies and the overall odds ratio (OR). The data from the three studies were illustrated on a forest plot. To emphasize larger studies, the size of the squares is proportional to variance (V[O-E]).
Since the evaluation of VTE was determined heterogeneously (i.e., 100 µCi of 125I-labeled fibrinogen, phlebography, and/ or duplex venous ultrasonography) in each of the three publications, the efficacy of prophylactic LMWH was ascertained from the per-protocol analysis. Safety, on the other hand, was assessed by the intention-to-treat analysis. The heterogeneity (I2) of the studies was tested with the χ2 statistic.
Of a search through 156 articles, three studies met the aforementioned inclusion and exclusion criteria for the current meta-analysis [
Within each individual study, the Chi-square comparisons of the incidences of VTE between LMWH and UFH chemoprophylaxis cohorts did not reach statistical significance [
Suspected chemoprophylaxis-related complications
In all three publications in the present meta-analysis, minor complications were uniformly defined as drops in postoperative hemoglobin/hematocrit requiring blood transfusions.[
Within each study, the Chi-square comparisons of the incidences of minor complications between LMWH and UFH chemoprophylaxis cohorts did not reach statistical significance [
Major complications encompassed all other salient adverse events. All four major adverse events included intracranial hemorrhages: three after prophylactic LMWH (1.4%) and one after prophylactic UFH (0.5%) (P = 0.992). Goldhaber et al. reported a 66-year-old female in LMWH cohort with intraventricular hemorrhage 7 days after a craniotomy for metastatic brain neoplasm (n = 1/75, 1.3%).[
In a meta-analyses that focus on studies that directly compare the two heparin injections in neurosurgery, we identified three articles, whose pooled results did not yield a statistically significant difference in the rates of VTE (P = 0.343), minor complications (P = 0.974), or major complications (P = 0.559) [
While the efficacy of prophylactic LMWH has been well validated in literature;[
Although the tests for heterogeneity (I2) in the set meta- analysis did not reach statistical significance for all three outcome measures – VTE episodes (I2 = 15.1%, P = 0.308), minor complications (I2 = 0.0%, P = 0.929), and major complications (I2 = 0.0%, P = 0.831) – all three studies utilized different doses of prophylactic LMWH. However, the frequency of injections was limited to once daily, whereas the dose and frequency of prophylactic UFH remained constant across all three studies.
This meta-analysis is also subject to a selection bias because the tight inclusion and exclusion criteria led to a review of only three studies. As such, a relatively small number of 429 patients were entered into the pooled analysis, which may limit our ability to detect a statistically significant difference between LMWH and UFH. Further, randomized clinical trials comparing prophylactic LMWH versus UFH are required to elucidate superior safety and efficacy in neurosurgical patients.
This is a meta-analysis of studies that directly compare prophylactic LMWH to UFH in neurosurgery. Prophylactic doses of both LMWH and UFH equally prevented VTE after neurosurgical operations. LMWH, compared to UFH, did not statistically significantly increase the odds of minor or major complications. While these results preliminarily suggest similar profiles of both chemoprophylactic heparin injections, further, randomized clinical trials comparing prophylactic LMWH versus UFH are required to elucidate superior safety and efficacy in neurosurgical patients.
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