Tinzaparin vs. Fraxiparin Safety and Efficacy in Neurosurgery

Background An outbreak of African swine fever (ASF) in China in 2020 has led to an unprecedented shortage of fraxiparin. Most patients, especially those kept in hospital for surgery, are currently treated with prophylactic anticoagulation (AC). In search of alternatives for fraxiparin, we found no sufficient data on alternatives for neurosurgical patients, such as tinzaparin of European origin. We compared fraxiparin and tinzaparin concerning adverse events (bleeding versus thromboembolic events) in neurosurgical patients. Methods Between 2012 and 2018, 517 neurosurgical patients with benign and malignant brain tumors as well as 297 patients with subarachnoid hemorrhage (SAH) were treated in the Department of Neurosurgery, University Hospital Leipzig receiving prophylactic anticoagulation within 48 hours. In 2015, prophylactic anticoagulation was switched from fraxiparin to tinzaparin throughout the university hospital. In a retrospective manner, the frequency and occurrence of adverse events (rebleeding and thromboembolic events) in connection with the substance used was analyzed. Statistical analysis was performed using Fisher’s exact test and the chisquared test. Results Rebleeding rates were similar in both fraxiparin and tinzaparin cohorts in patients being treated for meningioma, glioma, and SAH combined (8.8 vs 10.3%). Accordingly, the rates of overall thromboembolic events were not significantly different (5.5% vs 4.3%). The severity of rebleeding did not vary. There was no significant difference among subgroups when compared for deep vein thrombosis (DVT) or pulmonary embolism (PE). Conclusion In this retrospective study, tinzaparin seems to be a safe alternative to fraxiparin for AC in patients undergoing brain tumor surgery or suffering from SAH. Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 12 April 2021 doi:10.20944/preprints202104.0312.v1

I hereby confirm that the manuscript complies with all instructions to authors. The authorship requirements have been met and the final manuscript has been approved by all authors. This manuscript has not been published elsewhere and is not under consideration by another journal. We confirm adherence to ethical guidelines and that ethical approval was obtained from the IRB (see below). Conflict of interest statements for all authors have been included. We have followed the STROBE guidelines.
Abstract Background An outbreak of African swine fever (ASF) in China in 2020 has led to an unprecedented shortage of fraxiparin. Most patients, especially those kept in hospital for surgery, are currently treated with prophylactic anticoagulation (AC). In search of alternatives for fraxiparin, we found no sufficient data on alternatives for neurosurgical patients, such as tinzaparin of European origin. We compared fraxiparin and tinzaparin concerning adverse events (bleeding versus thromboembolic events) in neurosurgical patients.

Methods
Between 2012 and 2018, 517 neurosurgical patients with benign and malignant brain tumors as well as 297 patients with subarachnoid hemorrhage (SAH) were treated in the Department of Neurosurgery, University Hospital Leipzig receiving prophylactic anticoagulation within 48 hours. In 2015, prophylactic anticoagulation was switched from fraxiparin to tinzaparin throughout the university hospital. In a retrospective manner, the frequency and occurrence of Introduction All hospitalized patients are currently treated with prophylactic anticoagulation (AC) according to guidelines [1,2,3]. (Neuro-)surgical patients are at elevated risk of both thromboembolic events and intracranial rebleeding [4,5,6]. Data on low molecular weight heparin (LMWH) safety is therefore essential for safe prophylactic treatment. Due to an outbreak of African Swine Fever (ASF) in China [7], heparin doses are at risk of running short. Many hospitals use LMWH of Chinese production. Should there be an actual shortage, alternatives are required to maintain supply. Quite recently, the first case of ASF in wildlife was discovered in Germany, indicating a westward movement of the disease [8,9].
In our facility, anticoagulation was formerly administered using fraxiparin. For various reasons, in 2015, the preferred medication was switched to tinzaparin, which is made in Europe.
Tinzaparin supplies therefore need to be relatively independent of local ASF outbreaks [6].
Coincidentally, we retrospectively analyzed patient data on prophylactic anticoagulation from 2012 to 2018 [10], dividing the AC-treated cohorts almost equally between fraxiparin and tinzaparin. We considered a heterogenous collective of patients with acute, malignant and benign disease as representative. In this study, we present data directly comparing tinzaparin and fraxiparin in prophylactic doses regarding adverse events such as rebleeding as well as post-operative hemorrhage and thromboembolic events (TE).

Methods
The study was approved by the ethics committee of the Medical Faculty, University of Leipzig

Statistical analysis
To describe the cohort, nominal parameters are displayed as percentages.
The population was dichotomously classified depending on the occurrence or nonoccurrence of adverse events (intracranial rebleeding, systemic ischemia, and cerebral ischemia).
Dichotomous parameters were analyzed using the chi-squared test or Fisher's exact test.
Continuous data was analyzed with t-test, normality test was performed. P-values below 0.05 were considered statistically significant.

Results
We performed subgroup analysis for patients with preexisting anticoagulation for meningioma, SAH and glioma individually. For meningioma and glioma surgery, therapeutic AC was paused for surgery. Logically, we found no effect on adverse events. In SAH however, preexisting anticoagulation prior to the initial event increased the risk of intracranial rebleeding (p = 0.009, OR 2.417, 95% CI of OR 1.278-4.570). This effect turned out to be insignificant when groups were combined. There was no difference between tinzaparin and fraxiparin groups (p = 0.7101). Regarding hemorrhagic complications, we divided patients between those who did or did not undergo surgical treatment of rebleeding to gauge bleeding severity. The reasons for delayed or non-prophylactic treatment were severe rebleeding, acute pulmonary embolism, or securing aneurysm with a stent or flow-diverting devices, making therapeutic AC necessary. After combining the heterogenous groups of patients, differences between fraxiparin and tinzaparin were not significant. No differences were observed regarding the adverse events considered.

Discussion
Tinzaparin has been proven to be effective and safe in various patients [11,12,13]. Data on neurosurgical patients especially is scarce and does not compare specific substances, neither does it include different diseases [14,15].
The study is limited due to its retrospective character. Although the number of examined patients is relatively high (n = 814), the study is not sufficiently powered to securely exclude differences between the substances investigated. Patient groups are heterogenous regarding underlying disease. Despite differences in underlying pathomechanism of rebleeding and thromboembolism [16,17], we assume the combined cohort applicable to heterogenous neurosurgical patient collectives. When dividing into different subgroups regarding underlying disease, we did not find specific differences.
As AC is obligatory under current guidelines, we have no control group who is not treated with AC. For obvious reasons, we cannot draw any conclusions regarding the general safety or efficacy of prophylactic AC.

Conclusion
We suppose the application of tinzaparin in neurosurgical patients to be as safe as fraxiparin.
According to our data, tinzaparin is a suitable alternative to other anticoagulative substances and so could be used to counter supply shortages.