key: cord-0031084-ivwhcxjg
authors: Hallan, David R; Sciscent, Bao; Rizk, Elias
title: A Retrospective Comparative Cohort Study of Craniotomy and Prophylactic Enoxaparin Timing
date: 2022-04-06
journal: nan
DOI: 10.7759/cureus.23867
sha: ef2f948aefa25b61304e33e76fb7b3ed951b6348
doc_id: 31084
cord_uid: ivwhcxjg

Introduction: Post-operative venous thromboembolism (VTE) prophylaxis is the standard of care after craniotomy, but there is debate over when to initiate VTE prophylaxis to decrease the morbidity and mortality experienced by these patients. This study aims to determine the effects of starting enoxaparin on day one vs. day three after craniotomy. Methods: We used a multi-institutional health research network (TriNetX) to gather data from the electronic medical records of patients who started enoxaparin one day after craniotomy (cohort 1) and patients who started it three days later (cohort 2). Our primary endpoint was mortality, with the secondary endpoints of deep venous thrombosis (DVT), additional craniotomy, pulmonary embolism (PE), myocardial infarction (MI), ischemic stroke (IS), intracerebral hemorrhage (ICH), ventilator and tracheostomy dependence, or percutaneous endoscopic gastrostomy (PEG) tube dependence. Patients were propensity score-matched for demographics, common comorbidities, and anticoagulant and antiplatelet use. Results: After propensity score matching, 1,554 patients were identified in each cohort. In cohort 1, 21.171% of patients were deceased after five years vs. 26.126% in cohort 2 (p= 0.0012; OR 0.759, 95% CI (0.643,0.897)). The 30-day survival was 94.521% vs. 93.049%, the 90-day survival was 90.200% vs. 87.335%, and the 365-day survival was 80.619 vs. 76.817%. Deep venous thrombosis occurred in 5.277% of cohort 1 and 7.851% of cohort 2 (p=0.0038, OR 0.654, 95% CI [0.49,0.873]). There was no increase in intracerebral hemorrhage in cohort 1. There were no statistically significant differences in subsequent craniotomy rates, PE, MI, IS, ventilator/tracheostomy, or PEG tube dependence. Conclusion: Starting enoxaparin on day one after craniotomy was associated with decreased mortality and DVTs, with no difference in rates of PE, MI, IS, tracheostomy/PEG dependence, or further craniotomy.

Venous thromboembolism (VTE) is a common and potentially fatal postoperative complication of neurological surgery. The development of VTE is multifactorial and depends on the patient's age, comorbidities, and type of surgery performed [1] . Some incidences of VTE have been reported to be greater than 20%, especially in patients with glioblastoma. This supports the use of pharmacologic prophylaxis after craniotomy despite the serious risk of intracranial hemorrhage (ICH) [2] [3] [4] [5] . Low molecular weight heparins, such as enoxaparin, have been shown to reduce the risk of developing lower extremity deep venous thrombosis (DVT) without severe risk of ICH [6] . However, there is debate over when to initiate VTE pharmacologic prophylaxis after brain surgery [7] [8] . Appropriate timing of prophylactic treatment is crucial to prevention of long-term complications and increased mortality.

institutional review board (IRB) waiver was granted. The data is updated daily. Our use of this database and its validity were informed by previous literature, and the exact details of the network have been previously described [9] [10] [11] [12] .

Data extraction and analysis were performed on September 9, 2021. Datasets were retrospectively queried using diagnostic International Classification of Diseases, tenth revision, clinical modification (ICD-10) and current procedural terminology codes. The medical information included age at index date, sex, race, and the comorbidities of hypertension, acute kidney injury, diabetes, ischemic heart disease, heart failure, atrial fibrillation, disorders of lipoprotein metabolism and other lipidemias, obesity, history of nicotine dependence, chronic respiratory disease, cirrhosis, alcohol abuse or dependence, and peripheral vascular disease. These were recorded up to the date of the index date, which was set on the day of craniotomy.

The Analysis was performed using unmatched and propensity score-matched cohorts, using the greedynearest neighbor algorithm with a calliper of 0.1 pooled standard deviations. Hazard ratios were calculated using R's survival package v3.2-3 and were validated by comparing the output to SAS version 9.4. (SAS Institute Inc., Cary, NC, USA) Chi-square analysis that was performed on categorical variables. Our primary outcome of interest was mortality and DVT, with secondary outcomes of PE, IS, MI, tracheostomy and PEG. Outcomes were examined over five years, with interval analyses at 30-, 90-, and 365-days. Statistical significance was set at p<0.05.

After propensity score matching, 1,154 patients were identified in each cohort. The mean age at craniotomy of cohort 1 was 54.6 ± 17.4 years and 55.5 ± 17.9 years for cohort 2. Patients of the male sex comprised 53% of cohort 1 and 57% of cohort 2. Around 76% of cohort 1 and 81% of cohort 2 were Caucasian. Baseline demographics can be seen in Table 1 . 

In this study, we present outcomes of patients who were administered prophylactic enoxaparin following craniotomy. Based on our analysis, the initiation of enoxaparin within 24 hours after surgery was associated with improved mortality and DVT outcomes.

Current guidelines recommend use of prophylactic anticoagulation in neurosurgical patients following craniotomy. However, individual factors in deciding the timing of anticoagulation vary. For example, brain malignancies such as glioblastoma multiforme, which cause a pro-thrombotic state, put patients at an increased risk of VTE [13] [14] . Risk factors for postoperative ICH include older age, larger tumor size, and increased operative time among others [15] [16] [17] .

Previous studies report a range of rates of VTE and ICH following craniotomy after administration or prophylactic anticoagulation. Briggs et al. analyzed 1,087 patients who underwent craniotomy for tumor resection. Their study observed increased rates of VTE in patients with a high-grade glioma and increased operative time. However, prophylactic enoxaparin initiation within 72 hours decreased likelihood of VTE. Furthermore, rates of ICH were comparable between those who did and did not receive enoxaparin [8] . A similar report by Algattas et al. compared adult patients who received anticoagulation prophylaxis after undergoing craniotomy for tumor on day one and day two after surgery and reported no significant differences in risk of VTE or ICH. Conversely, a retrospective study by Cage et al. concluded that enoxaparin use within 48 hours after resections of meningiomas are associated with lower rate of VTE and noted no differences in the incidence of intracranial hemorrhage in these patients [18] . Other studies looked into VTE prophylaxis initiation at time of surgery. However, reports differ on its safety and the risk of ICH [19] [20] .

As shown in our study and prior reports, there is a narrow window for the optimal use of prophylactic enoxaparin. A delicate balance between individual potential risks and benefits must be considered. Timing of appropriate anticoagulation prophylaxis is multifactorial and complications of VTE and ICH can significantly decrease quality of life.

Our analysis was not without limitations. In our analysis, the exact neuropathology that required the craniotomy, the specific type of craniotomy technique used, and the total operative time were not identified. Also, the frequency in screening for VTE may account for some variation in results from our study and those previously reported. A disproportionate majority of our study population was Caucasian and so our results may not be generalized to all racial groups. The major limitation of this study was that it was retrospective in nature. Furthermore, due to the nature of the database, we were unable to collect patient level data on specific outcomes. We were unable to report on imaging information. We do not have information on the type of diagnostic test used for confirmation of disease. The data collected was for billing purposes, not for clinical use, and thus much clinical information is missing. In addition, some misidentification is inevitable in database studies.

Initiation of VTE prophylaxis on day one after craniotomy may provide a survival benefit for patients compared to administration on day three, as well as decrease the risk of DVTs. Studies that provide patient level data such as the neuropathology that required the initial craniotomy as well as the screening frequency for outcomes such as DVT and MI may offer additional insight into the optimal timing of anticoagulation prophylaxis.

Human subjects: Consent was obtained or waived by all participants in this study. Western Institutional Review Board issued approval n/a. Any data displayed on the TriNetX Platform in aggregate form, or any patient-level data provided in a data set generated by the TriNetX Platform, only contains de-identified data as per the de-identification standard defined in Section §164.514(a) of the HIPAA Privacy Rule. The process by which the data is de-identified is attested to through a formal determination by a qualified expert as defined in Section §164.514(b)(1) of the HIPAA Privacy Rule. This formal determination by a qualified expert, refreshed in December 2020, supersedes the need for TriNetX's previous waiver from the Western Institutional Review Board (IRB). More information can be found at: https://trinetx.com/wpcontent/uploads/2021/12/TriNetX-Empirical-Summary-by-Brad-Malin-2020.pdf. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

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We sought to determine the impact of starting enoxaparin on day one after craniotomy vs. day three, with the primary endpoints of mortality, intracerebral hemorrhage, DVT, pulmonary embolism (PE), ischemic stroke (IS), myocardial infarction (MI), and secondary endpoints of ventilator/tracheostomy dependence and percutaneous endoscopic gastrostomy (PEG tube) dependence.

This was a retrospective comparative cohort study. We used a multi-institutional healthcare database, the TriNetX research network, to collate information on patients who underwent craniotomy and subsequently were started on prophylactic enoxaparin one day after (cohort 1) vs. three days after (cohort 2) craniotomy. The TriNetX research network provides access to 56 health care organizations (HCOs) and their de-identified electronic medical record data. Data includes demographics, diagnoses, medications, laboratory values, genomics, and procedures. The identity of the HCOs and patients is not disclosed to comply with ethical guidelines against data re-identification. Due to the database's federated nature, an