Chang, Victor

Macki, Mohamed

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Henry Ford Health Henry Ford Health Scholarly Commons Neurosurgery Articles Neurosurgery 6-23-2021 Commentary: Comparison of the Safety of Prophylactic Anticoagulants After Intracranial Surgery Mohamed Macki Henry Ford Health, mmacki2@hfhs.org Victor Chang Henry Ford Health, vchang1@hfhs.org Follow this and additional works at: https://scholarlycommons.henryford.com/neurosurgery_articles Recommended Citation Macki M, and Chang V. Commentary: Comparison of the Safety of Prophylactic Anticoagulants After Intracranial Surgery. Neurosurgery 2021. This Article is brought to you for free and open access by the Neurosurgery at Henry Ford Health Scholarly Commons. It has been accepted for inclusion in Neurosurgery Articles by an authorized administrator of Henry Ford Health Scholarly Commons. COMMENTARYCommentary: Comparison of the Safety ofProphylactic Anticoagulants After IntracranialSurgeryMohamedMacki, MD, MPHVictor Chang, MDDepartment of Neurosurgery, Henry FordHospital, Detroit, Michigan, USACorrespondence:Victor Chang, MD,Department of Neurosurgery,Henry Ford Hospital,2799 W Grand Blvd,Detroit, MI 48202, USA.Email: vchang1@hfhs.orgReceived,May 13, 2021.Accepted,May 16, 2021.C© Congress of Neurological Surgeons2021. All rights reserved. For permissions,please e-mail:journals.permissions@oup.comD espite a national campaign topromote early ambulation, sequentialcompression devices, and chemo-prophylaxis, venous thromboembolic events(VTE), including deep venous thromboses andpulmonary emboli, pose a significant burden tomost hospitalized patients, especially with poormobility. As such, many surgical specialties havepublished randomized clinical trials to establishbest practices in prophylactic unfractionatedheparin (UFH) vs low-molecular-weight heparin(LMWH).1-3 Unfortunately, neurosurgery fora myriad of reasons has been slow to adapt,although chemoprophylactic techniques areimplemented in most, if not all, of our patients.Interest in comparing the two subcutaneousinjections was recently revived with a meta-analysis in neurosurgical procedures4 followedby a survey for spine operations.5 The authorsshould be congratulated for publishing theirfindings, “Comparison of the safety of prophy-lactic anticoagulants after intracranial surgery.”6The study presents a propensity score matchingof prophylactic anticoagulants after intracranialsurgery.The authors have remarkably paired 203cranial surgery patients with LMWH to 406patients with UFH in a 1:2 ratio. The propensityscore algorithm allows for assigning patientswho may not have an exact matching double.This addresses the difficulty in traditionalmatched cohort studies that often restrictsthe study population size7 – a difficulty thatwe encountered in our similarly paired studyin chemoprophylaxis with spinal applica-tions (currently in production). The author’smatched data unveiled a statistically significantlyhigher incidence of intracranial hemorrhagiccomplications with LMWH without a benefitin prevention of VTE. These results echoone of the first reports of LMWH in cranialsurgery: in 1998, Dickinson et al8 randomizedLMWH + sequential compression device tosequential compression device alone in patientsrequiring surgery for treatment of intracranialneoplasms. The study was terminated prema-turely because of the 10% rate of intracranialhemorrhage in the LMWH cohort vs nonein the sequential compression device alonecohort. While neurosurgeons were under-standably suspicious of LMWH as a result ofthis study, an important counterargument didbeg the question: Was the increased risk ofintracranial hemorrhage unique to LMWH or aphenomenon true to any comparison cohort ofchemoprophylaxis vs no pharmacological antico-agulant? Over 2 decades later, the authors of thecurrent study have attempted a more modernapproach with a more statistically nuancedanalysis. The former scenario seems to holdtrue. Hemorrhagic complications are unique toLMWH itself. The smaller molecular structureof LMWH compared to UFH confers higheranti-Xa/anti-IIa ratios.9 These biochemicalproperties permit nonspecific binding to bodyproteins and cell surfaces of the coagulationcascade (such as endothelia and platelets), whichexplains LMWH’s greater efficacy against VTEas well as complication profile with intracranialhemorrhages.As with any retrospective study, there areimportant potential confounders and hiddenbias to consider when interpreting these findings.While propensity matching can help modulatethe effect of potential confounders, this isdependent on the factors that are consideredin the model. One of the biggest limita-tions of this study is that many factors thatmay be associated with the primary outcomesare not considered. Specific morbidities relatedto frailty as well as propensity to hemor-rhage are not collected within the examineddata set. Additionally, both the retrospectivecohort arm as well as the meta-analysis aresubject to a calendar time bias. Earlier opera-tions may have utilized postoperative prophy-lactic UFH, whereas more recent operations mayhave preferred prophylactic LMWH. This posesNEUROSURGERY VOLUME 0 | NUMBER 0 | 2021 | 1Downloaded from https://academic.oup.com/neurosurgery/advance-article/doi/10.1093/neuros/nyab230/6308532 by Henry Ford Hospital user on 22 July 2021MACKI AND CHANGseveral problems. On one hand, newer developments in intra-operative hemostatic agents made a profound impact on theprevention of intracranial hemorrhage.10 This would suggestthat when controlling for these hemostatic agents, hemorrhagiccomplications would be even higher in the LMWH group.On the other hand, however, there may be potential biasbased on the aggressiveness and extent of resection, especiallyin the more modern cases in this series which may increasethe risk of intracranial hemorrhage. These operative nuancesthat affect the rates of intracranial hemorrhage were unlikelyto be captured in the propensity score matching on “surgicalprocedure.”Moreover, higher resolution in postoperative imagingmodalities over the years may identify subtle hemorrhages in themore recent LMWH cohort compared to the earlier UFH cohort.The authors also failed to mention preoperative antithromboticagents, which undoubtedly alter hemorrhage rates. As the numberof patients with chronic medical conditions rises, more patientsare taking antithrombotic drugs than in previous years.11 Andwhile Coumadin (Bristol Myers Squibb) prescriptions have fallen,the number of novel oral anticoagulants whose safety profile withintracranial hemorrhages has not been completely determined hasincreased.12 In summary, the higher incidence of hemorrhagiccomplications may reflect a change in the landscape of medicaland surgical practice, rather than a change from postoperativeprophylactic UFH to LMWH over the past decades.While this retrospective analysis is helpful, chemoprophylacticefficacy truly presides in a randomized clinical trial that wouldcompare weight-based dosing in LMWH vs UFH in a selectgroup of neurosurgical operations. But, as noted in the author’smeta-analysis, the small difference in VTE between LMWH andUFH would require an impractically sized study population toadequately power such a randomized clinical trial. A large-scalestudy would entail a multi-center design with funding, whichposes its own difficulties. Pharmaceutical companies may beapprehensive to support such a trial that may conclude that theirdrug was inferior to traditional UFH, or neurosurgeons may nottrust studies fraught in monetary conflicts of interest with bigpharma. In the end, our choice in chemoprophylactic techniquemay depend on the current body of evidence in the literaturemixed with anecdotal experience unique to our individualizedneurosurgical practice.FundingThis study did not receive any funding or financial support.DisclosuresThe authors have no personal, financial, or institutional interest in any of thedrugs, materials, or devices described in this article. Dr Chang receives researchfunding from Medtronic, who was not involved in this project, specifically. He isa consultant for Globus Medical, K2M, and SpineGuard.REFERENCES1. Geerts WH, Jay RM, Code KI, et al. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism aftermajor trauma. N Engl J Med. 1996;335(10):701-707.2. Turpie AG, Levine MN, Hirsh J, et al. A randomized controlled trial of alow-molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis inpatients undergoing elective hip surgery. N Engl J Med. 1986;315(15):925-929.3. McLeod RS, Geerts WH, Sniderman KW, et al. Subcutaneous heparin versus low-molecular-weight heparin as thromboprophylaxis in patients undergoing colorectalsurgery. Ann Surg. 2001;233(3):438-444.4. Macki M, Fakih M, Anand SK, Suryadevara R, Elmenini J, Chang V. Adirect comparison of prophylactic low-molecular-weight heparin versus unfrac-tionated heparin in neurosurgery: a meta-analysis. Surg Neurol Int. 2019;10:202.5. MackiM, Haider SA, Anand SK, et al. A survey of chemoprophylaxis techniques inspine surgery among American neurosurgery training programs. World Neurosurg.2020;133:e428-e433.6. Bell JS, Florence TJ, Phillips HW, et al. Comparison of the safety of prophylacticanticoagulants after intracranial surgery [published online ahead of print: 2021].Neurosurgery. doi: 10.1093/neuros/nyab221.7. Macki M, Basheer A, Lee I, Kather R, Rubinfeld I, Abdulhak MM. Surgicalsite infection after transoral versus posterior approach for atlantoaxial fusion: amatched-cohort study. J Neurosurg Spine. 2018;28(1):33-39.8. Dickinson LD,Miller LD, Patel CP, Gupta SK. Enoxaparin increases the incidenceof postoperative intracranial hemorrhage when initiated preoperatively for deepvenous thrombosis prophylaxis in patients with brain tumors. Neurosurgery.1998;43(5):1074-1079.9. Merli GJ, Groce JB. Pharmacological and clinical differences between low-molecular-weight heparins: implications for prescribing practice and therapeuticinterchange. P T. 2010;35(2):95-105.10. Gazzeri R, Galarza M, Callovini G, Alfieri A. Biosurgical hemostatic agentsin neurosurgical intracranial procedures. Surg Technol Int. 2017;30:468-476.11. Barnes GD, Lucas E, Alexander GC, Goldberger ZD. National trends inambulatory oral anticoagulant use. Am J Med. 2015;128(12):1300-1305.e2.12. Kirley K, Qato DM, Kornfield R, Stafford RS, Alexander GC. National trends inoral anticoagulant use in the United States, 2007 to 2011. Circ Cardiovasc QualOutcomes. 2012;5(5):615-621.2 | VOLUME 0 | NUMBER 0 | 2021 www.neurosurgery-online.comDownloaded from https://academic.oup.com/neurosurgery/advance-article/doi/10.1093/neuros/nyab230/6308532 by Henry Ford Hospital user on 22 July 2021

Commentary: Comparison of the Safety of Prophylactic Anticoagulants After Intracranial Surgery

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Commentary: Comparison of the Safety of Prophylactic Anticoagulants After Intracranial Surgery

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