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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 53  |  Issue : 5  |  Page : 159-164

Association between nonsteroidal anti-inflammatory drugs and lower incidence of surgical treatment of chronic subdural hematoma: A population-based study


1 Section of Neurosurgery, Department of Surgery, Chia-Yi Christian Hospital, Chia-Yi City; Department of Biotechnology, Asia University, Taichung City; Deparment of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
2 Deparment of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei; Division of Neurosurgery, Department of Surgery, Sijhih Cathay General Hospital, New Taipei City; School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
3 Section of Neurosurgery, Department of Surgery, Chia-Yi Christian Hospital, Chia-Yi City; Chung-Jen Junior College of Nursing, Health Sciences and Management, Chia-Yi Country, Taiwan
4 Department of Medical Research, Cathay General Hospital, New Taipei City, Taiwan
5 School of Medicine, Fu Jen Catholic University; Department of Anesthesiology, Cathay General Hospital, New Taipei City, Taiwan
6 Division of Neurosurgery, Department of Surgery, Sijhih Cathay General Hospital; School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan

Date of Submission02-Mar-2020
Date of Decision13-Apr-2020
Date of Acceptance06-Jul-2020
Date of Web Publication19-Oct-2020

Correspondence Address:
Chih-Ta Huang
Division of Neurosurgery, Department of Surgery, Sijhih Cathay General Hospital, No. 2, Ln. 59, Jiancheng Rd., Xizhi, New Taipei City 221
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/fjs.fjs_23_20

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  Abstract 


Background: Chronic subdural hematoma (CSDH) is a common neurosurgical disease and is considered an inflammatory angiogenic entity. An association between nonsteroidal anti-inflammatory drugs (NSAIDs) and surgical CSDH in patients following minor head injury without intracranial bleeding has not been reported. Therefore, we used a national population-based database to investigate the association between the use of NSAIDs and the incidence of surgical CSDH.To investigate the association between nonsteroidal anti-inflammatory drugs and the incidence of surgical chronic subdural hematoma.
Materials and Methods: We extracted analytical data from the Longitudinal Health Insurance Database (2010), a subset of the National Health Insurance Research Database. Patients aged younger than 50 years, who had undergone neurosurgical procedures or who had a head injury with intracranial bleeding, were excluded from the study.
Results: Of 67,296 patients with minor head injury without intracranial bleeding, 482 (0.72%) developed surgical CSDH. Patients who received NSAIDs were more likely to have comorbidities, including ischemic heart disease, stroke, diabetes mellitus, hypertension, hyperlipidemia, renal diseases, arrhythmia, heart failure, chronic liver disease, and valvular heart disease (P < 0.001). Surgical CSDH was more likely to develop in male patients who did not receive NSAIDs (adjusted odds ratio [OR] = 1.34, 95% confidence interval [CI] = 1.05–1.72, P < 0.05) and those aged >65 years (adjusted OR = 1.5, 95% CI = 1.15–1.92, P < 0.01). The adjusted OR of surgical CSDH in patients who did not receive NSAIDs was 1.37 (95% CI = 1.09–1.71, P < 0.01).
Conclusion: Surgical CSDH may be more likely to develop in patients aged >65 years, male patients, and patients who did not receive NSAIDs. NSAID use may be associated with a low incidence of surgical CSDH in patients following minor head injury without intracranial bleeding.

Keywords: Chronic subdural hematoma, intracranial bleeding, minor head injury, nonsteriodal anti-inflammatory drugs, surgical intervention


How to cite this article:
Sun JM, Hsieh CT, Chen YH, Chang JY, Wong CS, Huang CT. Association between nonsteroidal anti-inflammatory drugs and lower incidence of surgical treatment of chronic subdural hematoma: A population-based study. Formos J Surg 2020;53:159-64

How to cite this URL:
Sun JM, Hsieh CT, Chen YH, Chang JY, Wong CS, Huang CT. Association between nonsteroidal anti-inflammatory drugs and lower incidence of surgical treatment of chronic subdural hematoma: A population-based study. Formos J Surg [serial online] 2020 [cited 2020 Nov 24];53:159-64. Available from: https://www.e-fjs.org/text.asp?2020/53/5/159/298499




  Introduction Top


Chronic subdural hematoma (CSDH), a progressive collection of unabsorbed and liquefied hematoma in the subdural space, is one of the most common neurosurgical conditions and tends to affect older patients with the recent history of minor head trauma.[1],[2],[3] Osmotic theory and the theory of repeat bleeding from the capsule of the hematoma are generally considered to promote CSDH formation.[1],[4],[5] However, the exact pathophysiological mechanism underlying CSDH formation remains unclear. Currently, surgical interventions, including burr holes, craniostomy, and craniotomy, are the gold standard in the management of CSDH, with mostly favorable postoperative outcomes.[2],[5]

A cascade of inflammatory reactions, impaired coagulation, fibrinolysis, and angiogenesis are observed in the development of CSDH.[2],[5],[6] An abundance of inflammatory cells and markers, such as interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor-α, MCP-1, eotaxin-3, CXCL9, and CXCL10, are likely to contribute to the propagation of inflammatory responses that stimulate ongoing membrane growth and fluid accumulation.[6],[7] Various drug therapies, such as dexamethasone, atorvastatin, tranexamic acid, and angiotensin-converting enzyme inhibitors, are hypothesized to prevent CSDH formation or the need for multiple surgical interventions for CSDH.[8],[9],[10],[11],[12] However, the benefit of these medications in the management of CSDH is limited and based on small sample sizes and low-grade evidence.[13]

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to reduce pain, fever, and inflammation through the inhibition of cyclooxygenase (COX) enzyme activity.[14] The COX-2/prostaglandin E2 (PGE2) pathway is another inflammatory pathway involved in CSDH development. COX-2 was reported to be overexpressed in endothelial and inflammatory cells in the outer hematoma membrane.[13] However, the theoretical advantage of COX-2 inhibition in recurrent CSDH was not confirmed in the prospective randomized COXIBRAIN trial because of the high prevalence of comorbidities, excluding the administration of COX2 inhibitors.[15] Therefore, the association between the use of NSAIDs and the incidence of surgical CSDH remains unclear.

In this longitudinal cohort study, we used patient data from the Taiwan National Health Insurance Research Database (NHIRD) to analyze the association of the use of NSAIDs with the incidence of surgical CSDH in patients with minor head injury without intracranial bleeding.


  Materials and Methods Top


Data source

Data retrieved from the 2010 Longitudinal Health Insurance Database (LHID), a subgroup database of the NHIRD in Taiwan for the period from 1996 to 2012, were used in this study. The NHIRD contains inpatient and outpatient medical claims data of approximately 99% of Taiwan's 23 million residents. For medical research purposes, the NHIRD released the LHID, a medical claims database providing information of one million randomly sampled individuals; that is, approximately 5% of Taiwan's population. Diagnoses in claims data are coded using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. This study was approved by the Institutional Review Board of Cathay General Hospital (CGH-P107040). All data were de-identified and analyzed anonymously.

Sampled patients

This study included study and control groups. Patients who had head injury during a washout period from 1996 to 1999 were excluded from the study. Patients who received a first-time principal diagnosis of minor head injury without intracranial bleeding between January 1, 2000, and December 31, 2012, were enrolled in this study. Minor head injury without intracranial bleeding was defined as head injury or concussion without concomitant intracranial hemorrhages – including intracerebral, epidural, subdural, and subarachnoid hemorrhages (ICD-9-CM codes 800.0, 800.1, 800.4, 800.5, 800.6, 800.9, 801.0, 801.1, 801.4, 801.5, 801.6, 801.9, 802, 803.0, 803.1, 803.4, 803.5, 803.6, 803.9, 804.0, 804.1, 804.4, 804.5, 804.6, 804.9, 850, 851, 854, 870, 871, 872, 873, 910, 920, or 921). Patients aged younger than 50 years, patients who underwent surgery for head injury before the index date, and patients of unknown sex were excluded. The study group consisted of patients who had not received NSAIDs, including aceclofenac, celecoxib, diclofenac, etodolac, etoricoxib, ibuprofen, indometacin, ketoprofen, ketorolac, mefenamic acid, meloxicam, and naproxen, as identified in the Anatomical Therapeutic Chemical classification system (http://www.whocc.no/atc/application_for_atc_codes). The control group consisted of patients who received NSAIDs. The use of NSAIDs defined as the treatment of these medications within 1–6 months before the diagnosis of minor head injury without intracranial hemorrhage. Comorbidities were investigated, namely ischemic heart disease (ICD-9-CM 410-414), stroke (ICD-9-CM 430-438), diabetes mellitus (ICD-9-CM 250), hypertension (ICD-9-CM 401-405), hyperlipidemia (ICD-9-CM 272), chronic renal diseases (ICD-9-CM 585-586), arrhythmia (ICD-9-CM 427), heart failure (ICD-9-CM 428), chronic liver disease (ICD-9-CM 571), valvular heart disease (ICD-9-CM 424), and coagulopathy (ICD-9-CM 286-287).

Surgical CSDH was defined as a patient's first craniostomy procedure for CSDH removal after minor head injury without intracranial bleeding; this procedure corresponds with the NHI reimbursement procedure code 83038C and refers uniquely to craniostomy performed by neurosurgeons for removing CSDH. The nonsurgical group was defined as patients who received no other surgical intervention for traumatic brain injury. Other surgical interventions for traumatic brain injury were skull fracture reduction (NHI codes 83011B and 83012B), burr holes (NHI codes 83013C and 83014C), craniectomy (NHI code 83015C), removal of acute epidural hematoma (NHI code 83036C), removal of acute subdural hematoma (NHI code 83037C), removal of intracerebral hemorrhage (NHI code 83039B), external ventricular drainage (NHI code 83051B), vascular surgery (NHI codes 83064B, 83065B, 83066B, 83067B, 83068B, 83069B, 83070B, and 83071B), and intracranial pressure monitoring (NHI code 83080B).

For the study group, the index date year was the year, in which patients with a head injury received their first diagnosis of head injury; for the comparison group, the index date year was simply a matched year in which comparison patients utilized medical care. Furthermore, we assigned the first use of ambulatory care in the index year as the index date for the comparison group. We also ensured that no patients selected for comparison had ever received a head injury diagnosis before the index date. Based on the aforementioned definitions, the effects of NSAIDs on surgical CSDH in patients with minor head injury without intracranial bleeding were analyzed.

Statistical analysis

Continuous data are presented as means (±standard deviations). Categorical data are presented as numbers and percentages. All statistical analyses were performed using Statistical Analysis System software version 9.4 (SAS Institute, Cary, North Carolina, USA) for data extraction, computation, linkage, processing, and sampling. The distribution difference for continuous variables was analyzed using Student's t-test, and the Chi-square test was used to examine differences in characteristics between the two groups.

Logistic regression was used to estimate the odds for the surgical risk of CSDH following minor head injury after adjustment for potential confounding factors and the association between NSAID therapy and the incidence of surgical CSDH. P < 0.05 was set as the level of statistical significance.


  Results Top


[Figure 1] presents a flow diagram of patient enrollment in the database. A total of 11784 patients who did not receive NSAIDs following minor head injury without intracranial bleeding were included in the study group, and 55512 patients who received NSAIDs were included in the control group. [Table 1] presents the demographic characteristics of this study. The mean age of patients who did not receive NSAIDs was 65.8 ± 12.08 years, and the mean age of patients who received NSAIDs was 65.2 ± 10.95 years. The difference in the mean age was statistically significant (P< 0.001). Male patients were significantly more predominant among patients who did not receive NSAIDs than among patients who received NSAIDs (62.3% vs. 49.4%, P < 0.001).
Figure 1: Flow of case selection

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Table 1: Baseline characteristics of patients with a minor head injury but without intracranial bleeding

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Patients who did not receive NSAIDs following minor head injury without intracranial bleeding were less likely to have comorbidities, namely ischemic heart disease (30.8% vs. 51%, P < 0.001), stroke (31.7% vs. 41.1%, P < 0.001), diabetes mellitus (31.8% vs. 46.4%, P < 0.001), hypertension (31.1% vs. 51.2%, P < 0.001), hyperlipidemia (34.8% vs. 58.9%, P < 0.001), renal diseases (10.2% vs. 14.7%, P < 0.001), arrhythmia (18.9% vs. 31%, P < 0.001), heart failure (13.1% vs. 19.4%, P < 0.001), chronic liver disease (30.4% vs. 45.3%, P < 0.001), and valvular heart disease (6.2% vs. 11.7%, P < 0.001). Although more patients who received NSAIDs following minor head injury without intracranial bleeding developed coagulopathy (3.6% vs. 2.3%), the difference between the two groups was not statistically significant (P = 0.081).

A total of 482 patients (0.72%) who developed surgical CSDH after minor head injury without intracranial bleeding were analyzed; of 11784 patients who did not receive NSAIDs following minor head injury without intracranial bleeding, 112 (0.95%) developed surgical CSDH. However, in the control group, 370 patients (0.67%) who received NSAIDs received surgical interventions for CSDH. This difference was statistically significant (P< 0.001). Adjusted odds ratios (OR) were adjusted for age, sex, ischemic heart disease, stroke, diabetes mellitus, hypertension, hyperlipidemia, chronic renal disease, arrhythmia, heart failure, chronic liver disease, valvular heart disease, and coagulopathy. After adjustment for these confounding factors, the results of logistical regression analysis showed that male patients who did not receive NSAIDs after minor head injury without intracranial bleeding were more likely than their female counterparts to develop surgical CSDH (adjusted OR = 1.34, 95% confidence interval [CI] = 1.05–1.72, P < 0.05) [Table 2]. [Table 3] lists the associated risks of surgical CSDH in different age groups of patients with minor head injury without intracranial bleeding. Patients who did not receive NSAIDs and were aged >65 years were more likely than patients aged <65 years to develop surgical CSDH (adjusted OR = 1.5, 95% CI = 1.15–1.92, P < 0.01). Based on the aforementioned results, male patients who were aged >65 years and did not receive NSAIDs exhibited a higher incidence of surgical CSDH following minor head injury without intracranial bleeding.
Table 2: Crude and covariate-adjusted odds ratios for the presence of surgical, chronic subdural hematoma in patients with minor head injury but without intracranial bleeding, stratified by sex

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Table 3: Crude and covariate-adjusted odds ratios for surgical chronic subdural hematoma in patients with a minor head injury but without intracranial bleeding, stratified by age

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[Table 4] lists the associated risks of NSAID use in surgical CSDH in patients with minor head injury without intracranial bleeding. The crude OR in surgical CSDH patients who did not receive NSAIDs was 1.43 (95% CI = 1.16–1.77, P <.01), compared with that in patients who received NSAIDs [Table 2]. After adjustment for age, sex, and comorbidities, the adjusted OR was 1.37 (95% CI = 1.09–1.71, P < 0.01). These results indicated that the use of NSAIDs in patients with minor head injury without intracranial bleeding is associated with a lower risk of surgical CSDH.
Table 4: Crude and covariate-adjusted odds ratios for surgical chronic subdural hematoma in patients with minor head injury without intracranial bleeding, stratified by the use of nonsteroidal anti-inflammatory drug

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  Discussion Top


The overall incidence of CSDH varies, ranging from 1.72 to 20.6/100000 people/year.[16] The history of head trauma is considered an important predisposing factor in CSDH development.[1],[3],[17] Head trauma was retrospectively identified in only 50%–80% of patients with CSDH.[1] CSDH from the progression of traumatic acute CSDH is frequently posed, and the incidence ranges from 3% to 26%.[18] Few studies have specifically reported the rate of CSDH following minor head injury.[3],[17] In a 2-year prospective study of 277 patients with minor head trauma, only 20 patients (7.2%) developed CSDH that required surgical intervention.[17] These CSDH patients all exhibited combined hemorrhage, and the majority (75%) had an acute subdural hemorrhage. In a national population-based study, Tseng et al. demonstrated that 254 of 14,026 patients (1.8%) with minor head injury without intracranial bleeding and of an age exceeding 65 years developed surgical CSDH.[3] In this study, we extracted patient data from a similar national population-based database and included patients aged >50 years.[3] The risk of surgical CSDH following minor head injury without intracranial hemorrhage was 0.72%, which is approximately 100 times more than the CSDH rate in global studies.[16] Therefore, the actual incidence of surgical CSDH following minor head injury without intracranial bleeding is still unknown and should be prospectively investigated.

Although multifactorial mechanisms are involved in CSDH development, CSDH is commonly considered to be an inflammatory angiogenic disease.[6],[19] The presence of numerous inflammatory cytokines in the fluid and the overexpression of vascular endothelial growth factor in the outer membrane have been demonstrated to contribute to CSDH pathogenesis, which is stimulated by the COX-2/PGE2 pathway.[6],[7],[13] Clinically, NSAID is frequently used as an analgesic and anti-inflammatory therapy for numerous neurosurgical diseases, operating through the inhibition of the COX-2/PGE2 pathway. For recurrent CSDH, Schaumann et al. conducted a prospective, randomized, phase II/III clinical trial to evaluate the therapeutic effects of a selective COX-2 inhibitor on postoperative CSDH.[15] The results indicated that a selective COX-2 inhibitor could not reduce CSDH recurrence because of the high prevalence of comorbidities, excluding the administration of the COX-2 inhibitor. Because surgical intervention is the gold standard treatment in CSDH management, the therapeutic effects of NSAIDs on patients who received the first diagnosis of CSDH or recurrent CSDH remain unclear.[1],[2]

The NHIRD in Taiwan, covering >95% of cases, may be helpful for analyzing the effects of NSAIDs on surgical CSDH following minor head injury without intracranial bleeding. Compared with patients who receive NSAIDs, the adjusted OR of surgical CSDH in patients who did not receive NSAIDs was 1.37 (P< 0.01). This result indicates that NSAID use in patients with minor head injury without intracranial bleeding may be associated with a low incidence of surgical CSDH, potentially supporting the inflammation theory for the formation of CSDH.[6],[7],[13] However, because the sample size of surgical CSDH patients was small in this study, the most effective optional subtype of NSAID therapy to reduce the incidence of surgical CSDH could not be analyzed.

More advanced age, male sex, and presence of comorbidities, such as diabetes mellitus, hypertension, coagulopathy, and history of cerebral infarction, are considered important predisposing factors in CSDH development.[2],[3],[4],[5],[16] In our study of patients following minor head injury without intracranial bleeding, surgical CSDH was significantly presented in male patients, patients older than 65 years, and patients who did not receive NSAIDs. However, patients who received NSAIDs were more likely to exhibit comorbidities, including ischemic heart disease, stroke, diabetes mellitus, hypertension, hyperlipidemia, chronic renal disease, arrhythmia, heart failure, chronic liver disease, and valvular heart disease. These comorbidities may contribute to the increasing associated symptoms of minor head trauma or the demands of NSAID therapy. Although not all anticoagulant or antiplatelet agents result in coagulopathy, our study results demonstrated that the presence of coagulopathy did not imply significant differences between the two groups in this study. However, determining the exact association between NSAIDs and anticoagulant or antiplatelet agents in the incidence of surgical CSDH is difficult in this study.

The strength of this study lies in the use of a large database. However, several limitations still exist, including the miscoding dataset, potential bias due to a small number of surgical CSDH patients, limited demographics, the subtype of NSAIDs, the interaction between NSAIDs and anticoagulant or antiplatelet agents, and the unknown dosage and usage period of NSAID therapy. Despite the aforementioned limitations, this study demonstrated an association between NSAIDs and a low incidence of surgical CSDH in patients with minor head injury without intracranial bleeding. However, the actual therapeutic effects of NSAIDs on patients with CSDH should be individualized, evaluated, and confirmed by conducting a large randomized controlled trial.


  Conclusion Top


Based on the results of this study, patients aged >65 years, male patients, and patients who did not receive NSAIDs were found to have a higher risk of surgical CSDH following minor head injury without intracranial bleeding. NSAID use may be associated with a low incidence of surgical CSDH in patients following minor head injury without intracranial bleeding. These results suggest possible therapeutic effects of NSAIDs in patients with CSDH.

Acknowledgments

This study is supported by a grant from the Cathay General Hospital, Taipei, Taiwan (CGH-MR-B10709).

Financial support and sponsorship

This study is supported by a grant from the Cathay General Hospital, Taipei, Taiwan (CGH-MR-B10709).

Conflicts of interest

There are no conflicts of interest.



 
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