Chronic subdural hematoma (CSDH) occurs in 1–13.1 per 100,000 persons per year, but its morbidity rate is increasing due to aging of the population and increasing use of anticoagulation/antiplatelet agents.19 Twist-drill craniotomy or burr-hole craniostomy to evacuate hematoma remains the first-line treatment for symptomatic patients with CSDH; however, these techniques are accompanied by high rates of recurrence (20%) and complications.17,20,26 Therefore, various drug treatments have been considered, including the use of mannitol, glucocorticoids, angiotensin-converting enzyme inhibitors, tranexamic acid, and platelet activating factor receptor inhibitor,7,11,27 but few have been rigorously evaluated in a randomized clinical trial.22 High doses of dexamethasone (DXM) have been reported to reduce CSDH,4,10,23 but potential benefits of this treatment are offset by complications such as hyperglycemia, infection, gastritis, cellulitis, and cardiac disorders.5,23,31,35,36 The efficacy of low-dose DXM has not been previously studied.
In 2014, atorvastatin (ATO) was first reported to be safe and effective in prompting the absorption of hematoma based on the results of a preliminary study from 3 medical centers.33 Then, in an SDH rat model, ATO was demonstrated to reduce inflammation and hematoma.14 In 2017, Chan et al. found that CSDH patients treated with ATO had lower rates of deterioration and burr-hole drainage.6 In 2018, Tang et al. analyzed 245 consecutive adult patients undergoing burr-hole craniotomy for CSDH and found that perioperative ATO administration was associated with a lower rate of CSDH recurrence.30 There was also a systematic review which found that oral ATO may be beneficial in the management of CSDH.24 In a recent double-blind, randomized, placebo-controlled clinical trial, we showed that 20 mg ATO given daily for 8 weeks is safe and effective in reducing hematoma and improving the clinical outcomes of patients with CSDH.12 This trial was developed based on previous studies, including our own, showing that statins have an antiinflammatory effect and can mobilize endothelial progenitor cells (EPCs) for vascular repair.1,15,21 However, as approximately 11.2% of participants in our trial failed to respond to ATO treatment and more prolonged treatment could increase the risk of drug-related complications3 and noncompliance, we hypothesized that the clinical efficacy of ATO can be enhanced or accelerated when ATO is combined with a low-dose regimen of DXM. Such an approach might avoid complications associated with high-dose DXM. Herein, we report the results from a phase II clinical trial designed as an initial test of this hypothesis.
Methods
This open-label, evaluator-blinded, parallel, proof-of-concept, randomized trial was conducted at the General Hospital of Tianjin Medical University, Tianjin, China, between July 2014 and December 2018.
Patient Recruitment
The patients who met the inclusion criteria were adult (age ≥ 18 years) men and nonpregnant women with a diagnosis of primary supratentorial CSDH with minimal midline shift (< 1 cm) confirmed on brain CT or MRI who were determined by 2 attending surgeons to be at no risk of cerebral hernia and not in need of immediate surgery. In addition, participants had minimal loss of consciousness (Markwalder’s Grading Scale and Glasgow Coma Scale [MGS-GCS]18,29 grade < 3, Supplementary Table e-1) and no previous surgery for CSDH. These inclusion criteria were similar to those for our previously reported ATOCH (Effect of Atorvastatin on Chronic Subdural Hematoma) trial.12 Patients were excluded if they were allergic to statins; had a secondary cause of the hematoma (e.g., tumor or bleeding diathesis), severe comorbidity, or liver disease; had received a statin or steroid within the last week or were required to take statins in the next 3 months; had diabetes mellitus with poorly controlled blood glucose; had uncontrolled hypertension or infection; or had already participated in clinical trials in the previous 4 weeks. After patient recruitment, a random number sequence was generated with computer software by a statistician who was not involved in the study team, and patients were allocated to either the ATO group or the ATO+DXM group according to the random number. Since this was a proof-of-concept study, no formal calculation was performed to determine the sample size.8 However, based on a planned study period of 2014–2018, we estimated that 60 patients would be recruited into the 2-arm trial.
Standard Protocol Approvals, Registrations, and Patient Consent
The trial protocols and documentation were approved by the ethics committee of the Tianjin Medical University General Hospital Institutional Review Board, and written informed consent was obtained from each participant or his/her legal surrogate. The trial was registered on the website of the Chinese Clinical Trial Registry (http://www.chictr.org.cn/index.aspx) with the registration number ChiCTR-IPR-14005573. There were no important changes to the methods after trial commencement and no interim analyses were performed.
Treatment and Follow-Up
Sixty eligible patients were randomly assigned in a 1:1 ratio to one of the two treatment regimens: patients in the ATO group received 20 mg of oral ATO (Pfizer Inc.) once daily for 5 consecutive weeks and those in the ATO-DXM group received 20 mg of ATO and DXM (Tianyao Pharmaceutical Co. Ltd.) daily for 5 consecutive weeks. DXM was administered in the following doses: 2.25 mg daily for 2 weeks followed by 0.75 mg twice daily for 2 weeks and subsequently at 0.75 mg once a day for 1 week. All patients were then followed up for an additional 7 weeks after cessation of the drug treatment. Treatment compliance was monitored by regular contact with participants and their caregivers through telephone and during weekly visits for clinical evaluation and instructions on DXM dosage. Patients could be switched to surgery to evacuate the hematoma when their neurological dysfunction significantly deteriorated (worsened headache, progressive limb paralysis, or changes in the levels of consciousness) or when CT or MRI scans showed hematoma enlargement and/or a midline shift (> 1 cm) during follow-up.
Outcome Assessment
The primary endpoint was hematoma reduction between baseline and 5 weeks after the first dose, based on assessment of the CT and MR images by 3 neuroradiologists blinded to treatment allocation and other details. Hematoma volume (HV) was calculated using the Tada formula: maximal length × maximal width × maximal thickness of the hematoma, divided by 2.13 The HV was calculated bilaterally and the total HV was calculated as the HV of the left plus the HV of the right.
Secondary outcomes included MGS-GCS score at the time of the first drug dose and at the end of weeks 5 and 12, evaluated by 2 attending neurosurgeons blinded to treatment; reduction in HV at the end of weeks 2 and 12 after the first dose (during the follow-up period); neurological function assessed by the ability of a patient to perform activities of daily living (ADL) according to the modified Barthel Index (ADL-BI) and the patient’s Glasgow Outcome Scale–Extended (GOSE) score at the end of weeks 5 and 12 after the first dose; rate of surgical intervention; and laboratory results.
Fluorescence-Activated Cell Sorting Assessment
Of the 30 patients in each group, 24 patients in the ATO group and 26 patients in the ATO+DXM group had undergone blood collection on admission. Fluorescence-activated cell sorting (FACS) assessment was performed in all of these patients before the treatment as well as 2 and 5 weeks after the treatment. Peripheral blood samples were collected from a subgroup of patients using 0.32% sodium citrate as an anticoagulant (final concentration) for flow cytometry (FACS Aria III; BD Biosciences) analysis of EPCs, regulatory T cells (Tregs), and T lymphocyte subtypes at baseline (before treatment) and at weeks 2 and 5. These measurements were surrogate markers of systemic inflammation or vascular repair. To measure EPCs, mononuclear cells were isolated from whole blood by density gradient centrifugation at 300g for 20 minutes at room temperature and stained with fluorescein isothiocyanate (FITC)–CD34 and phycoerythrin (PE)–CD133 antibodies (Miltenyi Biotec).16 Tregs were detected by using a commercial kit (130-094-158; Miltenyi Biotec), according to the manufacturer’s instructions. T-lymphocyte subtypes were identified by FITC-CD4, PE-CD8, and peridinin-chlorophyll-protein complex (PerCP)–CD19 antibodies, as previously described.8 The flow cytometry data were analyzed using FlowJo software (Tree Star).
Laboratory Assays
Blood was analyzed for complete blood cell count, international normalized ratio, activated partial thromboplastin time, plasma fibrinogen and d-dimer, serum alanine aminotransferase, aspartate transaminase, gamma glutamyl transpeptidase, urea nitrogen, creatinine, and blood glucose at baseline and at weeks 2 and 5.
Safety Monitoring
We recorded all adverse events identified when patients were in the hospital or at outpatient clinic visits during follow-up. A serious adverse clinical event was defined as a significant hazard or adverse effects that were related to the trial drugs and required treatment. As ATO and DXM are associated with abnormal glucose metabolism, hyperglycemia and hyperglycemia-related nosocomial infections were also monitored.
Statistical Analysis
Using the intention-to-treat principle, we performed an efficacy analysis that included all the patients randomized (full analysis set). Adverse events were assessed in all patients who received at least one dose of a treatment drug before the end of follow-up.
We present continuous variables as means ± standard deviations and categorical variables as frequencies and percentages. Differences between treatment groups were assessed using the independent-samples t-test for continuous measures and the chi-square test for categorical variables (or Fisher’s exact test when the expected value was < 5).
For the primary endpoint, we used a linear mixed-effects model to estimate the difference in hematoma reduction. The model was fitted with treatment, time, interaction between treatment and time, baseline HV, age, and sex as fixed effects and the patient as the random effect. The last observation carried forward (LOCF) method was used to fill in missing data.
Correlations between HVs and cellular markers on FACS were determined using Pearson’s coefficient. All analyses were performed using SPSS statistical software (version 22.0; IBM Corp.) and SAS (version 9.4; SAS Institute), and the significance threshold was set at p < 0.05 (2-tailed).
Results
A flowchart of patient recruitment to this study is shown in Fig. 1. During July 2014 and December 2018, 315 CSDH patients were admitted to our department. In total, 212 of these patients were treated with surgery directly, and 103 patients were screened for eligibility of this trial. Of these 103 patients, 43 patients were excluded because they did not meet the inclusion criteria. Baseline demographic and clinical characteristics were comparable between the 2 patient groups (Table 1 and Supplementary Tables e-2-1 and e-2-2). Among the 103 patients screened, 60 were enrolled (mean age 66.6 ± 12.6 years). There were no deaths or dropouts during the trial, but 3 and 2 patients in the ATO and ATO+DXM groups, respectively, did not undergo neuroimaging at weeks 2 and 5. Table 1 shows that baseline HVs were comparable between the 2 groups (60.77 ± 27.62 vs 67.48 ± 21.22 ml; p = 0.296). Consistent with findings of our recent trial, patients receiving ATO alone had a 24.3% reduction in HV at the end of week 5. However, patients in the ATO+DXM group had a significantly greater reduction in HV than those in the ATO group at weeks 2 (7.02 ± 13.06 vs 23.11 ± 15.37 ml; p = 0.0056), 5 (23.32 ± 26.35 vs 43.27 ± 19.09 ml; p = 0.0005), and 12 (44.71 ± 35.92 vs 63.78 ± 25.45 ml; p = 0.0009) (Fig. 2A). Since the starting HV varied considerably, the relative hematoma reduction, measured as (HV at baseline − HV after treatment)/HV at baseline × 100%, was then compared between the 2 groups at different time points. The ATO+DXM group had an increased percentage of hematoma reduction compared with the ATO group at weeks 2 (34.47% ± 22.17% vs 12.16% ± 22.08%, p = 0.002), 5 (64.80% ± 26.46% vs 39.46% ± 41.61%, p = 0.0005), and 12 (92.52% ± 24.75% vs 78.50% ± 43.59%, p = 0.0422) (Fig. 2B). Patients in the ATO+DXM group also showed remarkably greater improvement in MGS-GCS scores than patients in the ATO group after 5 weeks of treatment (p = 0.0004) but not after 2 weeks of treatment (Table 2). Overall, 83.33% of patients treated with ATO+DXM and 32.14% of those treated with ATO alone achieved complete recovery of neurological dysfunction (MGS-GCS score 0) by week 5.
Schematic illustration of the trial protocol.
Baseline demographic and clinical characteristics of patients randomized to the ATO or ATO+DXM group
| ATO (n = 30) | ATO+DXM (n = 30) | p Value | |
|---|---|---|---|
| Age, yrs | 63.83 ± 13.73 | 69.37 ± 10.9 | 0.089* |
| Sex | 0.136† | ||
| Male | 20 | 25 | |
| Female | 10 | 5 | |
| CSDH w/ TBI history | 21 (70%) | 19 (63.33%) | 0.584† |
| MGS-GCS score | 0.687† | ||
| 0 | 3 | 4 | |
| 1 | 23 | 20 | |
| 2 | 4 | 6 | |
| ADL-BI score | 0.766† | ||
| ≥85 | 22 | 23 | |
| <85 | 8 | 7 | |
| Baseline hematoma vol, ml | 60.77 ± 27.62 | 67.48 ± 21.22 | 0.296* |
| Hematoma location | 0.160† | ||
| Right | 14 | 7 | |
| Left | 9 | 14 | |
| Bilateral | 7 | 9 | |
| Medical history | |||
| Hypertension | 7 (23.33%) | 10 (33.33%) | 0.39† |
| Diabetes | 5 (16.67%) | 5 (16.67%) | 1.000† |
| Cardiac disease | 6 (20%) | 9 (30%) | 0.371† |
| Medication history | |||
| Antiplatelet therapy | 3 (10%) | 2 (6.67%) | 1.000‡ |
| Anticoagulant therapy | 0 (0%) | 1 (3.33%) | 1.000‡ |
| Social history | |||
| Smoker | 10 (33.33%) | 9 (30%) | 0.781† |
| Drinker | 7 (23.33%) | 9 (30%) | 0.559† |
Values are presented as number of patients (%) unless otherwise indicated. Mean values are presented ± SD.
Independent-samples t-test.
Chi-square test.
Fisher’s exact test.
Reduction in HV after 2, 5, and 12 weeks of treatments. A: The absolute hematoma reduction was calculated as HV at baseline − HV after treatment. Patients treated with ATO+DXM had greater hematoma reduction than those treated with ATO alone after week 2 (7.02 ± 13.06 vs 23.11 ± 15.37 ml, mean difference 14.51 ml; 95% CI 4.31–24.71; p = 0.0056), week 5 (23.32 ± 26.35 vs 43.27 ± 19.09 ml; p = 0.0005), and week 12 (44.71 ± 35.92 vs 63.78 ± 25.45 ml; p = 0.0009) of treatment. B: The relative hematoma reduction was calculated as (HV at baseline − HV after treatment)/HV at baseline × 100%. The ATO+DXM group had an increased percentage of hematoma reduction at week 2 (34.47% ± 22.17% vs 12.16% ± 22.08%, p = 0.002), week 5 (64.80% ± 26.46% vs 39.46% ± 41.61%, p = 0.0005), and week 12 (92.52% ± 24.75% vs 78.50% ± 43.59%, p = 0.0422). The data are presented as mean ± standard deviation and were analyzed using a linear mixed model with treatment, time, interaction between treatment and time, baseline HV, age, and sex as fixed effects and the patient as the random effect. The missing data were filled in by using the LOCF method.
Clinical assessment of patients randomized to the ATO or ATO+DXM group
| Scale | ATO (n = 30)* | ATO+DXM (n = 30)* | p Value |
|---|---|---|---|
| MGS-GCS score | 0.687† | ||
| Baseline | |||
| 0 | 3 | 4 | |
| 1 | 23 | 20 | |
| 2 | 4 | 6 | |
| 2 wks | 0.435† | ||
| 0 | 7 | 11 | |
| 1 | 19 | 17 | |
| 2 | 4 | 2 | |
| 5 wks | 0.0004† | ||
| 0 | 9a | 25 | |
| 1 | 17a | 4 | |
| 2 | 2a | 1 | |
| 12 wks | 0.286† | ||
| 0 | 25b | 29c | |
| 1 | 1b | 0c | |
| 2 | 0b | 0c | |
| ADL-BI score | |||
| ≥85 | |||
| Baseline | 22 | 23 | 0.766† |
| 5 wks | 24a | 29 | 0.187‡ |
| 12 wks | 25b | 29c | |
| <85 | |||
| Baseline | 8 | 7 | 0.766† |
| 5 wks | 4a | 1 | 0.187‡ |
| 12 wks | 1b | 0c | 0.473‡ |
| ADL-BI 100 | |||
| Baseline | 17 (56.67%) | 10 (33.33%) | 0.069† |
| 5 wks | 18 (64.29%)a | 18 (60%) | 0.737† |
| 12 wks | 22 (84.61%)b | 25 (86.21%)c | 1.000‡ |
| GOSE score | |||
| ≥7 | |||
| 5 wks | 24a | 28 | 0.415‡ |
| 12 wks | 25b | 2 | 0.473‡ |
| <7 | |||
| 5 wks | 4a | 29 | 0.415‡ |
| 12 wks | 1b | 0c | 0.473‡ |
| 8 | |||
| 5 wks | 8 (28.57%)a | 13 (43.33%) | |
| 12 wks | 22 (84.62%)b | 26 (89.66%)c |
Values are presented as number of patients (%) unless otherwise indicated.
Number of patients switched to surgical treatment: a2, b4, c1.
Chi-square test.
Fisher’s exact test.
Figure 3 shows typical imaging findings in patients with CSDH treated with ATO and ATO+DXM, and Supplementary Fig. e-1 shows changes in imaging findings in the ATO and ATO+DXM groups. There were no statistically significant differences in the MGS-GCS scores between the ATO and ATO+DXM groups after 12 weeks of treatment (Table 2). The frequency of ADL-BI scores ≥ 85 or = 100 was comparable between the 2 groups at weeks 5 and 12 (ADL-BI ≥ 85, p = 0.187 and 0.473; ADL-BI = 100, p = 0.737 and 1.000, respectively). GOSE scores showed a trend toward improvement in patients receiving combined therapy at weeks 5 and 12 (GOSE ≥ 7, p = 0.415 and 0.473; GOSE = 8, p = 0.242 and 0.696, respectively).
Representative CT and MR images of CSDH patients treated with ATO or ATO+DXM. A–D: A typical case in the ATO+DXM group (patient 14), showing rapid absorption of hematoma. The HV was 90.10 ml at baseline (A), 40.54 ml at week 2 (B), 17.84 ml at week 5 (C), and 0 ml at week 12 (D). E–H: A typical case in the ATO group (patient 5), showing dynamic changes in HV. The volume was 95.33 ml at baseline (E), 50.75 ml at week 2 (F), and 30.28 ml at week 5 (G), and the hematoma had disappeared by week 12 (H). Figure is available in color online only.
Four patients from the ATO group and 1 from the ATO+DXM group (13.3% vs 3.3%, p = 0.353) were switched to surgery at 14, 16, 40, 48, or 36 days after the first dose due to increasing HVs and exacerbated neurological dysfunction, which was shown as an increased MGS-GCS score (Supplementary Tables e-2-1 and e-2-2). Two of the 4 patients in the ATO group were switched to surgery after 2 weeks of treatment and the other 2 patients after 5 weeks. In the ATO+DXM group, 1 patient underwent surgical hematoma drainage on day 48 after the first dose.
The baseline characteristics of the patients who received the FACS assessment showed no significant differences (Supplementary Table e-4). The numbers of circulating EPCs were similar between the 2 groups of patients at baseline but were significantly elevated in patients receiving ATO+DXM at week 2; however, the increase was no longer detectable at 5 weeks of treatment (Fig. 4B). The levels of circulating Treg cells were higher in patients receiving ATO+DXM at weeks 2 and 5 (Fig. 4C). Conversely, CD4+ T lymphocytes decreased from the baseline values in patients receiving ATO-DXM compared to those receiving ATO alone (Fig. 4D). Numbers of circulating CD8+ T cells and CD19+ B cells were similar between the 2 groups of patients (Fig. 4E and F).
FACS analysis of circulating EPCs and lymphocyte subtypes. A: Gating strategy for EPCs and lymphocyte subtypes. B: The number of EPCs increased after both the ATO and ATO+DXM treatments (#p < 0.05). EPCs were significantly increased in the ATO+DXM group compared with the ATO group at 2 weeks (*p < 0.05), but showed no difference at 5 weeks. C: The percentage of Tregs among the CD4+ T cells was higher in the ATO+DXM group than in the ATO group at 2 and 5 weeks (*p < 0.05). D: The counts of CD4+ cells were significantly lower in the ATO+DXM group than in the ATO group at 2 and 5 weeks (*p < 0.05). E and F: There were no differences in the CD8+ T-cell counts and CD19+ B-cell counts between the 2 groups (*p > 0.05). * = compared with the ATO group at the same time point; # = compared with pretreatment in the same group; FSC = forward scatter; SSC = side scatter; W = weeks. Figure is available in color online only.
One patient who was a carrier of hepatitis B virus at enrollment had elevated aminotransferase levels during the clinical trial, which returned to the baseline after 2 weeks of treatment with bicyclol and glutathione. Four patients had mild liver abnormalities and 1 patient had mild elevation of creatinine, which did not require treatment. Known steroid-related complications were also found, such as mild glycemia in 3 patients with a prior diagnosis of diabetes mellitus, nonspecific nausea in 2 patients, and weight gain in 8 patients. There were no cases of infection, gastrointestinal bleeding, muscle soreness, or rhabdomyolysis (Supplementary Table e-3). Moreover, there were no statistical differences in laboratory results between the 2 groups (Supplementary Table e-3).
Discussion
Our clinical trial showed that in patients with moderate-sized CSDH, the combined treatment with low-dose ATO and DXM resulted in quicker reduction in HVs, more rapid recovery of neurological function, and a reduced rate of surgery compared to treatment with ATO alone. The treatments were well tolerated during the 12-week trial. These results provide promise that short-term low-dose combination treatment might be effective for patients with mild to moderate forms of CSDH.
To explore the mechanisms underlying the accelerated hematoma reduction with combined treatment, several plasma markers of vascular repair (EPCs) and inflammation (T cells) were serially measured in a subgroup of patients. Changes in EPC and lymphocyte subpopulations in association with reduction in HVs during the course of treatment are consistent with findings of our previous reports that ATO possesses antiinflammatory activity and promotes angiogenesis.14,25,34 Our results provide further support for the synergistic action of low-dose DXM with ATO, as demonstrated by downregulation of CD4+ cells and upregulation of CD4+ Tregs, which are related to cellular immunity.9
Combination treatment also appears to increase the levels of circulating EPCs, which are important for vascular repair.2 We have previously shown that patients with CSDH have low levels of circulating EPCs, a condition that is associated with hematoma development and recurrence.28 ATO increases the levels of EPCs and promotes angiogenesis in mouse models.32,34 This study’s findings suggest an additive effect in increasing EPCs when using DXM in combination with ATO compared with ATO alone.
We recognize that our study is limited to being a hypothesis-generating proof-of-concept study and lacks sufficient power for reliable assessment of the treatment’s effects on clinical outcomes and subgroup analysis. Bias may also have been introduced from the open-label design, but there were no differences in patient background and standard management, and the imaging and clinical outcomes were assessed by physicians blinded to treatment allocation.
Study Limitations
Our previous studies demonstrated the beneficial effects of ATO therapy for CSDH patients. Therefore, treating CSDH patients without using medical therapy did not meet our ethical principles. This resulted in the lack of a control group with no medical treatment in this study, which was the major limitation of this study.
Conclusions
In summary, in this open-label, evaluator-blinded trial we found that compared with ATO alone, the combination of ATO and low-dose DXM accelerates hematoma reduction and neurological improvement in patients with CSDH. These results support the existence of potent synergistic effects between the 2 drugs, which act on immunoregulation and vascular repair. The positive proof-of-concept results provide justification to proceed with a formative phase III clinical trial to reliably assess the effects of this combination treatment in CSDH.
Acknowledgments
This study was funded by the National Natural Science Foundation of China (81671380 to D.W.; 81671221 to R.J.); the Tianjin Research Program of Application Foundation and Advanced Technology (17JCZDJC35900 to D.W.; 14ZCZDSY00179 to R.J.; 18ZLZXZF00270 to Z.W.); the Key Program for International S&T Cooperation Project of China (81720108015 to J.Z.); the Municipal Science and Technology Commission (15ZXLCSY00060 to J.Z.; 15ZXLCSY00040 to J.Z.); the Science & Technology Development Fund of the Tianjin Education Commission for Higher Education (2016YD02 to Y.W.); the Scientific Research Program Project of the Tianjin Education Commission (2018ZD03 to Z.W.); the Tianjin Science and Technology Projects in Key Areas of Traditional Chinese Medicine (2018001 to Z.W.); and the Clinical Study of Tianjin Medical University (2017kylc007 to R.J).
Disclosures
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
Author Contributions
Conception and design: Jiang, D Wang, J Zhang. Acquisition of data: D Wang, Gao, Xu, Tian, Wei, Quan, Y Wang, Z Wang, Lei. Analysis and interpretation of data: Jiang, D Wang, Gao, Xu, Chen, Tian, Wei, Quan, Anderson, J Zhang. Drafting the article: Jiang, D Wang, Gao, Xu, S Zhang, Yue, Dong, J Zhang. Critically revising the article: Jiang, D Wang, S Zhang, Anderson, Dong, J Zhang. Reviewed submitted version of manuscript: Jiang, Gao, Dong. Statistical analysis: Chen, Anderson. Administrative/technical/material support: Yue, Lei. Study supervision: Jiang, Yue, J Zhang.
Supplemental Information
Online-Only Content
Supplemental material is available with the online version of the article.
Supplementary Tables and Figure. https://thejns.org/doi/suppl/10.3171/2019.11.JNS192020.
References
- 1↑
Araújo FA, Rocha MA, Mendes JB, Andrade SP: Atorvastatin inhibits inflammatory angiogenesis in mice through down regulation of VEGF, TNF-alpha and TGF-beta1. Biomed Pharmacother 64:29–34, 2010
- 2↑
Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, et al.: Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967, 1997
- 3↑
Bakker-Arkema RG, Davidson MH, Goldstein RJ, Davignon J, Isaacsohn JL, Weiss SR, et al.: Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia. JAMA 275:128–133, 1996
- 5↑
Berghauser Pont LM, Dammers R, Schouten JW, Lingsma HF, Dirven CM: Clinical factors associated with outcome in chronic subdural hematoma: a retrospective cohort study of patients on preoperative corticosteroid therapy. Neurosurgery 70:873–880, 2012
- 6↑
Chan DY, Chan DT, Sun TF, Ng SC, Wong GK, Poon WS: The use of atorvastatin for chronic subdural haematoma: a retrospective cohort comparison study. Br J Neurosurg 31:72–77, 2017
- 7↑
Edlmann E, Giorgi-Coll S, Whitfield PC, Carpenter KLH, Hutchinson PJ: Pathophysiology of chronic subdural haematoma: inflammation, angiogenesis and implications for pharmacotherapy. J Neuroinflammation 14:108, 2017
- 8↑
Fu Y, Hao J, Zhang N, Ren L, Sun N, Li YJ, et al.: Fingolimod for the treatment of intracerebral hemorrhage: a 2-arm proof-of-concept study. JAMA Neurol 71:1092–1101, 2014
- 9↑
Gerriets VA, Kishton RJ, Johnson MO, Cohen S, Siska PJ, Nichols AG, et al.: Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat Immunol 17:1459–1466, 2016
- 10↑
Giamarellos-Bourboulis EJ, Dimopoulou I, Kotanidou A, Livaditi O, Pelekanou A, Tsagarakis S, et al.: Ex-vivo effect of dexamethasone on cytokine production from whole blood of septic patients: correlation with disease severity. Cytokine 49:89–94, 2010
- 11↑
Holl DC, Volovici V, Dirven CMF, Peul WC, van Kooten F, Jellema K, et al.: Pathophysiology and nonsurgical treatment of chronic subdural hematoma: from past to present to future. World Neurosurg 116:402–411.e2, 2018
- 12↑
Jiang R, Zhao S, Wang R, Feng H, Zhang J, Li X, et al.: Safety and efficacy of atorvastatin for chronic subdural hematoma in Chinese patients: a randomized clinical trial. JAMA Neurol 75:1338–1346, 2018
- 13↑
Kothari RU, Brott T, Broderick JP, Barsan WG, Sauerbeck LR, Zuccarello M, et al.: The ABCs of measuring intracerebral hemorrhage volumes. Stroke 27:1304–1305, 1996
- 14↑
Li T, Wang D, Tian Y, Yu H, Wang Y, Quan W, et al.: Effects of atorvastatin on the inflammation regulation and elimination of subdural hematoma in rats. J Neurol Sci 341:88–96, 2014
- 15↑
Lin LY, Huang CC, Chen JS, Wu TC, Leu HB, Huang PH, et al.: Effects of pitavastatin versus atorvastatin on the peripheral endothelial progenitor cells and vascular endothelial growth factor in high-risk patients: a pilot prospective, double-blind, randomized study. Cardiovasc Diabetol 13:111, 2014
- 16↑
Liu L, Wei H, Chen F, Wang J, Dong JF, Zhang J: Endothelial progenitor cells correlate with clinical outcome of traumatic brain injury. Crit Care Med 39:1760–1765, 2011
- 17↑
Liu W, Bakker NA, Groen RJ: Chronic subdural hematoma: a systematic review and meta-analysis of surgical procedures. J Neurosurg 121:665–673, 2014
- 18↑
Markwalder TM, Steinsiepe KF, Rohner M, Reichenbach W, Markwalder H: The course of chronic subdural hematomas after burr-hole craniostomy and closed-system drainage. J Neurosurg 55:390–396, 1981
- 19↑
Miranda LB, Braxton E, Hobbs J, Quigley MR: Chronic subdural hematoma in the elderly: not a benign disease. J Neurosurg 114:72–76, 2011
- 20↑
Motiei-Langroudi R, Stippler M, Shi S, Adeeb N, Gupta R, Griessenauer CJ, et al.: Factors predicting reoperation of chronic subdural hematoma following primary surgical evacuation. J Neurosurg 129:1143–1150, 2018
- 21↑
Oikonomou E, Siasos G, Zaromitidou M, Hatzis G, Mourouzis K, Chrysohoou C, et al.: Atorvastatin treatment improves endothelial function through endothelial progenitor cells mobilization in ischemic heart failure patients. Atherosclerosis 238:159–164, 2015
- 22↑
Poulsen FR, Munthe S, Soe M, Halle B: Perindopril and residual chronic subdural hematoma volumes six weeks after burr hole surgery: a randomized trial. Clin Neurol Neurosurg 123:4–8, 2014
- 23↑
Prud’homme M, Mathieu F, Marcotte N, Cottin S: A pilot placebo controlled randomized trial of dexamethasone for chronic subdural hematoma. Can J Neurol Sci 43:284–290, 2016
- 24↑
Qiu S, Zhuo W, Sun C, Su Z, Yan A, Shen L: Effects of atorvastatin on chronic subdural hematoma: a systematic review. Medicine (Baltimore) 96:e7290, 2017
- 25↑
Quan W, Zhang Z, Tian Q, Wen X, Yu P, Wang D, et al.: A rat model of chronic subdural hematoma: insight into mechanisms of revascularization and inflammation. Brain Res 1625:84–96, 2015
- 26↑
Rovlias A, Theodoropoulos S, Papoutsakis D: Chronic subdural hematoma: surgical management and outcome in 986 cases: a classification and regression tree approach. Surg Neurol Int 6:127, 2015
- 27↑
Soleman J, Nocera F, Mariani L: The conservative and pharmacological management of chronic subdural haematoma. Swiss Med Wkly 147:w14398, 2017
- 28↑
Song Y, Wang Z, Liu L, Wang D, Zhang J: The level of circulating endothelial progenitor cells may be associated with the occurrence and recurrence of chronic subdural hematoma. Clinics (São Paulo) 68:1084–1088, 2013
- 29↑
Sun TF, Boet R, Poon WS: Non-surgical primary treatment of chronic subdural haematoma: preliminary results of using dexamethasone. Br J Neurosurg 19:327–333, 2005
- 30↑
Tang R, Shi J, Li X, Zou Y, Wang L, Chen Y, et al.: Effects of atorvastatin on surgical treatments of chronic subdural hematoma. World Neurosurg 117:e425–e429, 2018
- 31↑
Thotakura AK, Marabathina NR: Nonsurgical treatment of chronic subdural hematoma with steroids. World Neurosurg 84:1968–1972, 2015
- 32↑
Wang B, Sun L, Tian Y, Li Z, Wei H, Wang D, et al.: Effects of atorvastatin in the regulation of circulating EPCs and angiogenesis in traumatic brain injury in rats. J Neurol Sci 319:117–123, 2012
- 33↑
Wang D, Li T, Tian Y, Wang S, Jin C, Wei H, et al.: Effects of atorvastatin on chronic subdural hematoma: a preliminary report from three medical centers. J Neurol Sci 336:237–242, 2014
- 34↑
Wang D, Li T, Wei H, Wang Y, Yang G, Tian Y, et al.: Atorvastatin enhances angiogenesis to reduce subdural hematoma in a rat model. J Neurol Sci 362:91–99, 2016
- 35↑
Yao Z, Hu X, Ma L, You C: Dexamethasone for chronic subdural haematoma: a systematic review and meta-analysis. Acta Neurochir (Wien) 159:2037–2044, 2017
- 36↑
Zhang Y, Chen S, Xiao Y, Tang W: Effects of dexamethasone in the treatment of recurrent chronic subdural hematoma. World Neurosurg 105:115–121, 2017
