Chronic subdural hematoma (CSDH) is a common neurologic disorder that mainly affects the elderly, and the morbidity of CSDH has been reported to be up to 20.6 per 100,000 persons per year (Yang and Huang, 2017). Besides the fact that the population of patients with CSDH is still growing in an aging society (Balser et al., 2015; Rauhala et al., 2019), slow bleeding from vascular injury after head trauma has been considered as the main cause of CSDH development, and treatment with burr-hole craniotomy often improves patients’ symptoms definitely, but a prominent problem is that CSDH often recurs (33%) and always results in poor outcomes (Zhang, 2021). However, the pathogenesis involved in the recurrence of CSDH remains unclear. Some literature indicated that the recurrence formation of CSDH mainly includes the theories of inflammation (Frati et al., 2004), angiogenesis (Hohenstein et al., 2005), exudates (Thomas et al., 2019), recurrent microbleeds, and local coagulopathy (Holl et al., 2018). Therefore, many related drug therapies that could help resolve the recurrence of CSDH have emerged, thus avoiding multiple repeat surgeries for CSDH. Steroids may bring antiangiogenic and anti-inflammatory effects (Kalamatianos et al., 2013), tranexamic acid (TXA) may exert an antifibrinolytic effect (de Faria et al., 2021), and goreisan (GRS) acts on aquaporin to regulate water permeability, so it can inhibit the formation and growth of CSDH theoretically. In the case of understanding the underlying pathophysiological processes described above, many previous clinical trials of drugs have been performed on CSDH patients after surgery to improve the recurrence, but few drugs have been rigorously compared and ranked according to their effectiveness in a study, and optimal drug interventions are still being debated (Holl et al., 2018). Accordingly, we had analyzed the existing evidence and presented a first Bayesian network meta-analysis (NMA) to identify the most effective drug intervention that could improve the recurrence in patients with CSDH from a macroscopic aspect by comparing multiple treatments simultaneously.

This study followed guidance and reports for systematic reviews in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) NMA checklist (Hutton et al., 2015) and the Cochrane Handbook (Cochrane Handbook for Systematic Reviews of Interventions, 2011). All the analyses were based on the previously published research; therefore, they do not require ethical approval and patient consent.

The results of our NMA summarized the available data, suggesting that the optimal drug intervention for CSDH to reduce recurrence is ATO+DXM (OR = 0.06, 95% CrI 0.01, 0.89, SUCRA = 89.40%, 95% CrI 0.29, 1.00), and we also observed corresponding definite curative effectiveness of DXM, TXA, and ATO on the recurrence improvement of CSDH. The remaining three drug therapies also showed better efficacy in improving recurrence compared with the PLB or SNT group (the efficacy was ranked GRS, CLX, and ATB from high to low), but this difference was not significant, and the results need to be discussed cautiously. These results may provide useful evidence for clinicians to prescribe effective drugs for patients with CSDH.

Presently, craniotomy or burr-hole craniotomy to remove hematoma was still the main treatment for symptomatic patients with CSDH. Nevertheless, these surgeries are also accompanied by a high rate of recurrence (10%) (Santarius et al., 2009; Soleman et al., 2019); besides, even conservative patients with less bleeding and who are asymptomatic still face the possibility of subdural progressive recurrent bleeding. Under these circumstances, regardless of whether surgery was performed, patients with CSDH also should undergo drug treatment that can effectively prevent recurrence.

An excessive inflammatory reaction reported to assist in outer membrane formation of CSDH was considered a potential mechanism to explain the recurrence (Edlmann et al., 2017). Therefore, inhibition of excessive inflammatory response and promotion of neovascularization have become therapeutic strategies to promote CSDH absorption. In a preliminary study, ATO, as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, was first reported to lead to a hematoma volume reduction in CSDH patients (Wang et al., 2014). Then, ATO was demonstrated to reduce inflammation and hematoma in an SDH rat model (Li et al., 2014). It is shown that statins have an anti-inflammatory effect (reducing MCP1 and TNF-α) and can mobilize endothelial progenitor cells for vascular repair in previous literature (Araújo et al., 2010; Lin et al., 2014). ATO did have definite curative effectiveness to reduce the incidence of recurrence, which requires surgery in our NMA. Our conclusion is consistent with that of a recent meta-analysis of 6 studies comprising 756 patients with CSDH, which also suggested that ATO could improve prognosis and neurological recovery (He et al., 2021). Additionally, some studies even suggest that ATO is as effective as surgery in patients with mild CSDH (Shofty and Grossman, 2016; Soleman et al., 2017). Currently, low-dose ATO has been used by many neurosurgeons to promote CSDH absorption and prevent the recurrence of CSDH (Wang et al., 2014; Chan et al., 2017; Tang et al., 2018). It is recommended that future clinical trials of ATO focus more on its improvement in life quality and outcomes in patients with CSDH.

DXM was shown to better improve recurrence as compared to ATO in our NMA, maybe because it can provide a stronger anti-inflammatory effect and antiangiogenic effects (Sun et al., 2005). It is known that DXM, as a synthetic version of naturally occurring corticosteroid hormone, inhibits the aggregation, phagocytosis, and release of inflammatory mediators by immune-inflammatory cells. Glover et al., in their early studies, indicated that DXM was demonstrated to cause significantly lighter and smaller blood clots in CSDH, and the underlying reason may be the inhibition of inflammatory response, which leads to improper development of the outer membrane (Glover and Labadie, 1976). Two recent meta-analyses (Holl et al., 2019; Shrestha et al., 2021) also indicated that treatment with DXM was associated with a lesser recurrence of CSDH, but the effect of DXM to improve neurological outcomes and reduce mortality was not observed. Moreover, it should be noted that most of their included studies were observational and nonrandomized; thus, the credibility of their conclusions is relatively insufficient. However, one of the major defects of DXM therapy is the significant side effect of intravenous application, which may outweigh the benefits, as retrospective trials indicated that the use of high-dose DXM (6–8 mg/day) could only save 17% of patients with CSDH from the operation but significantly increase treatment complications (Miah et al., 2020). Therefore, low-dose DXM treatment is always used clinically, and the duration should be no more than 4 weeks, but the application of DXM is still inevitably accompanied by side effects. The research of Wang et al. (2021)indicated that DXM increased the risk of all-cause mortality (relative risk (RR) = 1.96, 95% CrI 1.20, 3.28) of CSDH, and the adverse events resulting from DXM treatment were generally serious even with low doses.

Additionally, our studies found that the low-dose DXM combined with ATO resulted in the best effectiveness concerning reducing reoperation as compared to any other drug interventions. The intuitive reason was that low doses and short-term use of DXM in combination with ATO can further enhance the inhibition of inflammatory reaction, thereby reducing vascular leakage and decreasing the risk of hematoma expansion. The recent study by Gong et al. (2021) for the first time provided evidence that the underlying mechanisms of the improved efficacy of this combined therapy were primarily by increasing the presence of ATO in hematoma and macrophages and by regulating the alteration of the macrophage phenotype, promoting the transition from the proinflammatory phenotype to the anti-inflammatory phenotype. As a result, this combination therapy showed a better effect to correct imbalances between the CSDH injury factor and repair factor. Besides, this combination also can simultaneously avoid the adverse effects of large doses and long-term use of DXM. Interestingly, CLX (a selective COX-2 inhibition) works by the same mechanism, which is to inhibit inflammation, but fails to improve CSDH recurrence. Whether other anti-inflammatory drugs in general (except for ATO and DXM) can prevent the development of CSDH significantly raises an important question, but more trials in this field are needed. Equally interesting is the observation that the statistical results of ATB (OR = 0.89, 95% CrI 0.42, 1.82) were more likely to improve the recurrence in CSDH patients than the PLB or SNT group; this difference was not statistically significant, and the results obviously need to be discussed cautiously. Given the ATB sample size, the included studies of ATB were only prospective trials, and the difference was not statistically significant; therefore, the results interpreted here indicate more that ATB may not increase the risk of recurrence, instead of reducing recurrence significantly. In addition, whether ATB increases the risk of recurrence of CSDH remains controversial in the current literature. The application of ATB (optimal dose, withdrawal time, etc.) still needs to be evaluated in more well-designed clinical trials in the future.

Antifibrinolytic therapy of CSDH has attracted growing attention. Some studies have shown that in patients with CSDH hematoma fluid, outer membrane organization fibrinolytic enzyme activation, and fibrin degradation products, thrombosis regulatory protein increased significantly and repeatedly prompted high fibrinolytic associated with blood vessel leak blood (Fujisawa et al., 1995; Murakami et al., 2002; Katano et al., 2006; Shim et al., 2007). Antifibrinolytic drugs by inhibition of the fibrinolytic enzyme activation and fibrinolytic enzyme activity stop the bleeding. Currently, traditional meta-analysis to assess the efficacy of TXA in reducing recurrence of CSDH has not yet appeared. Some retrospective studies have concluded that TXA, as an antifibrinolytic drug, can be used to promote CSDH hematoma absorption and reduce recurrence (Kageyama et al., 2013; Stary et al., 2016; Tanweer et al., 2016). TXA also can play an indirect anti-inflammatory role through the kallikrein–kinin pathway (Hunt, 2015). Our NMA results showed that TXA is beneficial for the reduction of recurrence (SUCRA = 75.74%, 95% CrI 0.43, 1.00), which is consistent with the above studies. In addition, in our research, the effectiveness of TXA is weaker than that of DXM but higher than that of ATO.

GRS is an herbal medicine prescription developed as a new alternative treatment in patients with CSDH. It works by inhibiting aquaporin-4, which is expressed in the outer membrane of the CSDH (Kwon et al., 2019). GRS prevents the inflow of fluid into the hematoma, thereby preventing the development and recurrence of hematoma. Our NMA showed that GRS did not have a definite efficacy improvement in recurrence, and currently, relevant meta-analysis is also lacking in comparison with our results.

The drug interventions applied to CSDH are complex and multifaceted. The number of existing comprehensive and rigorously compared treatment studies for this disease is still largely insufficient. Recently, Wang et al. (2021) analyzed the efficacy and safety of five drug treatments on the drug management of CSDH and concluded that DXM was the best treatment to reduce recurrence. Our NMA included more drug interventions (ATO+DXM, CLX, and ATB) in conducting further analysis for the recurrence improvement, which showed that DXM did have a definite effect of reducing recurrence, but ATO in combination with DXM showed a stronger effect in this particular aspect; these are the strength of our research. But remarkably, this combination therapy may be accompanied by more adverse complications, and the analysis of Wang et al. of the safety of drugs in CSDH is clearly useful and necessary. Regrettably, the optimal dosage and duration that could provide the best benefit without serious adverse effects of DXM in CSDH remain unclear. For the application of DXM, we need to be extremely cautious. In addition, due to the limited evidence-based data, ATO+DXM therapy still needs to be further evaluated by more RCTs. Similarly, under the situation of considering the safety in advance, rigorous RCTs also need to be designed in the future to evaluate other drug combinations (e.g., DXM+GRS) that may have potential benefits.

The greatest advantage of our NMA is that we combined and summarized all eligible studies to make a comprehensive effectiveness comparison of drug interventions in patients with CSDH, thus making up for the lack of contrast studies of many drugs that are sufficiently innovative and have great clinical significance. However, the limitations of our NMA also need to be acknowledged. First, there are not enough RCTs or prospective studies on CLX, ATO+DXM, and other drug interventions, so the evidence based on its efficacy is limited, which may make it difficult for our NMA to draw a conclusion. Second, we did not analyze the side effects and outcomes of interventions, which also could influence clinical treatment options. Finally, the low quality of several trials may potentially threaten the validity of our NMA.

To sum up, our NMA concluded that ATO+DXM, DXM, ATO, and TXA had definite curative efficacy in improving the recurrence in CSDH patients. Among them, ATO+DXM is the optimal drug intervention in this particular population to reduce recurrence. At the same time, the evidence from our NMA also can guide the development of clinical guidelines and thus help clinicians make more effective and appropriate decisions in clinical practice. Moreover, multicenter RCTs are still needed to evaluate the role of various drug interventions in improving neurological function or outcome.