Kat Dakay, DO

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. 2018;75:1338-1346. [1]

Statins are a commonly used treatment in patients with hyperlipidemia, coronary artery disease, and ischemic stroke; however, the role of statins in intracranial hemorrhage is less clear. More recently, the role of statins in chronic subdural hematoma has been investigated.

Chronic subdural hematoma increases with aging and represents a clinical challenge; while surgical management with burrhole drainage can be successful, patients can also experience recurrence in approximately 1/3 of cases [2]. Additionally, the risk of surgery may be a concern, particularly in elderly patients or those with medical comorbidities. At this time, there is no clear established medical treatment for chronic subdural hematoma, but statins have been posited as a possible nonsurgical option for treatment of chronic SDH. In this study published in JAMA Neurology, Jiang and colleagues present the results of a randomized controlled trial of low-dose atorvastatin in patients with chronic subdural hematoma [1].

The ATOCH trial was a randomized, controlled trial including patients with a mild to moderate subdural hematoma aged 18-90 who were not previously on a statin and had not had a recent or immediately imminent surgery for their subdural hematoma. 200 patients were included and randomized to either 20 mg of atorvastatin daily or placebo. Patients were well-matched between both groups with regards to age, sex, and baseline hematoma volume (62.9 mL in the atorvastatin group versus 62.3 mL in the placebo group). The primary outcome was change in hematoma volume, and the secondary outcome was improvement in neurologic function at eight weeks after treatment.

The researchers found that reduction in hematoma volume was greater for patients who received atorvastatin (29.4 mL change in hematoma volume) versus placebo (16.85 mL change in hematoma volume). Atorvastatin was associated with a relative increase in hematoma absorption of 12.5 cc as compared to placebo (95% CI 0.9-23 mL; p – 0.008), as well as a decreased likelihood of need for surgical treatment (17.3% vs 11.2%; p = 0.08). During the trial, plasma LDL levels were measured as a marker of compliance with treatment and were significantly lower in the treatment group versus the placebo group; routine blood tests inclusive of coagulation markers (PT/PTT, D dimer, fibrinogen, hemoglobin, and platelets) were similar between the active treatment and placebo groups. Additionally, atorvastatin was also associated with a higher likelihood of neurologic improvement at 8 weeks (adjusted OR 1.96; 95% CI, 1.07-3.58, p =0.03). Some limitations of the study include potentially limited generalizability, as the trial was conducted in China, as well as the small number of patients. The authors suggest that atorvastatin may be an effective treatment in patients with chronic subdural hematoma.

The rationale behind the use of statins in chronic subdural hematoma is due primarily to the pleiotropic effects, separate from the inhibition of HMG-CoA reductase that statins are most notorious for. In subdural hematoma, it is thought that a minor traumatic event leads to tearing of the border cell layer, and extravasation of CSF into the subdural space. This transposition of CSF into the potential space sets off a cascade of inflammation, impaired coagulation, and angiogenesis; VEGF can lead to the formation of immature capillaries [3]. Statins can help reduce inflammation [4], mobilize endothelial progenitor cells, reduce VEGF, and promote angiogenesis [5]. In rat models of experimentally-induced subdural hematoma, statin administration is associated with improvement in hematoma volume, thicker neomembrane, and increased tissue markers of angioneogenesis [6]. Retrospective single-arm studies have shown atorvastatin to be associated with hematoma volume over one month [7]; another retrospective study of patients undergoing burr hole craniotomy for chronic SDH found that patients administered statins at the discretion of the neurosurgeon were less likely to have recurrence of their SDH compared to those patients not on a statin [8]. However, it is imperative to note that these studies are limited due to the potential for confounding bias, as these studies were nonrandomized and statin treatment was at the discretion of the treating physicians. There may be a paradoxical deleterious effect with high doses of statins, and it is notable that in in-vivo studies, high dose statins were not as beneficial as low-dose statin [6]. While the relationship of statins in spontaneous intraparenchymal hemorrhage has been more conflicting, it appears that in cSDH, there is some in-vivo and retrospective data to bolster the findings of the ATOCH trial.

This study suggests that there may be a benefit to statin treatment in patients with subdural hematoma with regards to neurological outcome, hematoma size, and reduced need for surgery. However, this relationship may be dosage-dependent based on the results of some in-vivo experimental studies [6], so the study does not necessarily support initiating or continuing a high-intensity statin in a patient with a subdural hematoma. Given that abrupt withdrawal of statin treatment may be associated with a rebound in CRP levels and inflammatory cascade [9], this study would lead me to avoid discontinuing a low to moderate intensity statin in patients presenting with cSDH. However, given the potential for side effects, particularly in an elderly population, additional studies to confirm the results of this trial would be beneficial in clarifying the role of statin therapy as medical treatment for cSDH.

References:

  1. 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. 2018;75:1338-1346
  2. 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. 2017;31:72-77
  3. 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. 2018;116:402-411 e402
  4. 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. 2014;341:88-96
  5. Zou H, Zhu XX, Ding YH, Zhang GB, Geng Y, Huang DS. Statins in conditions other than hypocholesterolemic effects for chronic subdural hematoma therapy, old drug, new tricks? Oncotarget. 2017;8:27541-27546
  6. 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. 2016;362:91-99
  7. Qiu S, Zhuo W, Sun C, Su Z, Yan A, Shen L. Effects of atorvastatin on chronic subdural hematoma: A systematic review. Medicine (Baltimore). 2017;96:e7290
  8. 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. 2018;117:e425-e429
  9. Endres M, Laufs U. Discontinuation of statin treatment in stroke patients. Stroke. 2006;37:2640-2643