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For Your Patients-Chronic Subdural Hematoma
Atorvastatin Reduces Chronic Subdural Hematoma Volume

ARTICLE IN BRIEF

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DR. LARRY B. GOLDSTEIN said the data are encouraging, but he noted the study had some limitations. Dr. Goldstein. “Participants were exclusively Chinese and there were regional biases in enrollment. Also, although the authors indicate improvement in quality of life, no data from a QoL scale were presented.”

Atorvastatin significantly improved neurological function in 45 percent of patients with chronic subdural hematoma volume compared to 28 percent given a placebo, according to a randomized clinical trial.

A multicenter study by researchers in China concluded that a two-month course of the blood thinner atorvastatin may safely reduce chronic subdural hematoma (CSDH) volume and provide other benefits to older male patients; the effects continued for at least 16 weeks after treatment, according to the findings of a randomized, placebo-controlled phase 2 study published online ahead of print July 30 in JAMA Neurology.

The investigators of the Effect of Atorvastatin on Chronic Subdural Hematoma (ATOCH) study compared atorvastatin with placebo in 196 patients, 86 percent of whom were men, over a one-year period.

CSDH is most commonly found in elderly patients who have experienced some type of head trauma. Nonsurgical treatments are both limited and ineffective, so surgery is the treatment of choice despite carrying a significant risk of recurrence and death, the study authors noted.

Surgery carries a recurrence rate of approximately 25.6 percent in high-risk patients, and elderly patients have a mortality rate of between 24 percent and 32 percent. Overall, the mortality rate in patients 90 years or older is around 38.4 percent regardless of treatment, said neurologist Jianning Zhang, MD, PhD, president of the Tianjin Medical University General Hospital and director of the Tianjin Neurological Institute in Tianjin, China.

Dr. Zhang shared co-authorship of the paper with Rongcai Jiang, MD, PhD, professor of neurology at the Tianjin Neurological Institute.

“With the continuous increase in life expectancy and the therapeutic or prophylactic use of anticoagulation and antiplatelet medications, the incidence of CSDH is expected to increase significantly worldwide,” the investigators said. A 2015 review of 875,842 patient visits to a VA hospital between 2000 and 2012 predicted that by 2030, about 60,000 cases of CSDH cases will occur in the United States each year.

“Atorvastatin may be more effective in patients 65 years and older with a hematoma of 30 mL or more,” they concluded, adding that the results will be explored further in a phase 3 trial to determine the efficacy of treatment.

DESIGN DETAILS

The trial compared atorvastatin against placebo in 196 CSDH patients, divided into two groups of 98; the median age was 69 years old. The groups received either 20 mg of atorvastatin or placebo daily for eight weeks, and each patient was then followed for 16 more weeks.

The primary outcome was change in hematoma volume (HV) by computed tomography after eight weeks of treatment. Secondary outcomes included HV after four, 12, and 24 weeks, and neurological function at week eight as measured by the Glasgow Coma Scale and the Barthel Index .

Atorvastatin significantly improved neurological function in 45 percent of patients compared to 28 percent given a placebo (p=0.03). The investigators reported that at eight weeks, mean hematoma volume reduction in patients taking atorvastatin was 12.55 mL greater than among those taking the placebo.

Eleven percent of patients who took atorvastatin and 23 percent of those who took the placebo underwent surgery during the trial for an enlarging hematoma and/or a deteriorating clinical condition. No significant adverse events were reported.

The study has several limitations, the authors noted. First, it was conducted exclusively in Chinese patients and it is unknown whether the findings would be reproducible in patients of other races and ethnicities.

The findings also raise the important question as to whether statins in general, or atorvastatin in particular, prevent the development of CSDH. In the United States, it has been estimated that as many as 23 percent of patients are taking statins.

In addition, they said the number of patients differed significantly among the participating medical centers and could have resulted in regional biases.

EXPERT COMMENTARY

CSDH is an area of neurology considered hazardous to treat in terms of morbidity and mortality, said Kevin N. Sheth, MD, FAAN, chief of the division of neurocritical care and emergency neurology and director of the Neurosciences Intensive Care Unit at Yale School of Medicine and Yale New Haven Hospital.

“Statins are really troubling to use clinically and as an alternative to surgery. There really is no good drug candidate. One of the biggest difficulties is the lack of research,” he told Neurology Today.

Dr. Sheth said: “On the surface, the study looks good, but it comes as a bit of a surprise. The trial design is pretty robust, and the findings are quite strong. It is pretty compelling.”

He said the number of cases of CSDH depends on how it is classified. Under one definition it can be as few as one to 10 in 100,000 in the general population, or as many as 100 cases in 100,000, he noted, adding that neurologists usually opt for conservative management because surgery is notoriously difficult, with a lot of potential complications, especially in older patients.

Dr. Sheth explained that there are several possible causes for the condition — tearing of the bridging vein, antiplatelet activity in a patient, or falls, where incidence is growing with the aging population.

Larry B. Goldstein, MD, FAAN, professor and chairman of the department of neurology, and co-director of the Kentucky Neuroscience Institute at the University of Kentucky, Lexington, also thought the paper was interesting. “This phase 2 trial suggests that atorvastatin 20 mg may reduce hematoma growth and improve neurological function in patients with a subdural hematoma not initially requiring surgery,” he told Neurology Today.

However, he said that it is important to note that symptoms were non-specific and included non-focal headache, limb weakness, and mental decline. Also important is the fact that patients were recruited from outpatient clinics rather than being hospitalized at baseline.

“Although hematoma growth was reduced, there was no significant improvement in at least some of the functional outcome measures,” said Dr. Goldstein. “There were also other limitations. Participants were exclusively Chinese and there were regional biases in enrollment. Also, although the authors indicate improvement in quality of life, no data from a QoL scale were presented.”

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DR. KEVIN N. SHETH: “Statins are really troubling to use clinically and as an alternative to surgery. There really is no good drug candidate. One of the biggest difficulties is the lack of research. On the surface, the study looks good, but it comes as a bit of a surprise. The trial design is pretty robust and the findings are quite strong. It is pretty compelling.”

Although there has been some prior research on using atorvastatin in such patients, the evidence has so far been mixed, Dr. Goldstein noted. One meta-analysis, published in June 2017, found only three studies investigating treatment. However, the researchers indicated that atorvastatin accelerated absorption of hematomas, recurrence, and need for surgery.

Even so, he said the data are “certainly encouraging” and should prompt a phase 3 efficacy trial.”

DISCLOSURES

The study authors and sources disclosed no conflicts of interest. Dr. Sheth serves on the editorial board of Neurology Today.

LINK UP FOR MORE INFORMATION:

• Jiang R, Zhao S, Wang R, et al. Safety and efficacy of atorvastatin for chronic subdural hematoma in Chinese patients: A randomized clinical trial https://jamanetwork.com/journals/jamaneurology/fullarticle/2694718. JAMA Neurol 2018; Epub 2018 Jul 30.
    • Qui S, Zhuo W, Sun C, et al. Effects of atorvastatin on chronic subdural hematoma: A systematic review https://insights.ovid.com/crossref?an=00005792-201706300-00035. Medicine 2017;96(26): e7290.
      • Balser D, Farooq S, Mehmood T, et al. Actual and projected incidence rates for chronic subdural hematomas in United States Veterans Administration and civilian populations http://thejns.org/doi/abs/10.3171/2014.9.JNS141550?url_ver=Z39.88-2003. J Neurosurg 2015: 123(5):1209–1215.
        • Karki K, Knight R, Han Y. Simvastatin and atorvastatin improve neurological outcome after experimental intracerebral hemorrhage https://www.ahajournals.org/doi/10.1161/STROKEAHA.108.544395. Stroke 2009;40(10): 3384–3389.