Effect of Rosuvastatin on Amnesia and Disorientation after Traumatic Brain Injury (NCT00329758)

Abstract

Amnesia is a common sequela following traumatic brain injury (TBI), for which there is no current treatment. Pleiotropic effects of statins have demonstrated faster recovery of spatial memory after TBI in animals. We conducted a double-blind randomized clinical trial add-on of patients with TBI (16-50 years of age), with Glasgow Coma Scale (GCS) scores of 9-13, and intracranial lesions as demonstrated by computed tomography (CT) scan. We excluded those patients with recent head injury or severe disability; administration of known drugs as modifiers of statin metabolism; multisystemic trauma; prior use of mannitol, barbiturate, corticosteroids, indomethacin or calcium antagonists; surgical or isolated lesion in brainstem; allergy to statins; previous hepatopathy or myopathy; previous management in another clinic; or pregnancy. Each patient received the same treatment and was randomly allocated to receive either rosuvastatin (RVS) or placebo over a period of 10 days. The primary outcome measures assessed were amnesia and disorientation times using Galveston Orientation Amnesia Test. Additionally, we evaluated plasma levels of interleukin (IL) 1beta, tumor necrosis factor (TNF) alpha, and IL-6, as well as disability at 3 months. We analyzed eight patients with RVS and 13 controls with similar basal characteristics. Using Cox regression analysis, administration of RVS showed a reduction of amnesia time with a hazard ratio of 53.76 (95% confidence interval [CI], 1.58-1824.64). This was adjusted for early intubation, basal leukocytes, basal Marshall and Fisher score, change of IL-1beta levels, and lesion side. IL-6 values at day 3 were increased in the RVS group (p = 0.04). No difference was detected in disability at 3 months. While statins may reduce amnesia time after TBI, possibly by immunomodulation, further trials are needed in order to confirm this positive association.

Do Statins Impair Cognition? A Systematic Review and Meta-Analysis of Randomized Controlled Trials

“…[12][13][14][15] All had placebo rather than standard care comparators. RCTs (reported in 23 publications [13][14][15][36][37][38][39][40][41][42][43][44][45][46][47][48][50][51][52]55,56,62,64 ) enrolled subjects with normal cognition at baseline, four RCTs (reported in seven publications 12,54,[57][58][59][60][61] ) enrolled patients with AD, and three RCTs enrolled other cognitively impaired subjects (traumatic brain injury, 53,63 and neurofibromatosis type 1 49 ). Simvastatin (eight trials), pravastatin (eight trials), and lovastatin (six trials) were most frequently utilized in the statin RCTs.…”

“…One showed no statistically significant cognitive benefit over 6 months, 53 and the other showed positive benefit over 4 months. 63 A small trial of 62 children with neurofibromatosis type 1, expected to have a high prevalence of learning disability, showed no significant effects for statin treatment. 49 …”

Selective Gelatinase Inhibitor Neuroprotective Agents Cross the Blood-Brain Barrier

“…19−21 Rosuvastatin in a small clinical trial in patients with moderate TBI improved amnesia; however, it showed no differences in 3-month outcomes. 22 This may be due to the inability of the hydrophilic rosuvastatin to enter the brain. 23 Progesterone has shown neuroprotective effects in animal models of spinal cord injury, stroke and TBI, 24−26 and has shown possible signs of benefit in clinical trials in patients after TBI.…”

Statins in Traumatic Brain Injury

“…No difference was found between the groups in the median IL-1␤ or TNF-␣ levels; in fact, contrary to animal models, median IL-6 levels were increased in the statin-treated group. 25 However, it is worth noting that rosuvastatin has limited CNS penetration, and thus it is difficult to draw definitive conclusions for the effect of statins on CNS inflammation based on of this small pilot study.…”

“…Of importance, the authors note that the rosuvastatin group had a somewhat worse degree of TBI at baseline than the placebo group. 25 After preclinical data suggesting neuroprotection, statins have also been considered in other forms of acute brain injury commonly associated with TBI. Clinical data on statins in ICH is mixed.…”