By Makoto Ishii, MD, PhD

Assistant Professor of Neuroscience and Neurology, Feil Family Brain and Mind Research Institute, Department of Neurology, Weill Cornell Medical College

Dr. Ishii reports no financial relationships relevant to this field of study.

SYNOPSIS: In a large population study, concussion in older adults resulted in significantly higher risk for dementia that was modestly lower among those taking a statin.

SOURCE: Redelmeier DA, Manzoor F, Thiruchelvam D. Association between statin use and risk of dementia after a concussion. JAMA Neurol 2019; May 20. doi: 10.1001/jamaneurol.2019.1148. [Epub ahead of print].

Due to the strong association of traumatic brain injury with chronic traumatic encephalopathy, concussions are a growing concern, especially for young adults playing contact sports. However, the long-term risk for dementia in older adults diagnosed with a concussion and whether any medications can affect this risk are unclear. Therefore, Redelmeier et al conducted a large population-based, double cohort study using linked databases to examine if statin and other medication use was associated with a higher or lower risk of dementia in older adults after a concussion.

Over a 20-year period (April 1, 1993, to April 1, 2013), patients 66 years of age and older who were diagnosed with a concussion were identified based on physician billing data using the ICD-9 code from the Ontario Health Insurance Plan. To reduce confounding from severe brain injury, patients who were admitted to a hospital within two days of a concussion or who survived less than 90 days were excluded. To reduce confounding from past neuropsychiatric conditions, patients with a history of dementia or delirium in the prior five years were excluded. The Ontario Drug Benefit Program database provided data on the prescription status of statin and other medications. The primary study outcome was a physician diagnosis of dementia based on ICD-9 codes.

Redelmeier et al identified 28,815 patients (median age, 76 years; 61.3% female) with a diagnosis of concussion, with 7,058 patients receiving a statin during the 90 days after a concussion. The demographic characteristics were similar between patients receiving statins and those who did not. A total of 4,727 patients in the study developed dementia over a mean follow-up of 3.9 years after a concussion. Statin use was associated with a modest 13% (95% confidence interval [CI], 7%-19%; P < 0.001) reduced risk of dementia compared with patients who did not receive a statin (relative risk, 0.87; 95% CI, 0.81-0.93; P < 0.001). After adjusting for all baseline characteristics, statin use was associated with a 16% (95% CI, 10%-22%; P < 0.001) reduction in risk of subsequent dementia.

Reduced dementia risk was specific to statins, as no other lipid-lowering or cardiovascular medications were associated with a consistent decrease in dementia risk, with the possible exception of angiotensin II receptor blockers. Additionally, benzodiazepines, thyroid supplements, gastric acid suppressors, inhaled bronchodilators, and glaucoma eye drops were not associated with a lower risk of subsequent dementia. Secondary analyses revealed the largest risk reduction with rosuvastatin and smallest with simvastatin.

Similarly, hydrophilic statins (i.e., rosuvastatin and pravastatin) were more beneficial than lipophilic statins (i.e., all other statins). A higher dose of statins produced similar benefits as a lower dose of statins. Furthermore, in a parallel analysis of dementia risk after an ankle sprain, the authors found that statin use was associated with only a 5% (95% CI, 3%-8%; P < 0.001) reduction in the risk of dementia. Finally, statin use was associated with an insignificant increased risk of depression after a concussion.

COMMENTARY

A major strength of this study was the relatively large sample size with long follow-up. This could be a result of the investigators leveraging a large population in Ontario with universal healthcare that was linked to multiple databases. Additionally, because of these databases, the investigators conducted detailed statistical analyses on the nuances of statin use (e.g., specific statin, type of statin, dosage of statin, etc.) that often are unavailable in similar studies. Another significant strength was the use of a second cohort to investigate the association of statin use and the development of dementia in patients after an ankle sprain, which helped to effectively differentiate the stronger beneficial effect of statin use specifically after brain injury.

This study was well designed, but there were significant limitations. First, this was not a randomized trial. There may be significant confounders due to earlier indications for statin use. Additionally, several important covariates, including smoking history, daily exercise, and other factors that may affect dementia risk, were missing from the dataset. Although ICD-9 codes for concussion are more reliable than using self-reported measures, diagnosis codes for concussion and dementia are not fully sensitive and may underestimate the true incidence. This study also would miss any patients who had sustained a concussion but never received medical attention.

Finally, the study authors relied on the use of aggregate data and broad diagnostic codes of concussion and dementia, which are highly varied disorders. It is unclear if these results could be translated to clinical care at an individual patient level.