Statins May Cut Postconcussion Dementia Risk

Batya Swift Yasgur, MA, LSW

June 03, 2019

Concussion in older adults is tied to a dramatically increased risk for dementia, but new research suggests statins may mitigate this risk.

For 4 years, investigators followed approximately 30,000 patients aged 65 years or older who had sustained a concussion. They compared these patients to a control group of patients who had sustained an ankle injury.

Of patients who had experienced concussion, 1 in 6 developed dementia during that period. However, those who had received a statin had a 13% reduced risk for dementia, compared to those who had not received a statin — an association that increased over time and that persisted after adjustment for potential confounders, such as use of cardiovascular medication and subsequent depression.

"We studied over 20,000 individuals who had been diagnosed with concussion for approximately 5 years to determine long-term risk of subsequent dementia and found that about 1 in 6 cases later developed dementia, which is far above the population norm and about twice as high as comparable patients who had only sprained their ankles," lead investigator Donald A. Redelmeier, MD, MSHSR, professor of medicine, University of Toronto, and director of clinical epidemiology, Sunnybrook Health Sciences Center, Canada, told Medscape Medical News.

"Patients receiving a statin had a modest lower risk of dementia than patients not receiving a statin, and no other cardiac medication — or noncardiac medication, for that matter — made a difference in lowering subsequent risk of dementia after concussion," said Redelmeier, who is also a senior scientist at the Institute for Clinical Evaluative Studies in Ontario.

The study was published online May 20 in JAMA Neurology.

"Regular People"

"The extent of complications after a concussion is uncertain, and effective pharmacologic treatments remain elusive," the authors write.

"Preclinical data suggest that statin use might mitigate injury-related brain edema, oxidative stress, amyloid protein aggregation, and neuroinflammation, [but] little previous research has examined the potential role of statins in recovery following a concussion," they add.

To investigate the question, the researchers examined data from a population-based cohort of Ontario-based adults (n = 28,815; median age, 76 years; 61.3% women) who had been diagnosed as having had a concussion from April 1, 1993, to April 1, 2013.

Patients who had been admitted to a hospital within 2 days of the concussion or who had a history of dementia or delirium during the previous 5 years were excluded.

Demographic information (age, sex, socioeconomic quintile, and home location) was obtained. A drug database was used to determine statin use.

The primary analysis compared patients who had received a statin prescription in the 90 days immediately following the concussion with patients who had not received a statin (n = 7058 [24.5%] and n = 21,757 [75.5%], respectively).

The researchers replicated their findings by conducting a secondary parallel analysis using the identical selection strategy, analytic method, and outcome measures and that focused on a second cohort of older adults who had been diagnosed as having experienced an ankle sprain (n = 307,890) rather than a concussion.

"We were looking specifically at regular people in the general population who sustained concussions through being involved with motor vehicle collisions, falling, sustaining injury through an assault, or similar occurrences, rather than looking at professional boxers or football players," Redelmeier recounted.

Less Reserve Capacity

On average, patients who had received statins tended to be taking more cardiovascular and neuropsychiatric medications and had more prior physician visits compared to the control patients.

Approximately one quarter (23.6%) of patients in each of the two groups had had a hospital admission in the prior year.

During a mean follow-up of 3.9 years after a concussion, 4727 patients developed dementia, with an absolute incidence of 1 case per 6 patients.

During 28,129 patient-years (mean, 4.0 years), patients who had received statins accounted for 1050 dementia cases, at an incidence of 37 cases per 1000 patients annually, which is twice the population norm.

The incidence among the control patients (3677 dementia cases over 85,339 patient-years; mean, 3.9 years), translated into 43 cases per 1000 patients annually, which is more than twice the population norm.

Together, statin use was associated with a 13% (95% confidence interval [CI], 7% – 19%; P < .001) reduced risk for dementia, compared with no statin use (relative risk, 0.87; 0.81 – 0.93; P < .001), yielding a number needed to treat of ~50 patients.

The association persisted after adjusting for patient characteristics. Statin use was associated with a 16% reduction in the risk for subsequent dementia (95% CI, 10% – 22%; P < .001; E-value, 1.67).

Analysis of additional medication use (eg, other cardiovascular medications, benzodiazepines, thyroid supplements, gastric acid suppressors, inhaled bronchodilators, glaucoma eyedrops, and neuropsychiatric medications) suggested that the decreased risk for subsequent dementia was specific to statins.

Secondary analyses that compared specific statins found that use of rosuvastatin (multiple brands) was associated with the largest risk reduction. Use of simvastatin (multiple brands) was associated with the smallest risk reduction.

Higher statin dosages conferred no greater benefit in comparison with lower dosages.

For those who began taking a statin after a concussion, there was a significant reduction in risk, whereas for those who discontinued taking a statin after a concussion, there was no significant risk reduction.

The parallel analysis identified 307,890 patients who were diagnosed as having had an ankle sprain. Of those patients, 25.3% received a statin.

A total of 25,956 patients developed dementia over a mean follow-up of 4.3 years.

Patients who were treated with statins accounted for 6239 dementia cases during 336,251 patient-years, which translates into an incidence of 19 cases per 1000 patients annually.

Control patients accounted for 19,717 dementia cases during 1,001,606 patient-years, at an incidence of 20 cases per 1000 patients annually.

Statin use was associated with a 5% reduction in dementia risk (3% – 8%; P < .001), yielding a number needed to treat of ~220 patients.

Trauma History Is Key

"Our single most important message is to underscore the role of prevention. The metaphor of James Bond getting knocked out in one scene and cracking jokes in the next scene, as if brain injuries are innocuous, is a poor representation of the patients I see in the hospital," said Redelmeier, who works at a trauma center.

"If you just had a concussion, avoid the second concussion — drive safely, walk mindfully, use protective gear, stay sober, and stay away from risky situations," he said.

"Our second message is that neurologists have got to pay attention to a patient's past trauma history. When you encounter an individual with early-onset dementia at age 60 or 70, don't only ask about stroke or Huntington's disease but also about concussions, even if they occurred decades earlier, because it might help to explain what's going on," he added.

Redelmeier noted that although the study was not powered to examine the mechanism by which statins might mitigate postconcussion dementia risk, "we know from other research that statins can mitigate injury-related brain swelling, inflammation, oxidative stress, and faulty microcirculation."

He suggested that a "small concussion can shear hundreds of neurons, thereby disrupting thousands of synapses, which therefore may not be there when you are 70 or 80 years old, and although the concussion may not necessarily cause dementia, I think it may eat into the amount of reserve capacity people will need in later life."

First Step

Commenting on the study for Medscape Medical News, Charles H. Tator, OC, MD, PhD, professor of neurosurgery, University of Toronto, and director, Canadian Concussion Center, Krembil Brain Institute, Toronto Western Hospital, Canada, who was not involved with the study, said that the researchers "have contributed another brilliant research study based on examining a huge number of concussed individuals and finding that those taking statins showed less likelihood of developing dementia."

He described the findings as "additional evidence that in some people, trauma leads to dementia and that this relationship can be altered by taking a statin."

The study "should encourage others to do additional work on the neuroprotective role of statins," he said.

In an accompanying editorial, Rachel Whitmer, PhD, of the Division of Epidemiology, Department of Public Health Sciences, University of California, Davis, cautioned that the study "cannot infer causality."

Nevertheless, "it is a first step in accumulating evidence for possible future therapeutic interventions post-TBI [traumatic brain injury] and a call for further pharmacoepidemiologic harnessing of integrated healthcare systems to discover other potential protective or risk factors for dementia after brain injury," she writes.

Redelmeier noted that "for those who are already prescribed a statin, keep taking the statin. It won't impair your recovery from concussion and might actually facilitate it."

Moreover, "Our data suggest that if you werent already on a statin, initiate it in the immediate aftermath of the concussion, during the 90-day period following," he said.

He added two important caveats.

"We don't think statins should be used in younger people with concussions, such as teenagers, since their brains are still growing and myelinating and still heavily dependent on blood lipid levels."

Statins are also "absolutely contraindicated in pregnant women," he cautioned.

The study was supported by a Canada Research Chair in Medical Decision Sciences, the Canadian Institutes of Health Research, the BrightFocus Foundation, and the Comprehensive Research Experience for Medical Students at the University of Toronto. Redelmeier and coauthors, Whitmer, and Tator have disclosed no relevant financial relationships.

JAMA Neurol. Published online May 20, 2019. Abstract, Editorial

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