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For Concussion, Statins May Be Beneficial
Why Some Experts Don't Agree

Article In Brief

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“If you are on the borderline of whether we should treat your low-density lipoprotein, this is one more argument in favor of initiating statin therapy.”

—DR. DONALD REDELMEIER

Researchers reported that older people who experienced a concussion had about double the risk of developing dementia in subsequent years compared with a similar age group in the general population.

A population-based study of older people with concussion found that those who were taking a statin drug had a 13 percent lower risk for developing dementia over the following few years than people who were not on a cholesterol-lowering drug around the time of their concussion.

The finding, drawn from data on nearly 30,000 patients with concussion— ages 66 or older in Ontario, Canada,—provides a hint that there might be some role for statin drugs in the treatment of concussion.

But, experts told Neurology Today, a randomized, controlled clinical trial would be needed to test that approach and determine its effectiveness.

The new study, published in the May 20 online edition of JAMA Neurology, found overall that older people who experienced a concussion had about double the risk of developing dementia in subsequent years compared with a similar age group in the general population.

“Concussion is often popularized as a problem in athletic youth and tends to be underdiagnosed in older individuals,” wrote the study authors from the University of Toronto and elsewhere. “The results of our study suggest that concussions are a common injury in older adults and indicate that dementia may be a frequent outcome years afterward.”

While the researchers didn't suggest that people should start taking a statin if they have a concussion or take the drug prophylactically, they noted that the drug's potential neuroprotective benefit may “encourage greater medication adherence for patients already on a statin.”

Lead investigator Donald Redelmeier, MD, professor of medicine at University of Toronto, told Neurology Today that the new findings related to concussion and dementia might, from his perspective, provide another reason to prescribe a statin to someone who has elevated cardiovascular risk.

“If you are on the borderline of whether we should treat your low-density lipoprotein, this is one more argument in favor of initiating statin therapy,” said Dr. Redelmeier, a staff physician at Sunnybrook Health Sciences Centre in Toronto and senior scientist at the Institute for Clinical Evaluative Sciences in Ontario.

Some preclinical data have suggested that statins, which are known to have an anti-inflammatory component, “mitigate injury-related brain edema, oxidative stress, amyloid protein aggregation, and neuroinflammation,” the study authors wrote. “The potential neuroprotective benefits from statins have also been speculated and include preserved cerebral blood flow, leading to decreased risks of Alzheimer disease, vascular dementia, and age-related cognitive decline.”

The few randomized and non-randomized trials that have been done on TBI and statins have been small and yielded conflicting results, some showing positive benefits, some showing no benefit, but none showing a detrimental effect, Dr. Redelmeier said.

Study Design, Findings

The new study on concussion in older adults used data collected as part of Ontario's universal health insurance plan and drug benefit program. The researchers identified 28,815 people 66 or older who had a diagnosis of concussion between April 1993 and April 2013. (They excluded severe cases resulting in hospitalization, individuals with a prior diagnosis of dementia, and those who died within 90 days.) Data were tracked up through March 2016, meaning all patients were followed for at least three years and some for at least five years.

Of the 28,815 patients with concussion, 24.5 percent (7,058 patients) received a statin within 90 days of the concussion, while 75.5 percent (21,757) did not.

A total of 4,727 concussion patients (1,050 on statins: 3,677 not on the drug) developed dementia during a mean follow-up of 3.9 years, which equaled about one case per every six patients, the researchers reported.

The incidence rate of dementia for concussion patients on statins was 37 cases per 1,000 patients annually, about double the population norm of 19 cases of dementia per 1,000 annually for adults 66 and older in Ontario, the researchers reported. The incidence of dementia was 43 cases per 1,000 patients annually for the non-statin concussion patients, they reported.

To further test the association between statin use and dementia, the researchers looked at a completely different cohort of patients—older adults who had been diagnosed with an ankle sprain. In that group, there was no reduced risk of dementia in patients who took statins compared with those who didn't.

“The relative reduction in dementia risk associated with statin use after a concussion was greatest for those taking rosuvastatin, was consistent for those receiving lower doses, was accentuated after adjustments for measured patients characteristics, and was distinct from the risk for patients after an ankle sprain,” the researchers reported.

They said no other cardiovascular or noncardiovascular medications were associated with a decreased risk of dementia after a concussion, “with the possible exception of angiotensin II receptor blockers.”

The study had limitations, including the fact that it was not a randomized, controlled trial. Diagnostic codes are not always accurate and prescribing information does not mean a patient is a taking the drug as prescribed. Information on other risk factors, such as smoking and exercise, were also lacking. The researchers said the study, while large, was not sufficiently powered to determine whether statins “make a contribution before, during, or after a concussion.” Another limitation is that the study included only people 66 and older, so it's impossible to say whether the findings apply to younger people with concussion.

Another limitation is that the study included only people 65 and older, so it's impossible to generalize the findings to younger people with concussion.

The researchers said the study's findings were significant enough to warrant further study, though they noted it would be difficult to design a randomized, controlled trial, given that concussions unexpectedly occur and there would be no way to assign a patient to a statin beforehand or keep them off the drug if they needed it for cardiovascular reasons.

An editorial that accompanied the study said the researchers did a rigorous job in considering the question, “if a concussion does increase the risk of dementia, is this risk mitigated among those taking a statin, and does the cerebrovascular or inflammatory milieu of an individual taking a statin differ such that a concussion has potentially less of a deleterious effect?”

The editorialist, Rachel Whitmer, PhD, professor and chief of epidemiology at University of California, Davis, also noted that “while this study cannot infer causality, it is a first step in accumulating evidence for possible future therapeutic interventions post-TBI.”

She said in a follow-up email to Neurology Today that “there needs to be additional well-executed pharmacoepidemiologic analyses of patients with and without concussion who can be followed prospectively.”

Expert Commentary

Randolph W. Evans, MD, FAAN, clinical professor of neurology at Baylor College of Medicine, said the Canadian study was interesting, but cautioned that “there are many limitations of this study including the retrospective design and ascertainment of the diagnosis of concussion and dementia.”

In an email, he said that “other studies have inconsistently found an association between mild traumatic brain injury and dementia.”

“Without confirmation in a prospective study, I would not recommend that people take a statin after concussion or that people at high risk for concussion, such as football players, be placed on statins for prevention,” Dr. Evans said.

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“Patients who took statins in the study had more frequent doctor visits and took more medicines, so perhaps they were a bit healthier than those who didn't get a statin.”

—DR. HOLLY E. HINSON

Holly E. Hinson, MD, MCR, FAAN, associate professor of neurology at Oregon Health & Science University, said “overall there were several methodological strengths in the Canadian study, but at the same time there are some big grains of salt to be taken with the conclusions.”

She said using diagnostic codes can be unreliable, so the researchers may have overlooked both some patients who had concussion and others with dementia, which would throw off the numbers. Also, “patients who took statins in the study had more frequent doctor visits and took more medicines, so perhaps they were a bit healthier than those who didn't get a statin,” Dr. Hinson said.

“There does seem to be an association between those receiving statins and decreased risk of dementia,” she said. But she said the study findings “don't tell us anything about causality.”

She applauded the researchers for looking at concussion in older adults, noting that while so much attention is being paid to sports-related concussions, older adults with concussion “are the most rapidly rising demographic.”

Renee M. Pazdan, MD, FAAN, medical director of the TRICARE Overseas Program for the Defense Health Agency, said she did not think the new findings would change her approach to concussion in any dramatic way.

“Based on this study and the current literature I would not start a patient on a statin prophylactically, nor would I if I was seeing someone after concussion,” she said. But she said the study will likely prod her to look more closely at cardiovascular risk factors in concussion patients and perhaps order a lipid panel to see if starting a statin would be warranted. (She said her comments represent her own clinical views and do not necessarily represent the views of the US Department of Defense.)

Dr. Pazdan, who also does TBI research at the Defense and Veteran Brain Injury Center at Ft. Carson, CO, said there is still a lot to learn about concussion. She said developing therapies for concussion and other TBIs has been slowed by a lack of identifiable biomarkers that could be used to indicate the extent of injury and whether a given treatment is making a difference.

“If we can understand what the pathophysiology is, then we can use it to see if an agent is modulating that pathophysiology,” Dr. Pazdan said.

Disclosures

Drs. Redelmeier, Whitmer, Hinson, Evans, and Pazdan had no disclosures.

Link Up for More Information

•. Redelmeier DA, Thiruchelvam Manzoor F. Association between statin use and risk of dementia after a concussion https://jamanetwork.com/journals/jamaneurology/fullarticle/2733673. JAMA Neurol 2019; Epub 2019 May 20.
    •. Whitmer R. Concussions and dementia-Are statins the salve in the wound https://jamanetwork.com/journals/jamaneurology/fullarticle/2733670. JAMA Neurol 2019; Epub 2019 May 20.