Lipid Lowering for Primary Stroke Prevention in Elderly?

May 19, 2015

The use of statins or fibrates to lower cholesterol was associated with a one third lower risk for stroke, but no reduction in coronary events, in older adults without previous vascular disease in a new observational study.

The authors suggest that if the results are replicated, lipid-lowering drugs might be considered for the prevention of stroke in older populations.

The study, published May 19 in the BMJ, was conducted a group led by Annick Alpérovitch, MD, from INSERM, Bordeaux, France.

Senior investigator Christophe Tzourio, MD, also from INSERM, France, commented to Medscape Medical News that these results were out of line with results from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) study, the only randomized clinical trial of statins in the elderly.

"PROSPER suggested a reduction in coronary deaths, but no effect on stroke. Our results show completely the opposite effect. I don't know how to interpret this," he said. "But our population is very different, in that they were much lower risk and they had been taking lipid-lowering medication for much longer — more than 12 years in most cases."

He added: "You can't really compare the patients enrolled in randomized trials and those in this 'real-world' study. Randomized trials may be the gold standard, but patients enrolled in them are highly selected."

Dr Tzourio said he had no explanation as to why they did not see an effect on cardiac events. In observational studies, there would normally be a higher rate of cardiovascular events in those taking the cardiovascular drugs because these patients are at higher risk, he said. "We call this an indication bias. We saw this for antihypertensives and aspirin, and for the lipid-lowering drugs for coronary heart disease events. This was expected.

"But when we looked at the stroke results, there was a reduction in stroke events in those taking the lipid-lowering drugs even before adjustment. That seems crazy," he added. "We didn't believe the result in the beginning."

Compelling Results

In an accompanying editorial, Graeme J. Hankey, MD, professor of neurology at the University of Western Australia, Perth, says the study "will not change guidelines because of its observational design and inherent potential for systematic error. However, the results are sufficiently compelling to justify further research testing the hypothesis that lipid lowering may be effective in the primary prevention of stroke in older people."

In the BMJ paper, the French researchers note that because most randomized trials exclude older patients, there is little information on the use of cholesterol-lowering drugs in the elderly.

To look at this issue, they examined data from the Three-City study, a prospective study aiming to assess the association between vascular diseases and risk for dementia in a random sample of community dwelling population aged 65 years and older living in three French cities: Bordeaux, Dijon, and Montpellier.

The current analysis involved 7484 men and women with a mean age of 74 years and no known history of vascular events at entry. Mean follow-up was 9.1 years, during which time participants were examined every 2 years and data were collected on medical history and drugs being taken.

This showed that 27.4% of the population reported using lipid-lowering drugs (13.5% statins and 13.8% fibrates) at baseline. Total cholesterol, low-density lipoprotein, and triglyceride levels were significantly lower in users than in nonusers, both for statins and fibrates.

Results showed that individuals who took lipid-lowering drugs were at decreased risk for stroke compared with nonusers.

Table. Risk for Stroke in Patients Taking Statins or Fibrates

Treatment Hazard Ratio (95% Confidence Interval)
Statin or fibrate 0.66 (0.49 - 0.90)
Statin 0.68 (0.45 - 1.01)
Fibrate 0.66 (0.44 - 0.98)

No association was found between lipid-lowering drug use and coronary heart disease (hazard ratio, 1.12; 95% confidence interval, 0.90 - 1.40).

Analyses stratified by age, sex, body mass index, hypertension, systolic blood pressure, triglyceride concentrations, and propensity score did not show any effect modification by these variables, either for stroke or for coronary heart disease.

Dr Tzourio says he would like these findings to lead to a randomized trial in elderly low-risk patients, but he believes such a study will be difficult to do.

"Because there are no other studies in this population, we wanted to publish our findings for the scientific community to see. Yes, they may be due to chance, but we would encourage other groups to look at their cohorts and see if they can replicate our findings."

The researchers are not making any recommendations for clinical practice based on their findings. Dr Tzourio commented: "At present, most guidelines do not recommend use of these agents in patients over 75. As this is only an observational study, we are not recommending that everyone over 75 starts taking these drugs. But perhaps if patients are already on these drugs, they should not stop taking them after age 75. It could be that there is an effect on stroke of very long-term use."

In his editorial, Dr Hankey says the study reinforces the need for more robust evidence from large randomized trials evaluating lipid lowering, specifically in older people without previous vascular disease.

He concludes: "Meanwhile, for clinicians and patients, the decision to start statins for primary prevention of vascular disease in people over 75 continues to be based on sound clinical judgment after consideration of each person's predicted vascular risk without and with statins, the predicted risk of adverse effects of statins (against a backdrop of increasing comorbidities, polypharmacy, and other safety considerations), and the patient's own priorities and preferences for treatment."

The Three-City Study was conducted under a partnership agreement among INSERM, the Victor Segalen-Bordeaux II University, and sanofi-aventis. The funding organizations played no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript. The authors have disclosed no relevant financial relationships. Dr Hankey has received an honorarium from sanofi-aventis for a single consultation on alirocumab for the prevention of recurrent stroke.

BMJ. Published online May 19, 2015. Article full text, Editorial full text


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