Long-Term Statin Use Associated With Lower Risk of Intracerebral Hemorrhage

David Gaist, MD, PhD

Results from a population-based, nationwide case-control study of more than 16,000 patients from the Danish Stroke Registry showed that current statin use and duration of treatment were associated with decreased risk of intracerebral hemorrhage (ICH).¹

In the study, senior author David Gaist, MD, PhD, Department of Neurology, Odense University Hospital, and colleagues identified 16,235 patients older than 45 who had first-ever ICH between 2005-2018. A total of 640,942 controls, matched for age and sex, were selected randomly from the general population and assigned to the index date of their corresponding case.

The 30-day case-fatality of patients with ICH was 30.7%. At the conclusion of the analysis, current statin use resulted in 25.9% lowered odds of ICH compared with 24.5% in the control group (adjusted odds ratio [aOR], 0.74; 95% CI, 0.71-0.78). Longer duration of statin use was also associated with a lower risk of ICH, demonstrated by differences in those who used treatment for less than 1 year (aOR, 0.86; 95% CI, 0.81-0.92) vs those who had been on treatment for more than 10 years (aOR, 0.53; 95% CI, 0.45-0.62; P <.001).

This duration-response pattern was also present within strata of high vs low-medium intensity statin therapy. Estimates of ICH risk stratified only by intensity of therapy were similar with aORs ranging from 0.71 to 0.75. Estimates of ICH risk for individual statins, which included simvstatin, atorvastatin, or rosuvastatin, by intensity of therapy, were not significantly different, albeit treatment with high intensity rosuvastatin and simvastatin had the lowest ORs for ICH (rosuvastatin: aOR, 0.55 [95% CI, 0.42-0.73]; simvastatin: aOR, 0.58 [95% CI, 0.40-0.85]).

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For the risk of ICH based on individual statin, those treated for 5 to 10 years and more than 10 years were collapsed into one analysis. Here, the duration-response pattern continued to show, although only simvastatin was significant (<1 year: aOR, 0.87 [95% CI, 0.82-0.94]; ≥1 to <5 years: aOR, 0.73 [95% CI, 0.68-0.77]; ≥5 years: aOR, 0.62 [95% CI, 0.56-0.68]; trend, P <.001). In analyses of duration of use within strata of therapeutic intensity, high dose atorvastatin also was associated with a lower risk of ICH (<1 year: aOR, 0.79 [95% CI, 0.66-0.82]; ≥1-year to <5 years: aOR, 0.75 [95% CI, 0.65-0.87]; ≥5 years: aOR, 0.51 [95% CI, 0.36-0.72]; trend, P = .035).

In subgroups defined by age, sex, and concurrent use of antiplatelet, antithrombotic, or antihypertensive drugs, the duration-response relationship remained. After classifying duration of statin use into shorter periods for the year before the index date, the risk of ICH was notably lower after at least 180 days of treatment.

"Although we adjusted for proxies for disorders indicative of high alcohol use and smoking, residual confounding by these and other unmeasured life-style factors cannot be excluded," the study investigators wrote. “We did not include information on education or income that could mitigate potential effects of socioeconomic status. It, however, is unlikely that socioeconomic status had an important impact on our results as previous analyses found that the addition of education and income to a model similar to the one employed in this study had very little impact on ICH risk estimates."

The finding that longer durations of statin use were associated with lower risks of ICH were consistent with results from the prior Danish cohort study, published in 2019. This study featured 519,894 stroke-free individuals on statins matched 1:5 to stroke-free reference subjects and followed for up to 10 years. During this period, 1409 ICHs occurred in statin users. Statin users had an overall adjusted hazard ratio of 0.85 (95% CI, 0.80-0.90) compared with nonusers, although this risk was modified by time since statin initiation. Statin users and nonusers had similar ICH risk during the first 6 months following statin initiation, while the risk decreased by 22% to 35% for those on statins thereafter.²

REFERENCES
1. Rudolph DA, Hald SM, Rodriguez LA, et al. Association of long-term statin use with the risk of intracerebral hemorrhage: a Danish nationwide case-control study. Neurology. Published online May 16, 2022. doi:10.1212/WNL.0000000000200713
2. Ribe AR, Vestergaard CH, Vestergaard M, et al. Statins and risk of intracerebral hemorrhage in a stroke-free population: a nationwide Danish propensity score matched cohort study. eClinicalMedicine. 2019;8:78-84. doi:10.1016/j.eclinm.2019.02.007