INTRODUCTION
According to the World Health Organization (WHO), stroke was the second leading cause of death in 2020 globally, accounting for up to 11% of the total deaths.1) More than 50% of patients with stroke are aged 70 years or older.2,3) Despite this demographic reality, older adults—particularly those aged ≥75 years—have been systematically underrepresented in major randomised controlled trials of statin therapy, leaving the optimal treatment intensity for this age group poorly defined.4)
The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial5) and Treat Stroke to Target (TST) trial6) demonstrated the importance of aggressive low-density lipoprotein cholesterol (LDL-C) lowering in patients with stroke or transient ischemic attack (TIA) to prevent recurrent events. Although a subgroup analysis from SPARCL suggested benefit regardless of age, both trials enrolled populations with a mean age of approximately 63–65 years, and patients aged ≥75 years comprised a relatively small proportion of these trial populations. Consequently, the applicability of these findings to the oldest patients encountered in clinical practice remains uncertain. Moreover, statin therapy at higher doses may be associated with an increased risk of statin-associated muscle symptoms (SAMS), a concern especially relevant in older adults.7,8)
The 2021 American Heart Association/American Stroke Association guidelines recommend high-intensity statin therapy (HIST) for patients with acute ischemic stroke (AIS) with LDL-C above 100 mg/dL or atherosclerotic disease, targeting LDL-C below 70 mg/dL.9) However, HIST is not uniformly recommended for patients aged ≥75 years owing to tolerability concerns and insufficient evidence specifically in this age group.10) As a result, the optimal statin intensity for very old adults with AIS remains unclear, particularly regarding functional outcomes and short-term safety in real-world settings.
To address this evidence gap, we conducted a real-world cohort study using a prospective stroke registry at a tertiary referral center. We aimed to compare functional outcomes and short-term safety between patients aged ≥75 years with AIS or TIA who received HIST versus MIST (moderate-intensity statin therapy) at discharge, and to characterise the clinical factors associated with statin intensity prescribing in this population.
MATERIALS AND METHODS
Study Design and Population
This retrospective, single-center cohort study was based on an ongoing prospective stroke registry that consecutively enrolled patients with AIS or TIA at Seoul National University Hospital, a tertiary referral center. From this registry, patients aged 75 years or older who were prescribed a statin at discharge from July 2019 to June 2022 were identified for review. Patients who did not start statin treatment at admission, who had already had a disability before the index stroke (modified Rankin scale [mRS]11) ≥2), or whose key information was not fully described in the medical record were excluded. Patients who started statin therapy but were lost to follow-up or discontinued the therapy within 3 months were excluded. Patients who consistently maintained statin therapy for 3 months were identified.
Patients who continued HIST for 3 months after admission were assigned to the HIST group, and those who started MIST and maintained it for 3 months or switched from a high-intensity statin to a moderate-intensity statin within 1 month and remained on MIST for at least 2 months were assigned to the MIST group. The classifications of high- and moderate-intensity statins are summarised in Supplementary Table S1.
Patient Data
The data collected from the registry database or electronic medical records included age, sex, statin prescription, pre-stroke statin use, Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification,12) initial National Institutes of Health Stroke Scale (NIHSS) score, aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK), LDL-C levels at admission, LDL-C levels at the 3-month follow-up, and 3-month mRS score. Patients’ initial blood tests were performed on the day after admission after fasting for at least 8 hours. Tests at 3 months were performed while fasting before the outpatient visit. The comorbidities assessed included a history of previous stroke or TIA, peripheral vascular disease, coronary artery disease, hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation, and smoking.
Outcome Parameters
The primary outcome was evaluated using a 3-month mRS score, with a score of 0–2 being considered favorable. Secondary outcomes included ischemic or hemorrhagic stroke recurrence at 3 months, LDL-C lowering effect, rate of statin discontinuation, and rate of adverse events. Stroke recurrence was confirmed by clinicians at the outpatient clinic or via telephone interviews. The LDL-C-lowering effect was measured using the patients’ LDL-C levels measured at baseline and after 3 months. We also calculated the percentage of patients who reached LDL-C <70 mg/dL, which is recommended by the clinical guidelines, after 3 months.10) The statin discontinuation rate was defined as patients stopping treatment within 3 months of initiation due to difficulty in taking the drug. The rate of adverse events was measured for 3 months based on the number of reports of hepatotoxicity and muscle-related events, which were evaluated using the WHO-Uppsala Monitoring Center (UMC) causality assessment.13) Hepatotoxicity was defined as an AST level, ALT level, or both >3 times the upper limit of normal (ULN, which is 40 IU/L). Patients who reported any muscle pain were considered to have myalgia. When a patient’s CK level was >10 times the ULN (270 IU/L), myopathy was considered. When a patient’s CK level was >40 times the ULN, rhabdomyolysis was considered.7)
Statistical Analysis
Categorical variables were compared using the chi-square test or Fisher exact test, and continuous variables using Student t-test. Univariate and multivariable logistic regression were performed with favorable 3-month functional outcome as the dependent variable. In addition to HIST use, candidate covariates were identified based on clinical relevance and prior literature14,15): age, sex, baseline NIHSS score, baseline LDL-C, previous statin use, TOAST subtype, and use of reperfusion therapy. Variables with p<0.10 in univariate analyses were entered into the multivariable model. Two pre-specified sensitivity analyses were additionally conducted: (1) a per-protocol analysis restricted to patients who consistently maintained their assigned statin intensity (HIST n=117; consistently-MIST n=145), excluding those de-escalated from HIST to MIST within the first month (n=75); and (2) an analysis additionally adjusting for atrial fibrillation regardless of its univariate significance.
Additional analyses addressing baseline stroke severity. To address residual confounding by stroke severity, NIHSS-stratified analyses (0–4 vs. ≥5) were performed using multivariable logistic regression within each stratum, with formal interaction testing by likelihood ratio test. An exploratory ordinal shift analysis of ΔmRS (3-month mRS minus premorbid mRS) was performed using proportional odds logistic regression with continuous baseline NIHSS as a covariate. To characterise patients with missing 3-month LDL-C data, baseline characteristics were compared between those with and without available data. Discharge destination was recorded and compared between groups, with a further sensitivity analysis additionally adjusting for discharge destination. Predictors of HIST prescription were characterised using multivariable logistic regression. Statistical analyses were performed using IBM SPSS Statistics version 27 and R version 4.3.4 (https://cran.r-project.org/). Statistical significance was set at p<0.05.
RESULTS
Patient Population and Baseline Characteristics
A total of 337 patients were included based on the patient selection criteria (Fig. 1). At statin initiation, 193 patients received HIST and 150 received MIST. After 6 patients discontinued statin therapy within 3 months and 75 HIST-initiated patients were de-escalated to MIST within the first month, the final 3-month cohort comprised 117 patients (34.7%) maintained on HIST and 220 (65.3%) on MIST. As shown in Table 1, there were no significant differences in age, male sex, and initial NIHSS scores between the HIST and MIST groups. However, the initial LDL-C levels were significantly different (HIST group 107.0±39.5 mg/dL, MIST group 90.1±33.8 mg/dL; p<0.001), whereas atrial fibrillation was more common in MIST (24.6% vs. 11.1%; p=0.005). Although the overall TOAST distribution did not differ significantly between groups (p=0.209), large-artery atherosclerosis (LAA) was numerically more common in the HIST group than in the MIST group (41.0% vs. 30.5%, p=0.068) (Supplementary Table S2). In a multivariable logistic regression model for predictors of HIST prescription, admission LDL-C (mg/dL) was the strongest independent predictor (odds ratio [OR]=1.01, 95% confidence interval [CI] 1.01–1.02; p<0.001), while atrial fibrillation independently predicted MIST assignment (OR=0.45, 95% CI 0.23–0.89; p=0.021) (Supplementary Table S3). Furthermore, there was no significant difference between the two groups in the use of ezetimibe combination therapy and the performance of reperfusion therapy.
Functional and Clinical Outcomes after AIS according to Statin Intensity
Favorable functional outcomes at 3 months were more frequent with HIST (70.9% vs. 55.9%; p=0.010) (Fig. 2). The entire patient population was divided into those with and without favorable functional outcomes at 3 months. As detailed in Supplementary Table S4, the favorable outcome group was significantly more frequently prescribed HIST (40.3% vs. 26.0%; p=0.010), younger (79.9±4.3 vs. 81.3±6.0; p=0.021), and had a lower initial NIHSS score (2.7±2.9 vs. 7.2±6.0; p<0.001), than the unfavorable outcome group. No significant difference was observed between the two groups regarding combined ezetimibe treatment, stroke mechanisms, vascular risk factors, or reperfusion therapy.
Clinical outcomes, including 3-month mortality and the recurrence of ischemic or hemorrhagic stroke, did not differ significantly between the HIST and MIST groups. Furthermore, while the mean LDL-C levels at 3 months were statistically comparable between the two groups (64.1±20.8 mg/dL vs. 70.8±22.0 mg/dL; p=0.061), a significantly higher proportion of patients in the HIST group achieved the clinical target of LDL-C <70 mg/dL (70.6% vs. 53.3%; p=0.025) (Supplementary Table S5).
Finally, after adjusting for covariates, HIST was independently associated with a favorable outcome in older patients with AIS (adjusted OR [aOR]=2.03, 95% CI 1.17–3.53) (Fig. 3). Both pre-specified sensitivity analyses confirmed the robustness of the primary finding (Fig. 4): in the per-protocol analysis (n=262; HIST n=117 vs. consistently-MIST n=145), the association was strengthened (aOR=3.48, 95% CI 1.97–6.17) (Supplementary Table S6); and after additional adjustment for atrial fibrillation, the association remained robust (aOR=2.21, 95% CI 1.26–3.89; p=0.006) (Supplementary Table S7).
Additional analyses addressing baseline stroke severity. In NIHSS-stratified analyses, HIST was independently associated with favorable outcomes in both the mild stratum (NIHSS 0–4, n=232; aOR=2.29, 95% CI 1.16–4.53; p=0.017) and the moderate-to-severe stratum (NIHSS ≥5, n=105; aOR=2.80, 95% CI 1.12–6.96; p=0.027). Sensitivity analyses additionally adjusting for continuous NIHSS within each stratum yielded consistent results (Table 2). There was no significant interaction between statin intensity and NIHSS stratum (p-value for interaction=0.687), suggesting that the association between HIST and favorable outcome was broadly consistent across baseline stroke severity. In the ordinal shift analysis, HIST was associated with a shift toward less disability (adjusted common OR=2.20, 95% CI 1.46–3.32; p<0.001) (Supplementary Tables S8, S9).
Statin Discontinuation, Adverse Effects, and LDL-C Lowering Effect
Regarding initial statin discontinuation rates, approximately 1.8% (6/343) stopped statin therapy within 3 months. There was no statistically significant difference in discontinuation between patients initially prescribed HIST and those initially prescribed MIST (Table 3).
Regarding the objectively observed adverse effects of statin treatment, no significant differences were observed in the incidence of hepatotoxicity. Furthermore, no significant difference was observed in the incidence of myopathy between the two groups, as determined by CK level; muscle pain; and WHO-UMC causality category (Table 3). Finally, LDL-C levels were measured at 3 months for 216 of 337 patients (64.1%). Baseline characteristics were well-balanced between patients with and without available 3-month LDL-C data across all examined variables (all p>0.05) (Supplementary Table S10), suggesting the missing data were unlikely to have introduced systematic bias. Regarding discharge destination, the distribution did not differ significantly between the HIST and MIST groups (overall p=0.206) (Supplementary Table S11). Notably, MIST patients were referred to inpatient rehabilitation facilities at a numerically higher rate than HIST patients (29.1% vs. 20.5%), indicating that differential rehabilitation access did not account for the observed outcome difference. In a sensitivity analysis additionally adjusting for discharge destination (n=337), HIST remained independently associated with a favorable 3-month outcome (aOR=2.20, 95% CI 1.08–4.46; p=0.029) (Fig. 4).
DISCUSSION
In this real-world, single-center cohort study of patients aged ≥75 years with acute ischemic stroke or TIA who maintained statin therapy for 3 months, HIST was independently associated with a significantly higher rate of favorable 3-month functional outcome compared with MIST (aOR=2.03, 95% CI 1.17–3.53), without evidence of increased adverse events, stroke recurrence, or early statin discontinuation. This association was consistent across multiple pre-specified sensitivity analyses—per-protocol (aOR=3.48, 95% CI 1.97–6.17), atrial fibrillation-adjusted (aOR=2.21, 95% CI 1.26–3.89), discharge destination-adjusted (aOR=2.20), and NIHSS-stratified analyses—all of which confirmed the robustness of the primary finding. These results add to the limited evidence base on statin intensity in the oldest-old stroke patients and support guideline recommendations for HIST use in this population when tolerated.16)
Current guidelines recommend HIST for patients with stroke aged ≥75 years if tolerated,17,18) though prescribing HIST in the oldest-old remains cautious owing to limited high-quality evidence and increased SAMS risk in this population. This pattern was reflected in our cohort, where the majority of patients (65.3%) received MIST. Nevertheless, prescribing decisions appeared to reflect guideline-concordant clinical reasoning rather than prognostic selection19): HIST was more frequently prescribed in patients with LAA and higher baseline LDL-C levels, while atrial fibrillation—for which the evidence base for HIST is weaker—independently predicted MIST assignment. This pattern supports the internal validity of the between-group comparison, as statin intensity appeared driven by clinical characteristics rather than by the clinician's overall assessment of patient prognosis.
Short-term safety of HIST was reassuring. Early statin discontinuation was uncommon (1.8%), and rates of hepatotoxicity, myopathy, and intracerebral hemorrhage did not differ significantly between groups, consistent with published statin trial data showing consistently low rates of serious adverse events even in older populations.20-22) Notably, 34.1% of MIST-group patients had briefly received HIST before de-escalation within the first month; however, the fact that statin therapy was maintained suggests any adverse effects were not substantial. While de-escalation appeared to occur in clinically stable patients, alternative explanations such as early tolerability concerns or clinician preference cannot be fully excluded. Regarding cerebral bleeding, atorvastatin did not increase intracerebral hemorrhage rates in SPARCL.23) These observations provide reassurance regarding the short-term safety of HIST in patients aged ≥75 years, although longer follow-up is needed to fully characterise tolerability in this age group. The functional benefit of HIST is mechanistically plausible beyond lipid lowering. Statins exert neuroprotective pleiotropic effects including anti-inflammatory and antioxidant properties.24-27) HIST achieves more rapid and effective LDL-C reduction than MIST,28) which may attenuate early neurological deterioration through atherosclerosis stabilisation and neuroprotection during the acute phase.29) The ordinal shift analysis further supports a functional benefit extending beyond the dichotomised mRS threshold.
The absence of a significant difference in 3-month stroke recurrence likely reflects the short observation period and correspondingly low event rate; recurrent events accumulate over time,30) and prospective studies with follow-up of at least 1 year are warranted to determine whether HIST provides sustained protection against recurrence. The higher proportion of HIST patients achieving the LDL-C target of <70 mg/dL (70.6% vs. 53.3%; p=0.025) suggests that the lipid-lowering benefit was clinically meaningful, although between-group LDL-C differences at 3 months did not reach statistical significance, possibly owing to the high proportion of missing LDL-C data.
This study has several limitations. First, the observational, single-center, retrospective design precludes causal inference and limits generalisability; residual confounding from unmeasured variables—including frailty, sarcopenia, and medication adherence—cannot be excluded. Although extensive sensitivity analyses were performed, residual confounding by unmeasured factors such as frailty, clinician judgment, and treatment tolerance cannot be fully excluded, and the observed association should therefore be interpreted with caution. Second, 3-month LDL-C data were missing in 35.9% of patients; however, baseline characteristics were well-balanced between those with and without available data (all p>0.05) (Supplementary Table S10), supporting a missing-at-random mechanism and suggesting that the missing data were unlikely to introduce systematic bias. Third, we were unable to adjust for the effects of antithrombotic or other concomitant medications during the acute stroke period, although all patients received guideline-concordant stroke management. Fourth, frailty indices and sarcopenia assessments were not collected in our registry and cannot be retrospectively added. However, age, initial NIHSS score, and the premorbid mRS 0–1 inclusion criterion serve as partial proxies for frailty and restrict the study population to functionally independent patients, limiting frailty heterogeneity at baseline. Fifth, outpatient rehabilitation participation after discharge was not systematically captured; however, discharge destination data showed no significant difference between groups (p=0.206), and MIST patients were referred to inpatient rehabilitation at a numerically higher rate (29.1% vs. 20.5%), indicating that differential rehabilitation access is unlikely to explain the observed outcome difference. The association also persisted after adjusting for discharge destination (aOR=2.20, 95% CI 1.08–4.46) (Fig. 4). Finally, 34.1% of the MIST group had brief early HIST before de-escalation within the first month. However, the per-protocol sensitivity analysis excluding these patients strengthened the association (aOR=3.48), confirming the primary main analysis was conservative. Furthermore, de-escalated patients had the highest favorable outcome rate (85.3%) and lowest initial NIHSS score, indicating de-escalation reflected clinical stability or tolerability rather than clinical deterioration. Regarding the observed atrial fibrillation imbalance, additional atrial fibrillation adjustment did not attenuate the association (aOR=2.21, 95% CI 1.26–3.89), confirming that the atrial fibrillation imbalance did not meaningfully confound the primary result. Further research is needed to define the optimal HIST duration and to evaluate alternatives such as ezetimibe when HIST is not tolerated. Accordingly, these findings should be viewed as supportive but not definitive evidence for high-intensity statin use in this population.
In conclusion, in older patients with AIS aged 75 years and older, when statin therapy was maintained for the initial 3 months, HIST showed no evidence of inferior safety compared to MIST and was independently associated with favorable functional outcomes. These findings are broadly consistent with current guideline recommendations supporting the use of HIST in patients with AIS when tolerated, and suggest that such recommendations may extend to patients aged 75 years and older. However, given the observational design of this study, a causal relationship cannot be established, and the results should be interpreted as hypothesis-generating. Prospective randomised studies in older patients are needed to confirm the efficacy and safety of HIST in this population.
PDF Links
PubReader
ePub Link
XML Download
Full text via DOI
Download Citation
agmr-25-0202-Supplementary-Table-S1.pdf
