Differential influences of LDL cholesterol on functional outcomes after intravenous thrombolysis according to prestroke statin use

In the analysis of over 4,500 patients with acute stroke treated with IV-tPA from a nationwide multicenter registry, the LDL-C level was not associated with functional outcomes at 3 months or death after IVT, consistent with previous studies showing no association between reduced LDL-C levels and functional outcomes19,20. However, a potential effect of the interaction between previous statin use and LDL-C groups was observed. In other words, the relationship between the LDL-C level and 3-month functional outcome varied depending on prior statin treatment. The lack of an association was consistently observed only for patients without prestroke statin treatment. Among the patients with prestroke statin use, the low and intermediate LDL-C groups were twice as likely to achieve a good functional outcome at 3 months compared with the high LDL-C group. These results suggest that modest lowering of LDL-C levels with prestroke statin treatment might help improve functional outcomes in patients with AIS after IVT.

Hypothetically, prestroke statin treatment is expected to exert neuroprotective effects by increasing angiogenesis, reducing clot formation or facilitating clot lysis, and upregulating endothelial nitric oxide synthase21,22,23. However, controversy exists regarding whether prestroke statin treatment improves the functional outcome after IVT in the clinic. As shown in Fig. 2, the predicted probability of a good outcome decreased sharply as the LDL-C level increased above a certain level in the prestroke statin user group. In contrast, this trend was not noticeable in the non-user group. The non-linear association of LDL-C levels with the functional outcome and the different effects of LDL-C levels on the functional outcomes of patients stratified according to prestroke statin treatment might partially explain the heterogeneity of the results of previous studies. Our results substantially improve our understanding of the clinical impact of LDL-C levels and statin treatment on patients with AIS treated with IVT.

Our results showed that the low LDL-C group (< 100 mg/dl) was most likely to have traditional vascular risk factors, a history of vascular diseases, and a medication use history including prestroke statin use. These findings are consistent with a previous study showing that prior statin use may be considered an indicator of demographic and vascular risk factors in IV-tPA-treated patients11. In our study, approximately 16% of all patients were on statin medication at the onset of stroke. Interestingly, 66.4% of prior statin users had LDL-C levels less than 100 mg/dl, in contrast to 36.2% of non-users. Accordingly, the low LDL-C group with prestroke statin treatment might be a well-controlled risk group, although the low LDL-C group appeared to have worse clinical risk profiles.

In contrast, it may be unexpected that the patients with no prestroke statin treatment in the low LDL-C group showed high vascular risk profiles. However, in the low LDL-C group, the no prestroke statin group, compared with that in prestroke statin group, had a less significant history of stroke (15.8% vs. 37.6%, respectively) and CAD (9.6% vs. 28.3%, respectively). The baseline characteristics of the patients with previous vascular diseases were mixed, which may have had an impact on stroke outcomes, thus potentially having an impact on the overall results of the research. More importantly, the low LDL-C group was more likely to have AF (40%) or CE subtype (39.7%) among the 3 LDL-C groups of patients with no prestroke statin use. Previously, low LDL-C levels were associated with a higher incidence of AF24,25. Therefore, among no prestroke statin users, history of stroke or history of CAD is likely to be related to AF pathology rather than LDL-C levels in the low LDL-C group. It is noteworthy to share real-world information regarding the characteristics of the LDL-C groups of AIS patients treated with IVT.

The results of our study showed that an LDL-C level of 100–130 mg/dl might have the highest predictive value for good outcome after IVT, especially in patients with prestroke statin use. Although the relationship of LDL-C levels with functional outcomes after IV-tPA treatment was not thoroughly investigated in previous studies, a U-shaped non-linear relationship between LDL-C levels and final infarct volume was observed in AIS patients treated with endovascular thrombectomy26. Also, the ‘lipid paradox’ might be partially related to our results. In the crude analysis, we observed that the low LDL-C group was more likely to have worse outcomes. The relationship between baseline LDL-C levels and early outcomes is complex, but LDL-C levels appear to be a potential indicator of the desired effect of statin pretreatment and might change the outcome after AIS. Further study would be warranted to confirm our results.

A long-standing dispute exists regarding the increased risk of SICH at lower LDL-C levels. Various reports have stated that low levels of cholesterol, including LDL-C, are associated with SICH or hemorrhagic transformation after IV or intra-arterial tPA treatment6,19, but others have reported no association8,20. In an analysis of 22,216 AIS patients treated with tPA27, statin treatment and LDL-C levels were not associated with the risk of SICH. In another study, a low level of LDL-C was independently associated with hemorrhagic transformation in patients with large artery atherosclerosis but not in patients with CE28. Unexpectedly, our study did not observe significant differences in the rates of SICH between LDL-C groups, but after adjustment for covariates, the low LDL-C group was 42% less likely to experience SICH than the high LDL-C group, regardless of the prestroke statin treatment. However, given the low incidence of SICH itself and the heterogeneous population, the results of the multivariable analysis should be interpreted with caution.

Our results provide additional information on the associations of other lipid profiles including non-HDL-C groups and TG groups with functional outcomes after IVT. While non-HDL-C groups were not associated with good outcomes at 3 months, the low TG group was less likely to have a good outcome at 3 months after IVT than the high TG group. The results for the non-HDL-C group were consistent with those of the LDL-C group, whereas the results of the TG group were not consistent. Previous studies have shown that a low TG concentration is associated with severe stroke and higher mortality after stroke29,30. However, further studies are warranted to explain these results.

Our study has several limitations. First, it is an inherently limited registry-based study of a patient cohort restricted to South Korea. Therefore, studies of other race-ethnicity groups are needed to confirm the generalizability of the results. Second, because of the retrospective design, we lacked clinical information on statin treatment profiles before starting statin therapy, the duration of therapy, the type and dosage of statins, and patient compliance. Moreover, the LDL-C cutoff values used in our study were based on recommendations in the guidelines for the prevention of vascular events, not the functional outcome. Third, despite multiple adjustments, unmeasured confounders might have influenced our findings. E-values were calculated as a sensitivity analysis to determine the likelihood that an unmeasured confounder existed that would negate the observed relationship between LDL-C levels and 3-month functional outcomes after IVT. This effect appears unlikely because the range of point estimates for the ORs for all known risk factors available in the data ranged from 0.65 to 2.33 (Supplemental Table III). The E-values for the confidence intervals closest to the null for the adjusted ORs for the associations between LDL-C groups (overall), prestroke statin users, and prestroke statin non-users ranged from 1 to 1.41. Fourth, we did not collect information about imaging predictors of functional outcomes such as the infarct volume, recanalization, collateral status, or leukoaraiosis severity. Finally, we cannot exclude the possibility that the acute phase reaction after stroke influenced lipid levels to some extent. Therefore, our results should be interpreted cautiously and confirmed in clinical trials.

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