the Department of Neurology (M.M., K.K., M.F.), University of Massachusetts Medical School, Worcester, Mass
Indevus Pharmaceuticals, Inc (U.S., B.W.S.), Lexington, Mass.
Abstract
Background and Purpose— Statins reduce the risk of stroke recurrence, but the benefits of statins in improving outcome of acute stroke patients have not been well explored.
Methods— We assessed potential effects of statins initiated before or within 4 weeks of stroke on 90-day outcome. Favorable outcomes were National Institutes of Health Stroke Scale (NIHSS) score 2 at 12 weeks and modified Rankin Scale (mRS) 2.
Results— Before stroke, 129 patients were receiving statins, 123 initiated statins within 4 weeks, and 600 patients were not on statins. Multivariate logistic regression analysis demonstrated that poststroke statins were associated with a significant probability of a favorable outcome at 12 weeks [NIHSS (P=0.002; OR, 1.92; CI, 1.27 to 2.91) and mRS (P=0.033; OR, 1.57; CI, 1.04 to 2.38)], whereas prestroke statins demonstrated a trend toward significance.
Conclusions— These preliminary results suggest that statin use may improve outcome of acute ischemic stroke.
Key Words: ischemia stroke stroke outcome
Introduction
Prospective studies have demonstrated that HMG-CoA reductase inhibitors (statins) reduce stroke recurrence by 20% to 25%.1,2 As suggested by animal studies, statins may also improve stroke outcome.3
Materials and Methods
The medication records and the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) data were collected from case report forms from the phase 3 citicoline trial and patients were divided into 3 groups: using statins before stroke, started statin after stroke onset, and patients not treated with statins at anytime.
Outcome Measures
Primary favorable outcome was defined as 2 on the NIHSS at week 12 after stroke and mRS score 2 at 12 weeks.
Statistical Analysis
Univariate statistical analyses (2 test for all variables except continuous age variable in which t test was performed) to study the associations of the demographic and medical and risk factors on NIHSS at week 12 (Table 1). Significant univariate predictors (P<0.05) were included in multivariate stepwise binary logistic regression analysis (Tables 2 and 3).
Results
Baseline NIHSS in the prestroke statin, poststroke statin, and the group never exposed to statin were 13.1±3.8, 12.9±4.1, and 13.1±3.7, respectively, and were not significantly different. Patients on citicoline were equally distributed in the 3 groups (Table 1).
There was a significant difference in outcome between statin groups (2=9.90; P=0.007), with statins after stroke having a better outcome than the other 2 groups (2=9.28, P=0.002). Prestroke statin group demonstrated a positive trend. Other significant differences in the univariate analysis were between stroke types (2=4.46; P=0.049), with patients with all other stroke subtypes having a better outcome than cardioembolic stroke (2=4.46; P=0.035). Diabetes (P=0.003), cardiac disease (P=0.007), peripheral vascular disease (P=0.031), previous stroke or transient ischemic attack (P=0.008), and antihypertensive medication use (P<0.001) were predictors of a poor outcome. Citicoline was not predictive of outcome. In multivariate analysis, statins were significant predictors of good outcome (P=0.008). Statins after stroke (P=0.002; OR, 1.92; CI, 1.27 to 2.91) were associated with favorable outcome, whereas prestroke statins demonstrated a trend toward good outcome (P=0.07; OR, 1.07; CI, 0.69 to 1.66). Other independent predictors of outcome are presented in Table 2.
The results of mRS 2 as the outcome measure were similar to the results of the outcomes of NIHSS 2. In the univariate analysis, poststroke statins were strong predictor of outcome compared with the other 2 groups (2=9.47; P=0.002). Stroke subtypes besides cardioembolic stroke were independently associated with better outcome (2=11.91; P=0.008). Patients on citicoline (P=0.046) were more likely to have a positive outcome. Hypertension (P=0.009), diabetes (P<0.001), cardiac disease (P<0.001), previous stroke or transient ischemic attack (P=0.007), or early antihypertensive medication use (P<0.001) were associated with poor outcome.
In the multivariate analysis, only statin use after stroke (P=0.033; OR, 1.57; CI, 1.04 to 2.38), treatment with citicoline (P=0.028; OR, 1.39; CI, 1.04 to 1.85), and small-vessel stroke (P=0.008; OR, 2.05; CI, 1.21 to 3.48) were positive and independent predictors of mRS 2. Predictors of poor outcome were similar to those on the NIHSS on the mRS 2 analysis (Table 3).
Discussion
Our data suggests that treatment within 4 weeks after acute ischemic stroke with statins was associated with improved stroke outcome at 90 days. There were insufficient numbers in each statin type to reliably analyze if one type of statin was better than others.
Acute lipid-lowering improves outcome from coronary attacks and reduces stroke risk and other properties of statins (improving endothelial function by enhancing endothelial nitric oxide production and antioxidant and anticoagulant effect) may be possible mechanisms of delayed improved outcome,4–6 the more likely explanation for poststroke statin use lies in their capability to induce angiogenesis, neurogenesis, and synaptogenesis, factors that may be important in enhancing neuronal recovery and hence stroke outcome.7,8 Improved functional outcome at day 14 was demonstrated in Wistar rats treated with atorvastatin beginning 1 day after stroke onset by inducing angiogenesis, neurogenesis, and synaptogenesis by induction of vascular endothelial growth factor, which promotes angiogenesis and brain cGMP, which promotes neurogenesis.7 These results suggest a potential explanation for the outcome in the group that started statins after stroke onset.
One prestroke statin treatment study demonstrated improved stroke outcome.9 In our study, prestroke statin use demonstrated a trend toward significance (NIHSS 2; P=0.07; OR, 1.07; CI, 0.69 to 1.66). Possible explanations include the short duration of treatment with statins before stroke onset, exclusion of subcortical stroke in the citicoline trial (more likely to have been on statins), and a possible saturation effect on potential enhancers of poststroke recovery in patients that had been on statins before stroke onset.7
Although previous studies7,9 and our t test results are suggestive of the usefulness of statins in improving ischemic stroke outcome, larger prospective trials are needed to confirm these observations.
References
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