(Stroke. 2001;32:2446-a.)
© 2001 American Heart Association, Inc.
Letters to the Editor |
Inflammation, Statins, and Outcome After Ischemic Stroke
Department of Neurology and Neurorehabilitation, Casa di Cura Villa Pini d’Abruzzo, Chieti, Italy
To the Editor:
In the recently article by Jonsson and Asplund,1 the authors demonstrate that statins have a moderate effect in improving the prognosis of ischemic stroke patients, underlying the possible complex role of statins in determining prognosis after ischemic stroke. Their data are in agreement with our preliminary results on the concurrent use of statins in patients with first-ever ischemic stroke.2 Previously, we found that the use of statins reduces the levels of C-reactive protein (CRP) after ischemic stroke, the initial neurological deficit, and improves the prognosis of stroke patients with a significant reduction of the 1-year risk of death or new vascular events.2 Recently, we have extended these observations in the same ischemic stroke cohort that had concluded the 2-year follow-up. All patients (n=193) were recruited in the period between March 1, 1998, and March 31, 1999. Design, methods, and baseline characteristics of our stroke data bank have been previously reported.3,4 We measured levels of CRP after stroke (within 24 hours), at 3 months, and at the end of the 2-year follow-up, together with total cholesterol, HDL and LDL subfractions, and triglycerides. Differences in proportions were evaluated by 
2 test. Continuous variables are described as mean±SD or median values with 25th and 75th percentiles, and comparisons between groups were evaluated with the Student t test or Mann-Whitney U test, when appropriate. The Kaplan-Meier technique (log-rank test) was applied in survival analysis. Log-normalized values of CRP were used to evaluate correlations over time.
At the entry, mean total cholesterol concentrations were 4.62±1.25 mmol/L in men and 5.31±1.06 mmol/L in women (P=0.001; Student t test). Mean HDL cholesterol concentrations were 0.95±0.39 mmol/L and 1.02±0.31 mmol/L (P=0.1977), mean LDL cholesterol concentrations were 3.97±1.32 mmol/L and 4.64±1.06 mmol/L (P=0.001), and mean triglycerides concentrations were 1.50±0.73 mmol/L (P=0.0255), respectively. Median CRP concentrations were 1.85 mg/dL in men (0.70 to 5.40) and 1.0 mg/dL in women (0.23 to 2.65; P=0.0020, Mann-Whitney U test) at the entry. Ninety-three patients (48.2%) had a total cholesterol concentration 
5.0 mmol/L at the time of ischemic stroke, 122 (63.2%) had a ratio of total cholesterol to HDL cholesterol 5, and 175 (90.7%) had LDL cholesterol 3.0 mmol/L. Fifty-two patients (26.9%) took statins: simvastatin (n=37; dose range 10 to 20 mg/d), pravastatin (n=10; range 20 to 40 mg/dL), and atorvastatin (n=5; range 10 to 40 mg/d) at the time of qualifying stroke; of these only 16 (8.3%) had a total cholesterol concentration <5 mmol/L.
Younger age (70.5±9.8 versus 73.7±8.8 years; P=0.0321, Student t test), a greater prevalence of arterial hypertension (90.4% versus 68.8%; P=0.0022, 2 test), and history of dyslipidemia (51.9% versus 31.2%; P=0.0081) were noted in statin group. Significantly lower median levels of CRP (0.6 mg/dL [0.3 to 1.5] versus 1.9 mg/dL [0.8 to 3.75]; P<0.0001, Mann-Whitney U test) within 24 hours after stroke, together with a significantly lower score on the Canadian Neurological Stroke Scale (7.5 [6.0 to 9.0] versus 6.0 [4.5 to 8.0]; P=0.0003) were also found in patients with statin therapy. No differences were found in terms of neuroradiological findings such as large infarcts, cortical involvement, hemorrhagic transformation, brain edema, or of stroke subtypes.
There was not a compulsive lipid-lowering treatment during follow-up, so only an additional 7 (3.6%) patients received statin therapy during their inhospital stay. Diet control was prescribed in all patients with total cholesterol level 5 mmol/L. No lipid-lowering drug therapy was prescribed by the referring physician. No patients stopped statin treatment. During the 2-year follow-up period, 76 patients (40%) had a combined end point (death or any new vascular event): 36 patients died (vascular death in 29), and 40 had a nonfatal vascular event (cardiac in 21 and cerebral in 19). Only 12 combined end points (3 death and 9 new non fatal vascular events) were registered in patients with statin therapy (20.3% versus 47.8%, P=0.0004, log-rank test). The Figure shows the cumulative risk at 2-year of a combined end point, according to tertiles of CRP and statin treatment. The absolute differences in risk between tertiles of CRP were 9.4%, 24.6%, and 28.2%, respectively. To prevent 1 combined end point at 2 years, 11 patients would take a statin treatment in the lower tertile but only 4 in the highest tertile.
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In the patients who remained free of the combined end point at the end of follow-up (n=117), CRP at 3 months and at 2 years were highly correlated (r=0.77; P<0.0001). However, among those without statin therapy, median CRP levels and the mean change in CRP tended to increase over time (median changes +25%; P=0.0279; mean changes +0.08 mg/dL; P=0.060). By contrast, median CRP levels and the mean change in CRP decreased over the time among those with statin therapy (median changes -15%; P<0.0001; mean changes -0.09 mg/dL; P=0.016). Thus, statistically significant differences were found at 2 years between patients with and without statin therapy in terms of median CRP levels (difference, -78.6%; P=0.0017), mean CRP levels (difference, -34.7%; P=0.028), and absolute mean change in CRP (difference, -0.15 mg/dL; P=0.031). However, there were no significant differences in the 2 groups in mean total cholesterol concentrations (difference, +3.8%; P=0.370) and mean HDL cholesterol concentrations (difference, -7.9%; P=0.147). In the statin group, 31 (68.9%) had a total cholesterol concentration 5.0 mmol/L, and 38 (84.4%) had a ratio of total cholesterol to HDL cholesterol >5 at the end of the 2-year follow-up.
The concomitant use of statins at the time of stroke appears to reduce the neurological deficit and improves the prognosis. This effect is apparently independent from the lipid concentrations, because at the end of the follow-up there were no significant differences in lipid concentrations between 2 groups. In the short-term period, the effect of statins is probably related to their anti-inflammatory properties more than lipid concentration reduction. A greater risk reduction was found in the subgroups of patients with higher levels of CRP, while lipid profile was similar in the 2 groups at the end of 2-year follow-up. However, some patients have an intense activation of inflammation system in response to a stroke with persistent elevated CRP levels.4,5 This activation is only partially reduced by statins.2 These patients, therefore, may benefit from a more careful clinical follow-up and probably from a more appropriate anti-inflammatory treatment.6
A direct neuroprotective effect of statins in ischemic brain damage has been suggested.7 There was no evidence of this effect in our stroke population, because no associations were found between statin therapy and neuroradiological findings. However, a strong and persistent acute-phase response after stroke is associated with larger infarcts,5 so the neuroprotective effect of statins is more complex in humans than that we can actually realize.
In conclusion, the proportion of patients with ischemic stroke who received statin treatment is low, and even an even lower proportion of them received efficacious control of hypercholesterolemia. A more extensive and aggressive use of statins in all patients at risk for and with first-ever ischemic stroke, and especially in patients with persistently higher CRP levels after ischemic stroke, should be developed into specific screening programs that will be appropriately funded and developed in a public health perspective.8
Written on behalf of the Villa Pini Stroke Data Bank Investigators, whose members also include Vittorio Bocola, MD, Donato Melchionda, MD, Rocco Santarelli, MD, and Antonina Faricelli, MD.
References
1.
Jonsson N, Asplund K. Does pretreatment with statins improve clinical outcome after stroke? A pilot case-referent study. Stroke. 2001; 32: 1112–1115.
2.
Di Napoli M. HGM-CoA reductase inhibitors (statins): a promising approach to stroke prevention. Neurology. 2000; 55: 1066–1067.
3.
Di Napoli M, Papa F, Bocola V. Prognostic influence of increased C-reactive protein and fibrinogen levels in ischemic stroke. Stroke. 2001; 32: 133–138.
4.
Di Napoli M, Papa F, Bocola V. C-reactive protein in ischemic stroke: an independent prognostic factor. Stroke. 2001; 32: 917–924.
5.
Di Napoli M, Papa F, Bocola V. Periodontal disease, C-reactive protein, and ischemic stroke. Arch Intern Med. 2001; 161: 1234–1235.
6.
Lagrand WK, Visser CA, Hermes WT, Niessen HWM, Verheught FWA, Wolbink G-J, Hack CE. C-reactive protein as a cardiovascular risk factor: more than an epiphenomenon? Circulation. 1999; 100: 96–102.
7.
Vaughan CJ, Delanty N. Neuroprotective properties of statins in cerebral ischemia and stroke. Stroke. 1999; 30: 1969–1973.
8.
Monkman D. Treating dyslipidaemia in primary care: the gap between policy and reality is large in UK. BMJ. 2000; 321: 1299–1300.
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