The effect of atorvastatin on the common carotid artery intima-media thickness in patients with ischemic stroke.

Occlusion of the initial segment of internal carotid artery is the most common reason for vascular events in the brain. The purpose of this study was to investigate the effect of one-year treatment with atorvastatin on intima-media thickness (IMT) of carotid arteries as a measure of atherosclerosis in stroke patients. In this prospective interventional study, 44 patients with ischemic stroke were investigated. Patients were treated with atorvastatin 40 mg once a day for one year. IMT of carotid arteries was measured by extracranial Doppler ultrasonography in the distal part of the common carotid artery at the beginning of the study, at 6 months and one year of treatment with atorvastatin. The IMT of both right and left carotid arteries decreased after 6- and 12-month atorvastatin treatment. Based on the results of this study, long-term administration of atorvastatin was associated with reduction in carotid artery IMT in patients with ischemic stroke. Such a decrease in IMT may prevent subsequent stroke or cardiovascular events in these patients.

Introduction

Stroke as an extremely frequent disorder accounts for considerable numbers of chronic disability, dementia and deaths cases in the United States (). Therefore, it is essential to reduce the risk of stroke by applying preventive methods. Moreover, rehabilitation strategies are important in reducing disabilities in these patients (). Ischemic and hemorrhagic strokes are the two main subgroups of stroke with the former subgroup containing almost 80% of cases. Ischemic stroke is classified into cardioembolic, atherosclerotic, lacunar, and other subtypes based on etiologic factors (). Several risk factors have been recognized for stroke based on etiologic classes, among them hypertension, hyperlipidemia, and atrial fibrillation (). Occlusion of carotid artery by carotid plaques is an underlying cause of stroke. These plaques are usually slow-developing or dormant for long times but may abruptly change and cause ruptures, fissures, or endothelial corrosions resulting in confined or distant obstructions (). Carotid intima-media thickness (IMT), as measured by high-resolution ultrasound techniques, has been generally used as an indicator of atherosclerosis. Several studies have shown the predictive value of IMT in vascular events independently of the routine vascular risk factors (). Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, which are widely used as effective lipid lowering drugs. These drugs can diminish cardiovascular events in several cardiovascular disorders (). Statins have beneficial effects by decreasing ischemia, lowering inflammatory responses and ameliorating atherosclerotic events. These effects might also be reflected in a remarkable decrease in IMT following administration of statins (). Meta-analyses of available data have indicated substantial reduction of IMT following treatment with some statins such as lovastatin and simvastatin (). In the present study, we aimed to evaluate the effects of long-term treatment with atorvastatin on carotid IMT reduction in patients with a history of ischemic stroke.

Patients and Methods

Patients

In the current prospective interventional study, 44 patients (21 females and 23 males) with ischemic stroke were enrolled. Patients were referred to Farshchian Hospital, Hamadan during 2016-2017. All patients were treated with atorvastatin 40 mg once a day for one year. The study protocol was approved by the Ethics Committee of Hamadan University of Medical Sciences (Ethics Code: IR.UMSHA.REC.1396.44, Clinical Trial Approval Number: IRCT201707129014N173). Written informed consent forms were obtained from all study participants. The inclusion criteria were patient ability to cooperate, history of ischemic stroke and age >50 years. Exclusion criteria were creatinine values >1.5 mg/dL, history of statin use in the previous one month, history of hepatic or muscular side effects following statin taking, taking anticoagulant or other anti-lipid agents, pregnancy and need for endarterectomy or carotid stent.

Measurements

Patients underwent extracranial Doppler ultrasonography (ECD) with two cylindrical and linear probes. IMT of carotid arteries was measured by a linear probe at the frequency of 5-7 MHz in the distal part of the common carotid artery at the beginning of the study, then at 6 months and one year of treatment with atorvastatin. To increase the accuracy, the artery wall thickness was measured in three regions and the mean values were recorded. Data were collected using a checklist that included demographic data and changes in the carotid artery IMT.

Statistical analyses

The suitable sample size was determined by G*Power 3 software considering type I and II errors of 5% and 20%, respectively. Data were analyzed using SPSS 16.0 software (IBM, Armonk, NY, USA). Quantitative and qualitative parameters were described by mean ± standard deviation (SD) and percentage (or proportions), respectively. T test was used for assessment of the effects of intervention on the corresponding parameters. P values less than 0.05 were considered significant.

Results

The mean age ± SD of study participants was 68.6 years. There was no significant age difference between female and male participants (68±8.9 vs. 69.2±10.5, p=0.695). The IMT of both right and left carotid arteries decreased after 6- and 12-month treatment with atorvastatin. Table 1 shows the IMT values after treatment with atorvastatin.

Table 1

Intima-media thickness (IMT) values after atorvastatin treatment

	Before treatment	After 6-month treatment	p value (t test)	After 12-month treatment	p value (t test)
Right carotid IMT	0.86±0.19	0.79±0.14	0.001	0.73±0.15	0.001
Left carotid IMT	0.92±0.19	0.83±0.15	0.001	0.77±0.13	0.001
Both carotids IMT	0.89±0.19	0.81±0.15	0.001	0.75±0.14	0.001

We also assessed the effects of treatment on the mentioned parameters in male and female subjects separately (Table 2). The IMT of the right carotid was not significantly different before treatment and after 6-month treatment in female subjects (p=0.229). However, 12-month treatment with atorvastatin resulted in a significant decrease in IMT of both carotids in both male and female subjects.

Table 2

Intima-media thickness (IMT) values after treatment with atorvastatin according to patient gender

Males						Females
p value (t test)	After 12-month treatment	p value (t test)	After 6-month treatment	Before treatment	p value (t test)	After 12-month treatment	p value (t test)	After 6-month treatment	Before treatment
0.023	0.75±0.16	0.229	0.80±0.09	0.84±0.17	0.001	0.7±0.14	0.001	0.78±0.7	0.88±0.21	Right carotid IMT
0.001	0.79±0.11	0.001	0.85±0.10	0.94±0.15	0.001	0.76±0.14	0.008	0.81±0.19	0.9±0.19	Left carotid IMT

Discussion

Carotid IMT has been recognized as an eminent alternative marker of subclinical atherosclerosis () and cardiovascular diseases () in diverse clinical settings. Meanwhile, statins have been shown to alleviate atherosclerotic processes and reduce carotid IMT (). In the current study, we assessed long-term effects of atorvastatin on IMT of carotid arteries in patients with previous ischemic stroke. Recurrent stroke is a devastating event, which is associated with high mortality and morbidity. The pathogenesis of this condition is most likely multifactorial and many recurrences cannot be explained by the routine risk assessments. However, some studies have indicated that common carotid IMT is an independent predictor of stroke recurrence (). Furthermore, Lorenz et al. have reported that carotid IMT is a robust forecaster of imminent vascular events. Notably, the relative risk of each IMT change was somehow greater for the endpoint stroke than for myocardial infarction (). Ultrasound assessment of carotid IMT is a noninvasive method for evaluation of the degree of arteriosclerosis, the risk of up-coming stroke, and appraisal of the efficacy of drug therapies (). In the current prospective study, we demonstrated the beneficial effects of atorvastatin in reducing carotid IMT at both time points in male subjects.

Our results are in accordance with a previous meta-analysis, which showed that treatment with atorvastatin significantly decreased carotid IMT in Chinese patients with type 2 diabetes (). Furthermore, Fang et al. showed that high-dose atorvastatin (40 mg) was superior to low-dose (10 mg) atorvastatin in reducing carotid IMT (). Based on these results, we only checked the effects of high-dose atorvastatin in our cohort of patients. Previous studies report controversial results regarding the effect of atorvastatin on IMT, which might be due to short duration of drug administration (). For instance, Kim et al. showed that 6-month use of statins amended endothelial function in patients with variant angina, but they did not detect significant decrease in carotid IMT in their patients (). Such duration-based effects were also demonstrated in our study. Although this intervention did not reduce right carotid IMT in female subjects after 6 months, one-year treatment with atorvastatin significantly decreased IMT of both arteries in both sexes. Therefore, we conclude that long-term administration of atorvastatin increases its effects in all patients and might decrease the risk of future strokes. However, additional studies are needed to verify our results in larger sample sizes. Moreover, assessment of long-term side effects of atorvastatin is needed. The current study had the strength of accurate measurement of artery wall thickness in three regions of the artery and assessment of patients from a similar ethnic group, which is expected to decrease the effects of confounding variables. However, our study had some limitations including the lack of control group and inclusion of patients of distinct age range, which might limit the generalizability of the results.