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      ORIGINAL ARTICLE Year : 2023  |  Volume : 71  |  Issue : 5  |  Page : 923-927

Effects of Serum Cholesterol on Severity of Stroke and Dosage of Statins on Functional Outcome in Acute Ischemic Stroke

Priyanka Shridharan1, Radhika Nair2, Sankar P Gorthi3, K Prakashini4, Aparajita Chatterjee5
1 Department of Neurology, KMC, Manipal, Karnataka, India
2 Department of Neurology, KMC, Manipal, Karnataka, India; Clinical Fellow, Stroke and Cerebrovascular Diseases, University of Alberta, Edmonton, AB, Canada
3 Department of Neurology, Bharati Vidhya Peeth (DTU), Medical College and Hospital, Pune, Maharashtra, India
4 Department of Radiodiagnosis, KMC, Manipal, Karnataka, India
5 Department of Neurology, Fortis Hospital, Anandapur, Kolkata, West Bengal, India

Date of Submission21-May-2021Date of Decision23-Nov-2021Date of Acceptance23-Nov-2021Date of Web Publication18-Oct-2023

Correspondence Address:
Radhika Nair
Unit 604, 11111, 82 Ave, NW, Edmonton AB, T6G 0T3

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/0028-3886.388115

Background: A high dose of statin is used to obtain an intensive lipid-lowering in stroke patients, even in patients with normal lipid levels. There are limited data on effect of dosage of statins and functional outcome in stroke patients.
Objectives:

To compare serum cholesterol levels with severity of stroke measured by infarct volume.To compare functional outcome measured by mRS at day 90 with the dose of statin.
Materials and Methods: This retrospective observational study was conducted in KMC Hospital Manipal, India between 2016 and 2018.
Result: A total of 100 consecutive patients were included in the study, out of which 60 (60.0%) were males. Hyperlipidemia was present in 65 (65.0%) patients. On comparing the serum cholesterol levels with infarct volume using MRI, patients with low volume of ≤70 ml had higher mean serum total cholesterol concentration (223.83 mg/dl), whereas patients with high volume of >70 ml had low mean cholesterol level (218.70 mg/dl). The patients were divided into those who received low dose (≤20 mg) versus high dose (≥40 mg equivalent) of Atorvastatin. On comparing the mRS values at baseline and on day 90 with the dose of statins, patients who received a higher dosage had a statistically significant fall in mRS (p-0.045) at day 90.
Conclusion: It was found that serum cholesterol levels were inversely related to the stroke severity. However, a higher the dose of statins resulted in better functional outcome and survival in post-stroke patients, possibly due to its neuroprotective effect.

Keywords: Functional outcome, ischemic stroke, serum cholesterol levels, statins
Key Message: Higher dose of statins are associated with improved functional outcomes in acute ischemic stroke

How to cite this article:
Shridharan P, Nair R, Gorthi SP, Prakashini K, Chatterjee A. Effects of Serum Cholesterol on Severity of Stroke and Dosage of Statins on Functional Outcome in Acute Ischemic Stroke. Neurol India 2023;71:923-7
How to cite this URL:
Shridharan P, Nair R, Gorthi SP, Prakashini K, Chatterjee A. Effects of Serum Cholesterol on Severity of Stroke and Dosage of Statins on Functional Outcome in Acute Ischemic Stroke. Neurol India [serial online] 2023 [cited 2023 Oct 19];71:923-7. Available from: https://www.neurologyindia.com/text.asp?2023/71/5/923/388115

Stroke is one of the leading causes of mortality and morbidity.[1] More than half of stroke survivors have residual deficits and are left with permanent disabilities, making them dependent on others for activities of daily living.[2] Due to improved healthcare facility and knowledge, there is increase in the post-stroke survival,[3] which demands for an effective treatment and secondary prevention of stroke.

Studies have shown that lower cholesterol levels are consistently been found to be strongly associated with lower risks of coronary artery diseases but not with lower risks of stroke.[4],[5],[6] However, the use of statins for secondary prevention of stroke is well established and previous studies support this[4],[7] Few studies have shown possible neuroprotective effects of statins.[8],[9] The neuroprotective property may enhance the recovery of central nervous system post stroke. The recommended dosage of statins post stroke is not clearly defined. But, few studies have concluded higher dose of statins is associated with reduction in recurrence rate of major stroke and better functional outcome.[5],[10],[11] However, the tolerability and side-effects are a major concern specially in Indian population. This concern is due to lower body mass index and relatively common polymorphisms of pathways (i.e., CYP 3A4 and C19) for statin metabolism, which increases the possibility of potential adverse side-effects.[12]

Pharmacokinetic studies suggest that Indians achieve higher levels of circulating statins compared to the Caucasian population when administered comparable doses.[13] The higher doses of statins equivalent to atorvastatin 80 mg is mostly not well tolerable in Indian population, leading to discontinuation of treatment.

The primary goal of this study was to see the effect of serum cholesterol levels on severity of stroke measured by the infarct volume and effect of dosage of statins on functional outcome following acute ischemic stroke in Indian population.

  Methodology 

This retrospective observational study was conducted in KMC Hospital Manipal, Karnataka, India. In this study, we included patients admitted in Department of Neurology, KMC Hospital Manipal between 2016 and 2018. Ethics approval is obtained 10th April 2019, IEC 307/2019.

Inclusion criteria

Patients who were presented within 7 days following an acute ischemic stroke in the anterior circulation territory, those who had a power of MRC grade 3/5 or less in the hemiplegic upper extremity at presentation.

Exclusion criteria

Patients with hemorrhagic stroke and stroke involving the vertebral-basilar circulation were excluded.

Cases were defined as per WHO definition of stroke. Hypertension was considered according to JNC 8 guidelines or if there was a history of hypertension or on antihypertensive medication, likewise diabetes, and history of smoking, harmful alcohol consumption was considered according to the standard guideline. Cardiac disease was considered if there was a history or electrocardiogram/echocardiogram showing evidence of the same. All the patients included in the study underwent a CT scan of the brain, followed by MRI brain. Infarct volume was calculated by using 3D slicer tool. The volume of ≤70 ml was considered as small and >70 ml considered as large stroke.

Data entry and statistical methods

Data was entered into Microsoft Excel and statistical analysis was carried out in SPSS software version 17.0. Qualitative variables were presented as frequency and percentages. Quantitative variables were presented as mean (standard deviation) or median (range) depending upon the distribution of data. Bar diagram and pie charts were used for graphical representation of data.

mRS categories on day 7 and day 90 were compared with statin dose (low dose vs. high dose) using Chi-square test. Also, mean difference (increase or decrease) in MRS score between day 7 and day 90 based on statin dose was assessed using Independent t-test. Similarly, A P value of less than 0.05 was considered as statistically significant.

  Result 

We included 100 consecutive patients admitted to the ward who fulfilled the inclusion criteria. There were 60 (60%) males and 40 (40%) females. Most of our patients belonged to the age group of 50-79 years. Hypertension was present in 52 (52%), and Type 2 diabetes mellitus was present in 24 (24%) patients. Thirty-two patients had cardiac co-morbidity (32.0%), out of which 18 (18.0%) had atrial fibrillation. Known smokers were 20 (20.0%) patients, hyperlipidemia was present in 65 (65.0%) patients [Table 1].

Infarct volume on MRI of >70 ml, considered as a large volume was seen in 23 (23.0%) patients. In the remaining 77 (77.0%) patients, a small infarct volume of 70 ml was seen. On comparing the serum cholesterol levels with infarct volume, patients who had lower volume of ≤70 ml had higher mean serum total cholesterol concentration (223.83 mg/dl) when compared to patients with infarct volume of >70 ml (218.70 mg/dl) [Table 2].

The patients were divided into two categories, those who received low dose (≤20 mg) versus those who received high dose (≥ 40 mg equivalent) of Atorvastatin. A total of 45 patients received low dose statin when compared to 55 patients who received high dose [Figure 1].

The functional independence was measured by mRS and at baseline (on day 7) score of ≤3 was present in 74 (74%) patients and 26 (26%) patients had mRS score >3. At 90 days, the functional independence improved, and 88 patients had mRS score ≤3, 12 patients had mRS score >3 which includes 4 patients who died within 90 days post stroke [Figure 2].

Figure 2: Distribution of patients based on the mRS on day 7 and day 90 following acute ischemic stroke

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On comparing the mRS values at baseline and on day 90 between the two groups, there was no statistically significant difference between [Table 3] and [Table 4]. However, when the mean reduction in the mRS values between the two groups were compared, there was a statistically significant reduction (p = 0.045) in mRS of patients receiving high dose versus low dose. Also, better functional outcome was observed in patients who received a higher dose [Table 5] and [Figure 3].

Table 3: Comparison of mRS score in patients with low dose (≤20 mg of atorvastatin) versus high dose (≥40 mg of atorvastatin) at day 7

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Table 4: Comparison of MRS score in patients with low dose (≤ 20 mg of atorvastatin) versus high dose (≥40 mg of atorvastatin) at day 90

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Table 5: Mean difference in MRS Score with low dose (≤ 20 mg of atorvastatin) versus high dose (≥40 mg of atorvastatin)

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  Discussion 

In this study, we evaluated the relation between serum cholesterol levels and severity of stroke by comparing the mean cholesterol levels with infarct volume. It was also evaluated whether the dosage of statin has prognostic value by comparing the functional outcome at 3 months with the patient's statin dose.

Of the 100 patients admitted with acute ischemic stroke in anterior circulation with hemiplegic upper limb power of at least MRC ≤3, number of males were 60%, mostly belonged to 60-79 years of age. Hypertension was present in 52% of patients and 32% had cardiac co-morbidity, and 11% patients had atrial fibrillation.

Serum cholesterol level and stroke

Hypercholesterolemia—>200 mg/dl (>5.17 mmol/L) was present in 65 patients, cholesterol level of >250 mg/dl (>6.46 mmol/L) was present in 25 patients. Though hyperlipidemia is a known prevalent risk factor for stroke, many trials and studies have failed to show strong association between the two. Previously published studies have given controversial report on how hypercholesterolemia affects stroke and post stroke outcomes.[14] In an earlier study it was reported that elevated levels of cholesterol (>7 mmol/L) were associated with increase in incidence of stroke.[15] Also in clinical trials and registries, it was noted that upto 60% of stroke patients had increased level of cholesterol.[16] This result is comparable with our study, wherein 65% of the study group had the serum cholesterol level >200 mg/dl. However, in the Framingham cohort no connection was found between the levels of cholesterol and the incidence of stroke.[17] Some studies have even reported a protective effect of hyperlipidemia in stroke patients by reducing mortality rates.[18],[19] In a study conducted by Iso et al.[20] the serum cholesterol levels under 4.14 mmol/L (80 mg/dl) were associated with increased risk of fatal intracranial hemorrhage, whereas the levels above 7.23 mmol/L (279.5 mg/dl) increased the risk of death from ischemic stroke.

Here, we also measured the infarct volume and correlated with the serum cholesterol level. There was an inverse relation; with higher infarct volume having low mean cholesterol levels and vice versa. Our study finding is consistent with the study done by Olsen et al.,[21] where 513 patients were evaluated for serum cholesterol levels and severity of stroke measure based on Scandinavian Stroke Scale. This study showed that higher cholesterol level favored development of minor stroke and the post-stroke mortality was inversely related to the total cholesterol. This was explained by higher cholesterol levels that favored the development of small-vessel disease and thereby less severe stroke and associated lower mortality. In a study by Tsuji H, it was concluded that lower total cholesterol level was associated with higher total ischemic stroke mortality in a Japanese general population cohort.[22] Most of the studies in literature on cholesterol and stroke have evaluated the impact of hyperlipidemia on stroke incidence and long-term mortality. But, important factors such as the size, type of stroke, and location of the initial lesions are not systemically evaluated.

Statins and functional outcome

High-dose statins are advised post stroke, even if the baseline lipid profile is within normal limits. The use of high-dose statins is always limited by tolerability, especially in Indian population. In routine practice, we often come across statin dose in post stroke patients varying between 10 and 40 mg Atorvastatin (or equivalent dosage). Here, we evaluated the effects of dose of statins post stroke and functional outcome at 90 days. We compared mRS at day 7 and day 90 with dose of statins (high dose vs. low dose) and mean difference of mRS between day 7 and day 90 between these two groups. There was no statistically significant difference of mRS between the high dose and low dose at day 7 and day 90. However, when we compared the mean fall in mRS between high dose versus low dose from day 7 to day 90, there was statistically significant fall of mRS in patients taking high dose of statins. This finding suggests significantly improved functional outcome in high-dose statin groups.

In a study by Vitturi et al.,[11] a total of 513 patients were included, 96 were without statins, 169 with simvastatin 20 mg, 202 with simvastatin 40 mg, and 46 with high-potency statins. Patients without statins and who presented poor adherence to statin were at increased risk of stroke recurrence and worse functional outcomes, whereas the early onset of statins use was associated with better outcomes. Patients with simvastatin 40 mg and high-potency statins presented the best functional recovery throughout the follow-up. This study is comparable with our study where a higher dose was associated with better functional outcome.

A randomized trial by Tuttolomondo et al.[10] enrolled large artery atherosclerotic acute ischemic stroke into two groups, first group of 22 patients who were treated with atorvastatin 80 mg from admission day until discharge and other group 20 patients who did not receive atorvastatin 80 mg until discharge. At 72 hours and day 7, patients who received Atorvastatin showed significantly lower levels of plasma inflammatory markers, NIHSS score, and mRS. The study concluded that early use of high dose of atorvastatin 80 mg is associated with a better functional and prognostic profile.

In another study by Chróinín DN, statin therapy at stroke onset was associated with improved early and late outcomes.[23] A systematic review by Hong KS concluded that pre-stroke statin use was associated with milder initial stroke severity and good functional outcome. This study also showed that in-hospital statin use was associated with good functional outcome in contrast to statin withdrawal, which was associated with poor functional outcome.[24]

The result of our study can be explained by effect of statins on inhibition of inflammatory activation during the acute phase, immunomodulation, endothelial function-enhancing effects in addition to lipid lowering effect.[25] Neuroprotection and regenerative effect of statin may also explain improved functional outcome of stroke patients on high-dose statins.

  Conclusions 

In this study, we found that serum cholesterol levels are inversely related to the stroke severity. Statins are beneficial in stroke patients; a higher dosage is associated with better functional outcome and survival. The effect is probably not related to statin's lipid lowering property but related to its neuroprotective effects and anti-inflammatory property. Large randomized controlled trials are required to prove the dosage for acute ischemic stroke in consideration with stroke subtypes, ethnicity, and other medical co-morbidities.

Limitation

This is a retrospective, single-center study. There are limited number of subjects in this study. The reason for choosing different strength of statins in different patient is not clear. We have looked into the infarct volume; however, we have not classified different subtype of stroke in this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]