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The effect of citicoline on stroke: A comparative study from the Eastern part of India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.166538
Background: Citicoline is a novel neuroprotective agent used in acute stroke with a significantly favorable outcome. Keywords: Citicoline; India; neuroprotective agent; stroke
Stroke is one of the major causes of death and disability in India. The estimated adjusted prevalence rate of stroke is 84–262/100,000 in the rural and 334–424/100,000 in the urban areas. The incidence rate is 119–145/100,000 based on the recent population-based studies.[1],[2] There are also wide variations in the case fatality rates with the highest being 42% in Kolkata.[3] A higher percentage of hemorrhagic strokes (19–46%) have been reported in most of the South Asian studies compared with Western countries, probably due to an increased prevalence and poor control of hypertension. The prevalence of intracerebral hemorrhage (ICH) is especially high in younger patients (15–45 years of age).[4] The primary aim in the acute management of stroke is to improve the stroke outcome through improved early emergency treatment and acute intervention. Thrombolytics in ischemic stroke, blood pressure regulation and control of intracranial pressure are the major therapeutic approaches. In the recent years, several novel agents, also called 'neuroprotective agents' have been tried in the management of stroke with the proposed objective of correcting the altered brain metabolism that is present as a consequence of the acute stroke.[5],[6] One of these new drugs, which may have the combined advantage of neurovascular protection and as well as the ability to carry out repair, is citicoline. Citicoline is an exogenous form of cytidine-5'-di phosphocholine, which is an essential intermediate in the generation of phosphatidylcholine and is essential for the biosynthesis of membrane phospholipids (which is degraded during brain ischemia to fatty acids and free radicals).[7] In addition, citicoline has been shown to restore the activity of mitochondrial ATPase and membrane Na+/K+ ATPase, to inhibit the activation of phospholipase A2, and to accelerate the reabsorption of cerebral edema in various experimental models. Citicoline, thus, acts at several levels of the ischemic cascade, and its ability to conduct repair of the brain at several levels, has been reported.[8],[9] The International Citicoline Trial on Acute Stroke (ICTUS), which was an international, multicenter, prospective, double-blind, randomized, placebo-controlled trial with participation of neurology services from 37 centers in Spain, 11 in Portugal, and 11 in Germany showed that the global recovery at 90 days was similar in patients who received citicoline and in those who received a placebo. The ICTUS trial stated that that administration of citicoline was safe but did not provide evidence that it is efficacious in the treatment of moderate-to-severe acute ischemic stroke.[10] A single clinical trial (FI-CDPc-HIC), which is a pilot, double-blind, randomized, placebo-controlled trial, has used citicoline in patients with hemorrhagic stroke. In this trial, citicoline was found to be a safe and an effective pharmacological product in patients with acute hemorrhagic stroke, and was recommended to be used in patients with an acute stroke even before radiological images have been obtained to differentiate between an ischemic or a hemorrhagic stroke.[11] In this study, the efficacy of citicholine in the management of acute ischemic and hemorrhagic stroke in a population from the Eastern part of India is being evaluated.
The present study was conducted in the Department of Medicine, College of Medicine and JNM Hospital, West Bengal University of Health Sciences, (COM and JNMH, WBUHS) Kalyani, West Bengal and at the Department of Neuromedicine, Calcutta National Medical College, Kolkata for a period of 1-year from January 2014 to January 2015, after getting clearance from the Institutional Ethics Committee. Consecutive stroke patients, both ischemic and hemorrhagic, in whom the presence of stroke had been established by a computed tomographic (CT) scan of the brain, and who presented to the hospital within 48 h of onset of the stroke were enrolled in the study. Critically ill patients with other systemic diseases, those with end-stage renal disease or advanced hepatic disease, those having the presence of a psychiatric illness, those suffering from a recurrent stroke or a severe cardiovascular disease associated with arrhythmias or transient ischemic attacks were excluded from the study. After the exclusion criteria had been assessed in each patient, a written informed consent (in the local language) in a specified form was taken from the patients themselves or their legal guardians (in the case of unconscious patients). Only those, who gave consent, were enrolled in the study. The selected 100 patients, were randomized, and one group was treated with citicoline along with standard stroke management. These patients were taken as the 'case' group. The other group, where the patients were treated utilizing the standard protocol of management of stroke without the administration of citicoline, was taken as the 'control' group. Treatment protocol and follow-up All the cases were treated with intravenous infusion of citicoline 1000 mg twice daily for 5 days followed by oral citicoline 500 mg twice daily for the next 25 days (the entire treatment was continued for 30 days). Medications like antihypertensives, osmotic diuretics, lipid-lowering agents, statins, and whereever necessary, antiplatelets agents like aspirin or clopidogrel, were given to both cases and controls. No patient received intravenous thrombolysis in our study. The follow up screening of the neurological status in these patients was conducted at the end of the 1st month and also at the end of the 3rd months following the commencement of therapy for the stroke. Assessments Baseline assessments The age and sex of each patient were recorded and information was collected on the following demographic variables: history of hypertension, diabetes or dyslipidemia; previous history of stroke; and, a family history of cardiovascular and cerebrovascular diseases. The information collected on CT scan findings included assessment regarding the type and location of the stroke. The severity of stroke was assessed by the National Institute of Health Stroke scale (NIHSS). Although, NIHSS is traditionally used to assess the severity of ischemic stroke and the (intracerebral hematoma) ICH score is used for the intracranial hemorrhagic stroke assessment, we used the former tool (NIHSS) for evaluation of the severity of hemorrhagic stroke also in this study for facilitating the statistical calculations as well as for a better comparison between the two types of stroke. Assessment of outcome The primary outcome this study was the 'functional outcome' determined by the Barthel Index score (BI) at the end of the 1st month and the 3rd month following the commencement of therapy for stroke. For the primary assessment, BI was categorized into six strata as death, 0, 1–40, 41–60, 61–84, and 85–100. Statistical analysis was done to determine if there were significant differences between the two groups (case vs. controls) in the distribution of patients in these six specified strata and to assess the difference, if any, in the incidence of mortality between the two groups at the end of the 1st month and 3rd month after the onset of stroke. SPSS version 20 (IBM, Chicago, IL, USA) was used to perform the statistical analysis. Statistical significance was set at P < 0.05.
The mean age was found to be 64.02 years in the control group and 60.04 years in the case group, respectively (P > 0.05). The highest incidence of stroke was observed in the age group 51–60 years in the case group (15 patients) where citicholine was administered; and, in the age group 61–70 years in the control group (24 patients). The male:female ratio in the series was found to be 3:2. Of the 100 patients, 63% were diagnosed to be having an ischemic stroke, and 37% a hemorrhagic one. Among the two groups, the citicoline group had an ischemic stroke in 28/50 (56%) and hemorrhagic stroke in 22/50 (44%) patients, whereas the control group had ischemic stroke in 35/50 (70%) and hemorrhagic stroke in 15/50 (30%) patients. The incidences of patients having a stroke involving either the right or the left hemisphere were 58% and 42%, respectively. Among the 100 patients, 36 patients (36%) were hypertensive (44% in the control vs. 28% in the case group). Diabetes was observed in 11% (8% in the control vs. 14% in the case group) patients. Dyslipidemia was detected in 12% (10% in the control vs. 14% in the case group) patients. Of the 36 hypertensive patients, 29 patients were getting amlodipine (5 mg/day), 16 telmisartan (40 mg/day), 6 losartan (50 mg/day), and 4 metoprolol (50 mg/day). Twenty-one patients were getting more than two antihypertensive medicines. Most of the hemorrhagic stroke patients (23 out of 37) had a history of missed doses of their medications or of self-discontinuation of their treatment. Among the 11 diabetic patients, 3 were getting an injection of human insulin and the rest were on oral hypoglycemic agents. Amongst them, the combination of glimepiride and metformin was the most frequently prescribed medication. The baseline characteristics of the patients are shown in [Table 1].
Distribution of BI in different categories, and the mean BI scores of all groups at the 1st month of follow-up and the 3rd month of follow-up are charted in [Table 2]. Distribution of the categorical and mean BI scores of patients both in the case and control groups having either an ischemic or a hemorrhagic stroke at the 1st and 3rd month of follow-up are listed in [Table 3] and [Table 4], respectively.
The mean BI score in the citicoline treatment group and in the control group at the 1st and at 3rd month, respectively, were 43.86 ± 28.3 versus 26.76 ± 16.08 (P ≤ 0.001) and 66.88 ± 34.8 versus 46.8 ± 27.3 (P = 0.002). Analysis of the categorized BI score showed that there was a significant difference in the number of patients in the categorized BI score (85–100) (at the 1st month of follow-up: 0% in control vs. 7% in case group [P < 0.05]; and, at the 3rd month of follow-up: 10% in control vs. 36% in citicoline case group [P < 0.05]). In subgroup analysis, both patients suffering from an ischemic or a hemorrhagic stroke (belonging to all categories of the BI score) in the citicoline treatment group showed a significantly higher mean BI score at the end of the 1st month (ischemic: P = 0.003, hemorrhagic: P = 0.04) and also at the end of the 3rd month (ischemic: P = 0.03, hemorrhagic: P = 0.03). An analysis of the categorized BI score (85–100) at the end of the 3rd month in both the hemorrhage as well as the ischemic subgroups showed a significant incidence of improvement in the citicoline-administered case group compared with the control group (hemorrhagic-- control: 6.66% vs. case: 31.81%, P < 0.05 and ischemic-- control: 11.41% vs. case: 35.71%, P < 0.05).
A statistical analysis of the two groups showed that the baseline characteristics, including all those factors considered important for prognostication, were distributed evenly among the case and the control groups. There was no significant difference noted in the patients' age, sex, incidence of hemisphere involved by stroke, time of initiation of treatment, preexisting medical conditions, and the baseline NIHSS (18.5 ± 11.18 vs. 18.38 ± 11.47, P = 0.95). The incidence of mortality was equal in both groups of patients. The mean BI scores of all categories at the 1st and 3rd month, respectively, were significantly higher in the citicoline treatment group. An analysis of the categorized BI score showed that there was a significant difference in the number of patients in the categorized BI score (85–100) between the two groups, showing a much higher score in the citicholine administered group both at one and three monthly follow up. In subgroup analysis, both types of patients, those suffering from an ischemic as well as those from a hemorrhagic stroke (including all categories of the BI score) in the citicoline-treated case group showed a significantly higher mean BI score at the end of the 1st month (ischemic: P = 0.003, hemorrhagic: P = 0.04) and also at the end of the 3rd month (ischemic: P = 0.03, hemorrhagic: P = 0.03). Analysis of patients in the categorical BI score (85–100) at the end of the 3rd month, of both hemorrhage and ischemic subgroups, showed a significantly higher score in the citicholine treated group (both in ischemic and hemorrhagic stroke groups). Hence, in our study, we found a tendency towards a favorable outcome and an increased probability of complete recovery following citicoline treatment in all types of strokes. A meta-analysis by Saver (comprising of 10 controlled clinical trials that used citicoline) studied 2279 patients, including those suffering from either an ischemic or a hemorrhagic stroke). It showed the following distribution of the included patients-- ischemic stroke: 1278 (1171 on citicoline vs. 892 controls) and 215 ICHs (107 on citicoline vs. 109 controls). In comparison with the placebo group, the patients treated with citicoline showed a significant reduction in the frequency of death or disability at follow-up (57.0% in the placebo group vs. 67.5% in the control group; odds ratio [OR] 0.64; 95% confidence interval [CI] 0.54–0.77; P < 0.001). The safety analysis showed no adverse effects of citicholine in comparison with the placebo (14.5% vs. 14.0%; OR 0.99; 95% CI: 0.77–1.21; P = 0.94).[12] Our study supports the result of the meta-analysis. Moreover, our data analysis corroborates the results of the ICTUS trial and FI-CDPc-HIC trial. The major limitations of our study are the small sample size; the fact that the study was conducted solely on hospitalized patients; and, that the authors evaluated the outcome themselves, were not blinded to the treatment administered and were involved in the management of the patients.
Treatment with citicoline in patients of stroke, presenting within 48 h of onset, increases the probability of recovery and a favorable outcome at the end of the 1st and the 3rd month in all stroke groups. A large randomized control trial is necessary in near future to support the results of this study. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4]
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