J Crit Rev, Vol 5, Issue 3, 11-14Review Article


IS THERE ANY BENEFIT OF CITICOLINE FOR ACUTE ISCHEMIC STROKE ? SYSTEMATIC REVIEW OF CURRENT EVIDENCES

RIZALDY TASLIM PINZON1, ROSA DE LIMA RENITA SANYASI2

1Neurology Department Faculty of Medicine Duta Wacana Christian University, Yogyakarta, Indonesia, 2Internship Doctor at dr. Efram Harsana Air Force Hospital, Magetan, East Java, Indonesia
Email: drpinzon17@gmail.com

Received: 01 Jan 2018 Revised and Accepted: 03 Apr 2018


ABSTRACT

Two main strategies have been suggested for the treatment of ischemic stroke including reperfusion and neuroprotection. Citicoline is one of neuroprotector agent that commonly used in ischemic stroke. A systematic review of citicoline focusing only on ischemic stroke has not yet performed. This systematic review aimed to identify the effectiveness of citicoline in patients with ischemic stroke history. A systematic research was performed using PubMed and Cochrane Library as the database. Keywords were: “citicoline and stroke”, “citicoline and ischemic stroke”, and “randomized controlled trial citicoline". The inclusion criteria were: (i) the trials conducted between 2007 to 2017, (ii) written in English, (iii) the studies performed in human, (iv) patients had ischemic stroke history, (v) citicoline was the main drug assessed in the study. The exclusion criteria i.e.: (i) the study was not a randomized controlled trial (RCT) and (ii) the full text was not available. The quality of RCT was determined by using Jadad score. A literature search revealed 541 journals from PubMed and Cochrane Library. After screening the title and abstract, adjusting for inclusion and exclusion criteria, adjusting for the irrelevant topic, and duplication the final result was 4 RCT studies. All studies had a good quality, indicated by Jadad score of 3 or more. Three studies conclude that no statistically significant difference in treatment outcome between citicoline and other groups. The last study revealed citicoline is effective in preventing post-stroke cognitive impairment.

Keywords: Systematic review, Citicoline, Ischemic stroke


INTRODUCTION

Stroke is the leading cause of disability and death worldwide [1-3]. There are 2 types of stroke: ischemic stroke and hemorrhagic stroke. The prevalence of ischemic stroke is greater than hemorrhagic stroke. A research on 757 stroke patients conducted by Shiber, et al. (2010) showed the incidence of ischemic stroke is 58.1% [4]. Another research revealed a higher percentage. According to research by Spurthi, et al., the incidence of ischemic stroke is 96% compared to hemorrhagic stroke (4%) [5].

Two main strategies have been suggested for the treatment of ischemic stroke. One treatment strategy is reperfusion. It is for salvaging ischemic tissue and improving functional outcome after ischemic stroke. The other potential approach is neuroprotection strategy. It is trying to impede the ischemic cascade by targeting various components of the cascade that is deemed to be of importance [6].

Neuroprotection acts to limit ischemic injury by preventing the salvageable neurons in the penumbra that surrounds the core from dying, limit infarct size, prolong the time window for thrombolytic therapy, or minimize post-ischemic reperfusion injury or inflammation [7]. Neuroprotective agents including calcium channel blockers, glutamate antagonists, GABA agonists, antioxidants or radical scavengers, phospholipid precursor, nitric oxide signal-transduction down-regulator, leukocyte inhibitors, hemodilution, and a miscellany of other agents. Another promising method for neuroprotection is therapeutic hypothermia, high-dose human albumin therapy, and hyperacute magnesium therapy [8].

A study by Mathew, et al. showed 14.1% from 100 stroke patients was given a neuroprotector and citicoline is the frequently used neuroprotectors [9]. Another study on 60 stroke patients revealed about 7.01% patients were given citicoline [10]. Previous studies on citicoline examined its effectiveness on many conditions i.e.: ischemic stroke, hemorrhagic stroke, traumatic brain injury, and vascular dementia. Each study showed a different result. It may be caused by different drug dosage, route of administration, length of the study, and a number of subjects. Furthermore, it is important in order to measure the quality of each study. Only qualified study could be a consideration on clinical judgement. Systematic review of citicoline focusing only on ischemic stroke has not yet performed. This systematic review aimed to identify the effectiveness of citicoline in patients with ischemic stroke history.

Method

Data sources

This study conducted a search for randomized controlled trial (RCT) of citicoline on ischemic stroke patients. The database was PubMed and Cochrane Library. Keywords were: “citicoline and stroke”, “citicoline and ischemic stroke”, and “randomized controlled trial citicoline". Fig. 1 showed the guideline selection process. It was made based on PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) four-phase flow diagram [11].

Study eligibility criteria, participants, and interventions

The trials that were included meet the following criteria: (i) the trials conducted between 2007 to 2017, (ii) written in English, (iii) the studies performed in human, (iv) patients had ischemic stroke history, (v) citicoline was the main drug assessed in the study. Subjects with an ischemic stroke history (acute ischemic stroke, first ischemic stroke event, recurrent ischemic stroke event, or post-ischemic stroke) were included. The study excluded if: (i) the study was not an RCT and (ii) the full text was not available. Eligibility assessment was carried out independently by two review authors.

Appraisal process

Quality assessment is important while electing research. The quality of RCT was determined by using the Jadad score. The scoring process was conducted by two appraisers independently. Studies were scored according to the presence of randomization, blinding, and reporting of loss to follow up. Jadad score has 5 items. One point is added if the study fulfils each item. Thus the maximum score is 5 [12]. The trials would be excluded if the score was lower than 3.

Review process

The selected studies were examined by two review authors using PRISMA checklist as the guidance. PRISMA checklist consists of 27 essential items to make a transparent systematic review and meta-analysis [11]. One review author extracted data from included studies and the subsequent review author checked the extracted data. Disagreements were addressed by discussion between two review authors. Variables for which data were sought i. e: authors, year of publications, number of subjects, description of drugs, and outcome. The outcome was described in the efficacy of citicoline compared to other drug or placebo, measured by odd ratio (OR), relative risk (RR), or p-value.

RESULTS

A literature search revealed 541 journals from PubMed and Cohcrane Library. Fifty-five journals were removed after screening the title and abstract. After adjusting for inclusion and exclusion criteria, there were 233 journals remained. Of these, 229 discarded because of irrelevant topic and duplication. The final result was 4 RCT studies.

Fig. 1: Study selection process

Table 1 showed the result of Jadad score for each study. All studies had a good quality, indicated by Jadad score of 3 or more. Four studies explained the randomization clearly. Unfortunately, only two studies are described as double-blind. These studies were also reviewed.

Table 2 summarized the selected studies. All selected studies were RCT issued in English within the last 10 y. Three studies focus on citicoline efficacy on ischemic stroke patients outcome. The latest study is the only study focus on citicoline efficacy on preventing a cognitive deficit in post ischemic stroke subjects.

Table 1: Jadad score

Author (Year) Was the study described as randomized? Was the method used to generate the sequence of randomization described and appropriate? Was the study described as double-blind? Was the method of double blinding described any appropriate? Was there a description of withdrawal and dropout?

Total

Score

Davalos, et al. (2012) [13] Yes Yes Yes No Yes 4
Grewal, et al. (2012) [14] Yes Yes No No Yes 3
Mittal, et al. (2012) [15] Yes Yes No No Yes 3
Sabin, et al. (2013) [16] Yes Yes Yes Yes Yes 5

Table 2: Summary of selected studies

Authors (Year) Subjects (n) Mean Age

Intervention

(Lenght of Study)

Outcome
Davalos, et al. (2012) [13] Acute ischemic stroke patients (2298)

Group 1: 72.9

Group 2: 72.8

Group 1: Citicoline 1000 mg every 12 h was administered every 12 h in a 100 ml saline solution bag and infused during 30–60 min during the first 3 d. From day 4 to the end of the treatment period, two 500 mg oral tablets were given every 12 h. In patients with swallowing problems, tablets were dissolved in 30–60 ml of tepid water and administered through a nasogastric tube. Group 2: placebo. (6 w)

Global recovery was similar in both groups

(OR: 1.03, 95% CI 0.86–1.25; p: 0.364). No significant differences were reported in the safety variables nor in

the rate of adverse events.

Grewal, et al. (2012) [14] Ischemic stroke patients (40)

Group 1: 60.65

Group 2: 61.7

Group 1: standard treatment of acute ischemic stroke, i. e antiplatelet, ACEi, statin, decongestif, and anticoagulant (if necessary).

Group 2: citicoline 1 g twice a day IV infusion dissolved in 100 ml normal saline for 7 d in addition standard therapy, followed by citicoline 500 mg twice a day per oral for 8 w (12 w).

Citicoline was found to be safe but with no statistically significant difference in treatment outcome between two groups. Statistically significant (p<0.05) improvement was seen in citicoline group on NIHSS score by 2nd and 3rd d of admission and then on 12th w. No significant improvement was seen on other measures which included mRs and MBI.
Mittal, et al. (2012) [15] Acute ischemic stroke patients (279)

Group 1: 57.36

Group 2: 54.83

Group 3: 55.6

Group 1: citicoline parenteral/oral 500 mg twice daily (6 w).

Group 2: edaravone 30 mg 12 hourly IV infusion over 60 min (14 d).

Group 3: supportive care, not given any neuroprotective agent.

Edaravone was found to be associated with better neurological outcome at 3 mo when compared with citicoline (p: 0.000) and control group (p: 0.000).
Sabin, et al. (2013) [16] First-ever ischemic stroke patients (347) 67.2

Group 1: citicoline oral 1 g/d

Group 2: no citicoline

(12 mo)

Citicoline-treated patients

had statistically significant better outcome in attention executive functions at 6 (p: 0.027) and 12 mo (p: 0.042). and better results in temporal orientation at 6 (p: 0.042) and 12 mo (p: 0.045).

ACEi: Angiotensin Converting Enzime inhibitor; OR: Odd Ratio; CI: Confidence Interval, NIHHS: National Institutes of Health Stroke Scale, mRs: Modified Rankin Scale, MBI: Modified Barthel Index, IV: intravenous

DISCUSSION

Davalos, et al. (2012) conducted a well-known RCT called ICTUS trial [13]. The research focused to confirm the efficacy of citicoline in moderate to severe acute ischemic stroke patients. The total of subjects was 2298, of these 1148 were assigned to citicoline and 1150 to placebo. A total 859 (75%) in the citicoline group and 838 (73%) in the placebo group completed the 90-day follow up.

There were some endpoints i.e.: (i) primary endpoint measured by global test combining three outcome scales: Barthel index, modified Rankin scale (mRs), and National Institute of Health Stroke Scale (NIHSS), (ii) secondary objectives, the rate of favourable response in the single scale (mRs, NIHSS, Barthel index the between-groups comparison of the full distribution of the mRs scores, and the absolute difference in the NIHSS) between baseline and 3 mo, and (iii) safety endpoints included death, serious adverse events, and no serious adverse events. Citicoline safety and tolerability assessed by blood pressure during the first 3 d of treatment and week 1 (or discharge).

Age older than 70 y (p: 0.001), moderate stroke severity (p: 0.021), and patients not treated with rt-PA (p: 0.041) had a more beneficial effect of citicoline. Global recovery at 90 d was the same in both groups. The median unbiased estimate of the adjusted odds ratio of the primary efficacy endpoint was 1.03 (95% CI: 0.86–1.25). The odds ratios were also neutral in the subgroups defined by the minimisation factors. Similar results were reported in the secondary objectives. Those results are expected to a conclusion that citicoline is safe but is not efficacious in the treatment of moderate to severe acute ischemic stroke. This study had a large sample of patients, describe the procedure clearly, including the randomization and blinding. The limitation of this study is no further explanation of placebo (dosage and drug type) and the protocol of administration.

Grewal, et al. (2012) performed a study in 40 acute ischemic stroke patients divided into 2 groups of 20 patients each [14]. Patients were assessed clinically and through neurological examination was done at admission and regularly throughout their hospital stay. Follow up on the patients was done at 3, 6, and 12 w after discharge using NIHSS, mRs, and Modified Barthel Index (MBI).

This study found that citicoline can be administered safely to acute ischemic stroke patients with minimal side effects. In this study, 1000 mg of citicoline given for 8 w significantly improved 12 w recovery as measured on acute assessment scale (p<0.05) in comparison to patients who did not take citicoline. However, no significant improvement was seen on other measures which included mRs and MBI. This study concludes efficacy of citicoline in the treatment of acute ischemic stroke is limited as a neuroprotective agent, but it is very safe drug as per adverse effect profile.

The strength of this study is did a follow up regularly: admission, throughout the hospital stay, discharge, and third, sixth, twelfth week after discharge. This study did not use a single drug as a control group. It may lead to heterogenous and ambiguous result. This study also did not describe the dosage and route of administration of drugs in the control group. Statistical analysis did not perform properly.

A study of two neuroprotective agents was conducted by Mittal, et al. (2012) [15]. The primary objective of this research was to compare the efficacy of edaravone and citicoline on acute ischemic stroke patients. Total of subjects were 279, after adjusting for inclusion and exclusion criteria, remained 71 subjects divided into 3 groups: group E treated with edaravone (22 subjects), group C treated with citicoline (24 subjects), and group N as a control group with neither agent (25 subjects). NIHSS and mRS were utilized to define neurological deficit.

The results showed that edaravone therapy is associated with a significantly better outcome at 3 mo in acute ischemic stroke patients when compared with citicoline and control group. The mean of mRs and NIHSS score at 3 mo were lowest in group E (p: 0.000), suggestive of better outcome in this group. When the patients of moderate to severe stroke were analyzed separately at 3 mo, patients in group E had significantly (p: 0.00) better outcome in comparison to group C and group N. This study summarized edaravone was found to be associated with better neurological outcome at 3 mo. Citicoline’s role, as a neuroprotective agent, however, remains controversial in acute ischemic stroke. This study compares citicoline to another neuroprotective agent. That makes this study superior. Unfortunately, this research did not explain the treatment in group N clearly.

A research by Sabin, et al. (2013) was the only research which focussed on vascular cognitive impairment [16]. Total 347 subjects were selected 6 w after suffering stroke. The objective has assessed the safety of long-term administration and its efficacy of citicoline in preventing a post-stroke cognitive decline in patients with first-ever ischemic stroke.

There were 6 neurocognitive domains assessed in this research. Attention and executive function tests were using Stroop Color Word Interference Test, Trails A and B and Symbol digits Modalities Test, Mental Control, Digit Span Backward and Forward. Memory tests were using Auditory Verbal learning Test and Visual Reproduction (WMS-III). Language tests were using Boston Naming Test (Naming), Verbal Fluency for Animals and Controlled Oral Word Association test, Pseudowords and Sentences Repetition and Token Test. Spatial perception test was using Judgement of Line Orientation. Motor speed tests were using Grooved Pegboard for Dominant and Nondominant Hand. Temporal orientation test was using Benton’s Temporal Orientation.

Citicoline-treated group evidenced less cognitive impairment during the follow-up, reaching statistical significance in the cognitive domains of attention-executive functions at 6 (p: 0.019) and 12 mo (p: 0.014) also temporal orientation at 6 (p: 0.042) and 12 mo (p: 0.050) treatment groups for each neurocognitive function. Logistic regressions models adjusted by risk factors and stroke severity showed that citicoline-treated patients had statistically significant better outcome in attention-executive functions at 6 (OR: 1.721, 95% CI: 1.065–2.781, p: 0.027) and 12 mo (OR: 2.379, 95% CI: 1.269–4.462, p: 0.007). Citicoline-treated patients showed also better results in temporal orientation at 6 (OR: 1.780, 95% CI 1.020–3.104, p: 0.042) and 12 mo (OR: 2.155, 95% CI: 1.017–4.566, p: 0.045).

This research is the first study to demonstrate that citicoline treatment for 12 mo after ischemic stroke is safe and possibly effective in preventing poststroke cognitive impairment. The research was using different tools to measure different neurocognitive functions. It may lead to a specific result of citicoline efficacy on specific neurocognitive function.

Cytidine-5’-diphosphocholine (CDP-choline or citicoline) is an essential intermediate in the synthesis of phosphatidylcholine, a major brain phospholipid [17]. Exogenous CDP-choline is hydrolyzed and absorbed as cytidine and choline, and CDP-choline is resynthesized by CTP-phosphocholine cytidylyltransferase, which is the rate-limiting enzyme in phosphatidylcholine synthesis [18]. The effectiveness of citicoline in acute ischemic stroke may be due to its pleiotropic neuroprotective functions with stabilization of cell membranes, attenuation of glutamate excitotoxicity, oxidative stress, apoptosis, and endothelial barrier dysfunction. Citicoline also modulates neurotransmitter metabolism, enhances neuroplasticity, and activates neurogenesis, synaptogenesis, and angiogenesis [19, 20].

CONCLUSION

There are three researches focusing on citicoline efficacy to acute ischemic stroke patients outcome. The results of those studies conclude that no statistically significant difference in treatment outcome between citicoline and other groups. The last research is the only research focusing on citicoline in preventing post-stroke cognitive decline in patients with first-ever ischemic stroke. This research revealed citicoline is effective in preventing post-stroke cognitive impairment.

AUTHORS CONTRIBUTIONS

All the author have contributed equally

CONFLICT OF INTERESTS

There is no conflict of interest

REFERENCES

  1. Zhou M, Offer A, Yang G, Smith M, Hui G, Whitlock G, et al. Body mass index, blood pressure, and mortality from stroke: a nationally representative prospective study of 212.000 Chinese Men. Stroke 2008;39:753-9.

  2. Toyoda K. Epidemiology and registry studies of stroke in Japan. J Stroke 2013;15:21-6.

  3. do Carmo JF, Morelato RL, Pinto HP, de Oliveira ERA. Disability after stroke: a systematic review. Fisioter Mov 2015;28:407-18.

  4. Fisher M. New approaches to neuroprotective drug development. Stroke 2011;42 Suppl 1:S24-7.

  5. Shiber JR, Fontane E, Adewale A. Stroke registry: hemorrhagic vs ischemic strokes. Am J Emergency Med 2010;28:331–3.

  6. Spurthi T, Gowthami B, Khyathi D, Vinod G. Risk elements and drug utilization in stroke patients. Int J Pharm Pharm Sci 2016;8:290-2.

  7. Fisher M. New approaches to neuroprotective drug development. Stroke 2011;42 Suppl 1:S24-7.

  8. Sutherland BA, Minnerup J, Balami JS, Arba F, Buchan AM, Kleinschnitz C. Neuroprotection for ischaemic stroke: translation from the bench to the bedside. Int J Stroke 2012;7:407-18.

  9. Ginsberg MD. Neuroprotection for ischemic stroke: past, present, and future. Neuropharmacology 2008;55:363-89.

  10. Mathew E, Chandrika C, Karanath PM, Srinivasa R. A prospective observational study on prescribing trends and adverse reaction in stroke patients. Int J Pharm Pharm Sci 2017;9:25-30.

  11. Wagle L, Thomas AA, Shrestha S. Drug utilisation study of stroke and other patients admitted to general ward of neurology unit at the quaternary care private hospital. Int J Pharm Pharm Sci 2017;9:23-8.

  12. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. Br Med J 2009;339:b2700.

  13. Berger VW, Alperson SY. A general framework for the evaluation of clinical trial quality. Rev Recent Clin Trials 2009;4:79–88.

  14. Davalos A, Sabin JA, Castillo J, Tejedor ED, Ferro J, Vila EM, et al. Citicoline in the treatment of acute ischemic stroke: an international, randomized, multicentre, placebo-controlled study (ICTUS trial). Lancet 2012;380:349-57.

  15. Grewal N, Sharma G, Mohan G, Singh J. TO study efficacy and safety of citicoline in acute ischemic stroke. Int J Basic Clin Pharmacol 2012;1:72-6.

  16. Mittal M, Goel D, Bansal KK, Puri P. Edaravone–citicoline comparative study in acute ischemic stroke (ECCS-AIS). JAPI 2012;60:36-8.

  17. Sabin JA, Ortega G, Jacas C, Santamarina E, Maisterra O, Ribo M, et al. Long-term treatment with citicoline may improve poststroke vascular cognitive impairment. Cerebrovasc Dis 2013;35:146-54.

  18. Grieb P. Neuroprotective properties of citicoline: facts, doubts and unresolved issues. CNS Drugs 2014;28:185-93.

  19. Davalos A, Secades J. Citicoline preclinical and clinical update 2009-2011. Stroke 2011;42 Suppl 1:S36-9.

  20. Martynov MY, Gusev EI. Current knowledge on the neuroprotective and neurodegenerative properties of citicoline in acute ischemic stroke. J Exp Pharmacol 2015;7:17-28.

  21. Hurtado O, Lizasoain I, Moro MA. Neuroprotection and recovery, recent data at the bench on citicoline. Stroke 2011;42 Suppl 1:S33-5.

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About this article

Title

IS THERE ANY BENEFIT OF CITICOLINE FOR ACUTE ISCHEMIC STROKE ? SYSTEMATIC REVIEW OF CURRENT EVIDENCES

Keywords

Systematic review, Citicoline, Ischemic stroke

DOI

10.22159/jcr.2018v5i3.24568

Date

01-05-2018

Additional Links

Manuscript Submission

Journal

Journal of Critical Reviews
Vol 5, Issue 3 (May-Jun), 2018 Page: 11-14

Online ISSN

2394-5125

Authors & Affiliations

Rizaldy Taslim Pinzon
Neurology Department Faculty of Medicine Duta Wacana Christian University, Yogyakarta, Indonesia
Indonesia

Rosa De Lima Renita Sanyasi
Internship Doctor at dr. Efram Harsana Air Force Hospital, Magetan, East Java, Indonesia
Indonesia


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