Original Article

Edaravone Citicoline Comparative Study in Acute Ischemic Stroke (ECCS- AIS)

Manish Mittal1, Deepak Goel2, Krishan K Bansal3, Prashant Puri4 1Associate Professor Neurology, 2Professor Neurology, 3Professor Neurosurgery, 4Postgraduate in Department of General Medicine, HIHT University, Swami Ram Nagar, Doiwala, Dehradun Received: 18.01.2011; Revised: 21.09.2011; Accepted: 14.11.2011 Abstract Background: Two new neuro-protective agents, Edaravone and Citicoline were recently found to be beneficial in acute ischemic stroke (AIS). But there is no study to compare these two agents on same protocol in AIS. This study was aimed to compare these two neuroprotective agents in AIS. Methods: All patients of age more than 18 years who presented within 24 hours of acute ischemic stroke were randomly treated with Edaravone (group E), Citicoline (group C) or none (group N) with other standard treatment of AIS. Modified Rankin Scale (MRS) and National Institute of Health Stroke Scale (NIHSS) were recorded on admission and at 3 months. Analysis was done using Anova t test to find out significant difference in outcome at 3 months. P value of 0.05 was labeled as significant. Results: Mean MRS and NIHSS scores at 3 months were lowest in group E (p=0.000), suggestive of better outcome in this group. After application of severity scale, 15 patients (68.1%) in group-E, 14 (58.3%) in group C and 18 (72%) in group N had moderate to severe stroke (NIHSS of more than 10). When the patients of moderate to severe stroke were analyzed separately at 3 months, patients in group E (mean 4.463.52) had significantly (p=0.00) better outcome in comparison to group C (mean 10.287.93) and group N (mean 9.386.44). Conclusions: Edaravone was found to be associated with better neurological outcome at 3 months. Citicolines role as a neuroprotective agent however remains controversial in acute ischaemic stroke. Introduction Acute Ischemic stroke (AIS) is a neurological emergency and requires early intervention to limit the neuronal injury. Despite tremendous efforts in stroke research and significant improvements in stroke care within the last decade, current therapy is still insufficient. The only approved treatment for AIS is intravenous recombinant tissue plasminogen activator (t-PA; alteplase) that effectively recanalizes the occluded vessel and improves neurological outcome.1 Hospital management for first 24 hours of AIS include thrombolysis therapy, temperature control, blood

sugar control, blood pressure management, controlling raised intracranial pressure (ICP) and neuroprotective agents.2 Out of these, thrombolysis is possible only within first 3 hours of AIS or can be extended up to 4.5 hours. Data around the world suggest that even at the best centers with all facilities of transportation, only few patients could reach for thrombolysis. The latest audit from one European study highlights that only 39% of patients were admitted to the hospital within the first 2 hours and only 9% could be thrombolyzed.3 Delay in reaching hospital and early access to scanning facilities, hinders AIS care. In developing countries like India thrombolysis is not possible in majority of patients, due to lack of infrastructure and high cost required for thrombolytic therapy in AIS.4 Thus for patients who reach after 3 hours of AIS only supportive treatment is offered. This creates the scope for the use of adjuvant therapy which may help to improve stroke outcome. Recently two neuroprotective agents were marketed and popularized to play a big role in improving neurological outcome in cases of AIS. First agent is Edaravone, a novel free radical scavenger, demonstrating neuroprotective effects by inhibiting vascular endothelial injury and ameliorating neuronal damage. It also has potent free radical quenching and antioxidant action. A placebo controlled trial found better outcome with Edaravone in AIS patients.5 The second agent is Citicoline. Citicoline is an agent that appears to stabilize membranes and has been used in several clinical studies. One meta-analysis reported that patient with moderate to severe stroke might be helped if Citicoline was started within 24 hours of onset of symptoms.6 No previous study has compared Citicoline and Edaravone in patients of AIS. Thus, we conducted this comparative study in acute ischemic stroke (ECCS-AIS). The main objective of this study was to compare the two neuroprotective agents in AIS patients. Methods Consecutive patients of AIS presenting after 3 hours but within 24 hours to our hospital were enrolled during 2008-09. After a written informed consent from patient of AIS or their legally accepted representative, patients were randomized using random number table into three groups based on digit ending with 1-3, 4-6 and 7-9. The first group was given Citicoline (C), second Edaravone (E) and third control group (N) was not given any neuroprotective agent and only given supportive care. Clearance from the institutional ethics committee was obtained. Patients of cerebral infarction with age more than 18 years, who presented within 24 hours of first neurological symptom to our hospital, were included in our study. Patients with hemorrhagic stroke and recurrent stroke were excluded. Disability Score Detail clinical parameters were recorded on a printed case record form. Two grading scales were used to define neurological deficit. They were the Modified Rankin Scale (MRS) (Table 1) and National Institute of Health Stroke Scale (NIHSS) (Table 2). MRS and NIHSS score on admission were compared from follow-up score at 3 months. NIHSS less than 10 was defined as mild stroke and more than 10 as moderate to severe stroke. Drug and Doses

The first group was treated with Edaravone (Group-E), second with Citicoline (Group-C) and third group i.e. control group with neither agent (Group-N). Edaravone in dose of 30 mg 12 hourly as intra-venous infusion over 60 minutes for 14 days and parenteral/oral Citicoline 500 mg twice daily for 6 weeks was given. These are the standard recommended doses. Outcome was assessed based on recovery in patients MRS and NIHSS at 3 months.

Analysis Statistical analysis was performed with SPSS software version 11. Test for normality was done using Kolmogorov-Smirnov test. It was an intent to treat analysis. Change in MRS and NIHSS score at 3 months between groups was evaluated with the help of Anova t test calculation.

Results A total of 279 patients were enrolled during the study period. Among all the patients, only 98 (35%) patients could reach the hospital within 24 hours of the symptoms. Among the patients who got admitted within 24 hours, 8 (8%) patients had multiple attacks and thus not enrolled. The remaining 90 (92%) patients were distributed to group E, C and N i.e. Edaravone, Citicoline and control group respectively. Six patients (20 %) in group E, 3 (10%) in group C, and 3 (10%) in group N were not traceable on follow-up and were excluded from the study. Finally 24 patients in group E, 27 in group C and 27 in group N were analyzed for outcome measures at 3 months. Two patients (6.7%) in group E, 3 (11.1%) in group C and 2 (6.7%) in group N expired during treatment. Finally 22, 24 and 25 patients were analyzed in group E, C and N respectively. Test of normality showed normal distribution of the data. Patients in all 3 groups were matched for age, gender, underlying diseases (hypertension, diabetes and cardio-embolic stroke cases) and MRS/NIHSS at the time of admission. An almost equal number of patients had anterior circulation (middle and anterior cerebral arteries) and posterior circulation (Vertibro-basillar and posterior cerebral arteries) stroke in each group. Dominant lobe involvement was also the same in all three groups. Details of these finding are given in Table 3. Mean MRS and NIHSS scores at 3 months were lowest in group E (p=0.000), suggestive of better outcome in this group (Table 4). After application of severity scale, 15 patients (68.1%) in group-E, 14 (58.3%) in group C and 18 (72%) in group N had moderate to severe stroke (NIHSS of more than 10). When the patients of moderate to severe stroke were analyzed separately at 3

months, patients in group E (mean 4.463.52) had significantly (p=0.00) better outcome in comparison to group C (mean 10.287.93) and group N (mean 9.386.44). Discussion Our results showed that Edaravone therapy is associated with significantly better outcome at 3 months in patients of AIS, when compared with Citicoline and control group. Our results are similar to other study that has shown no advantage with Citicoline in AIS.7-9 One study found that Citicoline can be useful in moderate to severe stroke,6 but our results did not show similar findings. In our study, even in patients with moderate to severe stroke, only Edaravone was associated with significant improvement. Moreover, practical advantages with Edaravone over Citicoline include, that it can be used up to 72 hours of onset of symptoms and has shorter duration of treatment i.e 2 weeks. But the disadvantage of Edaravone is its availability only as an intravenous therapy.

The possible explanation for why Edaravone had a better outcome is that it has a double impact on improving neuronal injury through: (a) membrane stabilization and (b) protection from free `radicals; while Citicoline primarily effects membrane stabilization. During the ischemic cascade, highly reactive free oxygen radicals that occur mainly in the reperfusion period of ischemia cause an excessive activation of excitatory amino acid receptors. Free radicals also act as toxic triggers for inflammation and apoptosis that further damage the ischemic brain.10 Thus, scavenging these free radicals reflects a possibly pathophysiologically oriented neuroprotective approach. Indeed as hypothesized, free radical scavengers were shown in numerous experimental studies to be neuroprotective.11 Primary objective of our study was to compare efficacy of two neuroprotective agents for patients who could not receive thrombolysis for AIS and presented to hospital > 3 hours but < 24 hours after the first onset of symptoms. The timing of hospital admission is very important in AIS patients. Nearly 1/3rd (35%) of our patients were admitted within 24 hours but only few patients could reach in 3 hours window period. Even these patients could not be thrombolysed because of high cost and poor availability of alteplase. This finding indicates towards a poor scope of thrombolysis therapy in our setup. In another study from India about 20% of patients reached hospital within 3 hours but none were thrombolyzed.4 Thus, if a patient of AIS reaches the hospital after 3 hours of first symptoms, all efforts are best directed towards those therapies that can limit the neuronal injury. The identification of the pathophysiological key events that contribute to the development of infarction led to studies mainly targeting single mechanisms of injury. The encouraging results of

the recent Stroke-Acute- Ischemic NXY-Treatment (SAINT) I trial have led to much enthusiasm in attempting neuro-protection.12 Therefore, many neuroprotective agents were studied in acute ischemic stroke (AIS) patients to improve outcome.2 Medications that limit the cellular effects of acute ischemia or reperfusion may limit neuronal injury after AIS. Potential therapeutic strategies have been targeted towards the effects of excitatory amino acids, intra-cellular activation of proteases, apoptosis, free radical damage, inflammatory responses and membrane repair. Although numerous interventions have shown promising results in experimental studies, most clinical trials testing these therapies have produced disappointing results.2 Results of our study was encouraging, it showed that mean MRS and NIHSS score at 3 months were significantly lower in Edaravone group when it was compared with Citicoline and control group. Even in patients of moderate to severe stroke, Edaravone group outcome at 3 months was significantly better than that of Citicoline and control group. Patients in Edaravone group were seen to have a longer stay in hospital, and although it may be argued, in a study on early supported discharges (ESD) a better outcome was seen at 3 months in a randomized controlled trial,13 this factor does not appear to have affected our study outcome. The limitations in our study were as follows: firstly, there was loss of a large proportion of patients on follow-up. Secondly this study is not a double blind study. The third limitation in our study was that cost effectiveness between the two therapies was not compared, which in countries with limited available resources to patients like India, is a major factor in determining therapy. Therefore we feel there is need for a large double blind randomized controlled trial to help confirm our results, which is also able to illuminate the financial salability of this approach. In summary, our study suggests that patients, who cannot be thrombolyzed in time in Acute Ischeamic Stroke, can be helped with Edaravone therapy to minimize neuronal injury and for a better outcome on follow up. References 1. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581 1587. 2. Adams HP, Zoppo GD, Alberts MJ, Bhatt DL. Guidelines for the early management of adults with ischemic stroke. Circulation 2007;115:478-534. 3. Rebecca L. An acute need for better stroke care. Lancet Neurology 2007;6:1. 4. Nandigam K, Narayan SK, Elangovan S, Dutta TK, Sethuraman KR, Das AK. Feasibility of acute thrombolytic therapy for stroke. Neurology India 2003;51:470-73. 5. Eiichi Otomo. Effect of a Novel Free Radical Scavenger, Edaravone (MCI-186), on Acute Brain Infarction. Cerebrovasc Dis 2003;15:222-229. 6. Davalos A, Castillo J, Alvarez-Sabin J, Secades JJ, Mercadal J, Lopez S, Cobo E, Warach S, Sherman D, Clark WM, Lozano R. Oral citicoline in acute ischemic stroke: An individual patient data pooling analysis of clinical trials. Stroke 2002;33:28502857. 7. Clark WM, Warach SJ, Pettigrew LC, Gammans RE, Sabounjian LA. Citicoline Stroke Study Group. A randomized dose-response trial of citicoline in acute ischemic stroke patients. Neurology 1997;49:671678.

8. Clark WM, Williams BJ, Selzer KA, Zweifler RM, Sabounjian LA, Gammans RE. A randomized efficacy trial of citicoline in patients with acute ischemic stroke. Stroke 1999;30:25922597. 9. Clark WM, Wechsler LR, Sabounjian LA, Schwiderski UE. Citicoline Stroke Study Group. A phase III randomized efficacy trial of 2000 mg citicoline in acute ischemic stroke patients. Neurology 2001;57:15951602. 10. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischemic stroke: An integrated view. Trends Neurosci 1999;22:391397. 11. Green AR, Ashwood T. Free radical trapping as a therapeutic approach to neuroprotection in stroke: Experimental and clinical studies with NXY-059 and free radical scavengers. Curr Drug Targets CNS Neurol Disord 2005;4:109118. 12. Lees KR, Zivin JA, Ashwood T, Davalos A, Davis SM, Diener HC, Grotta J, Lyden P, Shuaib A, Hardemark HG, Wasiewski WW. NXY-059 for acute ischemic stroke. N Engl J Med 2006;354:588600. 13. Hankey GJ, Langhorne P. Services for Reducing the Duration of Hospital Care for Acute Stroke Patients. Stroke 2006;37:276-277.