Citicoline for Acute Ischemic Stroke: a Systematic Review and Formal Meta-Analysis of Randomized, Double-Blind, and Placebo-Controlled Trials Julio J

Volume 25 Number 8 August 2016

Reprinted from J Stroke Cerebrovasc Dis. 2016;25(8):1984-96 Citicoline for Acute Ischemic Stroke: A Systematic Review and Formal Meta-analysis of Randomized, Double-Blind, and Placebo-Controlled Trials Julio J. Secades, José Alvarez-Sabín, José Castillo, Exuperio Díez-Tejedor, Eduardo Martínez-Vila, José Ríos and Natalia Oudovenko

9/13/2016 12:17:15 PM

Citicoline for Acute Ischemic Stroke: A Systematic Review and Formal Meta-analysis of Randomized, Double-Blind, and Placebo-Controlled Trials

Julio J. Secades, MD, PhD,* José Alvarez-Sabín, MD, PhD,† José Castillo, MD, PhD,‡ Exuperio Díez-Tejedor, MD, PhD,§ Eduardo Martínez-Vila, MD, PhD,‖ José Ríos, MSc,¶ and Natalia Oudovenko, PhD*

Background: Citicoline is a drug approved for the treatment of acute ischemic stroke. Although evidence of its efficacy has been reported, recently published results of a large placebo-controlled clinical trial did not show differences. This study aims to assess whether starting citicoline treatment within 14 days after stroke onset improves the outcome in patients with acute ischemic stroke, as compared with placebo. Methods: A systematic search was performed to identify all published, unconfounded, randomized, double-blind, and placebo-controlled clinical trials of citicoline in acute ischemic stroke. Results: Ten randomized clinical trials met our inclusion criteria. The administration of citicoline was associated with a significant higher rate of independence, independently of the method of evaluation used (odds ratio [OR] 1.56, 95% confidence interval [CI] = 1.12-2.16 under random effects; OR 1.20, 95% CI = 1.06-1.36 under fixed effects). After studying the cumulative meta-analysis, and with the results obtained with the subgroup of patients who were not treated with recombinant tissue plasminogen activator (rtPA) (OR 1.63, 95% CI = 1.18-2.24 under random effects; OR 1.42, 95% CI = 1.22-1.66 under fixed effects), our hypothesis of dilution of the effect of citicoline was confirmed. When we analyzed the effect of citicoline in patients who were not treated with rtPA and were receiving the highest dose of citicoline started in the first 24 hours after

From the *Scientific Department, Ferrer Group, Barcelona, Spain; †Department of Neurology, Hospital Universitari Vall d’Hebrón, Barce- lona, Spain; ‡Department of Neurology, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain; §Department of Neurology and Stroke Centre, Hospital Universitario La Paz, Madrid, Spain; ‖Department of Neurology, Clínica Universitaria de Navarra, Pamplona, Spain; and ¶Biostatistics and Data Management Core Facility, IDIBAPS (Hospital Clinic), Faculty of Medicine, Universitat Autònoma de Bar- celona, Barcelona, Spain. Received March 15, 2016; revision received April 11, 2016; accepted April 13, 2016. Funding: Ferrer Grupo funded this systematic review and provided the publications, translations, and, if needed, the databases of the available studies. Competing interests: J.J.S. and N.O. are full-time employees of the company funding this research. J.A.S., J.C., E.D.T., and E.M.V. received consultant fees and honoraria from Ferrer as member of the trial steering committee of the ICTUS trial and received honoraria for giving lectures for Ferrer. ICMJE Forms for Disclosure of Potential Conflicts of Interest from all authors are provided. Authors’ contributions: J.J.S. and N.O. reviewed the abstracts of articles retrieved in the search. J.J.S., J.A.S., J.C., E.D.T., and E.M.V. reviewed all retrieved papers to identify those trials meeting the inclusion criteria for the review. J.J.S. and N.O. independently extracted the efficacy data from eligible trials. J.A.S., J.C., E.D.T., and E.M.V. resolved discrepancies through discussion by referencing the original report. J.J.S. and J.R. performed separate analyses. Address correspondence to Julio J. Secades, MD, PhD. Scientific Department, Ferrer Group, Avda. Diagonal 549; 08029 Barcelona, Spain. E-mail: [email protected]. 1052-3057/$ - see front matter © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.04.010

1984 Journal of Stroke and Cerebrovascular Diseases, Vol. 25, No. 8 (August), 2016: pp 1984–1996 CITICOLINE IN ACUTE ISCHEMIC STROKE 1985 onset, based on more recent trials, there was no heterogeneity, and the size of the effect has an OR of 1.27 (95% CI = 1.05-1.53). Conclusions: This systematic review supports some beneﬁts of citicoline in the treatment of acute ischemic stroke. But, on top of the best treatment available (rtPA), citicoline offers a limited beneﬁt. Key Words: Acute ischemic stroke—therapy—neuroprotection—pharmacological treatment—CDP-choline—citicoline—systematic review—meta-analysis. © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Introduction over time was diluted in parallel with improved stan- dards of care for acute ischemic stroke. Despite global and regional health crises, global life ex- For this reason, we decided to perform an exhaustive pectancy has increased continuously and substantially over and systematic search for all double-blind and placebo- the past 40 years.1 This is associated with an increase in controlled clinical trials performed with citicoline worldwide, incidences of age-related diseases, such as ischemic stroke. and to conduct an updated meta-analysis to assess if treat- Stroke is the second leading cause of death in the world, ment with citicoline (started within 14 days after stroke and since 1990, a 26.5% increase in ischemic stroke mor- onset) improves the outcome (measured as a modified Rankin tality has been reported,2 with a parallel increase in the Scale [mRS] score of 0-2 or equivalent) in patients with rates of disability.3,4 acute ischemic stroke when compared with placebo. Only in recent years have advances allowed for relevant improvement in the outcome of this devastating disease. A new era in acute stroke care began in 1995, Methods when it was shown that early intravenous administra- Protocol and Registration tion of recombinant tissue plasminogen activator (rtPA) improved outcome in a carefully selected patient group The present systematic review and meta-analysis are with acute ischemic stroke.5 Together with the use of rtPA,6-9 based on a pre-existing protocol, adapted from a pub- 29 treatment in stroke units (SUs),10 the early use of aspirin,11 lished protocol in The Cochrane Library. The protocol and decompressive surgery12 are recognized as thera- has been submitted and registered at the PROSPERO reg- pies with proven efficacy in the management of acute ister, with registration number CRD42013005070. ischemic stroke. Thus, very early treatment with rtPA in an SU can be considered the gold standard,13 but can only Eligibility Criteria 14 be applied in a qualified center, in developed countries. Clinical trials that were double-blind, randomized, and 15 However, the use of rtPA remains very low in the world, controlled with placebo were included. No restrictions and there are substantial differences in the standard of regarding language, publication date, or publication status 16-20 care for acute ischemic stroke. Obviously, there is an were applied. Only trials in which the active study agent urgent need for available therapeutics for acute stroke. was CDP-choline were included, and trials comparing CDP- Citicoline, or CDP-choline, a drug that combines neu- choline treatment with any other active treatment were 21-23 rovascular protection and repair effects, has been used excluded. to treat acute ischemic stroke and other neurological All trials randomizing patients of any age or sex were 21 24 disorders, with an excellent safety profile. In 2002, a formal included, with index events of ischemic stroke and/or meta-analysis of trials of CDP-choline in acute and sub- presumed ischemic stroke (in studies without neuroimaging), 25 acute stroke suggested a beneficial and substantial treatment and with randomization occurring within 14 days after effect, with absolute reductions of 10%-12% in the rates of stroke onset. This broad treatment time window of 14 long-term death and disability. In a pooled data analysis days was chosen because citicoline may have effects at (PDA), the odds ratio (OR) of complete functional and neu- different stages in the evolution of ischemic brain injury rological recovery in patients with moderate-to-severe acute and repair. No restrictions were applied in regard to doses, ischemic stroke treated with oral citicoline for 6 weeks was route of administration, or duration of treatment. 1.33 (95% confidence interval [CI] = 1.10-1.62) when com- The primary efficacy measure was patient indepen- 26 pared with placebo. A further updated meta-analysis of dence at the end of a scheduled follow-up period. tabulated data confirmed these previous results, with a reduction in death or dependency (OR .65, 95% CI = .54-.77; Information Sources P = .00001; Number Needed to Treat 9.5).27 The recent ICTUS trial28 could not confirm the effica- Studies were identified by searching electronic data- cy of citicoline against placebo as an add-on therapy on bases, scanning reference lists of articles, and consulting top of the best standard of care. Also in the ICTUS trial, with experts in the field and at the drug company (Ferrer it was hypothesized that the beneficial effect of citicoline Group). 1986 J.J. SECADES ET AL. The search was applied to for any possible abstract that met the inclusion criteria - Cochrane Central Register of Controlled Trials were obtained. Five review authors (J.J.S., J.A.S., J.C., E.D.T., (CENTRAL) (The Cochrane Library, latest issue); and E.M.V.) reviewed all retrieved papers to identify those - MEDLINE (1966 to present); trials that met the inclusion criteria for the review. - PubMed (1940s to present); - Embase (1974 to present); Data Extraction and Management - Internet Stroke Center (stroke trials registry); and - National Institute of Health (ClinicalTrials.gov). Two review authors (J.J.S. and N.O.) independently ex- Also, an exhaustive search on the Internet and in the tracted the efficacy data from eligible trials. These review bibliographic database of Ferrer Group was performed authors resolved discrepancies through discussion with to detect studies published in journals that were not other authors (J.A.S., J.C., E.D.T., and E.M.V.) and by ref- indexed or included in databases. erencing the original report.

Search Strategy Data Items The following search strategy for MEDLINE was used The primary efficacy measure was patient indepen- and modified for the other databases when necessary. dence at the end of the scheduled clinical trial follow- MEDLINE up. If available, the mRS was used for this measure (mRS score of 0-2). In studies where the mRS measure was not 1) cerebrovascular disorders/ or basal ganglia cere- available, we used the most comprehensive measure of brovascular disease/ or exp brain ischemia/ or disability or handicap available from the trial. carotid artery diseases/ or carotid artery thrombosis/ The information was checked for the doses used, the or intracranial arterial diseases/ or cerebral arte- route of administration, and the duration of treatment rial diseases/ or exp “intracranial embolism and with CDP-choline. thrombosis”/ or stroke/ or exp brain infarction/ or cerebral infarction/ 2) ((maintain ischaemic or ischemic) adj5 (stroke$ or Assessment of Risk of Bias in the Included Studies apoplex$ or cerebral vasc$ or cerebrovasc$ or cva)).tw. The methodological quality of the selected studies was 3) ((brain or cerebr$ or cerebell$ or vertebrobasil$ or assessed using The Cochrane Collaboration’s tool for as- hemispher$ or intracran$ or intracerebral or sessing the risk of bias.30,31 Each of the following points infratentorial or supratentorial or middle cerebr$ was scored as “yes,” “no,” or “unclear” (where “yes” in- or mca$ or anterior circulation) adj5 (isch?emi$ dicates that the study is less open to bias): or infarct$ or thrombo$ or emboli$ or occlus$ or hypoxi$)).tw. 1) Method of randomization (selection bias) 4)1or2or3 2) Concealment of allocation (indication bias) 5) CDP-choline or cytidine diphosphate choline or 3) Blinding of investigators and patients (perfor- citicoline mance bias) 6) (choline or (cytidine adj5 diphosphocholine) or cy- 4) Blinding of outcome assessment (detection bias) tidine diphosphate choline or CDP-choline or 5) Adequate follow-up (attrition bias) citicoline or citicholine or cyticholine or cidifos).tw. 6) Other possible bias 7)5or6 Based on these criteria, we divided the studies into the 8) 4 and 7 following 3 categories: 9) limit 8 to humans • A—all quality criteria met: low risk of bias, The search in Cochrane CENTRAL, Clinicaltrials.gov, • B—one or more of the quality criteria only partly and Internet Stroke Center was performed using the term met: moderate risk of bias, and “CDP-choline” or “citicoline.” The broad search on the • C—one or more criteria not met: high risk of bias. Internet and PubMed was performed using the term “CDP- To avoid selection bias, only studies categorized as C choline OR citicoline OR cytidine-5′-diphosphocholine OR were rejected. Other studies not included were those per- cytidine-5′-diphosphate OR citicholine OR citocoline OR formed for other indications, such as hemorrhagic stroke citocholine.” The search in the bibliographic database of and those not reporting independence as an outcome. the Ferrer Group was performed using the terms “CDP- choline or citicoline and stroke.” Measures of Treatment Effect Dichotomous statistical meta-analytic methods were used, Selection of Studies and the Mantel–Haenzel method was applied for the es- Two review authors (J.J.S. and N.O.) reviewed the ab- timation of OR in fixed effects and DerSimonian–Laird stracts of articles retrieved in the search. Full-length papers for random effects to calculate the global treatment effect. CITICOLINE IN ACUTE ISCHEMIC STROKE 1987 Data Synthesis alistic estimation of the effect of citicoline when compared to the most usual acute care. Another additional analy- The formal meta-analysis was performed using the rmeta sis was based on patients not treated with rtPA and who packagea of the R softwareb. began the highest dose of citicoline (2 g/day/6 weeks) Hypothesis of statistical heterogeneity was quantified within the first 24 hours after onset, which was the dose by means of an I2 value defined as 100% × (Q − df)/Q, showing efficacy in the PDA26 and the dose used in the where Q is Cochran’s heterogeneity statistic and df the ICTUS trial,28 reflecting a more contemporary standard degrees of freedom and their P value. I2 values of the of care, as the studies are more recent. random effects represent the percentage contribution of To report this systematic review, we followed the a given random effect to the overall heterogeneity. Values PRISMA statement.32 of I2 around 25%, 50%, and 75% can be considered as low, moderate, and high levels of heterogeneity, 30 respectively. End points from individual studies were Results analyzed to compute individual and pooled OR with their 95% CI, by means of a random-effects model (which ac- Study Selection commodates clinical and statistical variations better). Searching the Embase database provided 1219 docu- To explore the hypothesis of a diluted effect of citicoline ments, with 45 documents on acute stroke. Searching the in parallel with the improvement of the standard of care MEDLINE database provided 350 documents, with 27 of acute ischemic stroke, we used the cumulative meta- documents on acute stroke. Searching the Cochrane analysis. In cumulative meta-analysis, experiments are CENTRAL provided 166 documents, with 29 docu- accumulated from the earliest to the latest, where each ments on acute stroke without duplicates. Searching the successive experiment includes a synthesis of all previ- PubMed database provided 1983 documents, with 24 docu- ous experiments. This chronological combination of the ments on acute stroke. Searching ClinicalTrials.gov provided experiments allows us to show if there is a consistency 33 documents, with only 1 completed study on acute isch- in the results of consecutive experiments and indicate if emic stroke. Searching the Internet Stroke Center provided the results continually favor 1 process, product, or 10 documents, with 5 completed studies on acute isch- treatment. emic stroke. Searching the Ferrer Group database provided The analyses were performed separately by J.J.S. and 243 documents, with 33 documents on acute stroke without J.R. Then the results were compared for discrepancies. duplicates. The studies were selected after reviewing the citation, the abstracts, and the full papers when avail- Risk of Bias across Studies able. Compiling all the results, 63 studies on acute stroke were selected to be fully reviewed for inclusion in the As presumed, heterogeneity existed among the studies systematic review (Fig 1). Among the 63 studies se- performed over 4 decades; so, the main analysis used the lected, only 10 fulfilled the criteria to be included in the random-effects model to determine if the effects of CDP- systematic review and meta-analysis. The reasons for ex- choline were statistically and significantly different from cluding the 53 studies were as follows: the control group. As there is evidence of between- 33-69 study heterogeneity (I2 > 50%), we compared the fixed- - Study categorized as C: 37 70-72 effects and random-effects estimates of the intervention - Duplicated publications: 3 73-76 effect.31 - Study not C but compared with an active drug: 4 - Study not C but no independence data were available: 377-79 Additional Analyses - Study not C but in hemorrhagic stroke: 280,81 82 There were nonprespecified subgroup analyses. In the - Study not C but other investigational product: 1 83 sensitivity analysis, we performed the same analyses with - Study not C but in chronic phase: 1 84 the rtPA-treated patients excluded, as rtPA can be con- - A preliminary report: 1 85 sidered responsible for the ceiling effect and because, in - Not a report of a clinical trial: 1 the ICTUS trial,28 a significant interaction with the use of rtPA was detected. Because the percentage of stroke Study Characteristics patients who are treated with rtPA is, in general, very low,15 this analysis is convenient and allows a more re- The 10 studies selected28,86-94 were double-blind, randomized, and placebo-controlled clinical trials studying a Lumley T. rmeta: Meta-Analysis. R package version 2.16; 2009. the effect of citicoline on the recovery of patients with Available at: http://CRAN.R-project.org/package=rmeta. acute ischemic stroke (Table 1). The oldest study was pub- b R Development Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, lished in 1980 and the most recent study was published Austria; 2005. ISBN 3-900051-07-0, URL http://www.Rproject.org. in 2012; thus, there is a gap of 32 years between the first [RRID:OMICS_00245]. and the last studies. 1988 J.J. SECADES ET AL.

Figure 1. Flow diagram of the study selection. Abbreviation: CDP-choline, cytidine diphosphate choline.

The included studies involved 4436 patients, but the the use of activators of cerebral metabolism (i.e., number of patients evaluated was 4420. All the patients hydergine), cerebral vasodilators (i.e., papaverine), vita- were 18 years or older, suffering from an acute isch- mins, and methods for reducing blood pressure. In emic stroke and treated within a time window of between some cases, patients were also treated with hypertonic 8 hours and 14 days. solutions, adrenocorticotropic hormone, or corticoste- Four trials were single centered,86-88,94 whereas all the roids. Many of these interventions are not valid today. other trials were multicentered. The treatments tested were During the 1990s, the studies were performed in the either citicoline, with doses ranging from 250 to 2000 mg United States, and the standard of care was more daily, or placebo. The duration of the treatment ranged homogeneous, including anticoagulants, antiplatelets, from 10 days to 6 weeks. Citicoline or placebo was ad- and the use of rtPA in a few cases (less than 13% of ministered intravenously in 4 studies,86-89 orally in another cases). The standard of care used in the study per- 4 studies,90-93 and both intravenously and orally in 2 formed in Venezuela94 included the use of antiplatelets, studies.28,94 Four of the included trials were performed calcium channel blockers, and vitamins. In the ICTUS in Europe,28,86-88 four studies were performed in the USA,90-93 trial,28 the standard of care included a very early and one study was performed in Japan,94 and one study in aggressive treatment (stroke code), with more than 80% Venezuela.94 of patients treated in SU and more than 46% of patients The primary end point was different among the trials, receiving rtPA. Other differences to consider among the but all have information about independence as at least trials are the therapeutic window, with 2 studies having as secondary outcome, allowing patient independence to a therapeutic window of more than 48 hours, including be evaluated in the efficacy of the intervention. The timing the baseline severity of the patients (Table 1). of outcome measures varies between 10 days and 12 weeks. Safety was evaluated in all of the studies. Synthesis of the Results Table 2 shows the methodological quality of the selected studies. One major difference between the The effect estimates and the conﬁdence intervals are trials is the standard of care applied. In the trials presented as a forest plot in Figure 2. All the results are performed in the 1980s, the standard of care comprised reported directly, as obtained from the original publication. IIOIEI CT SHMCSTROKE ISCHEMIC ACUTE IN CITICOLINE

Table 1. Summary of the included studies evaluating the efﬁcacy of citicoline in acute ischemic stroke

No. of Age (mean, Therapeutic Source patients range) Baseline severity window Dose Route Follow-up

Boudouresques and Michel86 52 63.6 Mild–moderate 48 h 750 mg/day/10 days i.v. 10 days Goas et al87 64 62.8 Mild–moderate 48 h 250-750 mg/d/20 days i.v. 90 days Corso et al88 33 71.5 Mild–moderate 7-10 days 1 g/day/30 days i.v. 30 days Tazaki et al89 272 29-90 Mild–moderate 14 days 1 g/day/14 days i.v. 14 days Clark et al90 (USA1) 259 67.8 NIHSS score higher than 4 24 h 500-2000 mg/day/6 weeks p.o. 12 weeks Clark et al91 (USA2) 394 70.5 NIHSS score higher than 4 24 h 500 mg/day/6 weeks p.o. 12 weeks Warach et al92 (USA3) 100 70.3 NIHSS score higher than 4 24 h 500 mg/day/6 weeks p.o. 12 weeks Clark et al93 (USA4) 899 67.5 NIHSS score higher than 7 24 h 2000 mg/day/6 weeks p.o. 12 weeks Alviarez and Gonzalez94 65 69.8 NIHSS score higher than 4 8 h 2000 mg/day/6 weeks i.v. (3 days) then p.o. 6 weeks Dávalos et al28 (ICTUS) 2298 72.8 NIHSS score higher than 7 24 h 2000 mg/day/6 weeks i.v. (3 days) then p.o. 12 weeks

Abbreviations: i.v., intravenous; NIHSS, National Institutes of Health Stroke Scale; p.o., oral.

Table 2. Quality measures of randomized controlled trials included

Method of randomization RCT Data Outcome and concealment stopped early Patients Health care collectors assessors Trial Classiﬁcation of allocation (attrition bias) blinded provider blinded blinded blinded

Boudouresques and Michel86 A Yes No Yes Yes Yes Yes Goas et al87 A Yes No Yes Yes Yes Yes Corso et al88 B Unclear No Yes Yes Yes Yes Tazaki et al89 A Yes No Yes Yes Yes Yes Clark et al90 (USA1) A Yes No Yes Yes Yes Yes Clark et al91 (USA2) A Yes No Yes Yes Yes Yes Warach et al92 (USA3) A Yes No Yes Yes Yes Yes Clark et al93 (USA4) A Yes No Yes Yes Yes Yes Alviarez and Gonzalez94 B Unclear No Yes Yes Yes Yes Dávalos et al28 (ICTUS) A Yes Yes Yes Yes Yes Yes

Abbreviation: RCT, randomized clinical trial. 1989 1990 J.J. SECADES ET AL.

Experimental Control Odds Ratio Study Events Total Events Total OR 95%−CI W(fixed) W(random)

Fixed effect model 2348 2072 1.20 [1.06; 1.36] 100% −− Random effects model 1.56 [1.12; 2.16] −− 100% Heterogeneity: I−squared=72.1%, tau−squared=0.149, p=0.0002

Figure 2. Effect estimates and confidence intervals of the intervention on the rates of independence (mRS score of 0-2 or equivalent) in comparison with the placebo. Abbreviations: CI, confidence interval; mRS, modified Rankin Scale; OR, odds ratio.

The administration of citicoline was associated with a reflecting the time gap of 32 years between the studies significant higher rate of independence (mRS score of 0-2), included in the meta-analysis. To explore this heteroge- independently of the method of evaluation used (OR 1.56, neity, a funnel plot was drawn. The funnel plot in Figure 3 95% CI = 1.12-2.16 under random effects; OR 1.20, 95% shows evidence of asymmetry, and this asymmetry re- CI = 1.06-1.36 under fixed effects). As the estimates are flects the progressive improvement of the standard of care similar, then we can consider that any small-study effect (placebo group) over time. The cumulative meta- has little effect on the intervention effect estimate. analysis presented in Figure 4 shows how the effect of the intervention decreases over time in parallel with expected improvements in the standard of care. There are Heterogeneity across Studies substantial differences between the standard of care for As expected, a significant level of heterogeneity across acute ischemic stroke patients in the 1980s compared with studies was identified (I2 = 72.1%; τ2 = .149; P = .0002), the standard of care now. All the included trials were

Figure 3. Funnel plot showing evidence of asymmetry. CITICOLINE IN ACUTE ISCHEMIC STROKE 1991 performed with the highest quality in their time, as all the studies were performed in qualified centers. In the sensitivity analysis, we performed the same analysis excluding those patients treated with rtPA from the studies USA496 and ICTUS.28 For this analysis, heterogeneity was lower (I2 = 64.5%; P = .004), still reflecting the time gap between the studies, but showing the appro- priateness of this additional analysis. The independence rate in patients treated with citicoline but who did not receive rtPA was higher (OR 1.63, 95% CI = 1.18-2.24 under random effects; OR 1.42, 95% CI = 1.22-1.66 under fixed effects) (Fig 5). Of the patients not treated with rtPA and beginning the highest dose of citicoline (2 g/day/6 weeks) within the first 24 hours after stroke onset (Fig 6), the analysis also shows a positive result, with an OR of 1.27 (95% CI = 1.05-1.53), and, in this case, heterogeneity was not significant (I2 = 29.1%, τ2 = .0193, P = .2375). Regard- ing safety, none of the studies detected any safety concerns related to the intervention.

Discussion In recent years, several clinical trials were conducted to find effective therapies,97 but no convincing results have been obtained. Although the randomized clinical trial has become the gold standard of evidence, there are some concerns about its overvaluation.98 In the field of acute ischemic stroke trials, a substantial change in the design and conduct of the trials has been demonstrated,99 but this has been accompanied by a reduction in external validity (or generalizability) of the results.96,98 There is concern Figure 4. Cumulative meta-analysis under random-effects (a) and fixed- among clinicians that external validity is often poor, and effects (b) models showing the dilution of the effect of the intervention over time. Abbreviations: CI, confidence interval; OR, odds ratio.

Experimental Control Odds Ratio Study Events Total Events Total OR 95%−CI W(fixed) W(random)

Fixed effect model 1757 1459 1.42 [1.22; 1.66] 100% −− Random effects model 1.63 [1.18; 2.24] −− 100% Heterogeneity: I−squared=64.5%, tau−squared=0.1326, p=0.0026

Figure 5. Effect estimates and confidence intervals of the intervention on the rates of independence (mRS score of 0-2 or equivalent) in comparison with placebo in patients not treated with rtPA. Abbreviations: CI, confidence interval; mRS, modified Rankin Scale; OR, odds ratio. 1992 J.J. SECADES ET AL.

Experimental Control Odds Ratio Study Events Total Events Total OR 95%−CI W(fixed) W(random)

USA 1 1997 29 65 22 64 1.54 [0.76; 3.13] 6.3% 11.0% USA 4 2001 154 396 107 368 1.55 [1.15; 2.10] 34.6% 38.6% Alviarez 2007 13 29 10 30 1.62 [0.57; 4.66] 2.8% 5.4% ICTUS 2012 152 613 147 615 1.05 [0.81; 1.36] 56.4% 45.0%

Fixed effect model 1103 1077 1.27 [1.05; 1.53] 100% −− Random effects model 1.30 [1.01; 1.68] −− 100% Heterogeneity: I−squared=29.1%, tau−squared=0.0193, p=0.2375

0.5 1 2 Figure 6. Effect estimates and confidence intervals of the intervention on the rates of independence (mRS score of 0-2 or equivalent) in comparison with the placebo in patients not treated with rtPA and who began the highest dose of citicoline (2 g/day/6 weeks) within the first 24 hours after stroke onset. Abbreviations: CI, confidence interval; mRS, modified Rankin Scale; OR, odds ratio; rtPA, recombinant tissue plasminogen activator. this has led to the underuse of effective treatments. In tematic reviews provide an essential mechanism in the most recent trials, the findings may only be appli- reviewing available evidence.104 cable to SUs that are participating in clinical trials and As mentioned before, the major differences between the may not be applicable in day-to-day clinical practice.100 trials included in this systematic review are related with The present systematic review and meta-analysis offer the changes of the standard for acute ischemic stroke treat- data on the effect of citicoline in the treatment of acute ment. This finding is relevant when we are trying to ischemic stroke in comparison with placebo. The studies evaluate today the efficacy of a product that has been included in the review are double-blind and placebo- on the market for more than 35 years. Furthermore, the controlled, and were conducted in academic centers. The changes in the standard of care across time is a well- studies are of the highest quality for the time they were known source of heterogeneity.95,105 Thus, we have to performed. We tried to minimize as much as possible the consider that when an active treatment is given, the overall risk of bias.95,101 We did not include 3 studies77-79 because response is the result of the treatment itself and the context only the abstracts of these studies were available (the in which it is given.106 studies were never published), so we could not verify Following the results obtained in the ICTUS trial,28 the the quality of the studies. It has to be considered that efficacy of citicoline could be questioned, but we have to our estimates coincide with those reported in previous consider the poor external validity of the trial. In fact, the meta-analyses25,27 showing that the use of citicoline was lesson we learnt with the ICTUS trial is that, in the case associated with a decrease on the rates of long-term death of a patient treated very early with rtPA in a multidisci- and disability. Also, the results obtained in the PDA26 co- plinary SU, citicoline is not able to provide any additional incide with our results, showing how citicoline increased beneficial effect. This can be considered the gold standard the rates of total recovery in patients with moderate to for the treatment of acute ischemic stroke but differs very severe ischemic stroke. much from actual clinical practice in the world.15,107 By definition, a systematic review is a summary of the Another point to consider is the controversy in re- medical literature that uses explicit methods to perform cruiting rtPA-treated patients in stroke trials,108 as we cannot a thorough literature search and critical appraisal of in- rule out a ceiling effect resulting from an already maximal dividual studies, and which also uses appropriate statistical improvement due to rtPA use. This fact has been argued techniques to combine these valid studies.102 It is rea- as a possible explanation for the failure of some recent sonable to suggest that a systematic review should be acute ischemic stroke trials.28,109,110 One argument in favor performed (or updated) after each and every study in of this hypothesis is the higher odds obtained in our sen- the development of a new intervention, and that doing sitivity analysis, which includes only patients not treated so will enhance decision making when deciding whether with rtPA. to proceed with further development, as well as when We investigated the source of heterogeneity among the implementing the positive findings for a new trials included in this review and we considered that the intervention.102,103 This process inevitably brings togeth- explanation of this heterogeneity was the difference in er studies that are diverse in their design, but it is the standard of care for patients, rather than the quality incontrovertible that treatment decisions should be based of the studies. This effect is evaluable in the cumulative on evidence when it exists and that good quality sys- meta-analysis. Thus, our conclusion that the effect of CITICOLINE IN ACUTE ISCHEMIC STROKE 1993 citicoline could be diluted over time in parallel with pro- management of ischaemic stroke and transient ischaemic gressive improvements in the standard of care for acute attack 2008. Cerebrovasc Dis 2008;25:457-507. doi:10.1159/ ischemic stroke patients appears to be valid. The anal- 000131083. 8. ESO News: Update Guidelines January 2009. Specific ysis performed with more recent studies (Fig 6), in patients treatment: thrombolysis. Cerebrovasc Dis 2009;27:619-620. who received the highest dose of citicoline in the first 9. Shinohara Y, Yanagihara T, Abe K, et al. II. Cerebral 24 hours without rtPA treatment, should be considered infarction/transient ischemic attack (TIA). J Stroke the real size of the effect of citicoline in a more contem- Cerebrovasc Dis 2011;20(Suppl 1):S31-S73. doi:10.1016/ porary context. This could help in defining what kind j.jstrokecerebrovasdis.2011.05.004. 10. Fuentes B, Díez-Tejedor E. Stroke units: many questions, of patients could benefit from treatment with citicoline. some answers. Int J Stroke 2009;4:28-37. doi:10.1111/ Further advantages of citicoline include the long time j.1747-4949.2009.00244.x. window compared to rtPA and the administration of the 11. Chen ZM, Sandercock P, Pan HC, et al. Indications for treatment not only in well-staffed, well-trained, and well- early aspirin use in acute ischemic stroke: a combined equipped stroke services administering thrombolysis but analysis of 40 000 randomized patients from the Chinese Acute Stroke Trial and the International Stroke Trial. also in much less advanced stroke services. On behalf of the CAST and IST collaborative groups. It can be concluded that the current systematic review Stroke 2000;31:1240-1249. and meta-analysis support some benefits of citicoline in 12. Vahedi K, Hofmeijer J, Juettler E, et al. Early decom- the treatment of acute ischemic stroke. It is confirmed pressive surgery in malignant infarction of the middle that the effect of citicoline has been diluted over time cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol 2007;6:215-222. in parallel with improvements in the standard of care. 13. Berglund A, Svensson L, Sjöstrand C, et al. Higher Consequently, on top of the best treatment available (rtPA), prehospital priority level of stroke improves thrombolysis citicoline offers a limited benefit. frequency and time to stroke unit: the Hyper Acute STroke Alarm (HASTA) study. Stroke 2012;43:2666-2670. Acknowledgments: The authors thank Georgina Casa- 14. Kleindorfer D, de Los Rios La Rosa F, Khatri P, et al. Temporal trends in acute stroke management. 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