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

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 ARTICLE IN PRESS

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 signifi-
cant 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 avail-
able 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. re-
viewed 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: jsecades@ferrer.com.
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

Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2016: pp ■■–■■ 1
 ARTICLE IN PRESS
2 J.J. SECADES ET AL.
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-

Despite global and regional health crises, global life ex-
pectancy has increased continuously and substantially over
the past 40 years.1 This is associated with an increase in
incidences of age-related diseases, such as ischemic stroke.
Stroke is the second leading cause of death in the world,
and since 1990, a 26.5% increase in ischemic stroke mor-
tality has been reported,2 with a parallel increase in the
rates of disability.3,4
Only in recent years have advances allowed for rele-
vant improvement in the outcome of this devastating
disease. A new era in acute stroke care began in 1995,
when it was shown that early intravenous administra-
tion of recombinant tissue plasminogen activator (rtPA)
improved outcome in a carefully selected patient group
with acute ischemic stroke.5 Together with the use of rtPA,6-9
treatment in stroke units (SUs),10 the early use of aspirin,11
and decompressive surgery12 are recognized as thera-
pies with proven efficacy in the management of acute
ischemic stroke. Thus, very early treatment with rtPA in
an SU can be considered the gold standard,13 but can only
be applied in a qualified center, in developed countries.14
However, the use of rtPA remains very low in the world,15
and there are substantial differences in the standard of
care for acute ischemic stroke.16-20 Obviously, there is an
urgent need for available therapeutics for acute stroke.
Citicoline, or CDP-choline, a drug that combines neu-
rovascular protection and repair effects,21-23 has been used
to treat acute ischemic stroke and other neurological
disorders,21 with an excellent safety profile.24 In 2002, a formal
meta-analysis of trials of CDP-choline in acute and sub-
acute stroke25 suggested a beneficial and substantial treatment
effect, with absolute reductions of 10%-12% in the rates of
long-term death and disability. In a pooled data analysis
(PDA), the odds ratio (OR) of complete functional and neu-
rological recovery in patients with moderate-to-severe acute
ischemic stroke treated with oral citicoline for 6 weeks was
1.33 (95% confidence interval [CI] = 1.10-1.62) when com-
pared with placebo.26 A further updated meta-analysis of
tabulated data confirmed these previous results, with a re-
duction in death or dependency (OR .65, 95% CI = .54-.77;
P = .00001; Number Needed to Treat 9.5).27
The recent ICTUS trial28 could not confirm the effica-
cy of citicoline against placebo as an add-on therapy on
top of the best standard of care. Also in the ICTUS trial,
it was hypothesized that the beneficial effect of citicoline
dards of care for acute ischemic stroke.
For this reason, we decided to perform an exhaustive
and systematic search for all double-blind and placebo-
controlled clinical trials performed with citicoline worldwide,
and to conduct an updated meta-analysis to assess if treat-
ment with citicoline (started within 14 days after stroke
onset) improves the outcome (measured as a modified Rankin
Scale [mRS] score of 0-2 or equivalent) in patients with
acute ischemic stroke when compared with placebo.
Methods
Protocol and Registration
The present systematic review and meta-analysis are
based on a pre-existing protocol, adapted from a pub-
lished protocol in The Cochrane Library.29 The protocol
has been submitted and registered at the PROSPERO reg-
ister, with registration number CRD42013005070.
Eligibility Criteria
Clinical trials that were double-blind, randomized, and
controlled with placebo were included. No restrictions
regarding language, publication date, or publication status
were applied. Only trials in which the active study agent
was CDP-choline were included, and trials comparing CDP-
choline treatment with any other active treatment were
excluded.
All trials randomizing patients of any age or sex were
included, with index events of ischemic stroke and/or
presumed ischemic stroke (in studies without neuroimaging),
and with randomization occurring within 14 days after
stroke onset. This broad treatment time window of 14
days was chosen because citicoline may have effects at
different stages in the evolution of ischemic brain injury
and repair. No restrictions were applied in regard to doses,
route of administration, or duration of treatment.
The primary efficacy measure was patient indepen-
dence at the end of a scheduled follow-up period.
Information Sources
Studies were identified by searching electronic data-
bases, scanning reference lists of articles, and consulting
with experts in the field and at the drug company (Ferrer
Group).
 ARTICLE IN PRESS
CITICOLINE IN ACUTE ISCHEMIC STROKE
The search was applied to
- Cochrane Central Register of Controlled Trials
(CENTRAL) (The Cochrane Library, latest issue);
- MEDLINE (1966 to present);
- PubMed (1940s to present);
- Embase (1974 to present);
- Internet Stroke Center (stroke trials registry); and
- National Institute of Health (ClinicalTrials.gov).
Also, an exhaustive search on the Internet and in the
bibliographic database of Ferrer Group was performed
to detect studies published in journals that were not
indexed or included in databases.
Search Strategy
The following search strategy for MEDLINE was used
and modified for the other databases when necessary.
MEDLINE
1) cerebrovascular disorders/ or basal ganglia cere-
brovascular disease/ or exp brain ischemia/ or
carotid artery diseases/ or carotid artery thrombosis/
or intracranial arterial diseases/ or cerebral arte-
rial diseases/ or exp “intracranial embolism and
thrombosis”/ or stroke/ or exp brain infarction/
or cerebral infarction/
2) ((maintain ischaemic or ischemic) adj5 (stroke$ or
apoplex$ or cerebral vasc$ or cerebrovasc$ or cva)).tw.
3) ((brain or cerebr$ or cerebell$ or vertebrobasil$ or
hemispher$ or intracran$ or intracerebral or
infratentorial or supratentorial or middle cerebr$
or mca$ or anterior circulation) adj5 (isch?emi$
or infarct$ or thrombo$ or emboli$ or occlus$ or
hypoxi$)).tw.
4) 1 or 2 or 3
5) CDP-choline or cytidine diphosphate choline or
citicoline
6) (choline or (cytidine adj5 diphosphocholine) or cy-
tidine diphosphate choline or CDP-choline or
citicoline or citicholine or cyticholine or cidifos).tw.
7) 5 or 6
8) 4 and 7
9) limit 8 to humans
The search in Cochrane CENTRAL, Clinicaltrials.gov,
and Internet Stroke Center was performed using the term
“CDP-choline” or “citicoline.” The broad search on the
Internet and PubMed was performed using the term “CDP-
choline OR citicoline OR cytidine-5′-diphosphocholine OR
cytidine-5′-diphosphate OR citicholine OR citocoline OR
citocholine.” The search in the bibliographic database of
the Ferrer Group was performed using the terms “CDP-
choline or citicoline and stroke.”
Selection of Studies
Two review authors (J.J.S. and N.O.) reviewed the ab-
stracts of articles retrieved in the search. Full-length papers
3
for any possible abstract that met the inclusion criteria
were obtained. Five review authors (J.J.S., J.A.S., J.C., E.D.T.,
and E.M.V.) reviewed all retrieved papers to identify those
trials that met the inclusion criteria for the review.
Data Extraction and Management
Two review authors (J.J.S. and N.O.) independently ex-
tracted the efficacy data from eligible trials. These review
authors resolved discrepancies through discussion with
other authors (J.A.S., J.C., E.D.T., and E.M.V.) and by ref-
erencing the original report.
Data Items
The primary efficacy measure was patient indepen-
dence at the end of the scheduled clinical trial follow-
up. If available, the mRS was used for this measure (mRS
score of 0-2). In studies where the mRS measure was not
available, we used the most comprehensive measure of
disability or handicap available from the trial.
The information was checked for the doses used, the
route of administration, and the duration of treatment
with CDP-choline.
Assessment of Risk of Bias in the Included Studies
The methodological quality of the selected studies was
assessed using The Cochrane Collaboration’s tool for as-
sessing the risk of bias.30,31 Each of the following points
was scored as “yes,” “no,” or “unclear” (where “yes” in-
dicates that the study is less open to bias):
1) Method of randomization (selection bias)
2) Concealment of allocation (indication bias)
3) Blinding of investigators and patients (perfor-
mance bias)
4) Blinding of outcome assessment (detection bias)
5) Adequate follow-up (attrition bias)
6) Other possible bias
Based on these criteria, we divided the studies into the
following 3 categories:
• A—all quality criteria met: low risk of bias,
• B—one or more of the quality criteria only partly
met: moderate risk of bias, and
• C—one or more criteria not met: high risk of bias.
To avoid selection bias, only studies categorized as C
were rejected. Other studies not included were those per-
formed for other indications, such as hemorrhagic stroke
and those not reporting independence as an outcome.
Measures of Treatment Effect
Dichotomous statistical meta-analytic methods were used,
and the Mantel–Haenzel method was applied for the es-
timation of OR in fixed effects and DerSimonian–Laird
for random effects to calculate the global treatment effect.
 ARTICLE IN PRESS
4 J.J. SECADES ET AL.
Data Synthesis
The formal meta-analysis was performed using the rmeta
packagea of the R softwareb.
Hypothesis of statistical heterogeneity was quantified
by means of an I2 value defined as 100% × (Q − df)/Q,
where Q is Cochran’s heterogeneity statistic and df the
degrees of freedom and their P value. I2 values of the
random effects represent the percentage contribution of
a given random effect to the overall heterogeneity. Values
of I2 around 25%, 50%, and 75% can be considered as
low, moderate, and high levels of heterogeneity,
respectively.30 End points from individual studies were
analyzed to compute individual and pooled OR with their
95% CI, by means of a random-effects model (which ac-
commodates clinical and statistical variations better).
To explore the hypothesis of a diluted effect of citicoline
in parallel with the improvement of the standard of care
of acute ischemic stroke, we used the cumulative meta-
analysis. In cumulative meta-analysis, experiments are
accumulated from the earliest to the latest, where each
successive experiment includes a synthesis of all previ-
ous experiments. This chronological combination of the
experiments allows us to show if there is a consistency
in the results of consecutive experiments and indicate if
the results continually favor 1 process, product, or
treatment.
The analyses were performed separately by J.J.S. and
J.R. Then the results were compared for discrepancies.
Risk of Bias across Studies
As presumed, heterogeneity existed among the studies
performed over 4 decades; so, the main analysis used the
random-effects model to determine if the effects of CDP-
choline were statistically and significantly different from
the control group. As there is evidence of between-
study heterogeneity (I2 > 50%), we compared the fixed-
effects and random-effects estimates of the intervention
effect.31
Additional Analyses
There were nonprespecified subgroup analyses. In the
sensitivity analysis, we performed the same analyses with
the rtPA-treated patients excluded, as rtPA can be con-
sidered responsible for the ceiling effect and because, in
the ICTUS trial,28 a significant interaction with the use
of rtPA was detected. Because the percentage of stroke
patients who are treated with rtPA is, in general, very
low,15 this analysis is convenient and allows a more re-
a
Lumley T. rmeta: Meta-Analysis. R package version 2.16; 2009.
Available at: http://CRAN.R-project.org/package=rmeta.
b
R Development Core Team. R: A language and environment for
statistical computing. R Foundation for Statistical Computing, Vienna,
Austria; 2005. ISBN 3-900051-07-0, URL http://www.Rproject.org.
[RRID:OMICS_00245].
alistic estimation of the effect of citicoline when compared
to the most usual acute care. Another additional analy-
sis was based on patients not treated with rtPA and who
began the highest dose of citicoline (2 g/day/6 weeks)
within the first 24 hours after onset, which was the dose
showing efficacy in the PDA26 and the dose used in the
ICTUS trial,28 reflecting a more contemporary standard
of care, as the studies are more recent.
To report this systematic review, we followed the
PRISMA statement.32
Results
Study Selection
Searching the Embase database provided 1219 docu-
ments, with 45 documents on acute stroke. Searching the
MEDLINE database provided 350 documents, with 27
documents on acute stroke. Searching the Cochrane
CENTRAL provided 166 documents, with 29 docu-
ments on acute stroke without duplicates. Searching the
PubMed database provided 1983 documents, with 24 docu-
ments on acute stroke. Searching ClinicalTrials.gov provided
33 documents, with only 1 completed study on acute isch-
emic stroke. Searching the Internet Stroke Center provided
10 documents, with 5 completed studies on acute isch-
emic stroke. Searching the Ferrer Group database provided
243 documents, with 33 documents on acute stroke without
duplicates. The studies were selected after reviewing the
citation, the abstracts, and the full papers when avail-
able. Compiling all the results, 63 studies on acute stroke
were selected to be fully reviewed for inclusion in the
systematic review (Fig 1). Among the 63 studies se-
lected, only 10 fulfilled the criteria to be included in the
systematic review and meta-analysis. The reasons for ex-
cluding the 53 studies were as follows:
- Study categorized as C: 3733-69
- Duplicated publications: 370-72
- Study not C but compared with an active drug: 473-76
- Study not C but no independence data were avail-
able: 377-79
- Study not C but in hemorrhagic stroke: 280,81
- Study not C but other investigational product: 182
- Study not C but in chronic phase: 183
- A preliminary report: 184
- Not a report of a clinical trial: 185
Study Characteristics
The 10 studies selected28,86-94 were double-blind, ran-
domized, and placebo-controlled clinical trials studying
the effect of citicoline on the recovery of patients with
acute ischemic stroke (Table 1). The oldest study was pub-
lished in 1980 and the most recent study was published
in 2012; thus, there is a gap of 32 years between the first
and the last studies.
 ARTICLE IN PRESS
CITICOLINE IN ACUTE ISCHEMIC STROKE
Figure 1. Flow diagram of the study selection. Abbreviation: CDP-choline, cytidine diphosphate choline.
The included studies involved 4436 patients, but the
number of patients evaluated was 4420. All the patients
were 18 years or older, suffering from an acute isch-
emic stroke and treated within a time window of between
8 hours and 14 days.
Four trials were single centered,86-88,94 whereas all the
other trials were multicentered. The treatments tested were
either citicoline, with doses ranging from 250 to 2000 mg
daily, or placebo. The duration of the treatment ranged
from 10 days to 6 weeks. Citicoline or placebo was ad-
ministered intravenously in 4 studies,86-89 orally in another
4 studies,90-93 and both intravenously and orally in 2
studies.28,94 Four of the included trials were performed
in Europe,28,86-88 four studies were performed in the USA,90-93
one study was performed in Japan,94 and one study in
Venezuela.94
The primary end point was different among the trials,
but all have information about independence as at least
as secondary outcome, allowing patient independence to
be evaluated in the efficacy of the intervention. The timing
of outcome measures varies between 10 days and 12 weeks.
Safety was evaluated in all of the studies.
Table 2 shows the methodological quality of the
selected studies. One major difference between the
trials is the standard of care applied. In the trials
performed in the 1980s, the standard of care comprised
5
the use of activators of cerebral metabolism (i.e.,
hydergine), cerebral vasodilators (i.e., papaverine), vita-
mins, and methods for reducing blood pressure. In
some cases, patients were also treated with hypertonic
solutions, adrenocorticotropic hormone, or corticoste-
roids. Many of these interventions are not valid today.
During the 1990s, the studies were performed in the
United States, and the standard of care was more
homogeneous, including anticoagulants, antiplatelets,
and the use of rtPA in a few cases (less than 13% of
cases). The standard of care used in the study per-
formed in Venezuela94 included the use of antiplatelets,
calcium channel blockers, and vitamins. In the ICTUS
trial,28 the standard of care included a very early and
aggressive treatment (stroke code), with more than 80%
of patients treated in SU and more than 46% of patients
receiving rtPA. Other differences to consider among the
trials are the therapeutic window, with 2 studies having
a therapeutic window of more than 48 hours, including
the baseline severity of the patients (Table 1).
Synthesis of the Results
The effect estimates and the confidence intervals are
presented as a forest plot in Figure 2. All the results are
reported directly, as obtained from the original publication.
 6
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

ARTICLE IN PRESS
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 8h 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

J.J. SECADES ET AL.

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.

 ARTICLE IN PRESS
CITICOLINE IN ACUTE ISCHEMIC STROKE 7

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

Figure 3. Funnel plot showing evidence of asymmetry.

 ARTICLE IN PRESS
8 J.J. SECADES ET AL.
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 anal-
ysis excluding those patients treated with rtPA from the
studies USA496 and ICTUS.28 For this analysis, heteroge-
neity 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 va-
lidity (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.
 ARTICLE IN PRESS
CITICOLINE IN ACUTE ISCHEMIC STROKE
Experimental Control
Study Events Total Events Total
USA 1 1997 29 65 22 64
USA 4 2001 154 396 107 368
Alviarez 2007 13 29 10 30
ICTUS 2012 152 613 147 615
Fixed effect model 1103 1077
Random effects model
Heterogeneity: I−squared=29.1%, tau−squared=0.0193, p=0.2375
0.5
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
the most recent trials, the findings may only be appli-
cable to SUs that are participating in clinical trials and
may not be applicable in day-to-day clinical practice.100
The present systematic review and meta-analysis offer
data on the effect of citicoline in the treatment of acute
ischemic stroke in comparison with placebo. The studies
included in the review are double-blind and placebo-
controlled, and were conducted in academic centers. The
studies are of the highest quality for the time they were
performed. We tried to minimize as much as possible the
risk of bias.95,101 We did not include 3 studies77-79 because
only the abstracts of these studies were available (the
studies were never published), so we could not verify
the quality of the studies. It has to be considered that
our estimates coincide with those reported in previous
meta-analyses25,27 showing that the use of citicoline was
associated with a decrease on the rates of long-term death
and disability. Also, the results obtained in the PDA26 co-
incide with our results, showing how citicoline increased
the rates of total recovery in patients with moderate to
severe ischemic stroke.
By definition, a systematic review is a summary of the
medical literature that uses explicit methods to perform
a thorough literature search and critical appraisal of in-
dividual studies, and which also uses appropriate statistical
techniques to combine these valid studies.102 It is rea-
sonable to suggest that a systematic review should be
performed (or updated) after each and every study in
the development of a new intervention, and that doing
so will enhance decision making when deciding whether
to proceed with further development, as well as when
implementing the positive findings for a new
intervention.102,103 This process inevitably brings togeth-
er studies that are diverse in their design, but it is
incontrovertible that treatment decisions should be based
on evidence when it exists and that good quality sys-
9
Odds Ratio
OR 95%−CI W(fixed) W(random)
1.54 [0.76; 3.13] 6.3% 11.0%
1.55 [1.15; 2.10] 34.6% 38.6%
1.62 [0.57; 4.66] 2.8% 5.4%
1.05 [0.81; 1.36] 56.4% 45.0%
1.27 [1.05; 1.53] 100% −−
1.30 [1.01; 1.68] −− 100%
1 2
tematic reviews provide an essential mechanism in
reviewing available evidence.104
As mentioned before, the major differences between the
trials included in this systematic review are related with
the changes of the standard for acute ischemic stroke treat-
ment. This finding is relevant when we are trying to
evaluate today the efficacy of a product that has been
on the market for more than 35 years. Furthermore, the
changes in the standard of care across time is a well-
known source of heterogeneity.95,105 Thus, we have to
consider that when an active treatment is given, the overall
response is the result of the treatment itself and the context
in which it is given.106
Following the results obtained in the ICTUS trial,28 the
efficacy of citicoline could be questioned, but we have to
consider the poor external validity of the trial. In fact, the
lesson we learnt with the ICTUS trial is that, in the case
of a patient treated very early with rtPA in a multidisci-
plinary SU, citicoline is not able to provide any additional
beneficial effect. This can be considered the gold standard
for the treatment of acute ischemic stroke but differs very
much from actual clinical practice in the world.15,107
Another point to consider is the controversy in re-
cruiting rtPA-treated patients in stroke trials,108 as we cannot
rule out a ceiling effect resulting from an already maximal
improvement due to rtPA use. This fact has been argued
as a possible explanation for the failure of some recent
acute ischemic stroke trials.28,109,110 One argument in favor
of this hypothesis is the higher odds obtained in our sen-
sitivity analysis, which includes only patients not treated
with rtPA.
We investigated the source of heterogeneity among the
trials included in this review and we considered that the
explanation of this heterogeneity was the difference in
the standard of care for patients, rather than the quality
of the studies. This effect is evaluable in the cumulative
meta-analysis. Thus, our conclusion that the effect of
 ARTICLE IN PRESS
10
citicoline could be diluted over time in parallel with pro-
gressive improvements in the standard of care for acute
ischemic stroke patients appears to be valid. The anal-
ysis performed with more recent studies (Fig 6), in patients
who received the highest dose of citicoline in the first
24 hours without rtPA treatment, should be considered
the real size of the effect of citicoline in a more contem-
porary context. This could help in defining what kind
of patients could benefit from treatment with citicoline.
Further advantages of citicoline include the long time
window compared to rtPA and the administration of the
treatment not only in well-staffed, well-trained, and well-
equipped stroke services administering thrombolysis but
also in much less advanced stroke services.
It can be concluded that the current systematic review
and meta-analysis support some benefits of citicoline in
the treatment of acute ischemic stroke. It is confirmed
that the effect of citicoline has been diluted over time
in parallel with improvements in the standard of care.
Consequently, on top of the best treatment available (rtPA),
citicoline offers a limited benefit.
Acknowledgments: The authors thank Georgina Casa-
novas (Statistician, Asociación Hipótesis Alternativa [H1]) for
technical assistance in the statistical analyses and Matt Elmore
for assistance with the technical writing.
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