Citicoline in Mexico

1. Methods and Findings in Experimental and Clinical Pharmacology 2010, 32(5): ???-??? THOMSON REUTERS
Copyright © 2010 Prous Science, S.A.U. or its licensors. All rights reserved.
CCC: 0379-0355/2010
DOI: 10.1358/mf.2010.32.5.1465004
ORIGINAL ARTICLE
CITICOLINE FOR ACUTE ISCHEMIC STROKE IN
MEXICAN HOSPITALS: A RETROSPECTIVE POST-
MARKETING ANALYSIS
C. León-Jiménez1, E. Chiquete2,3, C. Cantú4, M.J. Miramontes-Saldaña1, M.A. Andrade-Ramos5 and J. Ruiz-
Sandoval6
1
Department of Neurology, Hospital Regional Dr. Valentín Gómez Farías, Zapopan, México; 2Department of Internal Medicine, Centro
Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, México; 3Department of Internal Medicine, Hospital Civil de
Guadalajara Fray Antonio Alcalde; Guadalajara, México; 4Department of Neurology, Instituto Nacional de Ciencias Médicas y Nutrición
Salvador Zubirán, Mexico City, México; 5Department of Neurology and Neurosurgery, Hospital Civil de Guadalajara Fray Antonio Alcalde;
Guadalajara, México; 6Department of Neurosciences. Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara,
México
SUMMARY
Some neuroprotective agents have shown benefits in animal models, but disappointing results in humans. Citicoline is used in several
countries as coadjuvant treatment in acute ischemic stroke (AIS) patients; however, there are no retrospective postmarketing surveillances
on the experience of citicoline in Mexico. The aim of this study was to evaluate the correlation between citicoline exposure and functional
outcome at discharge and at 30 and 90 days post-stroke, in a retrospective case-control design on systematic descriptive databases from
three referral hospitals. Clinical records of 173 consecutively registered patients were analyzed, 86 of whom were treated with citicoline with-
in the first 48 h after AIS and the remaining 87 were untreated, randomly selected controls matched for age (± 5 years), gender and NIHSS
(± 1 point) at hospital admission. Pretreatment conditions were similar between groups. Compared with controls, exposure to citicoline was
associated with a significantly lower 30-day mean and median modified Rankin score (in both, P < 0.05). After paired multivariate analy-
ses (controlled for NIHSS, age, gender, hospital arrival in < 24 h, thrombolysis and comorbidities) citicoline was independently associated
with a lower 90-day mortality risk (P = 0.047) and with fewer in-hospital complications (mainly infections and sepsis, P = 0.001). In this
observational study, citicoline use was correlated with a better functional status and lower rates of short-term mortality, possibly due to
fewer in-hospital systemic complications. The putative benefits should be interpreted as clinical associations, since this is not a random-
ized, controlled, clinical trial.
INTRODUCTION currently used in several countries for the coadjuvant treatment of
A number of neuroprotective agents have shown beneficial effects in patients with AIS, with some clinical trials and a meta-analysis
acute ischemic stroke (AIS) in preclinical animal models, but disap- showing that the drug increases the probability of full recovery at 3
pointing results when tested in humans (1, 2). Compounds that are months post-stroke (4, 6, 10, 14). However, the use of citicoline is still
effective in the laboratory are not always the most efficacious when controversial and there is a need for evaluation of its beneficial
used in clinical practice and, therefore, marginal benefits in certain effects in retrospective postmarketing studies in Mexico. Thus, the
subgroups are seen when the selected drugs are used in humans (3). aim of our study was to evaluate the effects of citicoline on several
outcome events (case fatality rate, functional outcome and in-hospi-
Citicoline (CDP-choline, a choline precursor) is an intermediate mol- tal non-neurological systemic complications) during hospitalization
ecule in membrane phosphatide biosynthesis with neuroprotec- and at 30 and 90 days postischemic stroke.
tive/neurorestorative properties which have been proven in various
forms of brain injury, including ischemia (4-14). This compound is
SUBJECTS AND METHODS
Correspondence: Dr. José Luis Ruiz Sandoval, Servicio de Neurología y Neurocirugía, Study population
Hospital Civil de Guadalajara Fray Antonio Alcalde, Hospital 278, Col. El Retiro, Torre de
Especialidades, piso 8, Guadalajara, Jalisco, México. C.P. 44280. E-mail: jorulej-1n
This study was a retrospective observational, case-control study
@prodigy.net.mx. designed to evaluate the effects of citicoline exposure on short-term
1

2. CITICOLINE FOR ACUTE ISCHEMIC STROKE IN MEXICO C. León-Jiménez et al.
outcomes after acute brain infarction. Patients treated with citicoline primary study outcomes were mortality and functional status at hos-
and untreated controls were selected from three systematic descrip- pital discharge and at 30- and 90-day follow-up, as assessed by the
tive databases. These registries were originally intended for descrip- modified Rankin Scale (mRS), which evaluates functional neurolog-
tive analyses and do not include patients from clinical trials databas- ical status, including death. Other secondary outcomes analyzed in
es. All patients included in these registries were treated as usual by order to explore possible implications for the impact of citicoline
attending physicians from the three participating centers, with no exposure on primary study outcomes, other than the alleged neuro-
bias other than the natural clinical decisions in daily practice. The protective effect of citicoline, were in-hospital non-neurological sys-
authors of this paper admitted and treated some of these patients, temic complications (pneumonia, sepsis, inflammatory response
but before the present report was devised, analyzed and drafted. syndrome, shock, pressure ulcers, newly diagnosed arrhythmias or
From October 2004 to August 2006, consecutive patients with AIS organ failure) and the need for mechanical ventilation or open
managed in general wards were prospectively included in the craniectomy.
respective stroke registry databases of three tertiary referral centers:
Hospital Regional “Dr. Valentín Gómez Farías”, ISSSTE (Zapopan, Statistical analyses
Jalisco; Mexico); Hospital Civil de Guadalajara “Fray Antonio
Alcalde” (Guadalajara, Jalisco; Mexico) and Instituto Nacional de Pearson’s chi-square and Fisher exact tests were used to assess pro-
Ciencias Médicas y Nutrición “Salvador Zubirán” (Mexico City). A portions in nominal variables for bivariate and homogeneity (when
standardized, structured questionnaire was systematically used to more than two variables). To compare quantitative variables
collect data from the caregiver or the patient if possible regarding between two groups, Student’s t-test and Mann-Whitney U test were
demography, relevant antecedents and the current event. Clinical performed in distributions of parametric and nonparametric vari-
examinations and brain imaging variables were also registered. A ables, respectively. To find independent predictors for the outcomes
total of 87 adult patients with AIS who arrived to hospital in < 48 h of interest, multivariate analyses were constructed by forward step-
from the event onset and who received citicoline were identified and wise logistic regression. Adjusted odds ratios with the respective
selected from the databases of the three participating centers (1000 95% confidence intervals (CI) are provided. Input variables were cho-
mg twice a day for at least 2-4 weeks then 500 mg twice a day for 5- sen if P < 0.2 in bivariate analyses, but relevant risk factors were
7 weeks more, until completion of a total of 9 weeks of treatment). maintained in the models for adjustment. Hospital arrival in < 24 h
This time window was chosen due to the high rate of hospital arrival was included in the prediction analyses, as this is the therapeutic
within 24-48 h after stroke onset, with an off-time use of neuropro- window recommended by the citicoline manufacturer. The fitness of
tection, which was detected in our citicoline cohort (27%). Event the models was evaluated by the Hosmer-Lemeshow goodness-of-
onset was considered to be the precise hour in which the neurologi- fit test, which was considered as reliable when P > 0.2. All P values
cal deficit was first observed. Ischemic stroke was confirmed by brain are two-sided and considered as significant when P < 0.05. SPSS
imaging (head CT and/or MRI) and intracerebral hemorrhage was version 13.0 for windows (SPSS Inc., Chicago, IL, USA) was used in all
excluded accordingly. As untreated controls, the clinical records of calculations.
87 patients with AIS who arrived to hospital in < 48 h (23% arrived in
24-48 h from stroke onset) but who did not receive citicoline were RESULTS
selected, matched for age (± 5 years), gender (± 2 females) and score
We studied 174 patients with AIS who arrived at the hospital in < 48
of the National Institutes of Health Stroke Scale (NIHSS; ± 1 point) at
h, 87 of whom received citicoline for the coadjuvant management of
hospital admission. The random selection of controls was also per-
ischemic stroke and 87 who were matched controls; however, a
formed from a coalescent database integrated with the three inde-
patient belonging to the citicoline group was lost to follow-up after
pendent participating electronic registries. Random selection func-
hospital discharge and was excluded from the final analyses (Table
tion of the SPSS (SPSS Inc., Chicago, IL) software (version 13.0 for
I). No patient was managed in a stroke unit. A total of 23.1% of
windows) was used for this process and included matching protocols
patients arrived at the hospital in < 3 h from stroke onset (44.1% in <
for NIHSS, age and gender. After selection of 87 matched controls, a
6 h, 70% in < 24 h and 30% between 24 and 48 h). Relevant pre-
final study database was formed with cases and controls and
treatment variables (including hospital arrival, mechanisms of
researchers who performed selection and analysis of patients treat-
infarction and infarct territory) and risk factors were comparable
ed with citicoline and controls were blinded to study outcomes.
between the citicoline group and controls (Table I). The use of
Clinical evaluators admitted and treated the patients at their discre-
thrombolysis was also similar in both groups (Table II). Other in-hos-
tion and were not aware of the analysis. The internal Committee of
pital events such as the need for mechanical ventilation, open
Ethics of our centers approved this study and informed consent was
craniectomy and duration of hospitalization were not different
obtained from all patients or their closest relatives at inclusion in the
between groups. However, compared with no neuroprotection, citi-
observational databases.
coline use was associated with a lower rate of in-hospital non-neu-
rological complications in bivariate analyses (Table II) and a lower
Main operational definitions and outcome measures mean (3.09 vs. 3.69 points, respectively; P = 0.03) and median
Hypertension and diabetes were defined by the known diagnosis of (3.0 vs. 4.0 points, respectively; P = 0.03) mRS at 30 days post-
these conditions (according to standard guidelines) and/or pharma- stroke. These differences on mRS did not remain statistically signifi-
cological treatment to lower blood pressure or glucose. Smoking cant at 90 days post-stroke; nevertheless, trends towards better out-
was defined as the consumption of an average of 5 cigarettes or comes were consistently observed at 30 and at 90 days post-event
more for at least 2 days per week during 12 months or longer. The (Table II).
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3. C. León-Jiménez et al. CITICOLINE FOR ACUTE ISCHEMIC STROKE IN MEXICO
Table I. Clinical characteristics of the citicoline group and matched controls.
All patients Citicoline Controls
Variables (N = 173) (N = 86) (N = 87) P value*
Age, mean (range), y 69.1 (36-95) 68.6 (36-94) 69.6 (36-95) 0.67
Female gender, n (%) 90 (52) 44 (51.2) 46 (52.9) 0.82
Main risk factors
Hypertension, n (%) 128 (74.0) 61 (70.9) 67 (77.0) 0.36
Current smoking habit, n (%) 71 (41.0) 32 (37.2) 39 (44.8) 0.31
Diabetes, n (%) 56 (32.4) 27 (31.4) 29 (33.3) 0.78
Previous brain infarction, n (%) 32 (18.5) 14 (16.3) 18 (20.7) 0.45
Ischemic heart disease, n (%) 27 (15.6) 13 (15.1) 14 (16.1) 0.86
Transient ischemic attack, n (%) 17 (9.8) 8 (9.3) 9 (10.3) 0.82
Arrival to hospital in < 24 h, n (%) 130 (75.1) 63 (73.3) 67 (77.0) 0.57
NIHSS at hospital arrival, median (range) 14.32 (1-38) 14.30 (1-38) 14.33 (1-38) 0.98
Neurovascular syndrome (TOAST classification)
Large-artery atherosclerosis, n (%) 29 (16.8) 15 (17.4) 14 (16.1) 0.81
Cardioembolic, n (%) 41 (23.7) 20 (23.3) 21 (24.1) 0.89
Lacune, n (%) 39 (22.5) 22 (25.6) 17 (19.5) 0.34
Other specified causes, n (%) 6 (3.5) 2 (2.3) 4 (4.6) 0.41
Undetermined mechanism, n (%) 68 (39.3) 31 (36.0) 37 (42.5) 0.38
MCA territory, n (%) 130 (75.1) 65 (75.6) 65 (74.7) 0.89
Posterior circulation brain infarction, n (%) 29 (16.8) 13 (15.1) 16 (18.4) 0.56
MCA, middle cerebral artery; NIHSS, National Institutes of Health Stroke Scale; TOAST, Trial of ORG-10172 in Acute Atroke Treatment. *P value for differences
between patients treated with citicoline and controls; Pearson chi-square, Fisher exact test or Student’s t-test, as corresponded.
Table I. Main outcome measures in the citicoline group and matched controls.
All patients Citicoline Controls
Variables (N = 173) (N = 86) (N = 87) P value*
Use of thrombolysis, n (%) 2 (1.1) 1 (1.2) 1 (1.1) 0.89
Duration of hospitalization, median (range) 10.06 (1-92) 10.81 (1-92) 9.33 (1-55) 0.37
Mechanical ventilation, n (%) 21 (12.3) 10 (11.9) 11 (12.6) 0.88
Open craniectomy, n (%) 5 (2.9) 2 (2.4) 3 (3.4) 0.68
In-hospital systemic complications, n (%) 66 (38.6) 24 (28.6) 42 (48.3) 0.008
Urinary tract infections, n (%) 28 (16.4) 14 (16.7) 14 (16.1) 0.92
Pressure ulcers, n (%) 7 (4.1) 3 (3.6) 4 (4.6) 0.99
Acute renal failure, n (%) 9 (5.3) 3 (3.6) 6 (6.9) 0.50
Pneumonia, n (%) 40 (23.4) 16 (19.0) 24 (27.6) 0.19
Acute heart failure, n (%) 12 (7) 3 (3.6) 9 (10.3) 0.13
Arrhythmias, n (%) 22 (12.9) 7 (8.3) 15 (17.2) 0.08
Other systemic complications, n (%)† 50 (29.2) 18 (21.4) 32 (36.8) 0.03
30-Day post-stroke outcome
mRS = 0, n (%) 10 (5.8) 8 (9.3) 2 (2.3) 0.06
mRS = 0-1, n (%) 34 (19.7) 21 (24.4) 13 (14.9) 0.12
mRS = 0-2, n (%) 55 (31.8) 31 (36.0) 24 (27.6) 0.23
Death, n (%) 31 (17.9) 11 (12.8) 20 (23) 0.08
90-Day post-stroke outcome
mRS = 0, n (%) 19 (11.0) 12 (14.0) 7 (8.0) 0.21
mRS = 0-1, n (%) 44 (25.4) 26 (30.2) 18 (20.7) 0.15
mRS = 0-2, n (%) 65 (37.6) 37 (43.0) 28 (32.2) 0.14
Death, n (%) 36 (20.8) 13 (15.2) 23 (26.4) 0.06
mRS, modified Rankin score. *P value for differences between the citicoline group and controls; Pearson chi-square, Fisher exact test or Student’s t-test (for
means), as corresponded. †Deep vein thrombosis, pulmonary embolism, sepsis, systemic inflammatory response syndrome, multiorgan failure and shock.
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4. CITICOLINE FOR ACUTE ISCHEMIC STROKE IN MEXICO C. León-Jiménez et al.
Multivariate analyses were constructed to find predictors of the out- in our study compared to original clinical trials, where the therapeu-
comes of interest and to evaluate the independent effect of citicoline tic window was < 24 h and only supratentorial and mainly lobar
treatment on these clinical end points (Fig. 1). Adjusting for age, brain infarction cases were assessed. This could also account for the
gender, NIHSS at hospital admittance, hospital arrival in < 24 h and differences between our study and previous reports. Nonetheless,
relevant risk factors (such as hypertension, diabetes, smoking and the use of citicoline was associated with a modest reduction in mor-
other factors), citicoline treatment was independently associated tality during short-term follow-up.
with a lower 30- and 90-day mortality risk, as well as with a lower In Mexico where intravenous thrombolysis is used in only 0.6% of
rate of systemic non-neurological complications acquired during patients with AIS (24), citicoline could be a cost-effective coadjuvant
hospitalization (see Fig. 1A). However, after excluding patients who therapy given its benefits on short-term outcome. Longer periods of
received thrombolysis (n = 7, remaining 166 patients), citicoline observation are necessary in order to better clarify the benefits in
treatment was only marginally associated with a lower 90-day mor- preventing functional disabilities. As most expenses are incurred
tality risk, but was highly significant with respect to in-hospital non- during the first months after AIS and given that this burden is main-
neurological complications (see Fig. 1B). ly related to direct hospitalization costs (22, 25), a fairly safe and
low-cost therapeutic strategy with a low probability of in-hospital
DISCUSSION complications and severe sequelae or death at short-term would be
AIS is the second leading cause of death and the first cause of cost-effective. Moreover, the fact that citicoline can also have some
acquired adult disability in industrialized countries (15). Rapid inter- benefit in intracerebral hemorrhage (12) and given its wide thera-
vention after the onset of a stroke can limit the neurological damage peutic window, treatment with this drug can be initiated even before
a brain imaging study is obtained. Whether on-the-field administra-
and improve functional recovery (16). In many countries the only
tion of citicoline (i.e., before hospital arrival) results in added bene-
medical treatment approved for AIS is thrombolysis with alteplase,
fits to standard or recommended protocol is an issue that should be
and it can be initiated within the first 4.5 h after the event onset (17,
studied in the near future.
18). This strategy should be the standard of care in every country. But
its brief therapeutic window, the latent risk of bleeding, the absolute In the present study, the use of citicoline was associated with a lower
need for neuroimaging before treatment can be initiated and the risk of systemic non-neurological complications during hospitaliza-
required training with drug use have limited its use to less than 5% tion. Some previous reports suggest the rationale of this beneficial
of stroke patients (19). Developing nations still have pending issues effect, mainly related to outcome after systemic infections and organ
in acute care, as well as in primary and secondary stroke prevention. failure (26-29). Given the membrane-stabilizing, free-radical scav-
It is necessary that the best current standard-of-care treatments be enging and surfactant-precursor properties (11, 29), citicoline could
adapted to these scenarios, and that more cost-effective and widely have a pleiotropic effect in severely ill patients. In animal models citi-
applicable therapeutic strategies are available in developing nations coline has been shown to stabilize catecholamine release after brain
(19). Neuroprotective and neurorestorative strategies appear to be injury (30, 31). Attenuation of sympathetic activation by citicoline
feasible, but neuroprotection in patients with acute stroke has could be a predictor of a better outcome that occurs with beta-
demonstrated limited efficacy thus far (20, 21), and cost-effective blockers, for example (32, 33). However, it is necessary to explore
analysis of these strategies are difficult to perform in countries in these hypotheses in clinical studies designed ad hoc, since the pres-
which wide disparities are observed between the public and private ent study involved multiple testing, which suggests that a high rate
sectors (22). of false positives could be observed by chance only, especially when
determining secondary outcomes.
Unless otherwise stated with future results of the ICTUS study (23),
citicoline as a coadjuvant therapy in AIS appears to show benefit in Our study has several limitations, and therefore, the results should be
mid-term functional outcomes (10, 11, 14). In the present study, the interpreted with caution. Given that some technical violations to the
use of citicoline was associated with a lower risk of short-term mor- manufacturer’s recommendations were observed with the use of citi-
tality and trends that consistently showed better functional status coline in our population (mainly with respect to stroke severity, thera-
when compared to no neuroprotection. With a higher probability of peutic window and brain infarct territory) (seeTable I), it was difficult
surviving and a better short-term functional status, our study sug- to select a homogeneous and large sample size sufficiently powered
gests that citicoline could be efficacious and cost-effective when to detect minor differences in pretreatment variables and outcomes.
added to the standard management of ischemic stroke patients in This behavior in drug use is a common phenomenon observed after
general wards. Whether this drug adds some benefit to the patient market launching and it is not rare that some off-label use of drugs
managed completely in a stroke unit or with thrombolytics is a topic pave the way for new uses and indications. That the multivariate
that could not be explored in our study. However, none of the previ- analyses changed after excluding the few patients who received
ous studies (either experimental or observational) on the use of citi- thrombolysis could reflect the inherent problems of a small sample
coline in acute AIS reported a reduction in mortality (4-10, 12). This size. Nevertheless, as was shown in a previous large descriptive report
(14), it seems reasonable to administer citicoline, since its use in nor-
could be due to a significant correlation between citicoline use and a
mal clinical settings (outside clinical trials) has been associated with
low rate of systemic non-neurological complications during hospital
a better outcome compared with no neuroprotection.
stay, since the reduction of systemic complications was greater than
that for mortality. Alternatively, it is possible that patients with a bet- In conclusion, this postmarketing analysis shows that treatment with
ter chance of survival were intentionally given citicoline as a treat- citicoline is associated with several clinical benefits that should be
ment intervention. Citicoline was used in a slightly different scenario clarified in further experimental studies. This is a retrospective,
4 THOMSON REUTERS – Methods and Findings in Experimental and Clinical Pharmacology 2010, 32(5)

5. C. León-Jiménez et al. CITICOLINE FOR ACUTE ISCHEMIC STROKE IN MEXICO
Figure 1. Forest plots showing the odds ratios (95% CI) obtained in 10 multivariate analyses on the main outcome measures: 5 logistic regression models for
model 1, and the other 5 for model 2. (A) Model 1, including patients who received thrombolysis (total, n = 173). (B) Model 2, excluding patients who received
thrombolysis (total, n = 166). Variables analyzed in each model: age, gender, NIHSS at hospital admission, hospital arrival in < 24 h, citicoline use, diabetes,
hypertension, smoking and previous acute cerebrovascular disease. Only variables significantly associated with the outcome measures are shown in the table.
In all models Hosmer-Lemeshow test for goodness of fit had P > 0.20 (regarded as reliable).
THOMSON REUTERS – Methods and Findings in Experimental and Clinical Pharmacology 2010, 32(5) 5

6. CITICOLINE FOR ACUTE ISCHEMIC STROKE IN MEXICO C. León-Jiménez et al.
observational case-control analysis not sufficiently powered to 13. Fioravanti, M., Buckley, A.E. Citicoline (Cognizin) in the treatment of cog-
detect minor differences between groups. It implies a methodologi- nitive impairment. Clin Interv Aging 2006, 1(3): 247-51.
cal limitation when trying to explain benefits associated with drug 14. Cho, H.J., Kim, Y.J. Efficacy and safety of oral citicoline in acute ischemic
intervention. The finding that citicoline is associated with a lower risk stroke: Drug surveillance study in 4,191 cases. Methods Find Exp Clin
of systemic non-neurological medical complications is an issue that Pharmacol 2009, 31(3): 171-6.
should be investigated in the future. 15. Mackay, J., Mensah, G.A. (Editors): The Atlas of Heart Disease and Stroke.
World Health Organization. Myriad Editions Ltd., Brighton, 2004.
ACKNOWLEDGMENTS 16. Hacke, W., Donnan, G., Fiesch, C. et al. Association of outcome with early
stroke treatment: Pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA
This study was partially supported by Ferrer Grupo SA (Barcelona, stroke trials. Lancet 2004, 363(9411): 768-74.
Spain). The company did not participate, either directly or indirectly, 17. Hacke, W., Kaste, M., Bluhmki, E. et al. Thrombolysis with alteplase 3 to 4.5
in the study design, random selection of controls, patient selection, hours after acute ischemic stroke. N Engl J Med 2008, 359(13): 1317-29.
data capture, data analysis, manuscript draft or the decision to sub- 18. Wahlgreen, N., Ahmed, N., Dávalos, A. et al. Thrombolysis with alteplase
mit for publication. 3-4.5 h after acute ischaemic stroke (SITS-ISTR): An observational study.
Lancet 2008, 372(9646): 1303-9.
DISCLOSURES 19. Durai Pandian, J., Padma, V., Vijaya, P., Sylaja, P.N., Murthy, J.M. Stroke
and thrombolysis in developing countries. Int J Stroke 2007, 2: 17-26.
The authors state no conflicts of interest.
20. Lees, K.R., Asplund, K., Carolei, A. et al. Glycine antagonist (gavestinel) in
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