17. citicoline in ischemic stroke in mexico

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Citicoline in Mexico

Citicoline in Mexico

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  • 1. Methods and Findings in Experimental and Clinical Pharmacology 2010, 32(5): ???-??? THOMSON REUTERSCopyright © 2010 Prous Science, S.A.U. or its licensors. All rights reserved.CCC: 0379-0355/2010DOI: 10.1358/mf.2010.32.5.1465004 ORIGINAL ARTICLECITICOLINE FOR ACUTE ISCHEMIC STROKE INMEXICAN HOSPITALS: A RETROSPECTIVE POST-MARKETING ANALYSISC. León-Jiménez1, E. Chiquete2,3, C. Cantú4, M.J. Miramontes-Saldaña1, M.A. Andrade-Ramos5 and J. Ruiz-Sandoval61 Department of Neurology, Hospital Regional Dr. Valentín Gómez Farías, Zapopan, México; 2Department of Internal Medicine, CentroUniversitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, México; 3Department of Internal Medicine, Hospital Civil deGuadalajara Fray Antonio Alcalde; Guadalajara, México; 4Department of Neurology, Instituto Nacional de Ciencias Médicas y NutriciónSalvador 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 ofA number of neuroprotective agents have shown beneficial effects in patients with AIS, with some clinical trials and a meta-analysisacute ischemic stroke (AIS) in preclinical animal models, but disap- showing that the drug increases the probability of full recovery at 3pointing results when tested in humans (1, 2). Compounds that are months post-stroke (4, 6, 10, 14). However, the use of citicoline is stilleffective in the laboratory are not always the most efficacious when controversial and there is a need for evaluation of its beneficialused in clinical practice and, therefore, marginal benefits in certain effects in retrospective postmarketing studies in Mexico. Thus, thesubgroups 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 hospitalizationecule in membrane phosphatide biosynthesis with neuroprotec- and at 30 and 90 days postischemic stroke.tive/neurorestorative properties which have been proven in variousforms of brain injury, including ischemia (4-14). This compound is SUBJECTS AND METHODSCorrespondence: Dr. José Luis Ruiz Sandoval, Servicio de Neurología y Neurocirugía, Study populationHospital Civil de Guadalajara Fray Antonio Alcalde, Hospital 278, Col. El Retiro, Torre deEspecialidades, 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 thetive 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 ines. All patients included in these registries were treated as usual by order to explore possible implications for the impact of citicolineattending 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 responsebut before the present report was devised, analyzed and drafted. syndrome, shock, pressure ulcers, newly diagnosed arrhythmias orFrom October 2004 to August 2006, consecutive patients with AIS organ failure) and the need for mechanical ventilation or openmanaged 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 analysesJalisco; Mexico); Hospital Civil de Guadalajara “Fray AntonioAlcalde” (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 (whenstandardized, structured questionnaire was systematically used to more than two variables). To compare quantitative variablescollect data from the caregiver or the patient if possible regarding between two groups, Student’s t-test and Mann-Whitney U test weredemography, 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 outcomestotal 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 respectiveselected 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 were7 weeks more, until completion of a total of 9 weeks of treatment). maintained in the models for adjustment. Hospital arrival in < 24 hThis time window was chosen due to the high rate of hospital arrival was included in the prediction analyses, as this is the therapeuticwithin 24-48 h after stroke onset, with an off-time use of neuropro- window recommended by the citicoline manufacturer. The fitness oftection, 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 valuescal deficit was first observed. Ischemic stroke was confirmed by brain are two-sided and considered as significant when P < 0.05. SPSSimaging (head CT and/or MRI) and intracerebral hemorrhage was version 13.0 for windows (SPSS Inc., Chicago, IL, USA) was used in allexcluded accordingly. As untreated controls, the clinical records of calculations.87 patients with AIS who arrived to hospital in < 48 h (23% arrived in24-48 h from stroke onset) but who did not receive citicoline were RESULTSselected, matched for age (± 5 years), gender (± 2 females) and score We studied 174 patients with AIS who arrived at the hospital in < 48of the National Institutes of Health Stroke Scale (NIHSS; ± 1 point) at h, 87 of whom received citicoline for the coadjuvant management ofhospital admission. The random selection of controls was also per- ischemic stroke and 87 who were matched controls; however, aformed from a coalescent database integrated with the three inde- patient belonging to the citicoline group was lost to follow-up afterpendent participating electronic registries. Random selection func- hospital discharge and was excluded from the final analyses (Tabletion 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% ofwindows) 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 ofresearchers who performed selection and analysis of patients treat- infarction and infarct territory) and risk factors were comparableed with citicoline and controls were blinded to study outcomes. between the citicoline group and controls (Table I). The use ofClinical 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, openEthics of our centers approved this study and informed consent was craniectomy and duration of hospitalization were not differentobtained 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 lowerMain operational definitions and outcome measures mean (3.09 vs. 3.69 points, respectively; P = 0.03) and medianHypertension 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-eventmore for at least 2 days per week during 12 months or longer. The (Table II).2 THOMSON REUTERS – Methods and Findings in Experimental and Clinical Pharmacology 2010, 32(5)
  • 3. C. León-Jiménez et al. CITICOLINE FOR ACUTE ISCHEMIC STROKE IN MEXICOTable I. Clinical characteristics of the citicoline group and matched controls. All patients Citicoline ControlsVariables (N = 173) (N = 86) (N = 87) P value*Age, mean (range), y 69.1 (36-95) 68.6 (36-94) 69.6 (36-95) 0.67Female gender, n (%) 90 (52) 44 (51.2) 46 (52.9) 0.82Main 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) 0.82Arrival to hospital in < 24 h, n (%) 130 (75.1) 63 (73.3) 67 (77.0) 0.57NIHSS at hospital arrival, median (range) 14.32 (1-38) 14.30 (1-38) 14.33 (1-38) 0.98Neurovascular 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) 0.38MCA territory, n (%) 130 (75.1) 65 (75.6) 65 (74.7) 0.89Posterior circulation brain infarction, n (%) 29 (16.8) 13 (15.1) 16 (18.4) 0.56MCA, middle cerebral artery; NIHSS, National Institutes of Health Stroke Scale; TOAST, Trial of ORG-10172 in Acute Atroke Treatment. *P value for differencesbetween 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 ControlsVariables (N = 173) (N = 86) (N = 87) P value*Use of thrombolysis, n (%) 2 (1.1) 1 (1.2) 1 (1.1) 0.89Duration of hospitalization, median (range) 10.06 (1-92) 10.81 (1-92) 9.33 (1-55) 0.37Mechanical ventilation, n (%) 21 (12.3) 10 (11.9) 11 (12.6) 0.88Open craniectomy, n (%) 5 (2.9) 2 (2.4) 3 (3.4) 0.68In-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) 0.0330-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) 0.0890-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) 0.06mRS, modified Rankin score. *P value for differences between the citicoline group and controls; Pearson chi-square, Fisher exact test or Student’s t-test (formeans), as corresponded. †Deep vein thrombosis, pulmonary embolism, sepsis, systemic inflammatory response syndrome, multiorgan failure and shock.THOMSON REUTERS – Methods and Findings in Experimental and Clinical Pharmacology 2010, 32(5) 3
  • 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 lobartreatment on these clinical end points (Fig. 1). Adjusting for age, brain infarction cases were assessed. This could also account for thegender, 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% ofrate of systemic non-neurological complications acquired during patients with AIS (24), citicoline could be a cost-effective coadjuvanthospitalization (see Fig. 1A). However, after excluding patients who therapy given its benefits on short-term outcome. Longer periods ofreceived thrombolysis (n = 7, remaining 166 patients), citicoline observation are necessary in order to better clarify the benefits intreatment was only marginally associated with a lower 90-day mor- preventing functional disabilities. As most expenses are incurredtality 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-hospitalDISCUSSION complications and severe sequelae or death at short-term would beAIS is the second leading cause of death and the first cause of cost-effective. Moreover, the fact that citicoline can also have someacquired 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 beand 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. Butits brief therapeutic window, the latent risk of bleeding, the absolute In the present study, the use of citicoline was associated with a lowerneed 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 beneficialof stroke patients (19). Developing nations still have pending issues effect, mainly related to outcome after systemic infections and organin 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 couldadapted 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 citicolinefeasible, 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 exploreanalysis 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 ratesectors (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 bemid-term functional outcomes (10, 11, 14). In the present study, the interpreted with caution. Given that some technical violations to theuse 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 difficultsurviving and a better short-term functional status, our study sug- to select a homogeneous and large sample size sufficiently poweredgests 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 aftergeneral wards. Whether this drug adds some benefit to the patient market launching and it is not rare that some off-label use of drugsmanaged completely in a stroke unit or with thrombolytics is a topic pave the way for new uses and indications. That the multivariatethat could not be explored in our study. However, none of the previ- analyses changed after excluding the few patients who receivedous studies (either experimental or observational) on the use of citi- thrombolysis could reflect the inherent problems of a small samplecoline 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 withlow rate of systemic non-neurological complications during hospital a better outcome compared with no neuroprotection.stay, since the reduction of systemic complications was greater thanthat for mortality. Alternatively, it is possible that patients with a bet- In conclusion, this postmarketing analysis shows that treatment withter chance of survival were intentionally given citicoline as a treat- citicoline is associated with several clinical benefits that should bement 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 MEXICOFigure 1. Forest plots showing the odds ratios (95% CI) obtained in 10 multivariate analyses on the main outcome measures: 5 logistic regression models formodel 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 receivedthrombolysis (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 ischemicintervention. The finding that citicoline is associated with a lower risk stroke: Drug surveillance study in 4,191 cases. Methods Find Exp Clinof 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-PAThis 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 4.5in 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 alteplasemit 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 neuroprotection (GAIN international) in patients with acute stroke. A ran-REFERENCES domised controlled trial. GAIN International Investigators. Lancet 2000, 1. Gladstone, D.J., Black, S.E., Hakim, A.M.; Heart and Stroke Foundation of 355(9219): 1949-54. Ontario Centre of Excellence in Stroke Recovery. Toward wisdom from 21. Muir, K.W., Lees, K.R., Ford, I., Davis, S. Magnesium for acute stroke (intra- failure: Lessons from neuroprotective stroke trials and new therapeutic venous magnesium efficacy in stroke trial). A randomised controlled trial. directions. Stroke 2002, 33(8): 2123-36. Lancet 2004, 363(9407): 439-45. 2. Diener, H.C., Lees, K.R., Lyden, P. et al. NXY-059 for the treatment of 22. Martínez, H.R., Rangel-Guerra, R.A., Marfil-Rivera, A., Muñiz, C.E., acute stroke: Pooled analysis of the SAINT I and II trials. Stroke 2008, Sagástegui, A. Cost of stroke in Mexico. 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