Browsing by Author "Navarro, J.C."

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    Antiplatelet therapy and the effects of B vitamins in patients with previous stroke or transient ischaemic attack: a post-hoc subanalysis of VITATOPS, a randomised, placebo-controlled trial
    (Lancet Publishing Group, 2012) Hankey, G.J.; Eikelboom, J.W.; Yi, Q.; Lees, K.R.; Chen, C.; Xavier, D.; Navarro, J.C.; Ranawaka, U.K.; Uddin, W.; Ricci, S.; Gommans, J.; Schmidt, R.; VITATOPS trial study group
    BACKGROUND: Previous studies have suggested that any benefits of folic acid-based therapy to lower serum homocysteine in prevention of cardiovascular events might be offset by concomitant use of antiplatelet therapy. We aimed to establish whether there is an interaction between antiplatelet therapy and the effects of folic acid-based homocysteine-lowering therapy on major vascular events in patients with stroke or transientischaemic attack enrolled in the vitamins to prevent stroke (VITATOPS) trial. METHODS: In the VITATOPS trial, 8164 patients with recent stroke or transient ischaemic attack were randomly allocated to double-blind treatment with one tablet daily of placebo or B vitamins (2 mg folic acid, 25 mg vitamin B(6), and 500 μg vitamin B(12)) and followed up for a median 3•4 years (IQR 2•0-5•5) for the primary composite outcome of stroke, myocardial infarction, or death from vascular causes. In our post-hoc analysis of the interaction between antiplatelet therapy and the effects of treatment with B vitamins on the primary outcome, we used Cox proportional hazards regression before and after adjusting for imbalances in baseline prognostic factors in participants who were and were not taking antiplatelet drugs at baseline and in participants assigned to receive B vitamins or placebo. We also assessed the interaction in different subgroups of patients and different secondary outcomes. The VITATOPS trial is registered with ClinicalTrials.gov, number NCT00097669, and Current Controlled Trials, number ISRCTN74743444. FINDINGS: At baseline, 6609 patients were taking antiplatelet therapy and 1463 were not. Patients not receiving antiplatelet therapy were more likely to be younger, east Asian, and disabled, to have a haemorrhagic stroke or cardioembolic ischaemic stroke, and to have a history of hypertension or atrial fibrillation. They were less likely to be smokers and to have a history of peripheral artery disease, hypercholesterolaemia, diabetes, ischaemicheart disease, and a revascularisation procedure. Of the participants taking antiplatelet drugs at baseline, B vitamins had no significant effect on the primary outcome (488 patients in the B-vitamins group [15%] vs 519 in the placebo group [16%]; hazard ratio [HR] 0•94, 95% CI 0•83-1•07). By contrast, of the participants not taking antiplatelet drugs at baseline, B vitamins had a significant effect on the primary outcome (123 in the B-vitaminsgroup [17%] vs 153 in the placebo group [21%]; HR 0•76, 0•60-0•96). The interaction between antiplatelet therapy and the effect of B vitamins on the primary outcome was significant after adjusting for imbalance in the baseline variables (adjusted p for interaction=0•0204). INTERPRETATION: Our findings support the hypothesis that antiplatelet therapy modifies the potential benefits of lowering homocysteine with B-vitamin supplementation in the secondary prevention of major vascular events. If validated, B vitamins might have a role in the prevention of ischaemicevents in high-risk individuals with an allergy, intolerance, or lack of indication for antiplatelet therapy. FUNDING: Australia National Health and Medical Research Council, UK Medical Research Council, Singapore Biomedical Research Council, and Singapore National Medical Research Council.
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    B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial.
    (Lancet Pub. Group, 2010) Hankey, G.J.; Eikelboom, J.W.; Baker, R.I.; Gelavis, A.; Hickling, S.C.; Jamrozik, K.; van Bockxmeer, F.M.; Vasikaran, S.; Chen, C.; Eikelboom, J.W.; Lees, K.R.; Yi, Q.; Hankey, G.J.; Algra, A.; Chen, C.; Wong, M.C.; Cheung, R.; Wong, I.; Divjak, I.; Ferro, J.; De Freitas, G.; Gommans, J.; Groppa, S.; Hill, M.; Spence, J.D.; Lees, K.R.; Lisheng, L.; Navarro, J.; Ranawaka, U.; Ricci, S.; Schmidt, R.; Slivka, A.; Tan, A.; Tsiskaridze, A.; Uddin, W.; Vanhooren, G.; Xavier, D.; Armitage, J.; Hobbs, M.; Le, M.; Sudlow, C.; Wheatley, K.; Yi, Q.; Brown, W.; Bulder, M.; Eikelboom, J.W.; Hankey, G.J.; Ho, W.K.; Jamrozik, K.; Klijn, C.J.; Koedam, E.; Langton, P.; Nijboer, E.; Tuch, P.; Pizzi, J.; Tang, M.; Alaparthi, R.; Antenucci, M.; Chew, Y.; Chinnery, C.; Cockayne, C.; Holt, R.; Loh, K.; McMullin, L.; Mulholland, G.; Nahoo, B.; Read, E.; Smith, F.; Yip, C.Y.; Hankey, G.J.; Loh, K.; Crimmins, D.; Davis, T.; England, M.; Rakic, V.; Schultz, D.W.; Frayne, J.; Bladin, C.; Kokkinos, J.; Dunbabin, D.; Harper, J.; Rees, P.; Warden, D.; Levi, C.; Parsons, M.; Russell, M.; Spratt, N.; Clayton, P.; Nayagam, P.; Sharp, J.; Grainger, K.; De Wytt, C.; McDougall, A.; Donnan, G.A.; Grimley, R.; Neynens, E.; Reinhart, B.; Ropele, S.; Schmidt, R.; Stögerer, E.; Dedeken, P.; Schelstraete, C.; Vanhooren, G.; Veyt, A.; Andre, C.; De Freitas, G.R.; Gomes, S.E.; Mok, V.C.; Wong, A.; Wong, L.K.; Cheung, R.T.; Li, L.S.; Pais, P.; Xavier, D.; Joshi, S.; Parthasaradhi, S.; Roy, A.K.; Varghese, R.V.; Kochar, K.; Panwar, R.B.; Chidambaram, N.; Rajasekaharan, U.; Bala, S.; Pandian, J.D.; Singh, Y.; Karadan, U.; Salam, A.; Shivkumar, S.; Sundararajan, A.; Joshi, R.; Kalantri, S.P.; Singh, H.; Rath, A.; Balasubramanian, N.T.; Kalanidhi, A.; Babu, K.; Bharani, A.; Choudhary, P.; Jain, M.; Agarwal, A.; Singh, M.; Agarwal, R.R.; Gupta, R.; Kothari, S.; Mijar, S.; Wadia, R.S.; Paul, S.K.; Sekhar Nandi, S.; Mehndiratta, M.M.; Tukaram, U.; Mittal, K.; Rohatgi, A.; Kumar, S.; Vinayan, K.P.; Muralidharan, R.S.; Celani, M.G.; Favorito, I.; Mazzoli, T.; Ricci, S.; Righetti, E.; Blundo, M.; Carnemolla, A.; D'Asta, A.; Giordano, A.; Iemolo, F.; Favorito, L.; Mazzoli, T.; Ricci, S.; Righetti, E.; Gresele, P.; Guercini, F.; Caporalini, R.; De Dominicis, L.; Giovagnetti, M.; Giuliani, G.; Paoletti, S.; Pucci, E.; Cavallini, A.; Persico, A.; Casoni, F.; Costa, A.; Magoni, M.; Spezi, R.; Tortorella, R.; Venturelli, E.; Vergani, V.; Caprioli, S.; Provisione, M.; Zanotta, D.; Abdullah, J.M.; Damitri, T.; Idris, B.; Sayuthi, S.; Hong, J.J.; Tan, C.T.; Tan, K.S.; Dutca, G.; Grigor, V.; Groppa, S.; Manea, D.; Achterberg, S.; Algra, A.; Halkes, P.H.; Kappelle, L.J.; Boon, A.M.; Doelman, J.C.; Sips, R.; Visscher, F.; Kwa, V.I.; Ternede, O.A.; van der Sande, J.J.; Frendin, T.; Gommans, J.; Anderson, N.E.; Bennett, P.; Charleston, A.; Spriggs, D.; Singh, J.; Bourke, J.; Bucknell, R.; McNaughton, H.; Anwar, A.; Murtaza, H.; Uddin, W.; Ismail, J.; Khan, N.U.; Navarro, J.C.; Amor, V.G.; Canete, M.T.; Lim, C.; Ravelo, E.B.; Siguenza, M.; Villahermosa, M.O.; Siguenza, M.; Canete, M.T.; Cardino, M.J.; Cenabre, R.; Gara, M.; Salas, Z.; Batac, A.; Canete, M.T.; Conde, L.; Dumdum, P.; Garcia, F.S.; Libarnes, S.; Matig-a, N.; Olanda, N.; Arcenas, R.; Canete, M.T.; Loraña, A.; Surdilla, A.; Araullo, M.L.; Lokin, J.; Maylem, G.; Marques, E.; Veloso, M.; Correia, M.; Lopes, G.; Canhão, P.; Ferro, J.M.; Melo, T.P.; Dias, A.; Sousa, A.P.; Tsiskaridze, A.; Vashadze, T.; Divjak, I.; Papic, V.; Chang, H.M.; Chen, C.P.; de Silva, D.A.; Tan, E.K.; Ranawaka, U.K.; Wijesekera, J.C.; de Silva, H.A.; Wijekoon, C.N.; Dawson, U.K.; Higgins, P.; Lees, K.R.; MacDonald, L.; McArthur, K.; McIlvenna, Y.; Quinn, T.; Walters, M.; Curless, R.; Dickson, J.; Murdy, J.; Scott, A.; Cameron, S.; Darnley, K.; Dennis, M.; Lyle, D.; Hunter, A.; Watt, M.; Watt, M.; Wiggam, I.; Murdy, J.; Rodgers, H.; Dick, F.; Macleod, M.; McKenzie, A.; Jones, P.; Jones, S.; Hussain, M.; Albazzaz, M.K.; Elliott, K.; Hardware, B.; Bacabac, E.; Martin, H.; Sharma, A.; Sutton, V.; Baht, H.; Cowie, L.; Gunathilagan, G.; Hargrove, D.R.; Smithard, D.J.; Adrian, M.; Bath, P.; Hammonds, F.; Maguire, H.; Roff, C.; Datta-chaudhuri, M.; Diyazee, K.; Krishnamoorthy, S.; McNulty, K.; Okwera, J.; Hilaire, C.; Kelly, D.; Barron, L.; James, M.; Wedge, N.; Bruce, M.; Macleod, M.; Barber, M.; Esson, D.; Ames, D.; Chataway, J.; Bulley, S.; Jenkins, K.; Rashed, K.; Dafalla, B.E.; Venugopalan, T.C.; Ball, M.; Punnoose, S.; Justin, F.; Sekaran, L.; Sethuraman, S.; Goddard, H.; Howard, J.; McIlmoyle, J.; Diver-Hall, C.; McCarron, M.; McNicholl, M.P.; Clamp, B.; Hunter, J.; Oke, A.; Weaver, A.; Fraser, P.; McAlpine, C.; Chambers, J.; Dymond, H.; Saunders, G.; Langhorne, P.; Stott, D.; Wright, F.; Adie, K.; Bland, R.; Courtauld, G.; Harrington, F.; James, A.; Mate, A.; Schofield, C.; Wroath, C.; Duberley, S.; Punekar, S.; Niranjan, K.; Sandler, D.; Krishna, P.; Moussouttas, M.; Notestine, M.A.; Slivka, A.; Vallini, D.; Hwang, T.; Saverance, M.; Booth, K.; Murphy, D.
    BACKGROUND: Epidemiological studies suggest that raised plasma concentrations of total homocysteine might be a risk factor for major vascular events. Whether lowering total homocysteine with B vitamins prevents major vascular events in patients with previous stroke or transient ischaemic attack is unknown. We aimed to assess whether the addition of once-daily supplements of B vitamins to usual medical care would lower total homocysteine and reduce the combined incidence of non-fatal stroke, non-fatal myocardial infarction, and death attributable to vascular causes in patients with recent stroke or transient ischaemic attack of the brain or eye. METHODS: In this randomised, double-blind, parallel, placebo-controlled trial, we assigned patients with recent stroke or transient ischaemic attack (within the past 7 months) from 123 medical centres in 20 countries to receive one tablet daily of placebo or B vitamins (2 mg folic acid, 25 mg vitamin B6, and 0.5 mg vitamin B12). Patients were randomly allocated by means of a central 24-h telephone service or an interactive website, and allocation was by use of random permuted blocks stratified by hospital. Participants, clinicians, carers, and investigators who assessed outcomes were masked to the assigned intervention. The primary endpoint was the composite of stroke, myocardial infarction, or vascular death. All patients randomly allocated to a group were included in the analysis of the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT00097669, and Current Controlled Trials, ISRCTN74743444. FINDINGS: Between Nov 19, 1998, and Dec 31, 2008, 8164 patients were randomly assigned to receive B vitamins (n=4089) or placebo (n=4075). Patients were followed up for a median duration of 3.4 years (IQR 2.0-5.5). 616 (15%) patients assigned to B vitamins and 678 (17%) assigned to placebo reached the primary endpoint (risk ratio [RR] 0.91, 95% CI 0.82 to 1.00, p=0.05; absolute risk reduction 1.56%, -0.01 to 3.16). There were no unexpected serious adverse reactions and no significant differences in common adverse effects between the treatment groups. INTERPRETATION: Daily administration of folic acid, vitamin B6, and vitamin B12 to patients with recent stroke or transient ischaemic attack was safe but did not seem to be more effective than placebo in reducing the incidence of major vascular events. These results do not support the use of B vitamins to prevent recurrent stroke. The results of ongoing trials and an individual patient data meta-analysis will add statistical power and precision to present estimates of the effect of B vitamins. FUNDING: Australia National Health and Medical Research Council, UK Medical Research Council, Singapore Biomedical Research Council, Singapore National Medical Research Council, Australia National Heart Foundation, Royal Perth Hospital Medical Research Foundation, and Health Department of Western Australia.
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    Baseline characteristics and treatment response of patients from the Philippines in the CHIMES study
    (Wiley-Blackwell, 2014) Navarro, J.C.; Gan, H.H.; Lao, A.Y.; Baroque, A.C.; Hiyadan, J.H.; Chua, C.L.; San Jose, M.C.; Advincula, J.M.; Lee, C.F.; Bousser, M.G.; Chen, C.L.; CHIMES Study Investigators (38); de Silva, H.A. CHIMES Study Investigator; Ranawaka, U. CHIMES Study Investigator; Wijekoon, N. CHIMES Study Investigator
    BACKGROUND: The CHIMES Study compared MLC601 with placebo in patients with ischemic stroke of intermediate severity in the preceding 72 h. Sites from the Philippines randomized 504 of 1099 (46%) patients in the study. We aimed to define the patient characteristics and treatment responses in this subgroup to better plan future trials. METHODS: The CHIMES dataset was used to compare the baseline characteristics, time from stroke onset to study treatment initiation, and treatment responses to MLC601 between patients recruited from Philippines and the rest of the cohort. Treatment effect was analyzed using end-points at month 3 as described in the primary publication, that is, modified Rankin Score, National Institutes of Health Stroke Scale, and Barthel Index. RESULTS: The Philippine cohort was younger, had more women, worse baseline National Institutes of Health Stroke Scale, and longer time delay from stroke onset to study treatment compared with the rest of the cohort. Age (P = 0•003), baseline National Institutes of Health Stroke Scale (P < 0•001), and stroke onset to study treatment initiation (P  = 0•016) were predictors of modified Rankin Score at three-months. Primary analysis of modified Rankin Score shift was in favor of MLC601 (adjusted odds ratio 1•41, 95% confidence interval 1•01–1•96). Secondary analyses were likewise in favor of MLC601 for modified Rankin Score dichotomy 0–1, improvement in National Institutes of Health Stroke Scale (total and motor scores), and Barthel Index. CONCLUSIONS: The treatment effects in the Philippine cohort were in favor of MLC601. This may be due to inclusion of more patients with predictors of poorer outcome.
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    CHIMES-I: sub-group analyzes of the effects of NeuroAiD according to baseline brain imaging characteristics among patients randomized in the CHIMES study
    (Sage Publications, 2013) Navarro, J.C.; Chen, C.L.; Lagamayo, P.D.; Geslani, M.B.; Eow, G.B.; Poungvarin, N.; de Silva, A.; Wong, L.K.; Venketasubramanian, N.; CHIMES Investigators
    RATIONALE: The clinical effects of neuroprotective and/or neurorestorative therapies may vary according to location and size of the ischemic injury. Imaging techniques can be useful in stratifying patients for trials that may be beneficial against particular ischemic lesion characteristics. AIM: To test the hypothesis that the efficacy of NeuroAiD compared with placebo in improving functional outcome and reducing neurological deficit in patients with cerebral infarction of intermediate severity varies between sub-groups of patients randomized in the main Chinese Medicine Neuroaid Efficacy on Stroke study when categorized according to baseline imaging characteristics. DESIGN: This is a retrospective cohort sub-group analysis of patients who participated in the main Chinese Medicine Neuroaid Efficacy on Stroke study, a multicenter, double-blind, placebo-controlled trial that recruited 1100 patients within 72 h of ischemic stroke onset with National Institutes of Health Stroke Scale 6-14 and were randomized to either NeuroAiD or placebo taken four capsules three times daily for three months. Review of the baseline images to classify the acute stroke lesions in terms of size, location, and extent of involvement will be performed retrospectively by two readers who will remain blinded as to treatment allocation and outcomes of the subjects. STUDY OUTCOMES: The primary efficacy end-point in the main Chinese Medicine Neuroaid Efficacy on Stroke study is the modified Rankin Scale grades at three-months. Secondary efficacy end-points are the National Institutes of Health Stroke Scale score at three-months; difference of National Institutes of Health Stroke Scale scores between baseline and 10 days and between baseline and three-months; difference of National Institutes of Health Stroke Scale sub-scores between baseline and 10 days and between baseline and three-months; modified Rankin Scale at 10 days, one-month, and three-months; Barthel index at three-months; and Mini Mental State Examination at 10 days and three-months. Analysis of these primary and secondary end-points will be performed for sub-groups defined in this study after review of the baseline brain imaging: nonlacunar and lacunar, cortical and sub-cortical, hemispheric vs. brainstem, Alberta Stroke Program Early CT score <7 and 7-10, and score <8 and 8-10.
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    Chinese medicine NeuroAiD efficacy on stroke recovery - extension study (CHIMES-E): A multicenter study of long-term efficacy
    (Karger Publisher, 2015) Venketasubramanian, N.; Young, S.H.; Tay, S.S.; Umapathi, T.; Lao, A.Y.; Gan, H.H.; Baroque II, A.C.; Navarro, J.C.; Chang, H.M.; Advincula, J.M.; Muengtaweepongsa, S.; Chan, B.P.; Chua, C.L.; Wijekoon, N.; de Silva, H.A.; Hiyadan, J.H.; Suwanwela, N.C.; Wong, K.S.; Poungvarin, N.; Eow, G.B.; Lee, C.F.; Chen, C.L.
    BACKGROUND: The CHInese Medicine NeuroAiD Efficacy on Stroke recovery (CHIMES) study was an international randomized double-blind placebo-controlled trial of MLC601 (NeuroAiD) in subjects with cerebral infarction of intermediate severity within 72 h. CHIMES-E (Extension) aimed at evaluating the effects of the initial 3-month treatment with MLC601 on long-term outcome for up to 2 years. METHODS: All subjects randomized in CHIMES were eligible for CHIMES-E. Inclusion criteria for CHIMES were age ≥18, baseline National Institute of Health Stroke Scale of 6-14, and pre-stroke modified Rankin Scale (mRS) ≤1. Initial CHIMES treatment allocation blinding was maintained, although no further study treatment was provided in CHIMES-E. Subjects received standard care and rehabilitation as prescribed by the treating physician. mRS, Barthel Index (BI), and occurrence of medical events were ascertained at months 6, 12, 18, and 24. The primary outcome was mRS at 24 months. Secondary outcomes were mRS and BI at other time points. RESULTS: CHIMES-E included 880 subjects (mean age 61.8 ± 11.3; 36% women). Adjusted OR for mRS ordinal analysis was 1.08 (95% CI 0.85-1.37, p = 0.543) and mRS dichotomy ≤1 was 1.29 (95% CI 0.96-1.74, p = 0.093) at 24 months. However, the treatment effect was significantly in favor of MLC601 for mRS dichotomy ≤1 at 6 months (OR 1.49, 95% CI 1.11-2.01, p = 0.008), 12 months (OR 1.41, 95% CI 1.05-1.90, p = 0.023), and 18 months (OR 1.36, 95% CI 1.01-1.83, p = 0.045), and for BI dichotomy ≥95 at 6 months (OR 1.55, 95% CI 1.14-2.10, p = 0.005) but not at other time points. Subgroup analyses showed no treatment heterogeneity. Rates of death and occurrence of vascular and other medical events were similar between groups. CONCLUSIONS: While the benefits of a 3-month treatment with MLC601 did not reach statistical significance for the primary endpoint at 2 years, the odds of functional independence defined as mRS ≤1 was significantly increased at 6 months and persisted up to 18 months after a stroke. © 2015 S. Karger AG, Basel.
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    Chinese medicine neuroaid efficacy on stroke recovery: a double-blind, placebo-controlled, randomized study
    (Lippincott Williams and Wilkins, 2013) Chen, C.L.; Young, S.H.; Gan, H.H.; Singh, R.; Lao, A.Y.; Baroque, A.C.; Chang, H.M.; Hiyadan, J.H.; Chua, C.L.; Advincula, J.M.; Muengtaweepongsa, S.; Chan, B.P.; de Silva, H.A.; Towanabut, S.; Suwanwela, N.C.; Poungvarin, N.; Chankrachang, S.; Wong, K.S.; Eow, G.B.; Navarro, J.C.; Venketasubramanian, N.; Lee, C.F.; Bousser, M.G.; CHIMES Study Investigators
    BACKGROUND AND PURPOSE: Previous clinical studies suggested benefit for post stroke recovery when MLC601 was administered between 2 weeks and 6 months of stroke onset. The Chinese Medicine Neuroaid Efficacy on Stroke recovery (CHIMES) study tested the hypothesis that MLC601 is superior to placebo in acute, moderately severe ischemic stroke within a 72-hour time window. METHODS: This multicenter, double-blind, placebo-controlled trial randomized 1100 patients with a National Institutes of Health Stroke Scale score 6 to 14, within 72 hours of onset, to trial medications for 3 months. The primary outcome was a shift in the modified Rankin Scale. Secondary outcomes were modified Rankin Scale dichotomy, National Institutes of Health Stroke Scale improvement, difference in National Institutes of Health Stroke Scale total and motor scores, Barthel index, and mini-mental state examination. Planned subgroup analyses were performed according to age, sex, time to first dose, baseline National Institutes of Health Stroke Scale, presence of cortical signs, and antiplatelet use. RESULTS: The modified Rankin Scale shift analysis-adjusted odds ratio was 1.09 (95% confidence interval, 0.86-1.32). Statistical difference was not detected between the treatment groups for any of the secondary outcomes. Subgroup analyses showed no statistical heterogeneity for the primary outcome; however, a trend toward benefit in the subgroup receiving treatment beyond 48 hours from stroke onset was noted. Serious and nonserious adverse events rates were similar between the 2 groups.CONCLUSIONS:MLC601 is statistically no better than placebo in improving outcomes at 3 months when used among patients with acute ischemic stroke of intermediate severity. Longer treatment duration and follow-up of participants with treatment initiated after 48 hours may be considered in future studies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00554723.
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    Effect of B vitamins and lowering homocysteine on cognitive impairment in patients with previous stroke or transient ischemic attack: a prespecified secondary analysis of a randomized, placebo-controlled trial and meta-analysis
    (Lippincott Williams and Wilkins, 2013) Hankey, G.J.; Ford, A.H.; Yi, Q.; Eikelboom, J.W.; Lees, K.R.; Chen, C.; Xavier, D.; Navarro, J.C.; Ranawaka, U.K.; Uddin, W.; Ricci, S.; Gommans, J.; Schmidt, R.; Almeida, O.P.; van Bockxmeer, F.M.; VITATOPS Trial Study Group
    BACKGROUND AND PURPOSE: High plasma total homocysteine (tHcy) has been associated with cognitive impairment but lowering tHcy with B-vitamins has produced equivocal results. We aimed to determine whether B-vitamin supplementation would reduce tHcy and the incidence of new cognitive impairment among individuals with stroke or transient ischemic attack≥6 months previously. METHODS: A total of 8164 patients with stroke or transient ischemic attack were randomly allocated to double-blind treatment with one tablet daily of B-vitamins (folic acid, 2 mg; vitamin B6, 25 mg; vitamin B12, 500 μg) or placebo and followed up for 3.4 years (median) in theVITAmins TO Prevent Stroke (VITATOPS) trial. For this prespecified secondary analysis of VITATOPS, the primary outcome was a new diagnosis of cognitive impairment, defined as a Mini-Mental State Examination (MMSE) score<24 on ≥2 follow-up visits. Secondary outcomes were cognitive decline, and the mean tHcy and MMSE at final follow-up. RESULTS: A total of 3089 participants (38%) voluntarily undertook the MMSE>6 months after the qualifying stroke; 2608 participants were cognitively unimpaired (MMSE≥24), of whom 2214 participants (1110 B-vitamins versus 1104 placebo) had follow-up MMSEs during 2.8 years (median). At final follow-up, allocation to B-vitamins, compared with placebo, was associated with a reduction in mean tHcy (10.2 μmol/L versus 14.2 μmol/L; P<0.001) but no change from baseline in the mean MMSE score (-0.22 points versus -0.25 points; difference, 0.03; 95% confidence interval, -0.13 to 0.19; P=0.726) and no difference in the incidence of cognitive impairment (5.51% versus 5.47%; risk ratio, 1.01; 95% confidence interval, 0.69-1.48; P=0.976), cognitive decline (9.1% versus 10.3%; risk ratio, 0.89; 0.67-1.18; P=0.414), or cognitive impairment or decline (11.0% versus 11.3%; risk ratio, 0.98; 0.75-1.27; P=0.855). CONCLUSIONS: Daily supplementation with folic acid, vitamin B6, and vitamin B12 to a self-selected clinical trial cohort of cognitively unimpaired patients with previous stroke or transient ischemic attack lowered mean tHcy but had no effect on the incidence of cognitiveimpairment or cognitive decline, as measured by the MMSE, during a median of 2.8 years. CLINICAL TRIAL REGISTRATION: URL: http://www.controlled-trials.com. Unique identifier: ISRCTN74743444; URL: http://www.clinicaltrials.gov. Unique identifier: NCT00097669.
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    Effect of Combined Treatment with MLC601 (NeuroAiDTM) and Rehabilitation on Post-Stroke Recovery: The CHIMES and CHIMES-E Studies
    (Karger, 2018) Suwanwela, N.C.; Chen, C.L.H.; Lee, C.F.; Young, S.H.; Tay, S.S.; Umapathi, T.; Lao, A.Y.; Gan, H.H.; Baroque li, A.C.; Navarro, J.C.; Chang, H.M.; Advincula, J.M.; Muengtaweepongsa, S.; Chan, B.P.L.; Chua, C.L.; Wijekoon, N.; de Silva, H.A.; Hiyadan, J.H.B.; Wong, K.S.L.; Poungyarin, N.; Eow, G.B; Venketasubramanian, N.; CHIMES-E Study Investigators
    BACKGROUND AND PURPOSE: MLC601 has been shown in preclinical studies to enhance neurorestorative mechanisms after stroke. The aim of this post hoc analysis was to assess whether combining MLC601 and rehabilitation has an effect on improving functional outcomes after stroke. METHODS: Data from the CHInese Medicine NeuroAiD Efficacy on Stroke (CHIMES) and CHIMES-Extension (CHIMES-E) studies were analyzed. CHIMES-E was a 24-month follow-up study of subjects included in CHIMES, a multi-centre, double-blind placebo-controlled trial which randomized subjects with acute ischemic stroke, to either MLC601 or placebo for 3 months in addition to standard stroke treatment and rehabilitation. Subjects were stratified according to whether they received or did not receive persistent rehabilitation up to month (M)3 (non- randomized allocation) and by treatment group. The modified Rankin Scale (mRS) and Barthel Index were assessed at month (M) 3, M6, M12, M18, and M24. RESULTS: Of 880 subjects in CHIMES-E, data on rehabilitation at M3 were available in 807 (91.7%, mean age 61.8 ± 11.3 years, 36% female). After adjusting for prognostic factors of poor outcome (age, sex, pre-stroke mRS, baseline National Institute of Health Stroke Scale, and stroke onset-to-study-treatment time), subjects who received persistent rehabilitation showed consistently higher treatment effect in favor of MLC601 for all time points on mRS 0-1 dichotomy analysis (ORs 1.85 at M3, 2.18 at M6, 2.42 at M12, 1.94 at M18, 1.87 at M24), mRS ordinal analysis (ORs 1.37 at M3, 1.40 at M6, 1.53 at M12, 1.50 at M18, 1.38 at M24), and BI ≥95 dichotomy analysis (ORs 1.39 at M3, 1.95 at M6, 1.56 at M12, 1.56 at M18, 1.46 at M24) compared to those who did not receive persistent rehabilitation. CONCLUSIONS: More subjects on MLC601 improved to functional independence compared to placebo among subjects receiving persistent rehabilitation up to M3. The larger treatment effect of MLC601 was sustained over 2 years which supports the hypothesis that MLC601 combined with rehabilitation might have beneficial and sustained effects on neuro-repair processes after stroke. There is a need for more data on the effect of combining rehabilitation programs with stroke recovery treatments.
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    Treatment with B vitamins and incidence of cancer in patients with previous stroke or transient ischemic attack: results of a randomized placebo-controlled trial
    (Lippincott Williams and Wilkins, 2012) Hankey, G.J.; Eikelboom, J.W.; Yi, Q.; Lees, K.R.; Chen, C.; Xavier, D.; Navarro, J.C.; Ranawaka, U.K.; Uddin, W.; Ricci, S.; Gommans, J.; Schmidt, R.; VITAmins TO Prevent Stroke (VITATOPS) Trial Study Group
    BACKGROUND AND PURPOSE: To determine the effect of B vitamin treatment on the incidence of cancer among patients with stroke or transient ischemic attack. METHODS: A total of 8164 patients with recent stroke or transient ischemic attack were randomly allocated to double-blind treatment with 1 tablet daily of placebo or B vitamins (2 mg folic acid, 25 mg vitamin B(6), 500 μg vitamin B(12)) and followed for a median of 3.4 years for any cancer as an adverse event. RESULTS: There was no significant difference in the incidence of any cancer among participants assigned B vitamins compared with placebo (4.04% versus 4.59%; risk ratio, 0.86; 95% CI, 0.70-1.07) and no difference in cancer mortality (2.35% versus 2.09%; risk ratio, 1.09; 0.81-1.46). Among 1899 patients with diabetes, the incidence of cancer was higher among participants assigned B vitamins compared with placebo (5.35% versus 3.28%; adjusted risk ratio, 2.21; 1.31-3.73), whereas among 6168 patients without diabetes, the incidence of cancer was lower among participants assigned B vitamins compared with placebo (3.66% versus 5.03%; adjusted risk ratio, 0.67; 0.51-0.87; P for interaction=0.0001). CONCLUSIONS: Daily administration of folic acid, vitamin B(6), and vitamin B(12) to 8164 patients with recent stroke or transient ischemic attack for a median of 3.4 years had no significant effect, compared with placebo, on cancer incidence or mortality. However, a post hoc subgroup analysis raises the hypothesis that folic acid treatment may increase the incidence of cancer among diabetics and reduce the incidence of cancer among non diabetics with a history of stroke or transient ischemic attack.