Browsing by Author "Lees, K.R."

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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.
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.
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.
Glyceryl Trinitrate for Acute Intracerebral Hemorrhage: Results From the Efficacy of Nitric Oxide in Stroke (ENOS) Trial, a Subgroup Analysis
(Dallas : American Heart Association, 2016) Krishnan, K.; Scutt, P.; Woodhouse, L.; Adami, A.; Becker, J.L.; Berge, E.; Cala, L.A.; Casado, A.M.; Caso, V.; Chen, C.; Christensen, H.; Collins, R.; Czlonkowska, A.; Dineen, R.A.; Gommans, J.; Koumellis, P.; Lees, K.R.; Ntaios, G.; Ozturk, S.; Phillips, S.J.; Pocock, S.J.; de Silva, A.; Sprigg, N.; Szatmari, S.; Wardlaw, J.M.; Bath, P.M.
BACKGROUND AND PURPOSE: The Efficacy of Nitric Oxide in Stroke (ENOS) trial found that transdermal glyceryl trinitrate (GTN, a nitric oxide donor) lowered blood pressure but did not improve functional outcome in patients with acute stroke. However, GTN was associated with improved outcome if patients were randomized within 6 hours of stroke onset. METHODS: In this prespecified subgroup analysis, the effect of GTN (5 mg/d for 7 days) versus no GTN was studied in 629 patients with intracerebral hemorrhage presenting within 48 hours and with systolic blood pressure ≥140 mm Hg. The primary outcome was the modified Rankin Scale at 90 days. RESULTS: Mean blood pressure at baseline was 172/93 mm Hg and significantly lower (difference -7.5/-4.2 mm Hg; both P≤0.05) on day 1 in 310 patients allocated to GTN when compared with 319 randomized to no GTN. No difference in the modified Rankin Scale was observed between those receiving GTN versus no GTN (adjusted odds ratio for worse outcome with GTN, 1.04; 95% confidence interval, 0.78-1.37; P=0.84). In the subgroup of 61 patients randomized within 6 hours, GTN improved functional outcome with a shift in the modified Rankin Scale (odds ratio, 0.22; 95% confidence interval, 0.07-0.69; P=0.001). There was no significant difference in the rates of serious adverse events between GTN and no GTN. CONCLUSIONS: In patients with intracerebral hemorrhage within 48 hours of onset, GTN lowered blood pressure was safe but did not improve functional outcome. Very early treatment might be beneficial but needs assessment in further studies.
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.