Browsing by Author "Armitage, J."

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Advances in lipid-modification for the prevention of vascular disease
(Faculty of Medicine, University of Kelaniya, Sri Lanka, 2016) Armitage, J.
OBJECTIVES : 1. To understand the importance of different lipids to vascular disease risk and how genetics have helped 2. To reiterate the value and safety of statins as a first line therapy for lipid modification 3. To explain the potential role of newer lipid-lowering agents: PCSK9 inhibitors, cholesterol ester transfer protein inhibitors and small interfering RNAs to block lipid-related protein synthesis Observational studies indicate a clear, positive and continuous relationship between coronary heart disease risk and blood LDL- cholesterol levels and inverse associations with HDL-cholesterol. Recent genetic evidence also supports a causal role for CETP, lipoprotein (a) [Lp(a)], apoC3, ANGPLT3 and PCSK9 in vascular risk. Large, well-designed randomized trials of statins and meta-analyses of trials show that reductions of 20-25% in the risk of vascular events are seen per 1 mmol/L reduction in LDL-cholesterol, with larger reductions producing greater benefits. Statins are safe and well tolerated although the risk factors for the rare side-effect of myopathy need to be understood to allow their use most safely and effectively. The results of trials of HDL-raising have so far been disappointing, both because older drugs were toxic (niacin) and other studies may have been underpowered to detect plausible effects. An alternative explanation is that HDL-cholesterol is not causally related to vascular disease but only associated and there is supportive genetic data for this view. Newer agents such as monoclonal antibodies against PCSK9 and CETP inhibitors are currently in Phase 3 trials and clearly reduce LDL levels substantially with CETP inhibitors also increasing HDL-cholesterol and show promise for vascular risk reduction but are likely to be very expensive and are not yet proven. Results will emerge in the next couple of years.
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.
Bad cholesterol, vascular risk and dementia
(Faculty of Medicine, University of Kelaniya, Sri Lanka, 2016) Armitage, J.
The prevalence of dementia and cognitive impairment is increasing globally as lifespan lengthens and presents major health care challenges as well as creating significant social burdens. Although Alzheimer disease is the most common type of dementia, autopsy and neuroimaging studies show that the majority of dementia cases also have cerebral vascular pathology (such as infarcts, white matter lesions and cerebral microbleeds). In keeping with this, many studies and systematic reviews have shown that higher levels of vascular risk factors and cardiovascular disease predict future risk of dementia and cognitive decline. The extent to which modifying vascular risk factors such as blood cholesterol and blood pressure might prevent dementia has become an important question. Using data from 3 large randomised trials of cholesterol modification we have estimated the impact of different types of incident vascular events on cognitive aging to help understand the potential power of randomised studies to detect such effects. These data provide quantitative estimates of the impact of LDL-lowering on cognitive aging and will be presented.
Prevention of acute adverse reactions to snake antivenom after snakebite: multi-centre, randomized, controlled clinical trial
(Sri Lanka Medical Association, 2009) de Silva, H.A.; Ranasinha, C.D.; Pathmeswaran, A.; Jayamanne, S.; Kalupahana, R.; Ratnathilake, G.A.; Ariyasena, H.; Uluwatte, W.; Lalloo, D.; Armitage, J.; Aronson, J.K.; de Silva, H.J.
BACKGROUND: Antivenom is the most effective treatment for snakebite envenoming. Acute adverse reactions to the polyvalent antivenom (PAV) are common; anaphylactk reactions are particularly serious. OBJECTIVE: To determine whether promethazine, hydrocortisone, and low-dose adrenaline, alone and in all possible combinations, prevent reactions to antivenom. METHODS: The study was conducted in 3 hospitals in Sri Lanka from March 2005 to April 2008. It required 1000 patients to detect a 25% reduction in reactions at p<0.01 with 80% power. After informed consent, patients were randomized in a 2x2x2 factorial blinded design to receive each active intervention versus matching placebo immediately before administration of PAV. They were monitored for adverse reactions categorized as mild, moderate, severe, for at least 96 hours. The pre-specified primary analyses were of effects of each intervention on the incidence of severe reactions over 48 hours. Results: Of 1007 randomized subjects 776 (77.2%) were males, mean (sd) age 36.5 (13.6) yrs. Median time between snakebite and PAV administration was 4.25 hours. 752 (75%) patients developed acute reactions to PAV; 9% mild, 48% moderate and 43% severe. None of the drugs significantly reduced severe reactions to PAV at any time point. However, there was an 18% reduction in the rate of severe reactions at 1 hour with adrenaline (p-0.052) and a 33-3% reduction in signs of allergy (pruritus, urticaria, facial oedema, bronchospasm) with promethazine at 1 and 24 hours (p<0.001). CONCLUSIONS: Pre-treatment with promethazine, hydrocortisone, and low-dose adrenaline alone and in different combinations do not significantly reduce acute reactions to PAV.
VITATOPS, the Vitamins to prevent stroke trial: rationale and design of a randomised trial of B vitamin therapy in patients with recent transient ischaemic attack or stroke (NCT00097669) (ISRCTN74743444)
(Sage Publications, 2007) VITATOPS Trial Study Group; Hankey, G.J.; Algra, A.; Chen, C.; Wong, M.C.; Cheung, R.; Wong, L.; Divjak, I.; Ferro, J.; De Freitas, G.; Gommans, J.; Groppa, S.; Hill, M.; Spence, D.; Lees, K.; Lisheng, L.; Navarro, J. J.; Ranawaka, U.; Ricci, S.; Schmidt, R.; Slivka, A.; Tan, K.; Tsiskaridze, A.; Uddin, W.; Vanhooren, G.; Xavier, D.; Armitage, J.; Hobbs, M.; Le, M.; Sudlow, C.; Wheatley, K.; Yi, Q.; Bulder, M.; Eikelboom, J.W.; Hankey, G.J.; Ho, W.K.; Jamrozik, K.; Klijn, K.; Koedam, E.; Langton, P.; Nijboer, E.; Tuch, P.; Pizzi, J.; Tang, M.; Antenucci, M.; Chew, Y.; Chinnery, D.; Cockayne, C.; Loh, K.; McMullin, L.; Smith, F.; Schmidt, R.; Chen, C.; Wong, M.C.; De Freitas, G.; Hankey, G.J.; Loh, K.; Song, S.
BACKGROUND: Epidemiological studies suggest that raised plasma concentrations of total homocysteine (tHcy) may be a common, causal and treatable risk factor for atherothromboembolic ischaemic stroke, dementia and depression. Although tHcy can be lowered effectively with small doses of folic acid, vitamin B(12) and vitamin B(6), it is not known whether lowering tHcy, by means of B vitamin therapy, can prevent stroke and other major atherothromboembolic vascular events. AIM: To determine whether the addition of B-vitamin supplements (folic acid 2 mg, B(6) 25 mg, B(12) 500 microg) to best medical and surgicalmanagement will reduce the combined incidence of stroke, myocardial infarction (MI) and vascular death in patients with recent stroke or transient ischaemic attack (TIA) of the brain or eye. DESIGN: A prospective, international, multicentre, randomised, double blind, placebo-controlled clinical trial. SETTING: One hundred and four medical centres in 20 countries on five continents. SUBJECTS: Eight thousand (6600 recruited as of 5 January, 2006) patients with recent (<7 months) stroke (ischaemic or haemorrhagic) or TIA (brain or eye). RANDOMISATION: Randomisation and data collection are performed by means of a central telephone service or secure internet site. INTERVENTION: One tablet daily of either placebo or B vitamins (folic acid 2 mg, B(6) 25 mg, B(12) 500 mug). PRIMARY OUTCOME: The composite of stroke, MI or death from any vascular cause, whichever occurs first. Outcome and serious adverse events are adjudicated blinded to treatment allocation. SECONDARY OUTCOMES: TIA, unstable angina, revascularisation procedures, dementia, depression. STATISTICAL POWER: With 8000 patients followed up for a median of 2 years and an annual incidence of the primary outcome of 8% among patients assigned placebo, the study will have at least 80% power to detect a relative reduction of 15% in the incidence of the primary outcome among patients assigned B vitamins (to 6.8%/year), applying a two-tailed level of significance of 5%. CONCLUSION: VITATOPS aims to recruit and follow-up 8000 patients between 1998 and 2008, and provide a reliable estimate of the safety and effectiveness of folic acid, vitamin B(12), and vitamin B(6) supplementation in reducing recurrent serious vascular events among a wide range of patients with TIA and stroke throughout the world.