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Is There Really a Power Shortage in Clinical Trials Testing the “Homocysteine Hypothesis?”

2004; Lippincott Williams & Wilkins; Volume: 24; Issue: 8 Linguagem: Inglês

10.1161/01.atv.0000136385.50973.68

1524-4636

Graeme J. Hankey, John W. Eikelboom, K. Loh, Qilong Yi, J. Pizzi, Miaoling Tang, Siobhan Hickling, Minh-Phuong T. Le, Catharina J.M. Klijn, Petcharat Dusitanond, Frank van Bockxmeer, Anna Gelavis, Ross Baker, Konrad Jamrozik,

Health Systems, Economic Evaluations, Quality of Life

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 24, No. 8Is There Really a Power Shortage in Clinical Trials Testing the "Homocysteine Hypothesis?" Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBIs There Really a Power Shortage in Clinical Trials Testing the "Homocysteine Hypothesis?" G.J. Hankey, J.W. Eikelboom, K. Loh, Q. Yi, J. Pizzi, M. Tang, S. Hickling, M. Le, C.J. M. Klijn, P. Dusitanond, F. van Bockxmeer, A. Gelavis, R. Baker and K. Jamrozik G.J. HankeyG.J. Hankey Stroke Unit (G.J.H., K.L., J.P., M.T., C.J.M.K., P.D.), Departments of Haematology (J.W.E., R.B.), Pathology (F.v.B.), and Pharmacy (A.G.), Royal Perth Hospital, Perth, Australia;, School of Medicine & Pharmacology (G.J.H., J.W.E., F.v.B., R.B.), School of Population Health (S.H., M.L., K.J.), University of Western Australia;, Biostatistics Department (Q.Y.), Princess Margaret Hospital, Toronto, Canada;, Imperial College (K.J.), London, United Kingdom , J.W. EikelboomJ.W. Eikelboom Stroke Unit (G.J.H., K.L., J.P., M.T., C.J.M.K., P.D.), Departments of Haematology (J.W.E., R.B.), Pathology (F.v.B.), and Pharmacy (A.G.), Royal Perth Hospital, Perth, Australia;, School of Medicine & Pharmacology (G.J.H., J.W.E., F.v.B., R.B.), School of Population Health (S.H., M.L., K.J.), University of Western Australia;, Biostatistics Department (Q.Y.), Princess Margaret Hospital, Toronto, Canada;, Imperial College (K.J.), London, United Kingdom , K. LohK. Loh Stroke Unit (G.J.H., K.L., J.P., M.T., C.J.M.K., P.D.), Departments of Haematology (J.W.E., R.B.), Pathology (F.v.B.), and Pharmacy (A.G.), Royal Perth Hospital, Perth, Australia;, School of Medicine & Pharmacology (G.J.H., J.W.E., F.v.B., R.B.), School of Population Health (S.H., M.L., K.J.), University of Western Australia;, Biostatistics Department (Q.Y.), Princess Margaret Hospital, Toronto, Canada;, Imperial College (K.J.), London, United Kingdom , Q. YiQ. Yi Stroke Unit (G.J.H., K.L., J.P., M.T., C.J.M.K., P.D.), Departments of Haematology (J.W.E., R.B.), Pathology (F.v.B.), and Pharmacy (A.G.), Royal Perth Hospital, Perth, Australia;, School of Medicine & Pharmacology (G.J.H., J.W.E., F.v.B., R.B.), School of Population Health (S.H., M.L., K.J.), University of Western Australia;, Biostatistics Department (Q.Y.), Princess Margaret Hospital, Toronto, Canada;, Imperial College (K.J.), London, United Kingdom , J. PizziJ. Pizzi Stroke Unit (G.J.H., K.L., J.P., M.T., C.J.M.K., P.D.), Departments of Haematology (J.W.E., R.B.), Pathology (F.v.B.), and Pharmacy (A.G.), Royal Perth Hospital, Perth, Australia;, School of Medicine & Pharmacology (G.J.H., J.W.E., F.v.B., R.B.), School of Population Health (S.H., M.L., K.J.), University of Western Australia;, Biostatistics Department (Q.Y.), Princess Margaret Hospital, Toronto, Canada;, Imperial College (K.J.), London, United Kingdom , M. TangM. Tang Stroke Unit (G.J.H., K.L., J.P., M.T., C.J.M.K., P.D.), Departments of Haematology (J.W.E., R.B.), Pathology (F.v.B.), and Pharmacy (A.G.), Royal Perth Hospital, Perth, Australia;, School of Medicine & Pharmacology (G.J.H., J.W.E., F.v.B., R.B.), School of Population Health (S.H., M.L., K.J.), University of Western Australia;, Biostatistics Department (Q.Y.), Princess Margaret Hospital, Toronto, Canada;, Imperial College (K.J.), London, United Kingdom , S. HicklingS. Hickling Stroke Unit (G.J.H., K.L., J.P., M.T., C.J.M.K., P.D.), Departments of Haematology (J.W.E., R.B.), Pathology (F.v.B.), and Pharmacy (A.G.), Royal Perth Hospital, Perth, Australia;, School of Medicine & Pharmacology (G.J.H., J.W.E., F.v.B., R.B.), School of Population Health (S.H., M.L., K.J.), University of Western Australia;, Biostatistics Department (Q.Y.), Princess Margaret Hospital, Toronto, Canada;, Imperial College (K.J.), London, United Kingdom , M. LeM. Le Stroke Unit (G.J.H., K.L., J.P., M.T., C.J.M.K., P.D.), Departments of Haematology (J.W.E., R.B.), Pathology (F.v.B.), and Pharmacy (A.G.), Royal Perth Hospital, Perth, Australia;, School of Medicine & Pharmacology (G.J.H., J.W.E., F.v.B., R.B.), School of Population Health (S.H., M.L., K.J.), University of Western Australia;, Biostatistics Department (Q.Y.), Princess Margaret Hospital, Toronto, Canada;, Imperial College (K.J.), London, United Kingdom , C.J. M. KlijnC.J. M. Klijn Stroke Unit (G.J.H., K.L., J.P., M.T., C.J.M.K., P.D.), Departments of Haematology (J.W.E., R.B.), Pathology (F.v.B.), and Pharmacy (A.G.), Royal Perth Hospital, Perth, Australia;, School of Medicine & Pharmacology (G.J.H., J.W.E., F.v.B., R.B.), School of Population Health (S.H., M.L., K.J.), University of Western Australia;, Biostatistics Department (Q.Y.), Princess Margaret Hospital, Toronto, Canada;, Imperial College (K.J.), London, United Kingdom , P. DusitanondP. Dusitanond Stroke Unit (G.J.H., K.L., J.P., M.T., C.J.M.K., P.D.), Departments of Haematology (J.W.E., R.B.), Pathology (F.v.B.), and Pharmacy (A.G.), Royal Perth Hospital, Perth, Australia;, School of Medicine & Pharmacology (G.J.H., J.W.E., F.v.B., R.B.), School of Population Health (S.H., M.L., K.J.), University of Western Australia;, Biostatistics Department (Q.Y.), Princess Margaret Hospital, Toronto, Canada;, Imperial College (K.J.), London, United Kingdom , F. van BockxmeerF. van Bockxmeer Stroke Unit (G.J.H., K.L., J.P., M.T., C.J.M.K., P.D.), Departments of Haematology (J.W.E., R.B.), Pathology (F.v.B.), and Pharmacy (A.G.), Royal Perth Hospital, Perth, Australia;, School of Medicine & Pharmacology (G.J.H., J.W.E., F.v.B., R.B.), School of Population Health (S.H., M.L., K.J.), University of Western Australia;, Biostatistics Department (Q.Y.), Princess Margaret Hospital, Toronto, Canada;, Imperial College (K.J.), London, United Kingdom , A. GelavisA. Gelavis Stroke Unit (G.J.H., K.L., J.P., M.T., C.J.M.K., P.D.), Departments of Haematology (J.W.E., R.B.), Pathology (F.v.B.), and Pharmacy (A.G.), Royal Perth Hospital, Perth, Australia;, School of Medicine & Pharmacology (G.J.H., J.W.E., F.v.B., R.B.), School of Population Health (S.H., M.L., K.J.), University of Western Australia;, Biostatistics Department (Q.Y.), Princess Margaret Hospital, Toronto, Canada;, Imperial College (K.J.), London, United Kingdom , R. BakerR. Baker Stroke Unit (G.J.H., K.L., J.P., M.T., C.J.M.K., P.D.), Departments of Haematology (J.W.E., R.B.), Pathology (F.v.B.), and Pharmacy (A.G.), Royal Perth Hospital, Perth, Australia;, School of Medicine & Pharmacology (G.J.H., J.W.E., F.v.B., R.B.), School of Population Health (S.H., M.L., K.J.), University of Western Australia;, Biostatistics Department (Q.Y.), Princess Margaret Hospital, Toronto, Canada;, Imperial College (K.J.), London, United Kingdom and K. JamrozikK. Jamrozik Stroke Unit (G.J.H., K.L., J.P., M.T., C.J.M.K., P.D.), Departments of Haematology (J.W.E., R.B.), Pathology (F.v.B.), and Pharmacy (A.G.), Royal Perth Hospital, Perth, Australia;, School of Medicine & Pharmacology (G.J.H., J.W.E., F.v.B., R.B.), School of Population Health (S.H., M.L., K.J.), University of Western Australia;, Biostatistics Department (Q.Y.), Princess Margaret Hospital, Toronto, Canada;, Imperial College (K.J.), London, United Kingdom Originally published1 Aug 2004https://doi.org/10.1161/01.ATV.0000136385.50973.68Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:e147To the Editor:Results from a Substudy of the VITAmins TO Prevent Stroke (VITATOPS) TrialSince January 1, 1998 the United States and Canada have implemented policies mandating the fortification of cereal grain flour products with folic acid (0.4 to 1.4 mg/lb) to reduce the risk of neural tube birth defects in newborns.1 The disadvantage of this measure for researchers is that randomized, controlled trials of total homocysteine (tHcy)-lowering therapy, by means of folic acid and other multivitamin therapies, to prevent cardiovascular outcomes in the US and Canada are likely to achieve only ≈20% to 25% of the initially projected mean treatment effects of tHcy-lowering therapy (1.0 to 2.0 μmol/L versus 4.0 to 6.0 μmol/L).2,3 Indeed, the recently completed Vitamins In Stroke Prevention (VISP) Study, which compared high-dose multivitamins (including folic acid 2.5 mg, vitamin B12 0.4 mg, and vitamin B6 25 mg) with low-dose multivitamins (including folic acid 0.02 mg, vitamin B12 0.006 mg, vitamin B6 0.2 mg) in 3,680 stroke survivors, only achieved a mean 2.0 μmol/L reduction in tHcy.4,5 The results failed to reliably exclude a modest but clinically important effect of folic acid–based multivitamin therapy in reducing the risk of major vascular events and death by up to 20% and 30%, respectively.5The VITAmins TO Prevent Stroke (VITATOPS) Trial is the only large randomized, double-blind, placebo-controlled trial currently testing the "homocysteine hypothesis" in patients with previous transient ischemic attack (TIA) or stroke.6,7 It is being conducted in 19 countries, most where mandatory folic acid fortification of cereal grain products is not implemented. Patients are randomized to once daily treatment with placebo or the combination of folic acid 2.0 mg plus vitamin B12 0.5 mg plus vitamin B6 25 mg. The projected average treatment effect is a 4.0 μmol/L reduction in tHcy.7We examined the effect of the active VITATOPS trial medication on mean tHcy concentrations at 6 months after randomization, compared with placebo, among 285 consecutive patients with recent stroke or TIA randomized in one center in Perth, Australia. Fasting plasma tHcy was measured at baseline and at 6 months after randomisation using high-performance liquid chromatography (HPLC). The significance of any difference in plasma tHcy between multivitamin- and placebo-treated patients was examined using an independent t test. For the purposes of this analysis, only a third-party statistician (Q.Y.) not involved in any aspects of the design or day-to-day running of the trial was unblinded to treatment allocation.Patients in the two treatment groups were well matched at baseline with regard to demographic variables and cardiovascular risk factors, and 250 of the original cohort of 285 patients underwent repeat blood testing at 6 months. The mean baseline tHcy level was 13.4 μmol/L in patients randomized to multivitamins and 12.8 μmol/L in patients randomized to placebo. This is similar to mean baseline tHcy levels of around 13.5 μmol/L in the VISP study.5 At 6 months, mean tHcy levels were 9.1 μmol/L in patients randomized to multivitamins compared with 12.8 μmol/L in those randomized to placebo (difference=3.7 μmol/L, 95% confidence interval 2.7 to 4.7 μmol/L, P<0.001) (Table). Fasting Plasma tHcy Levels at Baseline and 6 MonthsOutcomePlacebo (n=125)Folic Acid+Vitamin B12+Vitamin B6 (n=125)P-Value*The difference between the two treatment groups in tHcy at 6 months after randomisation is 12.8−9.1 μmol/L= 3.7 μmol/L, 95% confidence interval: 2.7 to 4.7 μmol/L (P<0.0001).Baseline (μmol/L), mean (SD)12.8 (5.1)13.4 (8.5)0.416 Months (μmol/L), mean (SD)*12.8 (5.1)9.1 (2.5)<0.0001Difference from baseline, mean (SD)0 (3.8)−4.3 (4.2)<0.0001Based on these data, if elevated tHcy is causally related to atherothrombotic events of the heart, brain, and limbs, the 3.7 μmol/L reduction in plasma tHcy achieved with the VITATOPS tablets in our study should reduce the risk of subsequent serious vascular events by at least 15%,8,9 which is what our study was powered to detect with a type I error of 5% and type II error of 20%, assuming an average follow-up of 2 years.7The magnitude of homocysteine-lowering observed in our Australian population (where voluntarily fortification of foods with folic acid is increasing) may not be correlated to TIA and stroke patients in many other countries participating in the VITATOPS trial (eg, Hong Kong, India, Malaysia, Moldova, Pakistan, Philippines, Singapore, Sri Lanka) where nutritional status is likely to be lower and any effect of supplementation is also likely to be lower or nonexistent.However, our estimate of the effect of multivitamins on plasma tHcy is unlikely to be exaggerated by survival bias or loss to follow-up because a similar number died or declined repeat blood testing from each treatment group and baseline characteristics of these patients were similar to those of patients who underwent repeat blood collection at 6 months (data not presented). Furthermore, the observed treatment effect is likely to underestimate the true effect size because 9.1% of patients allocated active VITATOPS treatment ceased taking their VITATOPS tablets during the 6-month follow-up period, and some who were allocated placebo took up folic acid therapy.AcknowledgmentsThe VITATOPS trial is supported by the National Health and Medical Research Council of Australia (NHMRC), the National Heart Foundation of Australia (NHF), and the Health Department of Western Australia. The VITATOPS study tablets were supplied by Blackmores, Australia. C.J.M. Klijn is supported by a fellowship from the Niels Stensen Foundation and the Dr Jan Meerwaldt Foundation.1 Satchell FB, for the Food and Drug Administration, Health and Human Services. Food standards: amendments of standards of identity for enriched grain products to require addition of folic acid. Federal Register. 1996; 61: 8781–8797.Google Scholar2 Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet. 1999; 354: 407–413.CrossrefMedlineGoogle Scholar3 Bostom AG, Selhub J, Jacques PF, Rosenberg IH. Power shortage: clinical trials testing the "homocysteine hypothesis" against a background of folic acid-fortified cereal grain flour. Ann Intern Med. 2001; 135: 1333–1337.Google Scholar4 Spence JD, Howard VJ, Chambless LE, Malinow MR, Pettigrew LC, Stampfer M, Toole JF, for the VISP Investigators. Vitamin Intervention for Stroke Prevention (VISP) Trial: rationale and design. Neuroepidemiology. 2001; 20: 16–25.CrossrefMedlineGoogle Scholar5 Toole JF, Malinow R, Chambless L, Spence JD, Pettigrew LC, Howard VJ, Sides EG, Wang C-H, Stampfer M. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction and death. The Vitamin Intervention for Stroke Prevention (VISP) randomised controlled trial. JAMA. 2004; 291: 565–575.CrossrefMedlineGoogle Scholar6 Eikelboom JW, Lonn E, Genest J Jr., Hankey GJ, Yusuf S. Homocyst(e)ine and cardiovascular disease. A critical review of the epidemiological evidence. Ann Intern Med. 1999; 131: 363–375.CrossrefMedlineGoogle Scholar7 The VITATOPS Trial Study Group. The VITATOPS (VITAmins TO Prevent Stroke) Trial: rationale and design of an international, large, simple, randomised trial of homocysteine-lowering multivitamin therapy in patients with recent transient ischaemic attack or stroke. Cerebrovascular Diseases. 2002; 13: 120–126.CrossrefMedlineGoogle Scholar8 The Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke. A meta-analysis. JAMA. 2002; 288: 2015–2022.CrossrefMedlineGoogle Scholar9 Homocysteine Lowering Trialists' Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ. 1998; 316: 894–898.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Wang L, Cui W, Nan G and Yu Y (2015) Meta-analysis reveals protective effects of vitamin B on stroke patients, Translational Neuroscience, 10.1515/tnsci-2015-0014, 6:1, (150-156), Online publication date: 1-Jan-2015., Online publication date: 1-Jan-2015. Almeida O, Marsh K, Alfonso H, Flicker L, Davis T and Hankey G (2010) B-vitamins reduce the long-term risk of depression after stroke: The VITATOPS-DEP trial, Annals of Neurology, 10.1002/ana.22189, 68:4, (503-510), Online publication date: 1-Oct-2010. (2010) 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, The Lancet Neurology, 10.1016/S1474-4422(10)70187-3, 9:9, (855-865), Online publication date: 1-Sep-2010. Adragna N (2010) Homocysteine: to measure or not to measure? Focus on "Functional NMDA receptors in rat erythrocytes" , American Journal of Physiology-Cell Physiology, 10.1152/ajpcell.00111.2010, 298:6, (C1301-C1302), Online publication date: 1-Jun-2010. Carlsson C (2006) Homocysteine Lowering with Folic Acid and Vitamin B Supplements, Drugs & Aging, 10.2165/00002512-200623060-00004, 23:6, (491-502), . Hankey G (2006) Is plasma homocysteine a modifiable risk factor for stroke?, Nature Clinical Practice Neurology, 10.1038/ncpneuro0093, 2:1, (26-33), Online publication date: 1-Jan-2006. August 2004Vol 24, Issue 8 Advertisement Article Information Metrics https://doi.org/10.1161/01.ATV.0000136385.50973.68PMID: 15297291 Originally publishedAugust 1, 2004 PDF download Advertisement