Homocysteine is a sulfur-containing amino

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1 IN THE LITERATURE Approaching the End of the Homocysteine Hype? The following is a commentary on Jamison RL, Hartigan P, Kaufman JS, et al: Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease. A randomized controlled trial. JAMA 298: , Homocysteine is a sulfur-containing amino acid that occupies an important role in 1-carbon metabolism and nucleotide synthesis. Excess homocysteine is exported from the cell and can be measured in plasma. Increased plasma total homocysteine (thcy) concentration is a sensitive marker of folate and cobalamin deficiency. 1 Factors that determine thcy concentration include genetic, physiological, and lifestyle characteristics, as well as various diseases and drugs. In the era of food fortification with folic acid, cobalamin deficiency and impairment of kidney function are the most important determinants of plasma thcy levels. During the last decades, several retrospective and prospective studies showed associations between increased thcy concentrations and increased rates of cardiovascular (CV) events in the general population. 2 However, in patients with chronic kidney disease (CKD), results of prospective studies were inconclusive: some found increased risk of CV outcomes in subjects with greater thcy concentrations, 3 whereas other studies found an inverse association of CV disease (CVD) risk with increasing plasma thcy concentrations 4 or no such associations. 5 However, several experimental studies supported the concept of vascular damage induced by homocysteine and provided yet another rationale for intervention studies aimed at decreasing CV risk through a therapeutic decrease in thcy concentrations. 6 Specifically, clinical trials were designed to provide evidence that thcy-lowering therapy with folic acid and B vitamins may improve CVD outcomes. In the September 12, 2007, issue of the Journal of the American Medical Association, Jamison et al 7 presented such a trial and showed that folic acid, together with vitamin B 6 and vitamin B 12, failed to decrease mortality and CV outcomes in patients with advanced CKD. 7 WHAT DID THIS IMPORTANT STUDY SHOW? In a double-blind, randomized, and controlled multicenter trial (the Homocysteine Study), 2,056 patients aged 21 or older (98% men) from 36 US Department of Veterans Affairs medical centers who had advanced CKD (stages 4, 5, and 5D) and increased thcy concentrations ( 15 mol/l) were randomly assigned to receive either a daily capsule containing 40 mg of folic acid, 100 mg of pyridoxine hydrochloride (vitamin B 6 ), and 2 mg of cyanocobalamin (vitamin B 12 ) or placebo. 7 Recruitment for the study lasted from September 2001 to October 2003, and median follow-up was 3.2 years. A total of 1,024 patients (379 patients with CKD stage 5D, 645 patients with stage CKD 4 or 5) were assigned to placebo, and 1,032 patients (372 patients with CKD stage 5D, 660 patients with CKD stage 4 or 5) were randomly assigned to the vitamin intervention arm. Sample size calculation for that study was based on an estimated 3-year mortality rate of 28% and adjusted for a 7% loss to follow-up. In a population initially supposed to be composed of 78% patients with CKD stage 4 or 5 and 22% patients with CKD stage 5D, 2,006 patients were needed to detect a postulated 17% decrease in all-cause mortality (from 27.9% to 23.2% at 3 years) with statistical power of 80%. Prespecified secondary outcomes included myocardial infarction, stroke, amputation, a composite of death and the 3 aforementioned outcomes, plasma thcy concentrations at 3 months after treatment, and thrombosis of a vascular access in dialysis Address correspondence to Gere Sunder-Plassman, MD, Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, Austria. gere.sunder-plassmann@ meduniwien.ac.at 2008 by the National Kidney Foundation, Inc /08/ $34.00/0 doi: /j.ajkd American Journal of Kidney Diseases, Vol 51, No 4 (April), 2008: pp

2 550 patients. 8 In the published analysis, the investigators also assessed time to initiation of dialysis therapy in patients with CKD stage 4 or 5, not a prespecified end point. In May 2006, the Data and Safety Monitoring Board recommended that the study be stopped because the required number of primary end points had been reached. At 3 months, a significant 26% decrease in plasma thcy concentrations was observed in the intervention group ( 0.8 mg/l [ 6.2 mol/l], from mg/l [ mol/l] at baseline), whereas no significant change was present in the placebo group ( 0.05 mg/l [ 0.4 mol/l], from mg/l [ mol/l] at baseline). In contrast to the thcy-lowering effect of high-dose folic acid and B vitamins, there was no effect of treatment on the primary study end point, allcause mortality (hazard ratio, 1.04; 95% confidence interval [CI], 0.91 to 1.18). Overall, there were 884 deaths: 448 (43.4%) in the intervention group and 436 (42.6%) in the placebo group, representing an annual mortality rate of 11.8% versus 10.0%, respectively. Hazard ratios with 95% CIs for primary and secondary outcomes are listed in Table 1. Sunder-Plassmann, Winkelmayer, and Födinger HOW DOES THIS STUDY COMPARE WITH PRIOR STUDIES? Several other studies of vitamin intervention on homocysteine concentrations in patients with CKD were completed or are underway. Of note, these studies varied considerably in the composition and dose of the vitamin arms. Regarding this, an important study by Bostom et al 9 suggested that increased thcy plasma concentrations in dialysis patients may respond better to greater doses of folic acid (15 mg/d) and B vitamins than usually prescribed in the non-ckd population. More extreme doses of folic acid (30 or 60 mg) had no additional thcy-lowering effect compared with 15 mg in dialysis patients enrolled in The Vienna Multicenter Study. 10 In northern California, Wrone et al 11 randomly assigned 510 patients with CKD stage 5D to receive a multivitamin together with different doses of folic acid, but a placebo group was not included. During a median follow-up of 2 years, patients randomly assigned to receive 5 or 15 mg/d of folic acid experienced similar rates of mortality, CV events, and access thrombosis compared with those who received 1 mg of folic acid. 11 The Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in Chronic Renal Failure 12 randomly assigned 315 patients (CKD stages 4, 5, and 5D) to 15 mg of folic acid or placebo and failed to show an effect on progression of carotid artery intima-media thickness (difference, 0.01 mm/y; CI, 0.01 to 0.03; P 0.4) or the incidence of CV events (hazard ratio, 0.98; 95% CI, 0.66 to 1.47) after a median observation time of 3.6 years. 12 Most recently, Mann et al 13 presented data from a secondary analysis of the Heart Outcomes Prevention Evaluation (HOPE)-2 trial. In that trial, 5,522 high-risk patients were randomly assigned to receive a daily combination pill containing folic acid, 2.5 mg; vitamin B 6,50mg; and vitamin B 12, 1 mg or placebo. In 3,310 patients randomly selected from the full study population, serum samples were collected and Table 1. Primary and Secondary Outcomes of the Homocysteine Study No. (%) of Patients With an Event Vitamin Group (n 1,032) Placebo Group (n 1,024) Hazard Ratio (95% CI) P All-cause mortality 448(43) 436 (43) 1.04 ( ) 0.6 Myocardial infarction (fatal and nonfatal) 129 (13) 150 (15) 0.86 ( ) 0.2 Stroke (fatal and nonfatal) 37 (4) 41 (4) 0.90 ( ) 0.6 Amputation 60 (6) 53 (5) 1.14 ( ) 0.5 Composite 523 (51) 525 (51) 0.99 ( ) 0.9 Dialysis in CKD stage 4 or (55) 340 (53) 1.07 ( ) 0.4 Access thrombosis in CKD stage 5D 166 (24) 163 (23) 1.01 ( ) 0.97 Abbreviation: CKD, chronic kidney disease. Adapted with permission from Jamison et al. 7

3 In the Literature 551 Table 2. Results of Total Homocysteine Lowering Trials in the General Population Study, Reference, Journal, Year No. of Patients Outcome Trial Duration Risk/Hazard Ratio (95% confidence interval) IMPROVEMENT WITH INTERVENTION Swiss Heart Study, 17 N Engl J Med, Coronary restenosis after PTCA 6 mo 0.52 ( ) Swiss Heart Study, 18 JAMA, MACE after PTCA 1 y 0.68 ( ) FACIT, 19 Lancet, 2007* 818 Memory (change in z score) 3 y ( ) NO EFFECT OF INTERVENTION Liem et al, 20 J Am Coll Cardiol, Mortality & CVD events 2 y 1.05 ( ) VISP, 21 JAMA, ,680 Recurrent stroke 2 y 1.0 ( ) McMahon et al, 22 N Engl J Med, Cognitive function (combined score) 2 y 0.11 ( 0.2-0) HOPE-2, 23 N Engl J Med, ,522 CVD death, MI, stroke 5 y 0.95 ( ) HOPE-2, 24 Ann Intern Med, ,522 Venous thromboembolism 5 y 1.01 ( ) VITRO, 25 Blood, Recurrent venous thromboembolism 2.5 y 0.84 ( ) WORSE OUTCOME WITH INTERVENTION Lange et al, 26 N Engl J Med, In-stent restenosis 6 mo 1.30 ( ) NORVIT, 27 N Engl J Med, ,749 MACE after MI 40 mo 1.22 ( ) Abbreviations: PTCA, percutaneous transluminal coronary angioplasty; MACE, major adverse cardiovascular events; CVD, cardiovascular disease; MI, myocardial infarction; CVD, cardiovascular disease; FACIT, Folic Acid and Carotid-Intimamedia Thickness trial; VISP, Vitamin Intervention for Stroke Prevention; HOPE, Heart Outcomes Prevention Evaluation; VITRO, Vitamins and Thrombosis study; NORVIT, Norwegian Vitamin trial. *Secondary analysis, primary results not reported. Secondary analysis. serum creatinine was measured in a central laboratory. A total of 619 patients had an estimated glomerular filtration rate less than 60 ml/min/ 1.73 m 2 ( 1 ml/s/1.73 m 2 ) and were included in this post hoc analysis. After a median observation time of 5 years, active treatment did not decrease the risk of the primary outcome (composite of death from CVD, myocardial infarction, and stroke; relative risk, 1.19; 95% CI, 0.88 to 1.61; P 0.2), but increased the risk of hospitalization for heart failure (relative risk, 1.98; 95% CI, 1.21 to 3.26; P 0.007) or unstable angina (relative risk, 1.70; 95% CI, 1.02 to 2.83; P 0.04). 13 Enrollment for some other large thcy-lowering studies (Folic Acid for Vascular Outcome Reduction In Transplantation [FAVORIT] trial study population, 4,000 kidney transplant recipients 14 ); the Prospective Intervention Study from Magdeburg With Vitamins (PRISMAVIT) trial (study population, 650 patients with CKD stage 5D; Jutta Dierkes, Germany, personal communication, October 2007); the Vitamins To Prevent Stroke (VITATOPS) trial (study population, 8,000 patients with cerebrovascular disease 15 ); the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH; study population, 12,064 myocardial infarction survivors 16 ) was completed recently, and their results are being awaited with interest. Until now, only 1 study in the general population suggested a beneficial effect of folic acid and vitamin intervention on CVD outcomes (Table 2). All other studies showed no such effect or even worse outcomes in the intervention group. Thus, the lack of effect of thcy-lowering therapies in the general population (Table 2), as well as the negative results of the hitherto published studies in patients with CKD, do not suggest that the yet uncompleted studies will show a major effect of thcy-lowering interventions on CVD outcomes. WHAT SHOULD CLINICIANS AND RESEARCHERS DO? From the clinical point of view, thcy-lowering therapy can be considered to have no major effect on important CVD or kidney disease outcomes. Nevertheless, some experts in the field have claimed that one should not yet abandon the Hcy pathway for potential interventions aimed at curbing CV risk. 4 Our recommendation is more conservative. Folic acid alone can mask the megaloblastic anemia caused by cobalamin deficiency and thereby permit neurological dysfunction to

4 552 develop and sometimes become irreversible. 28 In addition, some of the aforementioned thcylowering trials in the general population, as well as in patients with CKD, even showed an increased risk of CV outcomes in patients treated with folic acid and B vitamins compared with those administered placebo (Table 2 and 13 ). We therefore do not support the opinion that decreasing homocysteine concentrations in patients with CKD is important even in the absence of trials showing the benefit of such intervention. In summary, at present, no evidence is available that supports the concept of thcy-lowering intervention with folic acid and B vitamins to improve CVD outcomes in the general population or patients with CKD. The study of Jamison et al 7 is yet another contribution to the growing number of large randomized intervention trials that failed to show improved outcomes in patients with CKD Thus, prevention of CKD per se moves to center stage and should have top priority on the research agenda. Gere Sunder-Plassmann, MD Medical University Vienna Vienna, Austria Wolfgang C. Winkelmayer, MD, ScD Harvard Medical School Boston, Massachusetts Manuela Födinger, MD Medical University Vienna Vienna, Austria ACKNOWLEDGEMENTS Support: None. Financial Disclosure: None. REFERENCES 1. Refsum H, Smith AD, Ueland PM, et al: Facts and recommendations about total homocysteine determinations: An expert opinion. Clin Chem 50:3-32, The Homocysteine Studies Collaboration: Homocysteine and risk of ischemic heart disease and stroke. A meta-analysis. JAMA 288: , Winkelmayer WC, Kramar R, Curhan GC, et al: Fasting plasma total homocysteine levels and mortality and allograft loss in kidney transplant recipients: A prospective study. J Am Soc Nephrol 16: , Zoccali C, Mallamaci F, Tripepi G: It is important to lower homocysteine in dialysis patients. Semin Dial 20: , 2007 Sunder-Plassmann, Winkelmayer, and Födinger 5. Menon V, Sarnak MJ, Greene T, et al: Relationship between homocysteine and mortality in chronic kidney disease. Circulation 113: , Loscalzo J: The oxidant stress of hyperhomocyst(e)inemia. J Clin Invest 98:5-7, Jamison RL, Hartigan P, Kaufman JS, et al: Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: A randomized controlled trial. JAMA 298: , Jamison RL, Hartigan P, Gaziano JM, et al: Design and statistical issues in the homocysteinemia in kidney and end stage renal disease (HOST) study. Clin Trials 1: , Bostom AG, Shemin D, Lapane KL, et al: High dose B-vitamin treatment of hyperhomocysteinemia in dialysis patients. Kidney Int 49: , Sunder-Plassmann G, Födinger M, Buchmayer H, et al: Effect of high dose folic acid therapy on hyperhomocysteinemia in hemodialysis patients: Results of the Vienna Multicenter Study. J Am Soc Nephrol 11: , Wrone EM, Hornberger JM, Zehnder JL, McCann LM, Coplon NS, Fortmann SP: Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease. J Am Soc Nephrol 15: , Zoungas S, McGrath BP, Branley P, et al: Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in Chronic Renal Failure: A multicenter, randomized, controlled trial. J Am Coll Cardiol 47: , Mann JF, Sheridan P, McQueen MJ, et al: Homocysteine lowering with folic acid and B vitamins in people with chronic kidney disease: Results of the renal HOPE-2 Study. Nephrol Dial Transplant 23: , Bostom AG, Carpenter MA, Kusek JW, et al: Rationale and design of the Folic Acid for Vascular Outcome Reduction In Transplantation (FAVORIT) trial. Am Heart J 152:e441-e448, 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. Cerebrovasc Dis 13: , Bowman L, Armitage J, Bulbulia R, Parish S, Collins R: Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH): Characteristics of a randomized trial among myocardial infarction survivors. Am Heart J 154: , Schnyder G, Roffi M, Pin R, et al: Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 345: , Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM: Effect of homocysteine-lowering therapy with folic acid, vitamin B 12, and vitamin B 6 on clinical outcome after percutaneous coronary intervention: The Swiss Heart Study: A randomized controlled trial. JAMA 288: , Durga J, van Boxtel MP, Schouten EG, et al: Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: A randomised, double blind, controlled trial. Lancet 369: , 2007

5 In the Literature Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, Jukema JW, van Veldhuisen DJ: Secondary prevention with folic acid: Effects on clinical outcomes. J Am Coll Cardiol 41: , Toole JF, Malinow MR, Chambless LE, et al: Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: The Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 291: , McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, Williams SM: A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med 354: , Lonn E, Yusuf S, Arnold MJ, et al: Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 354: , Ray JG, Kearon C, Yi Q, Sheridan P, Lonn E: Homocysteine-lowering therapy and risk for venous thromboembolism: A randomized trial. Ann Intern Med 146: , den Heijer M, Willems HP, Blom HJ, et al: Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: A randomized, placebo-controlled, double-blind trial. Blood 109: , Lange H, Suryapranata H, De Luca G, et al: Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med 350: , Bonaa KH, Njolstad I, Ueland PM, et al: Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 354: , Dhar M, Bellevue R, Carmel R: Pernicious anemia with neuropsychiatric dysfunction in a patient with sickle cell anemia treated with folate supplementation. N Engl J Med 348: , Klahr S, Levey AS, Beck GJ, et al: The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med 330: , Besarab A, Bolton WK, Browne JK, et al: The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 339: , Eknoyan G, Beck GJ, Cheung AK, et al: Effect of dialysis dose and membrane flux in maintenance hemodialysis. N Engl J Med 347: , Holdaas H, Fellstrom B, Jardine AG, et al: Effect of fluvastatin on cardiac outcomes in renal transplant recipients: A multicentre, randomised, placebo-controlled trial. Lancet 361: , Wanner C, Krane V, März W, et al: Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 353: , Singh AK, Szczech L, Tang KL, et al: Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 355: , Suki WN, Zabaneh R, Cangiano JL, et al: Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients. Kidney Int 72: , 2007