Effect of a Treatment Strategy Consisting of Pravastatin, Vitamin E, and Homocysteine Lowering on Carotid Intima-Media Thickness, Endothelial Function, and Renal Function in Patients With Mild to Moderate Chronic Kidney Disease: Results From the Anti-Oxidant Therapy in Chronic Renal Insufficiency (ATIC) Study | Cardiology | JAMA Internal Medicine | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Foley  RNParfrey  PSSarnak  MJ Epidemiology of cardiovascular disease in chronic renal disease.  J Am Soc Nephrol 1998;9 ((suppl)) S16- S23PubMedGoogle Scholar
Baigent  CBurbury  KWheeler  D Premature cardiovascular disease in chronic renal failure.  Lancet 2000;356147- 152PubMedGoogle ScholarCrossref
Henry  RMKostense  PJBos  G  et al.  Mild renal insufficiency is associated with increased cardiovascular mortality: The Hoorn Study.  Kidney Int 2002;621402- 1407PubMedGoogle ScholarCrossref
Muntner  PHe  JHamm  LLoria  CWhelton  PK Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States.  J Am Soc Nephrol 2002;13745- 753PubMedGoogle Scholar
Drey  NRoderick  PMullee  MRogerson  M A population-based study of the incidence and outcomes of diagnosed chronic kidney disease.  Am J Kidney Dis 2003;42677- 684PubMedGoogle ScholarCrossref
Vanholder  RMassy  ZArgiles  A  et al.  Chronic kidney disease as cause of cardiovascular morbidity and mortality.  Nephrol Dial Transplant 2005;201048- 1056PubMedGoogle ScholarCrossref
Cheung  AKSarnak  MJYan  G  et al.  Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients.  Kidney Int 2000;58353- 362PubMedGoogle ScholarCrossref
Stenvinkel  PPecoits-Filho  RLindholm  B Coronary artery disease in end-stage renal disease: no longer a simple plumbing problem.  J Am Soc Nephrol 2003;141927- 1939PubMedGoogle ScholarCrossref
Zoccali  C Cardiovascular risk in uremic patients—is it fully explained by classical risk factors?  Nephrol Dial Transplant 2000;15454- 457PubMedGoogle ScholarCrossref
Himmelfarb  JStanvinkel  PIkizler  TAHakim  RM The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia.  Kidney Int 2002;621524- 1538PubMedGoogle ScholarCrossref
Terawaki  HYoshimura  KHasegawa  T  et al.  Oxidative stress in enhanced in correlation with renal dysfunction: examination with the redox state of albumin.  Kidney Int 2004;661988- 1993PubMedGoogle ScholarCrossref
Vaziri  ND Roles of oxidative stress and antioxidant therapy in chronic kidney disease and hypertension.  Curr Opin Nephrol Hypertens 2004;1393- 99PubMedGoogle ScholarCrossref
Heinecke  JWRosen  HSuzuki  LAChait  A The role of sulfur-containing amino acids in superoxide production and modification of low density lipoprotein by arterial smooth muscle cells.  J Biol Chem 1987;26210098- 10103PubMedGoogle Scholar
Sakabe  KFukuda  NWakayama  KNada  TShinohara  HTamura  Y Lipid-altering changes and pleiotropic effects of atorvastatin in patients with hypercholesterolemia.  Am J Cardiol 2004;94497- 500PubMedGoogle ScholarCrossref
Zhang  BNoda  KMatsunaga  AKumagai  KSaku  K A comparative crossover study of the effects of fluvastatin and pravastatin (FP-COS) on circulating autoantibodies to oxidized LDL in patients with hypercholesterolemia.  J Atheroscler Thromb 2005;1241- 47PubMedGoogle ScholarCrossref
Ullegaddi  RPowers  HJGariballa  SE B-group vitamin supplementation mitigates oxidative damage after acute ischemic stroke.  Clin Sci (Lond) 2004;107477- 484PubMedGoogle ScholarCrossref
Harris  ADevaraj  SJialal  I Oxidative stress, alpha-tocopherol therapy, and atherosclerosis.  Curr Atheroscler Rep 2002;4373- 380PubMedGoogle ScholarCrossref
Wanner  CKrane  VMarz  W  et al.  Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.  N Engl J Med 2005;353238- 248PubMedGoogle ScholarCrossref
Wrone  EMHornberger  JMZehnder  JL McCann  LMCoplon  NSFortmann  SP Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease.  J Am Soc Nephrol 2004;15420- 426PubMedGoogle ScholarCrossref
Tonelli  MIsles  CCurhan  GC  et al.  Effect of pravastatin on cardiovascular events in people with chronic kidney disease.  Circulation 2004;1101557- 1563PubMedGoogle ScholarCrossref
National Kidney Foundation, K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification.  Am J Kidney Dis 2002;39 ((suppl 1)) S1- S266PubMedGoogle Scholar
Hodis  HNMack  WJLaBree  L  et al.  The role of carotid arterial intima-media thickness in predicting clinical coronary events.  Ann Intern Med 1998;128262- 269PubMedGoogle ScholarCrossref
Benedetto  FAMallamaci  FTripepi  GZoccali  C  Prognostic value of ultrasonographic measurement of carotid intima media thickness in dialysis patients.  J Am Soc Nephrol 2001;122458- 2464PubMedGoogle Scholar
Hasdan  GBenchetrit  SRashid  GGreen  JBernheim  JRathaus  M Endothelial dysfunction and hypertension in 5/6 nephrectomized rats are mediated by vascular superoxide.  Kidney Int 2002;61586- 590PubMedGoogle ScholarCrossref
Moens  ALGoovaerts  IClaeys  MJVrints  CJ Flow-mediated vasodilatation: a diagnostic instrument or an experimental tool.  Chest 2005;1272254- 2263PubMedGoogle ScholarCrossref
Holvoet  P Oxidized LDL and coronary heart disease.  Acta Cardiol 2004;59479- 484PubMedGoogle ScholarCrossref
Del Rio  DStewart  AJPellegrini  N A review of recent studies on malondialdehyde as toxic molecule and biological marker of oxidative stress.  Nutr Metab Cardiovasc Dis 2005;15316- 328PubMedGoogle ScholarCrossref
Henry  RMAKostense  PJSpijkerman  AMW  et al.  Arterial stiffness increases with deteriorating glucose tolerance status: The Hoorn study.  Circulation 2003;1072089- 2095PubMedGoogle ScholarCrossref
Nanayakkara  PWBTeerlink  TStehouwer  CDA  et al.  Plasma asymmetric dimethylarginine (ADMA) concentration is independently associated with carotid intima-media thickness and plasma soluble vascular cell adhesion molecule-1 (sVCAM-1) concentration in patients with mild to moderate renal failure.  Kidney Int 2005;682230- 2236PubMedGoogle ScholarCrossref
Henry  RMFerreira  IKostense  PJ  et al.  Type 2 diabetes is associated with impaired endothelium-dependent, flow-mediated dilatation, but impaired glucose metabolism is not: The Hoorn Study.  Atherosclerosis 2004;17449- 56PubMedGoogle ScholarCrossref
Lambert  JAarsen  MDonker  AJStehouwer  CDA Endothelium-dependent and -independent vasodilatation of large arteries in normoalbuminuric insulin-dependent diabetes mellitus.  Arterioscler Thromb Vasc Biol 1996;16705- 711PubMedGoogle ScholarCrossref
Shipchandler  MTMoore  EG Rapid, fully automated measurement of plasma homocyst(e)ine with the Abbott IMx analyser.  Clin Chem 1995;41991- 994PubMedGoogle Scholar
Levey  ASBosch  JPLewis  BJ  et al.  A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation: Modification of Diet in Renal Disease Study Group.  Ann Intern Med 1999;130461- 470PubMedGoogle ScholarCrossref
Cockcroft  DWGault  MH Prediction of creatinine clearance from serum creatinine.  Nephron 1976;1631- 41PubMedGoogle ScholarCrossref
Du Bois  DDu Bois  EF A formula to estimate the approximate surface area if height and weight be known: 1916.  Nutrition 1989;5303- 311PubMedGoogle Scholar
Holvoet  PVanhaecke  JJanssens  SVan de Werf  FCollen  D Oxidized LDL and malondialdehyde-modified LDL in patients with acute coronary syndromes and stable coronary artery disease.  Circulation 1998;981487- 1494PubMedGoogle ScholarCrossref
van de Kerkhof  JSchalkwijk  CGKonings  CJ  et al.  Nepsilon-(carboxymethyl)lysine, Nepsilon-(carboxyethyl)lysine and vascular cell adhesion molecule-1 (VCAM-1) in relation to peritoneal glucose prescription and residual renal function; a study in peritoneal dialysis patients.  Nephrol Dial Transplant 2004;19910- 916PubMedGoogle ScholarCrossref
Twisk  JW Longitudinal data analysis: a comparison between generalized estimating equations and random coefficient and random coefficient analysis.  Eur J Epidemiol 2004;19769- 776PubMedGoogle ScholarCrossref
Hillege  HLFidler  VDiercks  GFH  et al. Prevention of Renal and Vascular End Stage Disease (PREVEND) Study Group, Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population.  Circulation 2002;1061777- 1782PubMedGoogle ScholarCrossref
Shepherd  JCobbe  SMFord  I  et al.  Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.  N Engl J Med 1995;3331301- 1307PubMedGoogle ScholarCrossref
The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group, Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.  N Engl J Med 1998;3391349- 1357PubMedGoogle ScholarCrossref
Sacks  FMPfeffer  MAMoye  LA  et al.  The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.  N Engl J Med 1996;3351001- 1009PubMedGoogle ScholarCrossref
Brenner  BM Retarding the progression of renal disease.  Kidney Int 2003;64370- 378PubMedGoogle ScholarCrossref
The Scandinavian Simvastatin Survival Study (4S), Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease.  Lancet 1994;3441383- 1389PubMedGoogle Scholar
Sever  PSDahlof  BPoulter  NR  et al.  Prevention of coronary and stroke events with atorvastatin in hypertensives who have average or lower-than-average cholesterol concentrations, in the Scandinavian Cardiac Outcome Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.  Lancet 2003;3611149- 1158PubMedGoogle ScholarCrossref
Isbel  NMHaluska  BJohnson  DWBeller  EHawley  CMarwick  TH Increased targeting of cardiovascular risk factors in patients with chronic kidney disease does not improve atheroma burden or cardiovascular function.  Am Heart J 2006;151745- 753PubMedGoogle ScholarCrossref
Athyros  VGMikhailidis  DPPapageorgiou  AA  et al.  The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease: a subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study.  J Clin Pathol 2004;57728- 734PubMedGoogle ScholarCrossref
Tonelli  MMoye  LSacks  FMCole  TCurhan  GC Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease.  J Am Soc Nephrol 2003;141605- 1613PubMedGoogle ScholarCrossref
Agarwal  R Effects of statins on renal function.  Am J Cardiol 2006;97748- 755PubMedGoogle ScholarCrossref
Stehouwer  CDASmulders  YM Microalbuminuria and risk for cardiovascular disease: analysis of potential mechanisms.  J Am Soc Nephrol 2006;172106- 2111PubMedGoogle ScholarCrossref
Hernández-Perera  OPérez-Sala  DNavarro-Antolin  J  et al.  Effects of the 3-hydroxy-3-methylglutaryl-COA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells.  J Clin Invest 1998;1012711- 2719PubMedGoogle ScholarCrossref
Boaz  MSmetana  SWeinstein  T  et al.  Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial.  Lancet 2000;3561213- 1218PubMedGoogle ScholarCrossref
Original Investigation
June 25, 2007

Effect of a Treatment Strategy Consisting of Pravastatin, Vitamin E, and Homocysteine Lowering on Carotid Intima-Media Thickness, Endothelial Function, and Renal Function in Patients With Mild to Moderate Chronic Kidney Disease: Results From the Anti-Oxidant Therapy in Chronic Renal Insufficiency (ATIC) Study

Author Affiliations

Author Affiliations: Departments of Internal Medicine (Dr Nanayakkara), Nephrology (Drs ter Wee and van Ittersum), and Clinical Chemistry (Drs Scheffer and Teerlink) and Institute for Research in Extramural Medicine (Drs Twisk and Stehouwer), VU University Medical Center, Amsterdam, Department of Internal Medicine, Amphia Hospital, Breda (Dr van Guldener), Department of Nephrology, Kennemer Gasthuis, Haarlem (Dr van Dorp), and Department of Internal Medicine, University Hospital Maastricht, Maastricht (Dr Stehouwer), the Netherlands.

Arch Intern Med. 2007;167(12):1262-1270. doi:10.1001/archinte.167.12.1262

Background  Patients with chronic kidney disease have an increased risk of cardiovascular disease. Oxidative stress has been proposed to play a role in the development of cardiovascular disease among these patients.

Methods  We conducted a randomized, double-blind trial in 93 patients (Cockcroft-Gault equation: creatinine clearance, 38 ± 15 [mean ± SD] mL/min per 1.73 m2 [0.63 ± 0.25 mL/s per m2]) to investigate the effect of a treatment strategy designed primarily to achieve stepwise oxidative stress reduction on common carotid intima-media thickness (CC-IMT), brachial artery flow-mediated dilatation (BA-FMD), albuminuria, and renal function. The treatment group received a regimen of pravastatin to which vitamin E supplementation was added after 6 months and homocysteine-lowering therapy after another 6 months. Blood pressure in both groups was managed according to a standard protocol. The placebo group received matching placebos. Measurement of CC-IMT and BA-FMD was performed at randomization after 6, 12, and 18 months. Patients were followed up for 2 years. Generalized estimating equations were used for analysis.

Results  Compared with placebo, active treatment was associated with a decrease in CC-IMT (after 18 months: from 0.68 to 0.63 mm in the treatment group and from 0.65 to 0.71 mm in the placebo group; P<.001), an increase in BA-FMD (after 18 months: from 4.66% to 7.56% in the treatment group and from 6.21% to 4.73% in the placebo group; P<.001), and an attenuated increase in urinary albumin excretion over time (P = .04 for between-group difference after 24 months), but no effect was observed on renal function.

Conclusion  In patients with mild to moderate chronic kidney disease, 18 months of a treatment strategy along with well-controlled blood pressure reduced CC-IMT and urinary albumin excretion and increased BA-FMD.

Trial Registration  clinicaltrials.gov Identifier: NCT00384618