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CLINICAL RESEARCH: CLINICAL TRIAL

Cardiovascular Morbidity and Mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in Chronic Renal Failure

A Multicenter, Randomized, Controlled Trial

Sophia Zoungas, MBBS^_*, Barry P. McGrath, MBBS, MD^_*,_*, Pauline Branley, BMed, PhD, Peter G. Kerr, MBBS, PhD, Christine Muske, BSci(Nurs), Rory Wolfe, PhD, Robert C. Atkins, MBBS, DSc, Kathy Nicholls, MBBS, MD, Margaret Fraenkel, BMBS, PhD^||, Brian G. Hutchison, MBBS^¶, Robert Walker, MBChB, MD^# and John J. McNeil, MBBS, PhD

^_* Department of Vascular Sciences and Medicine, Centre for Vascular Health, Monash University, Dandenong Hospital, Dandenong, Victoria, Australia
Department of Epidemiology and Preventive Medicine, Monash University, Alfred Hospital, Melbourne, Victoria, Australia
Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia
Department of Nephrology, Royal Melbourne Hospital, Parkville, and Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
^|| Department of Nephrology, Austin Health, Heidelberg, Victoria, Australia
^¶ Department of Nephrology, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
^# Department of Nephrology, Dunedin Hospital, Dunedin, New Zealand

Manuscript received June 22, 2005; revised manuscript received September 30, 2005, accepted October 3, 2005.

^_* Reprint requests and correspondence: Prof. Barry P. McGrath, Department of Vascular Sciences and Medicine, Monash University, Dandenong Hospital, Dandenong 3175, Victoria, Australia. (Email: barry.mcgrath{at}med.monash.edu.au).

OBJECTIVES: The Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) aimed to establish whether high-dose folic acid would slow the progression of atherosclerosis and reduce cardiovascular events in patients with chronic renal failure (CRF).

BACKGROUND: Hyperhomocysteinemia is a potential contributor to the high rates of cardiovascular morbidity and mortality in patients with CRF.

METHODS: A total of 315 subjects with CRF, mean age 57 years (range 24 to 79 years) were randomized to 15 mg folic acid daily or placebo and followed for a median of 3.6 years. The primary intima-media thickness (IMT) and clinical end points were: rate of progression of mean maximum carotid IMT and a composite of myocardial infarction (MI), stroke, and cardiovascular death. Secondary end points included all cardiovascular events and change in pulse wave velocity, systemic arterial compliance and augmentation index. Data were analyzed by intention-to-treat.

RESULTS: Plasma total homocysteine was reduced by 19% in the folic acid group. There was no significant difference between the treatment groups in rate of change of IMT or any measure of artery function. Seventy-seven events occurred in the folic acid group (14.9 per 100 patient-years) as compared with 86 in the placebo group (16.3 per 100 patient-years). The rates of the primary and secondary clinical end points at five years were not significantly different after adjustment for baseline differences between the groups (adjusted hazard ratio for MI, stroke, and cardiovascular death: 0.98 [95% confidence interval: 0.66 to 1.47]; p = 0.94; for all cardiovascular events: 0.95 [95% confidence interval: 0.69 to 1.30]; p = 0.75).

CONCLUSIONS: High-dose folic acid does not slow atheroma progression or improve cardiovascular morbidity or mortality in patients with CRF.

Abbreviations and Acronyms   AIx = augmentation index   ASFAST = Atherosclerosis and Folic Acid Supplementation Trial   CI = confidence interval   CRF = chronic renal failure   GEE = generalized estimating equation   IMT = intima-media thickness   PWV = pulse wave velocity   SAC = systemic arterial compliance   tHcy = total plasma homocysteine

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