ArticlesSecondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial
Introduction
Chronic haemodialysis patients have an age-adjusted mortality rate 3·5–4 times that of the general population,1 more than 40% of which is attributable to cardiovascular disease.2 The cardiovascular-disease mortality rate in this patient group is estimated to be five to 20 times that of the general population.3 These high mortality rates may be partly explained by this population's enhanced oxidative stress compared with non-haemodialysis reference groups.4, 5, 6 Oxidative stress is greater in haemodialysis patients with cardiovascular disease compared with those without.7, 8 These observations support a role for oxidative stress in the pathogenesis of cardiovascular disease in haemodialysis patients.
Panzetta and colleagues9 found that oral supplementation of haemodialysis patients for 30 days with 50 IU/day vitamin E significantly decreased LDL susceptibility to copper-induced oxidation in vitro measured by increased lag time. In a similar study of copper-catalysed LDL oxidation kinetics, oral supplementation of haemodialysis patients for 12 weeks with 800 IU/day vitamin E increased LDL α-tocopherol content by 94% and prolonged the lag phase for conjugated diene formation.10 Further, it has been shown that malondialdehyde-rich LDL from haemodialysis patients is removed more slowly from circulation than LDL from healthy controls. Oral supplementation for 2 weeks with 600 IU/day vitamin E improved LDL clearance from the circulation and reduced the malondialdehyde content of LDL11.
Although few vitamin E intervention studies in end-stage-renal disease patients with clinical endpoints have been reported, findings are consistent with a protective effect of vitamin E in haemodialysis patients. The effect of cellulose-membrane dialysers modified by vitamin E on lipid metabolism and atherosclerosis was assessed in a 2-year intervention study. Compared with dialysis with traditional cellulose membranes, dialysis with the membrane modified by vitamin E was associated with reduced LDL-malondialdehyde and oxidised LDL. Additionally, the increase in percentage of aortic calcification index as measured by computed tomography was significantly reduced, indicating a slowing of atherosclerosis progression12.
The secondary prevention with antioxidants of cardiovascular disease in endstage renal disease, or SPACE study, was designed to test the effects of high-dose (800 IU/day), oral, vitamin E supplementation in
the prevention of secondary cardiovascular disease events in haemodialysis patients with history of cardiovascular disease. Reduction of cardiovascular-disease endpoint rate in individuals treated with vitamin E would support a role for antioxidant therapy in the secondary prevention of cardiovascular disease in this especially high-risk group.
Section snippets
Study design
SPACE is a double blind, placebo-controlled, randomised, secondary prevention intervention trial done at six haemodialysis centres in greater Tel Aviv, Israel. Two groups of haemodialysis patients with documented cardiovascular disease were compared: one group received 800 IU/day vitamin E (n=97) and the other received a matching placebo (n=99). Recruitment began on Nov 1, 1997, and continued until Jan 1, 1998. Analysis includes all endpoints occurring between Nov 1, 1997, and Dec 31, 1999. The
Results
Characteristics of the 196 patients are described in table 1. Median follow-up time was 519 (range 10–763) days. Treatment conditions did not differ significantly at baseline by age, sex, smoking status, diabetes, blood pressure, primary renal renal diagnosis, underlying cardiovascular-disease diagnosis, aspirin, anti-hypertensive or lipid-lowering therapy, blood chemistry, lipids, haemostatic factors, serum malondialdehyde, serum vitamin E, or Kt/V. Throughout the study, patients continued to
Discussion
Our trial was designed to detect a 40% reduction in composite cardiovascular-disease endpoints in haemodilaysis patients treated with high-dose vitamin E during 2 years' follow-up. A 46% reduction (including sudden death) was attained in the primary endpoint, contributed to largely by the reduction in total myocardial infarction (70%). These findings are consistent with those of the Cambridge Heart Antioxidant Study (CHAOS), in which patients with angiographically documented coronary artery
References (25)
- et al.
Cardiac function and hematocrit level
Am J Kidney Dis
(1995) Cardiac and cerebrovascular disease in chronic uremia
Am J Kidney Dis
(1993)- et al.
Morbidity and mortality due to hypertensive patients with renal failure
Am J Kidney Dis
(1993) - et al.
Effect of hemodialysis in lipid peroxidation and antioxidant systems in patients with chronic renal failure
Metabolism
(1992) - et al.
Serum malondialdehyde and prevalent cardiovascular disease in hemodialysis
Kidney Int
(1999) - et al.
Comparison of hemostatic factors and serum malondialdehyde as predictive factors for cardiovascular disease in hemodiaylsis patients
Am J Kidney Dis
(1999) - et al.
Comparative studies on different methods of malondialdehyde determination
Methods Enzymol
(1984) Which diet for which renal failure: making sense of the options
J Am Diet Assoc
(1995)- et al.
Randomised controlled trial ofvitamin E in patients with coronary disease: Cambrige Heart Antioxidant Study (CHAOS)
Lancet
(1996) - et al.
Mortality in the CHAOS trial
Lancet
(1999)