Elsevier

The Lancet

Volume 356, Issue 9237, 7 October 2000, Pages 1213-1218
The Lancet

Articles
Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial

https://doi.org/10.1016/S0140-6736(00)02783-5Get rights and content

Summary

Background

Excess cardiovascular mortality has been documented in chronic haemodialysis patients. Oxidative stress is greater in haemodialysis patients with prevalent cardiovascular disease than in those without, suggesting a role for oxidative stress in excess cardiovascular disease in haemodialysis. We investigated the effect of high-dose vitamin E supplementation on cardiovascular disease outcomes in haemodialysis patients with pre-existing cardiovascular disease.

Methods

Haemodialysis patients with pre-existing cardiovascular disease (n=196) aged 40–75 years at baseline from six dialysis centres were enrolled and randomised to receive 800 IU/day vitamin E or matching placebo. Patients were followed for a median 519 days. The primary endpoint was a composite variable consisting of: myocardial infarction (fatal and non-fatal), ischaemic stroke, peripheral vascular disease (excluding the arteriovenous fistula), and unstable angina. Secondary outcomes included each of the component outcomes, total mortality, and cardiovascular-disease mortality.

Findings

A total of 15 (16%) of the 97 patients assigned to vitamin E and 33 (33%) of the 99 patients assigned to placebo had a primary endpoint (relative risk 0·46 [95% CI 0·27–0·78], p=0·014). Five (5·1%) patients assigned to vitamin E and 17 (17·2%) patients assigned to placebo had myocardial infarction (0·3 [0·11–0·78], p=0·016). No significant differences in other secondary endpoints, cardiovascular disease, or total mortality were detected.

Interpretation

In haemodialysis patients with prevalent cardiovascular disease, supplementation with 800 IU/day vitamin E reduces composite cardiovascular disease endpoints and myocardial infarction.

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

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