Secondary Prevention With Antioxidants of Cardiovascular Disease in End-Stage Renal Disease (SPACE): Randomized Placebo-Controlled Trial - SPACE


SPACE was a multicenter, randomized, double-blind, placebo-controlled study conducted in Israel to evaluate the effect of high-dose vitamin E supplementation on cardiovascular disease outcomes in hemodialysis patients with pre-existing cardiovascular disease.


High-dose vitamin E supplementation will be associated with a reduction in cardiovascular endpoints in hemodialysis patients with pre-existing cardiovascular disease.

Study Design

Study Design:

Patients Screened: 598
Patients Enrolled: 196
Mean Follow Up: Median time of 519 days
Mean Patient Age: 40-75
Female: 31

Patient Populations:

Stable hemodialysis patients between the ages of 40 and 75 with a documented history of cardiovascular disease including myocardial infarction, ischemic stroke, angina, transient ischemic attack, or peripheral vascular disease unrelated to AV fistulas


Anticoagulant therapy with warfarin sodium; known history of malignant disease (except nonmelanoma skin cancer); active liver disease; treatment with hypolipemic agents for less than eight weeks before the study started; pregnant or planning to become pregnant during duration of the study; or any condition the treating physician deemed to preclude the patient on grounds of safety or study evaluation

Primary Endpoints:

Composite of acute myocardial infarction (fatal and nonfatal), ischemic stroke, peripheral vascular disease (excluding disease related to AV fistulas), and unstable angina, and sudden death

Secondary Endpoints:

Each of the individual components of the primary endpoint, cardiovascular mortality (fatal myocardial infarction, stroke, or sudden death), and total mortality

Drug/Procedures Used:

Patients were randomized to vitamin E 800 IU/day (n=97) or matching placebo (n=99) and followed for two years.

Concomitant Medications:

Erythropoietin, calcium channel blockers, aspirin, Lasix, beta-blockers, lipid-lowering agents, angiotensin-converting enzyme (ACE) inhibitors. Vitamin supplementation with folate, vitamin B6, and vitamin B12.

Principal Findings:

Median follow-up was 519 days. Baseline characteristics for the two arms were well matched in terms of age, gender, type of renal disease, cardiovascular history, diabetes, hypertension, and smoking. The primary endpoint of total cardiovascular events including myocardial infarction, death from myocardial infarction, sudden death, ischemic stroke, peripheral vascular disease, and unstable angina was significantly lower for the vitamin E arm (18.6% vs. 34.3%, relative risk [RR] 0.54, confidence interval [CI] 0.33-0.89, p=0.016). Myocardial infarction (fatal and nonfatal) was significantly lower in the vitamin E arm (8.2% vs. 18.2%, RR 0.45, CI 0.2-0.99, p=0.04).

The other components of the primary endpoint—nonfatal myocardial infarction, cardiovascular death, sudden death, stroke, peripheral vascular disease, or unstable angina—did not differ significantly between groups. Death from any cause was not significantly different between groups (31.2% vs. 29.3%, RR 1.09, CI 0.7-1.7, p=0.7).


Among hemodialysis patients with pre-existing cardiovascular disease, high-dose vitamin E supplementation was associated with a significant reduction in the composite cardiovascular disease endpoint and myocardial infarction. Trials of prevention of cardiovascular events with vitamin E supplements have shown mixed results. The larger HOPE trial of vitamin E compared with placebo in patients at high risk for cardiovascular events did not show a benefit associated with vitamin E therapy.


Boaz M, Smetana S, Weinstein T, et al. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet 2000;356:1213-18.

Clinical Topics: Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Hypertension, Smoking

Keywords: Risk, Myocardial Infarction, Stroke, Ischemic Attack, Transient, Vitamin E, Follow-Up Studies, Death, Sudden, Peripheral Vascular Diseases, Smoking, Renal Dialysis, Confidence Intervals, Hypertension, Diabetes Mellitus, Fistula

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