• Petra Schnell-Inderst, Beate Kossmann, Michael Fischereder, Volker Klauss, and Jürgen Wasem.
• Alfried Krupp von Bohlen und Halbach, Stiftungslehrstuhl für Medizinmanagement der Universität Duisburg-Essen, Campus Essen, Deutschland.
• GMS Health Technol Assess. 2006 Jan 1;2:Doc14.

IntroductionThe mortality from cardiovascular disease in patients with chronic renal failure is much higher than in the general population. In particular, patients with chronic renal failure with replacement therapies (dialysis patients and patients with renal transplantation) show both increased traditional risk factors and risk factors due to the dysfunction of the renal system. In combination with necessary medication for renal insufficiency oxidative stress is elevated. Progression of atherosclerosis is promoted due to increased oxidation of lipids and endothelium damage. This link between lipid oxidation and artherogenesis provides the rationale for the supposed beneficial effect of supplementation with antioxidative vitamins (vitamin A, C and E). Such an effect could not be demonstrated for patients with a history of cardiovascular disease and without kidney diseases. However, in high risk patients with chronic renal failure and renal replacement therapies this could be different.ObjectivesThe objective of this systematic literature review was to assess the clinical effectiveness and cost-effectiveness of supplementation with antioxidative vitamins A, C or E to reduce cardiovascular events in patients with chronic kidney diseases, dialysis-requiring patients and patients after a renal transplantation with or without cardiovascular diseases.MethodsA systematic literature review was conducted with documented search and selection of the literature, using a priori defined inclusion and exclusion criteria as well as a documented extraction and assessment of the literature according to the methods of evidence-based medicine.Results21 publications met the inclusion criteria for the evaluation of clinical effectiveness. No study could be identified for the economic evaluation. Two studies (four publications) analysed the effect of oral supplementation on the secondary prevention of clinical cardiovascular endpoints. Studies analysing the effect on patients without a history of cardiovascular disease could not be identified. 17 studies analysed the effect of oral supplementation or infusion with antioxidative vitamins or the supplementation with dialysis membranes coated with vitamin E on intermediate outcomes like oxidative stress or vessel parameters. The two randomized clinical trials analysing the effect of orally supplemented vitamin E on clinical endpoints in patients with mild-to-moderate renal insufficiency and for haemodialysis patients respectively reported different results. After 4.5 years supplementation with a daily dose of 400 IU vitamin E renal insufficiency patients showed neither a beneficial nor a harmful effect on a combined event rate of myocardial infarction, stroke or death by cardiovascular causes. The second study reported a 50% risk reduction (RR=0.46, 95%-KI: 0.27-0.78, p=0.014) on the combined event rate of fatal myocardial infarction, nonfatal myocardial infarction, stroke, peripheral vascular disease or unstable angina pectoris in the study arm with vitamin E-Supplementation of 800 IU daily. In 16 of 17 studies with intermediate endpoints the supplementation with vitamins was associated with a change of one or several of the examined endpoints in the expected direction. This means that the concentrations of the markers for oxidative stress decreased in the Vitamin E-group, the progression of aortic calcification (only one study) was reduced, the intima media thickness decreased and the lipid profile improved. No studies regarding costs or cost-effectiveness were identified.DiscussionA possible explanation for the different results in the two studies with clinical endpoints may be due to the different study populations with different risk profiles, to different dosage during the intervention or to variation by chance. Due to the absence of clinically meaningful endpoints, the relevance of studies analysing the effect of antioxidative vitamins on intermediate endpoints like oxidative stress markers is basically limited to show single intermediate steps of the postulated biological effect mechanisms by which a potentially preventive effect could possibly be mediated. The mainly unsatisfactory planning and reporting quality of the 17 identified studies and a possible "publication bias" are further limitations.ConclusionThe available evidence is not sufficient to support or to reject an effect of antioxidative vitamins on secondary prevention for cardiovascular disease for patients with chronic renal insufficiency or renal replacement therapy. There is a lack of randomized, placebo-controlled studies with a sufficient number of cases and clinical endpoints of cardiovascular disease, on the effect of antioxidative vitamins either orally applied or given by vitamin E-modified dialysers. No data are available about supplementation with antioxidative vitamins for primary prevention of cardiovascular disease. Therefore the current evidence does not allow to draw conclusions concerning this subject either. As opposed to patients with a history of cardiovascular disease without kidney diseases where there is enough evidence to exclude a beneficial effect on secondary prevention of cardiovascular disease for patients with chronic renal insufficiency and renal replacement therapy this question remains unanswered. Conclusions about costs and cost-effectiveness also cannot be drawn.

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