Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study

ASAP is a 6-year randomized trial to study the effect of supplementation with vitamin E plus slow-release vitamin C on carotid atherosclerotic progression. The main purpose of the ASAP study was to test the effect of reasonable supplemented doses of vitamin E and vitamin C and their combination on the progression of common carotid atherosclerosis in middle-aged high-risk men and women. Subjects were not entered into the trial if they had: regular intake of antioxidants, acetosalicylate or any other drug with antioxidative properties, severe obesity (BMI >32 kg/m2), type 1 diabetes, uncontrolled hypertension (sitting diastolic BP >105 mmHg), any condition limiting mobility, or severe disease shortening life expectancy. Premenopausal women and those taking oral estrogen therapy were also excluded.

The study consisted of 8-week dietary counseling and placebo lead-in phase, a 3-year double-masked treatment period and a 3-year open treatment period. After the lead-in the subjects were randomly allocated to receive twice daily with meal either (1) 91 mg of d-alfa-tocopherol (corresponding to 100 mg of d-alfa-tocopheryl acetate and 136 IU of vitamin E), (2) 250 mg slow-release ascorbic acid, (3) both d-alfa-tocopherol and slow-release ascorbic acid in a single tablet (CellaVie®), or (4) placebo only. All tablets were identical in appearance, size and color.  

After the double-blind 3-year period, the study was continued for another three years as an open study, during which period all the supplemented subjects received the vitamin combination and the placebo subjects continued without supplementation. The doses were chosen to keep the plasma ratio of vitamin C and E concentrations similar as in unsupplemented persons. The pilot studies established that a reasonably constant plasma level of vitamin C was achieved. The subjects were randomized separately in four strata of approximately equal size: (1) smoking (>5 cigarettes/day) men, (2) nonsmoking men, (3) smoking postmenopausal women, and (4) nonsmoking postmenopausal women. All participants signed a written informed consent. The study protocol was approved by the Research Ethics Committee of the University of Kuopio.

The subjects came to baseline visits and were randomized during 1994-95. Follow-up visits were 6, 12, 18, 24, 30, 36 and 72 months later. Supplements were given, returned tablets were counted and ultrasonographic assessment of common carotid artery (CCA) intima-media thickness (IMT) was carried out at all these eight visits. Of the 520 hypercholesterolemic men and women aged 45-69 years, 440 (84.6%) completed the study.

Dietary intake of nutrients was assessed quantitatively with a four-day food recording at the ASAP study baseline and 3-year examinations.

Our publications:

Nurmi T, Mursu J, Peñalvo JL, Poulsen HE, Voutilainen S. Dietary intake and urinary excretion of lignans in Finnish men. Br J Nutr 2010;103:677-85.

Voutilainen S, Morrow J, Roberts J, Alfthan G, Nyyssönen K, Salonen J. Correlation between Plasma Total Homocysteine Concentration and Plasma F2-Isoprostane in 100 men in Eastern Finland. Arteriosclerosis, Thrombosis and Vascular Biology 1999;19:1263-66.

Rissanen T, Voutilainen S, Nyyssönen K, Salonen R, Salonen JT. Low plasma lycopene concentration is associated with increased intima-media thickness of the carotid artery wall. Arteriosclerosis, Thrombosis and Vascular Biology 2000;20:2677-81.

Salonen R, Nyyssönen K, Kaikkonen J, Porkkala-Sarataho E, Voutilainen S, Rissanen T, Tuomainen T-P, Valkonen V-P, Ristonmaa U, Lakka H, Vanharanta M, Salonen JT, Poulsen H. Six-year effect of vitamin E and vitamin C supplementation on atherosclerosis progression: the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study. Circulation 2003;107:947-53.

Vanharanta M, Voutilainen S, Nurmi T, Kaikkonen J, Roberts JL, Morrow JD, Adlercreutz H, Salonen JT. Association between low serum enterolactone and increased plasma F2-isoprostanes, a measure of lipid peroxidation. Atherosclerosis 2002;160:465-69.

Salonen JT, Nyyssönen K, Salonen R, Kaikkonen J, Porkkala-Sarataho E, Voutilainen S, Lakka TA, Rissanen T, Lakka H, Leskinen L, Tuomainen T-P, Valkonen V-P, Poulsen H. Kolmevuotisen C- ja E-vitamiinilisän vaikutus kaulavaltimon ateroskleroosiin. Suomen Lääkärilehti 2001;26:395-400.