Many patients with atrial fibrillation (AF) require long-term oral anticoagulation with vitamin K antagonists.¹ Patients with AF often have coexisting vascular disease, such as ischemic heart disease, and, thus, an indication for platelet inhibitor therapy. Because platelet inhibitor therapy in patients with AF provides less protection against thromboembolic events than does regular oral anticoagulation therapy,^2,3 the physician may choose to combine aspirin or clopidogrel with a standard anticoagulant or even to use triple therapy with aspirin, clopidogrel, and an oral anticoagulant.^1,4 The safety of this approach is poorly documented and represents a major therapeutic dilemma. No studies address dual therapy with an oral anticoagulant and clopidogrel, and studies addressing triple therapy are small and lack documentation for the duration of treatment. Consequently, estimates of risk vary significantly.^5-11 Because undocumented combinations are endorsed in current international guidelines and expert statements for the treatment of AF,^1,12 it is imperative that better estimates of safety are provided in terms of the risk of bleeding complications. Thus, in the present study, we examined a nationwide cohort of 118 606 patients with AF discharged from hospitals in Denmark between January 1, 1997, and December 31, 2006, to analyze the risk of hospitalization or death due to bleeding after treatment with warfarin, aspirin, clopidogrel, and combinations of these drugs.

Virgin olive oils are richer in phenolic content than refined olive oil. Small, randomized, crossover, controlled trials on the antioxidant effect of phenolic compounds from real-life daily doses of olive oil in humans have yielded conflicting results. Little information is available on the effect of the phenolic compounds of olive oil on plasma lipid levels. No international study with a large sample size has been done. To evaluate whether the phenolic content of olive oil further benefits plasma lipid levels and lipid oxidative damage compared with monounsaturated acid content. Randomized, crossover, controlled trial. 6 research centers from 5 European countries. 200 healthy male volunteers. Glucose levels, plasma lipid levels, oxidative damage to lipid levels, and endogenous and exogenous antioxidants at baseline and before and after each intervention. In a crossover study, participants were randomly assigned to 3 sequences of daily administration of 25 mL of 3 olive oils. Olive oils had low (2.7 mg/kg of olive oil), medium (164 mg/kg), or high (366 mg/kg) phenolic content but were otherwise similar. Intervention periods were 3 weeks preceded by 2-week washout periods. A linear increase in high-density lipoprotein (HDL) cholesterol levels was observed for low-, medium-, and high-polyphenol olive oil: mean change, 0.025 mmol/L (95% CI, 0.003 to 0.05 mmol/L), 0.032 mmol/L (CI, 0.005 to 0.05 mmol/L), and 0.045 mmol/L (CI, 0.02 to 0.06 mmol/L), respectively. Total cholesterol–HDL cholesterol ratio decreased linearly with the phenolic content of the olive oil. Triglyceride levels decreased by an average of 0.05 mmol/L for all olive oils. Oxidative stress markers decreased linearly with increasing phenolic content. Mean changes for oxidized low-density lipoprotein levels were 1.21 U/L (CI, −0.8 to 3.6 U/L), −1.48 U/L (−3.6 to 0.6 U/L), and −3.21 U/L (−5.1 to −0.8 U/L) for the low-, medium-, and high-polyphenol olive oil, respectively. The olive oil may have interacted with other dietary components, participants' dietary intake was self-reported, and the intervention periods were short. Olive oil is more than a monounsaturated fat. Its phenolic content can also provide benefits for plasma lipid levels and oxidative damage. International Standard Randomised Controlled Trial number: ISRCTN09220811.

Oxidative DNA damage may be implicated in ageing, carcinogenesis and other degenerative diseases. Oxidative DNA damage can be assessed in humans in vivo from the urinary excretion of the DNA-repair product 8-hydroxydeoxyguanosine (8OHdG). We investigated factors influencing the excretion of 8OHdG in 24 h urine from 83 randomly selected healthy subjects (52 women) aged 40–64 years. For 2 weeks prior to urine collection the subjects kept a weighed diet record. 8OHdG was quantified by an automatic three-dimensional HPLC analysis with electrochemical detection. The 8OHdG excretion was 252 ± 103 (mean ± SD) pmol kg body weight/24 h with a range from 78 to 527. Multiple regression analysis identified three factors, smoking, body mass index (BMI) and gender, as significant predictors of the 8OHdG excretion. In 30 smokers the 8OHdG excretion was 320 ± 99 pmol/kg/24 h opposed to 213 ± 84 pmol/kg/24 h in 53 non-smokers. According to multiple regression analysis smokers excreted 50% (31–69%; 95% confidence interval) more 8OHdG than non-smokers. In 52 women the 8OHdG excretion was 240 ± 106 pmol/kg/24 h opposed to 271 ± % pmol/kg/24 h in 31 men. According to the multiple regression analysis men excreted 29% (10–48%) more 8OHdG than women. According to multiple regression analysis the 8OHdG excretion decreased with 4% (2–6%) per increment in BMI measured in kg/m2. The dietary distribution of energy demonstrated no important predictive value with respect to 8OHdG excretion. The intake of the antioxidant vitamins C and E and of vitamin A equivalents, including β-carotene, was not associated with 8OHdG excretion. The results suggest that smoking increases oxidative DNA damage by ∼50%. This effect implies potential serious health effects adding to the other well-known health hazards of smoking. The higher 8OHdG excretion in men and lean subjects may be related to a higher rate of metabolism with increased availability of reactive oxygen species. The apparent 7-fold individual variation in oxidative DNA damage carries implications regarding the rate of ageing and the risk of cancer and other degenerative diseases. The excretion of 8OHdG into urine offers a valuable tool for testing such hypotheses in humans.

Background— Self-selected supplementation of vitamin E has been associated with reduced coronary events and atherosclerotic progression, but the evidence from clinical trials is controversial. In the first 3 years of the ASAP trial, the supplementation with 136 IU of vitamin E plus 250 mg of slow-release vitamin C twice daily slowed down the progression of carotid atherosclerosis in men but not women. This article examines the 6-year effect of supplementation on common carotid artery (CCA) intima-media thickness (IMT). Methods and Results— The subjects were 520 smoking and nonsmoking men and postmenopausal women aged 45 to 69 years with serum cholesterol ≥5.0 mmol/L (193 mg/dL), 440 (84.6%) of whom completed the study. Atherosclerotic progression was assessed ultrasonographically. In covariance analysis in both sexes, supplementation reduced the main study outcome, the slope of mean CCA-IMT, by 26% (95% CI, 5 to 46, P =0.014), in men by 33% (95% CI, 4 to 62, P =0.024) and in women by 14% (not significant). In both sexes combined, the average annual increase of the mean CCA-IMT was 0.014 mm in the unsupplemented and 0.010 mm in the supplemented group (25% treatment effect, 95% CI, 2 to 49, P =0.034). In men, this treatment effect was 37% (95 CI, 4 to 69, P =0.028). The effect was larger in subjects with either low baseline plasma vitamin C levels or CCA plaques. Vitamin E had no effect on HDL cholesterol. Conclusions— These data replicate our 3-year findings confirming that the supplementation with combination of vitamin E and slow-release vitamin C slows down atherosclerotic progression in hypercholesterolemic persons.