Safety outcomes of direct oral anticoagulants in older adults with atrial fibrillation: a systematic review and meta-analysis of (subgroup analyses from) randomized controlled trials.

Balancing stroke prevention and risk of bleeding in patients with atrial fibrillation (AF) is challenging. Direct oral anticoagulants (DOACs) are by now considered standard of care for treating patients with AF in international guidelines. Our objective was to assess the safety of long-term intake of DOACs in older adults with AF. We included RCTs in elderly (≥ 65 years) patients with AF. A systematic search in MEDLINE and EMBASE was performed on 19 April 2022. For determination of risk of bias, the RoB 2 tool was applied. We pooled outcomes using random-effects meta-analyses. The quality of evidence was assessed using GRADE. Eleven RCTs with a total of 63,374 patients were identified. Two RCTs compared apixaban with either warfarin or aspirin, four edoxaban with either placebo, aspirin, or vitamin K antagonists (VKAs), two dabigatran with warfarin and three rivaroxaban with warfarin. DOACs probably reduce mortality in elderly patients with AF (HR 0.89 95%CI 0.77 to 1.02). Low-dose DOACs likely reduce bleeding compared to VKAs (HR ranged from 0.47 to 1.01). For high-dose DOACS the risk of bleeding varied widely (HR ranged from 0.80 to 1.40). We found that low-dose DOACs probably decrease mortality in AF patients. Moreover, apixaban and probably edoxaban are associated with fewer major or clinically relevant bleeding (MCRB) events compared to VKAs. For dabigatran and rivaroxaban, the risk of MCRB varies depending on dose. Moreover, subgroup analyses indicate that in the very old (≥ 85) the risk for MCRB events might be increased when using DOACs.Registration: PROSPERO: CRD42020187876.

Lycopene for advanced hormone refractory prostate cancer: a prospective, open phase II pilot study.

PURPOSE: We investigated the influence of lycopene on the clinical and laboratory course in men with hormone refractory prostate cancer. To our knowledge this study represents the first time that subjective assessments of the course of therapy have been recorded. MATERIAL AND METHODS: We performed a prospective, open phase II pilot study, in which patients with progressive hormone refractory prostate cancer were included. Lycopene supplementation (15 mg) was given daily for 6 months. Followup laboratory tests and clinical examinations were done monthly. Changes to analgesic use and quality of life (European Organisation for Research and Treatment of Cancer QLQ-C30) were measured. The study end point was a significant change in serum prostate specific antigen, clinical progression or the end of the 6-month observation period. RESULTS: A total of 18 patients 64 to 85 years old (median age 73) were enrolled in the study during a 20-month period, of whom 17 could be analyzed. Five of the 17 patients (29%) withdrew from the study prematurely, including 4 of 5 because of prostate specific antigen progression and/or tumor associated complications, and 1 due to an allergic reaction to lycopene. Median prostate specific antigen doubled in 6 months from 42.7 ng/ml (range 13.8 to 521.6) in 17 patients to 96.4 ng/ml (range 13.5 to 1,240) in 12. Stable prostate specific antigen was observed in 5 of 17 patients (29%). None of the patients had a greater than 50% decrease in prostate specific antigen. Patients experienced a slight deterioration in mean health status at the end of the study compared to the outset. However, two-thirds of the patients experienced an improved or unchanged situation regardless of the clinical and biochemical course. CONCLUSIONS: No clinically relevant benefits were shown for patients with advanced stages of the disease.

Plasma kinetics of lutein, zeaxanthin, and 3-dehydro-lutein after multiple oral doses of a lutein supplement.

BACKGROUND: Adequate intake of lutein is postulated to reduce the risk of age-related macular degeneration, but kinetic information for developing a dosing regimen is sparse. OBJECTIVE: The objective was to characterize lutein plasma kinetics in a multiple dosing design and to assess the effects of lutein intake on concentrations of other plasma carotenoids. DESIGN: After a run-in period of 7 d, 19 healthy volunteers were assigned to receive daily oral doses of 4.1 mg lutein (n = 8; group 1) or 20.5 mg lutein (n = 8; group 2) for 42 d or no lutein (n = 3; control group). The supplement contained 8.3% zeaxanthin relative to lutein (100%). The time profiles of plasma xanthophyll concentrations were monitored over the dosing phase, and samples were collected frequently on day 42 and for 24 d after dosing. RESULTS: Average plasma all-E-lutein concentrations increased from 0.14 to 0.52 +/- 0.13 and 1.45 +/- 0.69 micromol/L in groups 1 and 2, respectively. Dose-normalized lutein bioavailability in group 2 was approximately 60% of that in group 1. Kinetic disposition half-life did not differ significantly between groups. On average, dosing for 18 d was required to reach a >90% fraction of the steady state concentration, which is consistent with an effective half-life for accumulation of approximately 5.6 d. Plasma kinetics of all-E-lutein were paralleled by those of all-E-3-dehydro-lutein. Kinetic analysis indicated formation of all-E-3-dehydro-lutein from lutein. Lutein was well tolerated and did not affect the concentrations of other carotenoids. CONCLUSION: Long-term supplementation with 4.1 and 20.5 mg lutein as beadlets increased plasma lutein concentrations approximately 3.5- and 10-fold, respectively.

Comparative multiple dose plasma kinetics of lycopene administered in tomato juice, tomato soup or lycopene tablets.

BACKGROUND: Lycopene is mainly provided in tomato and tomato products in Western diet. Among other factors the systemic availability of lycopene from natural sources is dependent on release from the cell matrix as achieved by food processing. AIMS OF THE STUDY: The purpose of this study was to compare plasma concentration responses of total lycopene and its major isomers to dosing of the carotenoid as tomato juice, tomato soup or tablets containing synthetic lycopene. METHODS: Intake of lycopene rich food products was restricted throughout this randomized, parallel group study, including 6 volunteers per group. Following a 14 day lycopene depletion phase subjects ingested 20 mg of lycopene daily for 8 days as tomato juice, soup prepared from tomato paste or lycopene tablets. Lycopene plasma concentrations were monitored throughout the depletion and dosing phases and for 22 days post-dosing and kinetics were evaluated using both empirical and compartmental modelling. RESULTS: Irrespective of the lycopene treatment all-E lycopene was the predominant lycopene isomer, whereas 5-Z lycopene was the most abundant Z isomer. Plasma concentration response of total and all-E lycopene to dosing of the carotenoid in tablets and tomato soup was comparable but exceeded that of intake in tomato juice. No differences were noted in dose normalized 5-Z lycopene concentrations between groups. The estimates of efficient half-life were approximately 5 and 9 days for all-E and 5-Z lycopene, respectively. CONCLUSIONS: The systemic availability of synthetic lycopene from a tablet formulation is comparable to that observed from processed tomatoes (soup from tomato paste) and superior to that from tomato juice. No differences were observed in disposition kinetics of natural and synthetic lycopene. The synthetic lycopene tablet formulation used in this investigation may be of value for future clinical investigations.

Plasma kinetics of zeaxanthin and 3'-dehydro-lutein after multiple oral doses of synthetic zeaxanthin.

BACKGROUND: Zeaxanthin is hypothesized to reduce the risk of age-related macular degeneration; however, kinetic information is limited. OBJECTIVES: The objective was to investigate the plasma kinetics of synthetic zeaxanthin after repeated oral doses and to assess the possible influence of other carotenoids on plasma zeaxanthin concentrations. DESIGN: After a run-in of 3 d, 20 healthy volunteers assigned to 2 parallel dose groups received once daily oral doses of either 1 mg (1.76 micro mol) or 10 mg (17.6 micro mol) zeaxanthin for 42 d. Plasma concentration-time profiles on days 1 and 42, concentrations immediately before zeaxanthin intake during the dosing period, and concentrations after the last dose until day 76 were monitored. RESULTS: all-E-Zeaxanthin concentrations increased from 0.048 +/- 0.026 micro mol/L at baseline to 0.20 +/- 0.07 and 0.92 +/- 0.28 micro mol/L with 1 and 10 mg zeaxanthin, respectively. The dose-normalized bioavailability of all-E-zeaxanthin after the10-mg dose was 40% lower (P < 0.001) than after the 1-mg dose. Other kinetic parameters did not differ significantly between groups. After 17 d of dosing, >90% of steady state concentrations were reached, which was compatible with an effective half-life for accumulation of 5 d. The terminal elimination half-life was 12 +/- 7 d (n = 20). The time course of plasma all-E-3-'dehydro-lutein concentrations resembled that of all-E-zeaxanthin. The data provided evidence that all-E-3-'dehydro-lutein was derived from all-E-zeaxanthin. Concentrations of other carotenoids were not affected. Zeaxanthin was well tolerated. CONCLUSION: Long-term oral intake of 1 and 10 mg zeaxanthin as beadlets increases plasma zeaxanthin concentrations approximately 4- and 20-fold, respectively. Evidence that all-E-3-dehydro-lutein is formed from zeaxanthin was strong.

Plasma concentration response to drinks containing beta-carotene as carrot juice or formulated as a water dispersible powder.

BACKGROUND: Bioavailability of beta-carotene is highly variable and depends on the source, the formulation and other nutritional factors. OBJECTIVE: It was the aim of the study to compare beta-carotene plasma response to b-carotene dosing with two commercially available drinks, containing beta-carotene from carrot juice or as water dispersible beta-carotene powder. Design In a randomized, parallel group study design, 4 volunteers per group received daily beta-carotene doses of 6-7 or 18-22 mg of either drink over 6 weeks. Blood samples for determination of carotenoid and vitamin A plasma concentrations were collected before supplementation and over the dosing period. RESULTS: Apparent steady-state beta-carotene concentrations were attained after 40 days of supplementation. Consumption of the beverage containing beta-carotene as a water dispersible powder resulted in a higher response of beta-carotene plasma concentrations with increments of 3.84 +/- 0.60 micromol/L (p < 0.05, dose: 7.2 mg/d) and 5.04 +/- 0.72 micromol/L (p < 0.05, dose: 21.6 mg/d), respectively, in comparison to the carrot juice-based drink with increments of 0.42 +/- 0.33 micromol/L (dose: 6 mg/d) and 1.71 +/- 0.55 micromol/L (dose: 18 mg/d), respectively. beta-carotene was cleared from the plasma with an apparent half-life of 6-11 days. Plasma concentrations of alpha-carotene, beta-cryptoxanthin, lutein, zeaxanthin, and lycopene remained almost unchanged, whereas retinol plasma concentrations increased slightly. By contrast, with the exception of elevated 13-cis-retinoic acid in one group (21.6 mg/d, water dispersible powder), the concentrations of all-trans-retinoic acid, and the oxo-derivatives or retinoic acid were not significantly affected by b-carotene supplementation. CONCLUSIONS: The results confirm that the relative bioavailability of beta-carotene depends largely on the source of b-carotene and demonstrate the superior bioavailability of beta-carotene powder in comparison to that in carrot juice.