Emerging anticoagulant therapies for atrial fibrillation: new options, new challenges.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with an increased risk of stroke and systemic embolism. Oral anticoagulation with vitamin K antagonists (VKAs), such as warfarin, has historically been the mainstay of long-term thromboprophylaxis in AF patients. However, although highly effective, VKAs have a number of limitations that make their use difficult and cumbersome in clinical practice. They have a slow onset and offset of action, narrow therapeutic window, marked dose-response variability, and multiple food and drug interactions, and require frequent coagulation monitoring and dose adjustments. To overcome VKA drawbacks, several new oral anticoagulants have been recently developed for use in AF, and three of them, the direct thrombin inhibitor dabigatran etexilate and the direct factor Xa inhibitors rivaroxaban and apixaban, have completed phase III trials. New agents have proven to be noninferior or superior to warfarin for AF-related stroke prevention, with similar or better safety profiles. These new drugs, with their predictable anticoagulant effect that allows for fixed dosing with no need for coagulation monitoring, have the potential to greatly simplify anticoagulation therapy for AF. Dabigatran etexilate and rivaroxaban are already approved in the United States and Europe for stroke prevention in nonvalvular AF, and dabigatran etexilate has entered current AF guidelines as an alternative to warfarin. However, some issues with new compounds are still unresolved, such as the lack of antidotes and standardized tests to measure drug activity. Active postmarketing monitoring surveillance of effectiveness and safety is required in the implementation of new anticoagulant therapies.

Increased augmentation index and central aortic blood pressure in osteoporotic postmenopausal women.

UNLABELLED: Osteoporosis has been associated with cardiovascular disease. We found increased augmentation index, a measure of wave reflections and arterial stiffness, and central pressures in osteoporotic postmenopausal women. They also showed a higher estimated aortic pulse wave velocity, indicating a stiffer aorta. These changes may increase cardiovascular risk in postmenopausal osteoporosis. INTRODUCTION: Evidence suggests a link between osteoporosis and cardiovascular disease. We investigated whether augmentation index (AIx), a measure of pulse wave reflections and arterial stiffness, is increased and related to the osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B ligand (RANKL) system in postmenopausal osteoporosis. METHODS: AIx and central aortic haemodynamics were assessed using pulse wave analysis in 182 cardiovascular disease-free osteoporotic postmenopausal women and in 160 controls. Statistical analysis was performed by unpaired t test, Mann-Whitney test, Spearman's correlation coefficient, and multivariate linear regression analysis. RESULTS: AIx (37.2 +/- 7.0 vs. 29.6 +/- 9.2 %, P < 0.0001) and central aortic systolic (117.5 +/- 12.1 vs. 111.4 +/- 12.2 mmHg, P < 0.0001) and pulse (40.5 +/- 10.3 vs. 36.4 +/- 8.1 mmHg, P = 0.0007) pressures were significantly higher in osteoporotic patients than in controls. The estimated aortic pulse wave velocity (PWV) was also significantly higher in the osteoporotic group. In multivariate analysis for osteoporotic patients, femoral neck and lumbar spine bone mineral density T scores were independent negative predictors of AIx (P < 0.0001). AIx was not correlated with serum levels of OPG and RANKL. CONCLUSIONS: Osteoporotic postmenopausal women show increased AIx and central aortic pressures, and a higher estimated aortic PWV, indicating a stiffer aorta. Such alterations may increase cardiovascular risk in postmenopausal osteoporosis.

Increased formation of 8-iso-prostaglandin F(2alpha) is associated with altered bone metabolism and lower bone mass in hypercholesterolaemic subjects.

OBJECTIVES: To investigate the relationship of 8-iso-prostaglandin (PG) F(2alpha) levels, a reliable marker of in vivo oxidative stress and lipid peroxidation, with bone mineral density (BMD), bone turnover markers, osteoprotegerin (OPG) and receptor activator of nuclear factor-kappa B ligand (RANKL) in hypercholesterolaemia. DESIGN: Cross-sectional study. SETTING: University hospital centre. METHODS: Serum 8-iso-PGF(2alpha) levels were measured in 173 hypercholesterolaemic subjects and in 152 age- and sex-matched normocholesterolaemic controls. Femoral neck and lumbar spine BMD, serum bone-specific alkaline phosphatase (BAP), osteocalcin (OC), OPG and RANKL levels, as well as urinary levels of C-terminal telopeptides of type I collagen (CTX-I), were also assessed. RESULTS: Hypercholesterolaemic subjects showed higher (P < 0.0001) serum 8-iso-PGF(2alpha) levels than controls. They also had decreased (P < 0.0001) femoral neck and lumbar spine BMD, and lower (P < 0.0001) serum BAP and OC levels. No significant differences between hypercholesterolaemic and control subjects were found when comparing urinary CTX-I levels, or serum OPG and RANKL levels. In multivariate linear regression analysis, serum 8-iso-PGF(2alpha) was the only negative predictor for femoral neck BMD and serum BAP and OC levels in hypercholesterolaemic subjects. No significant correlation (all P > 0.25) was present between serum 8-iso-PGF(2alpha) levels and urinary CTX-I levels, or serum OPG and RANKL levels, in hypercholesterolaemic subjects. CONCLUSIONS: We found an association between increased serum 8-iso-PGF(2alpha) levels and lower bone mass and reduced serum BAP and OC concentrations in hypercholesterolaemic subjects. These results would suggest a possible role for oxidative stress in the development of lower bone mass in hypercholesterolaemia.