ximelagatran and Obesity

Obesity is well-established as a major cardiovascular (CV) risk factor. Obesity confers a greater risk for developing atrial fibrillation (AF), but the relation between obesity and established nonvalvular AF for stroke and all-cause death is still unclear. To ascertain the prevalence of overweight and obesity in patients with nonvalvular AF, their influence on adverse events, and the relation with anticoagulation control, we performed this post hoc analysis of the pooled Stroke Prevention using an Oral Thrombin Inhibitor in patients with atrial Fibrillation (SPORTIF) III and V data sets. For this study, we analyzed all patients assigned to the warfarin arm with data on body mass index (BMI). Time in therapeutic range was used as an index of the quality of anticoagulation control. The 3,630 patients eligible for this analysis were categorized as follows: (1) BMI 18.5 to 24.9 ("normal weight") in 24.1%; (2) BMI 25.0 to 29.9 ("overweight") in 39.8%; and BMI ≥30 ("obese") in 36.1%. Both overweight (hazard ratio [HR] 0.70) and obese (HR 0.59) categories were inversely associated with the composite outcome of stroke/all-cause death. A similar inverse association was seen for the end point of stroke (HR 0.61 and 0.47, respectively). Good anticoagulation control also attenuated the association between BMI categories and outcomes. In patients with time in therapeutic range >70%, BMI category was not significantly associated with the composite outcome of stroke/death and stroke. Stroke and all-cause death progressively reduced in overweight and obese anticoagulated patients with AF. The inverse relation of BMI categories to the risk of stroke and all-cause death was mitigated by good anticoagulation control.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Body Mass Index; Cohort Studies; Female; Humans; Male; Obesity; Prevalence; Stroke

Ximelagatran, an oral direct thrombin inhibitor, is currently in clinical development for the prevention and treatment of thromboembolic disease. Following oral administration, ximelagatran undergoes rapid bioconversion to its active form, melagatran, via two minor intermediates. Obesity, defined as body mass index (BMI) >30 kg/m(2), is a recognised risk factor for thrombosis. There is potential for differences in the pharmacokinetics and pharmacodynamics of drugs administered to obese versus non-obese patients, and some drugs may require alternative administration strategies in obese patients.. To investigate the effect of obesity on the pharmacokinetics and pharmacodynamics of melagatran after oral administration of ximelagatran.. This was an open-label, single-dose, group-matched study in which obese subjects (BMI 32-39 kg/m(2); six male and six female; age 21-40 years) were matched by sex and age (+/-2 years) with non-obese subjects (BMI 21-26 kg/m(2); six male and six female; aged 21-39 years). Each subject received a single oral dose of ximelagatran 24mg. Blood samples for determination of plasma concentrations of melagatran and activated partial thromboplastin times (APTT; a marker of melagatran pharmacodynamics) were collected up to 12 hours after administration.. There were no statistically significant differences in the pharmacokinetic properties of melagatran between obese and non-obese subjects. Values of area under the melagatran plasma concentration-time curve, maximum plasma concentration (C(max)), time at which C(max) occurred and terminal elimination half-life were approximately 1 micromol. h/L, 0.2 micromol/L, 2 hours and 3 hours in both obese and non-obese subjects, respectively. In addition, there was no statistically significant difference between the obese and non-obese subjects in the amount of ximelagatran, melagatran or the minor intermediates ethyl-melagatran and melagatran hydroxyamidine excreted in urine. When relating the prolongation of APTT ratio to the square root of plasma concentration of melagatran and obesity status (no/yes), no statistically significant interaction between plasma concentration and obesity status was observed. Ximelagatran was well tolerated in both obese and non-obese subjects, and no bleeding events or serious adverse events occurred.. No differences in the pharmacokinetics or pharmacodynamics of melagatran were detected between obese and non-obese subjects after oral administration of ximelagatran, suggesting that dose adjustment of ximelagatran in obesity (BMI up to 39 kg/m(2)) is not necessary.

Topics: Administration, Oral; Adult; Area Under Curve; Azetidines; Benzylamines; Female; Glycine; Half-Life; Humans; Inactivation, Metabolic; Male; Obesity; Thrombin