Body Weight Has Limited Influence on the Safety, Tolerability, Pharmacokinetics, or Pharmacodynamics of Rivaroxaban (BAY 59‐7939) in Healthy Subjects

Kubitza, Dagmar; Becka, Michael; Zuehlsdorf, Michael; Mueck, Wolfgang

doi:10.1177/0091270006296058

Cited by 315 publications

(303 citation statements)

References 20 publications

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“…2,6 This is an important finding when analyzing the efficacy and safety results for the ROCKET AF East Asian cohort and the remaining ROCKET AF population because it is consistent with previous observations showing that rivaroxaban can be used without dose adjustment for body weight. 18,19 Patients in the ROCKET AF East Asian cohort had higher levels of prior stroke/TIA/non-CNS systemic embolism compared with the remaining study population, a finding supported by a recent publication that reported a higher burden of stroke relative to ischemic heart disease in East Asia. 20 Conversely, fewer patients in the East Asian cohort had other risk factors for stroke (hypertension, congestive heart failure, diabetes mellitus).…”

Section: Discussionsupporting

confidence: 61%

Rivaroxaban for Stroke Prevention in East Asian Patients From the ROCKET AF Trial

Wong

Oomman

et al. 2014

Stroke

143

120

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(ROCKET AF) trial, the efficacy and safety of rivaroxaban, a novel, oral, direct factor Xa inhibitor, was assessed for the prevention of stroke in patients with atrial fibrillation (AF) and at moderate to high risk of stroke.1 Results from this study showed that rivaroxaban (20 mg once daily or 15 mg once daily in patients with a creatinine clearance [CrCl] of 30-49 mL/min) was noninferior to dose-adjusted warfarin for the prevention of stroke and systemic embolism in an intention-to-treat (ITT) analysis. Rates of major or nonmajor clinically relevant bleeding were Background and Purpose-In Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial, rivaroxaban was noninferior to dose-adjusted warfarin in preventing stroke or systemic embolism among patients with nonvalvular atrial fibrillation at moderate to high stroke risk. Because of differences in patient demographics, epidemiology, and stroke risk management in East Asia, outcomes and relative effects of rivaroxaban versus warfarin were assessed to determine consistency among East Asians versus other ROCKET AF participants. Methods-Baseline demographics and interaction of treatment effects of rivaroxaban and warfarin among patients within East Asia and outside were assessed. Results-A total of 932 (6.5%) ROCKET AF participants resided in East Asia. At baseline, East Asians had lower weight, creatinine clearance, and prior vitamin K antagonist use; higher prevalence of prior stroke; and less congestive heart failure and prior myocardial infarction than other participants. Despite higher absolute event rates for efficacy and safety outcomes in East Asians, the relative efficacy of rivaroxaban (20 mg once daily; 15 mg once daily for creatinine clearance of 30-49 mL/min) versus warfarin with respect to the primary efficacy end point (stroke/systemic embolism) was consistent among East Asians and non-East Asians (interaction P=0.666 2 The proportion of strokes that are hemorrhagic has also been shown to be higher in Asians than in whites.3,4 Conversely, there is evidence to suggest that cardioembolic strokes make up a greater proportion of strokes in white versus Asian populations.5 Data from 2 studies have also shown East Asian populations to be more sensitive to warfarin than Indian and white populations. 6,7 Warfarin may also interact with several food and herbal supplements commonly used in Asia, thereby complicating its use. 8There is a perception, and some supporting evidence, that the incidence of intracranial hemorrhage is increased in patients of Asian ethnicity (largely East Asian) who receive warfarin compared with other ethnic groups.9,10 As a result, anticoagulants are underprescribed 11,12 or underdosed 13 in patients within this region because of the fear that the risk of bleeding offsets any benefits.As a result of the differences in patient demographics, epidemiology, and stroke risk management in East Asia, outcomes and the rela...

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Section: Discussionsupporting

confidence: 61%

Rivaroxaban for Stroke Prevention in East Asian Patients From the ROCKET AF Trial

Wong

Oomman

et al. 2014

Stroke

143

120

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“…A subgroup analysis of the ARISTOTLE trial based on BW reported that higher BW and BMI were associated with lower all‐cause mortality rate and lower risk of stroke or systemic embolism 22. A pharmacokinetic study of healthy volunteers taking rivaroxaban reported that the area under the curve (AUC) was unaffected by BW,23 the volume of distribution was moderately influenced by BW in patients taking rivaroxaban,24 and a mean increase in BW of 83% resulted in a limited 23% decrease of the AUC in healthy volunteers taking apixaban 25. A large prospective study of real‐life patients receiving DOACs for treatment of atrial fibrillation or VTE, which included 98 patients with BMI >40 kg/m 2 , did not find any indication that high BMI is associated with reduced DOAC efficacy or safety 26.…”

Section: Resultsmentioning

confidence: 99%

Peak plasma concentration of direct oral anticoagulants in obese patients weighing over 120 kilograms: A retrospective study

Piran

Traquair

Chan

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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BackgroundDue to a paucity of data on the efficacy and safety of direct oral anticoagulants (DOACs) in patients with a body mass index >40 kg/m2 or a weight >120 kg, the use of DOACs in this group is not recommended.ObjectivesTo determine the proportion of obese patients with body weight >120 kg with a peak plasma concentration of DOACs lower than the expected median trough level derived from population pharmacokinetic studies for each DOAC.MethodsPatients with body weight >120 kg taking DOACs for any indication underwent a peak drug concentration measurement at steady state.Results38 patients were included in the analysis. The mean age was 64 ± 11 years, and 30 (79%) were males. The median body weight was 132.5 kg (interquartile range [IQR] 127‐146.5). The median peak concentrations (IQR) were 148 ng/mL (138‐240), 138 ng/mL (123‐156.5), 215 ng/mL (181‐249) for apixaban, dabigatran, and rivaroxaban, respectively. Two patients (5%, 95% confidence interval [CI]: 0.5%‐18%) had a peak plasma concentration lower than the median trough and eight (21%, 95% CI: 11%‐37%) had a peak plasma concentration below the fifth percentile (10th percentile for dabigatran) peak concentration.ConclusionsMost patients in our study had peak plasma concentration higher than the median trough level for each of the three DOACs. However, 21% had a peak plasma concentration that was below the usual on‐therapy range of peak concentration for the corresponding DOAC.

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“…Extremes in body weight (less than or equal to 50 kg or above 120 kg) showed little influence on the concentrations of rivaroxaban (less than 25%) compared to individuals with a body weight of 70 to 80 kg. There was also no significant inter-individual variability among ethnic groups (Caucasian, African-American, Hispanic, Chinese, Japanese) (Kubitza et al, 2007).…”

Section: Posology and Methods Of Administrationmentioning

confidence: 85%

Pharmacological profile of non-vitamin K antagonist oral anticoagulants

Silva¹

2017

Afr. J. Pharm. Pharmacol.

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female patients, oral anticoagulants are recommended, and considering shared decision between doctor and patient. However, they are contraindicated in patients with mechanical prosthetic valve and in patients with moderate-to-severe mitral stenosis and atrial fibrillation. They have also been approved for prevention and treatment of deep vein thrombosis and pulmonary embolism. Dabigatran, a direct thrombin inhibitor, was the first to be approved, followed by the factor Xa inhibitors, rivaroxaban, apixaban, and recently, in 2015, edoxaban. They have advantages such as the use of fixed-dose, with infrequent drug interaction, rapid onset of action and do not require monitoring of their anticoagulant action. Nonetheless, they have different half-lives, the need for dose adjustment according to renal function, weight and age of the patient. Its use in pregnant women and children or adolescents is not well established. There are also peculiarities about the risks of bleeding, effects on coagulation tests and specific antidotes. Through this review we discuss the pharmacokinetics and pharmacodynamics characteristics of direct oral anticoagulants, its indications, interactions and contraindications. Analysis of its efficacy, safety and risk-benefit ratio will also be addressed.

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Body Weight Has Limited Influence on the Safety, Tolerability, Pharmacokinetics, or Pharmacodynamics of Rivaroxaban (BAY 59‐7939) in Healthy Subjects

Cited by 315 publications

References 20 publications

Rivaroxaban for Stroke Prevention in East Asian Patients From the ROCKET AF Trial

Rivaroxaban for Stroke Prevention in East Asian Patients From the ROCKET AF Trial

Peak plasma concentration of direct oral anticoagulants in obese patients weighing over 120 kilograms: A retrospective study

Pharmacological profile of non-vitamin K antagonist oral anticoagulants

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