Dabigatran Etexilate in Atrial Fibrillation Patients With Severe Renal Impairment: Dose Identification Using Pharmacokinetic Modeling and Simulation

Lehr, Thorsten; Haertter, Sebastian; Liesenfeld, Karl‐Heinz; Staab, Alexander; Clemens, Andreas; Reilly, Paul; Friedman, Jeffrey

doi:10.1177/0091270011417716

Cited by 85 publications

(62 citation statements)

References 12 publications

(22 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…12 However, dose-identification studies (confirmed and supported by the US Food and Drug Administration's clinical pharmacology division) that used pharmacokinetic modeling and simulation have been performed that showed that dabigatran 75 mg BID was a recommended dose in patients with severe renal dysfunction (eGFR 15-30 mL/min). 24 Because the present study was not dimensioned for subgroup analysis, statistical power was relatively low for testing interactions, and a nonsignificant result does not rule out the possibility of treatment heterogeneity. A total of 162 patients had missing creatinine samples, although annual event rates in participants with available measurements were almost identical to the main trial results.…”

Section: Study Limitationsmentioning

confidence: 87%

Efficacy and Safety of Dabigatran Compared With Warfarin in Relation to Baseline Renal Function in Patients With Atrial Fibrillation

et al. 2014

Self Cite

View full text Add to dashboard Cite

I mpaired renal function is associated with a higher prevalence of atrial fibrillation (AF) [1][2][3] and with an increased risk of thromboembolic events in patients with nonvalvular AF. [4][5][6][7] Current guidelines recommend treatment with oral anticoagulants for AF patients at risk for stroke 8 ; however, impaired renal function also confers a substantially increased risk of major bleeding 9 and often contributes to underutilization of oral anticoagulation therapy in AF populations. 10,11 Clinical Perspective on p 970Background-Renal impairment increases the risk of stroke and bleeding in patients with atrial fibrillation. In the Randomized Evaluation of Long-Term Anticoagulant Therapy (RELY) trial, dabigatran, with ≈80% renal elimination, displayed superiority over warfarin for prevention of stroke and systemic embolism in the 150-mg dose and significantly less major bleeding in the 110-mg dose in 18 113 patients with nonvalvular atrial fibrillation. This prespecified study investigated these outcomes in relation to renal function. Methods and Results-Glomerular filtration rate was estimated with the Cockcroft-Gault, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and Modification of Diet in Renal Disease (MDRD) equations in all randomized patients with available creatinine at baseline (n=17 951), and cystatin C-based glomerular filtration rate was estimated in a subpopulation with measurements available (n=6190). A glomerular filtration rate ≥80, 50 to <80, and <50 mL/ min was estimated in 32.6%, 47.6%, and 19.8% and in 21.6%, 59.6%, and 18.8% of patients based on Cockcroft-Gault and CKD-EPI, respectively. Rates of stroke or systemic embolism, major bleeding, and all-cause mortality increased as renal function decreased. The rates of stroke or systemic embolism were lower with dabigatran 150 mg and similar with 110 mg twice daily compared with warfarin, without significant heterogeneity in subgroups defined by renal function (interaction P>0.1 for all). For the outcome of major bleeding, there were significant interactions between treatment and renal function according to CKD-EPI and MDRD equations, respectively (P<0.05). The relative reduction in major bleeding with either dabigatran dose compared with warfarin was greater in patients with glomerular filtration rate ≥80 mL/min. Conclusions-The efficacy of both dosages of dabigatran was consistent with the overall trial irrespective of renal function.However, with the CKD-EPI and MDRD equations, both dabigatran dosages displayed significantly lower rates of major bleeding in patients with glomerular filtration rate ≥80 mL/min. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600.

show abstract

Section: Study Limitationsmentioning

confidence: 87%

Efficacy and Safety of Dabigatran Compared With Warfarin in Relation to Baseline Renal Function in Patients With Atrial Fibrillation

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…In another study, dabigatran plasma concentrations obtained during the RE-LY trial were analyzed in a pharmacokinetic simulation model, and the relationship between CL CR and dabigatran exposure was found to be nonlinear. 16 Various regimens including 75 mg twice daily, 110 mg daily, and 150 mg daily in patients with a CL CR between 15 and 30 mL/min were expected to have similar drug exposure to that found among healthy subjects. Without any clinical data, the dose of 75 mg twice daily was chosen based on a lower peak-trough ratio than any single daily regimen and similar posology for all patient subgroups which might reduce medication errors and avoid a negative impact on adherence.…”

Section: Renal Impairmentmentioning

confidence: 98%

“…Without any clinical data, the dose of 75 mg twice daily was chosen based on a lower peak-trough ratio than any single daily regimen and similar posology for all patient subgroups which might reduce medication errors and avoid a negative impact on adherence. 16,17 …”

Section: Renal Impairmentmentioning

confidence: 99%

Direct oral anticoagulant considerations in solid organ transplantation: A review

Salerno

Tsapepas

Papachristos

et al. 2016

Clinical Transplantation

View full text Add to dashboard Cite

For more than 60 years, warfarin was the only oral anticoagulation agent available for use in the United States. In many recent clinical trials, several direct oral anticoagulants (DOACs) demonstrated similar efficacy with an equal or superior safety profile, with some other notable benefits. The DOACs have lower inter- and intrapatient variability, much shorter half-lives, and less known drug-drug and drug-food interactions as compared to warfarin. Despite these demonstrated benefits, the use of DOACs has not gained uniform acceptance because of lack of supportive data in special patient populations, including recipients of solid organ transplants maintained on immunosuppression. This review describes the properties of several novel DOACs including their pharmacology and mechanisms of action as they relate to use among solid organ transplant recipients. We have particularly focused on (i) dosing in patients with impaired renal and hepatic function; (ii) considerations for drug-drug interactions with immunosuppressive medications; and (iii) management of the anticoagulated patients at the time of unplanned surgery. The risks and benefits of the use of DOACs in solid organ transplant recipients should be carefully evaluated prior to the introduction of these agents in this highly distinct patient population.

show abstract

“… Note: Data from previous studies 6,7,46

Abbreviations: T max , time to maximum concentration; PPB, plasma protein binding; t ½ , half-life; F , bioavailability.

…”

Section: Tablementioning

confidence: 99%

Use of direct oral anticoagulants for the prevention and treatment of thromboembolic disease in patients with reduced renal function: a short review of the clinical evidence

Willett

Morrill

2017

TCRM

View full text Add to dashboard Cite

BackgroundThe use of direct oral anticoagulants (DOACs) is restricted by the limitations of clinical trials guiding therapy for patients with renal impairment, as many of these trials excluded patients with severe renal impairment. There are currently four agents available: dabigatran, rivaroxaban, apixaban, and edoxaban. The purpose of this review was to 1) describe current recommended dosing for each DOAC and published postmarketing data, including case reports, on the use of these agents in the renally impaired; and 2) discuss patient adherence and satisfaction and the cost of these agents.Materials and methodsA literature search was conducted using Medline and Embase with the terms “dabigatran” or “rivaroxaban” or “apixaban” or “edoxaban” and “renal impairment”. Clinical trials and case reports describing the use of DOAC therapy in patients with renal impairment were reviewed. A second search was conducted to find articles evaluating patient adherence, patient satisfaction, and pharmacoeconomics of DOACs.ResultsThere are a multitude of subgroup and post hoc analyses, as well as six case reports with dabigatran and one case report with apixaban, that provide insight for the clinical use of DOACs in patients with renal impairment. Dabigatran exhibits the greatest level of renal elimination, and there are data from clinical trials and several case reports that warrant reconsideration before use. Other DOACs may be a better option in patients with impaired renal function. Further, data from patient-adherence studies have suggested that DOACs that are dosed daily (rather than twice daily) are optimal and preferred. There does not appear to be a cost difference between DOACs and warfarin therapy.ConclusionDOAC therapy in patients with impaired renal function requires more critical review of study data, as these patients may have increased risk of bleeding. It is also valuable to consider patient preferences and cost when selecting the appropriate option for oral anticoagulation.

show abstract

Dabigatran Etexilate in Atrial Fibrillation Patients With Severe Renal Impairment: Dose Identification Using Pharmacokinetic Modeling and Simulation

Cited by 85 publications

References 12 publications

Efficacy and Safety of Dabigatran Compared With Warfarin in Relation to Baseline Renal Function in Patients With Atrial Fibrillation

Efficacy and Safety of Dabigatran Compared With Warfarin in Relation to Baseline Renal Function in Patients With Atrial Fibrillation

Direct oral anticoagulant considerations in solid organ transplantation: A review

Use of direct oral anticoagulants for the prevention and treatment of thromboembolic disease in patients with reduced renal function: a short review of the clinical evidence

Contact Info

Product

Resources

About