Thromboprophylaxis with Rivaroxaban in Acutely Ill Medical Patients with Renal Impairment: Insights from the MAGELLAN and MARINER Trials

AbstractPatients with renal impairment are at higher risk of thrombosis and bleeding than those with normal renal function. The optimal rivaroxaban dose for thromboprophylaxis in acutely ill medical patients with renal impairment is unknown. MARINER and MAGELLAN were multicenter, randomized clinical trials of rivaroxaban in acutely ill medical patients. Efficacy and safety outcomes in patients with renal impairment in MARINER (7.5 mg once daily) were compared with those in patients with normal renal function in MARINER (10 mg once daily) and in a subpopulation of MAGELLAN that excluded patients at high risk for bleeding at baseline (10 mg once daily). Compared with enoxaparin/placebo in the MAGELLAN subpopulation, the relative risk (RR) of symptomatic venous thromboembolism (VTE) and VTE-related death with rivaroxaban 10 mg in patients with renal impairment (RR = 0.62; 95% confidence interval [CI] 0.27–1.44) was similar to that in those with normal renal function (RR = 0.78; 95% CI 0.44–1.40), while in MARINER, the 7.5 mg dose did not reduce the risk in patients with renal impairment (hazard ratio = 1.00; 95% CI 0.52–1.92). Major bleeding with rivaroxaban 10 mg once daily was higher in patients with renal impairment than in those with normal renal function in MAGELLAN (1.54% vs. 0.98%) and in the MAGELLAN subpopulation (0.94% vs. 0.61%). At a dose of 10 mg once daily, rivaroxaban is effective for thromboprophylaxis in acutely ill medical patients with impaired or normal renal function. The safety of this regimen is enhanced without loss of efficacy by excluding patients at high risk for bleeding, but not by using a reduced-dose strategy. Trial Registration ClinicalTrials.gov identifiers: NCT00571649 for the MAGELLAN trial, NCT02111564 for the MARINER trial.

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Integrative assessment of the effect of renal function on ribociclib treatment and dose recommendation in advanced breast cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e13037 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e13037-e13037

Author(s):

Yan Ji ◽

Vitaly Yartsev ◽

Yingbo Wang ◽

Michelle Quinlan ◽

Paolo Serra ◽

...

Keyword(s):

Renal Function ◽

Steady State ◽

Renal Impairment ◽

Normal Renal Function ◽

Severe Renal Impairment ◽

Phase 1 ◽

Moderate Renal Impairment ◽

Efficacy And Safety ◽

Phase 3 ◽

Integrative Assessment

e13037 Background: Ribociclib is an orally administered CDK4/6 inhibitor used in combination with endocrine therapy (ET) to treat women with hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative advanced breast cancer (ABC). An integrative assessment was conducted to evaluate the effect of renal function on the pharmacokinetics (PK), efficacy and safety of ribociclib. Methods: To assess the effect of mild and moderate renal impairment, a subgroup analysis was performed to evaluate PK parameters of ribociclib following oral administration of 600 mg QD 3 weeks on/1 week off in two Phase 1/2 and one Phase 3 clinical trials. Steady-state PK exposures in ABC patients at the 600 mg dose was estimated by a population PK model developed based on a pooled dataset from five Phase 1 to 3 trials and were compared by renal function. Efficacy and safety were also analyzed by renal function in a Phase 2 and three Phase 3 trials in ABC patients. The effect of severe renal impairment on ribociclib PK was assessed in a Phase I study in non-cancer subjects following a single oral 400 mg dose. Results: PK analyses in cancer patients showed that both single-dose and steady-state exposure of ribociclib at the 600 mg dose in patients with mild or moderate renal impairment were comparable to patients with normal renal function. Estimated steady-state PK exposure in patients with mild or moderate renal impairment is also comparable to patients with normal renal function. The primary efficacy results of progression free survival (PFS) and the safety profiles were comparable across renal-function cohorts in ABC patients. In non-cancer subjects administered a single oral dose of 400 mg, ribociclib AUCinf and Cmax increased 2.67- and 2.30-fold in subjects with severe renal impairment, respectively, compared to subjects with normal renal function. Conclusions: PK, efficacy and safety of ribociclib are consistent across patients with normal renal function, mild or moderate renal impairment. Hence, no dose adjustment is required in mild or moderate renal impaired patients. Severe renal impaired patients are recommended to have a reduced dose based on PK data in non-cancer subjects.

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Efficacy and Safety of Non-Vitamin K Anticoagulants for Atrial Fibrillation in Relation to Different Renal Function Levels: A Network Meta-Analysis

Cardiovascular Therapeutics ◽

10.1155/2020/2683740 ◽

2020 ◽

Vol 2020 ◽

pp. 1-26

Author(s):

Hao Jin ◽

Kongbo Zhu ◽

Lina Wang ◽

Yifan Li ◽

Jingjun Meng ◽

...

Keyword(s):

Atrial Fibrillation ◽

Renal Function ◽

Renal Impairment ◽

Major Bleeding ◽

Normal Renal Function ◽

Meta Analysis ◽

Effective Drug ◽

Efficacy And Safety ◽

Systemic Embolism ◽

Mild Renal Impairment

Background. We performed a network meta-analysis (NMA) comparing the efficacy (stroke or systemic embolism) and safety (major bleeding) among different non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) and renal impairment, with the aim of recommending the proper drug and the dose based on renal function. Methods. We searched PubMed, EMBASE, Web of Science, and Cochrane Library with the items “dabigatran, edoxaban, apixaban, rivaroxaban, warfarin, and atrial fibrillation” through August 2019. NMA was analyzed with R (version 3.5.1, R Foundation for Statistical Computing) with the packages gemtc recalling JAGS (version 4.3.0) for the efficacy and safety of each drug with regard to different levels of renal function. NetMetaXL (version 1.6.1) and winBUGS (version 1.4.3) were used to obtain the cumulative ranking curve (SUCRA) of each drug. Result. In patients with normal renal function, dabigatran150 was ranked as the most effective drug (SUCRA 0.90), followed by dabigatran110 (SUCRA 0.68), apixaban (SUCRA 0.66), and rivaroxaban (SUCRA 0.59). With regard to the safety for preventing major bleeding, there was high probability that edoxaban30 (SUCRA 0.99) ranked first, compared to dabigatran110 (SUCRA 0.78) and edoxaban60 (SUCRA 0.66). For patients with mild renal impairment, with respect to the most effective drug for preventing stroke or systemic embolism, edoxaban60 ranked first (SUCRA 0.98), in comparison with dabigatran150 (SUCRA 0.74) and apixaban (SUCRA 0.64). Possibility of ranking first for the safest drug was edoxaban30 (SUCRA 0.99), followed by dabigatran110 (SUCRA 0.70) and apixaban (SUCRA 0.69). In patients with moderate renal function, dabigatran150 (SUCRA 0.95) ranked as the most effective drug in comparison with apixaban (SUCRA 0.66). Dabigatran110 (SUCRA 0.53), rivaroxaban (SUCRA 0.51), and edoxaban60 (SUCRA 0.50) had the similar probability of ranking third. When referred to the safest drug, probability of ranking first for preventing major bleeding was edoxaban30 (SUCRA 0.98), followed by apixaban (SUCRA 0.85) and edoxaban60 (SUCRA 0.64). Conclusion. In patients with AF and renal impairment and for patients with normal renal function, dabigatran 110 mg (bid) might have a better effect on the clinical results. And it does not coincide with patients taking dabigatran 110 mg with dose reduction for other factors including aged ≥75 years, renal impairment (CrCL 30–50 mL/min), gastritis, esophagitis, or gastroesophageal reflux, receiving concomitant verapamil, and so on. For patients with mild renal impairment, apixaban 5 mg (bid) would be a better choice for preventing stroke or systemic embolism and major bleeding, while apixaban 5 mg (bid) and edoxaban 60 mg (qd) were recommended for patients with moderate renal impairment. However, considering the fact of no RCTs for the head-to-head comparison, caution should be exercised over selecting each of NOACs for patients.

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Quality management in the prophylaxis of venous thrombembolism - Results of a survey including 464 medical and surgical patients

VASA ◽

10.1024/0301-1526/a000082 ◽

2011 ◽

Vol 40 (2) ◽

pp. 123-130

Author(s):

Klein-Weigel ◽

Richter ◽

Arendt ◽

Gerdsen ◽

Härtwig ◽

...

Keyword(s):

Renal Function ◽

High Risk ◽

Quality Management ◽

High Risk Group ◽

Surgical Patients ◽

Medical Patients ◽

Risk Status ◽

Vte Prophylaxis ◽

Safety Concerns

Background: We surveyed the quality of risk stratification politics and monitored the rate of entries to our company-wide protocol for venous thrombembolism (VTE) prophylaxis in order to identify safety concerns. Patients and methods: Audit in 464 medical and surgical patients to evaluate quality of VTE prophylaxis. Results: Patients were classified as low 146 (31 %), medium 101 (22 %), and high risk cases 217 (47 %). Of these 262 (56.5 %) were treated according to their risk status and in accordance with our protocol, while 9 more patients were treated according to their risk status but off-protocol. Overtreatment was identified in 73 (15.7 %), undertreatment in 120 (25,9 %) of all patients. The rate of incorrect prophylaxis was significantly different between the risk categories, with more patients of the high-risk group receiving inadequate medical prophylaxis (data not shown; p = 0.038). Renal function was analyzed in 392 (84.5 %) patients. In those patients with known renal function 26 (6.6 %) received improper medical prophylaxis. If cases were added in whom prophylaxis was started without previous creatinine control, renal function was not correctly taken into account in 49 (10.6 %) of all patients. Moreover, deterioration of renal function was not excluded within one week in 78 patients (16.8 %) and blood count was not re-checked in 45 (9.7 %) of all patients after one week. There were more overtreatments in surgical (n = 53/278) and more undertreatments in medical patients (n = 54/186) (p = 0.04). Surgeons neglected renal function and blood controls significantly more often than medical doctors (p-values for both < 0.05). Conclusions: We found a low adherence with our protocol and substantial over- and undertreatment in VTE prophylaxis. Besides, we identified disregarding of renal function and safety laboratory examinations as additional safety concerns. To identify safety problems associated with medical VTE prophylaxis and hot spots quality management-audits proved to be valuable instruments.

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Single-Dose Study to Evaluate the PKs of Pretomanid in Subjects With Renal Impairment Compared to Subjects With Normal Renal Function

Case Medical Research ◽

10.31525/ct1-nct03896750 ◽

2019 ◽

Author(s):

Keyword(s):

Renal Function ◽

Single Dose ◽

Renal Impairment ◽

Normal Renal Function ◽

Single Dose Study ◽

Dose Study

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SINGLE-DOSE PHARMACOKINETICS OF BMS-986177/JNJ-70033093 (BMS-177/JNJ-3093) IN PARTICIPANTS WITH NORMAL RENAL FUNCTION AND PARTICIPANTS WITH MODERATE OR SEVERE RENAL IMPAIRMENT

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(21)03195-8 ◽

2021 ◽

Vol 77 (18) ◽

pp. 1839

Author(s):

Vidya Perera ◽

Grigor Abelian ◽

Danshi Li ◽

Zhaoqing Wang ◽

Liping Zhang ◽

...

Keyword(s):

Renal Function ◽

Single Dose ◽

Renal Impairment ◽

Normal Renal Function ◽

Severe Renal Impairment

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P0234LOW URINARY CITRATE LEVELS ARE NOT SPECIFIC OF AUTOSOMAL POLYCYSTIC KIDNEY DISEASE (ADPKD) AND ARE PRESENT WHEN RENAL FUNCTION IS IMPAIRED IN ALL NEPHROPATIES

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0234 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Francisco-Jose Borrego-Utiel ◽

Enoc Merino Garcia ◽

Isidoro Herrera ◽

Clara Moriana Dominguez ◽

Victoria Camacho Reina ◽

...

Keyword(s):

Renal Function ◽

Uric Acid ◽

Kidney Disease ◽

Renal Impairment ◽

Polycystic Kidney Disease ◽

Normal Renal Function ◽

Serum Bicarbonate ◽

Polycystic Kidney ◽

Glomerular Diseases ◽

Urinary Citrate

Abstract Background and Aims In polycystic kidney disease (PKD) it is frequently found a reduction in urinary citrate that is related with degree of renal impairment but it is unknown if this alteration is specific or if it is also present in other nephropathies. Recently it has been suggested that urinary citrate could be a marker of covert metabolic acidosis and reflects acid retention in chronic kidney disease (CKD). Our aim was to compare urinary citrate in PKD with other renal diseases and to show its relation with serum bicarbonate and excretion of uric acid and calcium. Method We determined citrate, calcium and uric acid in 24-hour urine in patients with PKD and with other nephropathies with varied degree of renal impairment followed in a outpatient clinic of nephrology. Results We included 291 patients, 119 with glomerular diseases, 116 with PKD, 21 with other nephropathies, and 35 patients with normal renal function. Urinary citrate was higher in women (Females 309±251 mg/gCr vs. males 181±145 mg/gCr, p<0.001) and in patients with normal renal function (normal 380±210 mg/gCr; PKD 203±166 mg/gCr; glomerular 279±282 mg/gCr; p<0,001). PKD patients showed similar values of urinary citrate to patients with glomerular diseases and with other nephropathies. We observed a progressive reduction in urinary citrate parallel to degree of renal impairment, in a comparable way among patients with PKD and glomerular diseases. We did not observe a relationship between urinary citrate and serum bicarbonate levels. Calcium and uric acid elimination in ADPKD patients was similar to other nephropathies and lower to patients with normal renal function. However, serum uric acid was significantly higher in glomerular patients than other nephropathies after adjust with glomerular filtration rate and sex. Conclusion Hypocitraturia is not specific of PKD but it is also present in all nephropathies. Urinary citrate are related to degree of renal impairment and it is not related with serum bicarbonate. We think that it could be interesting to study urinary citrate as a marker of renal function and its role as prognostic factor of renal deterioration.

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Pharmacokinetics of lamivudine in human immunodeficiency virus-infected patients with renal dysfunction.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.6.1514 ◽

1996 ◽

Vol 40 (6) ◽

pp. 1514-1519 ◽

Cited By ~ 64

Author(s):

A E Heald ◽

P H Hsyu ◽

G J Yuen ◽

P Robinson ◽

P Mydlow ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Renal Function ◽

Renal Impairment ◽

Normal Renal Function ◽

Severe Renal Impairment ◽

Moderate Renal Impairment ◽

Pharmacokinetic Parameters ◽

Geometric Means ◽

Immunodeficiency Virus

The purpose of this study was to determine the safety and pharmacokinetics of lamivudine (3TC), a nucleoside analog that has shown potent in vitro and recent in vivo activity against human immunodeficiency virus. Sixteen human immunodeficiency virus-infected patients, six with normal renal function (creatinine clearance [CLCR], > or = 60 ml/min), four with moderate renal impairment (CLCR, 10 to 40 ml/min), and six with severe renal impairment (CLCR, < 10 ml/min), were enrolled in the study. After an overnight fast, patients were administered 300 mg of 3TC orally. Blood was obtained before 3TC administration and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 32, 40, and 48 h afterward. Timed urine collections were performed for patients able to produce urine. Serum and urine were assayed for 3TC by reverse-phase high-performance liquid chromatography with UV detection. Pharmacokinetic parameters were calculated by using standard noncompartmental techniques. The peak concentration of 3TC increased with decreasing renal function; geometric means were 2,524, 3,538, and 5,684 ng/ml for patients with normal renal function, moderate renal impairment, and severe renal impairment, respectively. The terminal half-life also increased with decreasing renal function; geometric means were 11.5, 14.1, and 20.7 h for patients with normal renal function, moderate renal impairment, and severe renal impairment, respectively. Both oral and renal clearances were linearly correlated with CLCR. A 300-mg dose of 3TC was well tolerated by all three patient groups. The pharmacokinetics of 3TC is profoundly affected by impaired renal function. Dosage adjustment, by either dose reduction or lengthening of the dosing interval, is warranted.

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