No accumulation of the peak anti-factor Xa activity of tinzaparin in elderly patients with moderate-to-severe renal impairment: the IRIS substudy

Abstract Abstract 172 The “Innohep® in Renal Insufficiency Study” (IRIS) was an international, multicentre, open, randomized, parallel group clinical trial with a primary objective to compare the safety of tinzaparin and unfractionated heparin in terms of clinically relevant bleeding (CRB) in elderly patients with impaired renal function for initial treatment of acute deep vein thrombosis. In the elderly, concerns have been raised about the risk of an accumulation effect and/or overdose due to the renal elimination of low molecular weight heparins (LMWH). In a subset of centres participating in the IRIS study, we conducted a substudy in order to assess whether there was an accumulation of anti-Xa activity and whether there was any relationship between anti-Xa activity and age, weight, creatinine clearance or clinical outcomes in patients treated with tinzaparin (175 IU/kg/24h) for venous thromboembolism. Plasma anti-Xa activity was to be analysed at peak level (4–6 hours after injection) on Day 2 or Day 3 and on Day 5 or at visit S (VS: day of visit at end of SC treatment) using a chromogenic assay (Rotachrom® heparin, Diagnostica Stago®). Of the complete IRIS study population who received tinzaparin (n=268), data from 87 patients (32%) were analysed. The patient characteristics (mean age 83±5 years [75–99 years], mean creatinine clearance (Cockcroft-Gault) 40.8 mL/min (SD 11.7, range 14–59) were consistent with those of the overall population of IRIS study. Of note, 24.1% had severe renal impairment (creatinine clearance < 30 mL/min). The mean peak anti-Xa activities, which were 0.86 (SD 0.34) and 0.87 (SD 0.31) IU/mL on Day2/3 and Day5/VS, respectively, were found close to the mean 0.85 IU/mL reported in the literature in patients receiving tinzaparin at therapeutic dose. There was no correlation between the anti-Xa activity and age, weight, or creatinine clearance. There was no significant difference in the anti-Xa levels between patients with, versus those without, severe renal impairment. The mean accumulation ratio (defined as anti-Xa activity on Day5/VS divided by the anti-Xa activity on Day2/3) was 1.06 (SD 0.30, 90% CI:1.01–1.11): as the 90% CI of the accumulation did not exceed the pre-defined upper limit of 1.25, no significant accumulation was detected. The mean anti-Xa activity did not differ significantly between the 8 patients experiencing a CRB during tinzaparin treatment and the 79 who did not experience a CRB during tinzaparin treatment. Among the 8 patients who had a CRB, one had an anti-Xa activity > 2.0 IU/mL (considered above therapeutic level) whereas the seven others had anti-Xa < 1.5 IU/mL. Interestingly, we found that the mean anti-Xa activities were significantly lower in the 12 patients with infectious disease at baseline compared to the patients without infectious disease: 0.66 (SD 0.18) vs 0.8 (SD 0.35) IU/mL on Day2/3, p=0.007; 0.62 (SD 0.23) vs 0.91 (SD 0.30) IU/mL on Day5/VS, p=0.002). These numbers are small but may require further investigation. There was no statistically significant difference in anti-Xa levels when comparing patients with versus those without ongoing malignancy. In conclusion, an IRIS substudy demonstrated no accumulation of anti-Xa activity in elderly patients with moderate to severe renal impairment receiving unadjusted recommended full dose of tinzaparin and confirms previous pharmacokinetic studies in similar populations. The high proportion of higher molecular weight moieties in tinzaparin may account for reduced dependence on renal elimination of the anti-Xa activity seen in elderly patients with renal impairment. Disclosures: Siguret: Leo-Pharma: this work was supported by a grant from Leo-Pharma. Leizorovicz:GSK: Consultancy. Gouin-Thibault:Leo-Pharma: this work was supported by a grant from Leo-Pharma.

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Effects of Renal Impairment on the Pharmacology of Rivaroxaban (BAY 59-7939) - An Oral, Direct, Factor Xa Inhibitor.

Blood ◽

10.1182/blood.v108.11.913.913 ◽

2006 ◽

Vol 108 (11) ◽

pp. 913-913 ◽

Cited By ~ 8

Author(s):

Atef Halabi ◽

Haidar Maatouk ◽

Norbert Klause ◽

Volkmar Lufft ◽

Dagmar Kubitza ◽

...

Keyword(s):

Renal Impairment ◽

Dose Adjustment ◽

Severe Renal Impairment ◽

Plasma Concentrations ◽

Factor Xa ◽

Direct Factor ◽

Pharmacokinetics And Pharmacodynamics ◽

Control Subjects ◽

Severe Impairment ◽

Mild Impairment

Abstract Rivaroxaban (BAY 59-7939) is an oral, direct Factor Xa (FXa) inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. It has predictable pharmacokinetics and pharmacodynamics in healthy subjects. Approximately 30% of rivaroxaban is excreted unchanged in the urine; therefore, renal excretion is an important route of elimination. This multicenter study was performed to evaluate the effect of renal impairment on the tolerability, pharmacokinetics, and pharmacodynamics of a single oral 10 mg dose of rivaroxaban. Subjects (N=32) were allocated to one of four groups (matched by age and gender), based on calculated creatinine clearance (CrCL): ≥80 mL/min (control); 50–79 mL/min (mild impairment); 30–49 mL/min (moderate impairment); and <30 mL/min (severe impairment). Rivaroxaban was well tolerated; treatment-emergent adverse events occurred in 62.5% of control subjects, and 12.5%, 12.5%, and 37.5% of those with mild, moderate, and severe renal impairment, respectively. All adverse events were mild to moderate in severity, and resolved by the end of the study. Decreased CrCL led to increased rivaroxaban plasma concentrations: AUC was 44%, 52%, and 64% higher in subjects with mild, moderate, and severe renal impairment, respectively, compared with control subjects (p<0.05); Cmax was relatively unaffected, and tmax was delayed in subjects with CrCL <50 mL/min (3 hours vs 2 hours for control). Renal clearance of rivaroxaban decreased with decreasing renal function; 29% of rivaroxaban was excreted via the urine in control subjects, compared with 20%, 13%, and 10% in those with mild, moderate, and severe renal impairment, respectively. The pharmacodynamic effects of rivaroxaban (inhibition of FXa activity and prolongation of prothrombin time [PT]) were increased with decreasing renal function. The AUC for inhibition of FXa activity increased by 50% (mild impairment), 86% (moderate impairment), and 100% (severe impairment) (p<0.01; Pearson’s correlation coefficient −0.49), and the AUC for prolongation of PT increased by 33%, 116%, and 144%, respectively (p<0.001; correlation −0.56), compared with control. The maximum effects (Emax) of rivaroxaban on inhibition of FXa activity or prolongation of PT did not differ to a relevant extent among the different groups. In conclusion, rivaroxaban plasma concentrations and, as a result, inhibition of FXa activity and prolongation of PT, are inversely correlated with CrCL. In phase II clinical studies of rivaroxaban, patients with mild or moderate renal impairment were included without dose adjustment. However, whether dose adjustment is necessary in patients with renal impairment will require investigation in future clinical trials.

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Factor Xa Inhibitors

Fibrinolytic and Antithrombotic Therapy ◽

10.1093/oso/9780195155648.003.0021 ◽

2006 ◽

Author(s):

Richard C. Becker ◽

Frederick A. Spencer

Keyword(s):

Renal Impairment ◽

Early Stage ◽

Severe Renal Impairment ◽

Subcutaneous Administration ◽

Factor Xa ◽

Drug Clearance ◽

Factor Xa Inhibitors ◽

Thromboembolism Prophylaxis ◽

Mild Renal Impairment ◽

St Segment Elevation

The importance of factor Xa in the initiation and propagation of coagulation, as well as its pluripotential cellular properties, has been discussed previously. Considered collectively, the effects exhibited by this particular protease make it an attractive target for pharmacologic inhibition. Factor Xa inhibition can be classified and subcategorized as follows: indirect (antithrombin [AT]-dependent), nonselective (e.g., unfractionated heparin); indirect, semi-selective (e.g., low-molecular-weight heparin); indirect, selective (e.g., fondaparinux); and direct, selective (e.g., DX-9065a [in early stage of development]). Oral factor Xa inhibitors are in phase II testing. Fondaparinux (Arixtra) is a synthetic pentasaccharide that requires AT for selective fXa binding (Petitou et al., 1991). Unlike heparin compounds, fondaparinux does not inhibit thrombin directly nor does it interact with platelets (or platelet-derived proteins). After subcutaneous administration in healthy volunteers, fondaparinux was nearly 100% bioavailable, and absorption was rapid (Cmax within 2 hours) (Donat et al., 2002). Clearance is through renal mechanisms with a terminal halflife of 17 ± 3 hours (slightly longer in elderly volunteers). Overall, drug clearance is 25% lower in patients with mild renal impairment (creatinine clearance [CrCl] 50–80 mL/min), approximately 40% lower in patients with moderate renal impairment (CrCl 30–50 mL/min), and 55% lower in patients with severe renal impairment (CrCl <30 mL/min). OASIS-5, the largest trial performed to date in non-ST segment elevation acute coronary syndromes (ACS), randomized 20,078 patients to fondaparinux (2.5 mg subcuaneous once daily) or enoxaparin (1 mg/kg twice daily) for 2 to 8 days. The primary outcome (composite of death, MI, and refractory ischemia on day 9) was 5.9% and 5.8%, respectively. Major bleeding rates were 2.1% and 4.0%, respectively (hazard ratio 0.53; p<.001). By 6-month follow-up, the endpoints of death, death/MI, stroke, and composite of death/MI/stroke were significantly reduced in those receiving fondaparinux. Catheter thrombosis (during PCI) was 3-fold higher in fondaparinux-treated patients compared to those receiving enoxaparin (1.3% vs. 0.5%, respectively) (European Society of Cardiology presentation, September 2005). The clinical use of fondaparinux for venous thromboembolism prophylaxis will be discussed in Chapter 22.

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Persistent Rivaroxaban Effect Due to Impaired Renal Clearance and Medication Effects

Laboratory Medicine ◽

10.1093/labmed/lmz044 ◽

2019 ◽

Author(s):

Chelsea Milito ◽

Hannah McRae ◽

Adrienne Victor ◽

Majed A Refaai ◽

Amy E Schmidt

Keyword(s):

Renal Function ◽

Renal Impairment ◽

Renal Clearance ◽

Active Site ◽

Severe Renal Impairment ◽

Factor Xa ◽

Direct Oral Anticoagulant ◽

Medication List ◽

Mild Renal Impairment ◽

Medication Effects

Abstract Rivaroxaban (Xarelto; Johnson & Johnson Services, Inc) is a direct oral anticoagulant (DOAC) that works by directly inhibiting the active site of factor Xa (FXa). Rivaroxaban is metabolized and cleared via the kidney and liver. The results of various studies have shown that patients with severe renal impairment should receive reduced dosages of rivaroxaban or another anticoagulant due to impaired clearance. Although it is not required, monitoring rivaroxaban is useful in some conditions; however, the assays required for such monitoring are not readily available. Herein, we present a case of a 68-year-old Caucasian male patient who was receiving rivaroxaban (20 mg/day) for atrial flutter and had mild renal impairment. The patient was found to have increased effect of rivaroxaban due to further impairment of renal clearance caused by several renally cleared medications. This case highlights the importance of closely examining the renal function of and medication list for a patient before starting DOACs such as rivaroxaban.

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