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A Randomized Study of 4-Factor Prothrombin Complex Concentrate and Authors: Jerrold H

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A Randomized Study of 4-Factor Prothrombin Complex Concentrate and Authors: Jerrold H A Randomized Study of 4-Factor Prothrombin Complex Concentrate and Tranexamic Acid on Bleeding, Thrombin Generation, and Pharmacodynamics After Punch Biopsies in Rivaroxaban Treated Subjects With Supratherapeutic Drug Levels Authors: Jerrold H. Levy, MD1; Kenneth T. Moore, MS2; Matthew D. Neal, MD3; David Schneider, MD4; Victoria S. Marcsisin, MS2; Jay Ariyawansa, MS2; Jeffrey I. Weitz, MD5 1Duke University School of Medicine, Durham, North Carolina, United States; 2Janssen Pharmaceuticals, Janssen Scientific Affairs, Titusville, New Jersey, United States; 3University of Pittsburgh, Pittsburgh, Pennsylvania, United States; 4University of Vermont, Burlington, Vermont, United States; 7057 Figure 3 dra 1.4 5 This tagline is for informaon only; McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada DO NOT PRINT Figure 3. Time course of (A) prothrombin time (PT) and (B) endogenous thrombin Introduction Results potential (ETP) on mean absolute values change from baseline for treatment with 4F-PCC (Group A), TXA (Group B), and placebo (saline control) (Group C). • Oral factor Xa (FXa) inhibitors, including rivaroxaban, are replacing vitamin K • Of the 147 subjects enrolled (49 in each of the 3 cohorts), 145 (98.6%) completed A End of 4F-PCC/Placebo Infusion antagonists such as warfarin for many thromboembolic indications the study End of TXA/Placebo Infusion • Reversal of the anticoagulant effects of FXa inhibitors is important in the event of • Subject characteristics were comparable between the 3 cohorts (Table 1) clinically relevant bleeding 4F-PCC – The majority of subjects enrolled were male (70.1%) and white (66.0%), with a 25 2 TXA • Currently, there are no therapies approved for reversing oral FXa inhibitors, but median age of 28.0 years and a mean BMI of 25.0 kg/m Saline 4-factor prothrombin concentrate (4F-PCC) and tranexamic acid (TXA) have been suggested for this purpose lues, seconds Table 1. Demographic and Baseline Characteristics (Safety Analysis Set) Va 20 • Recent studies in healthy volunteers have assessed the utility of both 3-factor PCC e and 4F-PCC to reverse the anticoagulant effects of rivaroxaban1,2 Rivaroxaban Rivaroxaban Rivaroxaban – Results demonstrated partial to complete reversal of the effects of rivaroxaban + 4F-PCC + TXA + Placebo on prothrombin time (PT) and endogenous thrombin potential (ETP), providing (Group A) (Group B) (Group C) Total 15 Pre-Study initial support for the potential utility of PCC for rivaroxaban reversal n = 49 n = 49 n = 49 N = 147 Baseline Day –1 PT Mean Absolut • Use of TXA, an antifibrinolytic agent, has also been suggested in patients with Pr 1h 2h 3h 3h 45 mi 4h 4h 15 mi 4h 30 mi 5h 6h 8h 10h 12h 14h 24h 48h 72h 168h rivaroxaban-associated bleeding Sex, % edos e – Although the efficacy of TXA in reversing anticoagulant effects is unclear, TXA is Female 30.6 30.6 28.6 29.9 n n n well tolerated and has been shown to reduce blood loss in patients undergoing Time Post-Rivaroxaban Post Dose, hr surgery and in those with trauma3 Male 69.4 69.4 71.4 70.1 • Objective: to examine the potential utility of 4F-PCC and TXA for rivaroxaban reversal B End of 4F-PCC/Placebo Infusion End of TXA/Placebo Infusion in healthy volunteers Race, % 4F-PCC • The rivaroxaban dosing regimen chosen was 20 mg twice daily (BID) so as to better TXA mimic reversal when potentially higher levels of rivaroxaban might be found (eg, in White 69.4 71.4 57.1 66.0 100 Saline the elderly or in patients with renal impairment) Black/African American 24.5 22.4 32.7 26.5 ) 80 Pre-Study – This regimen also covered the exposures expected with the 15-mg BID dosing UC Baseline Day –1 regimen used in the initial treatment of acute deep vein thrombosis (DVT)/ Asian 0 2.0 2.0 1.4 PA lues, nmol/L*second 60 pulmonary embolism (PE) Va A (ET e Ethnicity, % TG 40 Methods Hispanic/Latino 14.3 6.1 8.2 9.5 20 Pr 1h 2h 3h 3h 45 mi 4h 4h 15 mi 4h 30 mi 5h 6h 8h 10h 12h 14h 24h 48h 72h 168h Non-Hispanic/Latino 79.6 91.8 83.7 85.0 Mean Absolut • This was a double-blind, parallel-group, randomized, phase 1 study edos • Inclusion/exclusion criteria: Age, years, mean (SD) 29.8 (9.6) 31.0 (10.3) 29.8 (9.5) 30.2 (9.8) e n n n – Healthy men or women, 18 to 55 years of age, with body mass index (BMI) Time Post-Rivaroxaban Post Dose, hr Weight, kg, mean (SD) 76.0 (11.9) 72.8 (12.2) 76.4 (11.8) 75.1 (12.0) of 18 to 30 kg/m2, normal renal function, and normal PT and activated partial Abbreviations: 4F-PCC, 4-factor prothrombin complex concentrate; AUC, area under the plasma thromboplastin time (aPTT) BMI, kg/m2, mean (SD) 25.4 (3.0) 24.3 (3.1) 25.4 (3.2) 25.0 (3.1) concentration-time curve; TXA, tranexamic acid; TGA, thrombin generation assay. • A baseline punch biopsy was conducted on Day –1 (baseline). Rivaroxaban was given • PT: at a dose of 20 mg every 12 hours within 30 minutes after starting a standardized Abbreviations: 4F-PCC, 4-factor prothrombin complex concentrate; BMI, body mass index; meal on Days 1 through 3, to achieve steady state (SS) SD, standard deviation; TXA, tranexamic acid. – Following the administration of rivaroxaban 20 mg BID with the final dose on the morning of Day 4, the maximum PT value increased for • After their morning dose on Day 4, subjects were randomized to 3 cohorts to receive All subjects who received at least 1 dose of rivaroxaban were included in the safety analysis set. 7057 Figure 1 draft 1.4 all 3 treatment groups This tagline4F-PCC, is for information TXA, only; or saline (Figure 1) DO NOT PRINT – Following the infusion of 4F-PCC, PT partially reversed, whereas TX had no effect – Subjects received 50 International Units (IU)/kg 4F-PCC at a maximum rate (Figure 3, Panel A) of 210 IU/min or 1.0 g TXA administered over 10 minutes or saline control, Table 2. Summary of Pharmacokinetics Parameters of Rivaroxaban • ETP: all intravenously at Steady State (PK Data Analysis Set) – Following the administration of rivaroxaban 20 mg BID, with the final dose on the Figure 1. (A) Study design and (B) schematic of blinded treatments. Rivaroxaban + Rivaroxaban + TXA Rivaroxaban + morning of Day 4, ETP values decreased in all 3 treatment groups 4F-PCC (Group A) (Group B) Placebo (Group C) – Following the infusion of 4F-PCC, ETP fully reversed, whereas TXA had no effect n = 48 n = 48 n = 49 (Figure 3, Panel B) A Administration of: PCC, TXA, or Saline • Following the infusion of 4F-PCC, F1.2 levels increased, whereas D-dimer levels did (completed by 4 hr post last rivaroxaban dose) PK Parameter Mean SD CV% Mean SD CV% Mean SD CV% not. In contrast, the levels of F1.2 and D-dimer were unchanged after administration e of TXA or saline control (data not shown) ge rg ation C , ng/mL 130 30.2 40.6 131 32.2 41.0 130 26.5 34.7 Day –1 Day 1 to Day 3 Day 4 Day 5 to Day 7 trough • All treatments were well tolerated 7 y Rivaroxaban y 11 C , ng/mL 351 121 34.6 375 104 27.8 344 96.5 28.0 – There were no discontinuations because of adverse events and no deaths or Da max,ss 20 mg BID Da treatment-emergent serious adverse events Randomiz a Clinic Dischar Baseline Study Discha tmax,ss, h 3.75 (1.00-4.50) 3.00 (2.00-4.60) 4.25 (1.00-5.02) PD & Pre-dose Exploratory PK, PD, EB Biomarkers Post-dose AUC , ngh/mL 2,217 645 29.1 2,357 602 25.6 2,178 522 23.9 punch biopsy τ,ss Baseline (4 hr, 15 min) punch 4F-PCC, 4-factor prothrombin complex concentrate; AUCτ,ss, area under the plasma concentration-time biopsy Rivaroxaban curve during a dosing interval (t) at SS (AUC ); C , maximal concentration at steady state; C , trough Conclusions t SS max,ss trough 20 mg BID concentration; CV, coefficient of variance; PK, pharmacokinetics; SD, standard deviation; SS, steady state; tmax,ss, time to maximal concentration at steady state. a Median (min-max). • This study demonstrates that neither 4F-PCC nor TXA reverses punch biopsy Pre-dose/Trough PK Post-dose Post-dose 7057 Figure 2 draft 1.2 bleeding in subjects receiving supratherapeutic doses of rivaroxaban PK, PD, EB PD, EB This tagline is for information only; DO NOT PRINT – Neither 4F-PCC nor TXA had any effect on BD or BV • Mean trough plasma concentration values demonstrate that rivaroxaban reached SS – Although 4F-PCC partially reversed PT and completely reversed ETP, B Study Part 2, Day 4 concentrations by Day 3 of the study. Plasma PK parameters for rivaroxaban at SS on TXA did not affect these variables Day 4 are presented in Table 2 • The clinical relevance of these findings is uncertain; nevertheless, the PD changes 1,2 4-Factor PCC Saline Control observed with 4F-PCC administration are consistent with previous studies A (TXA) Figure 2. Effect of treatment with 4F-PCC (Group A), TXA (Group B), or placebo • Interestingly, however, our data are not in agreement with a recent report 20 mg wherein the same dose of 4F-PCC as used in the present study attenuated punch Saline Control TXA Punch (saline control) (Group C) on (A) bleeding duration (BD) and (B) bleeding volume rivaroxaban B 4 (4-Factor PCC) Biopsy (BV) mean ratio post-infusion vs baseline.
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