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Effects of rivaroxaban and apixaban on routine coagulation screening tests Sean Platton1*, Louise Bowles1, Peter MacCallum2 The Royal London Hospital,

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Presentation on theme: "Effects of rivaroxaban and apixaban on routine coagulation screening tests Sean Platton1*, Louise Bowles1, Peter MacCallum2 The Royal London Hospital,"— Presentation transcript:

1 Effects of rivaroxaban and apixaban on routine coagulation screening tests Sean Platton1*, Louise Bowles1, Peter MacCallum2 The Royal London Hospital, Barts Health NHS Trust, London, UK. Barts and the London School of Medicine and Dentistry, QMUL, London, UK *Contact author: Sean Platton : Introduction and Objectives Rivaroxaban and apixaban (oral direct Xa inhibitors) are licensed for stroke prevention in atrial fibrillation (SPAF) and the treatment and secondary prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in fixed doses without laboratory monitoring. In studies using in vitro spiked samples or ex vivo samples from normal patients, PT is considered to be more sensitive to the presence of rivaroxaban than APTT2,3, but Siemens Dade Innovin has been shown to be insensitive to rivaroxaban when compared to other thromboplastins4,5,6. In the twelve months to October 2015, Sysmex UK supplied 204 laboratories in England, Scotland and Wales with Innovin for PT, and supplied 209 laboratories with Actin FS for APTT. Thirty-two percent of participants in the UKNEQAS for Blood Coagulation scheme use Innovin and Actin FS1. Both the International Society on Thrombosis and Haemostasis7 and the British Committee for Standards in Haematology8 recommend that individual laboratories establish the sensitivity of their screening reagents using commercially available calibrators, but this practice is thought to under- estimate drug concentration9. Any conclusions related to these types of sample may be safer if also validated by analysis of samples from patients taking the drug9. Patients on rivaroxaban 10mg or 20mg od are predicted to have peak concentrations of 125ng/mL or 223ng/mL respectively10. Patients on apixaban 2.5mg or 5mg bd are predicted to have peak concentrations of 62ng/mL or 128ng/mL respectively11. Only 240 participants of the UKNEQAS for Blood Coagulation external quality assurance scheme returned results for anti-Xa assays for heparin in July 2015, whereas 862 return results for prothrombin time (PT) and 875 for activated partial thromboplastin time (APTT)1; this suggests that anti- Xa assays are not widely available. In many laboratories these tests may not be available out of hours, and may not be available for non-heparin anticoagulants. In this study we looked at the correlation between routine coagulation tests using Siemens reagents and rivaroxaban or apixaban concentrations in patients taking these drugs for either SPAF or treatment of DVT or PE, and assessed whether these reagents could be used to identify patients who were on these anticoagulants using local reference ranges. Sample Selection & Methods Results - Rivaroxaban Results - Apixaban 165 consecutive plasma samples, from 120 patients, received in the laboratory between June and December 2015 from patients taking rivaroxaban or apixaban for SPAF or treatment of DVT or PE were frozen at ‑80C before being rapidly thawed at 37C before analysis. Samples from patients who were also receiving warfarin, or who had abnormal liver function, were excluded, leaving 124 samples (91 patients) for rivaroxaban and 24 samples (22 patients) for apixaban. PT was measured using Siemens Dade Innovin reagent. APTT was measured using Siemens Actin FS. Rivaroxaban concentration was measured using the Hyphen Biomed BIOPHEN DiXaI assay. Apixaban concentration was measured using the Hyphen Biomed BIOPHEN Heparin LRT assay. All tests were performed on a Sysmex CS2100i coagulation analyser (Sysmex UK, Milton Keynes, UK). In all, 123 PT assays and 122 APTT assays were performed for patients receiving rivaroxaban. All 24 samples from patients receiving apixaban had PT and APTT assays performed. Table 1 – Rivaroxaban <125ng/mL <223ng/mL >223ng/mL Normal PT 65/67 (97%) 79/88 (90%) 10/37 (27%) Normal APTT 61/66 (92%) 73/87 (84%) Normal PT & APTT 58/65 (89%) 68/86 (79%) 6/37 (16%) Raised PT, Normal APTT 2/65 (3%) 5/86 (6%) 4/37 (11%) Normal PT, Raised APTT 5/65 (8%) 9/86 (10%) Raised PT & APTT 4/86 (5%) 23/37 (62%) Table 2 – Apixaban >5ng/mL Normal PT 20/23 (87%) Normal APTT 21/23 (91%) Normal PT & APTT 18/23 (78%) Raised PT, Normal APTT 3/23 (13%) Normal PT, Raised APTT 2/23 (9%) Raised PT & APTT Discussion Conclusions There is a moderate correlation between rivaroxaban concentration and PT using Innovin (r2=0.6192, figure 1) and APTT using Actin FS (r2=0.5595, figure 2). A significant number of patients on rivaroxaban have either a normal PT, normal APTT or both (table 1 above) using these reagents. These included one patient with rivaroxaban >500ng/mL with a normal PT, one patient with rivaroxaban of 400ng/mL with a normal APTT, and one patient with rivaroxaban of 370ng/mL with a short APTT (highlighted in red in figures 1 & 2). This correlation is improved when comparing with the increase from baseline PT (r2=0.7563, figure 3) or APTT (r2=0.7319, figure 4). However, obtaining baseline clotting results is problematic, particularly in the emergency situation; in this study, only 32 patients (35%) had a baseline clotting screen result available. There is a poor correlation between apixaban concentration and PT using Innovin (r2=0.0604, figure 5) and APTT using Actin FS (r2=0.2284, figure 6). Almost all patients with detectable apixaban had normal PT and APTT (table 2), and those with results outside the local reference range were only mildly abnormal. Using Siemens Innovin and Siemens Actin FS, although an abnormal PT and/or APTT is seen in most patients with levels of rivaroxaban within the on-therapy range, a normal PT and APTT do not exclude a higher or peak level. For apixaban the PT and APTT are even less sensitive and cannot be used to exclude apixaban within or above the on-therapy-range. References UKNEQAS for Blood Coagulation: unpublished data. Used with permission of Tim Woods on behalf of the Steering Committee, UKNEQAS for Blood Coagulation Baglin, T, The role of the laboratory in treatment with new oral anticoagulants. Journal of Thrombosis and Haemostasis, Volume 11 (Suppl. 1), pp Eby, C, Novel anticoagulants and laboratory testing. International Journal of Laboratory Hematology, Volume 35, pp Samama, MM et al., Assessment of laboratory assays to measure rivaroxaban - an oral, direct factor Xa inhibitor. Thrombosis and Haemostasis, Volume 103, pp Hillarp, A. et al., Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. Journal of Thrombosis and Haemostasis, Volume 9, pp Douxfils, J et al., Comparison of calibrated chromogenic anti-Xa assay and PT tests with LC-MS/MS for the therapeutic monitoring of patients treated with rivaroxaban. Thrombosis and Haemostasis, Volume 110, pp Baglin, T et al., Oral Direct Inhibitors (ODIs) of thrombin and factor Xa: a recommendation from the Subcommittee on Control of Anticoagulation of the Scientific and Standardisation Committee of the International Socoiety on Thrombosis and Haemostasis.. Journal of Thombosis and Haemostasis, Volume 11, pp Baglin, T et al., Effects on routine coagulation screens and assessment of anticoagulant intensity in patients taking oral dabigatran or rivaroxaban: Guidance from the British Committee for Standards in Haematology.. British Journal of Haematology, Volume 159, pp Gosselin, RC et al., Evaluating the use of commercial drug-specific calibrators for determining PT and APTT reagent sensitivity to dabigatran and rivaroxaban.. Thrombosis and Haemostasis, Jan, 113(1), pp Mueck, W et al., Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients udergoing total hip replacement. Thrombosis and Haemostasis, Volume 100, pp Frost, C et al., Safety, pharmacokinetics and pharmacodynamics of mulitple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects.. British Journal of Pharmacology, Volume 76, pp 138 Haemostasis and Thrombosis Effects of rivaroxaban and apixaban on routine coagulation screening tests. Sean Platton, Louise Bowles, Peter MacCallum


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