Abstract
Purpose
Patients treated with direct oral anticoagulants (DOACs) frequently undergo interventional procedures requiring temporary discontinuation of anticoagulant therapy. Little is known about remaining peri-procedural exposure to rivaroxaban in real-world patients.
Methods
Fifty-six patients with rivaroxaban treatment and scheduled cardiac catheterization were included in this prospective, observational, and single-center study. Rivaroxaban concentrations were determined by LC-MS/MS and a chromogenic anti-Xa assay. Population pharmacokinetic modeling was carried out on LC-MS/MS concentration data using NONMEM software, and results were applied to Monte Carlo simulations to predict appropriate rivaroxaban discontinuation intervals.
Results
Rivaroxaban concentrations ranged from <LLOQ to 300.6 ng/ml at the time of admission to hospital and from <LLOQ to 55.5 ng/ml at the beginning of the procedure. Times since last rivaroxaban intake were (mean ± SD) 51.0 ± 31.7 h (admission) and 85.5 ± 36.8 h (start catheterization). LC-MS/MS and anti-Xa assay results were in good agreement (r = 0.958); however, the anti-Xa assay may underestimate low rivaroxaban concentrations and overestimate rivaroxaban exposure when performed on plasma samples contaminated with heparins. Pharmacokinetics of rivaroxaban were adequately described, and simulations predicted that 95% of patients will have rivaroxaban concentrations ≤ 28.4 ng/ml (15 mg dose group) and ≤ 31.9 ng/ml (20 mg dose group) after 48 h of discontinuation.
Conclusions
In the majority of patients, rivaroxaban plasma concentrations dropped below 30 ng/ml after 48 h of treatment discontinuation which is considered hemostatically safe before surgery with high bleeding risk. For accurate determination of low rivaroxaban concentrations, LC-MS/MS is the preferred choice.
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References
Samuelson BT, Cuker A (2017) Measurement and reversal of the direct oral anticoagulants. Blood Rev 31(1):77–84. https://doi.org/10.1016/j.blre.2016.08.006
Levy JH, Spyropoulos AC, Samama CM, Douketis J (2014) Direct oral anticoagulants: new drugs and new concepts. JACC Cardiovasc Interv 7(12):1333–1351. https://doi.org/10.1016/j.jcin.2014.06.014
Samuelson BT, Cuker A, Siegal DM, Crowther M, Garcia DA (2017) Laboratory assessment of the anticoagulant activity of direct oral anticoagulants: a systematic review. Chest 151(1):127–138. https://doi.org/10.1016/j.chest.2016.08.1462
Dale BJ, Chan NC, Eikelboom JW (2016) Laboratory measurement of the direct oral anticoagulants. Br J Haematol 172(3):315–336. https://doi.org/10.1111/bjh.13810
Blaich C, Müller C, Michels G, Wiesen MH (2015) Multi-analyte analysis of non-vitamin K antagonist oral anticoagulants in human plasma using tandem mass spectrometry. Clin Chem Lab Med 53(12):1981–1990. https://doi.org/10.1515/cclm-2014-1108
Wiesen MH, Blaich C, Streichert T, Michels G, Müller C (2017) Paramagnetic micro-particles as a tool for rapid quantification of apixaban, dabigatran, edoxaban and rivaroxaban in human plasma by UHPLC-MS/MS. Clin Chem Lab Med 55(9):1349–1359. https://doi.org/10.1515/cclm-2016-0888
Al-Aieshy F, Malmstrom RE, Antovic J, Pohanka A, Ronquist-Nii Y, Berndtsson M, Al-Khalili F, Skeppholm M (2016) Clinical evaluation of laboratory methods to monitor exposure of rivaroxaban at trough and peak in patients with atrial fibrillation. Eur J Clin Pharmacol 72(6):671–679. https://doi.org/10.1007/s00228-016-2060-y
Gouin-Thibault I, Delavenne X, Blanchard A, Siguret V, Salem JE, Narjoz C, Gaussem P, Beaune P, Funck-Brentano C, Azizi M, Mismetti P, Loriot MA (2017) Interindividual variability in dabigatran and rivaroxaban exposure: contribution of ABCB1 genetic polymorphisms and interaction with clarithromycin. J Thromb Haemost 15(2):273–283. https://doi.org/10.1111/jth.13577
Testa S, Tripodi A, Legnani C, Pengo V, Abbate R, Dellanoce C, Carraro P, Salomone L, Paniccia R, Paoletti O, Poli D, Palareti G, Register ST-L (2016) Plasma levels of direct oral anticoagulants in real life patients with atrial fibrillation: results observed in four anticoagulation clinics. Thromb Res 137:178–183. https://doi.org/10.1016/j.thromres.2015.12.001
Sunkara T, Ofori E, Zarubin V, Caughey ME, Gaduputi V, Reddy M (2016) Perioperative management of direct oral anticoagulants (DOACs): a systemic review. Health Serv Insights 9(Suppl 1):25–36. https://doi.org/10.4137/HSI.S40701
Douketis JD, Spyropoulos AC, Kaatz S, Becker RC, Caprini JA, Dunn AS, Garcia DA, Jacobson A, Jaffer AK, Kong DF, Schulman S, Turpie AG, Hasselblad V, Ortel TL, Investigators B (2015) Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med 373(9):823–833. https://doi.org/10.1056/NEJMoa1501035
Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P, Advisors (2016) Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J. https://doi.org/10.1093/eurheartj/ehw058
Beyer-Westendorf J, Gelbricht V, Forster K, Ebertz F, Kohler C, Werth S, Kuhlisch E, Stange T, Thieme C, Daschkow K, Weiss N (2014) Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry. Eur Heart J 35(28):1888–1896. https://doi.org/10.1093/eurheartj/eht557
Shaw J, de Wit C, Le Gal G, Carrier M (2017) Thrombotic and bleeding outcomes following perioperative interruption of direct oral anticoagulants in patients with venous thromboembolic disease. J Thromb Haemost 15(5):925–930. https://doi.org/10.1111/jth.13670
Tripodi A (2016) To measure or not to measure direct oral anticoagulants before surgery or invasive procedures. J Thromb Haemost 14(7):1325–1327. https://doi.org/10.1111/jth.13344
Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P (2015) Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 17(10):1467–1507. https://doi.org/10.1093/europace/euv309
Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the S, Standardization Committee of the International Society on T, Haemostasis (2005) Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 3(4):692–694. https://doi.org/10.1111/j.1538-7836.2005.01204.x
Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, Hindricks G, Kirchhof P, Guidelines ESCCP (2012) 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 33(21):2719–2747. https://doi.org/10.1093/eurheartj/ehs253
Lindhoff-Last E, Samama MM, Ortel TL, Weitz JI, Spiro TE (2010) Assays for measuring rivaroxaban: their suitability and limitations. Ther Drug Monit 32(6):673–679. https://doi.org/10.1097/FTD.0b013e3181f2f264
Samama MM, Contant G, Spiro TE, Perzborn E, Guinet C, Gourmelin Y, Le Flem L, Rohde G, Martinoli JL, Rivaroxaban Anti-Factor Xa Chromogenic Assay Field Trial L (2012) Evaluation of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls. Thromb Haemost 107(2):379–387. https://doi.org/10.1160/TH11-06-0391
Lindbom L, Ribbing J, Jonsson EN (2004) Perl-speaks-NONMEM (PsN)—a Perl module for NONMEM related programming. Comput Methods Prog Biomed 75(2):85–94. https://doi.org/10.1016/j.cmpb.2003.11.003
Keizer RJ, van Benten M, Beijnen JH, Schellens JH, Huitema AD (2011) Pirana and PCluster: a modeling environment and cluster infrastructure for NONMEM. Comput Methods Prog Biomed 101(1):72–79. https://doi.org/10.1016/j.cmpb.2010.04.018
Bergstrand M, Karlsson MO (2009) Handling data below the limit of quantification in mixed effect models. AAPS J 11(2):371–380. https://doi.org/10.1208/s12248-009-9112-5
Passing H, Bablok (1983) A new biometrical procedure for testing the equality of measurements from two different analytical methods. Application of linear regression procedures for method comparison studies in clinical chemistry, part I. J Clin Chem Clin Biochem 21(11):709–720
Bland JM, Altman DG (1999) Measuring agreement in method comparison studies. Stat Methods Med Res 8(2):135–160. https://doi.org/10.1177/096228029900800204
Xarelto® (rivaroxaban) summary of product characteristics (2016). Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000944/human_med_001155.jsp&mid=WC0b01ac058001d124#product-info (Accessesd 11 Mai 2017)
Pernod G, Albaladejo P, Godier A, Samama CM, Susen S, Gruel Y, Blais N, Fontana P, Cohen A, Llau JV, Rosencher N, Schved JF, de Maistre E, Samama MM, Mismetti P, Sie P, Working Group on Perioperative H (2013) Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on perioperative haemostasis (GIHP)—March 2013. Arch Cardiovasc Dis 106(6–7):382–393. https://doi.org/10.1016/j.acvd.2013.04.009
Xu XS, Moore K, Burton P, Stuyckens K, Mueck W, Rossenu S, Plotnikov A, Gibson M, Vermeulen A (2012) Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndromes. Br J Clin Pharmacol 74(1):86–97. https://doi.org/10.1111/j.1365-2125.2012.04181.x
Mueck W, Eriksson BI, Bauer KA, Borris L, Dahl OE, Fisher WD, Gent M, Haas S, Huisman MV, Kakkar AK, Kalebo P, Kwong LM, Misselwitz F, Turpie AG (2008) Population pharmacokinetics and pharmacodynamics of rivaroxaban—an oral, direct factor Xa inhibitor—in patients undergoing major orthopaedic surgery. Clin Pharmacokinet 47(3):203–216. https://doi.org/10.2165/00003088-200847030-00006
Godier A, Martin AC, Leblanc I, Mazoyer E, Horellou MH, Ibrahim F, Flaujac C, Golmard JL, Rosencher N, Gouin-Thibault I (2015) Peri-procedural management of dabigatran and rivaroxaban: duration of anticoagulant discontinuation and drug concentrations. Thromb Res 136(4):763–768. https://doi.org/10.1016/j.thromres.2015.08.006
Godier A, Dincq AS, Martin AC, Radu A, Leblanc I, Antona M, Vasse M, Golmard JL, Mullier F, Gouin-Thibault I (2017) Predictors of pre-procedural concentrations of direct oral anticoagulants: a prospective multicentre study. Eur Heart J 38(31):2431–2439. https://doi.org/10.1093/eurheartj/ehx403
Eller T, Flieder T, Fox V, Gripp T, Dittrich M, Kuhn J, Alban S, Knabbe C, Birschmann I (2017) Direct oral anticoagulants and heparins: laboratory values and pitfalls in ‘bridging therapy’. Eur J Cardiothorac Surg 51(4):624–632. https://doi.org/10.1093/ejcts/ezw368
Dubois V, Dincq AS, Douxfils J, Ickx B, Samama CM, Dogne JM, Gourdin M, Chatelain B, Mullier F, Lessire S (2017) Perioperative management of patients on direct oral anticoagulants. Thromb J 15(1):14. https://doi.org/10.1186/s12959-017-0137-1
Chang SH, Chou IJ, Yeh YH, Chiou MJ, Wen MS, Kuo CT, See LC, Kuo CF (2017) Association between use of non-vitamin K oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation. JAMA 318(13):1250–1259. https://doi.org/10.1001/jama.2017.13883
Kolluri R, Fowler B, Nandish S (2013) Vascular access complications: diagnosis and management. Curr Treat Options Cardiovasc Med 15(2):173–187. https://doi.org/10.1007/s11936-013-0227-8
Sherev DA, Shaw RE, Brent BN (2005) Angiographic predictors of femoral access site complications: implication for planned percutaneous coronary intervention. Catheter Cardiovasc Interv 65(2):196–202. https://doi.org/10.1002/ccd.20354
Gunning MG, Williams IL, Jewitt DE, Shah AM, Wainwright RJ, Thomas MR (2002) Coronary artery perforation during percutaneous intervention: incidence and outcome. Heart 88(5):495–498. https://doi.org/10.1136/heart.88.5.495
Cappato R, Calkins H, Chen SA, Davies W, Iesaka Y, Kalman J, Kim YH, Klein G, Packer D, Skanes A (2005) Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circulation 111(9):1100–1105. https://doi.org/10.1161/01.CIR.0000157153.30978.67
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The authors thank the medical and nursing staff of the Department of Cardiology for kind and invaluable support.
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This study was approved by the local Ethics Committee of the University Hospital of Cologne (14-066) and carried out in accordance with the Helsinki declaration (DRKS00006002).
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Dr. Wiesen reports personal fees from Pfizer Pharma GmbH, outside the submitted work. All other authors report no conflicts of interest.
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Wiesen, M.H.J., Blaich, C., Taubert, M. et al. Residual rivaroxaban exposure after discontinuation of anticoagulant therapy in patients undergoing cardiac catheterization. Eur J Clin Pharmacol 74, 611–618 (2018). https://doi.org/10.1007/s00228-018-2421-9
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DOI: https://doi.org/10.1007/s00228-018-2421-9