Update on Direct Oral AntiCoagulants (DOACs)

Summary

Recent findings require an update of previous recommendations for the perioperative use of Direct Oral AntiCoagulants (DOACs). A break in preoperative treatment of 24–96 hours is recommended based on the pharmacokinetic profiles of DOACs and depends on individual patient characteristics, their renal and possibly liver function, and their surgery-related risk of bleeding. In cases of renal or hepatic insufficiency, whether to extend the preoperative interruption of IIa- and Xa-inhibitors is a clinical decision that must be reached on an individual patient basis. In cases of epidural or spinal anaesthesia, more conservative pausing-intervals are recommended due to the risk of persistent neurologic deficits (e.g., paraplegia) following the development of spinal subdural and epidural haematomas. Elective surgery should be postponed according to these recommendations. Preoperative “bridging” with LMWH (more precisely referred to as „switching”) should be omitted due to a significantly increased risk of bleeding. In addition, the incidence of perioperative thromboembolic risks, such as DVT, PE, and stroke, are no different whether interruption or “switching” is undertaken. Postoperatively, the DOACs can be reinstituted within the first 24 hours. In cases of major surgery or if there is a higher risk of bleeding, resumption of DOACS should only begin after 24–72 hours. In patients with an elevated thromboembolic risk, transient postoperative LMWH administration can be recommended during this period.

Interaction of DOACs with other drugs usually occurs during the absorption, transport and elimination of these drugs. Therefore, substance- specific restrictions and recommendations should be observed during these times. In everyday clinical practice, webbased, independent information portals on drug-interactions are very helpful in providing safe and rapid information about potential interactions when DOACs are used in combination with other drugs, especially during perioperative management.

Non-adherence to medications is a worldwide problem that has dangerous and costly consequences. Present data suggest that persistence is the primary factor that supports adherence. Despite the adherence data presented in the DOACS approval studies (e.g., persistence in the treatment of acute venous thromboembolism has been reported to be between 94–99%), the first registries and meta-analyses provide sobering results regarding the incidence of persistence and the success rate of interventions designed to improve adherence with DOACs in cases of long-term usage.

Zusammenfassung

Aktuelle Erkenntnisse erfordern die Aktualisierung früherer Empfehlungen zum perioperativen Einsatz von direkte orale Antikoagulanzien (DOAKs). Auf Grundlage der pharmakokinetischen Profile wird in Abhängigkeit von Nierenfunktion, ggf. Leberfunktion sowie individuellem und eingriffsspezifischem Blutungsrisiko eine präoperative Pausierung von 24–96 Stunden in Abhängigkeit von dem verwendeten DOAK empfohlen. Bei schwerer Nieren- oder Leberinsuffizienz ist es eine individuelle, klinische Entscheidung, die präoperative Pause für die Xa-inhibitoren zu verlängern. Für Patienten mit rückenmarksnahen Regionalanästhesieverfahren gelten aufgrund des Risikos von spinal sub- und epiduralen Hämatomen und dem Risiko bleibender schwerer neurologischer Defizite (Querschnittslähmung) sehr konservative Intervalle im oberen Pausierungsbereich. Ein bereits präoperativ beginnendes „Bridging” mit NMH (eigentlich „Switching”) sollte wegen signifikant erhöhter Blutungsrisiken unterbleiben. Das perioperative Thromboembolierisiko (z.B. Thrombose, Lungenembolie, Hirninfarkt) ist nach einer präoperativen Pause bzw. einem präoperativen „Switching” nicht unterschiedlich. Postoperativ können DOAKs innerhalb von 24 h, nach größeren Eingriffen bzw. höherem Blutungsrisiko erst nach 24–72 Stunden wiederaufgenommen werden. Eine postoperative, passagere Umstellung auf eine NMH-Gabe („Switching”) bei erhöhtem venösem Thromboembolierisiko kann in diesem Zeitraum erfolgen.

Medikamenteninteraktionen von direkten oralen Antikoagulanzien treten meist bei der Absorption, beim Transport und bei der Elimination von anderen Medikamenten auf. Hierbei sind substanzspezifische Einschränkungen und Empfehlungen zu beachten. Um im klinischen Alltag eine sichere und schnelle Information, auch über DOAKs in Kombination mit anderen Medikamenten im perioperativen Management, zu erhalten, sind webbasierte, unabhängige Informationsportale sehr hilfreich.

Die Non-Adhärenz von Medikamenten ist weltweit verbreitet, ist gefährlich und teuer in ihren Folgen. Die aktuellen Daten beschreiben vorwiegend die Persistenz als ein orientierendes Maß für die Adhärenz. Unabhängig von den Zulassungsstudien der DOAKs (Persistenz bei der Therapie akuter venöser Thromboembolien zwischen 94 – 99%) liefern erste Register und Metaanalysen ernüchternde Ergebnisse zur Persistenz und zur Verbesserung der Adhärenz der DOAKs in der Langzeitanwendung.

Keywords

DOACs - rivaroxaban - apixaban - edoxaban - dabigatran - “switching” - drug interactions - persistence

Schlüsselwörter

DOAKs - Rivaroxaban - Apixaban - Edoxaban - Dabigatran - „Switching” - Medikamenteninteraktionen - Persistenz

• References

• 1 Healey JS, Eikelboom J, Douketis J. et al. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: Results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Randomized Trial. Circulation 2012; 126: 343-348.
• 2 Patel MR, Mahaffey KW, Garg J. et al. Prevention of stroke and systemic embolism using the oral direct Factor Xa inhibitor rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: the ROCKET AF trial. N Engl J Med 2011; 365: 883-891.
• 3 Granger CB, Alexander JH, McMurray JJ. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992.
• 4 The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499-2510.
• 5 The EINSTEIN–PE Investigators. Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism. N Engl J Med 2012; 366: 1287-1297.
• 6 Turpie AGG, Lassen MR, Eriksson BI. et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost 2011; 105: 444-453.
• 7 The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499-2510.
• 8 Mega JL, Braunwald E, Mohanavelu S. et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 2009; 374: 29-38.
• 9 Giugliano RP. Edoxaban versus Warfarin in Patients with Atrial Fibrillation et al. N Engl J Med 2013; 363: 2093-104.
• 10 The Hokusai-VTE Investigators. Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism. N Engl J Med 2013; 369: 1406-1415.
• 11 Heidbuchel H, Verhamme P, Alings M. et al. Updated European Heart Rhythm Association (EHRA) Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015; 17 (10) 1467-1507.
• 12 Pernod G, Albaladejo P, Godier A. et al.; Working Group on Perioperative Haemostasis. 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 2013; 106 (6–7): 382-393.
• 13 Eisele R. et al. Perioperatives Gerinnungsmanagement bei oraler Antikoagulation. Chirurg 2014; 85: 513-519.
• 14 Giebl A, Gürtler K. Neue orale Antikoagulanzien in der perioperativen Medizin. Anaesthesist 2014; 63: 347-364.
• 15 Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AMWF). S3-Leitlinie Prophylaxe der venösen Thromboembolie (VTE). AWMF-Registernr 003/001 Klasse. S3 2015
• 16 von Heymann C, Koscielny J. Update: Patienten unter oraler Antikoagulation mit VKA oder NOAK – Perioperatives „Bridging” oder „„Switching”?” Anästh Intensivmed. 2016; 57: 316-331.
• 17 Waurick K, Riess H, Van Aken H. et al. S1-Richtlinie: Rückenmarksnahe Regionalanästhesien und Thromboembolieprophylaxe/ antithrombotische Medikation. 3. überarbeitete Empfehlung der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin, Anästh Intensivmed 2014; 55: 464-492.
• 18 Sporbeck B, Bechara FG, Häfner HM. et al. S3-Leitlinie zum Umgang mit Antikoagulation bei Operationen an der Haut. JDDG: Journal der Deutschen Dermatologischen Gesellschaft 2015; 13: 346-357.
• 19 EMA – Dabigatran. http://www.ema.europa.eu/docs/de_DE/document_library/EPAR_Product_Information/human/000829/WC500041059.pdf
• 20 EMA – Rivaroxaban. http://www.ema.europa.eu/docs/de_DE/document_library/EPAR_-_Product_Information/human/000944/WC500057108.pdf
• 21 Pfizer – Apixaban. http://www.pfizer.de/fileadmin/produktdatenbank/pdf/Eliquis_5mg_FI_01.pdf
• 22 EMA – Edoxaban. http://ec.europa.eu/health/documents/communityregister/2015/20150619132091/anx_132091_de.pdf
• 23 Beyer-Westendorf J, Förster K, Pannach S. et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden DOAC registry. Blood 2014; 124 (06) 955-962.
• 24 Beyer-Westendorf J, Gelbricht V, Förster K. et al. Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry. Eur Heart J 2014; 35 (28) 1888-1896.
• 25 Steinberg BA, Peterson ED, Kim S, Thomas L, Gersh BJ, Fonarow GC, Kowey PR, Mahaffey KW, Sherwood MW, Chang P, Piccini JP, Ansell J. Outcomes Registry for Better Informed Treatment of Atrial Fibrillation Investigators and Patients. Use and outcomes associated with bridging during anticoagulation interruptions in patients with atrial fibrillation: findings from the Outcome Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Circulation 2015; 131 (05) 488-494.
• 26 Camm AJ, Amarenco P, Haas S, Hess S, Kirchhof P, Kuhls S, van Eickels M, Turpie AGG. the XANTUS Investigators. XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation. Eur Heart J 2016; 37 14: 1145-1153.
• 27 Schulman S. et al. Perioperative Management of Dabigatran: A Prospective Cohort Study. Periop Dabigatran Study Group. Circulation 2015; 132 (03) 167-173.
• 28 Douketis JD. et al. Effect of standardized perioperative dabigatran interruption on the residual anticoagulation effect at the time of surgery or procedure. J Thromb Haemost 2016; 14 (01) 89-97.
• 29 Mallet L. et al. The challenge of managing drug interactions in elderly people. Lancet 2007; 370 9582 185-191.
• 30 Far E. et al. Validation of a transparent decision model to rate drug interactions. BMC Pharmacol Toxicol 2012; 13: 7.
• 31 WHO: Adherence to long-term therapies. Evidence for action. ISBN 92 4 154599 2. 2003: 1-209.
• 32 NEHI (New England Healthcare Institute). (2009). Thinking Outside the Pillbox: A System-wide Approach to Improving Patient Medication Adherence for Chorionic Disease. http://www.nehi.net/publications/44/thinking_outside_the_pillbox_a_systemwide_approach_to_improving_patient_medication_adherence_for_chronic_disease Last accessed October 2011.
• 33 Gräf M. Die volkswirtschaftlichen Kosten der Non-Compliance: Eine entscheidungsorientierte Analyse. Gesundheitsökonomie Band 56. Bayreuth, P.C.O.-Verlag, 2007
• 34 Chatterjee S. et al. Treatment Discontinuations With New Oral Agents for Long-term Anticoagulation: Insights From a Meta-analysis of 18 Randomized Trials Including 101,801 Patients. Mayo Clinic Proceedings 2014; 89 (07) 896-907.
• 35 Rodriguez RA, Carrier M, Wells PS. Non-adherence to new oral anticoagulants: a reason for concern during long-term anticoagulation?. J Thromb Haemost 2013; 11 (02) 390-394.
• 36 Beyer-Westendorf J. et al. Drug persistence with rivaroxaban therapy in atrial fibrillation patientsresults from the Dresden non-interventional oral anticoagulation registry. Europace 2015; 17 (04) 530-538.
• 37 Gomes T. et al. Persistence with therapy among patients treated with warfarin for atrial fibrillation. Arch Intern Med 2012; 172 (21) 1687-1689.
• 38 Gallagher AM. et al. Initiation and persistence of warfarin or ASA in patients with chronic atrial fibrillation in general practice: do the appropriate patients receive stroke prophylaxis?. J Thromb Haemost 2008; 06 (09) 1500-1506.
• 39 Shore S, Ho MP, Lambert-Kerzner A. et al. Sitelevel variation in and practices associated with dabigatran adherence. JAMA 2015; 313: 1443-1450.
• 40 Gorst-Rasmussen A, Skjøth F, Larsen TB. et al. Dabigatran adherence in atrial fibrillation patients during the first year after diagnosis: a nationwide cohort study. J Thromb Haemost 2015; 13: 495-504.
• 41 Yao X. et al. Effect of Adherence to Oral Anticoagulants on Risk of Stroke and Major Bleeding Among Patients With Atrial Fibrillation. J Am Heart Assoc 2016; 05 (02) 1-12.
• 42 Nieuwlaat R, Wilczynski N. et al. Interventions for enhancing medication adherence. Interventions for enhancing medication adherence. Cochrane Database Syst Rev 2014; 11: 1-732.
• 43 Garcia D, Alexander JH, Wallentin L, Wojdyla DM, Thomas L, Hanna M. et al. Management and clinical outcomes in patients treated with apixaban vs warfarin undergoing procedures. Blood 2014; 124: 3692-3698.
• 44 Breuer G, Weiss DR, Ringwald J. ‚New’ direct oral anticoagulants in the perioperative setting. Curr Opin Anaesthesiol 2014; 27: 409-419.
• 45 Koscielny J, Beyer-Westendorf J, von Heymann C, Braun J, Klamroth R, Lindhoff-Last E. et al. [Risk of bleeding and haemorrhagic complication with rivaroxaban--periprocedural management of haemostasis]. Hamostaseologie 2012; 32: 287-293.
• 46 Spannagl M, Bauersachs R, Debus ES, Gawaz M, Gerlach H, Haas S. et al. [Dabigatran therapy – perioperative management and interpretation of coagulation tests]. Hamostaseologie 2012; 32: 294-305.
• 47 Douketis JD, Healey JS, Brueckmann M, Eikelboom JW, Ezekowitz MD, Fraessdorf M. et al. Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had an elective surgery or procedure. Substudy of the RE-LY trial. Thrombosis and haemostasis 2015; 113: 625-632.
• 48 Beyer-Westendorf J, Ebertz F, Forster K, Gelbricht V, Michalski F, Kohler C. et al. Effectiveness and safety of dabigatran therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry. Thrombosis and haemostasis 2015; 113: 1247-1257.
• 49 Kessler P, Steinfeldt T, Gogarten W, Schwemmer U, Buttner J, Graf BM. et al. [Peripheral regional anesthesia in patients under general anesthesia: risk assessment with respect to parasthesia, injection pain and nerve damage]. Anaesthesist 2013; 62: 483-488.
• 50 Salazar DE. et al. Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation. Thromb Haemost 2012; 107 (05) 925-936.
• 51 Mueck W. et al. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol 2013; 76: 455-466.
• 52 Moore KT. et al. An open-label study to estimate the effect of steady-state erythromycin on the pharmacokinetics, pharmacodynamics, and safety of a single dose of rivaroxaban in subjects with renal impairment and normal renal function. J Clin Pharmacol 2014; 54 (12) 1407-1420.
• 53 Lehr T. et al. Dabigatran etexilate in atrial fibrillation patients with severe renal impairment: dose identification using pharmacokinetic modeling and simulation. J Clin Pharmacol 2012; 52 (09) 1373-1378.
• 54 Stangier J. et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallelgroup, single-centre study. Clin Pharmacokinet 2010; 49 (04) 259-268.
• 55 Mendell J. et al. The Effect of Rifampin on the Pharmacokinetics of Edoxaban in Healthy Adults. Clinical Drug Investigation 2015; 35 (07) 447-453.
• 56 Chang M. et al. Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban. J Clin Pharmacol 2016; 56 (05) 637-645.