Antithrombotische Therapie bei nicht valvulärem Vorhofflimmern

Zusammenfassung

Vorhofflimmern ist die häufigste anhaltende Herzrhythmusstörung und stellt eine häufige Indikation zur Verhinderung thrombembolischer Ereignisse bei Patienten mit zusätzli-chen Risikofaktoren dar. Über mehrere Jahrzehnte hinweg waren orale Vitamin-K-Antagonisten – trotz ihrer bekannten Limitationen wie die Notwendigkeit einer individuellen Dosierung, zahlreiche Interaktionen und das dadurch notwendige regelmäßige Monitoring der Antikoagulation – die Standardtherapie. Neu entwickelte Antikoagulantien beinhalten orale, direkte Thrombinantagonisten (Dabigatran) und Faktor-Xa-Antagonisten (Rivaroxaban, Apixaban). Neben einem geringeren Potenzial für Interaktionen und einer dadurch erleichterten klinischen Anwendung konnte für diese neuen Substanzen in großen randomisierten klinischen Studien eine mit VitaminK-Antagonisten vergleichbare Effektivität in der Verhinderung thrombembolischer Ereignisse bei gleichzeitiger Reduktion von hämorrhagischen Schlaganfällen bzw. intrakraniellen Blutungen – auch in der Sekundärprophylaxe bei Hochrisikopatienten – nachgewiesen werden.

Summary

Atrial fibrillation is the most frequent sustained cardiac arrhythmia and a common reason for therapeutic anticoagulation in patients exhibiting additional risk factors for thromboembolic events. For several decades, the mainstay therapy have been oral vitamin K antagonists despite their shortcomings in daily practice including difficult dosage due to food and drug interactions and the need for regular monitoring of the intensity of anticoagulation. Newly developed anticoagulants include oral, direct thrombin antagonists (dabigatran) and factor Xa antagonists (rivaroxaban, apixaban). Apart from a lesser potential for interactions and thereby greater ease of use, these substances have shown a favorable risk/benefit profile in large randomized clinical trials, preventing stroke and other systemic thromboembolic events at least as effective as warfarin while reducing hemorrhagic stroke and intracranial bleeding compared to warfarin. These findings were also consistent in subgroup analyses of high-risk patients in secondary stroke prophylaxis.

Schlüsselwörter

Vorhofflimmern - Antikoagulation - Schlaganfall

Keywords

Atrial fibrillation - antithrombotic therapy - stroke

• Literatur

• 1 Lewis T. Auricular fibrillation: a common clinical condition. Br Med J 1909; 2 2552 1528.
• 2 Grau AJ. et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke 2001; 32 (11) 2559-66.
• 3 Harmsen P. et al. Long-term risk factors for stroke: twenty-eight years of follow-up of 7457 middle-aged men in Göteborg, Sweden. Stroke 2006; 37 (07) 1663-7.
• 4 Jørgensen HS. et al. Acute stroke with atrial fibrillation. The Copenhagen Stroke Study. Stroke 1996; 27 (10) 1765-9.
• 5 Steger C. et al. Stroke patients with atrial fibrillation have a worse prognosis than patients without: data from the Austrian Stroke registry. Eur Heart J 2004; 25 (19) 1734-40.
• 6 Stroke Risk in Atrial Fibrillation Working Group. et al. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology 2007; 69 (06) 546-54.
• 7 Hohnloser SH. et al. Incidence of stroke in paroxysmal versus sustained atrial fibrillation in patients taking oral anticoagulation or combined antiplatelet therapy: an ACTIVE W Substudy. J Am Coll Cardiol 2007; 50 (22) 2156-61.
• 8 Nieuwlaat R. et al. Should we abandon the common practice of withholding oral anticoagulation in paroxysmal atrial fibrillation?. Eur Heart J 2008; 29 (07) 915-22.
• 9 Healey JS. et al. Subclinical atrial fibrillation and the risk of stroke. The New England journal of medicine 2012; 366 (02) 120-9.
• 10 Liao J. et al. Noninvasive cardiac monitoring for detecting paroxysmal atrial fibrillation or flutter after acute ischemic stroke: a systematic review. Stroke 2007; 38 (11) 2935-40.
• 11 Dam H. The antihaemorrhagic vitamin of the chick. Nature 1935; 135: 652.
• 12 Hirsh J. et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119 (01) 8S-21S.
• 13 Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146 (12) 857-67.
• 14 ACTIVE Investigators. et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. New England Journal of Medicine. [Multicenter Study] 2009; 360 (20) 2066-78.
• 15 ACTIVE Writing Group of the ACTIVE Investigators. et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367 9526 1903-12.
• 16 Camm AJ. et al. Guidelines for the management of atrial fibrillation: The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 12 (10) 1360-420.
• 17 Glader EL. et al. Persistent use of secondary preventive drugs declines rapidly during the first 2 years after stroke. Stroke 2010; 41 (02) 397-401.
• 18 Nabauer M. et al. The Registry of the German Competence NETwork on Atrial Fibrillation: patient characteristics and initial management. Europace 2009; 11 (04) 423-34.
• 19 Blech S. et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug metabolism and disposition: the biological fate of chemicals. [Randomized Controlled Trial] 2008; 36 (02) 386-99.
• 20 U.S. Food and Drug Administration (FDA).. Pradaxa – Highlights of prescribing information. 12.02. 2012; www.accessdata.fda.gov/drugsatfda_docs/label/2011/022512s004lbl.pdf.
• 21 U.S. National Institutes of Health (NIH).. Drug Interaction Study With Dabigatran Etexilate and Dronedarone in Healthy Subjects (NCT01306162). 12.02.2012; http://clinicaltrials.gov/ct2/show/NCT 01306162.
• 22 Weinz C. et al. Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug metabolism and disposition: the biological fate of chemicals. [Clinical Trial] 2009; 37 (05) 1056-64.
• 23 European Medicines Agency (EMA).. Rivaroxaban -Summary of Product Characteristics. 08.01.2012; www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000944/WC500057108.pdf.
• 24 Raghavan N. et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug metabolism and disposition: the biological fate of chemicals 2009; 37 (01) 74-81.
• 25 European Medicines Agency (EMA).. Apixaban – Summary of Product Characteristics. 08.01.2012; www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf.
• 26 Connolly S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. The New England journal of medicine 2009; 361 (12) 1139-51.
• 27 Patel MR. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. The New England journal of medicine 2011; 365 (10) 883-91.
• 28 Granger CB. et al. Apixaban versus warfarin in patients with atrial fibrillation. The New England journal of medicine 2011; 365 (11) 981-92.
• 29 Flaker G, Ezekowitz M, Yusuf S. Efficacy and safety of dabigatran compared to warfarin in patients with paroxysmal, persistent, and permanent atrial fibrillation: results from the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) Study. J Am Coll Cardiol 2012; 59 (09) 854-5.
• 30 Diener HC. et al. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial. The Lancet Neurology 2010; 9 (12) 1157-63.
• 31 Eikelboom JW. et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation. Circulation 2011; 123 (21) 2363-72.
• 32 Connolly SJ. et al. Newly identified events in the RELY trial. The New England Journal of Medicine 2010; 363 (19) 1875-6.
• 33 Uchino K, Hernandez AV. Dabigatran Association With Higher Risk of Acute Coronary Events: Meta-analysis of noninferiority randomized controlled trials. Archives of internal medicine 2012; 172 (05) 397-402.
• 34 Hohnloser SH. et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (randomized evaluation of long-term anticoagulation therapy) trial. Circulation 2012; 125 (05) 669-76.
• 35 Ertl G, Röther J, Oertel W, Meinertz T. Dabigatran: Gemeinsame Stellungnahme von DGK, Deutscher Herzstiftung, Deutscher Schlaganfall-Gesellschaft (DSG) und Deutscher Gesellschaft für Neurologie (DGN) – Patienten sollten das Medikament nicht voreilig absetzen. 15.01.201; http://dgk.org/presse/mitteilungen/2011-allgemeine-pressemitteilungen/dabigatran-gemeinsame-stellungnahmevon-dgk-deutscher-herzstiftung-deutscher-schlaganfall-gesellschaft-dsg-und-deutscher-gesellschaft-fur-neurologie-dgn-patienten-sollten-dasmedikament-nicht/.
• 36 Hankey GJ. et al. Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurology 2012; 11 (04) 315-22.
• 37 Fox KAA. et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J 2011; 32 (19) 2387-94.
• 38 Wieloch M. et al. Anticoagulation control in Sweden: reports of time in therapeutic range, major bleeding, and thrombo-embolic complications from the national quality registry AuriculA. Eur Heart J 2011; 32 (18) 2282-9.
• 39 Wallentin L. et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RELY trial. Lancet 2010; 376 9745 975-83.
• 40 Eerenberg ES. et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-Ccontrolled, crossover study in healthy subjects. Circulation 2011; 124 (14) 1573-9.
• 41 Dempfle C-E, Hennerici MG. Fibrinolytic treatment of acute ischemic stroke for patients on new oral anticoagulant drugs. Cerebrovascular diseases (Basel, Switzerland) 2011; 32 (06) 616-9.
• 42 Diener H. et al. Dabigatran in der Schlaganfallprävention bei Patienten mit Vorhofflimmern nach TIA oder ischämischem Insult: praktische Aspekte der Anwen-dung. Aktuelle Neurologie 2011; 38 (05) 261-6.
• 43 van Ryn J. et al. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thrombosis and Haemostasis 2010; 103 (06) 1116-27.
• 44 Samama MM. et al. Assessment of laboratory assays to measure rivaroxaban – an oral, direct factor Xa inhibitor. Thrombosis and Haemostasis 2010; 103 (04) 815-25.
• 45 Barrett YC. et al. Clinical laboratory measurement of direct factor Xa inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thrombosis and Haemostasis 2010; 104 (06) 1263-71.
• 46 National Institute for Health and Clinical Excellence (NICE).. Atrial fibrillation – dabigatran etexilate (TA249). 13.05.2012; http://guidance.nice.org.uk/TA249.
• 47 National Health Service Scotland (NHS Scotland).. Statement for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation. 13.05.2012; www.healthcareimprove/mentscotland.org/his/idoc.ashx?docid=05a9291c-f901—4a8e-85d0-de8/699a31757&version=-1.
• 48 European Medicines Agency (EMA).. Dabigatran – Summary of Product Characteristics. [08.01.2012; www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf.