Neue orale Antikoagulantien (NOAK) in der
                    Schlaganfall-Therapie

Clemens Küpper; Lars Kellert; Steffen Tiedt; Frank Arne Wollenweber

doi:10.1055/s-0043-118845

Fortschritte der Neurologie · Psychiatrie, Inhaltsverzeichnis

Fortschr Neurol Psychiatr 2018; 86(02): 117-124
DOI: 10.1055/s-0043-118845

Übersicht

Georg Thieme Verlag KG Stuttgart · New York

Neue orale Antikoagulantien (NOAK) in der Schlaganfall-Therapie

New oral anticoagulants (NOAC) in stroke treatment

Clemens Küpper

¹Klinik und Poliklinik für Neurologie, Klinikum der Universität München, Campus Großhadern, Ludwig-Maximilians-Universität LMU München

,

Lars Kellert

¹Klinik und Poliklinik für Neurologie, Klinikum der Universität München, Campus Großhadern, Ludwig-Maximilians-Universität LMU München

²Neurologische Klinik, Universitätsklinikum Heidelberg, Deutschland

,

Steffen Tiedt

¹Klinik und Poliklinik für Neurologie, Klinikum der Universität München, Campus Großhadern, Ludwig-Maximilians-Universität LMU München

³Institut für Schlaganfall- und Demenzforschung (ISD), Klinikum der Universität München, Campus Großhadern, Ludwig-Maximilians-Universität LMU München

,

Frank Arne Wollenweber

¹Klinik und Poliklinik für Neurologie, Klinikum der Universität München, Campus Großhadern, Ludwig-Maximilians-Universität LMU München

³Institut für Schlaganfall- und Demenzforschung (ISD), Klinikum der Universität München, Campus Großhadern, Ludwig-Maximilians-Universität LMU München

› Institutsangaben

Abstract

Zusammenfassung

Zur Prophylaxe des kardioembolischen Schlaganfalls stehen neben Vitamin K-Antagonisten in Deutschland seit 2011 die sogenannten neuen oralen Antikoagulantien (NOAK) zur Verfügung. Eine Zulassung besteht für nicht-valvuläres Vorhofflimmern. Obwohl in Deutschland eine intensive Kontroverse zu diesem Thema geführt wird, wird das Nutzen-Risiko-Verhältnis der NOAK im Vergleich zu Vitamin K-Antagonisten von den neurologischen und kardiologischen Fachgesellschaften als günstiger bewertet. Dieser Effekt wird insbesondere durch die Risikoreduktion für intrazerebrale Blutungen vermittelt. Ein spezifisches Antidot steht für Dabigatran zur Verfügung und ist für die Faktor Xa-Inhibitoren in der klinischen Prüfung. Aus Mangel an direkten Vergleichsstudien kann keines der NOAK dem anderen als überlegen angesehen werden. Die Auswahl eines NOAK sollte sich daher unter Berücksichtigung der Ergebnisse der Zulassungsstudien an praktischen Aspekten und Komorbiditäten des einzelnen Patienten orientieren.

Abstract

Since 2011, new oral anticoagulants (NOAC) can be prescribed for prevention of cardio-embolic ischemic strokes in addition to vitamin K antagonists. NOAC are indicated in patients with non-valvular atrial fibrillation. Although its use is a matter of debate in Germany, the neurological and cardiological societies recommend the use of NOAC over and above vitamin K antagonists due to a better benefit-to-risk ratio attributed to it, especially because of the lower risk of intracranial hemorrhage in NOAC use. A specific antidote is commercially available for the direct thrombin inhibitor dabigatran only. For the factor Xa inhibitors, an antidote is being investigated in clinical trials. To our best knowledge, there are no direct head-to-head studies between the NOACs. Therefore, none of them can be assumed to be superior and the decision for a specific NOAC should be based on the available scientific data from the NOAC trials considering the individual patient’s characteristics and comorbidities.

Schlüsselwörter

Schlaganfall - NOAK - Vorhofflimmern

Key words

stroke - NOAC - atrial fibrillation

Volltext

Referenzen

Literatur
1 Mortality GBD, Causes of Death C. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016; 388: 1459-1544
2 Centers for Disease C, Prevention. Prevalence and most common causes of disability among adults – United States 2005. MMWR Morbidity and mortality weekly report 2009; 58: 421-426
3 Adamson J, Beswick A, Ebrahim S. Is stroke the most common cause of disability?. Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 2004; 13: 171-177
4 Heuschmann PU, Busse O, Wagner M. et al. Schlaganfallhäufigkeit und Versorgung von Schlaganfallpatienten in Deutschland. Akt Neurol 2010; 37: 333-340
5 Lozano R, Naghavi M, Foreman K. et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2095-2128
6 Feigin VL, Krishnamurthi RV, Parmar P. et al. Update on the Global Burden of Ischemic and Hemorrhagic Stroke in 1990–2013: The GBD 2013 Study. Neuroepidemiology 2015; 45: 161-176
7 Grau AJ, Weimar C, Buggle F. et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke 2001; 32: 2559-2566
8 Brambatti M, Connolly SJ, Gold MR. et al. Temporal relationship between subclinical atrial fibrillation and embolic events. Circulation 2014; 129: 2094-2099
9 Kamel H, Okin PM, Elkind MS. et al. Atrial Fibrillation and Mechanisms of Stroke: Time for a New Model. Stroke 2016; 47: 895-900
10 Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Annals of internal medicine 2007; 146: 857-867
11 Eikelboom JW, Connolly SJ, Brueckmann M. et al. Dabigatran versus warfarin in patients with mechanical heart valves. The New England journal of medicine 2013; 369: 1206-1214
12 Kirchhof P, Benussi S, Kotecha D. et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. European heart journal 2016; 37: 2893-2962
13 Endres M, Diener H, Röther J. S3 Leitlinie Sekundärprophylaxe des ischämischen Insults. Stand 31.1.2015, Registernummer 030–133 www.awmf.org/leitlinien/detail/ll/030-133.html
14 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. The New England journal of medicine 2009; 361: 1139-1151
15 Granger CB, Alexander JH, McMurray JJ. et al. Apixaban versus warfarin in patients with atrial fibrillation. The New England journal of medicine 2011; 365: 981-992
16 Patel MR, Mahaffey KW, Garg J. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. The New England journal of medicine 2011; 365: 883-891
17 January CT, Wann LS, Alpert JS. et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130: 2071-2104
18 Giugliano RP, Ruff CT, Braunwald E. et al. Edoxaban versus warfarin in patients with atrial fibrillation. The New England journal of medicine 2013; 369: 2093-2104
19 Connolly SJ, Eikelboom J, Dorian P. et al. Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa). European heart journal 2013; 34: 1498-1505
20 Schiele F, van Ryn J, Canada K. et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013; 121: 3554-3562
21 Pollack Jr CV, Reilly PA, Eikelboom J. et al. Idarucizumab for Dabigatran Reversal. The New England journal of medicine 2015; 373: 511-520
22 Vosko MR, Bocksrucker C, Drwila R. et al. Real-life experience with the specific reversal agent idarucizumab for the management of emergency situations in dabigatran-treated patients: a series of 11 cases. Journal of thrombosis and thrombolysis 2017; 43: 306-317
23 Held V, Eisele P, Eschenfelder CC. et al. Idarucizumab as Antidote to Intracerebral Hemorrhage under Treatment with Dabigatran. Case reports in neurology 2016; 8: 224-228
24 Alhashem HM, Avendano C, Hayes BD. et al. Persistent life-threatening hemorrhage after administration of idarucizumab. The American journal of emergency medicine 2017; 35: 193 e193-193 e195
25 Ng FC, Bice J, Rodda A. et al. Adverse clinical outcomes after dabigatran reversal with idarucizumab to facilitate acute stroke thrombolysis. Journal of neurology 2017; 264: 591-594
26 Turine G, Peeters A, Hermans C. et al. Intravenous thrombolysis after reversal of dabigatran by idarucizumab: a moment to be a pioneer. Acta neurologica Belgica. 2017 DOI: 10.1007/s13760–017–0751–5
27 Mutzenbach JS, Pikija S, Otto F. et al. Intravenous thrombolysis in acute ischemic stroke after dabigatran reversal with idarucizumab – a case report. Annals of clinical and translational neurology 2016; 3: 889-892
28 Schulz JG, Kreps B. Idarucizumab elimination of dabigatran minutes before systemic thrombolysis in acute ischemic stroke. Journal of the neurological sciences 2016; 370: 44
29 Gawehn A, Ayari Y, Heuschkel C. et al. Successful thrombolysis with recombinant tissue plasminogen activator after antagonizing dabigatran by idarucizumab: a case report. Journal of medical case reports 2016; 10: 269
30 Berrouschot J, Stoll A, Hogh T. et al. Intravenous Thrombolysis With Recombinant Tissue-Type Plasminogen Activator in a Stroke Patient Receiving Dabigatran Anticoagulant After Antagonization With Idarucizumab. Stroke 2016; 47: 1936-1938
31 Schafer N, Muller A, Wullner U. Systemic Thrombolysis for Ischemic Stroke after Antagonizing Dabigatran with Idarucizumab – A Case Report. Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 2016; 25: e126-127
32 Kermer P, Eschenfelder CC, Diener HC. et al. Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany – A national case collection. International journal of stroke: official journal of the International Stroke Society 2017; 12: 383-391
33 Lu G, DeGuzman FR, Hollenbach SJ. et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nature medicine 2013; 19: 446-451
34 Siegal DM, Curnutte JT, Connolly SJ. et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. The New England journal of medicine 2015; 373: 2413-2424
35 Connolly SJ, Milling Jr TJ, Eikelboom JW. et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. The New England journal of medicine 2016; 375: 1131-1141
36 Yao X, Abraham NS, Sangaralingham LR. et al. Effectiveness and Safety of Dabigatran, Rivaroxaban, and Apixaban Versus Warfarin in Nonvalvular Atrial Fibrillation. Journal of the American Heart Association 2016; 5
37 Nielsen PB, Skjoth F, Sogaard M. et al. Effectiveness and safety of reduced dose non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. Bmj 2017; 356: j510
38 Larsen TB, Skjoth F, Nielsen PB. et al. Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. Bmj 2016; 353: i3189
39 Laliberte F, Nelson WW, Lefebvre P. et al. Impact of daily dosing frequency on adherence to chronic medications among nonvalvular atrial fibrillation patients. Advances in therapy 2012; 29: 675-690
40 Diener HC, Aisenberg J, Ansell J. et al. Choosing a particular oral anticoagulant and dose for stroke prevention in individual patients with non-valvular atrial fibrillation: part 2. European heart journal. 2016 DOI: 10.1093/eurheartj/ehw069
41 Hartter S, Koenen-Bergmann M, Sharma A. et al. Decrease in the oral bioavailability of dabigatran etexilate after co-medication with rifampicin. British journal of clinical pharmacology 2012; 74: 490-500
42 Hartter S, Sennewald R, Nehmiz G. et al. Oral bioavailability of dabigatran etexilate (Pradaxa(R)) after co-medication with verapamil in healthy subjects. British journal of clinical pharmacology 2013; 75: 1053-1062
43 Wang L, Zhang D, Raghavan N. et al. In vitro assessment of metabolic drug-drug interaction potential of apixaban through cytochrome P450 phenotyping, inhibition, and induction studies. Drug metabolism and disposition: the biological fate of chemicals 2010; 38: 448-458
44 Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. British journal of clinical pharmacology 2013; 76: 455-466
45 Mendell J, Zahir H, Matsushima N. et al. Drug-drug interaction studies of cardiovascular drugs involving P-glycoprotein, an efflux transporter, on the pharmacokinetics of edoxaban, an oral factor Xa inhibitor. American journal of cardiovascular drugs: drugs, devices, and other interventions 2013; 13: 331-342
46 Hohnloser SH, Hijazi Z, Thomas L. et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. European heart journal 2012; 33: 2821-2830
47 Hijazi Z, Hohnloser SH, Oldgren J. et al. Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis. Circulation 2014; 129: 961-970
48 Fox KA, Piccini JP, Wojdyla D. et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. European heart journal 2011; 32: 2387-2394
49 Bohula EA, Giugliano RP, Ruff CT. et al. Impact of Renal Function on Outcomes With Edoxaban in the ENGAGE AF-TIMI 48 Trial. Circulation 2016; 134: 24-36
50 Gage BF, Birman-Deych E, Kerzner R. et al. Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall. The American journal of medicine 2005; 118: 612-617
51 Kato ET, Giugliano RP, Ruff CT. et al. Efficacy and Safety of Edoxaban in Elderly Patients With Atrial Fibrillation in the ENGAGE AF-TIMI 48 Trial. Journal of the American Heart Association 2016; 5
52 Eikelboom JW, Wallentin L, Connolly SJ. et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 2011; 123: 2363-2372
53 Halperin JL, Hankey GJ, Wojdyla DM. et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Circulation 2014; 130: 138-146
54 Diener HC, Aisenberg J, Ansell J. et al. Choosing a particular oral anticoagulant and dose for stroke prevention in individual patients with non-valvular atrial fibrillation: part 1. European heart journal. 2016 DOI: 10.1093/eurheartj/ehv643
55 Paciaroni M, Agnelli G, Micheli S. et al. Efficacy and safety of anticoagulant treatment in acute cardioembolic stroke: a meta-analysis of randomized controlled trials. Stroke 2007; 38: 423-430
56 Reddy VY, Doshi SK, Sievert H. et al. Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation: 2.3-Year Follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) Trial. Circulation 2013; 127: 720-729
57 Whitlock R, Healey J, Vincent J. et al. Rationale and design of the Left Atrial Appendage Occlusion Study (LAAOS) III. Annals of cardiothoracic surgery 2014; 3: 45-54