Neurological Surgery 脳神経外科46巻11号

2018年11月発行

総説

虚血性脳卒中の急性期管理におけるDOAC

著者： 田中寛大¹ 豊田一則²

所属機関： ¹国立循環器病研究センター脳卒中集中治療科 ²国立循環器病研究センター脳血管部門

ページ範囲：P.959 - P.968

Ⅰ．緒　　言
　非弁膜症性心房細動（nonvalvular atrial fibrillation：NVAF）による脳卒中ないし全身塞栓症の予防に対する直接経口抗凝固薬（direct oral anticoagulant：DOAC）の有効性・安全性は確立している^{3,10,11,29,33)}．ワルファリンと比べてDOACは効果の発現が早く，薬剤や食事との相互作用が小さい^5,34)．また，アジア人はワルファリンによる頭蓋内出血合併が非アジア人より多いため³⁷⁾，ワルファリンよりも頭蓋内出血が少ないDOACは³³⁾，日本人において特に有利な選択肢と考えられる．
　2011年以降，トロンビン阻害薬のダビガトラン，第Ⅹa因子阻害薬のリバーロキサバン，アピキサバン，エドキサバンという4つのDOACが市場に登場し，広く使用されている．脳卒中二次予防におけるDOACの有効性・安全性は確立しているが^7,8,13,32)，急性期に直面する問題として，“いつ”抗凝固療法を開始するのか？という問いがある．ワルファリンの開始時期にしても高度のエビデンスはまだない．DOACの有効性・安全性を示した4つのランダム化比較試験（RCT）では，発症から7〜30日以内の急性期脳卒中患者が除外された^3,10,11,29)．そのため，頭蓋内出血リスクが低く，逆説的な凝固促進効果がないことから^2,33)，急性期においてワルファリンより有利と思われるDOACについても，“いつ”から開始するのが適切なのか，明確な指標はない．

参考文献

1) Arihiro S, Todo K, Koga M, Furui E, Kinoshita N, Kimura K, Yamagami H, Terasaki T, Yoshimura S, Shiokawa Y, Kamiyama K, Takizawa S, Okuda S, Okada Y, Nagakane Y, Kameda T, Hasegawa Y, Shibuya S, Ito Y, Nakashima T, Takamatsu K, Nishiyama K, Matsuki T, Homma K, Takasugi J, Tokunaga K, Sato S, Kario K, Kitazono T, Toyoda K：Three-month risk-benefit profile of anticoagulation after stroke with atrial fibrillation：the SAMURAI-Nonvalvular Atrial Fibrillation（NVAF）study. Int J Stroke 11：565-574, 2016

2) Azoulay L, Dell'Aniello S, Simon TA, Renoux C, Suissa S：Initiation of warfarin in patients with atrial fibrillation：early effects on ischaemic strokes. Eur Heart J 35：1881-1887, 2014

3) Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L：Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361：1139-1151, 2009

4) Connolly SJ, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Goodman S, Leeds J, Wiens BL, Siegal DM, Zotova E, Meeks B, Nakamya J, Lim WT, Crowther M：Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 375：1131-1141, 2016

5) De Caterina R, Husted S, Wallentin L, Andreotti F, Arnesen H, Bachmann F, Baigent C, Huber K, Jespersen J, Kristensen SD, Lip GY, Morais J, Rasmussen LH, Siegbahn A, Verheugt FW, Weitz JI：New oral anticoagulants in atrial fibrillation and acute coronary syndromes：ESC Working Group on Thrombosis-Task Force on Anticoagulants in Heart Disease position paper. J Am Coll Cardiol 59：1413-1425, 2012

6) Dewilde WJ, Oirbans T, Verheugt FW, Kelder JC, De Smet BJ, Herrman JP, Adriaenssens T, Vrolix M, Heestermans AA, Vis MM, Tijsen JG, van't Hof AW, ten Berg JM：Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention：an open-label, randomised, controlled trial. Lancet 381（9872）：1107-1115, 2013

7) Diener HC, Connolly SJ, Ezekowitz MD, Wallentin L, Reilly PA, Yang S, Xavier D, Di Pasquale G, Yusuf S：Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke：a subgroup analysis of the RE-LY trial. Lancet Neurol 9：1157-1163, 2010

8) Easton JD, Lopes RD, Bahit MC, Wojdyla DM, Granger CB, Wallentin L, Alings M, Goto S, Lewis BS, Rosenqvist M, Hanna M, Mohan P, Alexander JH, Diener HC：Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack：a subgroup analysis of the ARISTOTLE trial. Lancet Neurol 11：503-511, 2012

9) Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, Diaz R, Alings M, Lonn EM, Anand SS, Widimsky P, Hori M, Avezum A, Piegas LS, Branch KRH, Probstfield J, Bhatt DL, Zhu J, Liang Y, Maggioni AP, Lopez-Jaramillo P, O'Donnell M, Kakkar AK, Fox KAA, Parkhomenko AN, Ertl G, Störk S, Keltai M, Ryden L, Pogosova N, Dans AL, Lanas F, Commerford PJ, Torp-Pedersen C, Guzik TJ, Verhamme PB, Vinereanu D, Kim JH, Tonkin AM, Lewis BS, Felix C, Yusoff K, Steg PG, Metsarinne KP, Cook Bruns N, Misselwitz F, Chen E, Leong D, Yusuf S：Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 377：1319-1330, 2017

10) Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM：Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 369：2093-2104, 2013

11) Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L：Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365：981-992, 2011

12) Halvorsen S, Atar D, Yang H, De Caterina R, Erol C, Garcia D, Granger CB, Hanna M, Held C, Husted S, Hylek EM, Jansky P, Lopes RD, Ruzyllo W, Thomas L, Wallentin L：Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation：observations from the ARISTOTLE trial. Eur Heart J 35：1864-1872, 2014

13) Hankey GJ, Patel MR, Stevens SR, Becker RC, Breithardt G, Carolei A, Diener HC, Donnan GA, Halperin JL, Mahaffey KW, Mas JL, Massaro A, Norrving B, Nessel CC, Paolini JF, Roine RO, Singer DE, Wong L, Califf RM, Fox KA, Hacke W：Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack：a subgroup analysis of ROCKET AF. Lancet Neurol 11：315-322, 2012

14) Hori M, Matsumoto M, Tanahashi N, Momomura S, Uchiyama S, Goto S, Izumi T, Koretsune Y, Kajikawa M, Kato M, Ueda H, Iwamoto K, Tajiri M：Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation - the J-ROCKET AF study -. Circ J 76：2104-2111, 2012

15) Hori M, Matsumoto M, Tanahashi N, Momomura S, Uchiyama S, Goto S, Izumi T, Koretsune Y, Kajikawa M, Kato M, Ueda H, Iekushi K, Yamanaka S, Tajiri M：Rivaroxaban vs. warfarin in Japanese patients with non-valvular atrial fibrillation in relation to age. Circ J 78：1349-1356, 2014

16) Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC, Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, Popescu BA, Schotten U, Van Putte B, Vardas P：2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 37：2893-2962, 2016

17) Lip GY, Windecker S, Huber K, Kirchhof P, Marin F, Ten Berg JM, Haeusler KG, Boriani G, Capodanno D, Gilard M, Zeymer U, Lane D, Storey RF, Bueno H, Collet JP, Fauchier L, Halvorsen S, Lettino M, Morais J, Mueller C, Potpara TS, Rasmussen LH, Rubboli A, Tamargo J, Valgimigli M, Zamorano JL：Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions：a joint consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association（EHRA), European Association of Percutaneous Cardiovascular Interventions（EAPCI）and European Association of Acute Cardiac Care（ACCA）endorsed by the Heart Rhythm Society（HRS）and Asia-Pacific Heart Rhythm Society（APHRS). Eur Heart J 35：3155-3179, 2014

18) Lip GY, Hammerstingl C, Marin F, Cappato R, Meng IL, Kirsch B, van Eickels M, Cohen A：Left atrial thrombus resolution in atrial fibrillation or flutter：Results of a prospective study with rivaroxaban（X-TRA）and a retrospective observational registry providing baseline data（CLOT-AF). Am Heart J 178：126-134, 2016

19) Marsico F, Cecere M, Parente A, Paolillo S, de Martino F, Dellegrottaglie S, Trimarco B, Perrone Filardi P：Effects of novel oral anticoagulants on left atrial and left atrial appendage thrombi：an appraisal. J Thromb Thrombolysis 43：139-148, 2017

20) Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW, Gibson CM：Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 366：9-19, 2012

21) Mizoguchi T, Takagi M, Sato S, Yamagami H, Ide T, Yoshimoto T, Shiozawa M, Todo K, Yagita Y, Itabashi R, Terasaki T, Koga M, Toyoda K：Timing of starting DOACs and short- and long-term clinical outcomes for acute ischemic stroke patients with nonvalvular atrial fibrillation：the SAMURAI-NVAF study. Stroke 49：AWP398, 2018

22) 日本脳卒中学会脳卒中ガイドライン［追補2017］委員会（編）：脳卒中治療ガイドライン2015［追補2017］．2017, pp.115-122, http://www.jsts.gr.jp/img/guideline2015_tuiho2017.pdf

23) 日本脳卒中学会脳卒中医療向上・社会保険委員会「抗凝固療法中患者への脳梗塞急性期再開通治療に関する推奨」作業部会：抗凝固療法中患者への脳梗塞急性期再開通治療に関する推奨2017年11月．脳卒中40：123-135, 2018

24) O'Brien EC, Simon DN, Thomas LE, Hylek EM, Gersh BJ, Ansell JE, Kowey PR, Mahaffey KW, Chang P, Fonarow GC, Pencina MJ, Piccini JP, Peterson ED：The ORBIT bleeding score：a simple bedside score to assess bleeding risk in atrial fibrillation. Eur Heart J 36：3258-3264, 2015

25) Okada Y, Yamaguchi T, Minematsu K, Miyashita T, Sawada T, Sadoshima S, Fujishima M, Omae T：Hemorrhagic transformation in cerebral embolism. Stroke 20：598-603, 1989

26) Okumura K, Hori M, Tanahashi N, John Camm A：Special considerations for therapeutic choice of non-vitamin K antagonist oral anticoagulants for Japanese patients with nonvalvular atrial fibrillation. Clin Cardiol 40：126-131, 2017

27) Paciaroni M, Agnelli G, Falocci N, Caso V, Becattini C, Marcheselli S, Rueckert C, Pezzini A, Poli L, Padovani A, Csiba L, Szabó L, Sohn SI, Tassinari T, Abdul-Rahim AH, Michel P, Cordier M, Vanacker P, Remillard S, Alberti A, Venti M, Scoditti U, Denti L, Orlandi G, Chiti A, Gialdini G, Bovi P, Carletti M, Rigatelli A, Putaala J, Tatlisumak T, Masotti L, Lorenzini G, Tassi R, Guideri F, Martini G, Tsivgoulis G, Vadikolias K, Liantinioti C, Corea F, Del Sette M, Ageno W, De Lodovici ML, Bono G, Baldi A, D'Anna S, Sacco S, Carolei A, Tiseo C, Acciarresi M, D'Amore C, Imberti D, Zabzuni D, Doronin B, Volodina V, Consoli D, Galati F, Pieroni A, Toni D, Monaco S, Baronello MM, Barlinn K, Pallesen LP, Kepplinger J, Bodechtel U, Gerber J, Deleu D, Melikyan G, Ibrahim F, Akhtar N, Mosconi MG, Bubba V, Silvestri I, Lees KR：Early recurrence and cerebral bleeding in patients with acute ischemic stroke and atrial fibrillation：effect of anticoagulation and its timing：the RAF study. Stroke 46：2175-2182, 2015

28) Paciaroni M, Agnelli G, Falocci N, Tsivgoulis G, Vadikolias K, Liantinioti C, Chondrogianni M, Bovi P, Carletti M, Cappellari M, Zedde M, Ntaios G, Karagkiozi E, Athanasakis G, Makaritsis K, Silvestrelli G, Lanari A, Ciccone A, Putaala J, Tomppo L, Tatlisumak T, Abdul-Rahim AH, Lees KR, Alberti A, Venti M, Acciarresi M, D'Amore C, Becattini C, Mosconi MG, Cimini LA, Soloperto R, Masotti L, Vannucchi V, Lorenzini G, Tassi R, Guideri F, Acampa M, Martini G, Sohn SI, Marcheselli S, Mumoli N, De Lodovici ML, Bono G, Furie KL, Tadi P, Yaghi S, Toni D, Letteri F, Tassinari T, Kargiotis O, Lotti EM, Flomin Y, Mancuso M, Maccarrone M, Giannini N, Bandini F, Pezzini A, Poli L, Padovani A, Scoditti U, Denti L, Consoli D, Galati F, Sacco S, Carolei A, Tiseo C, Gourbali V, Orlandi G, Giuntini M, Chiti A, Giorli E, Gialdini G, Corea F, Ageno W, Bellesini M, Colombo G, Monaco S, Maimone Baronello M, Karapanayiotides T, Caso V：Early recurrence and major bleeding in patients with acute ischemic stroke and atrial fibrillation treated with non-vitamin-K oral anticoagulants（RAF-NOACs）study. J Am Heart Assoc 6, 2017. pii：e007034

29) Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM：Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365：883-891, 2011

30) Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY：A novel user-friendly score（HAS-BLED）to assess 1-year risk of major bleeding in patients with atrial fibrillation：the Euro Heart Survey. Chest 138：1093-1100, 2010

31) Pollack CV Jr, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kam CW, Kamphuisen PW, Kreuzer J, Levy JH, Royle G, Sellke FW, Stangier J, Steiner T, Verhamme P, Wang B, Young L, Weitz JI：Idarucizumab for dabigatran reversal-full cohort analysis. N Engl J Med 377：431-441, 2017

32) Rost NS, Giugliano RP, Ruff CT, Murphy SA, Crompton AE, Norden AD, Silverman S, Singhal AB, Nicolau JC, SomaRaju B, Mercuri MF, Antman EM, Braunwald E：Outcomes with edoxaban versus warfarin in patients with previous cerebrovascular events：findings from ENGAGE AF-TIMI 48（Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48). Stroke 47：2075-2082, 2016

33) Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM：Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation：a meta-analysis of randomised trials. Lancet 383（9921）：955-962, 2014

34) Savelieva I, Camm AJ：Practical considerations for using novel oral anticoagulants in patients with atrial fibrillation. Clin Cardiol 37：32-47, 2014

35) Seiffge DJ, Traenka C, Polymeris A, Hert L, Peters N, Lyrer P, Engelter ST, Bonati LH, De Marchis GM：Early start of DOAC after ischemic stroke：risk of intracranial hemorrhage and recurrent events. Neurology 87：1856-1862, 2016

36) Seiffge DJ, Paciaroni M, Wilson D, Koga M, Macha K, Cappellari M, Schaedelin S, Shakeshaft C, Takagi M, Bonetti B, Kallmünzer B, Bovi P, Schwab S, Tsivgoulis G, Lyrer P, Toyoda K, Werring D, Caso V, Engelter S, De Marchis G：Direct oral anticoagulants versus Vitamin K antagonists after a recent ischemic stroke - a pooled individual patient data analysis. EFNS Annual Meeting, 2018

37) Shen AY, Yao JF, Brar SS, Jorgensen MB, Chen W：Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation. J Am Coll Cardiol 50：309-315, 2007

38) Steinberg BA, Kim S, Thomas L, Fonarow GC, Hylek E, Ansell J, Go AS, Chang P, Kowey P, Gersh BJ, Mahaffey KW, Singer DE, Piccini JP, Peterson ED：Lack of concordance between empirical scores and physician assessments of stroke and bleeding risk in atrial fibrillation：results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation（ORBIT-AF）registry. Circulation 129：2005-2012, 2014

39) Takasugi J, Yamagami H, Okata T, Toyoda K, Nagatsuka K：Dissolution of the left atrial appendage thrombus with rivaroxaban therapy. Cerebrovasc Dis 36：322-323, 2013

40) Toyoda K, Arihiro S, Todo K, Yamagami H, Kimura K, Furui E, Terasaki T, Shiokawa Y, Kamiyama K, Takizawa S, Okuda S, Okada Y, Kameda T, Nagakane Y, Hasegawa Y, Mochizuki H, Ito Y, Nakashima T, Takamatsu K, Nishiyama K, Kario K, Sato S, Koga M：Trends in oral anticoagulant choice for acute stroke patients with nonvalvular atrial fibrillation in Japan：the SAMURAI-NVAF study. Int J Stroke 10：836-842, 2015

41) Yasaka M, Minematsu K, Toyoda K, Mori E, Hirano T, Hamasaki T, Yamagami H, Nagao T, Yoshimura S, Uchiyama S：Optimal timing to start rivaroxaban administration to prevent recurrent embolism in acute stroke patients with nonvalvular atrial fibrillation（NVAF）：the RELAXED study. Eur Stroke J 2（1 suppl）：15, 2017

42) Yoshimura S, Koga M, Sato S, Todo K, Yamagami H, Kumamoto M, Itabashi R, Terasaki T, Kimura K, Yagita Y, Shiokawa Y, Kamiyama K, Okuda S, Okada Y, Takizawa S, Hasegawa Y, Kameda T, Shibuya S, Nagakane Y, Ito Y, Matsuoka H, Takamatsu K, Nishiyama K, Fujita K, Kamimura T, Ando D, Ide T, Yoshimoto T, Shiozawa M, Matsubara S, Yamaguchi Y, Kinoshita N, Matsuki T, Takasugi J, Tokunaga K, Higashida K, Homma K, Kario K, Arihiro S, Toyoda K：Two-year outcomes of anticoagulation for acute ischemic stroke with nonvalvular atrial fibrillation-SAMURAI-NVAF study. Circ J 82：1935-1942, 2018