鄭亞如,葉利方(綜述),王利宏(審校)

(1.浙江大學(xué)醫(yī)學(xué)院附屬第一醫(yī)院心內(nèi)科，杭州 310003； 2.浙江省人民醫(yī)院心內(nèi)科，杭州 310014)

心房顫動合并慢性腎病的抗凝及藥物選擇

鄭亞如1△,葉利方1△(綜述),王利宏2※(審校)

(1.浙江大學(xué)醫(yī)學(xué)院附屬第一醫(yī)院心內(nèi)科，杭州 310003； 2.浙江省人民醫(yī)院心內(nèi)科，杭州 310014)

摘要：心房顫動(房顫)和慢性腎病發(fā)病率都隨著年齡的增長而增高，房顫合并慢性腎病患者腦卒中和出血風(fēng)險增加?？鼓委熆梢越档头款澔颊吣X卒中發(fā)生率，華法林是臨床上房顫患者最常用的抗凝藥物，但目前房顫合并終末期腎病患者從華法林治療中獲益的報道較少見。新型口服抗凝藥與華法林在房顫抗凝中同樣有效,且更加安全、有效、容易管理。目前房顫合并腎病抗凝治療的觀點仍存在爭議。

關(guān)鍵詞：心房顫動；腦卒中預(yù)防；華法林；抗凝治療

心房顫動(房顫)是臨床最常見的心律失常之一，是缺血性腦卒中的一項獨立危險因素。房顫可顯著增加心血管事件的住院率和病死率，尤其是腦卒中發(fā)生率，故抗凝治療顯得尤為重要。對于合并有非終末期腎病的房顫，越來越多的證據(jù)支持抗凝[1]。臨床研究結(jié)果顯示，在非瓣膜病房顫合并腎病的腦卒中預(yù)防中，新型口服抗凝藥(novel oral anticoagulants,NOAC)不劣于華法林，且無需常規(guī)監(jiān)測凝血、藥物食物相互作用少，但是NOAC也存在不足，如半衰期短、停藥后失效快、無特異性拮抗劑、腎功能不全患者需要調(diào)整劑量、價格較高等[2]。NOAC有不同程度的腎臟代謝，因此房顫合并慢性腎病抗凝需謹慎選擇?，F(xiàn)就房顫與慢性腎病相關(guān)性、房顫合并腎病患者抗凝指導(dǎo)及藥物選擇進行綜述。

1房顫與腎病相關(guān)性

慢性腎病易并發(fā)房顫，大約1/3的房顫患者合并有慢性腎臟疾病，并且比例逐年增加。部分由人口老齡化和生存率逐漸提高所致[1]。腎臟疾病和房顫有共同的風(fēng)險因子，包括高齡、高血壓、糖尿病、冠狀動脈疾病等，相關(guān)研究發(fā)現(xiàn)，慢性腎病可導(dǎo)致房顫發(fā)病率增加，終末期腎病最明顯[3]。一般人群房顫發(fā)生率達1%～8%，隨著年齡的增長而增高，終末期腎病房顫發(fā)生率是一般人群的2～3倍,發(fā)生率高達13%～23%[4]。研究發(fā)現(xiàn)，很多因素與慢性腎病容易并發(fā)房顫有關(guān)，合并高血壓、電解質(zhì)紊亂、流體過載、腎素-血管緊張素-醛固酮系統(tǒng)病態(tài)的激活及交感神經(jīng)系統(tǒng)的激活、血管內(nèi)皮功能障礙、血液高凝、慢性炎癥等促進房顫發(fā)生[4-6]，尿蛋白、腎小球濾過下降和心臟重要的功能和結(jié)構(gòu)異常，如超聲心動圖提示舒張功能不全、左心房擴張、二尖瓣環(huán)鈣化等促進腎病患者房顫的發(fā)生，在合并慢性腎病患者中更明顯。另外，腎病發(fā)展過程中心肌組織改變(包括間質(zhì)膠原蛋白沉積)也可能通過增加心房容積促進房顫發(fā)生[7]。

2房顫合并慢性腎病腦卒中風(fēng)險

一般房顫人群腦卒中發(fā)生率為每年3%～5%，出血發(fā)生率為1%，終末期腎病并維持透析腦卒中發(fā)生率是一般人群的4～10倍，出血并發(fā)癥是一般人群的4～6倍[8]，腎功能損害是腦卒中的強預(yù)測因子[9-10]，是出血的一項獨立危險因素，因此房顫合并慢性腎病患者腦卒中和出血風(fēng)險增加[10]。慢性腎衰竭發(fā)生栓塞與動脈粥樣硬化、反復(fù)血透期血液靜止、血液高凝狀態(tài)等有關(guān)[11]。最近關(guān)于房顫腦卒中風(fēng)險因素的研究結(jié)果提出，血栓栓塞的風(fēng)險增加與蛋白尿和腎小球濾過率下降等因素有關(guān)[8]。終末期腎病血細胞比容減少、血小板黏附聚集能力下降和血管壁的異常、尿毒癥環(huán)境和血透期間抗凝等可能增加出血風(fēng)險，合并有未控制的高血壓、糖尿病等均會增加腦卒中和出血的風(fēng)險[11-12]。

3房顫及合并慢性腎病抗凝指導(dǎo)

抗凝是房顫患者腦卒中最有效的預(yù)防措施，歐洲心臟協(xié)會及英國發(fā)布的房顫管理新指南推薦了CHA2DS2-VASc腦卒中風(fēng)險評分系統(tǒng)指導(dǎo)抗凝，其中年齡75歲、既往腦卒中/短暫性腦缺血發(fā)作/血栓栓塞分別為2分,余各1分。年齡<65歲的房顫患者和腦卒中風(fēng)險低(CHA2DS2-VASc評分為0分/女性評分1分)的患者，不需抗凝治療；CHA2DS2-VASc評分為1分的男性患者，可考慮給予口服抗凝藥預(yù)防腦卒中；CHA2DS2-VASc評分≥2分的房顫患者，建議口服抗凝藥物預(yù)防腦卒中?？鼓委熓且话选半p刃劍”，減少血栓栓塞風(fēng)險的同時增加了出血風(fēng)險。在對房顫患者抗凝治療前以及開始抗凝治療后，均應(yīng)當(dāng)評估HAS-BLED出血風(fēng)險積分,根據(jù)腦卒中和出血相對危險度以及臨床凈效益選擇抗凝。部分研究顯示，出血風(fēng)險高的房顫患者血栓栓塞風(fēng)險往往也較高，HAS-BLED評分≥3不應(yīng)作為抗凝禁忌，對于腦卒中高?；颊?，抗凝治療應(yīng)嚴格評估[13-14]。

3.1華法林抗凝華法林作為最常用的口服抗凝藥，主要用于預(yù)防房顫患者發(fā)生腦卒中[13]。一般的房顫患者，建議口服抗凝藥預(yù)防缺血性腦卒中，尤其是對老年和有合并有其他疾病的患者。腎臟疾病因內(nèi)源性血小板功能不全腦卒中風(fēng)險可降低，而華法林可通過加強慢性腎病患者血管鈣化而增加腦卒中風(fēng)險[15-16]。高血壓、腦血管疾病、缺血性腦卒中、嚴重心臟疾病、腎功能不全、高齡(年齡>80歲)等可增加房顫華法林抗凝治療期間的出血發(fā)生率，在透析人群中更加普遍[16-17]。一項研究結(jié)果表明，華法林可使非透析人群腦卒中風(fēng)險降低13%，出血風(fēng)險增加19%，透析人群腦卒中風(fēng)險沒有降低，出血風(fēng)險增加44%[18]。最新的研究表明，華法林可降低房顫合并慢性腎病患者腦卒中和系統(tǒng)性栓塞風(fēng)險，同時增加出血風(fēng)險[19-20]。以往預(yù)防血栓的治療僅限于華法林抗凝治療[21]。房顫所致栓塞或短暫性腦缺血發(fā)作是致殘性腦卒中的高危因素，房顫合并慢性腎病患者如果服用華法林保持國際標(biāo)準化比值平穩(wěn)并沒有發(fā)生出血的可繼續(xù)使用華法林預(yù)防腦卒中，目前沒有研究支持房顫合并透析患者使用華法林預(yù)防腦卒中，這與加拿大房顫指南及改善全球腎臟病預(yù)后組織的建議一致[22-23]。Lip[24]建議，房顫合并慢性腎臟疾病患者只有在腦卒中風(fēng)險較高(CHA2DS2-VASc評分≥2分,一般人群CHA2DS2-VASc評分≥1分)時接受華法林抗凝。總之，房顫合并慢性腎病患者由于慢性腎病栓塞風(fēng)險及抗凝所致出血風(fēng)險同時增加，需在嚴格抗凝效益評估后考慮華法林治療。

3.2NOACNOAC克服了華法林治療窗窄、不可預(yù)知的劑量-效應(yīng)特性、受多種食物和藥物干擾、需要頻繁監(jiān)測及劑量調(diào)整等缺點，其中一種口服直接凝血酶抑制劑達比加群和兩種口服Ⅹa因子抑制劑利伐沙班、阿哌沙班已經(jīng)被美國食品藥品管理局批準用于房顫患者腦卒中的預(yù)防，這些藥物在凝血級聯(lián)反應(yīng)中與特定酶結(jié)合,特點是起效快速、維持時間短，成為可替代華法林的藥物[25]。NOAC與華法林在非瓣膜房顫患者抗凝比較的3個隨機研究中[26-28]：ARISTOTLE研究認為，非瓣膜房顫人群阿哌沙班5 mg每日2次或2.5 mg每日2次 (存在以下2個以上因素：年齡≥80歲,體質(zhì)量≤60 kg,血肌酐≥133 μmol/L)在預(yù)防腦卒中較華法林更有效，嚴重出血事件較華法林低，同時研究表明對于不同時期腎病人群，阿哌沙班較華法林有效且出血率低[26,29]；RE-LY研究認為，達比加群110 mg每日2次在預(yù)防腦卒中不劣于華法林，嚴重出血事件較華法林更少見，同一人群中，達比加群150 mg每日2次,在預(yù)防腦卒中較華法林更有效,嚴重出血與華法林相當(dāng)，在中度腎病人群(肌酐清除率為30～50 mL/min),兩種劑量達比加群和華法林治療嚴重出血率相當(dāng)，達比加群150 mg每日2次較華法林可明顯降低腦卒中發(fā)生率,而達比加群110 mg每日2次與華法林相比，腦卒中發(fā)生率差異無統(tǒng)計學(xué)意義[27,30]；ROCKET AF研究認為，利伐沙班20 mg每日1次或15 mg每日1次(肌酐清除率為30～49 mL/min)預(yù)防腦卒中不劣于華法林，兩組主要與非主要臨床相關(guān)出血發(fā)生率差異無統(tǒng)計學(xué)意義，而利伐沙班組顱內(nèi)出血和致命性出血發(fā)生率顯著降低[28,31]。由此可知，達比加群、利伐沙班、阿哌沙班與華法林在房顫患者抗凝治療中同樣有效,且更加安全、有效、容易管理[21,32]，NOAC都部分通過腎臟代謝,有嚴重腎功能損害的患者(肌酐清除率≤25 mL/min)不在這些藥物評估的Ⅲ期臨床試驗中[33]。美國食品藥品管理局批準半劑量(75 mg每日2次)達比加群用于肌酐清除率為15～30 mL/min的腎病患者[34],歐洲藥品管理局對于肌酐清除率<30 mL/min腎病患者不推薦口服達比加群抗凝[31]。腎功能不全患者有可能抗凝藥作用時間延長和劑量累加，因此藥物的劑量、有效性、安全性需要特別評估[35]。NOAC用藥需要嚴格依從，藥物中斷增加栓塞風(fēng)險，其最大的缺點是沒有可逆轉(zhuǎn)辦法，當(dāng)前有研究建議NOAC所致出血治療包括使用活性炭減少藥物吸收、氨甲環(huán)酸增加藥物排泄、血液透析等。血液透析是降低達比加群濃度的有效手段，冷凝蛋白質(zhì)及去氨加壓素也有一定的治療前景[35]。利伐沙班及阿哌沙班一類的新型抗凝藥物與血液蛋白的親和力較大，因此很難通過透析來清除。Eerenberg等[36]指出，凝血酶原復(fù)合物濃縮劑可迅速完全逆轉(zhuǎn)利伐沙班對健康人的抗凝血效應(yīng),而對達比加群的抗凝效應(yīng)無影響。在臨床試驗中，NOAC對腦卒中和血栓的預(yù)防效果不比華法林差，有些甚至優(yōu)于華法林。從不良反應(yīng)來看，NOAC所致的嚴重出血與嚴格監(jiān)測的華法林抗凝治療相當(dāng)。而臨床相關(guān)顱內(nèi)出血或嚴重出血的風(fēng)險顯著降低。

4結(jié)語

口服抗凝藥是房顫患者長期預(yù)防腦卒中最有效的治療方案，歐洲心房顫動診治指南建議所有具有抗凝適應(yīng)證的非瓣膜病房顫患者經(jīng)過評估血栓和出血風(fēng)險后均應(yīng)優(yōu)先選擇NOAC。非瓣膜房顫合并輕中度腎病患者抗凝用藥，更加傾向于調(diào)整劑量的NOAC，對于終末期腎病或透析患者,如果有抗凝需要，華法林仍然作為首選藥[33,37]。達比加群和利伐沙班禁用于終末期腎病或透析患者，阿哌沙班近期已獲準用于透析患者，但少有關(guān)于該藥在這類患者中應(yīng)用的臨床經(jīng)驗[33,38]。終末期腎病肌酐清除率<25 mL/min的患者中，抗凝藥物的相關(guān)研究較少見，房顫合并終末期腎病抗凝治療及新藥的抗凝效益還需要進一步的研究。

參考文獻

[1]Hart RG,Pearce LA,Asinger RW,etal.Warfarin in atrial fibrillation patients with moderate chronic kidney disease[J].Clin J Am Soc Nephrol,2011,6(11):2599-2604.

[2]Hart RG,Eikelboom JW,Brimble KS,etal.Stroke prevention in atrial fibrillation patients with chronic kidney disease[J].Can J Cardiol,2013,29(7 Suppl):S71-78.

[3]Baber U,Howard VJ,Halperin JL,etal.Association of chronic kidney disease with atrial fibrillation among adults in the United States:REasons for Geographic and Racial Differences in Stroke (REGARDS) Study[J].Circ Arrhythm Electrophysiol,2011,4(1):26-32.

[4]Soliman EZ,Prineas RJ,Go AS,etal.Chronic Renal Insufficiency Cohort (CRIC) Study Group.Chronic kidney disease and prevalent atrial fibrillation:the Chronic Renal Insufficiency Cohort (CRIC)[J].Am Heart J,2010,159(6):1102-1107.

[5]Ng KP,Edwards NC,Lip GY,etal.Atrial fibrillation in CKD:balancing the risks and benefits of anticoagulation[J].Am J Kidney Dis,2013,62(3):615-632.

[6]Ahmad Y,Lip GY.Preventing stroke and systemic embolism in renal patients with atrial fibrillation:focus on anticoagulation[J].Contrib Nephrol,2013,179:81-91.

[7]Vaziri SM,Larson MG,Benjamin EJ,etal.Echocardiographic predictors of nonrheumatic atrial fibrillation.The Framingham Heart Study[J].Circulation,1994,89(2):724-730.

[8]Sood MM,Komenda P,Sood AR,etal.The intersection of risk and benefit:is warfarin anticoagulation suitable for atrial fibrillation in patients on hemodialysis [J].Chest,2009,136(4):1128-1133.

[9]Piccini JP,Stevens SR,Chang Y,etal.Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation:validation of the R(2)CHADS(2) index in the ROCKET AF (Rivaroxaban Once-daily,oral,direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) study cohorts[J].Circulation,2013,127(2):224-232.

[10]Lee M,Saver JL,Chang KH,etal.Low glomerular filtration rate and risk of stroke:meta-analysis[J].BMJ,2010,341:c4249.

[11]To AC,Yehia M,Collins JF.Atrial fibrillation in haemodialysis patients:do the guidelines for anticoagulation apply [J].Nephro-logy(Carlton),2007,12(5):441-447.

[12]Marinigh R,Lane DA,Lip GY.Severe renal impairment and stroke prevention in atrial fibrillation:implications for thromboprophylaxis and bleeding risk[J].J Am Coll Cardiol,2011,57(12):1339-1348.

[13]Nimmo C,Wright M,Goldsmith D.Management of atrial fibrillation in chronic kidney disease:double trouble[J].Am Heart J,2013,166(2):230-239.

[14]National Institute for Health and Clinical Excellence(NICE).NICE CG(180),atrial fibrillation(Update):the management of atrial fibrillation[EB/OL].(2014-06)[2014-08-18].http://guidance.nice.org.uk/CG180.

[15]Yang F,Chou D,Schweitzer P,etal.Warfarin in haemodialysis patients with atrial fibrillation:what benefit [J].Europace,2010,12(12):1666-1672.

[16]Chan KE,Lazarus JM,Thadhani R,etal.Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation[J].J Am Soc Nephrol,2009,20(10):2223-2233.

[17]Poli D,Antonucci E,Zanazzi M,etal.Impact of glomerular filtration estimate on bleeding risk in very old patients treated with vitamin K antagonists.Results of EPICA study on the behalf of FCSA (Italian Federation of Anticoagulation Clinics)[J].Thromb Haemost,2012,107(6):1100-1106.

[18]Shah M,Avgil Tsadok M,Jackevicius CA,etal.Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis[J].Circulation,2014,129(11):1196-1203.

[19]Hojs Fabjan T,Hojs R.Stroke and renal dysfunction[J].Eur J Intern Med,2014,25(1):18-24.

[20]Lai HM,Aronow WS,Kalen P,etal.Incidence of thromboembolic stroke and of major bleeding in patients with atrial brillation and chronic kidney disease treated with and without warfarin[J].Int J Nephrol Renovasc Dis,2009,2:33-37.

[21]Albert NM.Use of novel oral anticoagulants for patients with atrial fibrillation:systematic review and clinical implications[J].Heart Lung,2014,43(1):48-59.

[22]Herzog CA,Asinger RW,Berger AK,etal.Cardiovascular disease in chronic kidney disease.A clinical update from Kidney Disease:Improving Global Outcomes (KDIGO)[J].Kidney Int,2011,80(6):572-586.

[23]Skanes AC,Healey JS,Cairns JA,etal.Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines:recommendations for stroke prevention and rate/rhythm control[J].Can J Cardiol,2012,28(2):125-136.

[24]Lip GY.Chronic renal disease and stroke in atrial fibrillation:balancing the prevention of thromboembolism and bleeding risk[J].Europace,2011,13(2):145-148.

[25]Tendera M,Syzdó M,Parma Z.ARISTOTLE RE-LYs on the ROCKET.What′s new in stroke prevention in patients with atrial fibrillation[J].Cardiol J,2012,19(1):4-10.

[26]Granger CB,Alexander JH,McMurray JJ,etal.Apixaban versus warfarin in patients with atrial fibrillation[J].N Engl J Med,2011,365(11):981-992.

[27]Connolly SJ,Ezekowitz MD,Yusuf S,etal.Dabigatran versus warfarin in patients with atrial fibrillation[J].N Engl J Med,2009,361(12):1139-1151.

[28]Patel MR,Mahaffey KW,Garg J,etal.Rivaroxaban versus warfarin in nonvalvular atrial fibrillation[J].N Engl J Med,2011,365(10):883-891.

[29]Hohnloser SH,Hijazi Z,Thomas L,etal.Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation:insights from the ARISTOTLE trial[J].Eur Heart J,2012,33(22):2821-2830.

[30]Eikelboom JW,Wallentin L,Connolly SJ,etal.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[J].Circulation,2011,123(21):2363-2372.

[31]Fox KA,Piccini JP,Wojdyla D,etal.Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment[J].Eur Heart J,2011,32(19):2387-2394.

[32]Salim I,Al Suwaidi J,Ghadban W,etal.Anticoagulation in atrial fibrillation and co-existent chronic kidney disease:efficacy versus safety[J].Expert Opin Drug Saf,2013,12(1):53-63.

[33]January CT,Wann LS,Alpert JS,etal.2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation:a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society[J].J Am Coll Cardiol,2014,64(21):e1-76.

[34]Shen JI,Turakhia MP,Winkelmayer WC.Anticoagulation for atrial fibrillation in patients on dialysis:are the benefits worth the risks[J].Curr Opin Nephrol Hypertens,2012,21(6):600-606.

[35]Alikhan R,Rayment R,Keeling D,etal.The acute management of haemorrhage,surgery and overdose in patients receiving dabiga-tran[J].Emerg Med J,2014,31(2):163-168.

[36]Eerenberg ES,Kamphuisen PW,Sijpkens MK,etal.Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate:a randomized,placebo-controlled,crossover study in healthy subjects[J].Circulation,2011,124(14):1573-1579.

[37]Winkelmayer WC,Liu J,Setoguchi S,etal.Effectiveness and safety of warfarin initiation in older hemodialysis patients with incident atrial fibrillation[J].Clin J Am Soc Nephrol,2011,6(11):2662-2668.

[38]Mueck W,Schwers S,Stampfuss J.Rivaroxaban and other novel oral anticoagulants:pharmacokinetics in healthy subjects,specific patient populations and relevance of coagulation monitoring[J].Thromb J,2013,11(1):10.

Anticoagulation and Drug Selection for Atrial Fibrillation Combined with Chronic Kidney DiseaseZHENGYa-ru1,YELi-fang1,WANGLi-hong2.(1.DepartmentofCardiology,theFirstHospitalAffiliatedtoMedicalCollegeofZhejiangUniversity,Hangzhou310003,China; 2.DepartmentofCardiology,People′sHospitalofZhejiangProvince,Hangzhou310014,China)

Abstract：Incidence of chronic kidney disease(CKD) and atrial fibrillation(AF) generally increase with age.Patients with AF combined with CKD are at increased risk of both stroke and bleeding events.Anticoagulation treatment has been shown to reduce the risk of stroke.Warfarin is the most commonly used anticoagulant drugs in AF patients,while until now few studies indicated that patients with end-stage renal disease could benefit from warfarin therapy.The novel oral anticoagulants was shown non-inferior and more effective,safer and easier to administer compared to warfarin.There is controversy on the benefits of anticoagulation in patients with AF combined with renal diseases.

Key words:Atrial fibrillation; Stroke prevention; Warfarin; Anticoagulation treatment

收稿日期：2014-12-08修回日期：2015-02-28編輯：相丹峰

doi：10.3969/j.issn.1006-2084.2015.17.033

中圖分類號：R541.75

文獻標(biāo)識碼：A

文章編號：1006-2084(2015)17-3160-03