心房顫動相關缺血性卒中的研究進展

李姝雅，王伊龍，王擁軍

心房顫動（atrial fibrillation，AF）是最常見的室上性心動過速，人群總體患病率為0.4%～1.0%[1-2]。一些心房顫動患者缺乏明顯的、特征性的臨床表現，許多患者直到出現嚴重并發癥時才被檢出心房顫動。心房顫動是缺血性卒中的一個重要的獨立危險因素，約每6例卒中患者中有1例是心房顫動患者[3]。伴心房顫動的缺血性卒中患者復發率高、預后差，給社會和家庭造成沉重的負擔[4-9]。合理應用抗凝治療可降低心房顫動患者的卒中風險[10-11]，過度抗凝治療增加患者出血風險[12-13]。由于目前醫療水平的限制及循證醫學資料的匱乏，對于心房顫動患者的檢出和管理仍缺乏有效的、一致的意見，探索卒中合并心房顫動患者管理規范尤為重要。

1 心房顫動患者的卒中危險分層評估和新型抗凝藥物的發展

抗凝治療可以降低心房顫動患者卒中發生率，但因出血風險而限制其臨床應用。鑒于抗凝的利弊，評估心房顫動患者卒中發生風險和出血風險，平衡利弊，顯得極為重要。20世紀90年代初，學者們就致力于建立一個有效的心房顫動患者卒中危險評分工具（表1）[14-21]，經過20年的不斷發展，最新的卒中危險分層工具是CHADS2評分（Congestiveheart failure，Hypertension，Age＞75 yrs，Diabetes mellitus，prior Stroke and TIA）[22]和CHA2DS2_VASc評分［Congestive heart failure，Hypertension，Age≥75（Doubled），Diabetes，Stroke（doubled），Vascular disease，Age 65～74，and Sex category（female）］[23]（表2）。CHADS2評分和CHA2DS2_VASc評分已在歐洲、日本、韓國等多個地區心房顫動人群中進行驗證，得到其預測1年心源性卒中風險的曲線下面積（area under curve，AUC）（C值）在0.60～0.63[24-26]。2001年問世的CHADS2評分是基于專家共識產生的總分為6分的經典危險分層工具，在其產生隊列中顯示出良好的效度（C=0.82）。該評分因操作簡單，效度良好，一經問世即在臨床上廣泛應用，隨著臨床試驗的不斷檢驗，Lip等[27]根據臨床實踐修訂了CHADS2的危險分層標準。Gage等[28]將更改了分層方法的CHADS2評分在“心房顫動患者應用口服凝血酶抑制劑預防卒中研究”（Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation，SPORTIF）中進行驗證，約60%的患者被分為中危患者，指南中對于中危患者抗栓藥物選擇沒有明確推薦，限制了CHADS2評分對抗栓藥物應用的指導意義。2010年CHA2DS2_VASc評分是一種以危險因素為基礎評價非瓣膜性心房顫動患者的方法，改進了心房顫動患者發生卒中的危險分層。這一評分方法將CHADS2評分得到的中危人群比例降低到原來的1/4，進一步增強了評分工具對抗凝治療的指導意義[23]。根據上述評分標準，對于伴心房顫動的缺血性卒中患者，屬于存在既往卒中病史的心房顫動患者，至少得到2分，屬高危分層，需抗凝治療。

表1 心房顫動患者卒中風險評分工具

表2 CHADS2和CHA2DS2_VASc評分

卒中等血栓栓塞性并發癥是心房顫動患者致死、致殘的主要原因，合理的抗凝治療對于改善心房顫動患者生活質量和遠期預后具有重要意義。雖然國內外相關指南均建議給予高危心房顫動患者血栓預防治療，但迄今多數患者并未得到相應處理，這與口服抗凝藥物的選擇限制密切相關[29-30]。目前成熟的口服抗凝藥物只有維生素K拮抗劑華法林。華法林應用時需根據凝血酶原國際標準化比值（international normalized ratio，INR）調整劑量，且其抗凝效果受食物影響大，出院患者自行用藥風險極大。新型口服抗凝劑凝血因子Ⅹa抑制劑克服了上述困難，具備高效、安全、固定劑量、無需監測INR的特點，未來將占據口服抗凝藥物的市場，為抗凝治療帶來新的時代。達比加群酯（Pradaxa）、利伐沙班（rivaroxaban）和阿哌沙班（apixaban）是目前批準上市的新型抗凝藥物。這三類新型抗凝藥物都經過了大型臨床試驗的證實，在抗凝療效和出血風險方面不同程度地優于阿司匹林和華法林，這就意味著在心房顫動相關卒中預防中新型抗凝劑時代已經到來[22，31-35]。

2 伴心房顫動的缺血性卒中患者抗凝治療的出血風險

伴心房顫動的缺血性卒中患者的抗凝治療是一把雙刃劍，在對心房顫動患者進行抗凝治療的同時應當評估其出血風險（表3）。出血風險的研究略晚于心房顫動患者的卒中風險，最早的出血風險評分工具誕生于1998年[36]，以年齡、2周內胃腸道出血、卒中史及并發癥為危險因素，根據得分判斷出血風險，其用C值代表的預測大出血的效度為0.78。1年后，Kuijer等[37]提出了以年齡、性別和癌癥三種危險因素組成的抗凝治療出血風險預測評分，在其驗證隊列中，用C值代表的評分對大出血的預測效度為0.82［95%可信區間（confidence interval，CI）：0.66～0.98］。因出血風險與年齡呈正相關，Shireman等[38]提出了一個適用于年齡＞65歲心房顫動患者的評分工具，其低、中、高危患者的出血率分別為0.9%、2.0%和5.4%。2006年，Gage等[39]發表了出血危險的預測量表模型：肝臟或腎臟疾病、酗酒、惡性腫瘤、高齡、血小板計數或功能降低、再次出血、高血壓、貧血、基因因素、容易摔倒危險和卒中（Hepatic or renal disease，Ethanol abuse，Malignancy，Older age，Reduced platelet count or function，Re-bleeding，Hypertension，Anemia，Genetic factors，Excessive fall risk and Stroke；HEMORR2HAGES）評分工具，該評分方法較為繁瑣，但心房顫動患者抗凝治療的出血風險隨著得分的增加而增高。2010年Pisters等[40]提出的另一個預測模型：高血壓、肝/腎功能異常、卒中、出血史或易于出血因素、不穩定國際標準化比值、老年人、藥物/酒精（Hypertension，Abnormal renal/liver function，Stroke，Bleeding history or predisposition，Labile international normalized ratio，Elderly，Drugs/alcohol，HAS-BLED）評分量表因操作簡單，對單純抗血小板治療及非抗栓治療組出血風險的預測能力則強于其他評分系統（C值分別為0.91和0.80），成為歐洲心臟病協會（European Society of Cardiology，ESC）心房顫動管理指南對出血風險定量分析的推薦工具（表4）。該量表總分為9分，規定HAS-BLED評分≥3分為高危人群，1～2分為中危人群，0分為低危人群，對于高危人群，在應用抗凝藥物或阿司匹林時需密切注意全身出血傾向。

表3 心房顫動患者抗凝治療出血風險評分

表4 HAS-BLED評分

HAS-BLED評分指導抗凝治療需與心房顫動患者卒中風險評分工具合用。在心房顫動患者中同時應用CHADS2和HAS-BLED評分將會減少12%接受抗凝治療而出血的人數。當CHADS2評分≥2時，患者存在卒中高風險，推薦抗凝治療，若此時HAS-BLED評分大于CHADS2評分，則出血風險超過抗凝獲益。對于CHADS2評分=1分的患者，HAS-BLED評分與CHADS2評分相差不超過2分時，抗凝獲益大于出血風險[41]。

上述5種抗凝治療出血風險預測工具均是在未接受抗凝治療的研究隊列中產生和驗證，為進一步預測接受抗凝治療的患者自發性腦出血風險，Fang等[42]提出了基于心房顫動抗凝和危險因素的研究（Anticoagulation and Risk Factors in Atrial Fibrillation，ATRIA）評分。該研究在基于社區的大規模心房顫動患者隊列中建立了評估華法林相關出血風險評估的有效方法，在最終風險模型中識別出5個獨立變量，包括貧血、腎臟疾病（腎小球濾過率＜30 ml/min或接受透析）、年齡≥75歲、曾因出血住院和高血壓。效度分析得到的C統計值為0.74。評分劃分低危（0～3分）、中危（4分）和高危（5～10分）患者的主要出血事件發生率分別為0.8%、2.6%和5.8%。ATRIA評分產生后，Lip等[43]將HEMORR2HAGES評分，HAS-BLED評分和ATRIA評分的預測能力進行了比較。效度分析（relative operating characteristic，ROC分析）顯示HAS-BLED評分預測任何臨床相關出血方面最佳，但三者對出血風險均有較保守的預測能力（C值均＜0.7）。在改善分析（net reclassification index，NRI）中，HASBLED評分被證實相對于HEMORR2HAGES及ATRIA評分可以分別改善10.3%和13%。使用決定曲線分析（detrended correspondence analysis，DCA）顯示，HAS-BLED評分在臨床相關出血事件任何界值水平方面優于ATRIA和HEMORR2HAGES評分。另外，顱內出血是抗凝治療中最危險的并發癥，只有HAS-BLED評分對顱內出血具有預測價值。因此，HAS-BLED評分可能成為指南推薦工具。Lip教授[44]評論：“HAS-BLED高評分不能被認為是停止抗凝治療的指標，而是促使臨床醫師關注這類需要特別留意與隨訪的高危患者。HAS-BLED評分使臨床醫師考慮潛在的可糾正的出血風險因素，比如未控制的血壓，不穩定的INR值，以及合并用藥中的阿司匹林及非甾體抗炎藥。”來自中國臺灣[45]和西班牙[46]的數據同樣證實了HAS-BLED評分的優勢。目前，HAS-BLED評分是唯一國際指南推薦的抗凝治療風險預測評分[47－49]。

3 提高卒中患者伴發心房顫動的檢出率

陣發性和無癥狀性心房顫動難以檢出，因此隱源性卒中和短暫性腦缺血發作患者可能存在未診斷的心房顫動，心房顫動的檢出在卒中二級預防中處于關鍵優先地位。我國心源性卒中的整體出院診斷率為6%～7%，這與國外報道的20%比例相距甚遠[22，49]，從一個側面說明了我國心源性卒中的診斷率較低。研究證實通過新技術延長心電監測時間可提高心房顫動檢出率，但其成本效益存在爭議[50-54]。美國的一項研究對卒中患者心房顫動檢出（Score for the Targeting of Atrial Fibrillation，STAF）評分≥5分的患者進行連續21 d心電監測，心源性卒中的診斷率提高到13%，這比當時的總體診斷率提高了6%[51]。另一研究提出，通過延長心電監測時間每多診斷一位心源性卒中患者需要耗費的成本為44 000美元[52]。對患者進行心房顫動風險評估，針對高危患者延長心電監測時間，提高心房顫動檢出率，是符合成本效益的卒中二級預防內容。2010年Suissa等[55]提出了STAF評分系統，從4個方面對卒中患者進行評分，總分為8分（表5）。根據相應的受試者工作特征（receiver operating characteristic，ROC）曲線得出總得分＜5分，心源性卒中的可能性＜10%；如果總分≥5分，心源性卒中的可能性則可以達到90%，建議進一步延長心電監測時間。該評分識別心房顫動患者的敏感性為89%，特異性為88%。陣發性心房顫動和短陣心房顫動是提高心房顫動檢出率的關鍵。Suissa等[56]提出，STAF評分≥5分對于陣發性心房顫動和持續性心房顫動的作用無顯著性差異，兩者的C值分別為0.907和0.911，其識別陣發性心房顫動的敏感性為91%，特異性為77%。德國的一項研究進一步探討了STAF評分對于陣發性心房顫動的預測能力[57]。效度分析結果提示C值為0.84，STAF評分≥5分對于識別陣發性心房顫動的敏感性為79%，特異性為74%。繼STAF評分之后，Malik等[58]提出了用于卒中患者心房顫動風險預測的LADS評分（Left atrial diameter，Age，Diagnosis of stroke or TIA，and Smoking status）（表5）。該評分總分為6分，規定≥4分為心房顫動高風險患者，其識別心房顫動患者的敏感性為85.5%，特異性為53.1%。經過LADS評分的分類，可減少47%的卒中或TIA患者接受長時間心電監測。由于LADS評分的預測能力略低于STAF評分，目前尚無對LADS評分進一步驗證的相關研究。

STAF評分篩選出卒中患者中伴發心房顫動的高危人群，高危人群需延長心電監測時間進一步檢出心房顫動，目前相關指南尚未對心電監測時長給予建議，研究建議對卒中患者早期實施心房顫動篩查有助于提高心房顫動的檢出率，最短監測時間為4 d[59]。可插入心臟監測器這一新技術不僅較7 d的連續心電監測提高心房顫動的檢出率，且對患者而言更易耐受，無不良反應，將成為提高心房顫動檢出率的新方向[55，60]。

表5 STAF和LADS評分

4 伴心房顫動的缺血性卒中患者的不良預后量表

目前，尚無單純用于伴心房顫動的缺血性卒中患者的不良預后量表。用于心房顫動患者卒中危險分層的CHADS2和CHA2DS2_VASc評分，其組成元素均為卒中復發和卒中后死亡的獨立危險因素。由此推測，兩種評分工具可能對于發生缺血性卒中的心房顫動患者卒中復發和不良預后方面有一定的預測價值。既往研究將CHADS2和CHA2DS2_VASc評分應用于伴非瓣膜性心房顫動的缺血性卒中患者預后結局的預測，發現這兩種評分工具是不良預后和死亡的獨立危險因素[61-63]。希臘的一項研究將CHA2DS2_VASc評分應用于非心房顫動患者，中、高危分層患者的5年死亡率，卒中復發率和聯合心血管事件明顯高于低危分層的患者[64]。

心房顫動或不伴心房顫動患者的不良預后危險因素基本一致是CHA2DS2_VASc評分可用于不伴心房顫動患者預后評價的基礎。隨著大型高質量隊列研究的逐漸發展和完善，研究者們提出了多個不良預后風險預測模型（表6）。這些風險預測模型未將伴心房顫動的缺血性卒中排除在外，可初步作為心房顫動相關卒中的預后評估工具。

表6 缺血性卒中死亡和不良預后評估量表

iScore評分[65]是基于加拿大卒中登記的一項較早的預測模型，預測急性缺血性卒中患者30 d和1年的死亡風險。預測模型在建模隊列（30 d死亡，C=0.85；1年死亡，C=0.823）、內部驗證隊列（30 d死亡，C=0.851；1年死亡，C=0.84）和外部驗證隊列（30 d死亡，C=0.79；1年死亡，C=0.782）中均得到較好的預測效度。隨后，iScore評分分別用于不良預后風險預測，溶栓患者出血風險及預后轉歸預測，均得到理想結果[66-68]。PLAN評分[69]預測模型來源于另一個加拿大卒中登記，用于預測缺血性卒中患者出院30 d、1年的死亡率和出院時改良Rankin量表（modified Rankin Scale，mRS）評分5～6分。預測模型包括9項臨床指標，操作相對簡單，可以準確預測急性缺血性卒中患者30 d死亡（C=0.87），出院時死亡或嚴重致殘（C=0.88）、1年死亡（C=0.84）。同時也可以預測出院時的良好結局（mRS 0～2）（C=0.80）。美國心臟協會在其協作醫院的冠狀動脈疾病單元中推行的跟著指南走（Get-with-the-Guideline）建立了在院死亡模型[70]，其包括美國國立衛生研究院卒中量表（National Institutes of Health Stroke Scale，NIHSS）評分的預測模型對于院死亡的預測效度為0.85（0.84～0.86）。

洛桑卒中登記（The Acute STroke Registry and Analysis of Lausanne，ASTRAL）評分預測模型[71]主要預測不良預后風險，不良預后定義為mRS評分＞2分。在建模隊列中預測3個月不良預后風險的C值為0.86，在兩個其他隊列研究中進行外部驗證，C值分別為0.937和0.771，預測效度良好。博洛尼亞研究（the Bologna Outcome Algorithm for Stroke，BOAS）模型[72]是意大利博洛尼亞市登記隊列推出的用于預測9個月不良預后的模型，包括NIHSS評分、年齡、上肢永久癱瘓、吸氧和導尿5個危險因素，每個危險因素1分，總分為5分。0～1分為低危分組，2～5分為高危分組。該評分在建模隊列（C=0.891，95%CI 0.848～0.934）和驗證隊列（C=0.845，95%CI 0.770～0.920）中均表現出良好的預測能力。美國弗明漢心臟登記研究建立了用于心臟病一級預防的（Framingham Cardiovascular Risk Score，FCRS）模型[73]，將FCRS模型用于卒中二級預防出院時不良預后風險預測和出院去向預測，得到FCRS模型對于出院時mRS≥2分的比值比（odds ratio，OR）為4.9（95%CI 0.98～24.1），出院回家的OR=0.18（95%CI 0.04～0.86），FCRS模型是對缺血性卒中患者出院回家的保護性因素。

上述預測模型適用于缺血性卒中患者，缺血性卒中患者發病機制及病理生理特點異質性較強，建立針對伴心房顫動的缺血卒中患者的預測模型仍有待進一步研究。

5 伴心房顫動的缺血性卒中研究展望

美國心臟協會／美國卒中學會（American Heart Association/American Stroke Association，AHA/ASA）評選出2011年全球腦血管病最重要的十大研究進展中，與心房顫動相關的卒中占了三席，包括心房顫動的危險因素[74]、心房顫動患者的降壓藥物選擇[75]及新型口服抗凝藥物[31-36]，成為2011年卒中研究領域最搶眼的熱點。大約有1/5的卒中是由心房顫動所致，未被診斷的心房顫動即無癥狀性心房顫動很可能是原因不明卒中的病因。心房顫動所致的卒中相對嚴重，會導致長期的殘疾或死亡。心房顫動作為心源性卒中最常見的原因，提高其檢出率，指導一級預防、二級預防及預后評估對于卒中醫療質量改進及提高患者生活質量意義重大，任重而道遠。

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【點睛】

本文介紹了心房顫動患者卒中風險、出血風險、預后等方面預測模型和評分系統的發展和現狀。