本文選題：心房顫動 + 抗凝治療　； 參考：《北京協(xié)和醫(yī)學(xué)院》2016年博士論文

【摘要】：研究背景心房顫動(Atrial fibrillation, AF)簡稱房顫,是臨床最常見的心律失常之一,其最嚴重的后果是因腦血管事件而致殘致死,影響患者的生活質(zhì)量。AF在總體人群中的患病率為0.4～1.0%[1,2],其發(fā)病率隨年齡增加呈逐漸增加趨勢[3-5]。ATRIA研究提示,2000年美國有230萬例AF患者,預(yù)計到2050年將達560萬例[1],到2060年歐洲55歲以上的AF患者數(shù)量將達到1790萬[6]。2004年中國流行病學(xué)調(diào)查發(fā)現(xiàn)：我國14個省和直轄市自然人群中30～85歲人群中AF總患病率為0.77%,標(biāo)準(zhǔn)化后的患病率為0.61%,男性患病率約為0.9%,女性為0.7%,其中非瓣膜病AF的比例為65.2%[7]。近幾年,隨著AF發(fā)病率,伴發(fā)疾病以及治療措施的變化,缺乏對目前我國AF患者大規(guī)模研究,本研究為單中心前瞻性注冊研究,可以反映真實世界非瓣膜病AF疾病特點和治療方式以及預(yù)后情況。根據(jù)Framingham研究結(jié)果顯示,非瓣膜病AF腦卒中發(fā)生率是正常人5.6倍,占全部腦卒中事件的15%～20%,AF抗栓治療是其治療的核心[3,4,8]。口服華法林抗凝治療是預(yù)防AF患者發(fā)生卒中最為有效的手段,循證醫(yī)學(xué)證據(jù)表明,華法林治療可使AF血栓栓塞的風(fēng)險降低62.0%[9],而出血并發(fā)癥無顯著增加。然而,目前我國抗凝狀況不容樂觀,既往研究顯示我國抗凝率僅為2%左右,近幾年隨著指南的推薦和認識程度的提高,AF抗凝率較既往有所增加,但目前缺少大規(guī)模流行病學(xué)證據(jù)。既往有大量國外研究報道了華法林使用率低的原因[10-13],但影響我國非瓣膜病AF患者華法林使用的因素有待于深入探討。除了提高華法林使用率,華法林的抗凝質(zhì)量也是影響其預(yù)后的重要因素,TTR (Time in therapy range)為華法林抗凝質(zhì)量常用的評價指標(biāo),既往研究發(fā)現(xiàn)TTR65%患者才可明顯獲益,主要心血管事件的發(fā)生風(fēng)險降低2倍[14],我國目前尚無相關(guān)報道。本文通過單中心前瞻性注冊研究并進行長期隨訪分別對以上三部分進行探討：1)描述非瓣膜病AF患者的人口學(xué)資料、伴發(fā)疾病、抗凝以及預(yù)后情況；2)分析非瓣膜病AF患者卒中高危人群服用華法林影響因素； 3)探討非瓣膜病AF患者華法林抗凝質(zhì)量(TTR)及其影響因素。第一部分非瓣膜病AF患者抗凝情況和預(yù)后分析(單中心注冊研究)目的：通過單中心前瞻性注冊研究以及長期隨訪,探討目前非瓣膜病AF患者抗凝及預(yù)后情況。方法：入選2011年8月至2015年12月北京協(xié)和醫(yī)院就診的非瓣膜病AF患者。對入選患者以病例登記表形式收集患者基線的人口學(xué)資料、伴發(fā)疾病及心血管危險因素,相關(guān)治療情況。所有患者每6個月進行隨訪,記錄患者隨訪期間相關(guān)治療情況和相關(guān)臨床事件。結(jié)果：注冊的911例患者中,平均年齡為66.3±11.3歲,男性526例(57.7%)。常見的伴發(fā)疾病為高血壓(63.6%),糖尿病(20.2%),冠心病(15.3%),血栓栓塞(12.3%),心力衰竭(7.8%)等。280例(30.7%)患者基線服用抗心律失常藥物,558例患者(61.3%)使用控制心室率藥物。227例(24.9%)患者基線接受射頻消融治療,其中陣發(fā)AF患者射頻消融比例最高為35.7%。患者基線抗凝治療情況為414例(45.4%)患者使用華法林,427例(46.9%)患者使用阿司匹林,37例(4.1%)患者使用氯吡格雷,51例(5.6%)患者使用NOACs。非射頻消融患者中,華法林基線使用比例為33.8%,阿司匹林為56.4%,氯吡格雷為4.8%,NOACs為1%。CHA2DS2-VASc≥2分非消融患者中華法林使用比例為39.7%,阿司匹林為55%,氯吡格雷為5.7%,NOACs為1.0%。14.1%非瓣膜病AF患者在隨訪中開始使用華法林,隨訪中華法林停藥比例為15.5%,非射頻消融患者華法林長期規(guī)律服藥比例為31.1%,而射頻消融患者華法林服藥比例為10.0%。隨訪期間非瓣膜病AF患者全因死亡,心血管原因死亡,主要不良心臟事件(Major Adverse Cardiac Event, MACE)事件年發(fā)生率分別為2.76%,1.48%和5.2%。年齡(HR 1.064,95%CI 1.034～1.094,P=0.0001),心力衰竭史(HR 2.094, 95% CI 1.15～3.812, P=0.016),擴張性心肌病史(HR 6.799,95%CI 2.38～19.42, P=0.0001),慢性肺疾病史(HR 1.955,95%CI 1.10～3.474,P=0.022),貧血(HR 3.085,95%CI 1.707～5.574, P=0.0001),糖尿病(HR 1.727,95%CI 1.043～ 2.858, P=0.034)是非瓣膜病AF患者全因死亡的獨立危險因素。年齡(HR 1.06, 95%CI 1.019～1.102,P=0.004),心力衰竭史(HR 2.171,95%CI 1.273～6.217, P=0.011), DM(HR 2.018,95%CI 1.081～4.111,P=0.029),擴張性心肌病史(HR 5.142,95%CI 1.126～23.485, P=0.035),貧血(HR 4.434,95%CI 2.059～ 9.55,P=0.0001)是非瓣膜病AF患者因心血管原因死亡的獨立危險因素。年齡(HR 1.03,95%CI 1.01～1.049,P=0.003),心力衰竭史(HR 2.171,95%CI 1.36～3.419, P=0.001),擴張性心肌病史(HR 3.382,95%CI 1.348～8.488, P=0.009),血栓栓塞史(HR 1.726,95%CI 1.142～2.609,P=0.01),貧血(HR 2.04,95%CI 1.236～3.367, P=0.005),慢性肺疾病史(HR 1.808,95%CI 1.146～2.85, P=0.011)是非瓣膜病AF患者MACE的獨立危險因素。結(jié)論：1.本注冊研究中非瓣膜病AF患者常見并存疾病包括高血壓、糖尿病、冠心病、心力衰竭等。2.非瓣膜病AF患者選擇室率控制治療方案比例顯著高于抗心律失常藥物,約1/3陣發(fā)AF患者選擇行射頻消融治療。3.非瓣膜病AF患者基線華法林使用比例為45.4%,非消融患者基線華法林使用比例為33.8%,其中CHA2DS2-VASc評分≥2分患者基線華法林抗凝比例39.7%。4.非消融非瓣膜病AF患者華法林長期規(guī)律服藥比例為31.1%,而射頻消融患者華法林規(guī)律服藥比例為10.0%。5.非瓣膜病AF患者全因死亡年發(fā)生率為2.76%,因心血管死亡年發(fā)生率為1.48%, MACE年發(fā)生率為5.2%。年齡,心力衰竭史,貧血,慢性肺疾病史等因素與非瓣膜病AF患者預(yù)后相關(guān)。第二部分影響非瓣膜病AF患者卒中高危人群服用華法林因素分析目的：分析影響非瓣膜病AF卒中高危人群(CHA2DS2-VASc≥2分)啟用華法林和堅持服用華法林治療的因素。方法：納入2011年8月至2015年12月北京協(xié)和醫(yī)院登記注冊的非瓣膜病AF患者,且CHA2DS2-VASc評分≥2分。除外射頻消融患者�；颊叻譃榻邮苋A法林治療的華法林組和未接受華法林治療的對照組。采用單因素分析方法比較兩組患者基本情況,采用多因素Logistic回歸分析影響華法林使用的因素。用Kaplan-Meier曲線描述華法林組堅持抗凝用藥情況,并采用Cox回歸分析華法林組堅持抗凝用藥的影響因素。結(jié)果：611例非導(dǎo)管消融患者中,符合CHA2DS2-VASc評分≥2分患者481例,隨訪時間為38.9±13.8個月。華法林組患者共252例(52.4%),血栓栓塞(OR 2.543, 95%CI 1.525～4.241, P=0.0001),心力衰竭((OR 1.93,95%CI 1.064～3.501, P=0.03),持續(xù)性房顫(OR 2.236,95%CI 1.448～3.366,P=0.0001)患者更多服用華法林,而服用中藥(OR 0.628,95%CI 0.413～0.954, P=0.029),冠心病(OR 0.601,95%CI 0.37～0.974, P=0.039)以及與醫(yī)院距離遠者(OR 0.689,95%CI 0.584～0.897, P=0.003)華法林使用率較低。華法林組隨訪期間167例(66.3%)堅持服用華法林。Kaplan-Meier曲線中所有患者1年華法林堅持服藥率為81.3%,三年為67.0%。堅持服用華法林患者中,入組前已服用華法林患者69例(73.4%,69/94例),新啟用患者98例(62.0%,98/158例),前者總堅持服藥率明顯高于后者(P=0.008)。與華法林停用相關(guān)的因素為新啟用華法林(HR 1.786,95%CI 1.029～3.1,P=0.039),服用中藥(HR 1.687,95%CI 1.201～2.37,P=0.003),患者與就診醫(yī)院的距離較遠(HR 1.446,95%CI 1.121～1.865, P=0.005)。結(jié)論：1.華法林使用的獨立預(yù)測因素主要包括心衰,冠心病,血栓栓塞,長期就診醫(yī)院的距離等。其中患者居住地到長期就診醫(yī)院的距離與華法林使用顯著負相關(guān),與華法林停藥率顯著正相關(guān)。2. 新啟用華法林的AF患者華法林堅持服藥率明顯低于既往服用華法林患者。3. 中藥降低了華法林使用率,且與華法林停用率顯著相關(guān)。第三部分非瓣膜病AF患者華法林抗凝治療質(zhì)量(TTR)及影響因素研究目的：TTR是評估華法林抗凝質(zhì)量的常用方法,本研究探討非瓣膜病AF患者華法林長期抗凝中TTR水平及其影響因素。方法：納入2011年8月至2015年12月北京協(xié)和醫(yī)院登記注冊的非瓣膜病AF患者中長期服用華法林者,Rosendaal法評估患者的TTR水平。單因素和多元回歸方法對影響TTR因素進行分析。結(jié)果：符合入組標(biāo)準(zhǔn)的患者共118例,患者平均年齡為(70.3±8.7歲),男性患者共62例(52.5%)。隨訪期內(nèi)共記錄INR檢測結(jié)果2915個,患者平均INR監(jiān)測次數(shù)為24.7±12.6次,平均監(jiān)測的時間間隔是45.7±15.3天(范圍為13.8-84.5)天。患者平均TTR為55.5±19.3%(0%～99.0%)。低于TTR比例(INR2)為39.0±20.1%(0%～93.8%),高于TTR范圍為(INR3)比例4.69±8.60%(0%～60.52%)。多因素分析發(fā)現(xiàn)高血壓和心力衰竭為TTR水平的獨立影響因素(P0.05)。結(jié)論：非瓣膜病AF患者長期口服華法林TTR為55.5±19.3%,高血壓和心力衰竭為TTR水平的獨立影響因素。
[Abstract]:Atrial fibrillation (AF), abbreviated as atrial fibrillation, is one of the most common arrhythmia in clinic. The most serious consequence is death caused by cerebral vascular events. The prevalence of.AF in the population is 0.4 to 1.0%[1,2] in the population, and its incidence is gradually increasing with the age of [3-5].ATRIA. In 2000, 2 million 300 thousand cases of AF patients in the United States were expected to reach 5 million 600 thousand [1] in 2050. By 2060, the number of AF patients over 55 years old in Europe will reach 17 million 900 thousand [6].2004 year's Chinese epidemiological survey. The total AF prevalence rate of 30~85 year olds in 14 provinces and municipalities directly under the central government of our country is 0.77%, and the standardized prevalence rate is 0.6. 1%, the male prevalence rate is about 0.9%, and the female is 0.7%. The proportion of non valvular AF is 65.2%[7]. in recent years. With the incidence of AF, the disease and the change of treatment measures, there is no large-scale study on the current AF patients in our country. This study is a single center prospective registration study, which can reflect the characteristics and treatment of non valvular AF disease in the real world. Methods and prognosis. According to the results of Framingham study, the incidence of non valvular AF stroke is 5.6 times that of normal people, accounting for 15% to 20% of all stroke events. AF antithrombotic therapy is the core [3,4,8]. oral warfarin anticoagulant therapy is the most effective means to prevent the occurrence of apoplexy in AF patients, evidence based evidence-based medicine shows that China The risk of AF thromboembolism can be reduced by 62.0%[9] with no significant increase in bleeding complications. However, the current situation of anticoagulation in China is not optimistic. Previous studies have shown that the anticoagulant rate is only about 2% in our country. In recent years, the anticoagulant rate of AF has increased with the improvement of the recommendation and understanding of the guide, but there is a lack of large-scale flow at present. A large number of foreign studies have reported the cause of the low use of Hua Falin [10-13], but the factors affecting the use of Hua Falin in non valvular patients in China need to be discussed. In addition to improving the use of Hua Falin, the anticoagulant quality of Hua Falin is also an important factor affecting the prognosis of the patients. TTR (Time in therapy range) is the Chinese method. The evaluation indexes commonly used in the quality of anticoagulant forest in the forest have been found to be obvious in TTR65% patients. The risk of major cardiovascular events is reduced by 2 times [14]. There are no relevant reports in China. This paper discusses the above three parts by a single center prospective registration study and long-term follow-up: 1) the non valvular AF patients are described. Demographic data, concomitant diseases, anticoagulants and prognosis; 2) analysis of Hua Falin influence factors in patients with high risk of stroke in non valvular AF patients; 3) to explore the anticoagulant quality of Hua Falin in non valvular patients (TTR) and its influencing factors. The first part of the non valvular AF patients' anticoagulation and prognosis analysis (single center registration study) purpose Through a single center prospective registration study and long-term follow-up, the anticoagulation and prognosis of the current non valvular AF patients were investigated. Methods: the non valvular AF patients in Peking Union Medical College Hospital from August 2011 to December 2015 were selected to collect the demographic data of the patients' baseline in the form of case registration form, accompanied by disease and heart blood. All patients were followed up every 6 months to record related treatment and related clinical events. Results: of the 911 patients registered, the average age was 66.3 + 11.3 years, and the male 526 cases (57.7%). The common associated diseases were hypertension (63.6%), diabetes (20.2%), coronary heart disease (15.3%), thrombosis. Embolization (12.3%), heart failure (7.8%), and other.280 cases (30.7%) were taken antiarrhythmic drugs, 558 patients (61.3%) were treated with radiofrequency ablation in.227 cases (24.9%) with control ventricular rate (24.9%), of which the highest ratio of radiofrequency ablation in AF patients was 35.7%. patients with baseline anticoagulant therapy in 414 cases (45.4%). Hua Falin, 427 (46.9%) patients used aspirin, 37 (4.1%) patients used clopidogrel, 51 (5.6%) patients were treated with NOACs. non radiofrequency ablation, Hua Falin baseline was 33.8%, aspirin was 56.4%, clopidogrel was 4.8%, and NOACs was 1%.CHA2DS2-VASc > 2. The proportion of Chinese farIn was 39.7%, asin. Aspirin 55%, clopidogrel 5.7%, NOACs 1.0%.14.1% non valvular AF patients were followed up with Hua Falin, followed up by 15.5% of the Chinese Farlin, and 31.1% in the non radiofrequency ablation patient's long-term law of Hua Falin, while the proportion of Hua Falin in the radiofrequency ablation patients was all the death of non valvular AF patients during the 10.0%. follow-up period. Death, death of cardiovascular causes, the annual incidence of major adverse cardiac events (Major Adverse Cardiac Event, MACE) were 2.76%, 1.48% and 5.2%. (HR 1.064,95%CI 1.034 ~ 1.094, P=0.0001), heart failure history (HR 2.094, 95% CI 1.15 to 3.812, P= 0.016), dilated myocardial history (2.38 ~ 19.42,), slow The history of sexual lung disease (HR 1.955,95%CI 1.10 ~ 3.474, P=0.022), anemia (HR 3.085,95%CI 1.707 ~ 5.574, P=0.0001), diabetes (HR 1.727,95%CI 1.043 ~ 2.858, P=0.034) were independent risk factors for all causes of non valvular AF patients. Age (HR 1.06, 95%CI 1.019 to 1.102, 1.273 ~ 6.217. 0.011), DM (HR 2.018,95%CI 1.081 ~ 4.111, P=0.029), dilated myocardial history (HR 5.142,95%CI 1.126 ~ 23.485, P=0.035), anemia (HR 4.434,95%CI 2.059 to 9.55, P=0.0001) is an independent risk factor for the death of non valvular AF patients with cardiovascular causes. 1.36 to 3.419, P=0.001), the history of dilated cardiomyopathy (HR 3.382,95%CI 1.348 ~ 8.488, P=0.009), thromboembolism history (HR 1.726,95%CI 1.142 ~ 2.609, P=0.01), anemia (HR 2.04,95%CI 1.236 to 3.367, P=0.005), chronic lung disease history (HR 1.808,95%CI 1.146 to 2.85,) is an independent risk factor for non valvular disease patients. Conclusion 1. The common coexisting diseases of non valvular AF patients, including hypertension, diabetes, coronary heart disease, heart failure and other.2. non valvular AF patients, were significantly higher than anti arrhythmic drugs in this registered study, and about 1/3 in AF patients were selected for the use of radiofrequency ablation for the baseline warfarin ratio of.3. non valvular AF patients. For 45.4%, the proportion of baseline Hua Falin used for non ablation patients was 33.8%, of which the CHA2DS2-VASc score was more than 2 in patients with baseline Hua Falin anticoagulant ratio 39.7%.4. non ablative non valvular AF patients with long-term regular medication ratio of 31.1%, while Hua Falin regular medication in radiofrequency ablation patients was a total cause of death in AF patients with 10.0%.5. non valvular disease. The incidence was 2.76%, the annual incidence of cardiovascular death was 1.48%, the incidence of MACE years was 5.2%. age, heart failure history, anemia, and chronic lung disease history and other factors related to the prognosis of non valvular AF patients. The second part influenced the analysis of the use of warfarin factors in the high-risk group of AF patients with non valvular disease: analysis of the influence of non valvular AF stroke. High risk people (CHA2DS2-VASc > 2) enabled Hua Falin and insisting on Hua Falin's treatment. Methods: the non valvular AF patients registered in Peking Union Medical College Hospital from August 2011 to December 2015 were included in the CHA2DS2-VASc score of more than 2. The patients were excluded from the radiofrequency ablation group. The patients were divided into the Hua Falin group receiving Hua Falin treatment and unaccepted. In the control group treated by Hua Falin, the basic situation of two groups of patients was compared with the single factor analysis method. The factors affecting the use of Hua Falin were analyzed by multiple factor Logistic regression analysis. The Kaplan-Meier curve was used to describe the situation of anticoagulant drug use in Hua Falin group, and the factors affecting the anticoagulant medication in Hua Falin group were analyzed by Cox regression. Results: 611 In the patients with non catheter ablation, 481 cases with CHA2DS2-VASc score of more than 2 were followed up for 38.9 + 13.8 months. The warfarin group had 252 cases (52.4%), thromboembolism (OR 2.543, 95%CI 1.525 ~ 4.241, P=0.0001), heart failure (OR 1.93,95%CI 1.064 ~ 3.501, P=0.03), persistent atrial fibrillation (OR 2.236,95%CI 1.448 ~ 3.366, P=0.0001). The patients took more Hua Falin, while taking Chinese medicine (OR 0.628,95%CI 0.413 ~ 0.954, P=0.029), coronary heart disease (OR 0.601,95%CI 0.37 ~ 0.974, P=0.039) and the distance from the hospital (OR 0.689,95%CI 0.584 ~ 0.897, P=0.003) Hua Falin use rate was low. In the Hua Falin group, 167 cases (66.3%) persisted in taking the Hua Falin.Kaplan-Meier curve. Of all the patients in the 1 year, the rate of taking medicine was 81.3%, and the three year of 67.0%. persisted in Hua Falin patients. 69 cases (73.4%, 69/94 cases) had been taken before the entry group, 98 cases (62%, 98/158 cases) were newly opened, the former was significantly higher than the latter (P=0.008). The factors related to the discontinuation of Hua Falin were new Hua Falin (H R 1.786,95%CI 1.029 ~ 3.1, P=0.039), taking traditional Chinese medicine (HR 1.687,95%CI 1.201 ~ 2.37, P=0.003), the distance between the patients and the hospital was far away (HR 1.446,95%CI 1.121 ~ 1.865, P=0.005). Conclusion: the independent predictors of 1. warfarin mainly include heart failure, coronary heart disease, thromboembolism, distance to the hospital, and so on. The distance to the long term hospitalized hospital was significantly negatively correlated with Hua Falin's use, and a significant positive correlation with Hua Falin's drug withdrawal rate. The drug rate of Hua Falin in Hua Falin's AF patients was significantly lower than that of the previous Hua Falin patients with.3., which was significantly lower in the use rate of Hua Falin, and was significantly related to the withdrawal rate of Hua Falin. Third part of the non valvular disease was A. Study on the quality of anticoagulant therapy (TTR) and influencing factors of Hua Falin in F patients: TTR is a common method for assessing the quality of anticoagulation in Hua Falin. This study explored the TTR level and its influencing factors in the long-term anticoagulation of non valvular AF patients. Methods: the non valvular AF patients registered in Peking Union Medical College Hospital from August 2011 to December 2015 were included. The Rosendaal method was used to evaluate the TTR level of the patients in the middle and long term. The single factor and multiple regression method were used to analyze the influence of the TTR factors. Results: 118 patients were eligible for the entry group. The average age of the patients was (70.3 + 8.7 years), and the male patients were 62 (52.5%). A total of 2915 of the results were recorded during the visit period, and the average INR monitor of the patients was recorded. The measured times were 24.7 + 12.6 times, the average monitoring time interval was 45.7 + 15.3 days (range 13.8-84.5). The average TTR of the patients was 55.5 + 19.3% (0% to 99%). Lower than TTR (INR2) was 39 + 20.1% (0% ~ 93.8%), higher than TTR range (INR3) ratio 4.69 + 8.60%. The multiple factor analysis found that hypertension and heart failure were TTR level Independent influence factors (P0.05). Conclusion: long term oral warfarin TTR of non valvular patients with AF is 55.5 + 19.3%, and hypertension and heart failure are independent factors of TTR level.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R541.75

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