非瓣膜病房颤患者抗凝质量研究

发布时间：2018-05-31 02:13

本文选题：心房颤动 + 抗凝治疗　；参考：《北京协和医学院》2016年博士论文

【摘要】：研究背景心房颤动(Atrial fibrillation, AF)简称房颤,是临床最常见的心律失常之一,其最严重的后果是因脑血管事件而致残致死,影响患者的生活质量。AF在总体人群中的患病率为0.4～1.0%[1,2],其发病率随年龄增加呈逐渐增加趋势[3-5]。ATRIA研究提示,2000年美国有230万例AF患者,预计到2050年将达560万例[1],到2060年欧洲55岁以上的AF患者数量将达到1790万[6]。2004年中国流行病学调查发现：我国14个省和直辖市自然人群中30～85岁人群中AF总患病率为0.77%,标准化后的患病率为0.61%,男性患病率约为0.9%,女性为0.7%,其中非瓣膜病AF的比例为65.2%[7]。近几年,随着AF发病率,伴发疾病以及治疗措施的变化,缺乏对目前我国AF患者大规模研究,本研究为单中心前瞻性注册研究,可以反映真实世界非瓣膜病AF疾病特点和治疗方式以及预后情况。根据Framingham研究结果显示,非瓣膜病AF脑卒中发生率是正常人5.6倍,占全部脑卒中事件的15%～20%,AF抗栓治疗是其治疗的核心[3,4,8]。口服华法林抗凝治疗是预防AF患者发生卒中最为有效的手段,循证医学证据表明,华法林治疗可使AF血栓栓塞的风险降低62.0%[9],而出血并发症无显著增加。然而,目前我国抗凝状况不容乐观,既往研究显示我国抗凝率仅为2%左右,近几年随着指南的推荐和认识程度的提高,AF抗凝率较既往有所增加,但目前缺少大规模流行病学证据。既往有大量国外研究报道了华法林使用率低的原因[10-13],但影响我国非瓣膜病AF患者华法林使用的因素有待于深入探讨。除了提高华法林使用率,华法林的抗凝质量也是影响其预后的重要因素,TTR (Time in therapy range)为华法林抗凝质量常用的评价指标,既往研究发现TTR65%患者才可明显获益,主要心血管事件的发生风险降低2倍[14],我国目前尚无相关报道。本文通过单中心前瞻性注册研究并进行长期随访分别对以上三部分进行探讨：1)描述非瓣膜病AF患者的人口学资料、伴发疾病、抗凝以及预后情况；2)分析非瓣膜病AF患者卒中高危人群服用华法林影响因素； 3)探讨非瓣膜病AF患者华法林抗凝质量(TTR)及其影响因素。第一部分非瓣膜病AF患者抗凝情况和预后分析(单中心注册研究)目的：通过单中心前瞻性注册研究以及长期随访,探讨目前非瓣膜病AF患者抗凝及预后情况。方法：入选2011年8月至2015年12月北京协和医院就诊的非瓣膜病AF患者。对入选患者以病例登记表形式收集患者基线的人口学资料、伴发疾病及心血管危险因素,相关治疗情况。所有患者每6个月进行随访,记录患者随访期间相关治疗情况和相关临床事件。结果：注册的911例患者中,平均年龄为66.3±11.3岁,男性526例(57.7%)。常见的伴发疾病为高血压(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%)患者基线服用抗心律失常药物,558例患者(61.3%)使用控制心室率药物。227例(24.9%)患者基线接受射频消融治疗,其中阵发AF患者射频消融比例最高为35.7%。患者基线抗凝治疗情况为414例(45.4%)患者使用华法林,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。非射频消融患者中,华法林基线使用比例为33.8%,阿司匹林为56.4%,氯吡格雷为4.8%,NOACs为1%。CHA2DS2-VASc≥2分非消融患者中华法林使用比例为39.7%,阿司匹林为55%,氯吡格雷为5.7%,NOACs为1.0%。14.1%非瓣膜病AF患者在随访中开始使用华法林,随访中华法林停药比例为15.5%,非射频消融患者华法林长期规律服药比例为31.1%,而射频消融患者华法林服药比例为10.0%。随访期间非瓣膜病AF患者全因死亡,心血管原因死亡,主要不良心脏事件(Major Adverse Cardiac Event, MACE)事件年发生率分别为2.76%,1.48%和5.2%。年龄(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),扩张性心肌病史(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),贫血(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患者全因死亡的独立危险因素。年龄(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),扩张性心肌病史(HR 5.142,95%CI 1.126～23.485, P=0.035),贫血(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独立危险因素。年龄(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),扩张性心肌病史(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),贫血(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的独立危险因素。结论：1.本注册研究中非瓣膜病AF患者常见并存疾病包括高血压、糖尿病、冠心病、心力衰竭等。2.非瓣膜病AF患者选择室率控制治疗方案比例显著高于抗心律失常药物,约1/3阵发AF患者选择行射频消融治疗。3.非瓣膜病AF患者基线华法林使用比例为45.4%,非消融患者基线华法林使用比例为33.8%,其中CHA2DS2-VASc评分≥2分患者基线华法林抗凝比例39.7%。4.非消融非瓣膜病AF患者华法林长期规律服药比例为31.1%,而射频消融患者华法林规律服药比例为10.0%。5.非瓣膜病AF患者全因死亡年发生率为2.76%,因心血管死亡年发生率为1.48%, MACE年发生率为5.2%。年龄,心力衰竭史,贫血,慢性肺疾病史等因素与非瓣膜病AF患者预后相关。第二部分影响非瓣膜病AF患者卒中高危人群服用华法林因素分析目的：分析影响非瓣膜病AF卒中高危人群(CHA2DS2-VASc≥2分)启用华法林和坚持服用华法林治疗的因素。方法：纳入2011年8月至2015年12月北京协和医院登记注册的非瓣膜病AF患者,且CHA2DS2-VASc评分≥2分。除外射频消融患者。患者分为接受华法林治疗的华法林组和未接受华法林治疗的对照组。采用单因素分析方法比较两组患者基本情况,采用多因素Logistic回归分析影响华法林使用的因素。用Kaplan-Meier曲线描述华法林组坚持抗凝用药情况,并采用Cox回归分析华法林组坚持抗凝用药的影响因素。结果：611例非导管消融患者中,符合CHA2DS2-VASc评分≥2分患者481例,随访时间为38.9±13.8个月。华法林组患者共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),持续性房颤(OR 2.236,95%CI 1.448～3.366,P=0.0001)患者更多服用华法林,而服用中药(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)以及与医院距离远者(OR 0.689,95%CI 0.584～0.897, P=0.003)华法林使用率较低。华法林组随访期间167例(66.3%)坚持服用华法林。Kaplan-Meier曲线中所有患者1年华法林坚持服药率为81.3%,三年为67.0%。坚持服用华法林患者中,入组前已服用华法林患者69例(73.4%,69/94例),新启用患者98例(62.0%,98/158例),前者总坚持服药率明显高于后者(P=0.008)。与华法林停用相关的因素为新启用华法林(HR 1.786,95%CI 1.029～3.1,P=0.039),服用中药(HR 1.687,95%CI 1.201～2.37,P=0.003),患者与就诊医院的距离较远(HR 1.446,95%CI 1.121～1.865, P=0.005)。结论：1.华法林使用的独立预测因素主要包括心衰,冠心病,血栓栓塞,长期就诊医院的距离等。其中患者居住地到长期就诊医院的距离与华法林使用显著负相关,与华法林停药率显著正相关。2. 新启用华法林的AF患者华法林坚持服药率明显低于既往服用华法林患者。3. 中药降低了华法林使用率,且与华法林停用率显著相关。第三部分非瓣膜病AF患者华法林抗凝治疗质量(TTR)及影响因素研究目的：TTR是评估华法林抗凝质量的常用方法,本研究探讨非瓣膜病AF患者华法林长期抗凝中TTR水平及其影响因素。方法：纳入2011年8月至2015年12月北京协和医院登记注册的非瓣膜病AF患者中长期服用华法林者,Rosendaal法评估患者的TTR水平。单因素和多元回归方法对影响TTR因素进行分析。结果：符合入组标准的患者共118例,患者平均年龄为(70.3±8.7岁),男性患者共62例(52.5%)。随访期内共记录INR检测结果2915个,患者平均INR监测次数为24.7±12.6次,平均监测的时间间隔是45.7±15.3天(范围为13.8-84.5)天。患者平均TTR为55.5±19.3%(0%～99.0%)。低于TTR比例(INR2)为39.0±20.1%(0%～93.8%),高于TTR范围为(INR3)比例4.69±8.60%(0%～60.52%)。多因素分析发现高血压和心力衰竭为TTR水平的独立影响因素(P0.05)。结论：非瓣膜病AF患者长期口服华法林TTR为55.5±19.3%,高血压和心力衰竭为TTR水平的独立影响因素。
[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.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R541.75

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