1、 博士学位论文 具有多重动脉硬化危险因素的住院 患者中外周动脉疾病远期随访研究 姓 名：李宪凯 学 号：0710110020 所在院系：医学院 学科门类：医学 学科专业：内科学 指导教师：胡大一 教授 副指导教师：李 觉 教授 徐亚伟 教授 二一年五月 A dissertation submitted to Tongji University in conformity with the requirements for the degree of Doctor of Medicine May, 2010Candidate: Xiankai Li Student Number: 0710110
2、020 School/Department: Medical School Discipline: Medicine Major: Medicine Supervisor: Professor Dayi Hu Professor Jue Li Professor Yawei Xu The Long Time Follow-up of Peripheral Arterial Disease in Inpatients with at least Two Atherosclerotic Risk Factors 具有多重动脉硬化危险因素的住院患者中外周动脉疾病远期随访研究李宪凯同济大学学位论文版权
3、使用授权书 本人完全了解同济大学关于收集、保 存、使用学位论文的规定，同意如下各项内容：按照学校要求提交学位论 文的印刷本和电子版本；学校有权保存学位论文的印刷本和电子版，并采用影印、缩印、扫描、数字化或其它手段保存论文；学校有权提供目录检索以及提供本学位论文全文或者部分的阅览服务； 学校有权按有关规定向国家有关部门或者机构送交论文的复印件和电子版； 在不以赢利为目的的前提下，学校可以适当复制论文的部分 或全部内容用于学术活动。 学位论文作者签名： 年 月 日 同济大学学位论文原创性声明 本人郑重声明：所呈交的学位论文，是本人在导师指导下，进行研究工作所取得的成果。除文中已经注明引用的内容外，
4、本学位论文的研究成果不包含任何他人创作的、 已公开发表或者没有公开发表的作品的内容。对本论文所涉及的研究工作做出 贡献的其他个人和集体，均已在文中以明确方式标明。本学位论文原创性声明的法律责任由本人承担。 学位论文作者签名： 年 月 日同济大学 博士学位论文 摘要 I摘要 目的 : 外周动脉疾病 (Peripheral Arterial Disease， PAD)是动脉硬化性疾病的表现形式之一，国外的研究发现 PAD 患者的心血管事件发生率很高，国内在此方面的研究相对较少； 该研究旨在对具有多重动脉硬化危险因素的住院患者进行 PAD的临床流行病学研究，探讨该人群中 PAD 的基线情况，并进行随
5、访，研究三年随访时 PAD 与终点事件的关系，动脉硬化危险因素和 PAD 之间的关系等。 方法 : 自 2004 年 7 月至 2005 年 1 月，在上海和北京地区多家医院连续入选年龄35 岁，具有两个及两个以上动脉硬化危险因素 (糖尿病、高血压、吸烟和高脂血症 )的住院患者为研究对象，对所有患者进行踝臂指数 (Ankle Brachial Index, ABI)测量和包括危险因素、疾病史和治疗等情况的问卷调查，获得基线情况，并根据ACC/AHA PAD 指南，将 ABI0.9 定义为 PAD；自 2007 年 12 月至 2008 年 2 月对研究对象进行第三年随访，随访终点为研究对象死亡
6、或随访结束，主要终点事件为死亡，次要终点事件为再住院、新发疾病和药物治疗情况。 结果 : 在基线时 : 研究对象共 3732 例， (一 ) 一般情况：年龄为 6611 岁 (35-95岁 )，男性 1979 例 (53%)，女性 1753 例 (47%)，其中糖尿病患者占 39%，高血压为 73%，血脂紊乱约 43%，吸烟者为 39.1%； (二 ) PAD 患病情况：该研究对象中 PAD 的患病率为 25.8%，且随着年龄的增长而逐渐升高，绝大部分 PAD 患者发病年龄高于 60 岁。 PAD 组 ABI 显著低于非 PAD 组 (0.68 0.20 vs 1.09 0.00)，而年龄显著
7、高于非 PAD 组 (71.7 9.5 vs 65.2 11.1 岁 ) (P 均 0.001)，且 PAD 组的女性患者比例明显高于男性患者 (27.8 % vs 24%， P=0.005)； (三 ) PAD 和非 PAD组的比较：就动脉硬化危险因素而言， PAD 组合并糖尿病 (49.3% vs 35.5%)，高血压 (79.8% vs 70.4%)，血脂紊乱 (46.2% vs 41.6%)和吸烟 (42.2% vs 37.9%)的比例显著高于非 PAD 组 (P 均 0.05)；从既往病史看， PAD 组在冠心病史 (61.2% vs 52.3%)，心肌梗死 (21.1% vs 12
8、.8%)和心绞痛病史 (57.3% vs 49.9%)，缺血性脑卒中 (45.4% vs 28.2%)和间歇性跛行 (19.8% vs 5.8%)病史的比例显著高于非 PAD 组(P 均 0.001)。 (四 ) ABI 和危险因素：将 ABI 分为 0.4(严重外周动脉疾病 )，0.41-0.90(轻至中度外周动脉疾病 )， 0.91-0.99(临界值 )和 1.00-1.40(正常值 )四组，发现糖尿病 (59.8% vs 48.1% vs 39.4% vs 34.6%)和高血压的患病比例 (86.6% vs 79.0% vs 71.6% vs 70.2%)随着 ABI 的升高而逐渐降低；
9、校正相关因素后，与非PAD 组 (ABI=0.91-1.40)相比， ABI0.4 发生冠心病的 RR=1.728 (95% CI: 同济大学 博士学位论文 摘要 II1.015-2.941)， ABI=0.41-0.50 组的 RR=2.065(95% CI: 1.182-3.608)，随着 ABI 的升高发生冠心病的相对危险度有波动下降趋势。 三年随访结果 : 共随访 37.61.5 个月，共获得具有完整基线和完整随访资料的研究对象 3210 例。 (一 ) 一般情况 : 平均年龄为 70 岁，男性 1712 例 (53.3%)，女性 1498 例 (46.7%)；共有 503 例发生死亡
10、，男性 298 例 (59.2%)，女性 205 例(40.8%)； (二 ) 终点事件 : 主要终点事件 整个研究对象的三年累积全因死亡率为 15.7%，其中死亡原因为冠心病者有 163 例 (32.4%)，缺血性脑卒中为 33 例(6.6%)，出血性脑卒中为 35 例 (7.0%)，其他心血管疾病为 55 例 (10.9%)，其他疾病为 217 例 (43.1%)；其中，死亡病因为心血管疾病的有 286 例，故三年累积心血管疾病死亡率为 8.9%。 次要终点事件 再住院情况 : 有 46.4%的研究对象因疾病而再次住院，其中最主要的住院原因为冠心病，约占 21.4%；新发疾病情况 : 有高
11、达 24%的研究对象新发生疾病，新发冠心病比例最高，为 5.1%；药物使用情况 : 有高达 57.6%的研究对象正在使用降压药物，其中最主要的药物为 CCB 和 ACEI 类药物；有 26.2%的研究对象正在使用降糖药物，其中最主要的药物是双胍类和胰岛素；但是降脂类药物使用比例仅为 20.7%，在降脂类药物中有超过 91%的使用他汀类药物；阿司匹林的使用率仅为 45.8%。 (三 ) PAD 组与非 PAD 组与主要终点事件的关系 : PAD 组三年累积全因死亡率 (25.6% vs 12.3%)和心血管疾病死亡率 (15.6% vs 6.6%)显著高于非 PAD 组 (P 均 0.001)；
12、Kaplan-Meier 分析显示非 PAD 组的生存情况明显优于 PAD 组； Cox 回归校正相关因素后， PAD 组三年死亡风险是非 PAD 组的 1.66 倍 (95% CI: 1.33-2.08)，三年心血管疾病死亡风险是非 PAD 组的 2.10 倍 (95% CI: 1.58-2.79)； PAD 组三年再住院比例显著高于非 PAD 组 (60.4% vs 51.3%)，因糖尿病再住院比例明显高于非PAD 组 (27.3% vs 18.2%)(P 均 0.01)。 (四 ) 症状性 PAD 和主要终点事件关系 : 无论三年累积全因死亡率还是三年累积心血管疾病死亡率，症状性 PAD
13、 组高于无症状性 PAD 组和非 PAD 组 (分别为 27.2% vs 25.1% vs 12.3%和 17.7% vs 15.1% vs 6.6%， P 均 0.001)； Cox 回归校正相关因素后，症状性 PAD 组三年死亡风险和心血管疾病死亡风险分别是非 PAD 组的 1.834 倍 (95%CI: 1.225-2.746)和 2.243 倍 (95%CI: 1.363-3.691)，无症状性 PAD 组为非 PAD 组的 1.650 倍 (95%CI: 1.303-2.088)和 2.100 倍 (95%CI: 1.561-2.824)。 (五 ) 不同 ABI 值和主要终点事件关
14、系 : 将 ABI 分为 0.4， 0.41-0.90， 0.91-0.99 和 1.00-1.40 四组， Kaplan-Meier 分析显示随着 ABI 的降低， 生存情况逐渐恶化； Cox 回归校正相关因素后， ABI0.4组发生三年死亡风险和心血管疾病死亡风险分别是 ABI=1.0-1.40 组的 3.105 倍(95% CI: 1.936-4.979)和 4.794 倍 (95% CI: 2.740-8.388)， ABI=0.41-0.90 组是ABI=1.0-1.40组的 1.534倍 (95% CI: 1.199-1.962)和 2.031倍 (95% CI: 1.479-2.
15、789)；同济大学 博士学位论文 摘要 III进一步分析显示随着 ABI 的降低， 死亡风险呈波动上升趋势。 若进一步细分 ABI发现， ABI0.4 组三年死亡风险和心血管疾病死亡风险分别是非 PAD 组(ABI=0.91-1.40)的 3.239倍 (95% CI: 2.034-5.157)和 4.756倍 (95% CI: 2.753-8.219)；ABI=0.41-0.50 组分别是非 PAD 组的 2.428 倍 (95% CI: 1.422-4.416)和 3.005 倍(95% CI: 1.550-5.825)。 (六 ) PAD 合并糖尿病与主要终点事件关系 : 将研究对象分为
16、糖尿病合并 PAD 组、糖尿病合并非 PAD 组、非糖尿病合并 PAD 组、和非糖尿病且非 PAD 组，糖尿病合并 PAD 组三年累积全因死亡率最高为 25.9%，糖尿病合并非 PAD 组三年累积全因死亡率最低为 11.9%；非糖尿病合并 PAD 组三年累积心血管疾病死亡率最高为 15.8%，而糖尿病合并非 PAD 组的三年累积心血管疾病死亡率最低为 5.6%(P 均 0.001)； Cox 回归校正相关因素后，糖尿病合并PAD 组的三年发生死亡风险和心血管疾病死亡风险分别是非糖尿病且非 PAD 组的 1.729 倍 (95% CI: 1.262-2.369)和 2.073 倍 (95% CI
17、: 1.403-3.063)。 (七 ) PAD 合并高血压与主要终点事件关系 : 将研究对象分为高血压合并 PAD 组、高血压合并非 PAD 组、非高血压合并 PAD 组、和非高血压且非 PAD 组，高血压合并 PAD组三年累积全因死亡率和心血管疾病死亡率最高，分别为 26.3%和 16.5%，高血压合并非 PAD 组最低，分别为 12.0%和 6.3%，且差异有显著统计学意义 (P 均0.001)； Cox 回归校正相关因素后，高血压合并 PAD 组的三年发生死亡风险和心血管死亡风险分别是非高血压且非 PAD 组的 1.533 倍 (95% CI: 1.105-2.127)和1.926 倍
18、 (95% CI: 1.266-2.931)。 (八 ) PAD 合并吸烟与主要终点事件关系 : 将研究对象分为吸烟合并 PAD 组、吸烟合并非 PAD 组、非吸烟合并 PAD 组、和非吸烟且非 PAD 组， 吸烟合并 PAD 组三年累积全因死亡率和心血管疾病死亡率最高，分别为 27.3%和 16.5%，非吸烟且非 PAD 组最低，分别为 11.1%和 5.6%，且差异有显著统计学意义 (P均 0.001)； Cox回归校正相关因素后， 男性吸烟合并 PAD组的三年发生死亡风险和心血管疾病死亡风险分别是男性非吸烟且非 PAD 组的1.673 倍 (95% CI: 1.142-2.449)和 2
19、.107 倍 (95% CI: 1.285-3.456)； (九 ) 男性 PAD 与主要终点事件关系：将研究对象分为男性 PAD 组、男性非 PAD 组、女性 PAD组、和女性非 PAD 组，男性 PAD 患者的三年累积全因死亡率和心血管疾病死亡率最高，为 27.4%和 16.9%；女性非 PAD 组的三年累积全因死亡率和心血管疾病死亡率最低，分别为 10%和 5.1% (P 均 0.001)。 Cox 回归校正相关因素后，男性 PAD 组的三年发生死亡的风险是女性非 PAD 组的 2.091 倍 (95% CI: 1.446-3.024)， 三年发生心血管疾病死亡风险是女性非 PAD 组的
20、 2.831 倍 (95% CI: 1.745-4.593)。 结论 : 本研究对具有多重动脉硬化危险因素的住院患者的 PAD 基线和随访研究同济大学 博士学位论文 摘要 IV中发现 : PAD 的患病率较高， PAD 组合并动脉硬化危险因素，及冠心病、心肌梗死和脑卒中等病史的比例较高，随着 ABI 的降低冠心病发病风险升高；随访发现研究对象三年累积全因死亡率高达 15.7%，三年累积心血管疾病死亡率为8.9%；研究对象中再次住院患者比例和新发疾病比例均较高； PAD 组三年累积全因死亡率和心血管疾病死亡率， 以及三年死亡风险显著高于非 PAD 组； PAD组三年再住院比例显著高于非 PAD
21、组，尤其是因糖尿病再住院比例； ABI 水平越低，死亡风险越高，随着 ABI 的降低，死亡风险波动上升， ABI 是早期诊断 PAD 的方法，是三年累积全因死亡率和心血管事件的强有力的预测因子；症状性 PAD 患者无论三年全因死亡率还是心血管疾病死亡率均高于无症状性PAD，两者均高于非 PAD 组，即使无症状性 PAD 其死亡风险也高于非 PAD 组，采用 ABI 早期诊断无症状性 PAD 患者，可早期干预避免不良事件； PAD 合并糖尿病或高血压的患者，其三年死亡率显著高于单纯 PAD 患者，这些危险因素增加了 PAD 的死亡风险；无论吸烟与否， PAD 患者的死亡风险显著高于非吸烟且非 P
22、AD 者； PAD 的死亡风险有性别差异。 关键词 ：外周动脉疾病，动脉硬化，危险因素，住院患者，随访，全因死亡率，心血管疾病死亡率 Tongji University Doctor of Medicine Abstract VABSTRACT Objective: As a kind of atherosclerosis, peripheral arterial disease (PAD) associated with a high frequence of cardiovascular events. However, most of the epidemiology data were
23、 from foreign study, there were only few researches in China. This research focused on inpatients with at least two atherosclerotic risk factors, aimed to collect PAD baseline data and follow up data, and to evaluate the relationships between PAD and endpoints and the relationships between risk fact
24、ors and endpoints. Methods: Inpatients, with at least two atherosclerotic risk factors (DM, hypertension, smoking and hyperlipidemia) and aged over 35, were consecutively enrolled from hospitals in Shanghai and Beijing between July 2004 and Jan 2005. Ankle Brachial Index (ABI) was measured in each p
25、articipant. A questionnaire including risk factors, disease history, and treatments was collected to get the baseline. Inpatients with ABI 0.9 was diagnosed as PAD according to ACC/AHA PAD guideline. The participants were followed up till the participants died or the follow-up ended between Dec 2007
26、 and Feb 2008. Death is the primary endpoint, and re-admission, new disease and medicine treatment is the secondary endpoint. Results: BASELINE: A total of 3720 inpatients, General information: Aged 6611 (35-95 yrs) were enrolled including 1979 male (53%) and 1753 (47%) female. There were 39% inpati
27、ents with DM, 73% with hypertension, 43% with dyslipidemia and 39.1% inpatients smoking. PAD and prevalence: The prevalence of PAD in those inpatients was 25.8%, and increased with age. Most of the PAD patients aged over 60. Compared with non-PAD group, the PAD group had a statistically significant
28、lower ABI (0.68 0.20 vs 1.09 0.00), and older (71.7 9.5 vs 65.2 11.1 yrs) (All P0.001 ). There was more female patients than male patients in PAD group (27.8 % vs 24%， P=0.005). Comparison between PAD and non-PAD: As to the atherosclerotic risk factors, PAD group had a higher comorbidity DM (49.3% v
29、s 35.5%), hypertension (79.8% vs 70.4%), dyslipidemia (46.2% vs 41.6%) and current smoking (42.2% vs 37.9%) (All P 0.05 ), compared with non-PAD group. As to the disease history, the PAD group had a higher history of coronary heart disease (CHD) (61.2% vs 52.3%), myocardial infarction (21.1% vs 12.8
30、%), angina (57.3% vs 49.9%), ischemic stroke (45.4% vs 28.2%) and intermittent claudication (19.8% vs 5.8%) Tongji University Doctor of Medicine Abstract VIcompared with non-PAD group (All P 0.001 ). ABI and risk factors: ABI was divided into four groups, ABI 0.4, 0.41-0.90, 0.91-0.99 and 1.00-1.40.
31、 There was a positive correlation between DM (59.8% vs 48.1% vs 39.4% vs 34.6%), hypertension (86.6% vs 79.0% vs 71.6% vs 70.2%) and ABI, the higher ABI, the lower DM and hypertension. After adjusting for other factors, ABI 0.4 was 1.728 times and ABI=0.41-0.50 was 2.065 times as likely to have CHD
32、as ABI=0.91-1.4. THREE YEAR FOLLOWUP: After a 37.61.5 months followup, a total of 3210 participants with complete baseline and followup data was used in the database. General information: The participants has a mean age of 70 yrs, including 1712 male (53.3%) and 1498 female (46.7%) participants; Dea
33、th occurred in 503 participants, in whom 298 male (59.2%) and 205 female (40.8%) patients died. Endpoints: Primary Endpointthe 3-year all cause mortality was 15.7%, with 163 (32.4%) participants died from CHD, 33 (6.6%) from ischemic stroke, 35 (7.0%) from hemorrhagic stroke, and 55 (10.9%) from oth
34、er cardiovascular diseases, and 217 (43.1%) from other diseases. There were 286 participants died from cardiovascular disease, the 3-year cardiovascular mortality was 8.9%. Secondary EndpointA. Re-admission: 46.4% of the participants readmitted, and the most frequency reason was CHD (21.4%); B. New
35、Disease: 24% of the participants suffered new disease, especially CHD; C. Medicine Treatment: 57.6% of the participants were using anti-hypertension medicine, especially CCB and ACEI; 26.2% of the participants were using hypoglucose medicine, especially dimethyldiguanide and insulin; although only 2
36、0.7% of the participants used lipid-lower medicine, more than 90% used statins; only 45.8% of the participants used aspirin. PAD group, non-PAD group and primary endpoint: The 3-year all cause mortality (25.6% vs 12.3%) and cardiovascular mortality (15.6% vs 6.6%) were statistically significantly hi
37、gher in PAD group than in non-PAD group (All P 0.001); After adjusting for other factors with Cox model, PAD patients was 1.66 times (95% CI: 1.33-2.08) as likely to die and more than twice (95% CI: 1.58-2.79) as likely to die from cardiovascular disease as non-PAD patients. The re-admission rates w
38、ere significantly higher in PAD group than in non-PAD group (60.4% vs 51.3%), especially for DM (27.3% vs 18.2%) (P0.01). Symptomatic PAD and primary endpoint: No matter 3-year all cause mortality or cardiovascular mortality, the symptomatic PAD patients were highest, and asymptomatic PAD patients w
39、ere higher than non-PAD patients (27.2% vs 25.1% vs 12.3% and 17.7% vs 15.1% vs 6.6%, P 0.001 ). After adjusting for other factors Tongji University Doctor of Medicine Abstract VIIwith Cox model, symptomatic PAD patients were 1.834 times (95%CI: 1.225-2.746) as likely to die or 2.243 times (95%CI: 1
40、.363-3.691) as likely to die from cardiovascular disease as non-PAD patients; asymptomatic PAD patients were 1.650 times (95%CI: 1.303-2.088) as likely to die or 2.100 times (95%CI: 1.561-2.824) as likely to die from cardiovascular disease as non-PAD patients. ABI and primary endpoint: ABI was divid
41、ed into 0.4, 0.41-0.90, 0.91-0.99 and 1.00-1.40, Kaplan-Meier analysis showed the survival was aggravated as ABI decreased; The ABI 0.4 group was 3.105 times (95% CI: 1.936-4.979) as likely to die or 4.794 times (95% CI: 2.740-8.388) to die from cardiovascular disease as ABI=1.0-1.40 group. The ABI=
42、0.41-0.90 group was 1.534 times (95% CI: 1.199-1.962) as likely to die or 2.031 times (95% CI: 1.479-2.789) as likely to die from cardiovascular disease as ABI=1.0-1.40 group. With further analysis, the ABI 0.4 group was 3.239 times (95% CI: 2.034-5.157) as likely to die or 4.756 times (95% CI: 2.75
43、3-8.219) to die from cardiovascular disease as non-PAD group (ABI=0.91-1.40); While ABI=0.41-0.50 group were 2.428 (95% CI: 1.422-4.416) and 3.005 (95% CI: 1.550-5.825), respectively. PAD with DM and primary endpoint: All participants were divided into DM with PAD, DM with non-PAD, non-DM with PAD,
44、and non-DM with non-PAD groups, the DM with PAD patients had a highest 3-year all cause mortality (25.9%), while DM with non-PAD group was lowest (11.9%). The non-DM with PAD group had a highest cardiovascular mortality (15.8%), while DM with non-PAD patients had lowest 3-year all cause mortality an
45、d cardiovascular mortality (5.6%) (All P 0.001). After adjusting for other factors with Cox model, the DM with PAD group was 1.729 times (95% CI: 1.262-2.369) as likely to die or 2.073 times (95% CI: 1.403-3.063) as likely to die from cardiovascular disease as non-DM with non-PAD group. PAD with hyp
46、ertension and primary endpoint: All participants were divided into hypertension with PAD, hypertension with non-PAD, non-hypertension with PAD, and non-hypertension with non-PAD groups, the hypertension with PAD patients had a highest 3-year all cause mortality and cardiovascular mortality (26.3% an
47、d 16.5%, respectively), while hypertension with non-PAD patients had lowest 3-year all cause mortality and cardiovascular mortality (12.0% and 6.3%, respectively) (All P 0.001). After adjusting for other factors with Cox model, the hypertension with PAD group was 1.533 times (95% CI: 1.105-2.127) as
48、 likely to die or 1.926 times (95% CI: 1.266-2.931) as likely to die from cardiovascular disease as non-PAD and non-hypertension group. PAD with smoking and primary endpoint: All participants Tongji University Doctor of Medicine Abstract VIIIwere divided into smoking with PAD, smoking with non-PAD,
49、non-smoking with PAD, and non-smoking with non-PAD groups, the smoking with PAD patients had a highest 3-year all cause mortality and cardiovascular mortality (27.3% and 16.5%, respectively), while non-smoking and non-PAD patients had lowest 3-year all cause mortality and cardiovascular mortality (11.1% and 5.6%, respectively) (All P 0.001). After adjusting for other factors with Cox model, the smoking with PAD group (male) was 1.673 times (95% CI: 1.142-2.449) as li
