1、 解放军总医院解放军总医院 李小鹰教授李小鹰教授全面认识全面认识VTEVTEVTE VTE 是是可预防的严峻的公共卫生保健问题可预防的严峻的公共卫生保健问题1Cohen AT. Presented at the 5th Annual Congress of the European Federation of Internal Medicine; 2005.2Eurostat statistics on health and safety 2001. Available from: http:/epp.eurostat.cec.eu.int.VTEVTE所致死亡触目惊心所致死亡触目惊心VTEV
2、TE所导致的死亡例数所导致的死亡例数: 543,454: 543,4541 1 （20052005第第5 5欧盟内科年会）欧盟内科年会） VTEVTE所致死亡超过了以下原因所致死亡的总数所致死亡超过了以下原因所致死亡的总数: :AIDS AIDS 5,8605,8602 2乳腺癌乳腺癌 86,83186,8312 2前列腺癌前列腺癌 63,63663,6362 2交通事故交通事故 53,59953,5992 220062006年中国住院患者年中国住院患者PTEPTE死亡率达死亡率达9.74%9.74%内科患者内科患者VTEVTE：一个被低估的全球疾病负担：一个被低估的全球疾病负担1. Sand
3、ler DA et al. J R Soc Med 1989;82:203-5.2. Baglin TP et al. J Clin Pathol 1997;50:60910.3. Mismetti P et al. Thromb Haemost 2000;83:149.4. Anderson FA et al. J Vasc Surg 1992;19:557-8未经治疗时未经治疗时DVT 的危险性的危险性 0% 12% 22% 2833% 3050%内科内科脑卒中偏瘫脑卒中偏瘫 ICUAMI1. Leizorovicz and Mismetti. Circulation 2004;110(S
4、uppl IV):139. 2. Fraisse F,et al. Am J Respir Crit Care Med., 2000. 161: 1109-1114.3. Spyropoulos AC,et al. Chest 2005. 128: 958-969.4. Cohen AT, et al. Thromb Haemost 2005. 94: 750-759.1. Samama MM et al. N Engl J Med 1999;341:793800. 2. Leizorovicz A et al. Circulation 2004;110:87479.3. Cohen AT e
5、t al. BMJ 2005; in press.所有致死性所有致死性PE病例在死亡病例在死亡前得到诊断的不足一半前得到诊断的不足一半 11.Goldhaber SZ, et al. American Journal of Medicine 1982;73:822-826. 2. Lethen H, et al. American Journal of Cardiology 1997;80:1066-1069.3. Sandler DA, et al. J. Royal Soc. Med. 1989; 82:203-205.静脉血流缓慢静脉血流缓慢血管内皮受损血管内皮受损极高危极高危中中/高危
6、高危低低/中危中危高凝状态高凝状态中国中国PTEPTE发病并不少见发病并不少见全国全国PTE-DVT形成防治协作组报道的形成防治协作组报道的PTE病例数病例数（年）（年）VTE in Clinical Medical Elderly Patients (VTE-CMEP)0天天14-21天天90天天入选老年内科急症入选老年内科急症住院患者住院患者607例例首次随访首次随访CUS二次随访二次随访VTE事件，事件，CUS三次随访三次随访电话电话VTE事件事件VTE - CMEPVTE - CMEP 主要终点事件主要终点事件 90天内客观检查证实的天内客观检查证实的DVT； 90天内客观检查证实的致
7、死性或非致死性天内客观检查证实的致死性或非致死性PE； 客观检查证实的无症状的客观检查证实的无症状的DVT。 90天内全因死亡。天内全因死亡。 入选患者基础疾病情况入选患者基础疾病情况 % %VTE - CMEPVTE - CMEP 主要终点事件主要终点事件主要终点患病主要终点患病 率（）率（）9.7%01.534.567.59VTE事件事件7.3%2.1%DVTPEDVT+PE0.5%内科急症不同患者内科急症不同患者VTEVTE的发生率的发生率不同基础疾病VTE发生率 不同治疗措施患者不同治疗措施患者VTEVTE发生率发生率0246810121416MEDENOXPREVENTCMEPVTE
8、发病率（）发病率（）4.96%14.9%9.7%ARTEMIS10.5%内科高危患者接受内科高危患者接受VTEVTE预防不足预防不足VTE-CMEPVTE-CMEP研究预防研究预防VTEVTE治疗情况治疗情况 VTE-RAMPVTE-RAMP 研究研究 （VTERisk Assessment and Prophylaxis Treatment among Acute Medical Patients in ICU/CCU in China A cross-sectional Survey） ICU vs CCU 符合标准病人入组情况符合标准病人入组情况 ( ( N N = = 12471247
9、 ) )CCU(N =704)ICU(N =543)内科重症内科重症患者患者VTEVTE危险因素危险因素比例比例 评估的患者中，有评估的患者中，有99.0%的患者采用血栓预防治疗后受益的证据，其的患者采用血栓预防治疗后受益的证据，其中中57.8%患者有多重危险因素患者有多重危险因素危险因素个数* *ACCPACCP指南推荐的内科重症患者的预防方法包括：指南推荐的内科重症患者的预防方法包括：无药物预防禁忌患者使用普通肝素或低分子肝素无药物预防禁忌患者使用普通肝素或低分子肝素; ;有药物预防禁忌患者使用机械预防方法（弹力袜或充气加压装置）有药物预防禁忌患者使用机械预防方法（弹力袜或充气加压装置）E
10、NDORSE研究 -急症住院VTE危险患者流行病学国际评估研究ENDORSE - Epidemiologic InterNational Day for the EvaluatiOn of Patients at Risk of Venous Thrombosis in the Acute Hospital Care Setting外科患者外科患者(N =30,827)内科患者内科患者(N =37,356)主要研究目的42 % 存在存在VTE危险危险内科患者内科患者( n = 37,356 )次要研究目的40 % 接受了接受了 ACCP治疗推荐治疗推荐64 % 存在存在VTE危险危险59 %
11、接受了接受了ACCP推荐治疗推荐治疗外科患者外科患者( n = 30,827 )内科内科VTEVTE高危并接受推荐预防治疗的患者高危并接受推荐预防治疗的患者52 % 存在存在VTE危险危险50 % 接受了接受了ACCP推荐治疗推荐治疗总计总计( N= 68,183 ) 外科患者外科患者 内科患者内科患者8882665947髋髋/膝关节置换膝关节置换髋部骨折髋部骨折胃部疾病胃部疾病结肠疾病结肠疾病泌尿系统疾病泌尿系统疾病45414025急性呼吸系统疾病急性呼吸系统疾病急性心衰急性心衰肺部感染肺部感染缺血性卒中缺血性卒中0255075100 %0255075100 %Lacut K, et al.
12、 Neurology, 2005. 65: 865-869 内科内科VTEVTE药物预防疗效药物预防疗效 MEDENOX PREVENT PRINCE PRINCE-II ARTEMIS012345相对危险性相对危险性肝素较好肝素较好肝素较差肝素较差Belch 1981Dahan 1986Ibara-Perez 1988Bergmann 1996Gardlund 1996Fraisse 1998总总 PERR=0.480.34-0.68, P0.001 方差分析：方差分析：P=NS几项较大的研究结果显示，低分子肝素预防内科住院患者VTE显著优于安慰剂 研究病例数药物治疗VTE发病率OR 95%
13、CI NNTP MEDENOX 1102 依诺肝素 20mg,qd,14天 40mg,qd,14天5.50.370.22-0.639例 0.001 安慰剂 14天14.9 PREVENT 3681 达肝素 5000IU,qd,14天2.60.550.38-0.8045例=0.002 安慰剂 14天5.0 ARTEMIS 849Fondparinux 2.5mg,qd,14天 1.50.530.31-0.92=0.085 安慰剂3.4NNT:每挽救1例VTE所需要治疗的病人数0481216所有所有 静脉栓塞事件静脉栓塞事件所有近端所有近端 的深静脉血栓事件的深静脉血栓事件安慰剂安慰剂 (n=28
14、8)依诺肝素依诺肝素 40 mg (n=291)P=0.037P=0.0002NS患者患者 (%)DVT, 深静脉血栓深静脉血栓; PE, 肺栓塞肺栓塞NS, 无显著意义无显著意义; VTE, 静脉血栓栓塞静脉血栓栓塞; RRR, 相对风险降低相对风险降低RRR 63%RRR 65%Medenox 研究：患者随机分组，分别接受依诺肝素研究：患者随机分组，分别接受依诺肝素20毫克或依诺肝素毫克或依诺肝素40毫克治疗，或者给予安慰毫克治疗，或者给予安慰剂，接受依诺肝素剂，接受依诺肝素20mg治疗的患者与接受安慰剂治疗的患者相比，其预后没有显示显著差异。治疗的患者与接受安慰剂治疗的患者相比，其预后没
15、有显示显著差异。Samama et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999;341:793-800 MEDENOX研究研究 2121天时，达肝素（法安明）显著降低主要终点发生率天时，达肝素（法安明）显著降低主要终点发生率达达 45 主要终
16、点：主要终点：DVT/PE/猝死猝死法安明法安明5000IU组组安慰剂组安慰剂组主要终点发病主要终点发病 率（）率（）2.77%4.96%01234545P=0.0015Leizorovicz A, et al. Circulation 2004; 110: 874-879.MEDENOX n=11021PRINCE n=4512PRINCE II n=20630246810121416VTE; 第第1-14天天 (%)P0.001024681012VTE (%)024681012141618VTE (%)0510152025303540VTE (%)P=0.015 等效性检验AP=0.014
17、等效性检验AP=0.044依诺肝素 40 mg (4000 IU 抗Xa) qd依诺肝素 20 mg (2000 IU 抗Xa) qd安慰剂 qd肝素钙 5000 IU s.c. tidVTE, venous thromboembolic eventsLMWH, low-molecular-weight heparin1. Samama MM, et al. N Engl J Med 1999;341:793-800. 2. Kleber et al. Thromb Haemost 1999;(suppl)1552.3. Kleber et al. Unpublished DataA.等效性检
18、验：两种治疗等效，等效的定义是两组的最大差异为4%普通肝素更好普通肝素更好低分子肝素更好低分子肝素更好DVTPE死亡死亡大出血大出血P=NSP=NSP=NSP=0.049012相对危险性相对危险性Mismetti P, et al. Thromb Haemost 2000; 83: 14-19. 40岁以上因急性内科疾病住院患者，岁以上因急性内科疾病住院患者，和和 卧床卧床 3d ，同时同时 合并下列病症或危险因素之一合并下列病症或危险因素之一 呼吸衰竭、呼吸衰竭、COPD急性加重、急性脑梗死、心力衰竭（急性加重、急性脑梗死、心力衰竭（NYHA 或或级）级） 、急性感染性疾病（重症感染或感染中
19、毒症）急性感染性疾病（重症感染或感染中毒症） 、急性冠状动脉综合征、急性冠状动脉综合征、 VTE 病史、恶性肿瘤、炎性肠病、慢性肾脏疾病、下肢静脉曲张、病史、恶性肿瘤、炎性肠病、慢性肾脏疾病、下肢静脉曲张、 肥胖（体重指数肥胖（体重指数30 kgm ）及高龄（年龄）及高龄（年龄 75 岁）。岁）。机械性预防措施机械性预防措施机械性预防措施机械性预防措施 禁忌证禁忌证 严重下肢动脉硬化性缺血严重下肢动脉硬化性缺血 充血性心力衰竭充血性心力衰竭 肺水肿肺水肿 下肢下肢DVT（GCS 除外）除外） 血栓性静脉炎血栓性静脉炎 下肢局部严重病变（下肢局部严重病变（皮炎、坏疽、近期手术及严重畸形）皮炎、坏
20、疽、近期手术及严重畸形）LDUH 应用中需要特别重视的几个问题应用中需要特别重视的几个问题 密切观察出血并发症和严重出血危险密切观察出血并发症和严重出血危险发生出血，立即停用肝素，可静脉注射硫酸鱼精蛋白（发生出血，立即停用肝素，可静脉注射硫酸鱼精蛋白（1mg100 U肝素）肝素） 对高危人群监测对高危人群监测APTT 以调整剂量以调整剂量 年龄年龄75 岁岁 肾功能不全肾功能不全 进展期肿瘤进展期肿瘤 监测血小板计数，警惕监测血小板计数，警惕HIT患者是否属于高危人群是患者是否无法接受药物性血栓预防开始血栓预防治疗：法安明5000IU/依诺肝素4000IU 1/d或普通肝素5000IU 1/1
21、2h血栓预防治疗一般需要维持6-14天，同时应考虑其他临床因素或住院时间的长短以确定血栓预防的疗程随着病情的变化，对可能导致静脉血栓栓塞性疾病的危险因素进行重新评估考虑非药物血栓预防方法如弹力袜，间歇式气压治疗仪，足底泵否否是急性心肌梗死（急性心肌梗死（AMI ） 无需常规用药预防无需常规用药预防VTE 经评估经评估VTE 高危的高危的AMI 患者患者 如无禁忌证，可延长如无禁忌证，可延长LMWH 治疗时间至周治疗时间至周 延长治疗期间改为预防剂量延长治疗期间改为预防剂量 可联合使用机械性预防措施可联合使用机械性预防措施附一：肝素诱导的血小板减少症附一：肝素诱导的血小板减少症(略略)附二：内科
22、患者静脉血栓栓塞症治疗原则附二：内科患者静脉血栓栓塞症治疗原则(略略)535455Prevalence and Prevention of Venous Thromboembolismin Medical PatientsLi Xiao Ying, MDChinese PLA General Hospital BEIJING, CHINAClinical Review of Venous Thromboembolism The incidence of venous thromboembolism (VTE) is increasingthromboprophylaxis has been s
23、hown to be effective and safe for most VTE patientsA big challenge for public health and health care1 Cohen AT. Presented at the 5th Annual Congress of the European Federation of Internal Medicine; 2005.2 Eurostat statistics on health and safety 2001. Available from: http:/epp.eurostat.cec.eu.int.Th
24、e Shocking Mortality of VTEl VTE causes 543,454 death in hospital yearlyl More than combined total of deaths from AIDS, breast cancer, prostatic carcinoma and traffic accidents AIDS 5,860 breast cancer 86,831 prostatic carcinoma 63,636 traffic accidents 53,599l 9.74% of hospitalized Chinese patients
25、 died from pulmonary thromboembolism (PET) in 2006An Underestimate Burden in the World 10% of hospitalized patients die from PTE1severe hospitalized patients develop symptomatic DVT1. Sandler DA et al. J R Soc Med .1989,82:203-205.2. Baglin TP et al. J Clin Pathol. 1997,50:609-610.3. Mismetti P et a
26、l. Thromb Haemost. 2000,83:14-19.4. Anderson FA et al. J Vasc Surg. 1992,19:557-55859The Risk for VTE in Medical Hospitalized PatientsRisk of VTE with no prophylaxis in various groups of hospitalized patients 0% 12% 22% 2833% 3050%Internal MedicineAcute Ischemic Stroke ICUAMI1. Leizorovicz and Misme
27、tti. Circulation. 2004,110(Suppl IV):13-19. 2. Fraisse F,et al. Am J Respir Crit Care Med. 2000,161: 1109-1114.3. Spyropoulos AC,et al. Chest .2005,128: 958-969.4. Cohen AT, et al. Thromb Haemost.2005, 94: 750-759.60The Incidence of VTE in Medical Hospitalized Patients1. Samama MM et al. N Engl J Me
28、d. 1999,341:79-3800.2. Leizorovicz A et al. Circulation. 2004,110:874-879.3. Cohen AT et al. BMJ. 2005, in press.61l Pre-death diagnosis was made in less than 50% of fatal PE1.Goldhaber SZ, et al. American Journal of Medicine 1982;73:822-826. 2. Lethen H, et al. American Journal of Cardiology 1997;8
29、0:1066-1069.3. Sandler DA, et al. J. Royal Soc. Med. 1989; 82:203-205.62Medical Hospitalized Patients High Risk Population to Develop VTEvenous stasisendothelial injury Very high riskModerate / high riskLow / moderate riskhypercoaguabilityThe Incidence of PET in ChinaTimePET Incidencethe collaborati
30、on group on PTE-DVT prevention and treatment in China64VTE in Clinical Medical Elderly Patients 650 days14-21days90 daysl A total of 607 acutely ill medical hospitalized elderly patients were enrolled1st follow-up2nd follow-uplast follow-upCUS*CUS, VTE eventtelephone, VTE event* CUS: compressed ultr
31、asound66End Points of VTE-CMEPlObjectively verified DVTlObjectively verified fatal and non-fatal PElObjectively verified asymptomatic DVTlAll-cause mortality67Baseline Characteristics of the Patients 68Primary End Points of VTE-CMEPPrimary end points （）（）9.7%01.534.567.59VTE7.3%2.1%DVTPEDVT+PE0.5%69
32、VTE Incidence in Patients with Acute illness70VTE Incidence in Patients with Underlying Disorders71VTE Incidence in Patients Who Accepted Therapeutic Measures720246810121416MEDENOXPREVENTCMEPVTE incidence（）（）4.96%14.9%9.7%ARTEMIS10.5%73The Percentage of VTE High Risk Medical Patients Accepted Prophy
33、laxes Treatment74Pharmacological and Mechanical Prophylaxis Treatment in VTE-CMEP LMWH Limb Massage 75VTE-RAMP study VTE - Risk Assessment and Prophylaxis Treatment among Acute Medical Patients in ICU/CCU in China A cross-sectional Survey 76Patients in ICU or CCU Qualified for the Enrollment Criteri
34、a in RAMPCCU(N =704)ICU(N =543)7705101520253035404550123456789未未 知知The Percentage of VTE Risk Factors in Severe Medical Hospitalized Patients99.0% of patients benefited from effective prophylaxes against embolism. 57.8% of patients had multiple VTE risk factorsThe number of VTE risk factorsICU=543 C
35、CU=704Total=1247%78Prophylaxis by AACCP recommendations for severe medical patients or LMWH for patients who have no contraindications to anticoagulant therapyEpidemiologic International Day for the Evaluation of Patients at Risk of Venous Thrombosis in the Acute Hospital Care Setting80 The Enrolled
36、 Patients in ENDORSESurgical patients(N = 30,827)Medical patients(N =37,356)81Primary objectives41.5% at risk for VTEMedical patients( n = 37,356 )Secondary objectives39.5% received prophylaxis64.4% at risk for VTE 58.5 % received prophylaxisSurgical patients( n = 30,827 )The Findings of ENDORSE stu
37、dy51.8 % at risk for VTE50 % received prophylaxisTotal = 68,183 82Proportion of Surgical and Medical Patients at High Risk for VTE Who Received Prophylaxis medical patients surgical patients8882665947Hip/knee joint replacementFracture of hipGastric diseaseColonic diseaseUrinary disease45414025Acute
38、respiratory diseaseAcute heart failurePulmonary infectionIschemic shock0255075100 %0255075100 %83Mechanical Prophylaxis Measures Taken by Medical Patients Graduated Compression Stockings Intermittent pneumatic compression Venous foot pump Lacut K, et al. Neurology, 2005. 65: 865-86984 Pharmacologic
39、Prophylaxis MeasuresTaken by Medical Patients MEDENOX PREVENT PRINCE PRINCE-IIlFondaparinux ARTEMIS85012345Relative riskHeparin BetterHeparin WorseBelch 1981Dahan 1986Ibara-Perez 1988Bergmann 1996Gardlund 1996Fraisse 1998total PERR=0.480.34-0.68, P0.001 ANOVA：P=NS86 Compared with placebo, LMWH can r
40、educe the incidence of VTE in medical hospitalized patients significantly. StudiesCasesDrugVTEincidenceOR95%CINNTP MEDENOX 1102 Enoxaparin 20mg,qd,14 days 40mg,qd,14 days5.50.370.22-0.6390.001 Placebo 14 days14.9 PREVENT 3681 Dalteparin 5000IU,qd,14 days2.60.550.38-0.8045=0.002 Placebo 14 days5.0 AR
41、TEMIS 849 Fondparinux 2.5mg,qd,14 days1.50.530.31-0.92=0.085 Placebo 14 days3.4NNT: Number Needed to Treat87Samama et al. N Engl J Med. 1999, 341:793-800Results of MEDENOX studyl The benefit observed with 40 mg of enoxaparin was maintained at three monthsl There was no significant difference in the
42、incidence of VTE between the group that received 20 mg of enoxaparin and the placebo group0481216VTE eventsProximal DVT eventsPlacebo (n=288)Enoxaparin (40 mg) (n=291)P=0.037P=0.0002VTE incidence (%)RRR 63%RRR 65%14.9%5.5%RRR: relative risk reduction 4.9%88Results of PREVENT studyl Dalteparin reduce
43、d the primary end points events by 45% on day 21 l Primary end points：DVT/PE/ sudden death Dalteparin （5000IU）PlaceboPrimary end points（）（）2.77%4.96%012345P=0.0015Leizorovicz A, et al. Circulation. 2004, 110: 874-879891.00.502.01.52.53.03.54.0Total DVTTotal PETotal DeathsTotal Major BleedingsLMWH be
44、tterUFH betterRR = 1.07 (0.79-1.45), p = 0.661RR = 0.83 (0.56-1.24), p = 0.37RR = 0.74 (0.29-1.88), p = 0.52RR = 0.48 (0.23-1.00), p = 0.049* RR: Relative risk, with 95 % confidence interval91Who Need the Thromboprophylaxis? l Patients over the age of 40 with acute medical illness and/or reduced mob
45、ility with one of the following morbidities: respiratory failure, or COPD with acute respiratory failure, or with mechanical ventilation acute ischemic stroke acute inflammatory diseases acute coronary syndrome heart failure rheumatic disease previous VTE varicosis inflammatory bowel disease maligna
46、nt tumor obesity chronic renal failure metabolic diseases (such as diabetes mellitus, metabolic syndrome) central venous lines permanent pacemaker 92How to Prevent VTE in Medical Patients ?lIndications of mechanical thromboprophylaxis thromboprophylaxis should be given 93lContraindications to mechan
47、ical thromboprophylaxis Severe ischemic atherosclerosis in low extremity Congestive heart failure Pulmonary edema DVT in low extremity except GCS Thromboembolism venous inflammation Severe skin diseasesMechanical Thromboprophylaxis94 Hemorrhagic disease Coagulation disorderstrauma or operation Threa
48、tened abortion Malignant hypertension Bacterial endocarditisheparin95Observe carefully on symptoms and signs for major bleedingAdjust LDUH dose by Monitoring APTT in high risk patients age75 years renal inadequacy advanced carcinomaMonitor platelet count, in case of heparin-induced thrombocytopenia
49、(HIT)l Cautions in LDUH use96 Contraindications: 97contraindications to anticoagulantsYesNoenoxaparin 4000U qd or dalteparin 5000U qdor LMWH 5000U q12h, for 6-14 days*NoYesGCS, IPC, VFPreestimate the riskIn hospitalization* Other clinical conditions should be considered when determining thromboproph
50、ylaxis duration 98Routine anticoagulants prophylaxis for VTE is not recommended, because the current therapy for AMI has included enough LDUH and LMWH although the patients of AMI are at high risk for VTEThe patients who are at higher risk for VTE and without the contraindications to anticoagulants
