房颤为什么要抗凝

1、关于房颤为什么要抗凝第一张，PPT共五十七页，创作于2022年6月中国AF患者抗凝现状：令人堪忧胡大一等。中华内科杂志，2004；孙艺红等。中华内科杂志，2004；43：258-260第二张，PPT共五十七页，创作于2022年6月原 因预防性治疗：看不到效果、却有出血风险病人依从性差抗凝监测麻烦、费力未充分认识房颤与血栓栓塞的关系第三张，PPT共五十七页，创作于2022年6月房颤引起卒中？Strength of association（相关强度）Consistency（稳定性）Specificity（特异性）Temporality （时间性） Biological gradient（生物梯度）

2、Plausibility（合理性） Coherence（一致性） Accordance with experimental resultsAnalogy （类推）Stroke 2016; 47(3):895-900 为判断“A是否引起B”，流行病学家Bradford Hill提出以下标准（现已被广泛接受）第四张，PPT共五十七页，创作于2022年6月房颤导致血栓栓塞：合理 非瓣膜病房颤左房血栓约90%来源于左心耳。房径增大、左心耳内膜纤维化是诱发血栓形成的因素。房颤时心房肌细胞电激动紊乱心房收缩功能丧失血液瘀滞血栓形成合理第五张，PPT共五十七页，创作于2022年6月房颤卒中并不都是左心耳的错

3、10%的左心血栓并非来源于左心耳1、左室2、左房憩室：415例成人冠脉双源CT造影显示左房憩室样结构85例（20.5%） Circulation. 2008;117:1351-1352第六张，PPT共五十七页，创作于2022年6月房颤与卒中：密切相关中风风险5倍心衰风险3倍痴呆风险2倍死亡风险2倍医疗费用8700美元/年2014 ACC/HRS房颤指南房颤显著增加卒中风险卒中是AF的主要并发症AF患者卒中风险增高5倍2AF每年卒中发生率343每6个卒中患者有1个房颤患者4CHEST, 2001, 119(1_suppl): 300S-320S. Stroke 1991;22:983-988.

4、Stroke 2009;40:2607102012心房颤动：目前的认识和治疗建议第七张，PPT共五十七页，创作于2022年6月Several other Hill criteria do not support a straight forward relationship between AF and stroke.在某些老年病人，单次、短促的亚临床房颤发作即与2倍升高的卒中风险相关而在年轻以其他健康人群，即便具有临床显性房颤，其卒中风险却未见显著升高Stroke 2016; 47(3):895-900第八张，PPT共五十七页，创作于2022年6月Framingham 心脏研究：年脑卒中率：

5、 50-69岁1.5%80-89岁23.5%（平均4.9-6.9%）房颤卒中随年龄增加而增加Wolf et al. Stroke 1991;22:983-88. 房颤卒中发生率与年龄80-89第九张，PPT共五十七页，创作于2022年6月Annualized adjusted rate of thromboembolism (ischemic strokeand peripheral embolism) during off-warfarin periods amongwomen and men with AF with age, prior stroke, hypertension, CHF

6、, CAD, DM, and estrogen use controlled for. Age cutoffs of 75 and 75 years used as in the SPAF analysis. Circulation. 2005;112:1687-91女性房颤中风发生率显著高于男性第十张，PPT共五十七页，创作于2022年6月血管疾病、年龄、女性与房颤卒中风险欧洲心脏调查：共纳入5333例房颤患者，其中 1084例发生血栓栓塞事件，评估该人群的卒中风险因素血栓栓塞事件发生率(%)P=0.017P=0.022血管疾病与女性Gregory Y. H. Lip, et al. CHE

7、ST 2010; 137:26372Coppens M, et al. European Heart Journal. 2013; 34:1706.年龄65-74岁与女性风险因素风险比(95% CI)风险比(95% CI)*年龄 65岁11 65-74岁1.97 (1.442.74)1.90 (1.382.64) 75岁2.31 (1.473.58)2.24 (1.423.48)性别 男性11 女性1.45 (1.101.91)1.32 (1.001.75)校正年龄、外周动脉疾病或心肌梗死及性别因素后的多元分析第十一张，PPT共五十七页，创作于2022年6月CHA2DS2VASc评分危险因素评

8、分心力衰竭/左心室功能不全1高血压1年龄75岁2糖尿病1卒中/TIA/血栓-栓塞2血管疾病1年龄6574岁1性别因素(如女性)1总分9Lip GY，et al.Chest. 2010; 137:263-72.Olesen JB，et al. Thromb Haemost. 2012; 107:1172-9. Mason PK，et al. Am J Med 2012 ; 125:603.e1-6.卒中风险: 随CHA2DS2-VASc评分升高而升高CHA2DS2-VASc评分CHA2DS2-VASc评分卒中发生率(%/年)肾功能不全肥厚梗阻性心脏病第十二张，PPT共五十七页，创作于2022年6

9、月房颤与卒中的危险因素重叠 高龄、高血压、糖尿病、心衰、冠心病、慢性肾脏疾病、炎症、睡眠呼吸暂停、吸烟等，即是房颤的危险因素、也是卒中的危险因素 上述危险因素与房颤一样，常与心房内膜功能紊乱、纤维化、心房扩大、心房及LAA收缩功能下降等合并存在第十三张，PPT共五十七页，创作于2022年6月Updated Model for Mechanisms of Stroke in AF Stroke 2016; 47(3):895-900AF收缩功能障碍、血液瘀滞血栓栓塞 AF心房重构加重心房心肌病Once stroke occurs, autonomic changes and post-strok

10、e inflammation may transiently increase AF risk. 年龄、血管疾病、心衰等心房心肌病第十四张，PPT共五十七页，创作于2022年6月房颤卒中致残率高于非房颤卒中Neuroepidemiology. 2003;22:118-123. Odds ratio for bedridden state following stroke due to AF was 2.23（95% CI, 1.87-2.59; p0.0005）p0.0005卧床患者%4030201005041.2%23.7%With AFWithout AF第十五张，PPT共五十七页，创作于

11、2022年6月Stroke 1997;28:311-315P0.001有房颤：30.5%无房颤： 21.8% 卒中1年死亡率房颤卒中死亡率高于非房颤卒中第十六张，PPT共五十七页，创作于2022年6月房颤相关卒中复发率高于非房颤Marini C et al. Stroke 2005;36:11159AF组无AF组首次卒中后时间（月）累积复发概率 (%)1012864200246810P=0.0398第十七张，PPT共五十七页，创作于2022年6月房颤对国人的危害缺血性卒中经济负担直接经济损失1.1万元平均住院日18预期经济负担126.6196.6亿元房颤占心血管疾病住院治疗比逐年增高1缺血性卒

12、中造成的经济负荷加重22012心房颤动：目前的认识和治疗建议中国卫生经济.2003,22(12):18-20第十八张，PPT共五十七页，创作于2022年6月02468AFASAK58%7 81SPAF67%27 85BAATAF86%51 96 CAFA42%- 68 80SPINAF79%52 90TOTAL68%5079中风发生率 (%)p 0.03p 0.01p 0.2p 0.002p 90 87 54生物利用度(%) 6 80 5060Tmax(hrs)1-32-41-31-3半衰期(hrs)14-175-9 8-15 9-11用法2/日1/日2/日1/日肾脏清除(%) 80 36 2

13、5 40可透析清除YesUnlikelyUnlikelyUnlikelyCYP 代谢No30% CYP3A4, CYP2J215% CYP3A475岁)1高血压31INR易变81血小板数量减少或功能降低111老年人(65岁)1再次出血122药物9或酒精11高血压4 1贫血131遗传因素141容易跌倒151卒中1Apostolakis S,et al. JACC 2012; 60: 000000Hemoglobin 13 g/dl men; 12 g/dl womenEstimated glomerular filtration rate 160 mmHgPresence of chronic

14、dialysis or renal transplantation or serum creatinine 200 mmol/LChronic hepatic disease (eg cirrhosis) or biochemical evidence of significant hepatic derangement (eg bilirubin 2 x upper limit of normal, in association with aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase 3 x

15、upper limit normal, etc.)Unstable/high INRs or poor time in therapeutic range (eg 60%)Concomitant use of drugs, such as antiplatelet agents, non-steroidal anti-inflammatory drugs, or alcohol abuse etc. Cirrhosis, two-fold or greater elevation of AST or APT, or albumin 3.6 g/dlPlatelets 75,000, use o

16、f antiplatelet therapy (eg daily aspirin) or NSAID therapy; or blood dyscrasiaPrior hospitalization for bleedingMost recent hematocrit 30 or hemoglobin 75岁女性第四十五张，PPT共五十七页，创作于2022年6月肾功能不全：房颤卒中独立危险因素卒中或全身性栓塞累积发生率(%)随访时间(天)汇总ROCKET-AF和ATRIA研究结果，评估肾功能不全是否为房颤卒中的独立风险因素AMADEUS研究纳入4576例接受抗凝治疗的房颤患者，评估肾功能对抗凝

17、疗效的影响CrCl每下降10ml/min卒中或全身性栓塞风险增加11.5%无论CHA2DS2-VASc评分如何CrCl60ml/min显著增加卒中风险既往卒中且CrCl60ml/min既往卒中且CrCl60ml/min无既往卒中且CrCl4P0.001P0.001P0.001P0.001Coppens M, et al. European Heart Journal.2013; 34:1706.Stavros Apostolakis, et al. European Heart Journal 2013; 34:35729第四十六张，PPT共五十七页，创作于2022年6月CRYSTAL-AF试

18、验：无症状性房颤与不明原因脑卒中时间植入监测器n=221对照组n=220HRP值6个月8.9%1.4%6.430.000612个月29例（12.4%）2例（2.0%）7.320.00013年30.0%3.0%8.780.0001Sue Hughes. CRYSTAL-AF: Monitor Detects AF in Cryptogenic Stroke . Medscape. Feb. 15, 2014.不明原因卒中441例，对照组220例共进行了121次心电图、32次Holter和1次事件记录器检查，1年内仅发现4例房颤；另221例植入心电监测器，1年内发现房颤29例第四十七张，PPT共五

19、十七页，创作于2022年6月Even if the origin of stroke in AF is accepted to be the left atrium, other atrial factors in addition to AF may cause thromboembolism.房颤常与心房异常（内膜功能紊乱、纤维化、心房肌功能受损、腔室扩大、LAA机械功能下降等合并存在 These abnormalities have been documented in both experimental animal models26 and in humans.2730 Such f

20、actors have been associated with stroke risk in patients with AF31could these atrial abnormalities also arise independently of AF and cause stroke? If so, they should be associated with stroke even in the absence of AF. Indeed, premature atrial contractions,32 paroxysmal supraventricular tachycardia

21、,33 ECG-defined left atrial abnormality,3436 and left atrial size3739 have been associated with stroke independently of AF (Table). Markers of atrial dysfunction are specifically associated with cryptogenic or embolic stroke and not with in situ cerebral small-vessel occlusion,34,36,38 indicating th

22、at these markers signal a specific risk of atrial thromboembolism rather than general vascular risk.第四十八张，PPT共五十七页，创作于2022年6月 Proof of principle is offered by a homozygous mutation of the natriuretic peptide precursor A gene. Even though AF is absent, this disorder leads to atrial dilatation, progre

23、ssive loss of atrial activity with eventual atrial standstill, and thromboembolism.45第四十九张，PPT共五十七页，创作于2022年6月Updated Model for the Mechanisms of Stroke in AFthe mechanistic basis of stroke in patients with AF is likely to be more complex than currently appreciated. An up-to-date model must emphasiz

24、e systemic and atrial substrate as well as rhythm. Aging and systemic vascular risk factors abnormal atrial tissue substrate(atrial cardiopathy)thromboembolism and AF contractile dysfunction and stasis further increases the risk of thromboembolism. structural remodeling of the atrium, thereby worsen

25、ing atrial cardiopathy and increasing the risk of thromboembolism even further. In parallel, systemic risk factors increase stroke risk via other mechanisms outside the atrium, such as large-artery atherosclerosis, ventricular systolic dysfunction, and in situ cerebral small-vessel occlusion. Once s

26、troke occurs, autonomic changes and post-stroke inflammation may transiently increase AF risk.Stroke 2016; 47(3):895-900第五十张，PPT共五十七页，创作于2022年6月ConclusionsA straightforward直截了当的; 坦率的; 明确的association between AF and stroke does not convincingly demonstrate temporality, specificity, or a biological gra

27、dient, and it is not concordant with the totality of the available experimental evidence. A model in which thromboembolism is caused by both AF and abnormal systemic and atrial tissue substrate better fits the available data. Such a model has several important implications for stroke prevention stra

28、tegies. By emphasizing systemic and atrial substrate in addition to rhythm, it points to new strategies for identifying and treating patients at risk of thromboembolism. Further research to test this model and the various strategies it suggests may result in improvements in stroke care and a reducti

29、on in the burden of this disabling disease, which accounts for 10% of deaths worldwide.Stroke 2016; 47(3):895-900第五十一张，PPT共五十七页，创作于2022年6月房颤引起卒中？AF as a Cause of StrokeStroke 2016; 47(3):895-900The relationship between AF and stroke fulfills several of Hill criteria: 房颤时心房肌细胞电激动紊乱导致心房收缩功能丧失血液瘀滞，血栓形成

30、，故房颤引起卒中具有生物合理性房颤患者面临显著升高的卒中风险：Patients with AF face a strongly elevated risk of stroke3 to 5 fold higher after adjustment for risk factors.在不同队列人群中，房颤一直稳定地与卒中相关 AF has been consistently associated with stroke in different cohorts.Uncoordinated myocyte activity would explain the impaired atrial cont

31、raction seen in AF, and by Virchows triad, the resulting stasis of blood should increase thromboembolic riskA causal association is biologically plausible. 第五十二张，PPT共五十七页，创作于2022年6月Several other Hill criteria do not support a straight forward relationship between AF and stroke.虽然很多研究已经发现在房颤负荷与卒中之间存在

32、生物梯度，但其并非见于所有研究在具有血管危险因素的老年病人，单次、短促的亚临床房颤发作即与2倍升高的卒中风险相关 Furthermore, a single brief episode of subclinical AF is associated with a 2-fold higher risk of stroke in older patients with vascular risk factors, 而在年轻以及其他健康人群，即便具有临床显性房颤卒，其卒中风险并未见显著升高whereas young and otherwise healthy patients with clinic

33、ally apparent AF do not face a significantly increased stroke risk. 这些矛盾数据不足以确定房颤负荷与卒中之间存在明确的生物梯度，These conflicting data do not suffice to establish a clear biological gradient between the burden of AF and the risk of stroke. Stroke 2016; 47(3):895-900第五十三张，PPT共五十七页，创作于2022年6月Several other Hill crit

34、eria do not support a straight forward relationship between AF and stroke.在特异性方面也存在不足The relationship between AF and stroke also fails Hills criterion of specificity.如果房颤引起血栓，则房颤应该特异性地与栓塞性卒中相关 确实有研究证明房颤特异性地与栓塞性卒中相关但是，10%的腔隙性脑梗死患者合并房颤，此外，房颤患者大动脉粥样硬化是非房颤病人的2倍 上述房颤与非心源性栓塞性卒中的联系提示房颤卒中风险并不能完全用房颤直接引起卒中解释T

35、he link between AF and non-cardioembolic stroke indicates that stroke risk in AF cannot be entirely explained by AF directly causing stroke.Stroke 2016; 47(3):895-900第五十四张，PPT共五十七页，创作于2022年6月.房颤与卒中之间的关联并未完全满足Hills “时间”性标准 晚近病例交叉分析表明：卒中风险在房颤发作后短期内即见升高 其他2个研究发现：近三分之一的房颤与卒中患者，尽管数月持续心脏节律监护，直到卒中后才表现有房颤，2 other recent studies found that approximately one third of patients with both AF and stroke do not manifest any AF until after stroke, despite undergoing many months of continuous heart-rhythm monitoring before the stro