房顫為什么要抗凝

1、關(guān)于房顫為什么要抗凝第一張，PPT共五十七頁，創(chuàng)作于2022年6月中國AF患者抗凝現(xiàn)狀：令人堪憂胡大一等。中華內(nèi)科雜志，2004；孫藝紅等。中華內(nèi)科雜志，2004；43：258-260第二張，PPT共五十七頁，創(chuàng)作于2022年6月原 因預防性治療：看不到效果、卻有出血風險病人依從性差抗凝監(jiān)測麻煩、費力未充分認識房顫與血栓栓塞的關(guān)系第三張，PPT共五十七頁，創(chuàng)作于2022年6月房顫引起卒中？Strength of association（相關(guān)強度）Consistency（穩(wěn)定性）Specificity（特異性）Temporality （時間性） Biological gradient（生物梯度）

2、Plausibility（合理性） Coherence（一致性） Accordance with experimental resultsAnalogy （類推）Stroke 2016; 47(3):895-900 為判斷“A是否引起B(yǎng)”，流行病學家Bradford Hill提出以下標準（現(xiàn)已被廣泛接受）第四張，PPT共五十七頁，創(chuàng)作于2022年6月房顫導致血栓栓塞：合理 非瓣膜病房顫左房血栓約90%來源于左心耳。房徑增大、左心耳內(nèi)膜纖維化是誘發(fā)血栓形成的因素。房顫時心房肌細胞電激動紊亂心房收縮功能喪失血液瘀滯血栓形成合理第五張，PPT共五十七頁，創(chuàng)作于2022年6月房顫卒中并不都是左心耳的錯

3、10%的左心血栓并非來源于左心耳1、左室2、左房憩室：415例成人冠脈雙源CT造影顯示左房憩室樣結(jié)構(gòu)85例（20.5%） Circulation. 2008;117:1351-1352第六張，PPT共五十七頁，創(chuàng)作于2022年6月房顫與卒中：密切相關(guān)中風風險5倍心衰風險3倍癡呆風險2倍死亡風險2倍醫(yī)療費用8700美元/年2014 ACC/HRS房顫指南房顫顯著增加卒中風險卒中是AF的主要并發(fā)癥AF患者卒中風險增高5倍2AF每年卒中發(fā)生率343每6個卒中患者有1個房顫患者4CHEST, 2001, 119(1_suppl): 300S-320S. Stroke 1991;22:983-988.

4、Stroke 2009;40:2607102012心房顫動：目前的認識和治療建議第七張，PPT共五十七頁，創(chuàng)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，單次、短促的亞臨床房顫發(fā)作即與2倍升高的卒中風險相關(guān)而在年輕以其他健康人群，即便具有臨床顯性房顫，其卒中風險卻未見顯著升高Stroke 2016; 47(3):895-900第八張，PPT共五十七頁，創(chuàng)作于2022年6月Framingham 心臟研究：年腦卒中率：

5、 50-69歲1.5%80-89歲23.5%（平均4.9-6.9%）房顫卒中隨年齡增加而增加Wolf et al. Stroke 1991;22:983-88. 房顫卒中發(fā)生率與年齡80-89第九張，PPT共五十七頁，創(chuàng)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女性房顫中風發(fā)生率顯著高于男性第十張，PPT共五十七頁，創(chuàng)作于2022年6月血管疾病、年齡、女性與房顫卒中風險歐洲心臟調(diào)查：共納入5333例房顫患者，其中 1084例發(fā)生血栓栓塞事件，評估該人群的卒中風險因素血栓栓塞事件發(fā)生率(%)P=0.017P=0.022血管疾病與女性Gregory Y. H. Lip, et al. CHE

7、ST 2010; 137:26372Coppens M, et al. European Heart Journal. 2013; 34:1706.年齡65-74歲與女性風險因素風險比(95% CI)風險比(95% CI)*年齡 65歲11 65-74歲1.97 (1.442.74)1.90 (1.382.64) 75歲2.31 (1.473.58)2.24 (1.423.48)性別 男性11 女性1.45 (1.101.91)1.32 (1.001.75)校正年齡、外周動脈疾病或心肌梗死及性別因素后的多元分析第十一張，PPT共五十七頁，創(chuàng)作于2022年6月CHA2DS2VASc評分危險因素評

8、分心力衰竭/左心室功能不全1高血壓1年齡75歲2糖尿病1卒中/TIA/血栓-栓塞2血管疾病1年齡6574歲1性別因素(如女性)1總分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.卒中風險: 隨CHA2DS2-VASc評分升高而升高CHA2DS2-VASc評分CHA2DS2-VASc評分卒中發(fā)生率(%/年)腎功能不全肥厚梗阻性心臟病第十二張，PPT共五十七頁，創(chuàng)作于2022年6

9、月房顫與卒中的危險因素重疊 高齡、高血壓、糖尿病、心衰、冠心病、慢性腎臟疾病、炎癥、睡眠呼吸暫停、吸煙等，即是房顫的危險因素、也是卒中的危險因素 上述危險因素與房顫一樣，常與心房內(nèi)膜功能紊亂、纖維化、心房擴大、心房及LAA收縮功能下降等合并存在第十三張，PPT共五十七頁，創(chuàng)作于2022年6月Updated Model for Mechanisms of Stroke in AF Stroke 2016; 47(3):895-900AF收縮功能障礙、血液瘀滯血栓栓塞 AF心房重構(gòu)加重心房心肌病Once stroke occurs, autonomic changes and post-strok

10、e inflammation may transiently increase AF risk. 年齡、血管疾病、心衰等心房心肌病第十四張，PPT共五十七頁，創(chuàng)作于2022年6月房顫卒中致殘率高于非房顫卒中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臥床患者%4030201005041.2%23.7%With AFWithout AF第十五張，PPT共五十七頁，創(chuàng)作于

11、2022年6月Stroke 1997;28:311-315P0.001有房顫：30.5%無房顫： 21.8% 卒中1年死亡率房顫卒中死亡率高于非房顫卒中第十六張，PPT共五十七頁，創(chuàng)作于2022年6月房顫相關(guān)卒中復發(fā)率高于非房顫Marini C et al. Stroke 2005;36:11159AF組無AF組首次卒中后時間（月）累積復發(fā)概率 (%)1012864200246810P=0.0398第十七張，PPT共五十七頁，創(chuàng)作于2022年6月房顫對國人的危害缺血性卒中經(jīng)濟負擔直接經(jīng)濟損失1.1萬元平均住院日18預期經(jīng)濟負擔126.6196.6億元房顫占心血管疾病住院治療比逐年增高1缺血性卒

12、中造成的經(jīng)濟負荷加重22012心房顫動：目前的認識和治療建議中國衛(wèi)生經(jīng)濟.2003,22(12):18-20第十八張，PPT共五十七頁，創(chuàng)作于2022年6月02468AFASAK58%7 81SPAF67%27 85BAATAF86%51 96 CAFA42%- 68 80SPINAF79%52 90TOTAL68%5079中風發(fā)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/日腎臟清除(%) 80 36 2

13、5 40可透析清除YesUnlikelyUnlikelyUnlikelyCYP 代謝No30% CYP3A4, CYP2J215% CYP3A475歲)1高血壓31INR易變81血小板數(shù)量減少或功能降低111老年人(65歲)1再次出血122藥物9或酒精11高血壓4 1貧血131遺傳因素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歲女性第四十五張，PPT共五十七頁，創(chuàng)作于2022年6月腎功能不全：房顫卒中獨立危險因素卒中或全身性栓塞累積發(fā)生率(%)隨訪時間(天)匯總ROCKET-AF和ATRIA研究結(jié)果，評估腎功能不全是否為房顫卒中的獨立風險因素AMADEUS研究納入4576例接受抗凝治療的房顫患者，評估腎功能對抗凝

17、療效的影響CrCl每下降10ml/min卒中或全身性栓塞風險增加11.5%無論CHA2DS2-VASc評分如何CrCl60ml/min顯著增加卒中風險既往卒中且CrCl60ml/min既往卒中且CrCl60ml/min無既往卒中且CrCl4P0.001P0.001P0.001P0.001Coppens M, et al. European Heart Journal.2013; 34:1706.Stavros Apostolakis, et al. European Heart Journal 2013; 34:35729第四十六張，PPT共五十七頁，創(chuàng)作于2022年6月CRYSTAL-AF試

18、驗：無癥狀性房顫與不明原因腦卒中時間植入監(jiān)測器n=221對照組n=220HRP值6個月8.9%1.4%6.430.000612個月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，對照組220例共進行了121次心電圖、32次Holter和1次事件記錄器檢查，1年內(nèi)僅發(fā)現(xiàn)4例房顫；另221例植入心電監(jiān)測器，1年內(nèi)發(fā)現(xiàn)房顫29例第四十七張，PPT共五

19、十七頁，創(chuàng)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.房顫常與心房異常（內(nèi)膜功能紊亂、纖維化、心房肌功能受損、腔室擴大、LAA機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.第四十八張，PPT共五十七頁，創(chuàng)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第四十九張，PPT共五十七頁，創(chuàng)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第五十張，PPT共五十七頁，創(chuàng)作于2022年6月ConclusionsA straightforward直截了當?shù)? 坦率的; 明確的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第五十一張，PPT共五十七頁，創(chuàng)作于2022年6月房顫引起卒中？AF as a Cause of StrokeStroke 2016; 47(3):895-900The relationship between AF and stroke fulfills several of Hill criteria: 房顫時心房肌細胞電激動紊亂導致心房收縮功能喪失血液瘀滯，血栓形成

30、，故房顫引起卒中具有生物合理性房顫患者面臨顯著升高的卒中風險：Patients with AF face a strongly elevated risk of stroke3 to 5 fold higher after adjustment for risk factors.在不同隊列人群中，房顫一直穩(wěn)定地與卒中相關(guān) 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. 第五十二張，PPT共五十七頁，創(chuàng)作于2022年6月Several other Hill criteria do not support a straight forward relationship between AF and stroke.雖然很多研究已經(jīng)發(fā)現(xiàn)在房顫負荷與卒中之間存在

32、生物梯度，但其并非見于所有研究在具有血管危險因素的老年病人，單次、短促的亞臨床房顫發(fā)作即與2倍升高的卒中風險相關(guān) 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, 而在年輕以及其他健康人群，即便具有臨床顯性房顫卒，其卒中風險并未見顯著升高whereas young and otherwise healthy patients with clinic

33、ally apparent AF do not face a significantly increased stroke risk. 這些矛盾數(shù)據(jù)不足以確定房顫負荷與卒中之間存在明確的生物梯度，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第五十三張，PPT共五十七頁，創(chuàng)作于2022年6月Several other Hill crit

34、eria do not support a straight forward relationship between AF and stroke.在特異性方面也存在不足The relationship between AF and stroke also fails Hills criterion of specificity.如果房顫引起血栓，則房顫應該特異性地與栓塞性卒中相關(guān) 確實有研究證明房顫特異性地與栓塞性卒中相關(guān)但是，10%的腔隙性腦梗死患者合并房顫，此外，房顫患者大動脈粥樣硬化是非房顫病人的2倍 上述房顫與非心源性栓塞性卒中的聯(lián)系提示房顫卒中風險并不能完全用房顫直接引起卒中解釋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第五十四張，PPT共五十七頁，創(chuàng)作于2022年6月.房顫與卒中之間的關(guān)聯(lián)并未完全滿足Hills “時間”性標準 晚近病例交叉分析表明：卒中風險在房顫發(fā)作后短期內(nèi)即見升高 其他2個研究發(fā)現(xiàn)：近三分之一的房顫與卒中患者，盡管數(shù)月持續(xù)心臟節(jié)律監(jiān)護，直到卒中后才表現(xiàn)有房顫，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