Lesson Ninety-seven Intraprocedural anticoagulation in patients on non-vitamin K antagonist oral anticoagulants undergoing catheter abla-

Atrial fibrillation（AF）catheter ablation,usually performed in patients on oral anticoagulation—either traditional vitamin K antagonists （VKAs） or non-vitamin K antagonist oral anticoagulants（NOACs）-entails contrasting risks:on the one hand,a risk of major bleeding,including hemopericardium,and on the other hand,a high transient procedure-related risk of thromboembolism that necessitates particularly rigorous anticoagulation throughout the procedure.The latest international guidelines recommend performing AF catheter ablation with uninterrupted oral anticoagulant and to“administer heparin prior to or immediately following transseptal puncture,adjusted to achieve and maintain a target activated clotting time（ACT）of 300 seconds or greater.”Although these guidelines are appropriately evidence-based for VKA-treated patients,few scientific data support a similar reasoning for NOAC treated patients, especially with regard to intraprocedural anticoagulation strategy.

A thorough appreciation of the physiology of anticoagulation during AF catheter ablation and the relevant differences between VKAs and NOACs is required,while also understanding the limitations of ACT measurement with regard to accurate intraprocedural anticogulation monitoring.

Is NOACs uninterruption for AF catheter ablation evidence based?

TheCOMPARE randomized controlled trial showed that performing AF catheter ablation without warfarin interruption reduces both the risk of bleeding and thromboembolic complications compared with VKA interruption with low-molecular-weight heparin bridging.Uninterrupted VKA（with an international normalized ratio of 2-3） and intraprocedural unfractionated heparin（UFH）administration to achieve and maintain a target ACT≥300 seconds has become the standard of care for AF catheter ablation.The tendency to presume the same or even better results while adopting the same approach with NOACs was highly understandable given the significant performance of NOACs in terms of both reduction of thromboembolism and major bleeding events.However,blind extrapolation may be erroneous.For instance,in the RE-ALIGN study,dabigatran was associated with excess risk compared with warfarin in the presence of mechanicalheartvalves,thereby illustrating the importance of considering the particular clinical setting.Consequently,specific data on NOACs in the setting of AF catheter ablation are needed.

Several studies have reported similar safety and efficacy of NOACs and warfarin in the specific setting of AF catheter ablation,with pooled data showing no significant difference in occurrence of stroke（0.28 versus 0.19%）and major bleeding（1.10 versus 1.60%）between uninterrupted NOAC- and VKA-treated patients.However,almost all of those studies were observational,with a relatively small sample size and careful selection of patients,with,in some proportion,NOACs not being“truly”uninterrupted before the procedure（with short discontinuation according to various dose-timing protocols）.

What can be extrapolated from VKAs to NOACs regarding Intraprocedural anticoagulation management?

1.Rigorous Intraprocedural Anticoagulation Is Needed During AF Ablation

As stated previously,patients undergoing AF catheter ablation are exposed to a high periprocedural thromboembolic risk,with reported incidence of thromboembolic events varying from 0.9% to 5%depending on the diagnostic modality used.Several mechanisms have been implicated in this specific intraprocedural prothrombotic situation（Figure 1）:（1）contact of blood with foreign surfaces of the ablation hardware, （2） leftatrialendothelialinjuryand inflammatory response induced by the passage of transseptal sheaths and electrode catheters and the application ofablation energy, （3） release of prothrombotic components from damaged cells,and（4）altered blood flow after conversion to sinus rhythm.The previously mentioned factors activate both the extrinsic and intrinsic pathways of the coagulation cascade.Sufficient intraprocedural anticoagulation aims to reduce this thromboembolic risk,which persists despite chronic anticoagulation in uninterrupted VKA-treated patients.Conversely,because AF catheter ablation is also associated with major bleeding risk, excessive intraprocedural anticoagulation increases bleeding events.Thus,appropriately monitored anticoagulation is mandatory to prevent procedure-related complications.

Figure 1 Mechanisms behind coagulation activation during atrial fibrillation catheter ablation and anticoagulant targets.TF,tissue factor;UFH,unfractionated heparin;and VKA,vitamin K antagonist.

2.UFH Is the Best Anticoagulant to Prevent Procedure-Related Thrombosis

UFH is a multitargeted anticoagulant that acts as a cofactor of the physiological inhibitor antithrombin,affecting predominantly thrombin and activated factor X,part of the common pathway,and additionally the activated factors IX,XI,and XII,implicated in the intrinsic pathway,also known as the contact activation phase （Figure 1）.Consequently,UFH prevents thrombosis related to ablation damage,induced by tissue factor expression and subsequent extrinsic pathway activation,aswellascatheter-related thrombosis（thrombi formation on sheaths）,induced by intrinsic pathway activation,especially when administered timely（3-fold lower incidence when UFH is injected before transseptalpuncture）.By contrast,target-specific anticoagulants,such the synthetic pentasaccharide,fondaparinux,or NOACs that inhibit only factor Xa or thrombin,do not inhibit the contact activation phase and are thus probably much less effective in preventing artificial surface induced thrombosis.Consequently,UFH-based intraprocedural anticoagulation is required to prevent procedure-related thromboembolisms in uninterrupted NOAC-treated patients.Finally,necrotic debris generated at the ablation surface cannot be eliminated by any anticoagulant.

3.UFH Requires Reliable Monitoring

There is considerable intra-and interindividual variability in the dose-response relationship with either fixed or weight-adjusted UFH doses.Therefore,the effect of bolus administration of UFH in any individual is not predictable,and reliable monitoring is required.During AF catheterablation,the UFH effectis monitored using the ACT, a point-of-care measurement1that evaluates the intrinsic and common coagulation pathways.ACT measures the reaction of fresh whole blood with a given surface substrate without the addition of phospholipids and calcium.A strong correlation between ACT and the anti-Xa activity of UFH has been consistently reported,which confirms that the ACT effectively reflects the biological effect of UFH.

Whatarethegapsinknowledgeregarding intraprocedural anticoagulation with uninterrupted NOAC strategy?

Despite the increasing number of studies,including randomized controlled trials exploring AF catheter ablation in uninterrupted NOAC-treated patients,only a few have paid attention to intraprocedural anticoagulation management.

Overall,available data have reported a higher intraprocedural UFH requirement to achieve target ACT in uninterrupted NOAC-treated patients compared with uninterrupted VKA-treated patients.In a multicenter study,a greater（≈40%）amount of UFH was required with uninterrupted apixaban compared with VKA to achieve and maintain the target ACT≥300 seconds.Similarly,in the VENTURE-AF trial,a significantly higher dose of UFH was needed to achieve ACT＞300 seconds（13 871 versus 10 964 IU）,and the mean ACT level attained was even lower among patients in the rivaroxaban group compared with those in the VKA group （302 versus 332 seconds）.With dabigatran,a retrospective analysis showed that ACT after UFH bolus and mean ACT during the procedure were lower（284±48 versus 312±55 seconds）,and a greater amount of UFH administration was required（62±29 versus 58±27 IU/kg/h）compared with VKA.

Although the extent to which this issue may translate to clinical complications still remains unknown,a significant body of evidence now indicates that ACT cannot be considered as a reliable surrogate forthe overallanticoagulation status afterUFH administration in uninterrupted NOAC-treated patients.First,the level of baseline anticoagulation before UFH administration is unpredictable because of a large interindividualpharmacokinetic variability,NOAC concentration variations over time,and,to a lesser extent,a concentration decrease during long procedures.Second,similar to prothrombin time and activated partial thromboplastin time,the ACT is not sensitive to NOACs and thus poorly reflects NOAC concentration when the procedure starts.A concentration-dependent increase in the ACT follows a nonlinear flattened curve,with differences in ACT sensitivity according to the particulartype ofNOAC.Hence,high NOAC concentrations,in particular anti-Xa,may be associated with a normal ACT,and ACT can be different between NOACs despite comparable therapeutic level.Third,it has been shown that the impact of UFH on the ACT may significantly vary according to the type of uninterrupted NOAC.This cannot be fully explained by differences in baseline ACT or ACT insensitivity.

詞 匯

Entail v.牽涉,需要,蘊(yùn)含,使必要

hemopericardium n.心包積血

thromboembolism n.血栓栓塞

rigorous adj.謹(jǐn)慎的,徹底的,嚴(yán)格的

unfractionated adj. 未分級(jí)的

protocol n.方案，條約草案，協(xié)定書，規(guī)程，禮儀

periprocedural adj.圍手術(shù)期的

mandatory n.&adj. 受托者；指令的，強(qiáng)制的，法定的

pentasaccharide n.五糖;戊糖;戊聚糖鈉;五碳多醣thrombin n.凝血酶

注 釋

1.point-of-care measurement與 point-of-care testing（POCT）一樣，指快速床旁檢測(cè)，文中的ACT通?？赏ㄟ^POCT試劑盒在導(dǎo)管室內(nèi)即刻測(cè)定。

參考譯文

第97課 服用非維生素K拮抗劑抗凝患者房顫導(dǎo)管消融術(shù)中的抗凝

房顫導(dǎo)管消融通常在口服抗凝劑——傳統(tǒng)的維生素K拮抗劑（vitamin K antagonists，VKAs）或非維生素K拮抗口服抗凝劑（non-vitamin K antagonist oral anticoagulants,NOCAs）的患者中實(shí)施，這會(huì)涉及截然不同的危險(xiǎn)：一方面是大出血，包括心包積血，另一方面是手術(shù)相關(guān)的高發(fā)短暫血栓栓塞風(fēng)險(xiǎn)，這要求整個(gè)手術(shù)過程需要特別嚴(yán)格的抗凝。最新的國際指南推薦，房顫導(dǎo)管消融無需中斷口服抗凝劑，并且“于穿間隔之前或即刻使用肝素，達(dá)到并維持活化凝血時(shí)間（activated clotting time，ACT）目標(biāo)值300s或以上”。雖然這些指南對(duì)于VKA治療的患者具有相應(yīng)的依據(jù)，但對(duì)于NOAC治療的患者，很少有科學(xué)資料支持類似推理，特別是術(shù)中的抗凝方案。

有必要全面評(píng)估房顫導(dǎo)管消融術(shù)中抗凝生理學(xué)以及VKAs和NOACs之間的相關(guān)差異，同時(shí)了解有關(guān)精準(zhǔn)術(shù)中抗凝監(jiān)測(cè)方面ACT檢測(cè)的局限性。

房顫導(dǎo)管消融不中斷NOACs有依據(jù)基礎(chǔ)嗎？

COMPARE隨機(jī)對(duì)照試驗(yàn)表明，房顫導(dǎo)管消融不中斷華法林與中斷華法林而用低分子肝素橋接比較，出血與血栓栓塞并發(fā)癥風(fēng)險(xiǎn)均降低。不中斷VKA（國際標(biāo)準(zhǔn)化比值2～3）和術(shù)中予以普通肝素（UFH）達(dá)到并維持ACT≥300s已成為房顫導(dǎo)管消融的標(biāo)準(zhǔn)抗凝方案。鑒于NOACs在減少血栓栓塞和大出血兩方面的明顯效能，傾向于推斷相同的方案用于NOACs會(huì)取得一樣或更好的結(jié)果是高度理解的。然而，盲目的外推也許是錯(cuò)誤的。例如，RE-ALIGN研究中，在存在機(jī)械性心臟瓣膜時(shí)，達(dá)比加群的危險(xiǎn)性大于華法林，由此說明考慮特殊臨床背景的重要性。因此，在房顫導(dǎo)管消融方面需要有NOACs的相關(guān)資料。

多項(xiàng)研究報(bào)道，在房顫導(dǎo)管消融的特定背景下，NOACs和華法林有類似的安全性和和療效，合并數(shù)據(jù)顯示，不中斷NOACs和VKA治療的患者之間腦卒中（0.28%比0.19%）和大出血（1.10%比1.60%）的發(fā)生率無顯著差異。不過，幾乎所有研究都是觀察性的，樣本量較小，患者是精心挑選的，有一定比例的NOACs術(shù)前并非真正未中斷（根據(jù)不同的劑量-時(shí)間方案而短暫中斷）。

有關(guān)術(shù)中抗凝處理從VKAs到NOACs能夠外推的是什么？

1 房顫消融時(shí)需要嚴(yán)格的術(shù)中抗凝

如前所述，房顫導(dǎo)管消融過程中患者暴露于圍手術(shù)期血栓栓塞高風(fēng)險(xiǎn)中，已有報(bào)道血栓栓塞事件的發(fā)生率依據(jù)診斷模式的不同從0.9%至5%。多種機(jī)制涉及這種特殊的術(shù)中血栓高發(fā)狀態(tài)（圖1）：（1）血液與消融器械異物表面的接觸，（2）由穿間隔的鞘、電極導(dǎo)管和消融能量釋放引起的左心房內(nèi)皮損傷和炎癥反應(yīng)，（3）損傷的細(xì)胞釋放促血栓形成成分，（4）轉(zhuǎn)為竇性心律后的血流發(fā)生改變。上述提到的因素同時(shí)激活外源性和內(nèi)源性凝血瀑布反應(yīng)。充分的術(shù)中抗凝目的是為減少這一血栓栓塞風(fēng)險(xiǎn)，盡管不中斷VAK治療的患者處于長期抗凝中，這些風(fēng)險(xiǎn)仍然持續(xù)存在。相反，房顫導(dǎo)管消融也存在大出血風(fēng)險(xiǎn)，過度的術(shù)中抗凝增加出血事件。這樣，務(wù)必進(jìn)行合適的抗凝監(jiān)測(cè)以防范手術(shù)相關(guān)的并發(fā)癥。

2 UFH是預(yù)防手術(shù)相關(guān)血栓形成的最佳抗凝劑

UFH是一種多靶點(diǎn)抗凝劑，作為生理性抑制劑抗凝血酶的輔助因子，主要影響凝血酶和作為共同通路的活化Ⅹ因子，另外影響活化的Ⅸ、Ⅺ和Ⅻ因子，這些涉及內(nèi)源性通路，又稱為接觸激活途徑（圖1）。因此，特別在及時(shí)使用情況下（當(dāng)于穿間隔前注射UFH時(shí)發(fā)生率下降75%），UFH可阻斷由組織因子暴露和隨后的外源性通路激活引起的消融損傷相關(guān)血栓形成，以及由內(nèi)源性通路激活引起的導(dǎo)管相關(guān)血栓形成（鞘管上血栓形成）。相反，靶點(diǎn)特定的抗凝劑如合成的五糖-磺達(dá)肝葵鈉或只抑制活化X因子或凝血酶的NOACs，不抑制接觸激活途徑，導(dǎo)致阻斷異物表面接觸誘發(fā)血栓的作用明顯不足。因此，對(duì)于不中斷NOACs的患者，術(shù)中抗凝需要以UFH為基礎(chǔ)來防范手術(shù)相關(guān)的血栓栓塞。最后，消融組織表面產(chǎn)生的壞死碎片不能被任何抗凝劑清除。

3 UFH需要可靠的監(jiān)測(cè)

給予固定或體重調(diào)節(jié)劑量的UFH時(shí)，個(gè)體內(nèi)和個(gè)體之間存在一定的劑量-反應(yīng)關(guān)系變異性。因此，對(duì)于任何個(gè)體彈丸注射UFH的作用是不可預(yù)測(cè)的，需要可靠的監(jiān)測(cè)。在房顫導(dǎo)管消融期間，用ACT監(jiān)測(cè)UFH療效，這是一種評(píng)估內(nèi)源性和常見凝血通路的床旁檢測(cè)。ACT測(cè)定新鮮全血與提供的表層基質(zhì)之間的反應(yīng)，無需外加磷脂和鈣。一致報(bào)道ACT與UFH的抗活化Ⅹ因子活性相關(guān)性強(qiáng)，證實(shí)ACT能有效反映UFH的生物學(xué)效應(yīng)。

有關(guān)不中斷NOAC術(shù)中抗凝方案的知識(shí)空缺是什么？

盡管研究數(shù)量增加，包括隨機(jī)對(duì)照試驗(yàn)探究不中斷NOAC治療患者的房顫導(dǎo)管消融，僅有少數(shù)關(guān)注術(shù)中抗凝處理。

總之，現(xiàn)有資料表明，與不中斷VKA治療患者比較，不中斷NOAC治療患者要達(dá)到目標(biāo)ACT值，術(shù)中的UFH需要量較大。在一項(xiàng)多中心研究中，與VKA組比較，要達(dá)到并維持ACT≥300s，不中斷阿哌沙班組需要較大量（增量達(dá)40%）UFH。同樣，VENTURE-AF試驗(yàn)中，與VKA組比較，利伐沙班組達(dá)到ACT＞300s的UFH所需量顯著增加（13 871 U比10 964 U），維持的平均ACT值較低（302 s比332 s）。有關(guān)達(dá)比加群，回顧性分析顯示，與VKA組比較，彈丸注射UFH后的ACT值和手術(shù)過程中的平均ACT值較低[（284±48）s比（312±55）s]，所需的UFH量較大[（62±29）U·kg-1·h-1比（58±27）U·kg-1·h-1]。

雖然這導(dǎo)致臨床并發(fā)癥的程度仍然不清楚，現(xiàn)有大量證據(jù)表明，不中斷NOAC治療患者使用UFH后，ACT不能作為總體抗凝狀態(tài)的可靠替代指標(biāo)。首先，使用UFH前的基礎(chǔ)抗凝狀態(tài)因個(gè)體之間的藥代動(dòng)力學(xué)變異大而不可預(yù)測(cè)，影響小一些的是NOAC濃度隨時(shí)間而變化，長時(shí)間手術(shù)濃度下降。其次，與凝血酶原時(shí)間和部分凝血活酶時(shí)間相似，ACT對(duì)NOACs并不敏感，手術(shù)開始時(shí)難以反映NOAC的濃度。ACT的濃度依賴增加呈非線性扁平曲線，對(duì)于特定類型的NOAC，ACT的敏感性不同。因此，高NOAC濃度，特別是抗活化X因子的，可以有正常的ACT，不同的NOACs之間，盡管治療濃度可比，但ACT不同。第三，已表明UFH對(duì)ACT的影響依據(jù)不中斷NOAC的類型而變化很大。這不能用基礎(chǔ)ACT不同或ACT不敏感而加以完全解釋。

圖1房顫導(dǎo)管消融過程凝血激活機(jī)制及抗凝靶點(diǎn)。TF為組織因子；UFH為普通肝素；VKA為維生素K拮抗劑。