Lesson Ninety- three Management of antithrombotic therapy in atrial fibrillation patients undergoing PCI

Atrisl fibrillation （AF） increases the risk of thromboembolic complications, including stroke and extracranial systemic embolic events, which call for therapeutic prophylaxis with oral anticoagulation（OAC）. It is estimated that about 20% to 40% of patients with AF also present with coronary artery disease （CAD）,a sizeable proportion of whom requires revascularization using percutaneous coronary intervention（PCI）and stent implantation.Such patients need dual antiplatelet therapy （dual antiplatelet therapy，DAPT）to prevent the risk of stent thrombosis and additional thrombotic ischemic events.

The optimal antithrombotic treatment regimen for patients with AF undergoing PCI is a clinical conundrum. The combination of OAC and DAPT, a regimen also known as triple antithrombotic therapy（TAT）, is theoretically required to decrease both the risk of thromboembolism due to AF and the risk of thrombotic events due to coronary stents in patients with underlying CAD. However, TAT markedly increases the risk of major and fatal bleeding.

Antithrombotic Therapy for Patients with Nonvalvular AF

When it comes to stroke prevention for AF, OAC outperforms single antiplatelet therapy（SAPT）or DAPT（aspirin plus clopidogrel）. The ACTIVE W trial,comparing OAC with DAPT, was stopped early because of a clear evidence of superiority：OAC with a vitamin K antagonist（VKA）resulted in 31%fewer vascular events at 1 year.In AF patients who are deemed unsuitable for OAC with VKA, despite demonstration from the ACTIVE A trial that DAPT reduced the risk of major vascular events compared with aspirin monotherapy, the direct oral anticoagulant （DOAC）apixaban was found to reduce the risk of stroke or systemic embolism without increasing the risk of major bleeding when compared with aspirin.

The 2019 ACC/AHA/HRS guidelines for AF recommend that the selection of antithrombotic therapy for AF is based on the risk of thromboembolism assessed with the CHA2DS2-VASc score.In patients with AF and a CHA2DS2-VASc score ≥2 in men or ≥3 in women,OAC is recommended with warfarin or a DOAC,including dabigatran1, rivaroxaban, apixaban, or edoxaban.Notably,a DOAC is now preferred to warfarin in all DOAC-eligible candidates, unless they present with moderate-to-severe mitral stenosis or a mechanical heart valve. Male AF patients with a CHA2DS2-VASc score of 1 and female AF patients with a CHA2DS2-VASc score of 2 may receive OAC.Conversely, in male patients with a CHA2DS2-VASc score of 0 and female patients with a CHA2DS2-VASc score of 1 it is reasonable to omit OAC, which is not the case for AF patients with CAD undergoing PCI who are assigned by default a score of at least 1 （men）or 2（women）.

Antithrombotic Therapy for Patients UndergoingPCI

When it comes to thrombosis prevention for patients undergoing PCI,the benefit of DAPT over OAC is unequivocal. DAPT is the present standard of care after PCI both in the elective setting, with aspirin and clopidogrel, and in the course of an acute coronary syndrome（ACS）,with aspirin and,preferably,ticagrelor or prasugrel. Default DAPT durations in these settings are 6 and 12 months, respectively, but these durations are flexible depending on the individual risk of ischemia and bleeding.

Bleeding with Combination of OAC and Antiplatelet Therapy

Patients with AF on TAT experience high rates of major bleeding（e.g., bleeding requiring hospitalization or fatal bleeding）compared with patients on double antithrombotic therapy（DAT）or SAPT. In an updated nationwide Danish cohort study of 272,315 patients with AF patients aged 50 years or older,compared with VKA monotherapy over a total follow-up period of 1,373,131 patient-years, adjusted hazard ratios of major bleeding were 1.13 for DAPT, 1.82 for DAT with a VKA and SAPT, 1.28 for DAT with a DOAC and SAPT, 3.73 for TAT with VKA, and 2.28 for TAT with DOAC. The highest absolute rates of major bleeding were observed in patients treated with VKA-TAT who were older than 90 years （annualized rate 22.8% ）, had a CHA2DS2-VASc score ＞6（17.1%）, or presented with a history of major bleeding（17.5%）.

Procedural Considerations

PCI has become a safer procedure over the years.As part of a general periprocedural bleeding avoidance strategy, procedures should be carried out with radial access. Indeed, urgent or emergent procedures can be performed without withholding OAC. In general,patients on a DOAC undergoing elective or nonemergent procedures should withhold therapy for 24 h（or 48 h for patients with impaired renal function on dabigatran）. If the patient is on VKA, the North American recommendation suggests a wash-out period with target INR based on the type of vascular access（≤2 and ≤1.5 for radial and femoral access,respectively）,whereas the European document suggests that a strategy of uninterrupted VKA should be preferred over a strategy of interrupted VKA with heparin bridging. Both documents agree that patients with stable CAD can forgo bridging with parenteral anticoagulation. Additional unfractionated heparin should be administered as per usual practice to support PCI, at standard dose（70 to 100 U/Kg）in case of DOACs and reduced dose（30 to 50 U/Kg）in case of ongoing VKA.Bivalirudin may also be considered, particularly in patients at high bleeding risk, in those presenting with ACS, and if a femoral approach is being used. More potent therapies, such as cangrelor or glycoprotein IIb/IIIa inhibitors, are generally only recommended for selected cases at high,life-threatening risk for ischemic complications or for bail-out situations. Pretreatment with clopidogrel is indicated when PCI is likely or decided. Importantly,aspirin should be prescribed periprocedurally in all cases to decrease the risk of early stent-related thrombotic complications.

Risk Stratification for Thrombosis and Bleeding

After the indications for OAC and antiplatelet therapy are established, the North American and European consensus documents suggest that decisions should be guided by balancing the individual risk of atherothrombosis with the risk of major bleeding. A list of suggested criteria of high risk for ischemia/thrombosis and bleeding from the European focused update on DAPT is provided in Table 1.

Choice and Duration of Antithrombotic Strategies after PCI

In selecting the optimal antithrombotic regimen for an AF patient who received PCI, physicians have to consider some fundamental questions.As far as the type of OAC drug is concerned （first question）, in the absence of contraindications, DOACs should be preferred to VKAs due to the lower risk of bleeding previously demonstrated to be a class effect.

The second question deals with the duration of TAT. This spans from very short （e.g., until after successful PCI）to extended（e.g.,6 months）depending on various clinical scenarios. Notably, both the 2019 ACC/AHA/HRS guidelines for AF and the 2018 ESC Table 1 Criteria of High-Risk Features Tipping the Balance Toward More or Less Intense Antithrombotic Therapy for AF Patients Undergoing PCI guidelines for myocardial revascularization recommend DAT as an alternative to TAT to reduce bleeding,but in the European guidelines this indication is currently restricted to patients at baseline high bleeding risk.

Criteria of high stent-driven thrombotic risk Criteria of high bleeding risk that make the combination of OAC and antiplatelet therapy unfavorable Prior stent thrombosis on adequate antiplatelet therapy Short life expectancy,advanced age Ongoing malignanc with high bleeding potential Diffuse multivessel disease especially in diabetic patients Stenting of the last remaining patent coronary artery Poor expected adherence, poor mental status Chronic kidney disease（e.g.creatinine clearance＜60ml/min）Prior major bleeding/prior hemorrhagic stroke At least 3 stents in planted End stage renal failure Bifurcation with 2 stents in planted Chronic alcohol abuse Total stent length＞60mm Anemia Treatment of a chronic total occlusion Clinically significant bleeding on DAT

The third question deals with the specific antiplatelet drug to be discontinued in the transition from TAT to DAT.The consensus of the North American and European documents is that a P2Y12 inhibitor should be used without aspirin. This recommendation is based on the well-established notion that,post-PCI,the use of a P2Y12 inhibitor is pivotal for the prevention of thrombotic complications.

The fourth question deals with the dosing regimen of a DOAC for combination therapy in TAT or DAT regimens.In TAT regimens,both documents recommend using approved doses proven to be effective in regulatory trials of AF, with dose reductions as per the respective package labels（i.e.,due to reduced renal elimination in patients with chronic kidney disease）. In the case of dabigatran, the North American document suggests to use a higher 150-mg bid dose for patients who are at higher thrombotic risk; the European consensus documents, consistent with the 2018 ESC guidelines on myocardial revascularization, suggest using the 110-mg bid dose during TAT and the 150-mg bid dose during DAT,due to concerns of higher thrombotic risk with the lower dose.If rivaroxaban is used,the 15-mg od dose is considered a reasonable option. After discontinuation of the P2Y12 inhibitor, OAC should be continued at full stroke prevention doses. Therefore, if a reduced dose regimen of rivaroxaban（e.g., 15 mg od; 10 mg od in patients with renal dysfunction）was being used, it is important to resume the full recommended dose（20 mg od; 15 mg od in patients with renal dysfunction）after suspension of antiplatelet therapy.

The fifth question deals with the choice of P2Y12 inhibitor. In this category, clopidogrel should be regarded as the agent of choice.Prasugrel and ticagrelor are approved for patients with ACS, and there is limited data for their use in combination with OAC. The 2018 ESC guidelines on myocardial revascularization formally contraindicate the use of both prasugrel and ticagrelor in combination with OAC, whereas the 2019 ACC/AHA/HRS guidelines for AF recommend clopidogrel in TAT combinations.

Finally, a sixth question deals with the optimal management at 12 months from PCI,when the patient is typically on DAT unless the P2Y12 inhibitor has been discontinued earlier as suggested in both the North American and European consensus documents for patients at very high risk of bleeding. Ideally, the patients should continue on OAC alone, based on registry and other observational data showing that in patients with stable CAD（e.g., ＞1 year, with no acute events）, the addition of antiplatelet therapy to OAC increases bleeding without adding ischemic protection compared with OAC alone.

詞 匯

conundrum n. 難題，謎語;

triple adj. &v. 三部分的，三人的，三組的，三倍的，三重的;成為三倍，使增至三倍;

thromboembolism n. 血栓栓塞

superiority n. 優越性，優勢，土地權利

注 釋

1.Dabigatran（達比加群）是直接凝血酶抑制劑，rivaroxaban（利伐沙班）,apixaban（阿哌沙班）和edoxaban（依度沙班）均是直接活化X 因子的抑制劑，這4 種抗凝劑均為口服，呈競爭性可逆性抑制作用，半衰期在12h 左右，目前均不推薦用于瓣膜性房顫或心臟機械瓣患者。

參考譯文

第93 課 冠狀動脈PCI 合并心房顫動患者的抗栓治療

心房顫動（房顫）增加血栓栓塞并發癥的風險，包括腦卒中和顱外的全身性栓塞事件，這呼吁行口服抗凝劑（oral anticoagulation，OAC）預防性治療。估計20%～40%的房顫患者患有冠心病, 其中相當比例的患者需要行經皮冠狀動脈介入治療（percutaneous coronary intervention，PCI）和植入支架再血管化治療。這類患者需要血小板雙抗治療（dual antiplatelet therapy,DAPT）來防范支架血栓形成和其他血栓性缺血事件。

行PCI 治療房顫患者的優化抗栓治療是一臨床難題。對于冠心病患者，為減少房顫的血栓栓塞和冠狀動脈支架的血栓事件，理論上需聯合OAC 和DAPT，又稱三聯抗栓治療（triple antithrombotic therapy，TAT）。然而，TAT 明顯增加大出血和致命性出血的風險。

非瓣膜性房顫患者的抗栓治療

在涉及房顫的腦卒中預防時，OAC 優于血小板單抗（single antiplatelet therapy，SAPT）或DAPT（阿司匹林+ 氯吡格雷）。OAC 與DAPT 對比的ACTIVE W 試驗，因為優勢明顯而提前中止：使用維生素K 拮抗劑（vitamin K antagonist，VKA）OAC 減少31%的年血管事件。對于不適合VKA OAC的患者，盡管ACTIVE A 試驗證實DAPT 相比阿司匹林單一治療降低大的血管事件，直接口服抗凝劑（direct oral anticoagulant，DOAC）阿哌沙班與阿司匹林對比能降低腦卒中或全身栓塞而不增加大出血風險。

2019 ACC/AHA/HRS 房顫指南推薦基于CHA2DS2-VASc 評分的血栓栓塞風險選擇抗栓治療。當房顫患者CHA2DS2-VASc 評分≥2（男性）或≥3（女性）時，推薦的OAC是華法林或DOAC，包括達比加群、利伐沙班、阿哌沙班或依度沙班。值得注意的是對于所有DOAC 適用的患者，DOAC優于華法林，除非存在中重度的二尖瓣狹窄或機械心臟瓣膜。CHA2DS2-VASc 評分1 分的男性患者和2 分的女性患者可行OAC 治療。相反，CHA2DS2-VASc 評分0 分的男性和1分的女性不必OAC 治療，當房顫合并冠心病行PCI 治療時并非如此，因為此類患者的默認值為1 分（男性）或2 分（女性）。

PCI 患者的抗栓治療

在涉及PCI 患者的血栓預防時，DAPT 明確優于OAC。無論擇期或急性冠脈綜合征（acute coronary syndrome，ACS）PCI 后DAPT 都是目前的標準方案，前者選用阿司匹林和氯吡格雷，后者優選阿司匹林和替格瑞洛或普拉格雷。默認的DAPT 時間分別為6 和12 個月，這些時間可因個體的缺血和出血風險而調整。

聯合OAC 和抗血小板治療的出血風險

房顫患者TAT 治療與雙重抗栓治療（DAT）或SAPT 治療比較，大出血風險（即需要住院治療或致命的出血）發生率高。丹麥最新一項納入272,315 例年齡≥50 歲房顫患者的研究表明，與單獨VKA 治療比較，在隨訪1 373 131 病例后，調整后的風險比值DAPT 為1.13，VKA 聯合SAPT 的DAT 為1.82，聯合DOAC 和SAPT 的DAT 為1.28,使用VKA 的TAT為3.73，使用DOAC 的TAT 為2.28。使用VKA TAT 治療大出血絕對風險最高的是年齡超過90 歲（年發生率22.8%）、CHA2DS2-VASc 評分＞6 分（年發生率17.1%）,或既往有大出血病史（年發生率17.5%）的患者。

手術問題

多年來PCI 已成為較為安全的手術。作為避免常規圍手術期出血方案的一部分，手術應采用橈動脈徑路。事實上，急診手術時不停用OAC。通常情況下，服用DOAC 的患者行擇期或非急診手術時應停服24h（對于腎功能不全而服用達比加群者，停服48h）。如服用的是VKA，北美建議的清洗期是基于血管徑路的目標INR 值（橈動脈徑路≤2，股動脈徑路≤1.5）,而歐洲建議不中斷VKA 的方案優于肝素橋接的中斷VKA 方案。兩套建議均認為穩定型冠心病可以放棄腸外抗凝橋接。按照通常的PCI 治療，額外加用普通肝素，服用DOAC者予以標準劑量（70～100 U/Kg），而服用VKA 者則減量（30～50 U/Kg）。特別對于高出血風險、ACS 或采用股動脈徑路者，也可選用比伐盧定。更有力的治療如坎格雷洛或血小板糖蛋白Ⅱb/Ⅲa 抑制劑通常只能用于那些缺血并發癥風險高或危及生命者或救急情況下。當決定PCI 時，應預先服用氯吡格雷，重要的是對于所有患者為減少早期支架相關血栓并發癥，應予以阿司匹林。

血栓與出血的危險分層

在確立OAC 和抗血小板治療指征后，北美和歐洲的共識建議應平衡動脈血栓或出血的具體風險來指導臨床決策。表1 為歐洲聚焦DAPT 更新后推薦的缺血/血栓和出血高風險標準。

表1 房顫患者PCI 后促使平衡傾向較強或較弱抗栓治療的高危特征標準

PCI 后抗栓方案的選擇和時間

對于行PCI 治療的房顫患者的優化抗栓治療方案選擇，醫師應考慮一些基本問題。有關OAC 藥物的選擇（第一個問題），如無禁忌癥，DOAC 應該優于VKA，基于以前已證實的較低出血風險類效應。

第二個問題是TAT 的時間。這決定于各種臨床情況，從很短（如PCI 成功后）到延長（如6 個月）。值得注意的是2019 ACC/AHA/HRS 房顫指南和2018 ESC 心肌血管重建指南均推薦DAT 替代TAT 以減少出血，而歐洲指南中這一指征當前僅限于存在高出血風險者。

第三個問題涉及從TAT 轉換為DAT 過程中的特殊抗血小板藥物停用。北美和歐洲建議選用P2Y12 抑制劑而不用阿司匹林。這一推薦基于已確立的觀念，即PCI 后P2Y12 抑制劑是預防血栓并發癥的關鍵。

第四個問題是TAT 或DAT 治療中的DOAC 劑量。TAT方案中，兩套指南都推薦規范性房顫試驗中證實有效的劑量，根據各包裝盒上標注減量（如慢性腎臟疾病腎排泄下降時）。關于達比加群，北美建議較高血栓風險者予以150mg 2次/d，而歐洲建議與2018 ESC 心肌血管重建指南一致，建議TAT 時110mg 2 次/d 而DAT 時150mg 2 次/d，因考慮到較低劑量時血栓風險較高。如用利伐沙班，15mg od 是合理的。停用P2Y12 抑制劑后，應采用全量OAC 預防腦卒中。因此，低溫性J 波的電生理機制進行了相關研究。Brugada兄弟發現Brugada 綜合征患者的心電圖可間歇性出現J 波。日本學者報道部分特發性心室顫動患者的心電圖可有J 波，并稱為特發性J 波。目前多數學者認同J 波是心室提前復極產生，主要與心室肌Ito（短暫外向鉀電流）有關。心肌內外膜的動作電位存在差異，尤其在復極過程中，外膜心肌的Ito 大于內膜，在一些因素的影響下，如藥物、低溫、電解質紊亂（高鈣血癥）、自主神經損傷、缺血等情況下使得心外膜Ito 瞬間增大，與內膜心肌的復極梯度明顯增大，導致J 波出現以及相應的ST-T 改變。

神經源性J 波與自主神經興奮性不均衡，或與交感神經系統功能障礙相關。支持的依據有：（1）腦死亡者心電圖可出現J 波；（2）J 波出現后經注射腎如利伐沙班采用的是減量方案（如15 mg od，腎功能不全者10 mg od），當停用抗血小板治療后，采用推薦的全量（20 mg od;腎功能不全者15 mg od）很重要。

第五個問題涉及P2Y12 抑制劑的選擇。應選擇氯吡格雷。普拉格雷和替格瑞洛已獲批用于ACS，但與OAC 聯合應用的資料有限。2018 ESC 心肌血管重建指南禁止普拉格雷和替格瑞洛與OAC 聯用，而2019 ACC/AHA/HRS 房顫指南推薦TAT 中用氯吡格雷。

最后，第六個問題是PCI 后12 個月時的最佳處理。此時的治療是DAT，除非屬北美和歐洲共識中的出血風險高危者，已提前停服P2Y12 抑制劑。理想的是患者應繼以OAC 單獨治療，根據注冊的和其他觀察性治療資料，對于穩定型冠心?。ǎ? 年無急性事件發生）患者，與OAC 單獨治療相比，在OAC 基礎上加用抗血小板治療增加出血而不減少缺血事件。