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.

词 汇

conundrum n. 难题，谜语;

triple adj. &v. 三部分的，三人的，三组的，三倍的，三重的;成为三倍，使增至三倍;

thromboembolism n. 血栓栓塞

superiority n. 优越性，优势，土地权利

注 释

1.Dabigatran（达比加群）是直接凝血酶抑制剂，rivaroxaban（利伐沙班）,apixaban（阿哌沙班）和edoxaban（依度沙班）均是直接活化X 因子的抑制剂，这4 种抗凝剂均为口服，呈竞争性可逆性抑制作用，半衰期在12h 左右，目前均不推荐用于瓣膜性房颤或心脏机械瓣患者。

参考译文

第93 课 冠状动脉PCI 合并心房颤动患者的抗栓治疗

心房颤动（房颤）增加血栓栓塞并发症的风险，包括脑卒中和颅外的全身性栓塞事件，这呼吁行口服抗凝剂（oral anticoagulation，OAC）预防性治疗。估计20%～40%的房颤患者患有冠心病, 其中相当比例的患者需要行经皮冠状动脉介入治疗（percutaneous coronary intervention，PCI）和植入支架再血管化治疗。这类患者需要血小板双抗治疗（dual antiplatelet therapy,DAPT）来防范支架血栓形成和其他血栓性缺血事件。

行PCI 治疗房颤患者的优化抗栓治疗是一临床难题。对于冠心病患者，为减少房颤的血栓栓塞和冠状动脉支架的血栓事件，理论上需联合OAC 和DAPT，又称三联抗栓治疗（triple antithrombotic therapy，TAT）。然而，TAT 明显增加大出血和致命性出血的风险。

非瓣膜性房颤患者的抗栓治疗

在涉及房颤的脑卒中预防时，OAC 优于血小板单抗（single antiplatelet therapy，SAPT）或DAPT（阿司匹林+ 氯吡格雷）。OAC 与DAPT 对比的ACTIVE W 试验，因为优势明显而提前中止：使用维生素K 拮抗剂（vitamin K antagonist，VKA）OAC 减少31%的年血管事件。对于不适合VKA OAC的患者，尽管ACTIVE A 试验证实DAPT 相比阿司匹林单一治疗降低大的血管事件，直接口服抗凝剂（direct oral anticoagulant，DOAC）阿哌沙班与阿司匹林对比能降低脑卒中或全身栓塞而不增加大出血风险。

2019 ACC/AHA/HRS 房颤指南推荐基于CHA2DS2-VASc 评分的血栓栓塞风险选择抗栓治疗。当房颤患者CHA2DS2-VASc 评分≥2（男性）或≥3（女性）时，推荐的OAC是华法林或DOAC，包括达比加群、利伐沙班、阿哌沙班或依度沙班。值得注意的是对于所有DOAC 适用的患者，DOAC优于华法林，除非存在中重度的二尖瓣狭窄或机械心脏瓣膜。CHA2DS2-VASc 评分1 分的男性患者和2 分的女性患者可行OAC 治疗。相反，CHA2DS2-VASc 评分0 分的男性和1分的女性不必OAC 治疗，当房颤合并冠心病行PCI 治疗时并非如此，因为此类患者的默认值为1 分（男性）或2 分（女性）。

PCI 患者的抗栓治疗

在涉及PCI 患者的血栓预防时，DAPT 明确优于OAC。无论择期或急性冠脉综合征（acute coronary syndrome，ACS）PCI 后DAPT 都是目前的标准方案，前者选用阿司匹林和氯吡格雷，后者优选阿司匹林和替格瑞洛或普拉格雷。默认的DAPT 时间分别为6 和12 个月，这些时间可因个体的缺血和出血风险而调整。

联合OAC 和抗血小板治疗的出血风险

房颤患者TAT 治疗与双重抗栓治疗（DAT）或SAPT 治疗比较，大出血风险（即需要住院治疗或致命的出血）发生率高。丹麦最新一项纳入272,315 例年龄≥50 岁房颤患者的研究表明，与单独VKA 治疗比较，在随访1 373 131 病例后，调整后的风险比值DAPT 为1.13，VKA 联合SAPT 的DAT 为1.82，联合DOAC 和SAPT 的DAT 为1.28,使用VKA 的TAT为3.73，使用DOAC 的TAT 为2.28。使用VKA TAT 治疗大出血绝对风险最高的是年龄超过90 岁（年发生率22.8%）、CHA2DS2-VASc 评分＞6 分（年发生率17.1%）,或既往有大出血病史（年发生率17.5%）的患者。

手术问题

多年来PCI 已成为较为安全的手术。作为避免常规围手术期出血方案的一部分，手术应采用桡动脉径路。事实上，急诊手术时不停用OAC。通常情况下，服用DOAC 的患者行择期或非急诊手术时应停服24h（对于肾功能不全而服用达比加群者，停服48h）。如服用的是VKA，北美建议的清洗期是基于血管径路的目标INR 值（桡动脉径路≤2，股动脉径路≤1.5）,而欧洲建议不中断VKA 的方案优于肝素桥接的中断VKA 方案。两套建议均认为稳定型冠心病可以放弃肠外抗凝桥接。按照通常的PCI 治疗，额外加用普通肝素，服用DOAC者予以标准剂量（70～100 U/Kg），而服用VKA 者则减量（30～50 U/Kg）。特别对于高出血风险、ACS 或采用股动脉径路者，也可选用比伐卢定。更有力的治疗如坎格雷洛或血小板糖蛋白Ⅱb/Ⅲa 抑制剂通常只能用于那些缺血并发症风险高或危及生命者或救急情况下。当决定PCI 时，应预先服用氯吡格雷，重要的是对于所有患者为减少早期支架相关血栓并发症，应予以阿司匹林。

血栓与出血的危险分层

在确立OAC 和抗血小板治疗指征后，北美和欧洲的共识建议应平衡动脉血栓或出血的具体风险来指导临床决策。表1 为欧洲聚焦DAPT 更新后推荐的缺血/血栓和出血高风险标准。

表1 房颤患者PCI 后促使平衡倾向较强或较弱抗栓治疗的高危特征标准

PCI 后抗栓方案的选择和时间

对于行PCI 治疗的房颤患者的优化抗栓治疗方案选择，医师应考虑一些基本问题。有关OAC 药物的选择（第一个问题），如无禁忌症，DOAC 应该优于VKA，基于以前已证实的较低出血风险类效应。

第二个问题是TAT 的时间。这决定于各种临床情况，从很短（如PCI 成功后）到延长（如6 个月）。值得注意的是2019 ACC/AHA/HRS 房颤指南和2018 ESC 心肌血管重建指南均推荐DAT 替代TAT 以减少出血，而欧洲指南中这一指征当前仅限于存在高出血风险者。

第三个问题涉及从TAT 转换为DAT 过程中的特殊抗血小板药物停用。北美和欧洲建议选用P2Y12 抑制剂而不用阿司匹林。这一推荐基于已确立的观念，即PCI 后P2Y12 抑制剂是预防血栓并发症的关键。

第四个问题是TAT 或DAT 治疗中的DOAC 剂量。TAT方案中，两套指南都推荐规范性房颤试验中证实有效的剂量，根据各包装盒上标注减量（如慢性肾脏疾病肾排泄下降时）。关于达比加群，北美建议较高血栓风险者予以150mg 2次/d，而欧洲建议与2018 ESC 心肌血管重建指南一致，建议TAT 时110mg 2 次/d 而DAT 时150mg 2 次/d，因考虑到较低剂量时血栓风险较高。如用利伐沙班，15mg od 是合理的。停用P2Y12 抑制剂后，应采用全量OAC 预防脑卒中。因此，低温性J 波的电生理机制进行了相关研究。Brugada兄弟发现Brugada 综合征患者的心电图可间歇性出现J 波。日本学者报道部分特发性心室颤动患者的心电图可有J 波，并称为特发性J 波。目前多数学者认同J 波是心室提前复极产生，主要与心室肌Ito（短暂外向钾电流）有关。心肌内外膜的动作电位存在差异，尤其在复极过程中，外膜心肌的Ito 大于内膜，在一些因素的影响下，如药物、低温、电解质紊乱（高钙血症）、自主神经损伤、缺血等情况下使得心外膜Ito 瞬间增大，与内膜心肌的复极梯度明显增大，导致J 波出现以及相应的ST-T 改变。

神经源性J 波与自主神经兴奋性不均衡，或与交感神经系统功能障碍相关。支持的依据有：（1）脑死亡者心电图可出现J 波；（2）J 波出现后经注射肾如利伐沙班采用的是减量方案（如15 mg od，肾功能不全者10 mg od），当停用抗血小板治疗后，采用推荐的全量（20 mg od;肾功能不全者15 mg od）很重要。

第五个问题涉及P2Y12 抑制剂的选择。应选择氯吡格雷。普拉格雷和替格瑞洛已获批用于ACS，但与OAC 联合应用的资料有限。2018 ESC 心肌血管重建指南禁止普拉格雷和替格瑞洛与OAC 联用，而2019 ACC/AHA/HRS 房颤指南推荐TAT 中用氯吡格雷。

最后，第六个问题是PCI 后12 个月时的最佳处理。此时的治疗是DAT，除非属北美和欧洲共识中的出血风险高危者，已提前停服P2Y12 抑制剂。理想的是患者应继以OAC 单独治疗，根据注册的和其他观察性治疗资料，对于稳定型冠心病（＞1 年无急性事件发生）患者，与OAC 单独治疗相比，在OAC 基础上加用抗血小板治疗增加出血而不减少缺血事件。