<International Circulation>: The new American atrial fibrillation guidelines recommend both warfarin and the new oral anticoagulant agents for the prevention of stroke. How should we choose between warfarin and the NOAGs?

　　《国际循环》：美国新发布的房颤指南推荐，华法林和新型口服抗凝剂都可用于卒中预防。在华法林和新型口服抗凝剂之间应如何选择？

　　Dr. Gersh: We are in a new era. The novel oral anticoagulants (NOAGs) are here to stay and I think the time has come to stop calling them novel anymore. They have been tested on 75000 patients and they are effective. I think we need a new name - perhaps the direct-acting oral anticoagulants or the non-vitamin K oral anticoagulants.We do need to reassess where we are with warfarin and how that involves these newer drugs.

　　Warfarin is a drug that was developed in the 1940s and 50s. Yes， it is rat poison and has that reputation. But it is very well tested. However， everyone seems to dislike warfarin; patients don’t like it， doctors don’t like it， media don’t like it， no one likes warfarin. But it is a very effective drug and it is very cheap. If you look at the trials for warfarin versus placebo or aspirin， they all took place in the 1980s and in those trials， warfarin reduced stroke by 68%. That is huge. It does increase bleeding but serious bleeding， such as intracranial bleeding， is pretty uncommon actually. Up until recently， the biggest problem has not been warfarin but that fact that we aren’t using it. In China for example， there is a very low rate of warfarin usage and a high rate of hypertension and atrial fibrillation. Although everybody criticized warfarin， that it has drug-drug interactions， you have to check the INR at regular intervals， it interacts with food， and it has all of these disadvantages.Warfarin is not an easy drug to give because the INRs fluctuate， some people are more sensitive (probably genetically) to it than others， but the fact remains that warfarin is a very effective drug and is very cheap.  About 7 or 8 years ago， there was a very important meeting held in Washington by Duke University and I was one of the people attending. We met with the Federal Drug Agency， with academia， with industry and asked， how are we going to design alternatives to warfarin and particularly drugs that don’t need to be checked with an INR?  When it came down to that kind of discussion， it was not that easy.  It is easy to dislike warfarin， but how do you demonstrate that a drug is better?  Firstly， we felt that we couldn’t do placebo trials any longer. It would be unethical. So it would have to be warfarin versus one of the new oral anticoagulants. That means a non-inferiority trial is required and these are difficult to design and require large numbers of people. With the novel oral anticoagulants， there isn’t an INR; you can’t measure them. How do you know that people are taking them?What about side effects and so on?

　　The end result of this was four trials: dabigatran， apixaban， rivaroxaban and now， edoxaban. 70000 patients. It is difficult to compare one drug with another because the people in the trial are different but some general statements can be made. The novel oral anticoagulants are safer.There is a much lower rate of bleeding and there is a lower rate of intracranial bleeding (almost 50% lower).Overall， if you put all four trials together， there is a 10% reduction in mortality.  Some of the trials showed non-inferiority and others showed superiority.  For the high dose of dabigatran， there was less thromboembolism and stroke.  With apixaban， there was a lower rate of stroke and thromboembolism. With the lower dose of dabigatran and with rivaroxaban， there was non-inferiority (the drugs didn’t reduce stroke but they reduced bleeding). If you put it all together， they certainly reduced bleeding， they reduced intracranial bleeding and some of the drugs at higher doses reduced stroke. So we now have four new drugs. When we try to compare them， it is difficult.I think we can say that the cheapest drug is warfarin. All of the new drugs are excreted by the kidney therefore renal function is very important.  The one that is excreted the most by the kidney is dabigatran. We have to be very careful when using these drugs in people with severe renal disease. I wouldn’t use them. In older people over the age of 75 with high dose dabigatran， there is increased bleeding. Rivaroxaban tested in high-risk people was very safe.Apixaban was interesting.In that trial， there was efficacy， reduction in stroke and reduction in bleeding.  The decision in the end of which drug to use will also come down to a question of price because warfarin is very cheap.  In terms of using the drugs， we are still in a learning phase. One thing I have learned is that all of the drugs， except rivaroxaban， are twice daily dosing. If you patient is non-compliant， they should not be on the new drugs because they have to be taken twice a day due to the drugs’ short half-life.  Renal function is so important and renal function changes with time， so I would always obtain a measurement of creatinine clearance or glomerular filtration rate when I start the drug， but I check it again at three months or six months or one year. This is important because the dose may change as renal function changes.  Right now， if you bleed we do not have an antidote but we will in two years time. With warfarin， there is vitamin K. So once clinical testing is complete， there will be antidotes for the anti-factor Xa inhibitors and the direct thrombin inhibitors.  In the meantime， if bleeding does occur with these new drugs (and that’s uncommon)， it is a big problem.

　　The other clinical issue we have to tackle is if someone is bleeding or needs a procedure， laboratory studies do not help us a great deal to see if they are anticoagulated. With warfarin it is easy to know if they anti-coagulate by using the INR. APTT will tell us if there is an anticoagulant effect but it won’t tell us how much of an effect.  If you have a patient on dabigatran and they have to go to surgery and you do an aPTT and its normal， you can say they are not anticoagulated.  If the APTT is abnormal， you can say there is an anticoagulant effect but you can’t measure it.  The important thing though is that the new drugs are here to stay. They are safer drugs and what I would say to cardiologists in hospitals is that you have to develop the protocols that will work in your institution. You have to have the protocols in place. How many days before an operation do you stop the drug? How soon afterwards can you start the drug?  What do you do if someone bleeds? These protocols have to be in place. We have had warfarin for sixty years and now we have had these drugs for two years. The question remains， is there still a need for warfarin?  Yes. It’s cheap. Prosthetic valves. Dabigatran has been tested with prosthetic valves and it doesn’t work， which leaves a strong indication for warfarin. There are people where you are worried about bleeding and it is helpful to control the INR and keep it low， then you need warfarin.  For people with severe renal dysfunction， you need warfarin. There is still a place for warfarin.  At least in Europe and the United States， everyone is very excited about these new drugs， but we don’t give up warfarin where so many people should be on warfarin. The message I would give is to stop using aspirin and put people on an anticoagulant whether it is an old one or a new one， but warfarin is much better than nothing. And there is no role for aspirin， at least routinely.

　　Gersh：在抗凝剂的选择方面我们处于一个新时代。已有7.5万例患者接受过新型口服抗凝剂治疗，被证实有效。 我认为我们需要为这些药起一个新名字——比如直接作用的口服抗凝剂或非维生素K类口服抗凝剂。在华法林和新型药物并存的情况下，我们确实需要重新评估应当如何选药。

　　华法林是上世纪四、五十年代发展起来的药物，以“毒鼠强”著称。但是华法林一直饱受诟病，无论医生、患者还是媒体。但华法林确实廉价又有效。回顾关于比较华法林和安慰剂或阿司匹林的试验，华法林能减少卒中发生率68%，这是相当强的作用。尽管会引发出血，但是严重出血如颅内出血很罕见。 直到现在，最大的问题也从未在华法林上发生过，因为其未被充分应用。 例如在中国，高血压和房颤高发但华法林应用率很低。

　　华法林服用并不方便，INR会波动，部分患者更敏感（可能与遗传有关）。7、8年前，美国华盛顿杜克大学举办了一场非常重要的会议，会上我们接到来自FDA、学术界以及厂家的提问，我们如何研发可替代华法林、不需要检测INR的药物？这种讨论并不容易得出结论。但如何证明新药更好？首先，不做安慰剂对照试验是不合常理的，所以必须用华法林和新型抗凝剂作对照。 这意味着需进行非劣效性试验，这非常难设计，且需要大样本人群。 对新型抗凝剂来说，不存在INR的问题，不需要监测。 那如何知道患者是否服药？不良反应如何？

　　目前有四项临床试验回答了上述问题，分别为达比加群、阿哌沙班、利伐沙班和依杜沙班。试验共纳入7万例患者，但比较药物之间的差异很难，纳入试验的患者各有特点，但也有些共同点。新型口服抗凝剂更安全，出血风险更低，尤其是颅内出血风险（降低50%），总死亡率降低10%。部分试验结果为非劣效性，而部分展现出显著优势。服用大剂量达比加群和阿哌沙班者，血栓栓塞和卒中发生率更低；小剂量达比加群和阿哌沙班则展现出非劣效性，不降低卒中发生率但能降低出血风险。新型口服抗凝剂确能降低出血风险，降低颅内出血，部分药物大剂量还能减少卒中发生。

　　所有新型口服抗凝剂均由肾脏代谢，因此肾功能是重要考量指标。由肾脏排泄最多的是达比加群，对部分有肾脏疾病的患者需要慎重用药，我个人不会用。对75岁以上人群应用大剂量达比加群会增加出血； 高危人群应用利伐沙班较安全；阿哌沙班还需进一步研究。最终，决定用何种药还是考虑到价格问题，我认为最划算的药物还是华法林，毕竟华法林非常便宜。另外注意到一件事是，所有新型口服抗凝剂除了利伐沙班，每日均需服用2次。如果患者依从性不佳，则不应处方新型口服抗凝剂。肾功能随时间变化，所以我在用药前通常检测患者的肌酐清除率和肾小球率过滤，而且每隔3个月、6个月或1年就重新检测一次。用药剂量随肾功能变化是很重要的。如果服用新型口服抗凝剂的患者发生出血，目前没有相应的拮抗剂，而华法林有维生素K可以拮抗。因此需要研发Ⅹa因子抑制剂和直接凝血酶抑制剂。在此期间，如果新型药物确实引发出血（尽管不常见），那将是一个严重的问题。

　　另一个 需要解决的临床问题是，如果患者发生出血或需要治疗，实验室研究并不能帮助识别是否因服用抗凝剂导致。部分凝血活酶时间（APTT）能帮助我们知道抗凝是否有效，但不知道有效的程度。如果患者正在服用达比加群，而且他们需要做手术，医生需要检测APTT是否正常，如果正常，才能说明他们未服用抗凝剂；如果APTT不正常，说明患者正在进行抗凝治疗，但无法测量抗凝的效果。但新型抗凝剂已经上市，我建议心血管住院医生发展一套适用于自己医院的流程，包括在手术前几天停止用药，术后几天开始用药，发生出血后如何处理？ 这些方案需要适时执行。华法林已经问世6年，新型口服抗凝剂只有2年。问题始终在持续：我们是否还需要华法林？是的，我们需要，因为它价格低廉，尤其对人工心脏瓣膜置入者有效。达比加群对置入人工新脏瓣膜患者无效，提示依然需要华法林治疗。另有患者疑似出血风险高，需要通过控制低水平INR，这时也需要华法林。对严重肾功能不全的患者，需要用华法林。华法林依然有用武之地。

　　在欧美国家，很多人都对新型口服抗凝剂感兴趣，但我们没有放弃华法林，因为还有很多患者需要它。我建议停用阿司匹林，应用抗凝治疗，无论传统抗凝剂还是新型口服抗凝剂。华法林比什么都没有要好得多，阿司匹林一般无效，至少常规用药无效。

　　<International Circulation>: You mentioned it is quite difficult to monitor the use of NOAGs to check for compliance. What are your recommendations for checking this? Do laboratory tests have a role?

　　《国际循环》：您提到监测口服抗凝剂的依从性难度很大。对此您有哪些建议？实验室数据有发现吗？

　　Dr. Gersh: No. There is no role for routinely testing at all. The only role for performing aPTT.

　　Gersh：没有。目前没有发现常规检测方法，唯一指标就是APTT。

　　<International Circulation>: So how do we monitor these drugs?

　　《国际循环》：那我们如何监测这些药物。

　　Dr. Gersh: That is one of the problems. What I do like about warfarin is that I can monitor its effect. So if you think the patient is non-compliant， just don’t use the novel oral anticoagulants in the first place and use warfarin. I think compliance is a much bigger problem than we appreciate and the other area where it is a huge problem is in hypertension.

　　Gersh：这是问题之一。我倾向于用华法林是因为它的疗效便于监测。所以如果认为患者依从性不佳，初始治疗就不要用新型抗凝剂，而要用华法林。我认为依从性是更需要重视的问题。

　　<International Circulation>: When an AF patient is on anticoagulation therapy and undergoing PCI， what is the best strategy to follow after PCI?

　　《国际循环》：当房颤患者进行抗凝治疗时接受PCI，PCI术后应当如何用药？

　　Dr. Gersh: This is the most difficult area in cardiology. What do you do with PCI and acute coronary syndrome? This is where a trial is needed. Atrial fibrillation patients will either be on warfarin or a novel oral anticoagulant. Do they need double therapy or do they need triple therapy? How long do they need it for? At the moment， it is probably twelve months – aspirin， clopidogrel. I don’t think we know enough about ticagrelor as the second at the moment， but certainly if its an acute coronary syndrome its twelve months of triple therapy. I think in the next year or two， that will change. Maybe with the newer stents it is going to come down to six months of triple therapy.

　　Gersh：这在心血管领域是非常困难的问题。PCI围术期和急性冠脉综合征（ACS）患者应当如何处理，依然需要临床试验数据。房颤患者接受华法林或新型口服抗凝剂治疗时，是否需要双重治疗或者三药治疗，需要治疗多长时间？现下推荐用阿司匹林+氯吡格雷12个月。我认为对替格瑞洛了解还不充分，但对ACS患者来说可作为三药治疗12个月的组分之一。在明年或后年，治疗方案将会有所变化。也许更新的支架会在三联疗法6个月后介入。

　　<International Circulation>: The interventionists are talking about three months with the new drug-eluting stents.

　　《国际循环》：介入专家指出新型药物洗脱支架应在3个月后介入。

　　Dr. Gersh: They are. We have to wait for the trials. This is going to be an important year for that question. There are a lot of trials ongoing. The other interesting question is， do we really need triple therapy or can we just get away with clopidogrel or ticagrelor and an oral anticoagulant. I think this is an area where I would say to people that 2014/15 will be a big year for this very difficult area. People on triple therapy bleed.

　　Gersh：是的。我们正在等待试验结果。这一年将是解决这些问题的关键时期，也有很多试验正在进行。另一个有意思的问题是，我们是否真的需要三联疗法，或者我们只用氯吡格雷/替格瑞洛和口服抗凝剂就能治愈。我认为2014-2015年将发布重大数据。三联疗法的患者存在出血现象。

　　<International Circulation>: So you would still be recommending twelve months on triple therapy?

　　《国际循环》：所以您依然推荐三联疗法治疗12个月？

　　Dr. Gersh: But I am individualizing because there are some patients that just can’t do it. In some people I am stopping aspirin and just using warfarin with an INR of 2 instead of 2.5-3. It is a difficult area and I think you need to individualize， as not all patients are the same.

　　Gersh：但我推荐个体化用药，因为部分患者不能耐受三联疗法。对部分患者我停用阿司匹林，仅用华法林并维持INR=2而非2.5～3。这是很难解决的，我认为用药需要个体化，不是所有患者都一样。