International Circulation: As the new anti-coagulant， fondaparinux has been studied to be used clinically but there are still relatively few trials investigating it. Which issues do you feel future trials with fondaparinux will focus on?

《国际循环》: 作为一种新的抗凝药物，磺达肝癸钠已被研究用于临床，但是研究它的试验仍然相对较少。您觉得将来的磺达肝癸钠试验将集中关注哪些问题？

Prof. Bassand: Fondaparinux used in acute coronary syndromes is different from general use but in acute coronary syndromes it is true that we have only two Phase III trials. It is also true that we have two other trials with fondaparinux， a Phase II trial， which was a dose ranging study testing different doses of fondaparinux versus enoxaparin in a setting of acute coronary syndrome. This Phase II trial is a pivotal trial because it showed that there is no relationship between the dose and effect of ischemic events. The 2.5 mg dose was shown to be equally effective as higher doses but there was less bleed. That is why this dose was selected for OASIS 5 & 6. There is another trial less frequently referred to， called ASPIRE， that tested fondaparnux in a setting of PCI with two different doses， 2.5 mg and 5mg IV， given at the time of PCI versus unfractionated heparin. There was no difference in ischemic events but less bleeding with fondaparinux. These are two trials which served as pivotal trials to start Phase III trials. In OASIS 5 the message is very clear， 20 000 plus patients， significant risk reduction for bleeding， significant risk reduction for death， myocardial infarction， and stroke. Particularly death as a single event was significant reduced. It was the first time that this was looked at over time. The most important is the link of risk reduction for bleeding and is true for every category of patients， low risk， medium risk， and high risk， elderly， non-elderly， men， women， and renal failure patients. Irrespective of the initial category and the subset of patients there was the same beneficial effect， less bleeding and an impact on outcome. In the PCI setting there was an excess of stent thrombosis without control consequences that was kept under control by adding unfractionated heparin at the time of angioplasty but only if angioplasty is carried out. This led to a better efficacy in terms of death， MI， stroke， and bleeding versus enoxaparin. In other words， by adding unfractionated heparin it may be possible to get rid of thrombosis and not increase the risk of bleeding. For OASIS 5 these are the main results. In OASIS 6 we have just duplicated the same results with better efficacy using fondaparinux when compared to any competitor with a significant risk reduction for death， death by MI， and stroke. Again， death alone was reduced with fondaparinux. This was particularly true for patients who were not submitted to reperfusion and for patients who were submitted to telemetry treatment. There was no efficacy in the setting of primary PCI and a trend toward an excess of events， which was linked to the event of catheter thrombosis also observed in OASIS 6. Now if the question is what new trials can we develop and run in the setting of acute coronary syndrome using fondaparinux， the answer is very clear that we need a trial testing the efficacy of heparin reducing or eliminating the risk of stent thrombosis. This trial is underway and is called FUTURA with this aim. We should get the final results about the risk of catheter thrombosis with fondaparinux on board a year from now because the results will most probably be available at this time next year. So far we know from observational data in OASIS 5 that we can eliminate catheter thrombosis with unfractionated heparin added on top of fondaparinux during PCI but we are confirming that in a separate clinical trial. We know also from registry data particularly that is coming from my own department that if implement fondaparinux on a daily routine practice then you observe the same as was observed in OASIS 5， a 50% reduction of bleeding. It is a dream come true， fondaparinux makes it possible to reduce bleeding and reduce ischemic events. This is the first time this has been observed with an anticoagulant.

Bassand教授: 磺达肝癸钠用于急性冠脉综合征与一般应用有所不同，但是在急性冠脉综合征中我们确实只有两个III期临床试验。我们还有另外两个应用磺达肝癸钠的试验，一个是有关剂量范围研究的II期临床试验，在急性冠脉综合征的设计条件中将不同剂量的磺达肝癸钠与依诺肝素相比较。这一II期临床试验很关键，因为它显示剂量和缺血事件之间没有关系。研究显示，2.5 mg的剂量与更高的剂量等效，但是出血较少。这就是为什么该剂量被选择用于OASIS 5和6试验。另外还有一个较少被提及的试验，被称作ASPIRE，研究在PCI的设计条件中用两种不同剂量的磺达肝癸钠2.5 mg和5 mg静脉注射，在PCI时给药，并将其与普通肝素相比较。结果显示，缺血事件没有差异，但是使用磺达肝癸钠出血较少。这两个试验是开启III期临床试验的关键性试验。在OASIS 5中获得的信息非常明确，超过20 000名患者，出血、死亡、心肌梗死和卒中的风险显著降低。特别是，作为单一事件的死亡得到显著的降低，这在它被长期观察研究以来尚属首次。最重要的是与出血风险降低之间的关系，对于各种类型的患者，包括低危、中危、高危、老年、非老年、男性、女性、以及肾功能衰竭患者，其效果均为真实肯定。无论最初的类型和患者亚组，有益作用、出血较少以及对转归的影响均相同。在PCI条件下，支架血栓发生略多，可以通过在血管成形术时加用普通肝素使之得到控制，但是这仅发生于实施血管成形术的情况下。这导致与依诺肝素相比，包括死亡、心肌梗死、卒中和出血等方面的疗效更好。换言之，通过加用普通肝素，有可能免除血栓形成且不增加出血的风险。以上这些就是OASIS 5试验的主要结果。在OASIS 6 试验中，我们恰恰重复了相同的结果，磺达肝癸钠与任何竞争药物相比，效果更好，死亡、心肌梗死和卒中所致死亡的风险显著降低。死亡这一单独结果再次在应用磺达肝癸钠的组中被降低，对于没有接受再灌注的患者和接受了遥测监护治疗的患者尤为确定。在OASIS 6 试验中，磺达肝癸钠在直接PCI的条件下无效，有事件增多的趋势，这同样与导管内血栓形成相关。如果现在的问题是我们在急性冠脉综合征的条件下使用磺达肝癸钠，可以规划进行什么样的新试验，答案是非常明确的，我们需要一个试验来验证肝素降低或者消除支架血栓风险的效果。为了这一目的的试验正在进行中，名为FUTURA 。我们应该能在从现在开始的一年后得到有关使用磺达肝癸钠的导管血栓风险的最终结果，因为结果将很可能在明年的这个时候得到。到目前为止，我们从OASIS 5的观察性数据中可以知道，PCI过程中在磺达肝癸钠之外额外加用普通肝素可以消除导管血栓形成，但是我们正在用另一单独的临床试验对其进行确定。我们也从登记资料，特别是那些来自我自己部门的资料中知道，如果在日常实践中使用磺达肝癸钠，就可以观察到OASIS 5试验中所见到的相同结果，即出血率降低达50%。这就是梦想实现，磺达肝癸钠使出血降低和缺血事件减少得以成为可能，这在抗凝药物的使用中尚属首次。

International Circulation: Could you please talk about your opinion of the result of OASIS 5， particularly regarding the trial design limitations?

《国际循环》:能否请您谈论一下您对于OASIS 5试验结果的看法，特别是关于试验设计的局限性？

Prof. Bassand: Regarding the trial design I don’t believe there were any limitations. The design used in OASIS 5 was the same design as the in trial done in 2003 when we knew that 2.5 mg of fondaparinux was needed. So it was a single dose for everyone. For the enoxaparin group we just designed the trial according to the labeling of the drug， which， in 2003， was 1 mg/kg body weight twice each day. The labeling has not changed in the meantime. The only thing that has changed is the use of anticoagulants in cases of PCI is needed with enoxaparin on board. In 2003 the recommendations were to use an additional bolus of unfractionated heparin on top of enoxaparin at the time of PCI. The labeling has changed in the meantime， now you can go to PCI with enoxaparin but you need an additional bolus of eno