International Circulation: Some experts believed that the expectation of ticagrelor was too optimistic， what’s your opinion?
　　国际循环：有些专家认为，目前对替卡格雷的期望过于乐观。您对此有何看法？
　　Prof. Kereiakes: My response is that the utility of a medication， any medication， is the combination of efficacy， safety and tolerability. Ticagrelor clearly reduced primary endpoint events which were cardiovascular death， non-fatal MI， non-fatal stroke， relative to clopidogrel. It accomplished the primary efficacy endpoint with a high degree of statistical significance. There was a 16% relative reduction in a trial of almost 19000 patients. That was a highly statistically significant relative benefit of ticagrelor.
　　With respect to safety， ticagrelor had no difference in overall major bleeding. Either PLATO protocol defined major bleed or TIMI  major bleed were similar in the ticagrelor versus clopidogrel treated patients. This fact a reflection of the subcomponents non-CABG related bleeding was actually increased by ticagrelor compared to clopidogrel. In fact to a similar extent， the difference between ticagrelor treated patients to clopidogrel treated patients for non-CABG related major TIMI bleeding was 0.6% and had a p-value of 0.025. The difference between CABG related major bleeding seen in ticagrelor versusclopidogrel trended lower. There was actually less， but not statistically significant lower non-CABG related bleeding in the ticagrelor treated patients. This shift in the occurrence of major bleeding between the non-CABG and the CABG patients actually balanced each other out. So in the net， there was no major difference in bleeding between the two treatment arms. This clearly differed from TRITON-TIMI 38 where non-CABG related major TIMI bleeding increased by the novel P2Y12 receptor prasugrel. To a similar extent it was in TRITON as it was in PLATO with a 0.6% with a p-value of 0.03. However， in TRITON， prasugrel was associated with a highly significant increase in CABG related major bleeding. Overall， major bleeding is increased in the TRITON trial because it would be the sum of non-CABG plus CABG-related. There wasn’t the counterbalancing effect we saw in PLATO. Prasugrel was associated with a highly significant increase in CABG-related major bleeding， but risk associated with prasugrel related to clopidogrel was similar to the risk associated with ticagrelor relative to clopidogrel for non-CABG related major bleed.
　　Finally， tolerability， there are specific aspects of ticagrelor that are different， even unique if you will， and include dyspnea in 14%， but only required termination of the study drug in 1%. But this is probably a central nervous system adenosine mediated effect of ticagrelor. It’s been shown that there are absolutely no differences in blood gas exchange in pulmonary function test associated with dyspnea. But that is disconcerting certainly in some populations like in the US where obesity is rampant and shortness of breath is the most common symptom we see as a clinician. This potentially complicates our existence.
　　Number two was ventricular pauses of three seconds or more. This is really another potential issue when patients are admitted with an ACS and you start them on a medication and they have pauses in their electrocardiogram and their pulse. It can be challenging. Also there was an increase in uric acid which is a curiosity， but this has no clinical relevance that we know of at this point and an increase in creatinine in a significant portion of ticagrelortreated patients compared to clopidogrel.
　　In the US， where we， in most aggressive， high volume centers do angiography early within 48 hours. In fact that it is a Class 1 recommendation according to the ACC/AHA guidelines for patients that are high risk with ACS. We have some concern that the bump in creatinine with ticagrelor may be confused with contrast induced nephropathy or maybe potentiate that with contrast induced nephropathy is a quality performance parameter that is being tracked at this point. Having these other issues at times can interfere， complicate or interact， if you will， the care of patients with ticagrelor.
　　Kereiakes教授：我认为，对于任何药物来说，药物的效用都是疗效，安全性和耐受性的三者组合。与氯吡格雷相比，替卡格雷显著降低了主要终点事件，即心血管性死亡，非致命性心肌梗死和非致命性中风的发生率。替卡格雷达到了主要疗效终点，并且具有相当高的统计学意义。在一个大约19000名患者的试验中，其相对降低率高达16%。这一结果显示，替卡格雷的相对获益具有高度的统计学意义。
　　在安全性方面，替卡格雷对整体主要出血事件无差异。无论是在PLATO研究还是在TIMI研究中，接受替卡格雷治疗的患者与接受氯吡格雷治疗的患者相比，两者的主要出血事件发生率均相似。在非冠状动脉搭桥术（CABG）的患者中，替卡格雷与氯吡格雷相比实际上增加了相关的出血事件。在相似程度上，采用替卡格雷的患者与采用氯吡格雷的患者相比，在非CABG相关的主要TIMI出血事件的差别是0.6%，P值为0.025。关于CABG相关的主要出血事件，替卡格雷与氯吡格雷相比则显示出了降低的趋势。接受替卡格雷的患者中，非CABG相关性出血事件数值上是减少的，但是没有统计学意义。这种非CABG与CABG患者之间主要出血事件发生率的转变实际上让两者实现了平衡。所以，在两组治疗组中，出血事件的发生率没有显著不同。这显然不同于TRITON-TIMI 38的研究结果，采用新型P2Y12受体普拉格雷增加了非CABG相关的主要TIMI出血事件的发生率。在类似程度上，TRITON研究同PLATO研究一样，差别为是0.6%，而P值为0.03。然而，在TRITON试验中，普拉格雷与CABG相关的主要出血事件发生率的显著升高具有相关性。总体而言，在TRITON试验中，主要出血事件是升高的，这是由于该发生率是非CABG和CABG相关出血事件发生率的总和。没有出现我们在PLATO试验中所看到的制衡作用。普拉格雷与CABG相关的主要出血事件的显著增加具有相关性，但是对于非CABG相关的主要出血事件来说，普拉格雷对比氯吡格雷的相关风险与替卡格雷对比氯吡格雷的相关风险是类似的。
　　最后，在耐受性方面，替卡格雷具有一些特别的方面，甚至可以说的独一无二的，其中包括呼吸困难的发生率占14%，但是需要终止研究用药的只占1%。但是，这可能是替卡格雷的一种中枢神经系统的腺苷介导作用。有研究已经表明，在呼吸困难相关的肺功能测试中，血气功能检查完全没有差别。但是，对于某些人群来说仍然令人很不安，比如美国，对于医生来说，该国肥胖症非常普遍而且气短是最常见的症状。这可能让我们的处境更加复杂。
　　其次是心室停顿间隔在3秒或3秒以上。这的确是另一个潜在问题，当患者诊断为急性冠脉综合征并开始接受药物治疗时，发现该患者的心电图和脉搏有停顿。这可能非常具有挑战性。还有一个奇特的地方在于尿酸的升高，但是就我们所知，这一表现并没有临床相关性，与氯吡格雷相比，接受替卡格雷治疗的患者肌酐水平的升高很显著。
　　在美国治疗最积极的大型医疗中心，早在48小时以内就开始进行血管造影治疗。事实上，这是ACC/AHA指南推荐的针对高危ACS患者的一类建议。但是我们有些担心替卡格雷引起的肌酐升高会与造影剂导致的肾病相混淆，或者可能加强了造影剂导致的肾病，该方面为正在进行研究的高质量性能参数。时不时出现的其它问题可能对替卡格雷患者的管理带来干扰，使其复杂化或者产生相互作用。
　　International Circulation: PLATO study showed ticagrelor increased risk of bleeding compared with clopidogrel， but there was no significant difference in mortality， which some experts have expressed confusion， what’s your opinion?
　　国际循环：PLATO研究显示，替卡格雷与氯吡格雷相比，能够增加出血的危险性，但是死亡率没有显著性差异，许多专家都对此表示了困惑，您对此有何看法呢？
　　Prof. Kereikes:To clarify the issue， PLATO showed a 20% reduction in mortality in favor of ticagrelor compared to clopidogrel. In fact that is single outstanding aspect of the PLATO study was the relative survival advantage seen with ticagrelor. The reduction in mortality in the STEMI cohort where there were 7500 STEMI patients in PLATO was 18%. Interestingly， in the TRITON trial， prasugrel compared to clopidogrel in the STEMI subpopulation where there 3500 patients analyzed， there is a 24% relative reduction in relative mortality with prasugrel compared to clopidogrel.
　　It is really complex and no one has been able to adequately explain the mortality reduction with ticagrelor and the apparent survival advantage. Is it due to the reduction in major bleeding events which were in large part related to CABG? That is one potential explanation. We know that major bleeding is linked to mortality at one year. We know that from the ACUITY trial， the HORIZONS AMI trial. We know from most modern clinical research trial analyses that major bleeding significantly increases mortality at one year. It is possible then that at the reduction of major bleeding with ticagrelor is in part responsible for this reduction in mortality with ticagrelor. Secondly， there has been an attribute of blocking adenosinere-uptake by red blood cells that ticagrelor does. It has been shown to do this. This may cause the dyspnea associated with the medicine. It may also provide the anti-ischemic effect as we know that adenosine is a potent vasodialator of the small vessels in the heart. This would be called an off-target effect， meaning that it is not related to the P2Y12 receptor which is the primary focus of ticagrelor effect.
　　I also think there are a number of other aspects of the PLATO study such as significantly less complete follow-up. The follow-up was complete in somewhere of 85% of patients. They did not have the 99% complete follow-up that characterizes TRITON-TIMI 38. There is also marked variability in the benefit of ticagrelor on a geographic basis. Ticagrelor was not associated with benefit in North America. In fact the hazard ratio for ticagrelor was 1.27 and the confidence intervals of the hazard ratio did not overlap with the confidence intervals for ticagrelor benefit in the rest of the world outside the US. This has never been adequately explained that why in a sizable group of patients enrolled in the trial， in North America there was no benefit， and actually trend toward harm in ticagrelor versus clopidogrel.
　　Lastly， concerning this new revelation that aspirin dose effects the benefit attributable to ticagrelor，  it’s clear in the analysis of PLATO that low aspirin dose clearly and markedly enhances the relative benefit of ticagrelor. Aspirin doses of less than 100mg are in fact optimal compared to higher aspirin doses. It is important to note that a similar analysis done with clopidogrel or with prasugrel in the TRITON trial did not show a significant effect of aspirin dose on the relative benefit associated with prasugrel compared to clopidogrel. So this aspirin sensitivity with respect to outcomes is specific and rather unique to ticagrelor.
　　Kereikes教授：首先要澄清这个问题，PLATO研究显示，替卡格雷与氯吡格雷相比，能够使死亡率降低20%。事实上，替卡格雷的相对生存优势是PLATO研究惟一显著的方面。在PLATO研究中，STEMI组中共有7500名STEMI患者，该组患者死亡率降低了18%。有趣的是，在TRITON研究中，普拉格雷与氯吡格雷相比，在STEMI亚群中相对死亡率的相对降低为24%，该研究中STEMI亚组共有3500名患者接受了分析。
　　这实在是很复杂的，没有人能够充分解释接受替卡格雷治疗的患者其死亡率的降低以及明显生存优势的原因。是否是因为降低了主要出血事件呢（该出血事件很大程度上是CABG相关的）？这是一个可能的解释。我们知道，主要出血事件与一年的死亡率相关。这一点我们可以从ACULTY研究和HORIZONS AMI研究中得知。从最现代的临床研究试验的分析中可以了解到，主要出血事件显著增高了第一年的死亡率。那么，替卡格雷降低了主要出血事件有可能在部分上解释了为什么替卡格雷能够降低患者的死亡率。其次，替卡格雷有阻止红细胞摄取腺苷的作用。这一点已经得到了证实。该作用可能会导致药物相关的呼吸困难。替卡格雷可能还具有抗缺血作用，据我们所知，腺苷是心脏小血管的潜在血管扩张剂。这种作用即所谓的脱靶效应，这意味着它与P2Y12受体不相关，而后者为替卡格雷作用的主要焦点。
　　我也认为，PLATO研究还有其他一些方面值得讨论，比如完整的随访调查较少。随访完整的患者大概只占85%。并没有TRITON-TIMI38研究的引入注目的99%的完整随访率。替卡格雷在不同地区患者的受益也具有明显的变异性。采用替卡格雷的北美患者并没有获益。事实上，替卡格雷的风险比为1.27，风险比的可信区间与美国以外的其他地区患者的风险比可信区间并不重叠。为什么该试验入选的大量北美患者接受替卡格雷与接受氯吡格雷相比，不但没有获益，甚至实际上还有损害的趋势，还没有得到充分解释。
　　最后，关于阿司匹林的剂量影响替卡格雷受益率的新启示，在PLATO研究的分析中，该表现很明显，低剂量的阿司匹林清晰并且显著的增大了替卡格雷的相对受益率。事实上，阿司匹林的剂量低于100mg优于高剂量的阿司匹林。还有一点需要注意，在另一项类似的关于氯吡格雷或普拉格雷的试验（即TRITON研究）中，普拉格雷与氯吡格雷相比，阿司匹林的剂量对前两者的相对收益并不具有显著影响。因此，阿司匹林与替卡格雷之间的敏感性是特别的，甚至可以说是独一无二的。