Jeffrey J Popma博士 哈佛医学院波士顿贝斯以色列女执事医疗中心
<International Circulation>: Transcatheter aortic valve replacement (TAVR) offered a new therapeutic option to patients with aortic stenosis who are at high surgical risk or with contraindications to surgery. What about its efficacy and safety in elderly patients with severe aortic stenosis who are at high surgical risk?
Dr. Popma: It’s a very important question. Our understanding of the appropriate patient for TAVR has evolved dramatically over the last five years. Initially， the clinical trials addressed those patients who had severe symptomatic aortic stenosis with very strictly defined criteria who by the surgeons were deemed to be either extreme risk for a complication (specifically death at 30 days)， or were felt to have a high risk of death or other major irreversible comorbidity， in other words， inoperable patients. And the initial studies done with the SAPIEN device and more recently the CoreValve device suggest that， in that patient population， dramatic there are reductions in that patient population over the first year that are sustained after three years， and there’s improvement in the quality of life (patients feel better) as a result of that. It’s not without complications， as we learned in the early experience but certainly the complications we address related to the early mortality or stroke， leakage， perivalvular regurgitation of the valve， all are very acceptable given the profound benefit this has for patients. After we demonstrated that in the extreme risk patient population， there is a lengthening of life and an improvement in symptoms， the next challenge was to address that in patients who are higher risk for surgery (those with predicted mortality within 30 days of surgery >15%)， which is around 10% of the population. In the SAPIEN trial that have been done， the PARTNER 2 trial， that was shown to be equivalent to surgical aortic valve replacement， with some improvement of life and at least in that population， a cost-effective therapy for an improved outcome. Now， the final challenge is what about patients at intermediate risk? And there’s ongoing randomized trials evaluating TAVR therapy versus surgical therapy for intermediate at-risk patients.
《国际循环》：经导管主动脉瓣置换术（TAVR）为不能行手术换瓣的主动脉瓣狭窄患者提供了新的治疗之选。在老年严重主动脉瓣狭窄这一手术高危人群中，TAVR的疗效及安全性如何？
Popma博士：这是一个非常重要的问题。在过去5年间，我们对适合行TAVR患者的理解发生了显著改变。最初，临床试验采用严格的界定标准对严重症状性主动脉瓣狭窄进行了定义，外科医生认为这些患者存在极高的并发症（尤其是30天内死亡）发生风险或较高的死亡或其他严重不可逆合并症风险。换句话说，这些患者不能进行手术。采用SAPIEN瓣膜及近期的CoreValve瓣膜开展的初步研究表明，在老年严重主动脉瓣狭窄患者中，实施TAVR后存在严重主动脉瓣狭窄的患者数量显著减少，并在治疗3年后持续减少；同时患者的生活质量显著改善。我们的早期经验发现，并不是不存在并发症，而是鉴于治疗能为患者带来显著获益，这些早期并发症（早期死亡或卒中、主动脉瓣漏、瓣周反流等）均是可以接受的。随后我们发现TAVR能延长这一极高危患者群的生存期并改善其症状。接下来的挑战就是手术极高危患者（手术后30天内死亡率>15%）占该人群的10%。SAPIEN试验及PARTNER 2试验结果表明，TAVR与外科手术具有同等疗效，并能改善患者生活，至少是改善手术高危患者结局极具成本效益的治疗之选。最终的挑战是其对中危患者群的价值如何。目前，评价TAVR治疗与手术治疗中高危患者的随机试验正在进行中。
<International Circulation>: You mentioned the complications， valve leakage， etc. When we look at these numbers， what has lead to these improvements of the devices?
Dr. Popma: There are several factors that have contributed to the improved outcomes that we see now， even compared to the early days of TAVR. I put them in three different “bins”， the first being patient selection. We’ve learned that not every patient is appropriate for TAVR therapy. Those with very high comorbidity scores， we use the STS as an example of more than 15， they don’t benefit much compared with optimal therapy. We’ve learned that patients who are disabled (assisted living center or cannot otherwise take care of themselves very well) don’t have much an improvement in quality of life after treatment. We’ve learned， first of all from a patient selection standpoint， how to take out some of those risker patients for therapy.
The second piece we have learned is how to do better pre-procedural planning. Specifically， when we go into a TAVR， we know everything there is to know about the anatomy and have switched from just using trans-thoracic or trans-esophageal ECHO to using sophisticated methods， like CT-angiography to assess both the size of the valve and the dimensions of the coronary vessel and the location of the coronary artery and the peripheral vasculature. So now， our pre-procedural planning is much better.
Finally， we’ve learned best practice guidelines. Once we have the patient on the table， we’ve learned how to minimize the amount of trauma during the operation; that has been very， very important. So between patient selection， pre-procedural planning and best practices in the lab， I think we’ve been able to see substantial improvements in the outcome.
《国际循环》：您提到了瓣膜漏等并发症，从数量上看，哪些措施能改善这些并发症？
Popma博士：与TAVR发展早期相比，有以下几种因素与结局改善有关。我将其分为3大类，首先是患者选择，我们已知道并不是每例患者都适合行TAVR治疗。与优化治疗相比，合并症评分较高（STS评分>15）的患者无法从TAVR治疗中进一步获益。存在残疾的患者（需要借宿中心或不能很好地自理）治疗后的生活质量无法得到太大改善。因此，首先从患者选择角度来说，我们要知道应如何排除存在治疗风险的患者。第二要学习如何更好地进行术前计划。具体来说，在实施TAVR时我们应知道解剖情况，从仅使用经胸或经食管超声转为使用更为复杂的方法如CT血管造影评估瓣膜大小及冠状动脉血管直径、冠状动脉及周围血管位置。现在我们的术前计划要好得多。最后，我们有了最佳的实践指南可学习。面对患者时我们已经知道如何最大限度地减少手术操作过程中的创伤，这点非常重要。因此，我认为，做好患者选择、术前计划及最佳实践，就能改善患者的结局。
<International Circulation>: What do you think of the challenge for the widely application of TAVR? And how do you think about its relevant technical development direction and its broader application?
Dr. Popma: The broader application comes in two forms: broader application to more hospitals and to more patients.
Let’s start with hospitals first. If we’re honest about the whole thing， the major limitation to expanding to more hospitals is the development of a multi-disciplinary team. A real， multi-disciplinary team， including cardiac surgeons， interventional cardiologists， non-invasive cardiologists， geriatricians， and imaging specialists because the success of a program is really based on the fact that， with a multi-disciplinary team， that work together to optimize planning and procedures， it’s hard for many hospitals in the United States to dedicate the time to put everybody in the same room and work on these patients. It becomes a very time-intensive piece， and not everybody gets paid for what they do. So I think the biggest challenge beyond the centers that are currently performing the procedures today is having the technical expertise together at the institution that where people will devote the time to do it. If they devote the time and they’ve got the volume， certainly can have that multi-disciplinary team.
The second challenge is expanding to more patients， and although we understand that now the bar is shifting a bit from high-risk surgery patients， we still need to complete our randomized trials. The PARTNER 2 trial has completed its enrollment and is in two-year follow-up， the TAVI trial with the CoreValve trial is ongoing randomization， and we are randomizing patients in that group of STS risk scores between 4 and 10 (~30% of population)， and then you get that proven， I think we’ll move on next to lower STS scores. But that has to be combined with improvements in the devices that we have. Those efforts are ongoing with newer generations of the SAPIEN device and new iterations of the CoreValve device and other new entrants into the market， like the Portico with St. Jude， Lotus Valve with Boston Scientific and the Direct Flow Valve from Direct Flow. So those are all on the horizon in the United States， all starting clinical trials. I think that having better technology will really allow us to expand these into other subsets of patients.
《国际循环》：您认为TAVR广泛应用尚面临哪些挑战？您如何看待其相关技术的发展方向及广泛应用？
Popma博士：TAVR更广泛应用有2种形式，一种是更广泛地用于更多医院，另一种是应用于更多患者。我们先谈一下医院。坦白地说，TAVR广泛应用于更多医院面临的最大挑战是多学科团队的发展。因为一个手术的成功实施需由多学科团队共同努力优化手术计划及操作程序，一个真正的多学科团队应包含心脏外科医生、介入心脏病专家、内科心脏病学家、老年医学家和影像学专家等。但美国的很多医院是难以有时间让上述专家聚在一起讨论的。多学科团队的工作需在密集的时间段内实施，但却并不是每位参与者都能得到相应的报酬。因此，我认为目前正在开展的TAVR中心面临的最大挑战是如何让技术专家们共同花时间进行多学科协作。如果他们能投入时间，当然可创建多学科团队。第二个挑战是如何应用至更多的患者。虽然我们现在已知道外科手术高危患者可应用TAVR，但仍需进行和完成随机临床试验。其中，PARTNER 2试验已完成入选工作，目前正开展为期2年的随访；CoreValve试验正在进行随机化，其中也入选了 STS风险评分4~10分（约占30%）的患者，如果能证实TAVR能为这些患者带来获益，我认为我们将能进一步下调TAVR的STS评分。但这需要我们所应用的瓣膜设备也能随之改善。新一代SAPIEN瓣膜及CoreValve瓣膜正在进行这方面努力，其他竞争产品（如圣犹达的Portico、波士顿科学公司的Lotus瓣膜、Direct Flow的Direct Flow瓣膜）也已进入市场。这些都在美国上市，并开始进行临床试验。我认为更好的技术能使TAVR应用至更广泛的患者群。
<International Circulation>: When it comes to technology， will we see a similar progression as in stents?
Dr. Popma: Well， we’re dealing with first-generation valves so the predicate SAPIEN valve， which is commercially available now， is going to be replaced wholly by the SAPIEN XT when that becomes available， hopefully soon. And that will ultimately be replaced by another iteration， so each company has its next generation. For instance， the Medtronic CoreValve device called Evolut， so if we look back three or four years from now and say， are we really going to be using the devices of today， the answer is probably no. Will we be using the next generations or be into other industry components that have very different structure to them?
《国际循环》：就技术而言，我们是否能看到和支架相似的进展？
Popma博士：在SAPIEN XT 瓣膜可应用后，将有希望很快完全取代目前正在应用的第一代瓣膜即目前市售的SAPIEN瓣膜。而SAPIEN XT 瓣膜将来也最终会被其下一代取代。所以，每个公司都有自己新一代的产品。例如，美敦力研发了CoreValve瓣膜的新一代产品Evolut瓣膜。所以，3或4年前，我们会想象将应用现在的瓣膜产品吗？答案可能是否定的。同理，我们将来是否会应用下一代产品或与现在的产品有着不同结构的其他工业产品，现在还无法回答。