confluence concepts and opinions in interventional cardiovascular medicine issue eight April 2014 EDITOR-IN-CHIEF CHRISTIAN HAMM GERMANY

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1 issue eight April 2014 confluence concepts and opinions in interventional cardiovascular medicine EDITOR-IN-CHIEF CHRISTIAN HAMM GERMANY EDITORIAL BOARD ISABELLE DURAND-ZALESKI FRANCE ROSSELLA FATTORI ITALY ANTHONY GERSHLICK UK HENNING KELBÆK DENMARK IRENE LANG AUSTRIA CHAIM LOTAN ISRAEL VINCENT RIAMBAU SPAIN LUIS RUILOPE SPAIN ALEC VAHANIAN FRANCE ARNOUD VAN T HOF THE NETHERLANDS THOMAS WALTHER GERMANY Perspectives on the latest SYMPLICITY data: HTN-3 and the Global SYMPLICITY Registry Taking a closer look at bifurcations: A conversation about Visible Heart Is paravalvular leakage the single most important complication of TAVI? First experience with a new renal denervation device and technology: the Spyral device FRANZ WEIDINGER AUSTRIA Supported by an unrestricted educational grant from Medtronic, Inc IMAGE: Medtronic, Inc.

2 Christian Hamm EDITOR-IN-CHIEF Dear colleagues, I am delighted to welcome you to the eighth issue of Confluence: concepts and opinions in interventional cardiovascular medicine. New technologies afford those in the cardiovascular medicine community the opportunity to improve treatment for our patients; not only can we offer better outcomes to those in our care, but we become able to treat those for whom management options were once limited. In order to provide us with the confidence to use such technologies safely in our patients, they must undergo not only a rigorous development process, but also thorough assessment in the clinic through clinical trials and registries. In this issue of the journal, hot off the heels of their release at the recent 2014 American College of Cardiology (ACC) Scientific Sessions (29 31 March, Washington, DC, USA), we examine the latest SYMPLICITY data. We discuss with Dr David Kandzari the SYMPLICITY Hypertension-3 trial, its results and the next steps for renal denervation trials. We also chat to Professor Michael Böhm about the positive results from the Global SYMPLICITY Registry. Elsewhere in this issue, Dr Alexander Plehn presents his clinical initial experiences with a new renal denervation device: the SYMPLICITY Spyral. This updated design allows operators to carry out renal denervation in patients with challenging anatomies that would have previously been unsuitable or difficult to treat. Dr Yves Louvard and Dr Francesco Burzotta present the Visible Heart, an educational programme to understand bifurcation treatment techniques, complications and outcomes based on a combination of imaging technologies and computer simulation. This fascinating use of technology is allowing physicians to see for the first time the result of different stenting techniques in bifurcation lesions in situ. If you are attending EuroPCR (20 23 May, Paris, France) this year, make sure to attend Dr Louvard and Dr Burzotta s presentation on this very topic, where they will discuss the Visible Heart initiative in more detail. Their session, Stent behavior in bifurcations like you have never seen before A first look comparing intravascular Visible Heart videoscope versus computational modeling and traditional imaging techniques will take place on Tuesday 20 May, 17:00 18:00. While any intervention in cardiovascular medicine is associated with some risk, we can often reduce such risk through careful preparation and planning. This is precisely the case with paravalvular leakage related to TAVI implantation. We discuss with Dr Nicolas M. Van Mieghem about the complications associated with TAVI and the precautions that can be taken to minimize the likelihood of paravalvular leakage occurring. Also on the topic of TAVI, we take a look at the International Consortium of Transcatheter Valve Registries Initiative (ICCR-ICTVR) established by the United States Food and Drug Administration. This programme will bring together international registries to fill evidence gaps related to transcatheter aortic valve replacement procedures and devices in a real-life setting. Finally, this issue will examine the latest evidence and future perspectives in the use of thrombus aspiration. In our opinion piece, I introduce the topic and briefly discuss the past, present and future of this therapy. Dr Mony Shuvy and Professor Chaim Lotan review the options for protecting patients from distal embolization and the role of aspiration in ACS. Finally, Dr Sanjit Jolly provides an insightful commentary on the topic and looks to the future data that will provide more information on this topic. Additionally, the successful use of thrombus aspiration is demonstrated in Dr Flavio Ribichini and colleagues interesting case study, in which they describe how STEMI can be managed using with Export alone to carry out aspiration of multiple branches with no balloon, or stent implantation. Please visit which has launched recently. You will be able to find all of Confluence s articles, allowing you access whenever you need it. Finally, your opinions are important to us, so please do let us know your feedback on this issue, the journal in general or our website by ing us at confluence@axon-com.com. We would be delighted to receive proposals from you on topics to cover in future issues. Christian Hamm 1 confluence issue eignt April 2014

3 Contents Interview Perspectives on the latest SYMPLICITY data: HTN-3 trial results 3 David Kandzari An update from the Global SYMPLICITY Registry 8 Michael Böhm IMAGE: Medtronic, Inc. Interview Taking a closer look at bifurcations: A conversation about Visible Heart 10 Yves Louvard, Francesco Burzotta Interview Is paravalvular leakage the single most important complication of TAVI? 14 Nicolas M. Van Mieghem Case study First experience with a new renal denervation device and technology: the Spyral device 18 Alexander Plehn Case study STEMI treatment with Export alone 22 Michele Pighi, Carlo Zivelonghi, Mattia Lunardi, Flavio Ribichini Expert opinion and commentaries 1. How does TAPAS TASTE? Thrombus aspiration in daily practice 25 Christian Hamm 2. Protection from distal embolization and role of aspiration in ACS 26 Mony Shuvy, Chaim Lotan 3. Perspectives on thrombectomy on clinical practice 28 Sanjit Jolly Hot topic FDA establishes International Consortium of Transcatheter Valve Registries Initiative (ICCR-ICTVR) to fill evidence gaps related to transcatheter aortic valve replacement procedures and devices 30 With input from Art Sedrakyan Call for case studies! Case reports should be no more than 1,000 words and submitted to confluence@axon-com.com. On the final page of this issue you can find a submission template for case studies. Alternatively, please visit to download the template and submit your case. 2 confluence issue eignt April 2014

4 INTERVIEW David Kandzari Perspectives on the latest SYMPLICITY data: HTN-3 trial results At the American College of Cardiology (ACC) 2014 Scientific Sessions (29 31 March, Washington, DC, USA), it was reported that the SYMPLICITY Hypertension-3 (HTN-3) renal denervation trial had failed to achieve its primary efficacy endpoint. However, the trial also demonstrated the excellent safety profile of this therapy. Confluence spoke with Dr David Kandzari, Chief Scientific Officer and Director of Interventional Cardiology at Piedmont Heart Institute, Atlanta, GA, USA, and one of the Primary Investigators on HTN-3 about the trial, its results and the future of renal denervation. Could you give us some background on the SYMPLICITY HTN-3 study? The SYMPLICITY HTN-3 study is not only the largest, but also the first, controlled clinical trial in renal denervation therapy to be both randomized and blinded. This study falls against the background of numerous single-arm studies, as well as one randomized but unblinded clinical trial of smaller size, which have consistently demonstrated significant reductions in both systolic blood pressure measured in the clinic so-called office blood pressure as well as ambulatory blood pressure between pre-treatment and 6-month values, if not longer. Those previous studies have also demonstrated the durability of renal denervation therapy now through 3 years of follow-up and beyond for selected patients. 1 5 There remains, however, a need to study more carefully the role of renal denervation therapy against a background of maximized or optimal medical therapy for patients who are identified with treatment-resistant hypertension. To that purpose, the SYMPLICITY HTN-3 study randomized 535 patients in a 2:1 fashion to either renal denervation therapy or control therapy. Patients were deemed eligible for enrollment by having an office systolic blood pressure of at least 160 mm/hg on at least two separate clinic visits. In addition, their 24-hour ambulatory blood pressure must have been at least 135 mm/hg. Finally, patients must have been on at least three maximally dosed or maximally tolerated medications according to hypertension guidelines and one of these therapies must have been a diuretic agent. Patients were blinded through a masked blinding process or sham controlled process such that, following enrollment and determination of eligibility for randomization, randomization occurred only after the patients were blinded to their treatment status following renal angiography. All randomized patients (treatment and control groups) were managed identically following renal angiography to maintain blinding. Of the 535 patients enrolled, a total of 364 patients underwent renal denervation, while 171 patients were randomized to the sham control group. At the 6-month follow-up, 350 patients (96%) were available for follow-up in the renal denervation group and 169 patients (99%) were available for follow-up in the control group. Importantly, in both groups, patients were instructed per protocol to maintain their same medications, with the allowance of medication changes only for certain exceptions. The role of this was to maintain the background of medical therapy so that we could more truly discern the treatment effect of renal denervation. Is it fair to say that all the patients were treatment resistant? That is right. By treatment resistance, we mean that they are taking medical therapy and yet we cannot get their blood pressure down to achievable goals. While patients may have been on multiple medications, if we were to withdraw those medications perhaps their blood pressure would go even higher and their risk of stroke would accordingly be even greater, along with other complications of hypertension. 3 confluence issue eignt April 2014

5 This study truly identified a treatment-resistant patient population but unlike the Hypertension-2 study, it required patients not only to have a blood pressure greater than 160 mm/hg, but it also an ambulatory blood pressure over 24 hours of at least 135 mm/hg. When we look at the patient demographics, the average office blood pressure for the total study population was approximately 180 mm/hg and the 24-hour mean ambulatory blood pressure was approximately 160 mm/hg. This represented quite a treatment-resistant, hypertensive patient population. Can you describe the demographics for this patient population? Yes, this is important to consider especially in the context of previous studies. Some of the important issues were that, unlike previous studies, this study was performed in the United States in approximately 80 centres and about 25% of the patient population were African-American in ethnic origin. There was also a very high prevalence of diabetes about 45%. Consistent with previous studies, the average number of anti-hypertensive medications was quite high, with the average number being about five medications per patient. Again, along with the blood pressure values that I shared, that represents a very treatment-resistant patient population. Could you give us an overview of the results from the trial? The study had two primary endpoints. One was a safety endpoint, which was a composite of major adverse events that included bleeding and vascular complications. The major adverse event rate in the study was compared against a performance goal, which was an estimate derived from previous studies involving the treatment of renal artery stenosis with stenting. It also had a factor within it of the likelihood for patients coming back with hypertensive urgencies or emergencies. The major adverse event rate not only represented procedural complications, but also the possibility that patients could have hypertensive emergencies during the follow-up period as well. However, this event rate, for which the estimated goal was 9.8%, was in fact much lower at only 1.4%. This really underscores the consistency across previous clinical trials of the safety of this procedure. The second component of the primary endpoint was one of efficacy. It is important to note that, in contrast to previous studies of renal denervation typically reporting the difference and relative significance between baseline blood pressure and 6-month follow-up blood pressure, HTN-3 instead compared the difference in blood pressure at 6 months between the renal denervation group and the sham control group. The pre-specified definition for superiority was that the difference must have exceeded roughly 5 mm/hg. When we incorporate some statistical modelling into that and assumptions around confidence intervals, put simply, the difference required between the two groups was probably required to be about 10 mm/hg. In HTN-3, among patients receiving renal denervation therapy, the reduction in systolic office blood pressure at 6 months was about 14 mm/hg, while in the sham control group it was 12 mm/hg: specifically, 14.1 mm/hg in the renal denervation group and 11.7 mm/hg in the sham group. Therefore, the difference was less than expected it was a difference of only 2.4 mm/hg and therefore the study did not achieve its statistical significance in its pre-specified primary endpoint. It should be noted, however, that the pharmaceutical industry spends billions of dollars each year to devise pharmaceutical agents that are intended to reduce the blood pressure by 3 5 mm/hg. In this context, the reductions observed in this trial in both groups may be clinically significant; however, the renal denervation aspect of the procedure did not show a significant difference from the control group itself. An important secondary endpoint of the trial was 24-hour ambulatory blood pressure at 6 months. These differences are generally expected to be less than the office systolic blood pressure measurements and indeed, in this trial, the renal denervation group reduction in ambulatory blood pressure at 6 months was 6.8 mm/hg. It was 4.8 mm/hg in the sham group. This difference also did not achieve its intended superiority margin and therefore was also not significant. What explanations might there be for these results? Since the announcement of the overall results of this trial, there has been expectedly great speculation regarding why the results of this study 4 confluence issue eignt April 2014

6 might be discordant with previous trial results and a large body of clinical experience, as exemplified by the Global SYMPLICITY Registry (GSR), which was also presented at ACC Some of these reasons for differences have been suspected to be related to the trial design; to the study population; to opportunities for observer and patient biases; to the Hawthorne effect (whereby participants alter their behaviour as a result of being part of a study); and also to perhaps the procedure itself. This study, in contrast to previous studies, was not only the largest but it was the only randomized, sham-controlled, blinded clinical trial. Furthermore, HTN-3 also enrolled a more esoteric group of patients with treatment-resistant hypertension than previous trials. The protocol mandated that doses of medications must be maximally adjusted, creating an artificial scenario not commonly found in clinical practice. In addition, patients were enrolled on the basis of ambulatory blood pressure, rather than office blood pressure alone. Furthermore, the study enrolled a high prevalence of patients with African-American ethnicity. It is interesting to note that in a subgroup analysis, while both African-American and non-african- American patients responded similarly to renal denervation; African-American patients derived a considerably greater benefit in the control arm. It is important to recognize, however, that among the non-african-american patients, although the reduction in systolic blood pressure with renal denervation was significant, the overall reduction in blood pressure was still less than 10 mm/hg. While we may see some signals in sub-group analyses with regard to younger patients, non- African-American patients, or patients with preserved renal function deriving a potential significant reduction in blood pressure, the relative blood pressure reductions remain modest. It is important to note that these remain exploratory analyses in the context of an overall negative study. In addition to differences in study population, it has also been supposed that perhaps patients may have an opportunity to behave differently in clinical trials, the so-called Hawthorne effect. While the observation of simply a blood pressure reduction in the control group was not surprising (as such effects occur in many trials across multiple therapeutic areas), the degree to which this occurred was. As an example, the recent CORAL study 6, which randomized patients to either renal stenting or medical therapy, was not blinded and it was not therefore sham-controlled but, interestingly, once patients were enrolled in the study in both cohorts, the blood pressure was significantly reduced by roughly 13 mm/hg. That reduction was sustained in both cohorts during 3 years of follow-up. This highlights the potential impact of the Hawthorne effect; that patients may somehow behave differently in the context of participating in a clinical trial than they might otherwise. In particular, this may be related to changes in dietary or lifestyle habits, but it may also reflect a greater compliance with medications, too. While we assessed the medical compliance in the HTN-3 trial, we only assessed it in the early phase of enrollment and towards the later phase of the 6-months primary endpoint ascertainment. We assayed it according to patient reports, rather than with other more sophisticated methods, such as drug monitoring, pill counts or even urinary samples for drugs as well. I think that in future, trials will have to reconsider how to mitigate the occurrence of a placebo or Hawthorne effect. Part of this may be related to medical compliance and there has been a great deal of discussion for future designs of clinical trials about how we may more carefully monitor medical adherence. Perhaps having a longer run-in period, in which we allow many of these differences to settle, so to speak, prior to active randomization to control or renal denervation might be an option. A great deal of speculation has also been raised regarding potential differences in the procedure, or even in the catheter itself. Earlier studies in renal denervation had used a slightly different version of the catheter compared with that used in the HTN-3 study. However, subsequent analyses have probably dismissed that specific issue as a significant contributor. Another confounding factor might be differences in how the procedure is performed this is an area of ongoing interest and study. In SYMPLICITY HTN-3, 86 of 88 sites had no prior experience with renal denervation procedure, despite being experienced cardiologists. However, in the SYMPLICITY Hypertension-2 (HTN-2) trial, a study which demonstrated a significant reduction in blood pressure, 50% of centres had prior 5 confluence issue eignt April 2014

7 experience with renal denervation. At first glance, there appears to be a high prevalence in both studies of operators who are unfamiliar with the procedure. However, in the HTN-3 study, there were a far greater number of operators who performed two or fewer procedures, and so therefore their total experience in performing renal denervation was more limited than operators in previous studies. There is currently investigation into whether more ablations in the vessel was associated with a greater reduction in blood pressure in the HTN-3 study. We need to truly revisit the basic science of this therapy to better understand the translation of the device therapy to the pathophysiology, to understand whether a difference in technique or method might somehow have influenced the results. Again, this remains very much speculative and by no means could be considered to be the singular issue that led to the decline and failure to meet the primary efficacy endpoint. How will patients enrolled in HTN-3 be followed up? Patients in HTN-3 will be followed for 5 years. At the moment we still have quite limited follow-up, even at 1 year in the trial. I believe it is essential to follow these patients very carefully over the long term. Such long-term follow-up of these patients will allow us to investigate whether there is any difference in outcome once patients are unblinded to their treatment. One might expect that after patients have been made aware of their treatment status at the 6-month follow-up visit that those patients who were assigned to the control group and did not receive renal denervation may begin to return to their more normal or more usual lifestyle habits. This may also include differences in medical compliance. One might expect if these patients were to relapse to bad habits that their blood pressure would perhaps return upwards towards higher levels, whereas, if renal denervation therapy is effective, these patients may have a sustained reduction in blood pressure. Importantly, however, this remains to be seen. What further studies are being carried out to investigate the factors that may have led to the failure of the trial? We are more intensively examining the procedure itself, in the context of the SYMPLICITY HTN-3 trial results. We will also make some comparisons with the Global SYMPLICITY Registry. In addition, pre-clinical studies will more carefully examine the dose/response relationship to renal denervation and reductions in, for example, norepinephrine levels as well. Our view is that, with regard to the need to revisit the basic science of this therapy, we should be reminded that, to date, there is no consistent predictor of a treatment response to renal denervation in human patients, other than having simply a very high blood pressure at baseline. Secondly, this is a procedure for which, unlike most if not all other device therapies, we have no procedural biomarker or surrogate of procedural efficacy. This means that we do not know when we perform renal denervation, whether we are effectively achieving complete or perhaps incomplete denervation of the renal efferent and afferent nodes. Further investigation of these factors will be valuable. The HTN-3 trial was carried out in the United States alone, whereas the previous trials (HTN-1 and HTN-2) had international patient populations. Could this have had an impact on the outcomes seen in the HTN-3 trial? While the issue of geographical differences has been raised, it is unlikely that these differences contributed to the disparate results of this trial versus others, except that in the sense that this trial involved a higher prevalence of African-American patients who seemed to derive a differential non-response to non-african-american patients. I don t believe that any geographical differences in where the studies were conducted played a role particularly when we realise that this study, by the criteria we discussed, addressed a very treatment-resistant, high-risk, patient population. One difference, however, is that in the United States, most of the patients came from cardiovascular programmes that were not necessarily specialist hypertension centres, unlike in the European, Australia and New Zealand experiences. How do you reconcile these HTN-3 data with that real-world experience from the Global SYMPLICITY Registry? To begin with, the GSR once again highlights the safety of this procedure. In the first 1,000 patients treated with this technology, included in the 6 confluence issue eignt April 2014

8 Address for correspondence David E. Kandzari, MD, FACC, FSCAI Director, Interventional Cardiology and Chief Scientific Officer, Piedmont Heart Institute, Atlanta, GA Tel: registry, the event rate of adverse safety events is extremely low and consistent with the HTN-3 study. First of all, that is a very reassuring and consistent message. Despite the limitations of comparing the GSR, a single-arm, non-randomized experience, with the randomized, blinded controlled HTN-3 study, the reduction in blood pressure is slightly larger at 6 months than in the GSR. However, it is important to note that this represents a much broader, less selective patient population than those patients included in clinical trials with more rigorous enrollment criteria. For example, only approximately one-third of the patients in the GSR had the blood pressure measurements that were required of the HTN-3 study. Nevertheless, when we look at the GSR for patients who would have fulfilled similar blood pressure criteria as the HTN-3 study, these patients achieved quite remarkable reductions in office blood pressure at 6 months. Their reductions were about 20 mm/hg and, again, keep that in mind in the context of the 14 mm/hg for patients who received renal denervation in the HTN-3 study. Due to the registry nature of the study it is, however, difficult to account for the potential for a placebo effect, or what the placebo effect might contribute to it. It is also important to note the differences in the population and we have talked about African-Americans, who were enrolled very infrequent in the GSR. There were also differences in the intensity of anti-hypertensive therapy. What message do you have for the physicians using renal denervation in their clinical practice? We recognise that there is still a great deal of enthusiasm for renal denervation globally, given that these patients often represent what might be considered a no alternative patient population. That said, I think there will be greater caution and reservation in patient selection for renal denervation in those regions where the therapy is commercially available. However, when it is performed I think we can clearly reassure patients regarding the safety of the procedure itself. Perhaps the most important point is that, when renal denervation is to be performed in clinical practice, these patients are subject to careful and continued follow-up with regard to the safety and efficacy of this treatment. REFERENCES: 1. Krum H, et al. Lancet 2009;373: Symplicity HTN-2 Investigators, et al. Lancet 2010;376: Symplicity HTN-1 Investigators. Hypertension 2011;57: Krum H, et al. J Am Coll Cardiol 2012;60(17_S). 5. Mahfoud F. Early results following renal denervation for treatment of hypertension in a real world population: the global SYMPLICITY registry. Presentation at EuroPCR Scientific Meeting Cooper CJ, et al. New Engl J Med 2014;370: DISCLOSURES: DK has received research and grant support, and consulting honoraria from Medtronic, Inc., and Boston Scientific. 7 confluence issue eignt April 2014

9 INTERVIEW Michael Böhm Perspectives on the latest SYMPLICITY data: An update from the Global SYMPLICITY Registry The Global SYMPLICITY Registry is a large, multinational registry that is providing valuable insights into the outcomes of patients undergoing renal denervation in real-world settings. With the first data from the trial having been released at American College of Cardiology (ACC) 2014 Scientific Sessions (29 31 March, Washington, DC, USA), Confluence spoke to Professor Michael Böhm, Saarland University Hospital, Homburg/Saar, Germany, and Lead Investigator of the study to find out more about the trial, its results and the future of renal denervation. Please can you give us a brief overview of the Global SYMPLICITY Patient Registry? The primary goal of the Global SYMPLICITY Registry (GSR) was to provide safety and effectiveness data on the use of renal denervation in real-world settings. This is important because investigators and patients in the clinic might differ from those involved in clinical trials, which have extensive proctoring and strict adherence to protocols. The GSR aims to enrol 5,000 patients to provide insights into the long-term outcomes with renal denervation. In this study, patients will be followed up for a period of 5 years. At the ACC Scientific Sessions, the blood pressure reduction and safety results of the first 1,000 patients from the GSR were reported. The majority of patients came from Western Europe, but about one third came from other nations such as Australia, New Zealand, Canada and South Africa, as well as from countries in Asia. What differentiates this registry from clinical trials in renal denervation? The unique feature of the registry is to provide data from the real world in a broad population of patients. This means that the data in the GSR not only covers patients with resistant hypertension, but also those in whom the procedure was carried out due to comorbidities such as arrhythmias and heart failure. Therefore, all together, the GSR provides data on a much broader population than in trials with different levels of blood pressure at baseline and comorbidities. It is important to compare such diverse patient populations with different baseline blood pressures and an array of comorbidities. Such data will help to drive the generation of hypotheses that can be tested in future controlled clinical trials. Furthermore, by looking at such a spectrum of patients, we can have greater confidence in treating the diverse patient populations seen in clinics. How should data from the GSR be viewed alongside data from the SYMPLICITY-HTN studies? The first difference is geographical; the GSR provides data in countries where the technique is introduced. Therefore, the investigators in the GSR have more experience than the SYMPLICITY HTN-3 study investigators because in America the technique is not yet approved. The vast majority of HTN-3 investigators performed less than 5 procedures, which then immediately were incorporated in the SYMPLICITY HTN-3 trial. This might be one reason why the reduction in blood pressure in the GSR was slightly more pronounced than in the HTN-3 study. Will the registry also collect data for other diseases characterized by elevated sympathetic drive? If so, what information do you hope to gain from the GSR that can inform the use of renal denervation in treating different conditions? Several patients with heart failure and arrhythmia will be included in the GSR. Long-term follow-up of 8 confluence issue eignt April 2014

10 Address for correspondence Direktor Prof. Dr M. Böhm Universitätsklinikum des Saarlandes Klinik für Innere Medizin III Kardiologie, Angiologie und internistische Intensivmedizin Germany these patients will help us to judge whether there is potential to use this technology beyond hypertension. We also expect to be able to analyze information on the impact of different comorbidities of hypertension. What long-term data have been shown so far from the registry, and how will long-term data from the registry inform clinical practice? At the ACC, the 6-month data from the first 1,000 patients enrolled in the GSR were presented. The next milestone will be the presentation of the 12-month data for approximately 1,000 patients and potentially the 6-month data for 1,500 2,000 patients. These analyses will also include endpoints. However, the influence of renal denervation on the rate of adverse events cannot be judged because the registry does not provide information on a control group. Patients were included not only for office blood pressure, but also for high results from ambulatory blood pressure monitoring (ABPM). Furthermore, the decision to treat these patients with renal denervation followed clinical decisions based on resistance to pharmacotherapies or patient preference. As the majority of these patients were treated according to the guidelines, these data provide a picture of how they are responding in the clinic under standard operating procedures. In future, how can teams work together more effectively to identify and treat patients who may benefit from renal denervation? Renal denervation programmes should be collaborations between hypertension specialists, interventional cardiologists and general practitioners, who identify patients at risk and arrange for their referral to a specialist renal denervation centre. What will the impact of the HTN-3 data be on the registry? As the GSR is independent of the HTN-3 trial, we do not think there will be any impact. We believe that the GSR will help to provide better insights into renal denervation and allows for an alternative strategy for data generation avoiding some of the limitations from HTN-3. DISCLOSURES: MB has received scientific support from St. Jude Medical, Inc., Medtronic, Inc., Servier and Boston Scientific. Call for case studies! Case reports should be no more than 1,000 words and submitted to confluence@axon-com.com. On the final page of this issue you can find a submission template for case studies. Alternatively, please visit to download the template and submit your case. 9 confluence issue eignt April 2014

11 INTERVIEW Yves Louvard Francesco Burzotta Taking a closer look at bifurcations: A conversation about Visible Heart The Visible Heart model is a novel tool to visualize the internal workings of a beating heart. Confluence spoke with Dr Yves Louvard, Institut Hospitalier Jacques Cartier, Massy, France, and Dr Francesco Burzotta, Catholic University of the Sacred Heart, Rome, Italy, who pioneered the use of this model for imaging the stenting of bifurcation lesions. Can you tell us how the Visible Heart initiative began? Dr Yves Louvard (YL): The Visible Heart initiative is supported by the European Bifurcation Club, which I helped to found 10 years ago and Medtronic (Medtronic, Inc., Minneapolis). Within the Club, we have been working to improve stenting of bifurcation lesions for many years and we have had many discussions about theory, cases and data to try and do so. One of our key challenges is trying to show what is invisible in the clinic that which cannot be seen with X-rays while deploying of stents. To date we have done this by modelling simulations of virtual bifurcations coming directly from the anatomy of a patient. The Visible Heart is based on the work of the Visible Heart Lab, which houses a beating heart model that enables us to gain a greater perspective on interventions than if we performed an angioscopy in the clinic. Last year, Medtronic proposed that we use this pre-existing model developed by the University of Minneapolis to help visualize a stent implantation in a bifurcation lesion. Dr Francesco Burzotta (FB): Our ability to work in the Visible Heart Lab, whose work focussed on electrophysiology and structural heart disease, has now allowed us to provide more information about coronary interventions. While the Visible Heart Lab had been used up until then for anatomical studies by the team at the University of Minnesota, no studies had been performed by this lab to investigate coronary circulation. Since the European Bifurcation Club is a working group of experts in percutaneous treatment of coronary bifurcations, the idea was for them to test how bifurcation prevention could be visualized using the Visible Heart Lab. Can you explain the concept behind the Visible Heart Lab and what the technique entails? FB: The Visible Heart Lab has pioneered a unique system in which a recently harvested beating pig heart is suspended in a clear blood-like solution and is connected to a resuscitation machine. This enables the visualization of a beating heart and gives you have the opportunity to place interventional devices inside the heart, allowing you to investigate the parameters in different chambers for example, the pressure. With the use of optical probes, you can also monitor how the heart behaves during beating. It is extremely interesting to have high-quality pictures from inside the coronary artery since this is not possible routinely. This means it is very difficult to imagine the end result of percutaneous interventions, especially complex interventions like bifurcations, where the interactions between the stent and the coronary artery wall are less predictable. YL: This system enables us to use a probe to enter the coronary arteries and visualize what we want to see. In this case, we are using this model to look specifically at the bifurcations. We are able to enter each of the tree arteries simultaneously and visualize how the stents are deployed in a coronary bifurcation following different insertion techniques. We can also use this system for many other situations, not just bifurcation stenting; for example, I have seen a registered case of valve implantation with double angioscopy from the aorta and from the apex (videos from the Visible Heart Lab can be found at and 10 confluence issue eignt April 2014

12 fig. 1 Visible Heart image. Resolute Can you describe your personal involvement in the project? YL: I was asked to propose some other operators from the European Bifurcation Club, or elsewhere, to perform the stent implantations using the Visible Heart Lab. I recommended Francesco Burzotta because he is very involved in the practical management of patients. Within the European Bifurcation Club, he has very frequently presented different bifurcation stenting techniques. FB: When I was invited by Yves Louvard to take part in the initiative, I was the first interventional cardiologist to perform stent implantations in the Visible Heart Lab. I performed a double-stenting implantation in the Visible Heart model according to my preferred bifurcation intervention, the T And Protrusion (TAP) technique. This is an established technique that enables the implantation of an additional stent into a side branch, even if you start by stenting the main vessel. During this first day, we worked on two hearts from two pigs, which had been harvested sequentially. The Visible Heart Lab is specially equipped for these experiments, to allow us to perform our intervention exactly as we do in our routine practice in the catheterization labs. This meant that we could visualize on an angiographic machine our interventions and manipulations as we were performing the procedure. We were able to insert the guide-wires and the guiding catheter through the aorta, so that the method of cannulation of the coronary artery was exactly as we do in our coronary patients, using the trans-femoral approach. After the coronary angiography, we decided which bifurcations were suitable to receive stents, and we continued with the procedure, recording everything with multiple cameras. IMAGE: Medtronic, Inc. What is the clinical application of the Visible Heart initiative? YL: The first time I was able to see a stent deployed using Visible Heart Lab really was an outstanding experience. Using the Visible Heart Lab we are able to show different methods of stent implantation, performed by different interventionalists and we are able to see the outcomes of these stenting procedures. A sample image is shown in figure 1. In the clinic, we have radiological tools like the StentBoost (Philips Healthcare), angioscopies, intravascular ultrasounds (IVUS) or optical coherence tomography (OCT), to enhance visualization of the stent, but these tools do not let us see inside the vessels to visualize the stent position. Using the Visible Heart model, I have now seen stent deployment. Furthermore, I have seen the implantation of a CoreValve (Medtronic, Inc.) in an aortic pig valve imaged from both sides the back of the ventricle and through the angle of the aorta; you can see how the valve is moving and whether the deployment is eccentric or not. FB: The unique feature of the Visible Heart Lab is that it allows for the insertion of another probe, an angioscopy probe, inside the coronary artery. This means we can record each step of the stent insertion visually. The procedure is performed using angio-guidance, as in the clinical practice, but each step is checked with this endoscopic device. Performing the TAP technique myself, it personally allowed me to observe the morphological associations of my routine stenting practices. Normally, when we implant the stent in the coronary artery we don t know the exact anatomical aspect of the stent the interaction between the stent and the wall. The Visible Heart model allows us to do this in a wonderful way because the system is perfused not by blood but by a saline solution, specifically designed to accommodate the optical tools. How will it benefit the wider cardiology community? YL: My colleagues, especially younger operators, will probably view the images from the Visible Heart Lab with such surprise and wonder because they probably don t really know what is actually occurring to their stent inside the coronary artery. A website is currently being developed to store the uploaded 11 confluence issue eignt April 2014

13 images of different stent implantations that have been performed using different techniques on living pig hearts. This model will help provide a link between the radiology data and cardiac morphology; if we see a protrusion in some techniques in the middle of the other branch in the results then I hope that if we are collecting the data we will see the consequences of this. This is what is important for the treatment of patients. People interested in the topic of bifurcation stenting will then be able to see what they are doing and what the outcome will be if they use one of these techniques. FB: All the main images will be put on the Medtronic Visible Heart Lab website ( and made freely available to registered doctors. This project was carried out with the specific aim of allowing everybody to have access to, and reap the benefit from, these images. This Visible Heart is really useful to check if different techniques are associated with specific problems or benefits and may therefore be very informative for investigating different stenting interventions. As I mentioned previously, we don t know exactly, at the anatomic level, the nature of the interaction between the stent and the vessel. We perform our chosen intervention based on the angiography and sometimes we also use an imaging device, but there is no way to check exactly how the stent is positioned inside the artery. I think this experimental technique will be very useful to better understand the nature of the different stenting techniques and to evaluate these methods. I think this may be an important application of this technology; if you have a new technique, or if you have a new device for coronary intervention, then why not check the result how the device is associated with the vessel with the Visible Heart? Do you think the Visible Heart Lab is likely to influence clinical practice? YL: There are a number of different strategies available for stent implantation in bifurcation lesions. We aim to have images from a variety of different stenting techniques and I believe that by showing cardiologists the outcomes of different stenting techniques, this will inform clinical practice. From the studies carried out in Europe 1 for example, we learned that it is better, if possible, to put only one stent in a bifurcation, even if there are two diseased branches. It is considered best practice in Europe to insert a stent in one of the branches and a kissing balloon in the other. 1 In the US, however, they frequently use systematic double stenting and frequently begin stenting by the side branch. Despite European data showing that it is probably better to insert only one stent, many US cardiologists believe that we probably don t see the same lesions as they do, and that perhaps the lesions seen in the US are more complex. Thus, there is still some controversy as to best practice for stenting bifurcated lesions. I think the Visible Heart initiative will help cardiologists to understand the impact of their interventions, particularly when using some exotic techniques, such as the classical crush technique or simultaneous kissing stents. This latter technique involves the simultaneous deployment of two stents with a double barrel in the proximal main part of the bifurcation. If we show this kind of technique with an angioscope, you will see an impressive neo-carena in the middle of the main vessel proximal to the bifurcation, but this is a true vessel, a moving vessel in a living heart. Using the Visible Heart Lab, US cardiologists may appreciate the concerns raised regarding this technique and they may choose to follow the advice from Europe, where many studies and meta-analyses show that one stent is better. Conversely, if the US patients are really different, it will help the US cardiologists to design their own clinical studies on their own patients to investigate single stent implantation in US patients with different anatomies and different severities of lesions. The Visible Heart initiative will help cardiologists make an informed decision about clinical practice having viewed how the stent looks in a real coronary artery. I am convinced it will change the vision of the operators about what they are doing in the patient. What are the limitations of the Visible Heart Lab? FB: One of the main limitations is the fact that the pig hearts we tested were from a healthy animal, whose coronary arteries were not diseased. Using Visible Heart, you are testing a theoretical condition, which is never encountered in clinical 12 confluence issue eignt April 2014

14 Address for correspondence Dr Yves Louvard FSCAI, Institut Hospitalier Jacques Cartier 6 rue du Noyer Lambert Massy, France y.louvard@angio-icps.com Dr Francesco Burzotta Institute of Cardiology Catholic University of the Sacred Heart Rome, Italy francescoburzotta@gmail.com practice you are treating a normal coronary artery. A clear progression of this technology could be testing hearts that are unhealthy, in an experimental condition that allows you to have coronary arteries which are diseased. Looking to the future, I believe that the relevance this technique will continue to improve if diseased hearts are used. Another limitation is that the beating heart doesn t last in this condition for ever. This means that you have a limited timeframe to perform your test. For example, very complex situations for which you have very long interventions may be affected by the fact that there is a time limitation issue. YL: There are limitations with all simulation projects. A clear limitation in this living pig heart is that there is no stenosis, so not the problem we encounter in patients with stenosis. What we propose with the Visible Heart is lesion-free bifurcation stenting, so it s not exactly the same as the patient; but does provide an idea of what we are doing in patients. What are the future applications of the Visible Heart Lab? YL: For the moment, the aim of the Visible Heart initiative is for operators with different ideas about bifurcation stenting to investigate these various techniques, allowing them to see the end results and make informed decisions. Following this, we may ask other operators to go to Minneapolis and use the Visible Heart Lab to perform even more exotic techniques, to populate a visual library of simulated cases. With the images obtained from the Visible Heart Lab, we will try to help people learn stent bifurcation practices. This model could definitely be used for teaching purposes. Indeed, we have already experienced some mistakes while performing stenting using the Visible Heart Lab, which are useful for teaching purposes; we know why these mistakes occurred and we want to teach people about the practical problems of bifurcation stenting using the images produced. The Visible Heart can help cardiologists to understand why the problems occurred and how to correct them. I always say to my Fellows that the best way to learn the job is to go and discuss the complications with colleagues, so they can see exactly how to avoid the problems. With the Visible Heart, we can see the problem and then try to solve it. As this is a pig heart and not a patient, we have to create the problem first and then explain how it can be solved, but I believe this is definitely a worthwhile process. In the future, we want to use the Visible Heart to compare different imaging techniques, such as angioscopy, with OCT or IVUS to help us better plan operations. REFERENCE: 1. Katritsis DG, et al. Circ Cardiovasc Interv 2009;2: DISCLOSURES: FB is involved in advisory board meetings for Medtronic, Inc. YL has no conflicts of interest. EuroPCR 2014, Paris, France May If you are attending EuroPCR 2014, be sure not to miss Dr Louvard and Dr Burzotta discuss the Visible Heart initiative! Their seminar Stent behavior in bifurcations like you have never seen before A first look comparing intravascular Visible Heart videoscope versus computational modeling and traditional imaging techniques will take place on Tuesday 20 May, 2014 in room 242AB, 17:00 18:00 13 confluence issue eignt April 2014

15 INTERVIEW Nicolas M. Van Mieghem Is paravalvular leakage the single most important complication of TAVI? While there are a number of potential complications involved with transcatheter aortic valve implantation (TAVI), paravalvular leakage is a complication that can be easily avoided with careful preparation. Confluence spoke to Nicolas M. Van Mieghem, Interventional Cardiologist at the Thoraxcenter, Erasmus MC, Rotterdam, The Netherlands to find out more. What are the major complications associated with TAVI? In my opinion, stroke is the most severe complication related to TAVI. The second most important issue is aortic regurgitation (AR) due to paravalvular leakage. Other complications include bleeding and conduction disturbances. The problem of stroke was first highlighted in the PARTNER trial, which compared surgical aortic valve replacement with TAVI. 1,2 It turned out that when they looked at all kinds of neurological events, i.e., transient ischaemic attacks, or minor or major stroke, there was a higher incidence of events in the TAVI group. That is, of course, an important signal because stroke can result in death or severe impairment to quality of life. However, a recent study from the US, the CoreValve US Pivotal High Risk Study, has demonstrated that the rates of stroke were not statistically different in patients undergoing valve replacement with TAVI or surgery. At 30 days post-surgery, rates of stroke were 4.9% in patients treated with Medtronic s CoreValve (Medtronic, Inc.) and 6.2% in the surgical group (P=0.46); at 1 year, these rates were 8.8% and 12.6%, respectively (P=0.10). 3 The study also demonstrated that stroke rate with the CoreValve System is low, stable and, in contrast to other TAVR studies 1, comparable to surgical valve replacement in high-risk patients. The study showed that at 1 year, the all-cause mortality rate for CoreValve was superior to surgical valve replacement (14.2% vs. 19.1%, non-inferiority P<0.001; superiority P=0.04). 3 Paravalvular leakage, and associated AR, is also a significant issue. Moderate or moderate to severe ARs have been shown to have a clear impact on long-term survival. 4-6 There has, however, been some discussion on the importance of mild or even trivial AR. Analysis of the 2-year results from the PARTNER trial suggested that there was a correlation between even mild paravalvular AR and mortality. 7 However, this was, in my opinion, overstated because that data stems from univariate analysis, not multivariate analysis. That is a big difference. I am not convinced that mild AR is directly correlated with mortality per se. In a study of 795 patients, change in the mean aortic-valve gradient from baseline to 1 year in the TAVI group was non-inferior to that in the surgical group (P<0.001). 3 Furthermore, the rate of moderate or severe paravalvular regurgitation at 1 year was 6.1% in this study, which is favourable compared with rates of 7 16% in other multicentre series. 6, 8-12 Although the rates of moderate or severe paravalvular regurgitation were higher after TAVI than after surgical valve replacement, they did not appear to have a negative impact on survival. 3 Other relatively common procedure-related events are bleeding and vascular complications. These problems impact the patient from the start and may or may not be correlated with late mortality. 13 That is still controversial, but there are some indications and studies that suggest that there is a correlation between the use of packed cells and bleeding and late mortality. Moreover, these bleeding and vascular complications are also associated with longer in-hospital stay and a slower recovery. This potentially jeopardises one of the big advantages of TAVI, namely the increased quality of life compared with surgery. Conduction disturbances and need for a permanent pacemaker are the final complications. In general, this involves left bundle branch block and permanent pacemaker implantations. While this might not impact the patient in the short-term, they can have a major impact on patients wellbeing over time. However, the outcomes associated with conduction disturbances are again controversial. There are 14 confluence issue eignt April 2014

16 the Italian data that say there is no correlation with 1-year mortality and the occurrence of new bundle branch block, whereas data from The 14, 15 Netherlands suggest the opposite. Do you find that the complications that you have just described vary by the population you are treating? Are some more common in more serious cases than others? Some subgroups of patients have a higher risk for stroke or vascular complications, but if there is no alternative, you have to act. For instance, patients with a history of stroke or peripheral arterial disease have a higher risk of stroke after TAVI and they also have a higher risk of vascular and bleeding complications, but you are not going to exclude them from therapy just because they had a stroke or have peripheral arterial disease. Furthermore, while we are learning more about this all the time, experience tells us that the more calcium we see in the valves and aortic roots, the higher the risk for significant post-procedural AR. Therefore, procedural planning is becoming more and more important. This is illustrated by a clear move away from 2D transoesophageal and transthoracic echocardiography for pre-procedural planning to 3D modalities, especially of course multi-slice CT (MSCT) scans, but also 3D transoesophageal echo. Transcatheter valve selection, either using a Medtronic CoreValve or an Edwards Sapien valve (Edwards Lifesciences Corporation) may also affect the incidence of paravalvular AR. For instance, if there is a big piece of calcium in the left ventricular outflow (LVOT) tract there may be an argument to move away from an Edwards valve, preferring instead another device because there is a clear correlation between left ventricular outflow tract calcium and aortic root ruptures with the Sapien device. This is due to the valves mechanical concepts: the Edwards valve is balloon expandable while the Medtronic CoreValve is self-expanding. When it comes to expanding the non-compliant balloon, you will crush the calcium and you can cause perforations and ruptures by doing that. This does not mean that I have a preference for a particular device in general, but in certain anatomies it may be more sensible to use one valve over the other. Another issue is the height of the coronary arteries. If the coronaries are implanted rather low down, I would refrain again from an Edwards valve. However, if there is relative low calcium score in the aortic root, I would be more in favour for an Edwards valve because there is a potential for valve pop-outs with CoreValve in aortic roots with low calcium score. 16 In terms of outcomes, however, I believe that, at present, there are no clear differences between the two valves, as was recently demonstrated by the PRAGMATIC collaboration. 17 The Comparison of Balloon-Expandable vs Self-expandable Valves in Patients Undergoing Transcatheter Aortic Valve Replacement (CHOICE) clinical trial showed a significantly lower frequency of residual morethan-mild aortic regurgitation and permanent pacemaker implantation when using balloon expandable versus self-expanding valves. 18 However, the small sample size may have been responsible for some sex-based bias in this study, and the results of this study was not designed to demonstrate any long-term difference in critical outcomes such as death or stroke; indeed, there was no difference in 30-day mortality between the two treatments. 18 What measures can be employed to help prevent such complications from occurring? In order to prevent bleeding and vascular complications the choice of vascular access is critical. John Webb s group in Vancouver, consistently present very low vascular complication rates of 1% and less, through optimized access site selection and procedural technique. 19 For example, if you see that there is significant calcium in the iliofemoral tree, despite the fact that the vessels might be of a decent calibre, it may be an argument to move to an alternative access, either transapical, direct aortic or trans-subclavian. In principle in TAVI you carry out pre-dilatation with a balloon and then you implant the valve in the aortic root. However, if there is a lot of calcium in the aortic root you may choose not to employ pre-dilatation. There is a very small study that suggests avoiding pre-dilatation in such patients will result in fewer strokes. 20 This may be due to a correlation between manipulation and instrumentation in the aortic root and embolization of debris into the brain. In Rotterdam, we are selective with pre-dilatation and do not use it in all of our patients. 15 confluence issue eignt April 2014

17 We also have a low threshold for the use of embolic protection devices. The reason being that we have documented that in 75% of patients there was macroscopic debris in the filters. 21 However, we have not yet shown that the use of such protection devices is associated with reduced risk of neurological complications. This is because the risk of stroke is 5% or less, so the number of events is not that large. Stroke-related TAVI is due not only to tissue embolization, but can also be caused by thromboembolism or bleeding associated with inefficient anticoagulant therapy. The patients undergoing TAVI are often elderly, with pre-existent cerebral vascular disease and atrial fibrillation. Up to one third of all patients treated with TAVI will develop atrial fibrillation or paroxysmal atrial fibrillation, and that alone is a risk for stroke. Why does paravalvular leakage occur and what does it involve? Proper sizing of the aortic valve is important; if you undersize you risk a paravalvular leak. Since we have moved to 3D imaging modalities, we see that our sizing is becoming more accurate. The second reason is the appearance of calcium; when there is a high aortic root calcium score there is a higher risk of paravalvular leakage. Calcium causes suboptimal deployment of the valve and suboptimal apposition of the devices to the aortic wall. The third issue is, of course, if the position of the valve is not optimal. If you position it too high or too low then you can have paravalvular leakage. This is due to the skirts surrounding the transcatheter valves. The skirts are meant to prevent paravalvular leak, but if you put the bioprosthesis too low, the skirt will be in the LVOT and not at the proper location in the root to express its sealing design. How do patients with that leakage present? How does it affect them? When there is a massive AR then there is an immediate haemodynamic compromise and the operator will notice subsequent haemodynamic compromise right away. If there is moderate AR, then these patients will typically show less improvement, as compared to a patient with no leakage. We typically see our patients after 30 days for the first time after discharge. We see that patients who have moderate to severe AR tend to have a higher New York Heart Association class after the intervention. Not only does it appear that patients with moderate to severe AR have higher mortality, but according to the literature and our own dataset, it also appears that their quality of life may be reserved. Can you always treat AR? You cannot always treat the paravalvular AR and that is the problem. Sometimes, for instance, if you undersized the valve then what do you do? The only option is surgery and to expose the patient to risks which were the reason why the patient was treated with TAVI in the first place! Alternatively, you can try to do aggressive post-dilatation with a balloon, but you risk overstretching the valve leaflets and with that affecting the integrity of the transcatheter valve. If you position the valve too high or too low you can do a valve-in-valve procedure. The results of valve-in-valve procedures are quite good. There are no reports suggesting that valve-in-valve procedures are associated with worse outcomes. That being said, in concordance with other groups, our data from Rotterdam, suggests that increasing the number of manipulations in the aortic root is correlated to stroke risk. 22 It is important to remember that such salvage procedures to treat paravalvular AR are not without risk. The experience with plug closure of paravalvular leakage is, as far as I know, relatively limited. So, in conclusion, the best way to manage paravalvular AR is to prevent it in the first place! That is why most centres are now very meticulous in their pre-procedural planning, relying on multi-modality imaging protocols. How do you work with other members of the Heart Team to manage paravalvular AR? Again, the MSCT scan is key. In Rotterdam, experienced radiologists report the pre-procedural MSCT scans first. They are responsible for the overall scan interpretation including the evaluation of non-vascular structures. The interventionalist will subsequently and independently assess the scan zooming in on the anatomy that is relevant to the TAVI procedure itself, using a dedicated software program. Both parties will assess the peripheral arterial tree and the aortic root. This parallel evaluation warrants optimal sizing and may improve access site selection. In case of significant discordance, both the radiologist and the interventionalist gather to discuss the scan in more detail together. 16 confluence issue eignt April 2014

18 Address for correspondence Nicolas M. Van Mieghem MD, FESC Interventional Cardiology Thoraxcenter, Erasmus Medical Center s-gravendijkwal 230, 3015 CE Rotterdam The Netherlands What improvements in technology are we likely to see in the next couple of years that are potentially going to reduce paravalvular leakage associated with TAVI? The second generation of valves, the repositionable and retrievable devices, may provide a breakthrough. I am a believer that by using these repositionable systems you may have a considerable impact on the incidence of AR. However, when you have a repositionable system, repositioning of the device still means additional manipulation in the aortic root with all the potential sequelae, such as embolization. At the end of the day, the question is whether the second-generation devices will reduce the overall incidence of complications? That remains to be seen. Refinements to software tools will help predict how a transcatheter valve will behave in the aortic root. That means that given a certain anatomy, with a certain amount of calcium, you could predict how a bioprosthesis would be deployed in that particular anatomy. For example, it may be that you could predict malapposition or underexpansion, and this may eventually help with the selection of devices. Looking even further forward, what does an ideal valve look like? An ideal valve would have a harness that is very compliant and able to accommodate different anatomies. In case of excessive and protruding aortic root calcifications, the bioprosthesis could then accommodate and wrap around protrusions without leaving lacunes that could create paravalvular leaks. Furthermore, I do believe that repositionable and retrievable valves are the way to go; I believe this is an essential feature in the immediate future. Of course, durability is an important issue; the ideal valve should last for life. At present, we only have data for about 5 years; so far we have no indication that there is accelerated degeneration of the bioprosthesis as compared with surgical valves. However, we must continue to monitor this. What do you see as being the crucial studies that need to be carried out in this field? Long-term data are vital. The initial wave of data showed us that the short-term and 1-year outcomes are positive, but now we need more information on how the valve will behave after 10 years. That is the goal of all the registries looking at TAVI and I hope that these efforts will continue. For instance, data from SOURCE or ADVANCE, as well as long-term follow-up of national registries will be very relevant. 23 This will demand not only continued effort, but also continued investments in long-term research. REFERENCES: 1. Smith CR, et al. N Engl J Med 2011;364: Miller DC, et al. J Thorac Cardiovasc Surg 2012;143: e Adams DH, et al. N Engl J Med 2014;Mar 29:Epub ahead of print. 4. Abdel-Wahab M, et al. Heart 2011;97: Gilard M, et al. N Engl J Med 2012;366: Moat NE, et al. J Am Coll Cardiol 2011;58: Kodali SK, et al. N Engl J Med 2012;366: Athappan G, et al. J Am Coll Cardiol 2013;61: Généreux P, et al. J Am Coll Cardiol 2012;59: Hahn RT, et al. J Am Coll Cardiol 2013;61: Sinning J-M, et al. J Am Coll Cardiol 2012;59: Tamburino C, et al. Circulation 2011;123: Van Mieghem NM, et al. Am J Cardiology 2012;110: Testa L, et al. Circulation 2013;127: Houthuizen P, et al. Circulation 2012;126: Van Mieghem NM, et al. Catheter Cardiovasc Interv 2013;127: Chieffo A, et al. J Am Coll Cardiol 2013;61: Abdel-Wahab M, et al. JAMA 2014;311: Barbanti M, et al. EuroIntervention 2013;9: Grube E, et al. JACC Cardiovasc Interv 2011;4: Van Mieghem NM, et al. Circulation 2013;127: Nuis RJ, et al. Am J Cardiology 2012;109: Thomas M, et al. Circulation 2011;124: DISCLOSURES: NMVM is Consultant for Medtronic and Boston Scientific. EuroPCR 2014, Paris, France May If you are attending EuroPCR 2014, be sure not to miss Dr Jeffrey Popma s presentation of the CoreValve US IDE clinical study. These unique data of the randomized clinical trial comparing TAVI to surgical replacement in high-risk surgical patients will be presented during the TAVI symposium sponsored by Medtronic on Thursday 22 May in the Theatre Havane, 12:30 14:00 17 confluence issue eignt April 2014

19 CASE STUDY Alexander Plehn First experience with a new renal denervation device and technology: the Spyral device Symplicity Spyral renal denervation system in challenging anatomies Background Catheter-based renal sympathetic denervation (RDN) has shown to significantly reduce blood pressure (BP) in patients with resistant hypertension. 1-4 Although several devices have entered the renal denervation market, to date, available clinical data are almost entirely derived from the Symplicity Flex System (Medtronic, Inc., Minnesota, USA). This second generation device is both well established and approved, but has several limitations. The catheter shaft is rigid and may hinder the steerability and motion of the tip in the renal artery in cases of aortic and/or pelvic elongation. Furthermore, procedures using this device can be time consuming due to the need for sequential positioning of single ablation points in the renal artery; 2 minutes each, 4 6 times per side. Non-compliant balloon or cage based systems, like the Vessix (Boston Scientific, CA, USA) or EnligHTN (St Jude Medical, St Paul, MN, USA) devices, are faster, ablating multiple points simultaneously, and they are also not without drawbacks. Variations in the renal anatomy such as small (<3.5mm) as well as big (>8mm) vessels, early bifurcations (stem <20mm), or severe elongation of the abdominal aorta or renal arteries are frequently found in patients. However, such anatomies cause considerable operating challenges when existing devices are employed and, as such, these patients are frequently excluded in the current trials. The next generation Symplicity Spyral device has been designed to overcome many of these shortcomings. The device has a unique spiral architecture in which four electrodes simultaneously deliver energy, leading to a shorter ablation interval of approximately 60 seconds. To date, we have used the catheter in about 25 patients with resistant hypertension. Here, we share our experience of seven anatomically challenging cases. Case presentation All patients are Caucasians who attended our outpatient clinic on a regular basis due to their resistant hypertension. At baseline, these patients used a mean of 5.9 antihypertensive medications. Treatment regimens had been altered several times over the course of the last few years without a sufficient effect on BP, which remained above 160 mmhg for office-based measurements and above 135 mmhg systole for ambulatory blood pressure monitoring (ABPM). Secondary causes of hypertension were excluded. A 24h Holter blood pressure monitoring was recorded for 24 hours before and after RDN. Investigation During the RDN procedure we encountered a number of anatomical situations (Table 1) that would have been very challenging while using the Symplicity Flex device. Notably, a kinked aorta or tortuous renal arteries would have prevented controlled positioning of the desired ablation points. Furthermore, the catheter tip very often had less wall contact in big vessels leading to recurrent error messages. By using the Spyral device, those anatomic pitfalls were easy to overcome, while still providing fast, successful and controlled energy delivery. Figures 1 7 illustrate the position of the Spyral catheter in the different anatomical cases. Despite a significant increase of energy delivery points (5 10 per side), overall procedure time was considerably reduced, taking average of 14 minutes. However, the question about the effectiveness of the new system still remains. Early ambulatory blood pressure drop analyses (ABPM) in our centre revealed a Symplicity Flex equivalent BP decrease of 17.9 / 5.7 mmhg 24 hours after denervation (figure 8). 18 confluence issue eignt April 2014

20 table 1 Patient Anatomical Findings Figure 1 Early bifurcation 1 2 Tortuous renal artery 2 3 Kinking of the abdominal aorta 3 4 Kinking of the abdominal aorta 4 5 Large vessel diameter 5 6 Proximal atherosclerotic lesion & early bifurcation 6 7 Large vessel diameter 7 fig. 1 Early bifurcation of the left renal artery; Symplicity Spyral RDN catheter positioned in the inferior main branch; IMA 6F 55cm guide catheter (Cordis); HI-TORQUE Iron Man guide wire (Abbott Vascular) fig. 2 Tortuous right renal artery; Symplicity Spyral RDN catheter positioned in the distal part of the main artery; IMA 6F 55cm guide catheter (Cordis); HI-TORQUE Iron Man guide wire (Abbott Vascular) 19 confluence issue eignt April 2014

21 fig. 3 Kinking of the abdominal aorta; Symplicity Spyral RDN catheter positioned in the left renal artery; free floating IMA 6F 55cm guide catheter (Cordis); HI-TORQUE Iron Man guide wire (Abbott Vascular) fig. 4 Kinking of the abdominal aorta; Symplicity Spyral RDN catheter positioned in the right renal artery; free floating IMA 6F 55cm guide catheter (Cordis); HI-TORQUE Iron Man guide wire (Abbott Vascular) fig. 5 Large vessel diameter of left main renal artery (9.6mm); Symplicity Spyral RDN catheter with adequate alignment; IMA 6F 55cm guide catheter (Cordis); HI-TORQUE Iron Man guide wire (Abbott Vascular) fig. 6 Proximal atherosclerotic lesion; Early bifurcation; Symplicity Spyral RDN catheter positioned across the first main branching; IMA 6F 55cm guide catheter (Cordis); HI-TORQUE Iron Man guide wire (Abbott Vascular) 20 confluence issue eignt April 2014

22 fig. 7 Large vessel diameter of left main renal artery (9.8mm); Symplicity Spyral RDN catheter with adequate alignment; IMA 6F 55cm guide catheter (Cordis); HI-TORQUE Iron Man guide wire (Abbott Vascular) 0 ABPM SPYRAL systolic BP 24h systolic BP day diastolic BP 24h diastolic BP day fig. 8 Changes in ABPM 24h after RDN compared with baseline Change from baseline to 24h (mmhg) ** * -5.70** -9.00* mixed models(*p<0.001, **p<0.05) -25 Address for correspondence Dr Alexander Plehn MD Department of Medicine III (Cardiology, Angiology, Intensive Care Medicine, Sports Medicine, Geriatrics) Hospital of the Martin Luther University Halle-Wittenberg Ernst-Grube-Str. 40D Halle(Saale), Germany Tel.: alexander.plehn@uk-halle.de Conclusions Summing up, the Spyral catheter system enables interventionalists to overcome anatomical situations, which to date have proven difficult or even impossible to manage using renal sympathetic denervation. The device is soft, has good steerability and adapts well to challenging anatomies. Additionally, energy delivery points can be selectively deactivated and thus, the length of the renal artery main stem is no longer a limiting factor as the device can be positioned across a bifurcation while deactivating the electrode at the branching. REFERENCES: 1. Krum H, et al. Lancet 2009;373: Krum H, et al. Lancet 2014;383: Mahfoud F, et al. Circulation 2013;128: Persu A, et al. J Hum Hypertens 2014;28: Take-home messages The newly developed Symplicity Spyral renal denervation system has several key features that overcome some of the challenges with current devices: The helically shaped monorail catheter is easy to deploy and treats a wider range of renal anatomies By using a multi-electrode approach and reducing the ablation interval to 60 seconds, the overall procedure time gets reduced significantly It provides an efficient helical ablation pattern in most patients and has a good safety profile DISCLOSURES: AP has no conflicts of interest. 21 confluence issue eignt April 2014

23 CASE STUDY Flavio Ribichini STEMI treatment with Export alone Management of myocardial infarction with ST-segment-elevation using only Medtronic s Export AP aspiration catheter to aspirate multiple coronary branches Michele Pighi Carlo Zivelonghi Mattia Lunardi Background Myocardial infarction with ST-segment elevation (STEMI) is typically caused by sudden thrombotic occlusion of a coronary artery, triggered by the disruption of the fibrous cap of an atherosclerotic plaque. 1 Manual thrombus aspiration is an adjunctive procedure that prepares the vessel before stenting in acute STEMI by reducing the thrombotic burden. This simple maneuver is intended to reduce the occurrence of low flow within vessels and improve myocardial reperfusion, offering potential advantages for left ventricular function and long-term survival. 2 Indeed, manual thrombus aspiration has entered routine practice as part of percutaneous coronary interventions (PCI) in STEMI, as advised by recent guidelines. 3, 4 However, thrombus aspiration may not be necessary in all STEMI cases, and its value in reducing early mortality has been recently challenged by the TASTE investigators. 5 In some rare cases, thrombotic coronary occlusion may occur even in the absence of significant atherosclerotic disease as detected by angiography, the main reason being coronary embolization in patients with paroxysmal atrial fibrillation. 6 Although coronary embolism is considered an uncommon cause of acute coronary syndromes, a large number of patients suffer from atrial flutter/fibrillation, which is a leading cause of emboli formation and migration into the vascular system. Moreover, the lack of a standard recommended therapeutic algorithm for this rare event represents a challenging condition to manage. Case presentation Here we report the case of a 57-year-old male patient with a known diagnosis of dilated cardiomyopathy (DCMP), admitted to the emergency room with typical chest pain that began 2 hours before. The patient had severe hypotension (80/60 mmhg) and bradycardia (50 bpm). On examination, an arrhythmic pulse was observed, but there was no cardiac murmur by auscultation and complete normal respiratory signs. ECG revealed atrial flutter with 3:1 A-V block and incomplete right bundle branch block, typical signs on inferior STEMI with associated right ventricle infarction (ST-segment elevation in V3) and reciprocal ST depression in V4-V5-V6 (fig. 1a). Investigation Transthoracic echocardiography performed in the emergency room showed an ejection fraction of 20%, severe dilation, and hypokinesia of both ventricles, moderate left atrium dilation, mild aortic regurgitation, minimal mitral regurgitation, and mild tricuspid regurgitation with systolic pulmonary artery pressure of 40 mmhg. Acetyl-salicylic acid (300 mg) and clopidogrel (loading dose of 600 mg), together with an intravenous unfractioned heparin (UFH) bolus (5,000 units) plus an i.v. infusion (10,000 units diluted in 250 cc of saline solution), were given as antithrombotic agents. fig. 1 ECG a) before and b) after thrombus removal from RCA 22 confluence issue eignt April 2014

24 fig. 2 Angiogram showing normal Left Coronary Artery The patient was transported to the catheterization laboratory for coronary angiography and primary PCI. Haemodynamic support with dopamine and crystalloids was necessary to obtain adequate blood pressure values. Coronary angiography showed normal left anterior descending and circumflex coronary arteries without evidence of significant stenosis or atherosclerosis (fig. 2). The right coronary artery (RCA) was totally occluded by a large thrombus located in the proximal segment of the vessel, causing a thrombolysis in myocardial infarction (TIMI) grade 0 flow (fig. 3a). Differential Diagnosis No data were available regarding a possible pro-thrombotic state The previous history of DCMP, supported by the normal aspect of the left coronary system, and the rhythm disturbance, raised suspicion of a possible embolic occlusion of the RCA Therefore, manual thrombus aspiration was considered as the first-line treatment of the coronary occlusion causing STEMI Management A 6-F Judkins right guiding catheter (Medtronic, Inc.) engaged the coronary ostium, which allowed the thrombotic occlusion to be crossed with a coronary guidewire followed by a 6-F Export Aspiration Catheter (Medtronic, Inc.). A large amount of the thrombus was removed from the coronary artery (fig. 3b). After several aspirations, angiography revealed reperfusion of the acute marginal branches, with a rapid improvement in haemodynamic status. There was a clear migration of the residual thrombotic material to the distal segment of the RCA, involving the bifurcation of the posterior descending artery and the postero-lateral artery (fig. 4a d). fig. 3 a) Angiogram showing a complete proximal RCA occlusion by a thrombus; b) thrombo-embolic material aspirated from RCA with the Export catheter A B The aspiration catheter was then advanced to the site of occlusion at the crux cordis. By directing the guide-wire towards two different postero-lateral branches and the posterior descendent artery (followed by the easy advancement of the Export catheter) a large amount of thrombus was retrieved. Angiography showed a brisk TIMI grade 3 flow in all the branches of the distal RCA. There was minimal residual embolic material in the most distal segment of one postero-lateral branch, with no evidence of atherosclerosis along the whole right coronary artery (fig. 5a,b). 23 confluence issue eignt April 2014

25 fig. 4 Angiogram showing thrombus migration from a) the proximal, to b,c) medium tract of RCA and d) distal bifurcation fig. 5a, b Angiogram showing fully restored blood flow over all RCA length, although the persistence of a minimum quantity of embolic material in the postero-lateral branch of RCA (black arrows) Following aspiration, clinical signs improved dramatically, with complete ST-segment elevation resolution and regression of symptoms. Angiography demonstrated no evidence of ongoing coronary stenosis and, therefore, no further interventions were performed. The patient was then transferred to the coronary care unit, in stable haemodynamic conditions. However, following this transfer, ECG showed atrial fibrillation with a rapid ventricular response (fig. 2b). The patient was subsequently treated with intravenous metoprolol (1.25 mg) and digoxin (0.625 mg) preceded by an i.v. loading dose. The i.v. infusion of UFH was maintained over the next 12 hours. Subsequent Holter electrocardiography, performed to investigate cardiac arrhythmias, identified the presence of several episodes of paroxysmal atrial fibrillation and atrial flutter that mandated persistent oral anticoagulation therapy. The patient s subsequent hospital course was uneventful. Take-home messages Coronary embolism is an uncommon cause of acute coronary syndromes. The known etiologies of this phenomenon are numerous and heterogeneous including infective endocarditis, mural thrombi, thrombotic material from prosthetic aortic and mitral valves, neoplasms, and calcium deposits from manipulation of calcified valves during cardiac surgery Address for correspondence Prof. Flavio Ribichini Director Cardiovascular Interventional Unit Department of Medicine, Division of Cardiology University of Verona Piazzale Aristide Stefani , Verona, Italy Tel: flavio.ribichini@univr.it Atrial fibrillation is the most common cause of STEMI secondary to coronary embolism Unlike proximal or distal embolic protection and mechanical thrombus aspiration 7, manual thrombus aspiration reduces infarct size and improves long-term survival in patients presenting with STEMI, and is recommended by current guidelines as a main technical step in the treatment of STEMI by primary PCI 4 The case described here demonstrates the efficacy of this simple device to safely address the challenges posed by massive intracoronary thrombosis in STEMI patients REFERENCES: 1. Epstein FH, et al. N Engl J Med 1992;326: Vlaar PJ, et al. Lancet 2008;371: Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC), et al. Eur Heart J 2010;31: Authors/Task Force Members, et al. Eur Heart J 2012;33: Röbert O, et al. N Engl J Med 2013;369: Libby P. Braunwald s Heart Disease: A Textbook of Cardiovascular Medicine. Elsevier; Gick M, et al. Circulation 2005;112: DISCLOSURES: The authors have no conflicts of interest. 24 confluence issue eignt April 2014

26 EXPERT OPINION AND COMMENTARY Christian Hamm 1. How does TAPAS TASTE? Thrombus aspiration in daily practice Percutaneous interventions in acute coronary syndromes are highly effective in reducing mortality. The challenge of such procedures is the intracoronary thrombus burden that is characteristic, particularly in STEMI. Background antithrombotic therapy is efficient in reducing the risk of low flow or no-reflow in our most critical cases. However, pharmacological therapy has limitations and cannot not remove heavy thrombus load completely. Therefore, mechanical aspiration of thrombus seems a reasonable approach. So is this rather crude approach really the answer? While TAPAS says yes, TASTE says no, is there TOTAL confusion now? No, not really; without going into details with respect to study designs and limitations, daily practice can offer us some crucial insights. As always in life: the truth is usually somewhere in the middle. In many cases, straight forward stenting gives us excellent results, while the mechanical approach often appears too simplistic. From the clinical trial data, it appears to be very clear from current evidence that routine use of aspiration is not the answer. Interestingly, this was already acknowledged by operators who frequently perform primary PCI. However, the same clinicians also recognise that removal of thrombus helps in individual cases whereby the patient has a heavy thrombotic burden. While the efficacy of thrombus aspiration remains dependent on patient circumstances, it is reassuring that all study data to date have demonstrated the favourable safety profile of the intervention and that we will do no harm in using it. Therefore, the door has been left open for individual decision making. Although, I am a strong believer in evidence from randomized controlled trials, I am convinced that we need personalized approaches, particularly when we have our back against the wall in trying to provide optimal care to patients. And this is how many of us interpret the diverging results in our daily practice; we are happy to have these instruments as tools in our arsenal, but we are also relieved that we retain the decision as to when to employ them. Common sense often remains a good guide for clinicians. Address for correspondence Prof. Dr. Christian Hamm, Kerckhoff-Klinik ggmbh Herz- und Thoraxzentrum Benekestrasse 2-8, D Bad Nauheim Germany c.hamm@kerckhoff-klinik.de In this issue of Confluence, Dr Shuvy and Prof. Lotan give a critical overview of all mechanical approaches to remove thrombus. It is good that he reminds us of the limitations of this technique and reminds us not to get carried away your patient, undergoing primary PCI, wants you to treat him based not only on the best scientific knowledge available but also as an individual. Therefore, at the end of the day, their care depends on your expertise and skills in judging the optimal treatment pathway. DISCLOSURES: CH has no relevant disclosures to declare. 25 confluence issue eignt April 2014

27 EXPERT OPINION AND COMMENTARY Chaim Lotan Mony Shuvy 2. Protection from distal embolization and role of aspiration in ACS Background Acute coronary syndrome (ACS) is characterized by rupture of an atherosclerotic plaque, which initiates thrombus formation at the site of plaque rupture. 1 Activation of thrombin and the coagulation cascade, and the central role of activated platelets, result in clot formation, which impair blood flow to the peripheral circulation of the coronary vessel. 2 Persistent and complete thrombotic occlusion of a coronary artery results in ST elevation myocardial infarction (STEMI), while incomplete occlusion may cause non-st elevation myocardial infarction (NSTEMI). Current guidelines recommend a comprehensive approach that combines pharmacological treatment with reperfusion therapy. 3,4 In this article we provide an overview of pharmacological therapy and revascularization in ACS. We then discuss the role of mechanical intervention and review the data associated with different thrombectomy devices. Pharmacological therapy Since the thrombotic burden plays an important role in ACS pathogenesis, most treatment options target the different mechanisms involved in thrombus formation. Therapy needs to include anticoagulant drugs as well as antiplatelet therapy. All ACS patients should receive anticoagulant therapy, with it being started as soon as possible. 3 Such agents include low molecular weight heparin, fondaparinux and in some centres direct thrombin inhibitors such as bivalirudin. Aspirin therapy should be given to all patients with ACS 5, 6, and the Guidelines recommend dual antiplatelet therapy with either one of the thienopyridins (clopidogrel or prasugrel) or ticagrelor. These combinations are essential in ACS treatment regimen. Glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, and tirofiban) should be considered for patients with a large thrombus burden or in those who are suffering thrombotic complications during PCI. 7 Revascularization therapy Coronary reperfusion after STEMI improves outcome; reperfusion can be achieved by fibrinolytic therapy or by percutaneous coronary intervention (PCI). PCI is the preferred strategy, as it provides better coronary perfusion and better clinical outcomes compared with fibrinolytic therapy alone, although it may not be superior in certain circumstances to the pharmaco-invasive strategy. In patients undergoing primary PCI, pharmacological treatment forms the mainstay of treatment in decreasing thrombus burden. However, despite aggressive antithrombotic/ antiplatelet therapy, PCI only restores normal (distal, micro-vascular) myocardial perfusion in approximately two thirds of ACS patients. 8 Several risk factors are associated with non-optimal primary PCI results including: age, diabetes, longer time to reperfusion and low ejection fraction. 9 It is clear that an important feature of the pathology and natural history of ACS is the presence of thrombus; large thrombus burden is related to distal embolization, which causes microvascular obstruction despite adequate epicardial perfusion (no-reflow). 10 The no-reflow phenomenon is in turn related to increased risk of stent thrombosis and mortality. 11 A recent study followed 1,406 patients with STEMI treated by primary PCI and showed that the no-reflow phenomenon is a strong predictor of 5-year mortality. Interestingly, the no-reflow phenomenon was associated with worse prognosis, independent of infarct size. 9 In order to decrease thrombus burden and no-reflow, several interventions have been suggested and are described below. Mechanical interventions Mechanical interventions during PCI include proximal and distal protection devices, as well as aspiration devices; all of these are designed to prevent/attenuate the potential harmful effects of the thrombus. Some are deployed at the distal side of the target lesion, such as the distal protection device. Distal protection devices have failed to show immediate, short-, or intermediate-term benefits of the adjunctive device. 12, 13 Further, the DEDICATION (Drug Elution and DIstal protection in Acute 26 confluence issue eignt April 2014

28 Address for correspondence Prof. Chaim Lotan, Heart Institute Hadassah Medical Center, PO Box Jerusalem Israel myocardial infarction) trial results suggested that routine use of distal protection increased the incidence of stent thrombosis and TLR. 14 Current recommendations support the use of distal protection devices only during PCI in saphenous vein grafts. 3 Thrombectomy, performed in the initial phase of PCI, is another potential approach to improving reperfusion in patients with STEMI, through mitigation of thrombus effects. Thrombectomy can be carried out using manual thrombus aspiration or mechanical thrombectomy devices. Thrombectomy devices are designed to aspirate thrombus to reduce the risk of embolisation, generally prior to stent deployment. Active thrombectomy devices include the AngioJet rheolytic thrombectomy system (Possis Medical Inc, Minneapolis, Minn) and the X-Sizer (ev3 Inc, Plymouth, Minn) catheters. The beneficial effects of these devices have been demonstrated in several studies. However, while the devices may improve early markers of reperfusion, they do not improve 30-day post-mi mortality, re-infarction and stroke. 15 These devices should be used only in selected patients with large caliber vessels and heavy thrombus burden, such that their routine use is not supported. 16 Devices involving manual aspiration have had more favourable results, including a mortality benefit, as demonstrated in the TAPAS (Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarctions) study 8, a single-centre all-comers study that enrolled 1,071 STEMI patients. It showed that aspiration improved myocardial blush, ST resolution and significantly improved the 1-year mortality. Following the results of this study, the European Society of Cardiology gave a 2A recommendation for routine thrombus aspiration during treatment of STEMI. 3 However, meta-analyses have since failed to show absolute benefit from routine thrombus aspiration. 15 Furthermore, the recently published INFUSE AMI trial, which enrolled 452 patients with STEMI randomized to thrombus aspiration versus no aspiration, failed to show any advantage of routine aspiration. 17 Results from the Thrombus Aspiration in ST- Elevation myocardial infarction in Scandinavia (TASTE) trial have been published recently. TASTE was a multicentre, prospective, randomized, controlled, open-label trial that evaluated whether thrombus aspiration during primary PCI reduces mortality in patients with STEMI. In total, 7,244 patients from Sweden, Denmark and Iceland were randomly assigned either to conventional PCI or to thrombus aspiration followed by conventional PCI. The mortality rate at 30 days post-procedure was not statistically different between the groups. Similarly, there was no difference between the two groups for secondary endpoints, including risk of MI, stroke and complications related to the treatment. Even high-risk groups such as smokers, patients with diabetes or patients with large clots had similar results with either approach. 18 At present, there are clearly conflicting efficacy and safety data surrounding mechanical interventions. However, a further large-scale clinical trial the TOTAL (ThrOmbecTomy with PCI versus PCI Alone) trial is currently in progress and will provide further valuable evidence in this field. This study will randomize patients to PCI with or without manual aspiration thrombectomy and is designed to enroll 10,700 patients. The primary endpoint of the trial is a composite of cardiovascular death, recurrent MI, cardiogenic shock, or new or worsening New York Heart Association (NYHA) class IV heart failure at 6 months. TOTAL study is due to report in Summary While PCI is the primary treatment for STEMI, the presence of thrombus in the infarct-related vessel is associated with worse outcome due to embolic micro-vascular damage. Several approaches have been developed to improve PCI outcome. The pharmacological approach combines anticoagulation, oral antiplatelet therapies and possibly parenteral glycoprotein IIb/IIIa inhibitors. However, despite aggressive pharmacological therapy, clinical results after PCI in patients with ACS are still not optimal. Aspiration devices in general failed to show benefit, and some of them may even be harmful. While there have been positive data on the use of proximal manual aspiration devices, additional studies are required to define the role of these devices in ACS treatment, hopefully to define the subpopulations that may benefit from such devices. 27 confluence issue eignt April 2014

29 REFERENCES: 1. Falk E, et al. Circulation 1995;92(3): Fuster V, et al. New Engl J Med 1992;326(5): Task Force on Myocardial Revascularization of the European Society of Cardiology, et al. Eur Heart J 2010;31(20): Writing Committee M. Circulation 2012;126(7): Lewis HD, et al. New Engl J Med 1983;309(7): Cairns JA, et al. New Engl J Med 1985;313(22): Hanna EB, et al. JACC Cardiovascular interventions 2010;3(12): Vlaar PJ, et al. Lancet 2008;371(9628): Ndrepepa G, et al. J Am Coll Cardiol 2010;55(21): Rezkalla SH and Kloner RA. Circulation 2002;105(5): Cura FA, et al. Am J Cardiol 2001;88(2): Stone GW, et al. JAMA 2005;293(9): Gick M, et al. Circulation 2005;112(10): Kaltoft A, et al. J Am Coll Cardiol 2010;55(9): Mongeon FP, et al. Circ Cardiovasc Interv 2010;3(1): Costopoulos C, et al. Int J Cardiol 2011;163(3): Stone GW, et al. JAMA 2012;307(17): Fröbert O, et al. New Engl J Med 2013;369: DISCLOSURES: CL is Medical Director of InspireMD Ltd. MS has no relevant disclosures to declare. Sanjit Jolly 3. Perspectives on thrombectomy on clinical practice Primary percutaneous coronary intervention (PCI) has become the dominant reperfusion method for ST elevation myocardial infarction (STEMI) across most of Europe and North America. However, a significant limitation of primary PCI is the inability to achieve reperfusion or normalized flow at the microvascular level. Up to a third of patients who have undergone primary PCI have impaired microvascular flow, as measured by myocardial blush grade, and these patients have a marked increased risk of mortality (fig. 1). 1 Thrombectomy has the potential to reduce distal embolization and improve microvascular perfusion during PCI for STEMI. Meta-analyses of largely small trials have shown that manual thrombectomy improved myocardial blush grade, reduced distal embolization and no reflow. 2,3 Enthusiasm for thrombectomy grew with the results of the TAPAS trial, a single center trial (N=1,071) that showed improvement in the primary outcome of myocardial blush, but more importantly, a reduction in mortality at 1 year. 4,5 However, recently, a much larger randomized trial, the TASTE trial (N=7,244), showed no different in all-cause mortality with manual thrombectomy. 6 An important caveat to the interpretation of the TASTE trial results is that the trial had a much lower than expected mortality and so the trial was not powered to detect modest but important reductions in mortality (i.e., 20 30%). In this issue of Confluence, Dr Shuvy and Professor Lotan describe the conflicting data and correctly determine that the efficacy of routine manual thrombectomy in STEMI remains uncertain. fig. 1 Relationship of Myocardial Blush Grade and Mortality after PPCI 1 Cumulative survival 100% 80% 60% 40% 20% Final Blush score (all patients) Blush 1-year mortality 3 6.8% % P= /1 22.0% 3 2 0/1 0% Months 28 confluence issue eignt April 2014

30 Address for correspondence Sanjit S. Jolly Rm. C3-118 DBCSVRI Building Hamilton General, Hospital 237 Barton St. East, Hamilton On, Canada, L8L 2X2 Tel: Fax: Ongoing Trials: TOTAL trial The ongoing TOTAL trial (N=10,700) is a randomized trial of routine manual thrombectomy plus PCI vs. PCI alone during primary PCI for STEMI, on a 1:1 basis. 7 The trial is the largest trial to examine this area and will have appropriate power because it is an event driven trial. It is clear with mortality rates of 2 3% that trials utilizing mortality as the primary outcome are impractical because they would require in excess of 30,000 patients. As a result, the TOTAL trial is using a primary outcome that is a composite of cardiovascular death, myocardial infarction, cardiogenic shock or new or worsening NYHA class IV heart failure up to 180 days. The hypothesis of the trial is that thrombectomy i) can prevent distal embolization and no reflow and thus prevent shock, heart failure and death and ii) thrombectomy can reduce thrombus surrounding the stent and thereby reduce risk of stent thrombosis and thus myocardial infarction. The TOTAL trial has recently been revised to be powered to detect a relative risk reduction of 20%, which would put the treatment effect thrombus aspiration on par with other recognized therapies, such as aspirin. 7 The TOTAL trial will provide important new information on the clinical benefit of thrombectomy during STEMI. Results are expected from the trial in Implications for Practice Until further evidence, operators should use clinical judgement to selectively choose cases where thrombectomy may be useful (i.e., large thrombus burden). At the current time, thrombectomy is simply another tool in the PCI toolkit to help operators achieve an optimal angiographic result. REFERENCES: 1. Stone GW, et al. J Am Coll Cardiol 2002;39(4): Mongeon FP, et al. Circ Cardiovasc Interv;3(1): Bavry AA, et al. Eur Heart J 2008;29(24): Svilaas T, et al. N Engl J Med 2008;358(6): Vlaar PJ,et al. Lancet 2008;371(9628): Frobert O, et al. N Engl J Med 2013;369(17): Jolly SS, et al. Am Heart J 2014;167(3): e1. DISCLOSURES: SJ has received grant support from Medtronic, Inc., and speaker s honoraria from Astra Zeneca. Call for case studies! Case reports should be no more than 1,000 words and submitted to confluence@axon-com.com. On the final page of this issue you can find a submission template for case studies. Alternatively, please visit to download the template and submit your case. 29 confluence issue eignt April 2014

31 HOT TOPIC Art Sedrakyan FDA establishes International Consortium of Transcatheter Valve Registries Initiative (ICCR-ICTVR) to fill evidence gaps related to transcatheter aortic valve replacement procedures and devices With expert input from Art Sedrakyan While transcatheter aortic valve replacement (TAVR) is becoming increasingly commonplace in the clinic, there are relatively few long-term data available for the devices used in this procedure. This paucity of data is due, in part, to the cost and logistical challenges posed by large, randomized clinical trials. The United States Food and Drug Administration (FDA) noted that information obtained from clinical trials is often limited due to small size, short followup, and lack of generalizability. Observational studies and registries are often limited in scope and size to a specific country, region, or health care provider system. 1 In order to deliver these crucial data to interested parties, the FDA has turned to international registries to facilitate inter-registry collaboration that can help all parties provide an effective means of developing real-life clinical evidence. The data collected will help to identify knowledge gaps, patient selection, regional differences in practice, potential problems that may arise with specific techniques, and novel management strategies. While registries together offer the potential for the analysis of very large data sets, the collection of long-term safety and efficacy, quality of life and device performance data, by this means, is complicated by varied patient populations, numerous devices that are rapidly being updated, and the necessity for common definitions to allow the full recording of datasets. As such, collaboration between the various international registries is crucial to ensure the successful development of an international programme to assess TAVR devices. Moreover, a rigorous and systematic methodology, combined with the requisite expertise, would be vital to provide dependable data. The FDA convened an initial meeting of the International Consortium of Cardiovascular Registries (ICCR) Transcatheter Valve Replacement Registry initiative (ICTVR) in April This meeting, attended by a variety of stakeholders including representatives from academia, industry, payors, physicians and regulators, laid the groundwork for the initiative. Representatives from five national registries in the USA, UK, Germany, Canada and the Netherlands discussed the design and status of their national registries, with a view to developing methodologies that would allow them to collaborate as part of one of the largest registry networks in the world. The objectives of the ICTVR initiative are four-fold: 1. Development and testing of innovative methodological approaches: to use, develop and adapt relatively new registry analytical tools to study TAVR devices 2. Forum for discussion: to bring together stakeholders in workshops and conferences to discuss gaps in evidence, datasets, and best practices 3. Comparative outcomes studies: to help establish best clinical practice through comparison of both surgical/interventional techniques and TAVR devices. Such data will also be used to inform regulatory decision making 4. Publications: collaboration in the development of peer-reviewed manuscripts and white papers, in order to share the knowledge and expertise developed by the group Led jointly by the registries and FDA, with inclusion of numerous key stakeholders, this initiative is likely to provide valuable data that will drive clinical excellence in the field of TAVI. Dr Art Sedrakyan, 30 confluence issue eignt April 2014