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issue twelve February 2016

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

FranZ wEiDinGEr aUSTrIa

supported by an unrestricted educational grant from medtronic, inc

concepts and opinions in interventional cardiovascular medicine

confluence

Next generation stent technology: the era of complete freedom from polymers has begunFigure originally presented at TCT, 2015, San Francisco, CA, USA

Dear colleagues,It is with great pleasure that I welcome you to the 12th issue of Confluence: Concepts and opinions in interventional cardiovascular medicine.

Over the lifetime of Confluence, we have reported on numerous advances in the field of interventional cardiovascular medicine. Such innovation in both technology and thinking has provided more options for physicians and improved outcomes for patients.

This issue of the journal is no different, and we cover a raft of new technology with leading specialists in their fields. First, Professor Michael Böhm discusses the challenges faced by renal denervation in its early years, and the technological and scientific advances that are helping to improve the treatment of resistant hypertension in the clinic. We speak with Professor Stephen Worthley about the clinical trials investigating the next generation of drug-eluting stent technology, a polymer-free stent with microscopic holes drilled in the structure of the stent itself to delay the release of the anti-proliferative medication. Elsewhere, Dr Stephen Brecker shares his thoughts on the latest clinical evidence for the new CoreValve® Evolut R™ transcatheter aortic valve. In an interesting case study, a German Interventional Cardiologist [name withheld for regulatory reasons] describes how we can expand treatment options in percutaneous coronary intervention, using a Medtronic Resolute Onyx™ for the management of left main bifurcations and small anatomies.

Christian hamm EDITOR-IN-CHIEF

Innovation is not just about novel technology, however; fresh thinking about how we use technologies, new or old, to manage patients is vital. With this in mind, Editorial Board member, Professor Chaim Lotan, discusses the digital health revolution, which I am sure many of you are already experiencing in your clinical practice. Dr Bernhard Voss took the opportunity to speak with Confluence about the novel use of the Profile 3D ring, a profiled annuloplasty ring, for the management of degenerative mitral regurgitation. Elsewhere in the issue, Professor Thomas Zeller and Professor Frank Vermassen consider the benefits of a drug-coated balloon for the treatment of superficial femoral artery lesions persisting at 2 years. Finally, Dr Jan-Malte Sinning provides an interesting clinical example of coronary access with the Medtronic CoreValve® valves.

As always, your opinions are important to us, so please let us know your feedback on this issue, the journal in general or our website, by emailing us at [email protected]. We would be delighted to receive your proposals on topics to cover in future issues.

Christian hamm

1

Call for case studies!Case reports should be no more than 1,000 words and submitted to [email protected].

On the final page of this issue you can find a submission template for case studies. Alternatively, please visit www.confluencejournal.com

to download the template and submit your case.

confluence issue twelve February 2016

Case study Expanding treatment options in percutaneous coronary intervention: Resolute Onyx™ for left main bifurcations and small anatomies 20Interventional Cardiologist, germany

Interview IN.PACT SFA: benefits of a drug-eluting balloon for the treatment of superficial femoral artery lesions persisting at 2 years 23Thomas Zeller, Frank Vermassen

Interview The future of digital health 29Chaim Lotan

Interview The Profile 3D® ring: is a profiled annuloplasty ring suitable for repair of degenerative mitral regurgitation? 34Berhard Voss

ContentsInterview Is renal denervation dead or alive? 3michael Böhm

Interview CoreValve® Evolut R™: insights from the latest clinical evidence 7Stephen Brecker

Case study Coronary access with the Medtronic CoreValve® transcatheter aortic valve replacement bioprosthesis 11Jan-malte Sinning

Interview Next generation drug-eluting stent technology: the polymer-free era has begun 14Stephen Worthley

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To find this and all previous issues of Confluence online, including video content, please visit:

www.confluencejournal.com


michael Böhm

INTERVIEW

Is renal denervation dead or alive? Hypertension is a medical problem that, for many people, is difficult to control with medication and lifestyle measures. Renal denervation (RDN), the process of disrupting the nerves surrounding the renal artery (for example, by applying radiofrequency energy), has been approved for the treatment of uncontrolled hypertension and offers another treatment strategy for patients. However, in the SYMPLICITY HTN-3 trial, although a reduction in blood pressure was seen following RDN, and the primary safety endpoint was met, a significant efficacy benefit for RDN over a sham procedure was not observed.

Confluence spoke with Professor Michael Böhm, Director of the Clinic for Internal Medicine and Chief of Cardiology at the University of the Saarland, Homburg/Saar, Germany, to discuss the limitations of the trial, what the trial has taught us about the uncontrolled hypertension population, and how this has informed the design of the next generation of RDN trials that are now underway.

What treatment options are available to patients with medication-resistant hypertension? Professor michael Böhm (mB): Even before any medication is prescribed, the first steps that are usually taken for hypertensive patients are general lifestyle modifications, like increased exercise, reduction in alcohol and salt consumption, as well as adjustment of the other risk factors, and this usually brings blood pressure down a little, assuming the patient is willing to comply. However, in patients whose hypertension is poorly controlled on medication, these measures have usually already been tried. Patients with medication-resistant hypertension have usually also tried several drugs or combinations of drugs to control their high blood pressure. This lack of treatment options for these patients led to the development of interventional techniques. Among them is renal denervation (RDN), where the largest investigation of this technique in the world is currently taking place.

Can you outline some of the research into RDN that has been carried out to date? mB: The first attempt at RDN for medication-resistant hypertension was the SYMPLICITY programme with the HTN-11 and HTN-22 trials, followed by the more recent HTN-3.3 HTN-3 was

3 confluence issue twelve February 2016

not successful for a number of reasons: there were concerns over the impact of changes made to blood pressure medication during the follow-up period of the study, and potentially suboptimal procedures. Moreover, these patients were also very late in their medical journey, so they were very truly resistant hypertension patients that may not have been the most amenable to RDN therapy.

The problem in the SYMPLICITY HTN-3 trial was not that blood pressure did not go down – it went down – but there was also a very strong effect in the sham procedure control group, which meant the difference in effect between the treatment groups was not significant. There was, however, a wide variation in blood pressure among patients who had the sham procedure. Our current thinking is that these patients were initially controlled on very high doses of medication, but eventually became non-adherent after the procedure. This resulted in a small difference in the initial study but could explain the limited long-term blood pressure reduction in the sham group. The data from the follow-up study was presented at the 2014 European Society of Cardiology congress. Patients who had RDN maintained low blood pressure values, while in those going out of the trial and maybe off medication, because their adherence is so poor, their blood pressure started to increase again.

Is there anything that you can do in future trials to improve medication adherence? mB: Yes, there is a new trial design that is being used for the new RDN clinical trials, referred to as the SPYRAL HTN Global Clinical programme. There will be two initial trials in the SYPRAL programme. In one study, patients will be taken off all of their current medication, so adherence will not be an issue (SPYRAL HTN OFF-MED). In the second study, patients will stop all pre-trial medication and instead receive three drug classes; a thiazide diuretic, a calcium antagonist, and an ACE inhibitor or angiotensin receptor antagonist (SPYRAL HTN ON-MED). These drug classes can either be in the form of a single combination pill, or separate medications. Having these two trials with different medication regimens will help us to better understand the impact of RDN on blood pressure, by ensuring that the pharmaceutical management of all patients is clearly defined.

An added benefit of using the single combination pill therapy is that we think we can achieve optimal adherence. Furthermore, all patients will undergo urinary screening to test for treatment adherence or to check if there are decreases in medication, which is another potential challenge in the on-medication arm. Patients are told that we are going to monitor whether they take their medication or not, so this may also help to improve adherence.

These treatment adherence data will help us to figure out what happens to those patients who are not compliant. However, as we use an intention-to-treat design, these patients will remain in the primary endpoint analysis. We hope that the measures we have taken – having a very simplified treatment strategy, and also telling patients that we will test whether they are taking their medication – will result in much better adherence than in the previous trials.

What lessons were learned from the SYMPLICITY HTN trials, and how have these influenced the design of the SPYRAL trials? mB: After HTN-3, we reinvestigated the technical and physiological aspects of the technology, and conducted several new animal studies to answer some of the questions generated by the HTN-3 results. We found that in the proximal renal artery (close to the aorta), the nerves are quite far away from the lumen and are therefore less susceptible to radiofrequency ablation, with perhaps only


fig. 1

Symplicity Spyral™ catheter

10–20% of nerves affected. Animal research identified that by ablating in the distal portion of the main stem of the renal artery, and also the renal artery branches lying beyond the main vessel, there was a greater reduction in norepinephrine in study animals, and also the scatter and the deviation of the individual norepinephrine reduction was reduced.

In HTN-3 we employed a mono-electrode device, the Symplicity Flex™ catheter system, which is positioned by sight in order to achieve the circumferential ablation. It turned out that only a small proportion of patients in HTN-3 had four-quadrant ablation.4 We also found a differential blood pressure response between those with and without an evenly-distributed four-quadrant ablation, with a greater reduction in systolic blood pressure in the former. In the SPYRAL HTN programme, we will be using a new technology, the Symplicity Spyral™ catheter (figure 1), which takes on a helical conformation within the artery, and has four electrodes that automatically position evenly around the lumen of the artery, providing a greater potential to achieve full circumferential ablation.

There was also some evidence of severe under-treatment in HTN-3, and a post hoc analysis found that blood pressure response was greater after six to eight ablations per vessel, compared to two or three ablations.4 The approach we are now investigating is to perform more intensive ablation, beyond the main artery, and in some patients we can now do this with the Symplicity Spyral™ device in the branches, achieving up to 40 ablation points per patient, so this is really a strong difference.

In the new trial, the combination of the Symplicity Sypral™ device improving circumferential ablation and including treatment of the periphery may help reduce sympathetic activity further than was achieved in HTN-3.

Another difference is that we are moving a little bit away from the most severe forms of hypertension and towards forms of hypertension that might be easier to treat. According to the literature, patients with resistant hypertension who are not controlled on three or more drugs, including a diuretic at appropriate doses, represent 9–15% of all cases. By contrast, patients who are not controlled on one to three drugs represent the vast majority, maybe 80%, of uncontrolled patients, so these are the patients you are more likely to see in the clinic. There is also one arm in these trial programmes looking at off-medication patients, and I think the study of the possibility of treating patients with RDN as an alternative to medical treatments is the direction in which the new data may direct us.

The last point I would like to make is that operator experience is important. In HTN-3, 31% of operators carried out one procedure during the trial, and over half carried out no more than two.4 In the SPYRAL HTN programme we will use more experienced global investigators. This is one reason for expanding the trial to other countries, where more procedures have been done before.

Are there any differences between the SYMPLICITY and SYPRAL clinical trial programmes in terms of the endpoints that you are using? mB: I think we have had to rethink our endpoints in hypertension trials in general. Office blood pressure has been used historically due to the fact that for endpoint reduction, you need huge numbers to see differences in stroke, myocardial infarction or cardiovascular death. In SPYRAL HTN, we use the gold standard of ambulatory blood pressure monitoring (ABPM), in addition to office blood pressure, which was used to assess outcomes in HTN-3. As ABPM is measured over a 24-hour period, it is not as susceptible to regression to the mean or placebo effects as office blood pressure. As mentioned above, the patients in this trial have slightly lower blood pressure than in those in HTN-3, so we are expecting maybe a little bit less of a reduction in blood pressure. Although we will have smaller reductions, we can be more precise and therefore better able to reliably detect true changes in blood pressure, so the use of ABPM is a major difference.

Do you think that these trials will answer the question as to whether RDN is a clinically viable option? mB: SPYRAL HTN is not the final step, but it is the penultimate step we have to take. On the basis of these two trials, ON and OFF medication, we will perform the power calculation for the pivotal trial, which is expected to be larger and require more patients. If one of these initial trials fails unexpectedly, prior to the pivotal trial, of course we will have to analyse what went wrong, but hopefully that situation will not arise. We have implemented many changes and adaptations to the protocol that we hope will lead to greater efficacy in blood pressure reduction with RDN, but we will have to wait to see the results.

What levels of blood pressure reduction should we be aiming for and how much clinical impact do smaller blood pressure reductions have? mB: The numbers do not mean anything, because when you look at clinical practice and clinical trials for drug treatments there is only a 4–5 mmHg reduction, but in practice this is higher due to individual variation in technique, the white coat effect and other factors; so in practice everything is greater than in clinical trials.

I would not extrapolate reduction – whether it is 8, 10 or 15 mmHg – to the situation in the clinic. Epidemiologically, a 2 mmHg decrease in systolic blood pressure equates to a 10% reduction in stroke mortality and a 7% reduction in deaths from ischaemic heart disease.5 Therefore, every mmHg counts, particularly in those patients who are unwilling to take, or non-compliant with medication. These adherence problems do not affect the interventional procedure; once that is done, it is done, and therefore, over time, we hope that there will be a much greater reduction than with any drug therapy we have had before.

How do you think the results of something like the SPRINT trial are going to impact thinking in terms of treating and managing hypertension? mB: SPRINT is most interesting, and there are two different points to make.6 Patients with a systolic blood pressure of ≥130 mmHg were randomised to a target systolic blood pressure of <120 mmHg (intensive) or <140 mmHg (standard), and rates of clinical events, including myocardial infarction,


6

other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes were compared between the two groups. Intensive treatment reduced the risk of experiencing the composite endpoint of cardiovascular outcomes (listed above) by 25%, which is interesting, and I think there will be a discussion on whether we change the target values in the published guidelines. If the target value is reduced to 120 mmHg, this obviously creates a much larger population that requires strict blood pressure control. This probably equates to somewhere between four to six times as many patients as those that are classified as uncontrolled under current guidelines.

Therefore, patients who start with a blood pressure of 180 mmHg and manage to reduce this to 140 mmHg with drug treatment before side effects lead to discontinuation of drugs, could represent a population in whom interventional techniques are of particular interest. We are moving away from the very late stage patients, towards patients who are really present in the clinic; patients who take three drugs and when they require more than this, they do not take them because they have so many

side effects. This is the real-life population, who are present in our society of millions of people, who will suffer from stroke after a couple of years.

What role do you see RDN playing in hypertension management? Do you see it becoming a mainstay, or is it going to be for selected patients only? mB: First of all, we have to verify that the therapy is effective. If it is effective, we have to figure out which patients are benefiting the most from a blood pressure effect. If it is effective and we understand which patients to use it for, it will become a mainstay in reducing blood pressure.

The next step, which in my view is even more interesting, is to look at high-risk patients with maybe borderline blood pressure or uncontrolled blood pressure who have already had an event. These patients are at particularly high risk of another event. If we can obtain experimental data showing that we can prevent heart failure or atherosclerosis or atrial fibrillation, or even that we might be able to address some forms of ventricular arrhythmias, then we have a mainstay treatment, not only for hypertension but in cardiovascular therapies in general.

address for correspondence Professor Michael Böhm

Department of Internal Medicine III, Cardiology, Angiology and

Intensive Care Medicine Saarland University Hospital

Homburg/Saar Germany

michael.Boehm@ uniklinikum-saarland.de

1. Wang Y. Lancet 2014;383(9932):1885.2. Esler MD, et al. eur heart J 2014;35(26):1752–9.3. Bhatt DL, et al. n engl J med 2014;370(15):1393–401.

4. Kandzari DE, et al. eur heart J 2015;36(4): 219–27.5. Lewington S, et al. Lancet 2002;360(9349):1903–13. 6. Wright JT Jr, et al. n engl J med 2015;373(22):2103–16.

rEFErEnCEs:

DisCLosUrEs: MB has a consulting relationship with Medtronic, Bayer, Novartis and SERVIER, and is a Global Principal Investigator of the SPYRAL HTN Global Clinical Trial Programme.


Stephen Brecker

INTERVIEW

CoreValve® Evolut R™: insights from the latest clinical evidence Transcatheter aortic valve replacement (TAVI) is an established treatment for aortic stenosis in patients unsuitable for surgery or at high risk from surgery. Medtronic’s latest device, the Evolut R™, was designed for transcatheter valve implantation for use in patients with extreme or high risk who have severe aortic stenosis. Confluence spoke to Dr Stephen Brecker from St George’s Hospital in London to discuss the design features of the valve that contribute to its performance, and the latest clinical data from the Evolut R™ CE trial. Long-term data for the CoreValve® and the implications of this for future TAVI use were also discussed.

Could you describe the structural and functional differences between the Evolut R™ and the CoreValve®? Dr stephen Brecker (sB): There are a number of differences between these two types of valve that have led to better outcomes with Evolut R™ (figure 1); these relate to the design of the frame and the design of the skirt of the valve itself. Firstly, there have been some changes in the geometry of the cell design and the structure of the frame. These differences mean that at a target implant depth, the actual frame of the Evolut R™ is a little larger for any given valve size than CoreValve®. Secondly, the shape of the frame is less tapered with Evolut R™, which provides better anchoring with less paravalvular leak (PVL). Thirdly, the overall frame height of Evolut R™ is reduced. And finally, the radial force characteristics of the frame are


fig. 1

CoreValve Evolut R™ transcatheter

aortic valve (A) and CoreValve Evolut R™

system, including CoreValve Evolut R™ transcatheter aortic

valve, EnVeo™ R delivery system and

EnVeo™ R loading system (B).

A

B

improved, with more consistent radial force across the range of annular sizes for which a given valve size is designed. Those are the changes in the frame.

With respect to the skirt, in Evolut R™ this extends downwards, filling at least half of the bottom half-cell of the frame, whereas in CoreValve®, the whole of the bottom half-cell is unfilled. The end result of all of these changes is a better fit with better sealing and less PVL.

Finally, unlike the CoreValve®, Evolut R™ is fully recapturable and repositionable in case the correct position is not achieved on first attempt.

Can you tell us about the Evolut R™ CE trial, in terms of the trial design, types of patients involved, and the trial objectives and endpoints? sB: This was a multi-centre, prospective, non-randomised study that included 60 patients.1 It was a CE mark trial, carried out in centres already experienced with CoreValve® implantation. The trial enrolled high-risk patients undergoing TAVI, so really they were all-comers undergoing TAVI. The study was designed to test safety and efficacy of the Evolut R™ valve, with the aim of achieving a CE mark. All of the conventional endpoints used in any valve study were assessed, so 30-day and 1-year survival rate, 30-day stroke rate, the rate of any complications and then haemodynamic performance. Also assessed were valve areas, PVL rate and then finally new pacemaker implant rate. Really it was a very standard valve study.

What were the key findings from the trial? sB: When interpreting the results, I should point out that one has to bear in mind the fact that it was a relatively small study, predominantly used to test safety and efficacy. The primary endpoints of clinical performance were that there were no procedural deaths and in 98% of cases (59/60 patients) there was correct positioning of one valve in the proper location. There were only four cases (just over 6.7%) of more than mild aortic regurgitation present; all cases were moderate. At 30 days that had reduced to 3.4%. In other words, there was some evidence that those who had a moderate leak at implantation got better. At 1 year, the rate of moderate PVL was 4.3%. There were no cases of severe PVL at implantation or at 1 year. It is important to comment that this

lack of PVL was an independently adjudicated assessment from a core lab.

Looking at safety endpoints, when one goes out to 1 year, all-cause mortality rate was extremely low at 6.7%. Indeed, this is the lowest mortality reported in any TAVI trial. When we look at stroke rates, these were also very low; zero at 30 days and 3.4% at 1 year, which is very low. At 1 year, these are the lowest rates of stroke and mortality that have been reported compared with other studies.

There were no cases of coronary obstruction and no cases of annular rupture. Pacemaker implantation rates were 11.7% at 30 days and 15.2% at 1 year – again this is very low. I do think there can be further reductions in these rates, but when you compare these rates with rates of pacing with other second-generation valves, like Sapien 3 (Edwards Lifesciences, Irvine, CA, USA) and Lotus™ (Boston Scientific, Natick, MA, USA), they are very favourable.

When we look at valve performance, there are some of the highest effective orifice areas recorded in any TAVI study with effective orifice areas of 1.9 cm2, which was consistent over the period from implant to 1 year. Mean gradients were between 7.5 and 9.2% from implant to 1 year.

What do you think it is about the Evolut R™ that makes patients less susceptible to requiring pacemaker implant? sB: There are two things: first of all, the position of the implant. One of the issues that we recognised in previous studies was that low implants were associated with higher pacing rates, so the deeper into the ventricle you implant the valve, the higher the rate of pacing. Previously, if you implanted the CoreValve® too deeply, there wasn’t a lot you could do. Now if you implant the Evolut R™ too deeply, you can recapture it, retrieve it and redeploy it higher up. That is the first thing.

The second thing is that there is a more optimal radial force exerted, particularly when the valve is being implanted into the smallest size annulus for that valve size. With CoreValve®, there would have been relatively more radial force; with Evolut R™ there is a more consistent degree of radial force, such that excessive radial force is not exerted, so that is the second reason why pacing rates may be lower.


How does your clinical experience of using the Evolut R™ valve compare with the results from the trial? sB: Our clinical experience in high- and intermediate-risk patients, just based on the clinical use of the valve since it has had the CE mark, very much mirrors the trial experience. We are seeing very low rates of anything more than mild PVL. We are seeing very good haemodynamic results and low rates of pacing as well.

Although we do not yet have long-term data for Evolut R™, we have not seen any issues with CoreValve® in terms of durability and I would be very surprised if we did with Evolut R™. Thinking about the future, I fully expect Evolut R™ to be widely used in clinical practice.

What impact do you think physician experience has on outcomes? Is the Evolut R™ an easy system to use? sB: I can give you my experience of teaching the procedure to completely inexperienced operators, operators who have not done TAVI ever before, and I can tell you that it is a very easy system to teach.

Have you done any valve-in-valve procedures with the Evolut R™? sB: Yes, plenty. It is really ideal for valve-in-valve, where it is really important to get the valve correctly positioned, because it is a recapturable system so you can reposition it. You need to implant it such that the Evolut R™ has supra-annular function, because then you get better haemodynamics. You need to implant it relatively high, but if you don’t like the position, or if there is a concern about coronary flow, you can recapture it.

Moving on to think about CoreValve®, there are a few studies that have published longer-term data (ADVANCE trial has 3-year outcomes,2 4-year outcomes from the CoreValve® CE pivotal study,3 and 5-year outcomes from an Italian registry4). Based on these, what do you think we have learned about the longer term use of CoreValve®? sB: TAVI has only really been done for 7 to 8 years in most countries, so many of these studies started early in the TAVI experience. Where one is getting the 4/5/6-year data, these are patients that were implanted very early on in the experience with TAVI. What we have learned, is how to select

patients now. In the past, the late mortalities were dominated by the fact that these were very elderly patients with a lot of comorbid pathologies, so we have certainly learned how to select patients better. I think we have learned how to implant patients better, so I think we know a lot more than we did when these trials started. We also know how to manage complications better. Those trials have taught us that long-term outcomes are robust and reliable, and the other key thing is that there are no fatal flaws with the technology. Sometimes with new technologies you start to see problems after 3, 4, 5 years, and we have certainly seen this with various forms of other technologies. We have not seen that really with CoreValve®; patients are not presenting with valve thrombosis, valve failure or valve stenosis.

Do you think these encouraging long-term data will mean TAVI is used in a greater proportion of patients in the future? sB: My suspicion is there will be a gradual increase in the percentage of patients requiring aortic valve replacement who are treated with TAVI and a gradual reduction in surgery. There will always be some patients who need to have surgery, particularly if they need other valves operated on or coronary artery bypass surgery or other issues, but I think there is going to be a gradual increase in the percentage of patients that are treated with TAVI compared to surgery.

What data do we need, to see TAVI becoming an option in intermediate- or low-risk patients? sB: There are two trials in progress at the moment, SURTAVI5 and UK TAVI,6 that are looking at intermediate-risk patients. There are already some data from the US pivotal trial of the intermediate subgroup, and they did better with TAVI than surgery.

Leaflet thickening data from Dr Raj Makkar’s have been published,7 and were presented at the 2015 Transcatheter Cardiovascular Therapeutics conference. What do you think the data tell us about this complication of aortic valve replacement? sB: This is an interesting study.7 There has been a further study subsequent to Dr Raj Makkar’s paper, from the Mayo Clinic, showing that a significant proportion of patients with failed


aortic bioprostheses have leaflet thrombosis.8 There probably is a genuine syndrome of leaflet thrombosis, but it is far too early for us to know. There is more that we don’t know about this than we do know at present, and it is an interesting observation. It is seemingly more common with certain types of valve, and this includes surgical valves. There are a number of points that this raises, and they are these: first, some patients who present with what is thought to be surgical bioprosthetic valve stenosis may have leaflet thrombosis and may respond to a period of anticoagulation. Second, the syndrome has also been seen with TAVI valves, but is not commonly recognised with CoreValve® or Evolut R™; that is not to say it couldn’t happen, and the number of patients in which it has been seen is small. Theoretically, having a supra-annular valve like CoreValve® or Evolut R™ may make patients less prone to this problem. Third, we have no real idea how best to treat these patients following TAVI insertion – whether it should be single antiplatelet therapy, dual antiplatelet therapy, warfarin, a novel anticoagulant, or some combination thereof. We don’t know what the best regime is.

Those are my observations on it. It does seem to be a real phenomenon, because it occurs with

both TAVI valves and surgical valves, but we have got a lot to learn about the significance and management of it.

Is there any suggestion as to why it occurs with some valves and not others? sB: There are not enough data at this point to be clear on that. In Makkar’s paper,7 there were only four patients with CoreValve® studied, and they did not have any reduced leaflet mobility, but this is a really small number of patients so you can’t come to a conclusion on just four patients. I think we just simply do not have enough data at this point, but as we get more data it will become clearer.

Are there any questions you think we still need to answer regarding TAVI devices? sB: There are lots and lots of questions we still have to answer. There are some big questions about whether patients should have coronary revascularisation before TAVI, whether patients having TAVI should have cerebral protection with devices. We have ongoing questions on patient selection, subsets of patients who may or may not benefit, patients with low gradient aortic stenosis – there are still more data required. Yes, there are lots of unanswered questions at this point, but there are studies ongoing in all of these issues.

10

DisCLosUrEs: SB has acted as a consultant for Medtronic and Boston Scientific.

address for correspondence Dr Stephen Brecker Cardiology Clinical

Academic Group St George's Hospital

Blackshaw Road London

UK

[email protected]

+44 20 8725 3556

1. Manoharan G. Presented at TCT 2015, San Francisco, Ca, USa.2. Bleiziffer SB, et al. Presented at euro PCr 2015. Paris, France.3. Kovac JS, et al. J am Coll Cardiol 2014;63(12):A1713.4. Barbanti MP, et al. J am Coll Cardiol Intv 2015;8(8):1084–91.5. https://clinicaltrials.gov/ct2/show/NCT01586910.

6. UK TAVI – The United Kingdom transcatheter aortic valve implantation trial. ISRCTN 57819173. Available from: http://public.ukcrn.org.uk/search/StudyDetail.aspx?StudyID=14550.7. Makkar RR, et al. n engl J med 2015;373(21):2015–24.8. Holmes DR, Mack MJ. n engl J med 2015;373(21):2080–2.

rEFErEnCEs:


Jan-malte Sinning

CASE STUDY

Coronary access with the Medtronic CoreValve® transcatheter aortic valve replacement bioprosthesis

Background Transcatheter aortic valve implantation (TAVI) is an established alternative treatment strategy to surgical aortic valve replacement (SAVR) for patients with severe aortic stenosis (AS) and high or intermediate perioperative risk.1,2 However, up to 50% of elderly patients undergoing TAVI also suffer from coronary artery disease (CAD), and some of these patients may be in need of additional coronary revascularisation.3,4

A debate is ongoing as to whether a patient should undergo PCI before TAVI, combined with the TAVI procedure, or only if symptoms persist after TAVI. Combined percutaneous coronary intervention (PCI) and TAVI have been shown to be feasible, but more data are required before a firm recommendation can be made for this approach. The question of whether to proceed, as well as the chronology of interventions, should be the subject of a discussion for each individual patient, taking into account the patient’s clinical condition, coronary anatomy, and myocardium at risk.4 Another essential aspect is the choice of the transcatheter heart valve (THV). Prostheses differ with respect to the stent design, stent height, implantation steps, and handling of the application device. Some prostheses are implanted in a fully subcoronary position, whereas others are implanted in a partially supracoronary position with supra-annular valve plane.

The CoreValve® transcatheter aortic valve (Medtronic, Minneapolis, MN, USA) with its supra-annular leaflet position – where the frame is least constrained – optimises blood flow, maximising the potential effective orifice area (EOA). The next generation Evolut™ R valve retains the supra-annular valve function and the cell design of the CoreValve®, facilitating access to the coronary arteries due to a larger cell design, while preserving conformability for fit in non-circular or calcified annuli. The majority of PCIs are performed with 6 French (Fr) catheters. The

smallest cells of the Evolut™ R stent frame are able to accommodate coronary catheters up to 10 Fr.5

Case presentation An 88-year-old male patient presented at our institution 6 years after TAVI implantation with a Medtronic CoreValve® 29 mm, suffering from acute chest pain. In 2009, he had initially presented to our hospital with an ST-elevation myocardial infarction (STEMI), and occlusion of the right coronary artery and severe stenosis of the left anterior descending coronary artery (LAD). Following complete revascularisation with bare metal stents (BMS), the heart team discussed his case and decided to schedule him for TAVI due to several comorbidities, such as chronic obstructive pulmonary disease (COPD), chronic renal failure, and frailty.

The patient was admitted to our chest pain unit with a troponin elevation of 0.64 ng/ml and underwent invasive coronary angiography the same day. Although non-invasive stress testing by dobutamine stress echocardiography 2 years earlier had not shown any wall motion abnormalities during exercise, we found two severe de novo stenoses in the right coronary artery (RCA) proximal to the BMS, which was implanted to treat the STEMI in 2009 (figure 1A).

Management For proper channelling of both coronary ostia, it was necessary to lead the catheter tip through the diamond-shaped frame cells of the prosthesis. In this case, we were able to properly engage the RCA ostium with a 6 Fr Judkin's Right (JR) 4 catheter. This provided enough support and backup to advance a 0.014" Balance Middleweight angioplasty guidewire (Abbott Vascular, Santa Clara, CA, USA) into the RCA, and implant two Xience V (Abbott Vascular) drug eluting stents measuring 3.5/18 mm and 3.5/12 mm. The procedure was completed without complications (figure 1B).


Quiz Questions1. what size of coronary guiding catheter can be used in a patient after taVi with a CoreValve® Evolut™ r?

The Evolut™ R stent frame can accommodate coronary catheters up to 10 Fr, meaning that even a rotational atherectomy is possible in these patients.

2. what catheters can be used to selectively engage the coronary ostia?

An extra backup (EBU) catheter would be the optimal choice to assist channelling of the coronary vessels.

3. what can be done to increase backup for a PCi in patients after implantation of a thV in a partially supracoronary position?

A supporting guidewire (‘buddy wire’) or microcatheter might be helpful in achieving sufficient stability.

fig. 1

Coronary access with the medtronic CoreValve® and the

Evolut™ r

Case: PCI is performed with a Judkin’s Right 4 catheter to selectively

intubate the ostium of the right coronary

artery (A and B).

In another patient, after implantation of

Evolut™ R, selective intubation of the left

coronary ostium was not possible with a Judkin’s

Left 4 catheter (C), but better results were achieved with an EBU

catheter (D).


Take-home messages• Ascoronaryguidingcatheters are supported by the CoreValve® Evolut™ R stent frame, and not by the aortic wall, it is essential to use a catheter with a large distance between the tip and the primary curvature, and as much backup as possible, to achieve a proper selective channelling of the coronary vessels.

• ItispreferabletouseanEBUcatheter,overaJudkin'sLeftcatheter(figures1Cand1D),toperform PCI of the left coronary artery.

• Fortherightcoronaryostium,anAmplatzRightorevenanAmplatzLeftcathetermightprovide better support, since it is more curved than the Judkin’s Right 4, and therefore adapts better to the curvature required by the prosthesis frames.

• Incaseswithnon-selectiveintubationofthecoronaryarteries,theuseofanadditionalsupporting guidewire (‘buddy wire’) or microcatheter might be helpful in achieving sufficient stability.

• Inthefuture,theneedtoperformPCIthroughaTHVprosthesiswillincrease,giventhewidespread use of TAVI and the longer survival and follow-up time for these patients. However, if proper precautions are taken, such as those mentioned above, then PCI in TAVI patients is feasible and safe, even after implantation of a THV in a partially supracoronary position.

address for correspondence Dr Jan-Malte Sinning, MD, FESC

Heart Centre Bonn Department of Medicine II

University Hospital Bonn Sigmund-Freud-Str. 25

53105 Bonn Germany

jan-malte.sinning@ ukb.uni-bonn.de

+49 228 287 16670

1. Leon MB, et al. n engl J med 2010;363:1597–607. 2. Smith CR, et al. n engl J med 2011;364:2187–98. 3. Sinning JM, et al. J am Coll Cardiol 2012;59:1134–41.

4. Vahanian A, et al. eur heart J 2012;33:2451–96. 5. Sinning JM, et al. euroIntervention 2012;8(Suppl Q):Q94–6.

rEFErEnCEs:


DisCLosUrEs: JMS has received speaker honoraria and research grants from Medtronic, Edwards Lifesciences, Direct Flow Medical, and Boston Scientific.

Stephen Worthley

INTERVIEW

Next generation drug-eluting stent technology: the polymer-free era has begun Stenting efficacy has improved with the use of stents that release antiproliferative drugs. Traditionally, the drug has been released from a polymer coating; however, this coating can be associated with inflammation. Confluence discussed the concept of polymer-free drug-filled stents and the ongoing trial of such a stent with Professor Stephen Worthley, Helpman Chair of Cardiovascular Medicine at the University of Adelaide.

Could you start by explaining what a drug-filled stent is? stephen worthley (sw): To give some background, the current standard of care for treating patients with severe coronary lesions are so-called drug-eluting stents (DES) and there are a number of these available. They are basically metallic, thin strut stents that have a medication on the stent that reduces the risk of restenosis. The anti-proliferative medication is embedded in a polymer, or plastic coat, that surrounds the stent, such that it is slowly released over a period of 3–4 months – this is important because that is the time frame during which restenosis can occur. The polymer is important because if you dipped the metallic stent in a medication, it just completely dissolves or elutes off the stent immediately. The polymers allow the medication to elute over several months, helping to stop the re-narrowing.

The problem with polymers is that when the medication has gone, they remain in the vessel and can induce inflammation in the vessel wall. It is this inflammation that delays the healing of the vessel at the stent site. DES have been a great step forward in terms of efficacy of stenting, meaning they reduce the risk of re-narrowing of the vessel, but at the same time they delay the healing, and this has led to concerns around stent thrombosis. Some novel therapies use what are called ‘bioresorbable polymers’, which means that the polymer itself can dissolve away over a period of time. However, even they run the risk that in the process of dissolving they may induce inflammation, and so delay healing.

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fig. 1

Release of antiproliferative

drug from the drug-filled stent.

Drug coats the inner lumen of the stent

(A), and is eluted microscopic through

abluminal holes (B). This allows uniform

distribution of the drug in the stented vessel (C).

Figure originally presented at TCT 2015,

San Francisco, Ca, USa.


The perfect scenario would be if we could find a way to slowly release a medication, a little like drip-feeding, if you like, without using a polymer or coating. In theory you have then achieved the Holy Grail where you could still have slow release of medication, thereby stopping the re-narrowing process, and by avoiding use of any polymer the vessel could heal rapidly so you have a lower risk of clot formation. That is the premise of the drug-filled stent – it used exactly that concept; finding a way to slowly release the medication and yet have no polymer.

This was achieved using a reservoir of medication that is held within the stent scaffold itself, which contains abluminal laser-drilled holes, 20 microns in diameter, that allow elution of the anti-proliferative medication (sirolimus [Rapamune®, Pfizer, New York, NY, USA] in this example). Prolonged drug release is achieved through this unique technique of microscopic holes, meaning that there is no polymer (figure 1). The early pre-clinical work confirmed what we thought we would see, which is that there is prevention of re-narrowing and yet an early healing process.

Is there anything else that is different about the structure or anything else that is important? sw: Yes, it is an amazing feat of biomedical engineering. The stent is fashioned to leverage Medtronic’s Continuous Sinusoid Technology, which is in the Integrity® stent (Medtronic, Minneapolis, MN, USA). What that means is that, rather than making the stent from a solid tube and then laser-cutting components out of it, which is how the traditional stents are formed, this stent uses a single extruded wire fashioned into a sinusoidal pattern, and the stent structure is formed of repeating circular elements of this sinusoidal extruded wire (figure 2A). This allows the drug-filled stent to make use of a tri-layered wire (figure 2B). There is an outer cobalt chromium component, the middle layer is a very thin layer of tantalum, which is very radiopaque and allows us to see the stent more clearly on x-ray, and an inner sacrificial layer that is removed, forming a continuous inner lumen that is coated with the drug. Then, the 20 micron holes are laser-drilled through the outer layer of the stent that faces the vessel wall, to enable delivery of the drug into the tissue.

15

fig. 2

The drug-filled stent is formed of a continuous

sinusoidal wire (A). The wire has a tri-layer

structure, comprising an outer cobalt chromium

layer providing strength, a middle tantalum layer

providing radiopacity, and an inner lumen

that is coated with the antiproliferative drug (B).



There is also another element to it. The strut itself is said to be swaged, which means that the circular wire is flattened to form an oval, giving a very narrow strut, approximately 80 microns thick. This means that the distance the cells have to grow from the vessel wall over the top of the strut is less. This property utilises data that we have had for a long time, which shows that in the bare-metal stent, the thinner the strut was, the lower the restenosis rate. We do have evidence from bare-metal stents that thinner struts are associated with a more efficacious stent (even in the absence of anti-proliferative medication).1

What would improve healing and lower inflammation mean in a clinical setting for the patient? sw: That is a good question, and what it means, in theory, is that if we had a stent that was as effective at reducing restenosis as a DES and yet healed more rapidly, there is the potential to get patients off the aggressive blood thinning therapies that we use currently, sooner. For example, in the USA, the FDA mandates that with the current DES, patients should be on dual antiplatelet therapy for 12 months – usually aspirin and clopidogrel,


16

fig. 3

Study design for the RevElution trial (A) and

detail regarding the OCT imaging cohort (B).



a

B


but it can be any other products like aspirin and ticagrelor (Brillique®, AstraZeneca, London, UK) or aspirin and prasugrel (Efient®, Eli Lilly, Indianapolis, IN, USA) – although we do have reasonable safety data for 6 months of therapy. Many of the patients that we treat now are elderly, and they may have high bleeding risk or may need early surgery after a stent implant, so potentially being able to interrupt antiplatelet therapy at a much earlier time point, for example after 1 month, is very attractive. With a stent that, in theory, heals more rapidly you could minimise the patient’s exposure to prolonged blood thinning therapy.

Could you tell us about the RevElution trial? sw: We started the RevElution trial2 in July 2015 in Australia. It has a slightly complicated design. It is a 100-patient study that is basically divided into two cohorts of 50. The primary endpoint for the first 50-patient cohort is late lumen loss at 9 months, which is basically the amount of re-narrowing inside the stent. In the second 50-patient cohort, the primary endpoint is late lumen loss at 24 months (figure 3A).

Furthermore, to gain some insight into the concept of early healing, we have embedded a number of sub-studies within these two 50-patient cohorts, using a high resolution intravascular imaging technology called optical coherence tomography (OCT; figure 3B). This is an intravascular probe that is placed inside the coronary artery at the time of an angiogram procedure, which gives very high resolution imaging of the tissue as it heals around the stent struts, providing an indication of healing within the coronary arteries.

Within each of the two major 50-patient cohorts, we have two 15-patient cohorts, so a total of 30 patients, that will get OCT. The two 15-patient cohorts from the 9-month primary endpoint group will have OCT at 1 month and 3 months, as well as the primary endpoint at 9 months. The remaining 20 patients in this group won’t have any imaging at 1 or 3 months, only at 9 months.

In the 24-month primary endpoint group, one subset of 15 patients will have OCT imaging at 2 months, and another, separate 15 will have imaging at 6 months, both in addition to the primary endpoint at 24 months. Likewise, there will be 20 remaining patients who will just have the imaging at 24 months.

What that allows us to do in a slightly complicated design, is gain information from OCT across this 100-patient cohort at 1, 2, 3, 6, 9 and 24 months. Although of course they are not all paired datasets, it is information that we will be able to gain around this healing and efficacy story. It is a very rich dataset from just 100 patients that will enable us to work out if the early healing signal is real, and if it is real, then we can design an appropriately powered clinical trial to answer the question of whether 1 month of dual antiplatelet therapy is enough.

Are there any interim data available from RevElution? sw: We presented some of our early data in October 2015 at the Transcatheter Cardiovascular Therapeutics (TCT) meeting in San Francisco.2 We saw exactly what we had hoped to see in terms of early OCT imaging. In those patients who had the drug-filled stent implanted, there was early healing and early coverage of the struts. At 1 month, 90% of the struts were covered or had a healing process, yet there was no severe proliferative healing seen in those early patients. To date we have treated 41 patients out of this 100-patient study, and over the next 12–24 months we will gather more information around the healing process and the efficacy of the drug-filled stent platform out to 12 and 24 months.

How does this stent compare to other polymer-free stents? sw: There really is only one other polymer-free drug-coated stent that is under investigation at the moment; the BioFreedom™ stent (Biosensors International Ltd., Singapore). BioFreedom™ was recently studied in a trial looking at the safety of this stent versus bare-metal stents in patients who needed to come off blood thinning therapy at an early time frame of 1 month. The results were presented at TCT this year. Interestingly, the BioFreedom™ stent is simply a bare metal stent with a micro-structured, or scratched, abluminal surface that increases surface area. That surface is coated with an antiproliferative medication, BA9, which seems to remain in some of the crevices and nooks on the scratched out surface and is released over time. One important distinction between the BioFreedom™ platform and the polymer-free stent is that the majority of the drug is eluted from the scratched surface within the first 30 days, compared


with a delayed elution over 90 days for the polymer-free stent. Although the BioFreedom™ stent was superior to a bare metal stent in terms of efficacy, this shorter elution period does raise a question about its efficacy in preventing restenosis versus current generation DES, especially in more complex patient groups.

Are similar trials being done with stent and polymers over more traditional drug-eluting stents? sw: Yes, there have been, but we don’t have any at 1 month though. We have seen, for example, that there was a small study with the XIENCE stent (Abbott Vascular, Santa Clara, CA, USA) looking at strut coverage at 3 months, and in that study it was about 70%.

To be fair, there is some variation in how we define strut coverage. It is such a new technique, and if you like we are forging the field ahead in terms of using this technique to assess the efficacy of the stent, so it is hard to compare studies. Having said that, it is very exciting that in this early patient group we are seeing 90% strut coverage at 1 month – that is far better than we thought we would see.

Thinking about some of the patients in the RevElution trial, what are the characteristics of their lesions? sw: They are typical first-in-human type patients. On the whole, the lesions are fairly simple and straightforward. Patients need to have ischaemic-induced problems, so haemodynamically significant coronary artery lesions in a coronary vessel between 2.25 and 3.5 mm in diameter. The lesion length must be less than 27 mm without excessive calcification or tortuous coronaries. The lesion cannot be in a left main artery, it cannot be a chronic total occlusion and there cannot be bifurcation of the lesions.

Patients do need to be able to tolerate dual antiplatelet therapy with aspirin and clopidogrel for at least 6 months and, as part of the trial, consent to the follow-up imaging that is an intrinsic part of the protocol.

These patients are reasonably reflective of the patients that we would see in the cath lab with stable coronary disease, although as coronary intervention has become more complex we have extended it to chronic total occlusion intervention and acute infarct angioplasty, and these two patient subsets would be excluded from the study.

Do you see this technology being able to expand to and become suitable for use in these more challenging type of patients? sw: Absolutely, and in fact, they are the exact patient group who potentially may experience the greatest benefits from this therapy. Drug-filled stents may show the greatest clinical utility in more complicated lesions where healing may be impeded, or for example, where there may be an issue when you have overlapping stents.

In the RevElution trial, there has been one patient so far at the 1-month time point that had overlapping stents. Sometimes when we put a stent in a patient there might be an extra section or injury, and then we will place another stent overlapping the first stent. What has worried us in the past is that if you have two stents, then the distance for the healing to occur over is twice as far, potentially requiring twice the concentration of medication. The OCT images in that one patient showed beautiful healing over the overlapping stent; however, this example gives us a sample size of only one, so we are cautious about making too many overarching statements based on this. Clearly this dataset will empower us to do a future all-comers type of study, where chronic total occlusions or infarct percutaneous coronary intervention and bifurcations are included to confirm whether the safety and efficacy signal is translated into all-comer patients.

In terms of the data presented at TCT, are there any other key standout findings that we should be talking about? sw: The strut coverage, for me, was probably the most striking thing. Ninety percent strut coverage at 1 month was definitely better than we had thought we would achieve, bearing in mind that there is not a lot of benchmarking available in that early timeframe. We will look to populate the image dataset over the next 6 months with the other patient timepoints.

In terms of efficacy, the neointimal hyperplasia area was 0.5 mm2 and the neointimal diameter loss was 0.06 mm. One month is an early timepoint to be getting too excited about efficacy, but all of the results are commensurate with what we would expect to see. Although there is healing over the stent strut, it is thin, and consistent with the fact that there has been suppression of excessive neointimal proliferation.


Are there any other benefits or challenges associated with the technology? sw: The polymeric stents that we use now, which are a plastic, are a little bit sticky or adhesive, so the fact that we have a non-polymeric drug eluting platform means the stents are easier to deliver. They are smoother, if you like, as you track them through the coronary artery, so there is a little extra benefit in terms of deliverability from a technical perspective for the interventionalist.

The challenges that we face, simply, are discovering whether there is a downside. Conceptually there is not, and at the moment we are in the midst of making sure that we do a good job of the clinical trials to ensure that we get good, robust data from which we can accurately identify what the signals are.

The one comparator to add might be, for example, that there has been a lot of excitement in the coronary intervention space about bioresorbable stents. This is the concept of a stent that you could implant that would dissolve away over time, and in 2 or 3 years’ time there would be no scaffold left behind at all, so the coronary artery goes back to its normal biology.

The drug-filled stent is a metallic stent that will stay in situ, but a lot of data have come out in the last few months from the most studied bioresorbable scaffold – the Absorb stent (Abbott Vascular). In the Absorb trials, ABSORB II3 and ABSORB III,4 the issue has been that the stents have very thick struts of 160 microns; this is twice the thickness of the struts in the drug-filled stent. The bioresorbable stents are not very compliant and don’t have very high radial force so if you try to embed them and over-expand them, they can unravel and rip. They are basically a plastic, made of poly-L-lactic acid (PLLA).

What we have seen with the ABSORB II and the ABSORB III studies is that, in the first 12 months

there is a higher stent thrombosis rate in the patients who receive the bioresorbable stent versus the current-generation DES. This is because, although these stents dissolve, they do still induce inflammation, and they are very thick stent struts. So we have not seen the bioresorbable stents stand up to the current-generation DES with regard to that endpoint. At the moment, this polymer-free drug-filled stent technology looks like it could be the future of current intervention, until such time as we can get that bioresorbable scaffold improved. Currently we do not have the technology to be able to make a bioresorbable scaffold that would induce no inflammation and have the same healing capacity that we see with something like the polymer-free stent.

Is there anything else you think we need to know? sw: Just that it is early days. It is an important caveat to note that we are at the start of the journey with the drug-filled stent, so whilst we are seeing a lot of excitement, we do need to watch this space to see how things go in the longer term. The early signals are exciting, but clearly the completion of the trials and the presentation of the data will be important. To date we have 41 patients treated, and we have not seen anything yet that has raised a concern, and all the early signals have been as promising, if not more promising, than we thought they might be. All 50 patients were enrolled by the end of 2015, so that will mean that for the 9-month primary endpoint cohort, we should see late breaking data at TCT next year in the US. We are presenting the 3-month OCT data at the American College of Cardiology meeting in Chicago in 2016, so there will be some data coming through the year that will add to the story, but watch TCT next year for the primary endpoint.

address for correspondence Professor Stephen Worthley

University of Adelaide Adelaide SA 5000 Australia

stephen.worthley @adelaide.edu.au

+61 8 8222 5608

1. Foin N, et al. Int J Cardiol 2014;177(3):800–8. 2. Worthley SA, et al. Presented at TCT 2015, San Francisco, Ca, USa. Poster TCT-579.3. Serruys PW, et al. Lancet 2015;385(9962):43–54.4. Ellis SG, et al. n engl J med 2015;373(20):1905–15.

rEFErEnCEs:

DisCLosUrEs: Honoraria/consultancy from Medtronic and St Jude Medical.


Interventional Cardiologist germany

(due to local regulations in germany, the physician who

performed the procedure and wrote this case study

cannot be identified.)

CASE STUDY

Expanding treatment options in percutaneous coronary intervention: Resolute Onyx™ for left main bifurcations and small anatomiesBackground Enormous progress has been made in the design of drug-eluting stents (DES) in recent years. Besides the improved safety and prognostic profiles offered by state-of-the-art DES platforms, new features, such as DES coated with bioresorbable polymers and optimised deliverability, have become available on the market. However, so far the treatment of very large or small vessel anatomies with specially designed stent systems has not been a focus. This unmet need is now addressed with a new DES platform, comprising a cobalt-platinum backbone, covered with a durable polymer eluting zotarolimus: the Resolute Onyx™ DES (Medtronic, Inc., Minneapolis, MN, USA).

So why is it important to have a specially designed DES for large diameter vessels? Stretching a 4.0 mm DES far beyond its extension limits can result in suboptimal strut coverage of the vessel wall, which can reduce radial strength and lead to problems such as restenosis or stent thrombosis. Furthermore, when over-expanding a durable polymer-coated stent, the polymer coating itself could develop microfissures, exposing uncovered metal to the blood stream, and thereby increasing the risk for stent thrombosis or restenosis. At the other end of the DES diameter spectrum, small vessel anatomies require individualised stent diameters, especially when they supply a large area of the myocardium. Oversizing of such small vessels with stent diameters that are too large can result in (distal) edge dissections, and therefore in acute vessel closure.

Case presentation and management Case 1: Treatment of large vessels with the Onyx™ A 48-year-old woman with ST-elevation myocardial infarction (STEMI), showing significant ST-elevations in V2 to V6, was referred to our hospital for acute treatment. From a cardiovascular point of view, her

20

previous medical history was remarkable for hypertension, a positive family history (father died of acute myocardial infarction at 60 years), and smoking (20 pack years [packs per day x years smoking]). Coronary angiogram revealed an intermediate stenosis of the proximal right coronary artery (RCA) and a subtotal left main (LM) occlusion, with significant plaques reaching into the proximal left anterior descending (LAD) and the dominant left circumflex (LCX) arteries (figure 1A). LCX and LAD were wired with regular front-line wires (BMW; Abbott Vascular, Chicago, IL, USA), and kissing balloon dilatation was performed (3.0/12 mm for LCX, 2.5/12 mm for LAD; Trek balloon; Abbott Vascular). A 4.5/18 mm Onyx™ DES was implanted into the LM/LCX axis with a good angiographic result (figure 1B). After rewiring the LAD via distal ostial stent struts, a soft balloon dilatation with a 2.0/12 mm balloon was performed. A 2.75/8 mm Onyx™ was placed in the LAD with minimal protrusion into the LM (figure 1C), and kissing stent/balloon inflation with a 4.0/8 mm non-compliant balloon in the main vessel (LAD) was performed. The final angiographic result was excellent, and the patient was discharged free of symptoms 3 days later. Remarkably, passage of the 4.0/18 mm LM/LCX Onyx™ with the 2.75/8 mm Onyx™ was very easy, highlighting the individual rate of crown fusing in different Onyx™ sizes. Furthermore, the platinum core of the Onyx™ allowed safe identification of the stent location on flouroscopy.

Case 2: Treatment of small vessels with Onxy™ A 57-year-old male patient, who had percutaneous coronary intervention (PCI) of a significant LAD stenosis 1 week before, was referred to our hospital with ongoing chest pain on exertion. A chronic total occlusion (CTO) of a marginal branch (figure 2A, white arrow) was intentionally not treated


21

fig. 1

A) Subtotal LM occlusion with plaques

reaching into the proximal LAD and LCX

B) 4.5/18 mm Onyx™ DES implanted into the

LM/LCX axis

C) 2.75/8 mm Onyx™ in the LAD with minimal

protrusion into the LM and kissing stent/

balloon inflation

D) Final angiographic result

fig. 2

A) CTO of a marginal branch (white arrow) and collateralisation

of the distal vessel (blue arrow)

B) After wiring, a 2.0/22 mm Onyx™ DES

was implanted into the distal lesion and a

2.25/18 mm Onyx™ DES implanted proximally

C) Final result

in the index PCI due to a small vessel diameter and collateralisation of the distal vessel (blue arrow). Since no other significant stenosis was now evident, besides the marginal branch, we crossed the CTO with a full polymer hydrophilic wire (Asahi Filder XT; Abbott Vascular) and performed balloon dilatation with a 2.0/12 mm balloon. Although vessel diameter was small, the remote myocardial region was significant. We decided to implant a 2.0/22 mm Onyx™ DES (figure 2B) in order to avoid compromise of the small diameter distal vessel. Another 2.25/18 mm Onyx™ DES was implanted in the proximal vessel with an excellent final result, showing a smooth transition from the stented region into the distal vessel region (figure 2C, arrow). The patient was discharged home 1 day later, and has been free of symptoms since then.

a B

C D

a

B

C


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Quiz Questions1. what are the risks of using undersized stents in large vessels?

Choosing an undersized stent can cause acute/late stent thrombosis due to malapposition. Overstretching of such a stent results in insufficient strut coverage of the lesion, and may create microfissures in the polymer covering the DES.

2. why is an alloy involving platinum an advantage in DEs design?

Platinum alloys improve DES visibility on fluoroscopy.

3. how can we further improve on the current gold-standard, the DEs?

We can make use of more compatible or bioresorbable coating polymers, improve deliverability of the DES, and increase the available diameter range of DES systems.

4. what are the risks of using an overstretched stent in large vessels?

Excessive stent overexpansion leaves large gaps between strut scaffolding, which runs the risk of the plaque prolapsing between struts. Distortion of the stent crowns may cause damage to the polymer coating, reducing the ability of the antiproliferative drug to prevent restenosis. An overstretched stent can also produce higher arterial injury with a subsequent inflammatory response, increasing the risk of neointimal proliferation.

address for correspondence Interventional Cardiologist

germany

(due to local regulations in germany, the physician who

performed the procedure and wrote this case study

cannot be identified.)

Take home messages• onyx™ DEs increases the range of vessel sizes that can be treated, by offering a treatment option for large and small vessels; it is available in sizes from 2.0 up to 5.0 mm (onyx™)

• individually-designed stents suitable for different vessel sizes may improve patient outcomes, by avoiding acute/late stent problems

• treating bifurcations in large vessels or Ctos in small vessels is technically feasible with the new stent design

• the cobalt-platinum alloy is easily visible on fluoroscopy, thereby facilitating orientation in complex procedures


Thomas Zeller

INTERVIEW

IN.PACT SFA: benefits of a drug-coated balloon for the treatment of superficial femoral artery lesions persisting at 2 years Drug-coated balloons are the latest addition to the endovascular toolbox for the treatment of peripheral artery disease. These balloons release an antiproliferative drug to limit restenosis of the vessel, a problem that is frequently seen after percutaneous transluminal angioplasty. Confluence spoke to Professor Thomas Zeller, Head of the Department of Angiology at the University Heart Centre Freiburg-Bad Krozingen, and Professor Frank Vermassen, Professor in Vascular and Thoracic Surgery at Ghent University, to discuss the recently presented 2-year results from the IN.PACT SFA study. The study investigated the use of the IN.PACT® Admiral® drug-coated balloon, compared with percutaneous transluminal angioplasty for the treatment of femoropopliteal lesions.

What is peripheral arterial disease? thomas Zeller (tZ): Peripheral arterial disease (PAD) is a systemic manifestation of arteriosclerosis. Besides the peripheral arteries, it can also affect the coronary and cerebral circulation. About 50% of patients suffering from PAD also have concomitant manifestation at the heart and the brain. For the last few years we have seen the incidence of PAD increase, because the disease is directly linked with the prevalence of diabetes mellitus, which we are also seeing increase due to rising body mass indexes.

In PAD in the lower limbs, we distinguish between claudication and critical limb ischaemia. Claudication is characterised by symptoms such as muscle pain, which may affect the calf or the entire leg, and limitation of walking distance. Critical limb ischaemia is an advanced stage of PAD, where the limb is at risk of amputation within weeks to months. Patients usually suffer from rest pain and/or wounds that heal slowly or not at all. The diabetic population, in particular, may progress directly to critical limb ischaemia without having had significant claudication, and such patients may not have complained of any limitation in walking distance prior to developing wounds.


Frank Vermassen

What treatments are available for such patients? tZ: We would use a staged treatment strategy starting with so-called conservative treatment, which includes risk factor modification, i.e. controlling hypertension and hyperlipidaemia – so statins are a key part of conservative management. Next, we would aim to control the diabetes, if present, and, of course, nicotine cessation. For claudicant patients, we also recommend supervised exercise training. If this basic, conservative treatment is not effective in improving the patient’s quality of life sufficiently, the next step is revascularisation therapy.

Today, in the claudicant population, revascularisation means an endovascular revascularisation for more than 80% of the cases; the indication for surgical revascularisation has become rare. There are two main indications for surgical interventions; firstly, involvement of the common femoral artery (with or without involvement of the femoral bifurcation) is a valid indication for an endarterectomy, and secondly in some cases of aorto-iliac artery disease, particularly if the aorta is occluded, there is still an indication for bypass surgery. Due to the high primary success rates of endovascular therapy, femoropopliteal bypass has become a rare indication in the claudicant population.

Frank Vermassen (FV): It has been over 20 years since the first stents were used in the superficial femoral artery (SFA), and the history of stents in the SFA has been one of successes and failures. Stents are very good for treating problems such as dissection or early restenosis, but in the longer term, because the stent is a foreign object implanted in the vessel, it does not really prevent late restenosis. If you have restenosis in a stented area, it is more difficult to treat than restenosis in an artery where there is no stent.

Over the past few decades, we have been looking for methods to improve results after percutaneous transluminal angioplasty (PTA) in the SFA. Many strategies have been tried to prevent restenosis, including atherectomy, cryoplasty, lasering and covered stents, but none of these methods have proven to be more effective than simple balloon angioplasty and stenting.

We had the same problem with restenosis, as was seen after simple angioplasty in the coronary arteries, and to a large extent this was solved by drug-eluting stents; putting a drug that prevents late restenosis on the stent. In the beginning we thought that the same solution would work for every blood vessel, but that is not the case, illustrating that, although these are all blood vessels, vessels in one territory have other properties and need different treatments than vessels in another territory Now, for the first time, there is a method which might actually prove to be effective in the peripheral arteries. We use a drug-coated balloon (DCB) to deliver the drug to the blood vessel and not worry about stents. This seems to be at least as effective as drug-eluting stents in preventing late restenosis, while at the same time avoiding the presence of foreign material in the SFA.

We also see that the stent rate for acute problems, such as flow-limiting dissection and recoil, is far less in the DCB trials than historical studies, without negatively influencing the results.

Are efficacy and safety outcomes better with endovascular procedures than surgical procedures? tZ: The main reason for not operating in claudication is basically safety. With surgical procedures there are certain complication risks, which are considered to be lower with endovascular procedures, and this is one reason

why claudicants are mainly treated by endovascular means. The other reason is that over the last decade, the outcome of endovascular procedures has improved significantly, mainly as the result of the introduction of drug-eluting technologies, like drug-eluting stents and DCBs.

Critical limb ischaemia it is a somewhat different situation and bypass surgery is still considered a viable alternative option compared to an endovascular approach.

Could you give an overview of the study design, objectives and endpoints of the IN.PACT SFA study? tZ: The IN.PACT SFA study was a pivotal study designed to support the approval of the IN.PACT® Admiral® DCB (Medtronic Inc. Minneapolis, MN, USA) from the US Food and Drug Administration in the US market.1 The study compared the IN.PACT® Admiral® DCB against plain balloon angioplasty. We enrolled about 150 patients in Europe, followed by an additional 181 patients in the US.

FV: It was quite a large controlled trial with over 300 patients, randomised 2:1 to the active treatment, which was the DCB.

tZ: There were two primary endpoints. The efficacy endpoint was primary patency, so patents without a redo procedure. The safety endpoint was a composite, defined as freedom procedure or device-related death to 30 days and freedom from major amputation of a target limb or clinically-driven target vessel revascularisation (CD TLR) to 12 months.

The inclusion criteria allowed most of the indications that are commonly treated in the SFA. The mean lesion length, as compared to that in many previous studies, was actually quite long at almost 9 cm. Increasing lesion length results in a higher probability of developing restenosis. As such, the lesions permitted in the inclusion criteria of the IN.PACT SFA trial were somewhat more challenging compared to those in earlier bare metal stent trials. Despite the longer length, these lesions are still classified as Trans-Atlantic Inter-Society Consensus (TASC) II A or B lesions, which are not considered to be very challenging lesions. The IN.PACT Global study is a non-randomised study that enables us to look into complex lesions, such as very long length lesions or in-stent lesions.2


What were the findings from the IN.PACT SFA study? FV: Looking at the results obtained after the first year, these are already extremely good results. There were no device- or procedure-related deaths and no major amputations.1 Primary patency was higher with DCB than PTA (82.2% vs 52.4%; p<0.001) and there was also a significantly lower rate of CD TLR with DCB than PTA (2.4% vs 20.6% p<0.001). Both arms had a low rate of vessel thrombosis (1.4% after DCB, 3.7% after PTA; p=0.10). These results have now been confirmed in the second year.3 This means that not only is there a large difference between the DCB and the plain balloon, but also that the results with the IN.PACT® Admiral®, compared to studies performed

in similar populations, are probably the best that have been achieved, with almost 80% primary patency at 2 years. Of course, as in every study, not all patients with femoral artery lesions could be included, but only those that fulfilled the inclusion criteria. We have to await the results of other studies, such as the IN.PACT Global study, to know whether these results can be extended to all lesions in the SFA.

tZ: In this well-matched, randomised study, the DCB clearly outperformed the plain balloon cohort in terms of a highly significant better primary patency rate at 2 years (78.9% in the DCB group vs 50.1% in the PTA group, p<0.001; figure 1).3 In addition, significantly more patients reached the composite safety end point in the


fig. 1

Kaplan–Meier estimate of primary patency (A) and

freedom from clinically driven target lesion revascularisation (B)

in the IN.PACT SFA trial at 2 years. Error bars

represent 95% confidence interval.

reproduced with permission, copyright Journal of

the american College of Cardiology, 2015.3

DCB group than the PTA group (87.4 vs 69.8%, p<0.001). This was mainly driven by the TLR rate, which was clearly in favour for the DCB. In the DCB cohort, TLR rate at 1 year was only 2.4%, which is the lowest revascularisation rate ever reported for a peripheral artery trial so far, so the device has proven to be highly effective in improving patient outcomes. At 2 years, the TLR benefit was sustained, meaning there was still a difference of about 20% in absolute numbers in favour of the DCB (9.1% vs 28.3%, p<0.001). These data are in line with those from the ILLUMINATE FIM study,4 which was a small, single-arm feasibility study using the Stellarex™ DCB (Spectranetics, Colorado Springs, CO, USA). Two-year outcomes from both of these studies outperformed those from the LEVANT 2 study,5 in which the performance of the Lutonix™ 0.35 DCB (Bard Peripheral Vascular Inc., Tempe, AZ, USA) was investigated in almost 500 patients compared to regular balloon.

What do you think it is about the IN.PACT® Admiral® DCB that has given such good efficacy results? FV: It is not only about the balloon, but also about the drug and the way the drug is delivered to the blood vessel. The balloon can deliver the drug to the vessel wall. There are a lot of DCBs in development and coming to the market now. A simple balloon is a purely, or mostly, mechanical device. This is not the case with DCBs. There is much more involved here; the way that the drug is delivered to the blood vessel, the way the drug is bonded to the balloon, the concentration and formulation of the drug, all can vary from one DCB to the next. All of this means that you cannot take for granted that results obtained with one DCB will be the same with another one. This might well be the reason why results from the LEVANT trial,6 which are also positive for the Lutonix DCB (Bard Peripheral Vascular Inc.) are, let’s say, less good than the results from the IN.PACT SFA study.

tZ: The technical performance of DCBs, in terms of drug delivery to the vessel wall and drug persistence in the vessel wall, depends on multiple components, such as the interaction of the antiproliferative drug, paclitaxel, with the excipient, the binding energies between the balloon material and the drug, and the crystallinity of the drug coating (as compared to a more

amorphous condition of the drug coating). All of these factors seem to be balanced with the IN.PACT® Admiral® coating, resulting in the positive clinical outcomes in femoropopliteal lesions treated with IN.PACT® DCBs.

We understand that the results from the IN.PACT SFA study have been analysed in different subgroups. Were any differences identified for specific populations? tZ: The subgroup analysis showed that all patient groups benefitted from the use of DCBs. What we know from other trials is that there are some interventional procedures where, for example, diabetics do not benefit as much as non-diabetics. This has been found in earlier bare-metal stent studies.7 The IN.PACT SFA study is unique in that all patient groups benefitted from the use of the DCB. This includes both female and male patients, diabetics and non-diabetics, and every lesion length. This differs from the findings of, for example, the LEVANT 25 study, where female patients in particular did not benefit from the use of the Lutonix DCB (Bard Peripheral Vascular Inc.). It is a unique finding from IN.PACT SFA, that there were no exceptions in terms of benefit, regardless of which subcohort of patients was investigated. The lesson here is that not every DCB is alike. There are differences in performance between different DCBs and, in terms of their efficacy, there is no generalisable effect. Therefore, the performance of each individual DCB has to be investigated individually and every new device which comes to the market has to show that it is effective. You cannot simply refer to another study outcome to demonstrate a class effect.

What effect do you think these positive outcomes from the trial will have on clinical practice? FV: I believe these results will change practice. When the 1-year results were published, everybody was a bit astonished that this difference had been obtained. There were already a lot of smaller studies indicating that this would probably work, but the fact that the concept was shown to work in larger studies was important. With a lot of studies, after 1 year you start to see a catch-up effect, so although the 1-year results were promising, this is a bit short. Now we have seen that the treatment effect is sustainable at 2 years, so yes, I think that


this proves in the longer term that these DCBs will be effective. I think that this will convince quite a lot of people who were a bit reluctant to use it at first, because once we have the 2-year results, these are usually also confirmed in the longer term.

tZ: In my institution we have adopted the use of DCBs as the first-line strategy for more than 3 or 4 years now. This means that about 90% of all patients with superficial femoral artery disease seen at our institution are treated with DCBs. There are also other German centres, for example Leipzig, where they do the same. There are some indications for atherectomy device or for primary stenting but, besides that, the mainstream treatment strategy is to use DCBs in this indication. Stenting should be reserved as a last resort.

We have good evidence that DCBs, in particular the IN.PACT® Admiral®, do work in all kinds of lesions, including short lesions, called TASC II type A lesions, which, in the past, have been considered an indication for plain balloon angioplasty. The IN.PACT SFA study clearly showed that even short lesions do better if a DCB is used as compared to a plain balloon. Furthermore, based on the outcome of the IN.PACT SFA Global study,2 which included long lesions and in-stent restenotic lesions, we see that the performance of DCBs seems to be almost independent of lesion length. That means even long lesions show exciting benefits in terms of high primary patency rates (91.1% at 1 year) and low re-intervention rates (6.0%). It seems that the IN.PACT technology, in particular, is extremely effective in almost every kind of femoral popliteal lesion morphology.

Is there a need for treatment guidelines to change to reflect this? tZ: Yes, of course, and this will come soon. The next time international guidelines are updated, the published evidence on DCB angioplasty will be implemented in those guidelines. The European Society of Cardiology (ESC) is in the process of updating their guidelines, and the German Vascular Society has recently finished an update of their guidelines, which will be published in the first quarter of 2016.

The problem with publishing guidelines is that they only include data published in peer reviewed journals; data presented at congresses are not allowed. This means that if up-to-date study

outcomes are presented at global meetings, those data cannot be included in a guideline paper, and this basically means that guidelines are not up-to-date. Usually, the process of publishing new guidelines takes about 3 years, so after finishing the analysis of the published literature, it will take 1.5–3 years for those guidelines to be published, and in the meantime, new, more up-to-date data are published or presented.

When the last ESC guidelines were published in 2011, only first-in-man studies for DCBs had been published. What is considered class I evidence, i.e. randomised, controlled trials or meta-analyses, had not been published at that time. The new, upcoming guidelines will include the evidence from the published data of IN.PACT SFA 1- and 2-year outcomes, and also the LEVANT 2 study.5 Those studies have shown a benefit as compared to plain balloon angioplasty and that means those DCBs will be added as a first-line strategy in the treatment of femoropopliteal disease in future guidelines.

There is a move towards trying to avoid stenting in peripheral lesions. How often do you find yourself having to resort to adding a stent in particularly challenging lesions? tZ: Two different schools of thought exist in the interventional community. One school believes in stents and uses them in almost every lesion, either drug-eluting stents or bare-metal stents, like the Supera stent (Abbott Vascular, Santa Clara, CA, USA). The other opinion is to avoid stenting as much as possible and it is this school that is promoting the use of DCBs. If indicated, prepare the vessel up front with atherectomy or plaque modulation balloons, such as Cutting Balloon (Boston Scientific, Marlborough, MA, USA) or Scoring Balloon (Spectranetics), in order to avoid secondary stent placement as much as possible, so that patients do not have a foreign body in situ in the long term. The beauty of DCBs is that their use results in really outstanding patency results in almost all lesion morphologies without a clear need for stents.

Studies have shown that as lesion length increases, the stent rate also increases. In the IN.PACT SFA study, stent use was about 7% in the DCB arm with a mean lesion length of about 9 cm. If you look


at the Long Lesion cohort of the IN.PACT Global study, where the mean lesion length was 26 cm, the stent rate was about 40% for the entire cohort. Within this registry there was a subgroup analysis looking at lesions 15–25 cm, and another cohort with lesions longer than 25 cm. In the shorter lesions cohort (up to 25 cm), the stent rate was 33%, so that means every third patient received at least a focal stent. In the really long lesions cohort (over 25 cm, up to 40 cm), every second patient (about 53%) needed a stent.

However, another study from an Italian registry was recently presented by Antonio Micari, also looking at long lesions with a mean lesion length of 26 cm.8 They used a dedicated balloon angioplasty protocol, resulting in much lower stent rates of about 10%. They used an aggressive protocol with prolonged pre-dilatation of the lesion (3 minutes), prolonged DCB inflation (3 minutes) and even post-dilatation with a plain balloon if the outcome was not satisfactory after the DCB up to 5 minutes. If you follow such dedicated balloon angioplasty protocols, the need for stenting is still in the range of only 10–20%, even in long lesions. This is due to persisting dissection or acute recoil, mainly induced by severe vessel calcification.

There are a number of different DCBs on the market. What factors do you think should influence a physician’s choice around which particular balloon to use? FV: As I already mentioned, you cannot assume that the results for one balloon will also be obtained with another one. This is because the excipient is different, the concentration of the drug can be different, the way the drug is applied to the balloon may be different, so there are a lot of parameters which can vary from one balloon to the next. Physicians should use whichever DCB has been shown to be effective during clinical studies.

Do you think that the DCB will become the standard of care for SFA disease? FV: I think it will for the vast majority of cases, yes. The subgroup analysis from IN.PACT Global study shows that it is also effective in long lesions of over 20 cm. We know that in very calcified lesions it might be less effective so some additional treatment might be indicated, and there are still some lesion types in which we do not yet know for sure. For instance, in restenosis we are expecting more data soon, but I am convinced that for the vast majority of native lesions it will prove to be effective.

There is still the issue of price, and perhaps for people with very simple lesions it might still be appropriate to use a simple PTA, but for the vast majority of lesions, and maybe even for all lesions, this will become the first choice of treatment.

tZ: Reimbursement is one of the challenges to the adoption of DCBs. Some countries, such as France and Italy, will only reimburse stents, while in Germany and some other countries, they will also reimburse DCBs. In my view, DCBs do have many advantages over stenting and there is no reason not to switch.

Are there any further studies needed in order to convince us of the effectiveness and usefulness of this type of treatment? FV: We not only have the randomised clinical study, but also the IN.PACT Global study, which is a registry with a lot of patients. These registry data will provide more information about subgroups that were not included in the IN.PACT SFA study.

Of course, you can always argue that more studies are necessary. For example, there are no randomised head-to-head comparisons between two different DCBs. You could consider doing studies investigating a combination of, for instance, atherectomy and DCB, or DCB and bioresorbable stent, but for clinical practice, we already know a lot from the IN.PACT SFA and the IN.PACT Global studies, these already tell us a lot.


address for correspondence Professor Thomas Zeller University Heart Centre Freiburg-Bad Krozingen

Bad Krozingen Germany

thomas.Zeller@ universitaets-herzzentrum.de

+49 7633 4022431

Professor Frank Vermassen Department of Thoracic

and Vascular Surgery Ghent University Hospital

Ghent Belgium

[email protected]

+32 933 26388

1. Tepe G, et al. Circulation 2015;131(5): 495–502.2. Scheinert D. Presented at EuroPCR 2015, Paris, France.3. Laird JR, et al. J am Coll Cardiol 2015;66(21):2329–38.4. Schroeder H, et al. Catheter Cardiovasc Interv 2015;86(2): 278–86.

5. Jaff MR, et al. am heart J 2015;169(4):479–85.6. Scheinert D, et al. JaCC Cardiovasc Interv 2014;7(1):10–9.7. Sabeti S, et al. J endovasc Ther 2005;12(1):6–12.8. Micari A. Presented at EuroPCR 2015, Paris, France.

rEFErEnCEs:

DisCLosUrEs: TZ has received honoraria from Abbott Vascular, Angioslide, Bard Peripheral Vascular, Veryan, Biotronik, Boston Scientific Corp., Cook Medical, Cordis Corp., Covidien, Gore & Associates, Medtronic, Spectranetics, Straub Medical, TriReme, VIVA Physicians. Consulted for Abbott Vascular, Bard Peripheral Vascular, Boston Scientific Corp., Cook Medical, Gore & Associates, Medtronic, Spectranetics, ReCor. Research, clinical trial, or drug study funding received from 480 biomedical, Bard Peripheral Vascular, Veryan, Biotronik, Cook Medical, Cordis Corp., Covidien, Gore & Associates, Abbott Vascular, Medtronic, Spectranetics, Terumo, TriReme, Volcano. FV is a consultant and speaker for Medtronic.

Chaim Lotan

INTERVIEW

The future of digital health Digital technology is rapidly advancing and affects almost every aspect of our lives, including how we, and physicians, manage our healthcare. These advances bring many benefits, from the ability to more closely monitor patients with particular medical needs, to more efficient or convenient consultations with physicians and specialists. However, the development of huge numbers of new healthcare devices, applications and systems brings with it vast quantities of data, which raises many questions and challenges that will need to be answered. Confluence spoke with Professor Chaim Lotan, Director of the Heart Institute, Hadassah-Hebrew University Medical Centre, to discuss these issues and what digital technology means for the future of medicine.

How would you define digital health? Chaim Lotan (CL): It is actually very hard to define digital health, because it is an evolving topic encompassing the interaction between big data from many sources, and the use of new tools via the internet and cellular phones etc. This totally changes the classic doctor–patient relationship, leading to an entirely new way of practicing medicine.

We are right at the very beginning of a revolution. On one hand, the more we dig into digital health, the more potential we see. On the other hand, there are numerous unresolved issues that need to be addressed. The digital health revolution started with telemedicine – using telecommunication and information technologies to enable remote healthcare delivery. Today, with the internet dominating our lives, digital health means that the wellbeing of the patients is not only the domain of physicians, but it is accessible to everyone, and primarily to patients themselves. Sometimes the patient does not have to come into the clinic, they


can talk to the doctor over the phone or send pictures, they can get a prescription sent over the internet to the pharmacy, and then get the pharmacy to send it to their home, so the patient can get the entire circle of care without ever being physically seen by the physician.

I see the digital revolution on a daily basis. For example, if the Fellow has a problematic ECG at night in the cath lab, he takes a picture and within a second, using WhatsApp, I can see it from home and help him. The entire way of practising medicine today is changing.

It is also changing physicians’ relationship with industry. Traditionally at scientific meetings we would have attendees from companies such as Medtronic, Boston Scientific and Abbott. However, today when you have a meeting in the cardiology world and you also have Yahoo, Google, Samsung and Qualcomm as attendees, because healthcare – and life – is becoming so linked together.The social network companies, the big data companies, the drug companies and the device companies are all starting to work together to realise the potential of digital healthcare.

Do you think that this availability of information makes things easier or more difficult for physicians? CL: It can make things both easier and more challenging. For example, the other day I saw a lady who asked about a rare condition called postpartum cardiomyopathy, where women get dilatation of the heart and weakening of the

heart muscles immediately after labour. She had it several years ago and came to consult about a second pregnancy. It is a very rare disease and I would see such a patient maybe once every year or two – it is certainly not a condition one reads about on a daily basis. This patient was asking me questions based on the most recent literature about the disease, and she actually knew much more about it than I ever will know, so I was kind of embarrassed. On the one hand, she had the publications, however, she didn’t have knowledge to analyse and interpret the data, which means that a totally new type of patient/physician interaction is required.

Patients know about their own health, sometimes even better than physicians, because they have access to so much information. Patients can read about their disease and know as much as their physician knows, so the role of controlling the disease is moving from the doctor to the patient. However, the challenge here is that having access to the information is not the same as being able to understand what it means. This means that the communication between the physician and the patient is also changing.

Are there any wearable devices or smartphone applications that can help with patient care? CL: There are about 200,000 health applications today and a high volume of applications being developed. Applications started from the wellness side and then we were flooded with wearable devices that could monitor everything in your life: blood pressure, heart rate, temperature, oxygen saturation (figure 1). The question we need to answer is, how do you consolidate all of this information? Patient data previously came from hospitals, but with digital technology we can now get data on patients during their normal daily life, and this might shed light on how problems develop. We may be able to identify warning signs that tell us that something is wrong earlier on, and that the patient needs to go to the hospital. Previously, we didn’t have this type of data because there was no way to collect it at home.

I have a very good friend who starts his talks on the digital world by showing that about 1.2 billion people in the world have a toothbrush, but 1.5 billion people have an advanced cell phone. This widespread access to smartphones


means that your ability to deliver healthcare is much better. There are start-up companies trying to show that smartphone applications can improve patient compliance, for example in the elderly population who don’t remember if they took their pills or not, or what type of pill they should be taking. An application was developed at the Mayo Clinic to remind patients about their medication. Today in cardiology, one of the most important reasons for readmission of patients to the hospital is heart failure. Many hospitals are researching how to monitor the patient at home to prevent readmission, and one way to do this is by implanting sensors under the patient’s skin. CardioMEMS (St Jude, Saint Paul, MN, USA) is a system in which a very small device is implanted in the pulmonary artery to measure the pulmonary pressure. It can detect when a patient goes into heart failure, as the pressure increases, and this is transmitted via telephone to their physician. Another company wants to put sensors that can detect flow on coronary stents that are implanted to open the artery. If a noticeable reduction in flow is detected, it will be transmitted via cell phone and could alert the doctor and the patient that there may be restenosis.

The world of sensors is very big. Sensors can be very small, and range from very simple to very sophisticated. Using a smartphone with a camera and a very powerful microphone, you can monitor many things. For example, patients have very slight variability in heart rate that needs to be mathematically analysed to detect the variation.

fig. 1

Examples of monitoring devices.

A) CareLink® remote monitoring network

B) Reveal LINQ™ insertable cardiac

monitoring system

A

B

The variations are related to the status of the patient, sympathetic activation, mood, etc. Heart rate variability could predict changes in mood or stress and, for example, this could be an indicator of a diabetic patient whose glucose levels are not well-controlled.

In terms of development of the actual tools, the software, the devices, will this be driven predominantly by first world nations, or is it accessible to poorer nations too? CL: I think that every country will be able to develop applications.You just need smart guys and an unmet need, and that is it. Applications can range from very easy, to very complicated. Each region in the world has their own problems and their own unmet needs, so they will be able to meet their own needs in their own countries and regions.

For example, China is one of the countries where, in the villages, there are more patients with cell phones than with toothbrushes, and they are now trying to build a network of better health using digital technologies. A colleague of mine told me that they are looking at using digital technology to bring them all the data before the consultation, some from the hospital records and some provided from the patient via their cell phone. The challenge for the doctor is how to integrate all of these data and analyse them in the approximately 8 minutes that are available per consultation.

You’ve mentioned that with all of these new technologies, there is a tremendous amount of data being generated. Are there any challenges associated with having access to this level of data about individual patients? CL: How to control the data is a big issue, not only for the patient and the physician, but also the insurance companies, Health Maintenance Organisations (HMO) and governments. At the recent Innovations in Cardiovascular Interventions (ICI) meeting held in Israel, we had a long day focused on digital health, including how to handle so much data. How do you capture it? How do you analyse it? How do you bring it to the patient in a useful format? How do you bring it to the physician in such a way that he knows what is normal and what is it abnormal?

Moreover, cybersecurity is an important but underdeveloped topic in all domains of medicine at present. Today, you can monitor patients who have pacemakers without the patient coming to the hospital. You can check the pacemaker via the telephone, and adjust it if the parameters require changing. Still, I see patients coming to the clinic, usually very elderly patients who have to come with their children or their carers. When you consider why these patients are still coming to clinic, there are two issues. One is cybersecurity: for example, when it is possible to adjust a device’s parameters over the internet, there is a possibility that hackers will also be able to change these – and if a patient has an implantable cardioverter-defibrillator, they could even kill the patient. The second thing is reimbursement models. Who pays for consultations that are carried out digitally? In the old model, you sold the device, the hospital paid and that was it. Now we need a total reimbursement model. Will the hospital/ patient/HMO pay if you can show them that they save money? Who is responsible for it? I know that a lot of people are trying to build new reimbursement models for the digital age.

Another issue that we haven’t yet mentioned is regulation. Even the US Food and Drug Administration (FDA) does not know how to cope with digital health today in regulatory terms. With any device there is a very precise regulatory pathway, that of both the FDA and the CE. Digital regulation is still in its infancy and there are many unanswered questions, such as who is responsible (the patient, the application, the regulator, the HMO)? When do you need regulation? When don’t you need the regulation?

What about data protection issues? Who does and who should have the right to look at patients’ data? CL: Indeed, who owns the data? Is it the patient or the HMO? Are insurance companies entitled to look at it? How do you protect the patient’s data? We recently learnt about a 15-year-old girl who consulted a physician via the internet for birth control pills, and the next day her father could open her file and see that she has been prescribed birth control pills, without his knowledge. How do you allow one person (the patient) to access the information while protecting it from a second person (the father)?


Also, how do you prevent hackers from accessing the data? Insurance companies would pay a lot of money to access some patient data if it points to risk factors for particular conditions. On the other hand, if an insurance company was aware that you are a compliant patient who takes your medication as prescribed and we see, for example, that your blood pressure is well-controlled, maybe you should get the medication for free, because it means that you will be less likely to be hospitalised again. Patients can be incentivised or penalised by insurance companies on the basis of such data. There are a lot of small ethical questions that are still unsolved with the entire transition to digital health.

Do you think that the changes are going to happen gradually over time, or will we see bouts of revolutions following technological advances? CL: This is a huge revolution and I think it will be quick, but there will be hurdles. First of all, considerable amounts of money are going into digital, and the number of applications and start-ups in the field is huge. In the last year, in Israel alone, which is a relatively small country, we had about 450 digital heath start-ups.

The second point is that every year there is a new iPhone and new Android phones; it is a revolution but we don’t feel it because we are in the midst of it. Think back to what we had 10 years ago compared with what we have now, and then think about what we will have in 10 years from now with digital. We are going to practise a totally different kind of medicine in all fields, and cardiology will be very much affected.

As I have already mentioned, however, there are a lot of issues that I am sure will be resolved over the next few years: regulation, cybersecurity, data ownership, rights of access to data. All of this needs to be resolved, and during this process all of those questions will have to be answered.

Are there any aspects of medicine that are particularly resistant to digital technology? Do you think there needs to be a change in mind-set or are people willing to embrace it readily? CL: I don’t think any part of medicine will be able to avoid digital technology and this will start right from the medical schools and continue throughout practise. A lot of education in the medical schools

is very much affected by digital technologies and applications. People will say “Well, surgeons will do the same surgery”, but this is not true. They will use things like Google Glass, through which they will be able to access all the data on the glasses and have access to a huge electronic library. This will give them the ability to adapt what they decide to do next. Today surgeons can operate from another room using a robotic system, but in the future, this may be possible even more remotely if there is a stable network. You can compare it to the laparoscopic revolution, where surgeons went from carrying out open abdominal surgery to the minimally invasive techniques. The digital health revolution will be the same and will affect every area of medicine, and definitely cardiology.

For the older generation, my generation, it will take time to adopt these new digital technologies, but it will be much easier for young people who are exposed early to social networks and to the web. For example, in a recent competition at Beersheba University about digital health platforms for medical students, about 20 ideas for start-ups that can improve education in medical schools were submitted – all of them were applications. Moreover, today, with the help of computers and digital applications, you can visualise things on your iPad, and the way that teaching is done is totally different. Like the interaction with patients, medicine will be taught on a different level and in a different way.

Do you think that anything is lost by not actually seeing the patient and not having that personal interaction with them? CL: One of the most important questions is “What is the importance of the patient/doctor relationship?” Going back 10–15 years, a patient visiting their GP with shortness of breath would be referred to many sub-specialists: a cardiologist, a physiologist, a pulmonologist, but the patient would come and say “I lost touch among all the sub-specialists” I remember at that time we had a lot of debate; on the one hand, you need the sub-specialist expertise, but on the other hand, you need a physician who can integrate everything and offer the personal touch, i.e. a GP. The relationship between physicians and patients is a very important relationship and I think we will definitely lose something if we don’t retain it.


The other element is that patients are receiving a better and a higher level of medicine, more quickly, which is what a lot of people want today. If you are a mother and your baby is crying at 2 am, there are two options. You can go to the Emergency Room, wait to be checked by an ENT to find that the baby has otitis media, then run to the pharmacy for antibiotics. Or you can send a picture – today there is a little device that connects to a cell phone and takes a picture of the eardrum – and send it to the physician, and then if you need something, it can be sent from the pharmacy to your home. Wouldn’t you prefer the second option?

We will need a balance between those two. There are always pros and cons in each revolution, but I believe that the digital revolution is inevitable, and we will see how we find the balance between the role of the physicians and the use of technologies.

What do you think is the most important thing for readers to know about digital health in the future within interventional cardiology? CL: That is a tough question, but I think that technology will allow earlier analysis and follow-up of patients. Digital health may actually allow better communication with patients because, rather than only seeing a patient every 3, 6 or 12 months in person, with digital, you may not see them physically, but you will have some form of interaction – a way to reach the patient

and for the patient reach you – before, during and after the procedure.

The entire planning of the procedure in the digital world will be different. We are going to do a valve-in-valve procedure later today, on a very complex patient. We did a CT scan and then we had three-dimensional printing of their entire heart. This is another powerful tool in digital health. Using a 3D printing device you can simulate whatever procedure you are planning to do on the patient before you actually work on the patient’s heart. The 3D print exactly replicates the patient’s problem, so that when you come to operate on the patient, everything has been tried. You can have all the digital data, and also a 3D print of the device which allows you to visualise the solution.

Digital health will help us to monitor the patient better before the procedure, help us prepare better during the procedure, and help us monitor the patient after the procedure.

Medicine will change significantly in the next 10 years as a result of all the changes in the digital world, and each one of us will give his own share and contribution. I think that we are in the midst of a very big revolution, and there are many, many questions that will need to be answered in the next few years in order really to change the entire way that medicine is practised today.

DisCLosUrEs: None.

address for correspondence Professor Chaim Lotan

Heart Institute Hadassah-Hebrew University

Medical Centre Jerusalem

Israel

[email protected]

+972 2677 6564


INTERVIEW

Bernhard Voss

The Profile 3D® ring: is a profiled annuloplasty ring suitable for repair of degenerative mitral regurgitation? Degenerative mitral valve disease typically leads to annular dilatation and flattening of the three-dimensional (3D) mitral annulus, affecting proper closing of the mitral valve during systolic closing. However, the majority of currently available annuloplasty rings are flat and unable to restore the 3D shape of the mitral annulus in patients suffering from degenerative mitral valve disease. The Profile 3D® ring (Medtronic Inc., Minneapolis, MN, USA) was originally developed to repair functional mitral valve disease. Encouraged by the 3D design, and therefore the possibility of reshaping the mitral valve annulus to its native shape, the Profile 3D® ring started to be used in patients with degenerative mitral valve disease, and is now widely used in this indication.

Confluence spoke with Dr Bernhard Voss, Senior Cardiac Surgeon at the German Heart Centre, Munich, who was one of the investigators in the Profile 3D® ring trial, to discuss the results.

What are the treatment options available for patients with degenerative mitral regurgitation? Bernhard Voss (BV): The goal of mitral valve repair for degenerative mitral regurgitation is to correct the annular dilatation and repair any leaflet pathologies that are present. In almost every patient, the recommended treatment would be ring dilatation by annuloplasty. The repair of mitral valve pathologies could be achieved through a wide variety of different repair techniques, such as leaflet resection or chordae repair. The repair technique has to be carefully chosen, and is an individual decision for each patient. In our hospital, the policy is to respect, rather than resect, mitral valve tissue by using artificial chordae.

When you perform a ring annuloplasty, what role does the ring play and what is the importance of the shape of the ring? BV: The normal mitral valve annulus is physiologically saddle-shaped, with its highest points located anteriorly and posteriorly in the middle of the respective annulus, and its lowest points located below both commissures.


fig. 1

Profile 3D® ring

In degenerative mitral valve disease, the mitral annulus is dilated: it becomes more circular and also flattened. By using 3D rings, we reshape the flattened mitral annulus back to a nearly physiological shape. In this way, we reduce the stress on the leaflets and increase the coaptation area.

Are there any comorbidities or anatomical features that would influence your decision regarding the choice of ring? BV: In comparison with other rings, the rigid Profile 3D® ring has a relative small anterior–posterior diameter (figure 1). This could be critical in cases where the anatomical configuration confers a high risk for postoperative systolic anterior motion (SAM). In these patients, the implantation of a

more flexible ring with a larger anterior–posterior diameter could be an advantage.

What are the advantages and the disadvantages of the different type of rings available, for example, 3D, rigid, flexible or semi-rigid rings? BV: The normal mitral valve annulus is physiologically flexible to allow increased inflow during diastole. When using flexible or semi-rigid rings, there is less interference with the normal movements of the mitral annulus and, theoretically, less impairment of ventricular filling, compared to rigid rings. However, in my opinion, this feature of annuloplasty rings is not as important when repairing degenerative mitral valves. This is because, in most cases, we see greatly dilated rings and there is enough valve tissue to allow the implantation of large annuloplasty rings without affecting ventricular inflow. However, after a couple of months, flexible rings tend to lose their flexibility due to ingrowing connective tissue, which surrounds the flexible ring. Therefore, I think that ring flexibility is less important in these cases of mitral valve repair. Rigid 3D rings are the only option to restore the native 3D shape of the mitral annulus, which leads to improved coaptation and less chord tension.

In which circumstances would you recommend the use of these rigid 3D rings over semi-rigid or flexible rings? BV: Rigid 3D annuloplasty rings could be recommended for almost every patient suffering from degenerative mitral valve disease without a predicted risk for the development of SAM.

Are there any features, such as calcification, that affect this? BV: If annuloplasty ring implantation is feasible and leaflet motion is not impaired by severe calcification, a mitral valve repair using a 3D ring could be performed with excellent results. However, if there are isolated calcifications in the anterior part of the native mitral annulus, the implantation of an open annuloplasty ring could be advantageous to avoid the need for stitching through calcified areas.

Could you tell us more about the Profile 3D® ring for functional mitral valve disease? BV: Originally, the Profile 3D® ring was developed by Medtronic for functional mitral valve disease.

Functional mitral regurgitation is a disorder of regional or global left ventricular remodelling in which anatomically normal leaflets fail to coapt adequately due to increased tethering forces. The key goal in surgical repair of such valves is to reduce the anterior–posterior diameter of the mitral annulus in order to restore leaflet coaptation. Conventional ‘undersized’ annuloplasty rings, however, decrease both the anterior–posterior and the commissure–commissure annular dimensions, which may excessively decrease the mitral orifice area. This can be associated with high rates of recurrent mitral regurgitation. In contrast, the Medtronic Profile 3D® ring is designed with a disproportionally reduced anterior–posterior dimension, to avoid the need for aggressive ring downsizing. For example, the anterior–posterior diameter of the 36 mm Profile 3D® ring is about 20% smaller than that of the classical 36 mm Physio II ring (Edwards Lifesciences, Irvine, CA, USA), despite both having the same numerical size.

Would you say that patients with degenerative disease are more challenging to treat? BV: Yes and no. In general, treatment of degenerative mitral valve disease is more complex and the decision regarding which reconstructive technique to use for restoration of the presented mitral valve leaflet pathologies requires a lot of experience. Additional annuloplasty is generally recommended. For the treatment of classical functional mitral valve disease, it is usually sufficient to perform a simple annuloplasty to achieve sufficient downsizing. However, some cases are more complex, for example, those requiring augmentation patch techniques.

You were recently involved in a study investigating the use of the Profile 3D® ring for degenerative mitral valve disease. Can you tell about this study? BV: The trial enrolled 200 patients with severe degenerative mitral regurgitation, who underwent mitral valve repair using the Profile 3D® annuloplasty ring. For mitral valve repair, large ring sizes (over 34 mm) were implanted in two-thirds of patients. Additional chord implantation was performed in 85% of the treated patients, while leaflet resection was only necessary in 5%. At 3 years’ follow up, we found excellent results with freedom from reoperation of up to 97%.


Thinking about the patients with degenerative mitral valve disease that you were treating, were they patients with quite severe disease, or was it a typical patient population? BV: The composition of the study population ranges from simple P2 prolapse with ring dilatation to complex Barlow valves with excessive leaflet tissue and combined pathologies. Therefore, the study population reflects a typical spectrum of degenerative mitral valve disease.

What were the key findings from the study using the Profile 3D® ring in this new population? BV: The main conclusion of our study is that the Profile 3D® ring could be used as a perfect alternative for the treatment of degenerative mitral valve disease, which is underlined by the excellent mid-term results for freedom of reoperation.

Do you expect the long-term data for the Profile 3D® ring to remain as good? BV: We expected the long-term data to be as good as the short- and mid-term data. This assumption is based on the 3D restoration of the native valve annulus, which leads to a sufficient reduction of chord tension. Additionally, since we started using the ring in 2009, we have seen very few patients readmitted to our hospital with the need for mitral valve reoperation. A more definitive answer could be given in a couple of years when we have more data available.

What features of the ring do you think account for the low reoperation rates found? BV: I would point out that the ring design is based on 3D echocardiogram and CT scans of the normal mitral valve and I think reshaping the ring to a nearly physiological situation offers the best chance of achieving the good long-term results.

What proportion of patients with functional disease and degenerative disease is the Profile 3D® ring suitable for? BV: From my point of view, around 90% or even more degenerative mitral valve disease patients could be treated by implantation of the Profile 3D® ring. The main exception would be those with high risk for SAM. The estimation of patients with functional mitral valve disease that are sufficiently treated by 3D rigid annuloplasty rings is much more difficult.

Are there similarities between the Profile 3D® ring and the Contour 3D™ (Medtronic Inc.) ring for tricuspid valve repair, in terms of their design and functionality, that you think allow for these results? BV: Both the Profile 3D® ring and the Contour 3D™ ring were designed based on 3D echocardiogram and CT scans of the natural valve shape. Like the mitral valve, the tricuspid valve also loses its 3D shape by progressive ring dilatation. Therefore, the implantation of 3D annuloplasty rings for tricuspid valve repair could confer a huge advantage with respect to valve durability and functionality.

36

DisCLosUrEs: Consultant for Medtronic.

address for correspondence Bernhard Voss

Department of Cardiovascular Surgery

German Heart Centre Munich

Germany

[email protected]

+49 (0) 89 1218-4119


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