confluenceconfluencejournal.com/wp-content/uploads/2016/02/Confluence10_Feb... · del Valle Fernández and Dr César Morís de la Tassa report the transcatheter implantation of the

issue ten February 2015

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

Perspectives on the use of Resolute® Onyx™ drug-eluting stent in percutaneous coronary intervention

Lessons learned from HTN-3: pharmacological non-adherence in hypertension and the potential of Spyral™

CoreValve® Evolut™ R 23 for the treatment of severe regurgitation in a Mitroflow® 21 prosthesis

Investigating the potential benefits of minimally invasive cardiac surgery for mitral valve repair

Supported by an unrestricted educational grant from Medtronic, Inc.

IMAGE: ©Medtronic, Inc.

concepts and opinions in interventional cardiovascular medicine

confluence

Dear colleagues,It is with great pleasure that I welcome you to a landmark in the history of Confluence: Concepts and opinions in interventional cardiovascular medicine – the publication of our 10th issue!

When we launched the journal more than 5 years ago, our aim was to bring together cardiologists, cardiac surgeons and interventionists to discuss all issues around invasive cardiology. Our ultimate goal was to develop a diverse and easily readable journal that would provide clinical insight to those involved in invasive cardiology. We hope that you agree that we have both met and exceeded these goals.

Interventional cardiology and cardiac surgery – and the technologies associated with them – have always formed a key part of the content of the journal and, with our usual focus on clinical perspectives and optimal patient outcomes, this issue is no different. In the present issue, two case studies demonstrate the positive impact that new technologies can have in a clinical setting. Firstly, Dr Francesco Giannini and Dr Elvin Kedhi describe the successful first-in-man implantation of a new zotarolimus-eluting stent, the Resolute® Onyx™ for the treatment of a complex multivessel disease. They describe how the stent exerts extremely good trackability and pushability, even across long, heavily calcified and tortuous lesions. Secondly, Dr Raquel del Valle Fernández and Dr César Morís de la Tassa report the transcatheter implantation of the new, fully recapturable valve, CoreValve® Evolut™ R 23. In a valve-in-valve procedure, the prosthesis proved an effective tool to manage a complex patient. This device also features in our interview exploring the options for transcatheter aortic valve implantation, where Dr Ganesh Manoharan provides a fascinating commentary on the subject and evaluates the current evidence around self-expanding and balloon -expandable valves.

On the surgical front, Confluence spoke with Dr Hugo Vanermen about the use of minimally invasive cardiac surgery for mitral valve repair. Dr Vanermen, the inventor of this technique, describes the potential such surgery has to reduce pain, leave minimal scarring and afford quicker rehabilitation compared with conventional surgery. Furthermore, Dr Massimo Lemma discusses the 1- year results of the On-Off clinical trial, in which patients at high risk of operative complications,

Christian Hamm EDITOR-IN-CHIEF

who required coronary artery bypass grafting, were randomized to surgery with or without cardiopulmonary bypass. The results from this study are very positive for off-pump surgery; however, we discuss the importance of operator experience in delivering such outcomes.

I think it is testament to the dynamism of the cardiovascular community that, even during its lifetime, Confluence has had to evolve to include articles on an increasingly broad range of topics, as the treatments we can provide continue to grow beyond coronary care. Our final three articles provide perfect examples of this diversification.

The updated ESC guidelines on type B aortic dissection provide critical guidance for both cardiology specialists and emergency room staff, in a condition where time is of the essence. Professor Christoph Nienaber provides first-hand experience on how the guidelines were developed and their impact on clinical care.

Finally, we have two articles focused on the vital topic of pharmacologic non-adherence in hypertension. Editorial Board member Professor Luis Ruilope provides a succinct overview of the importance and potential complications that can arise from non-adherence to medication. Furthermore, Dr Justin Davies looks to the potential solutions to this challenging dilemma. Following the disappointing results from the Symplicity HTN-3 trial last year, he investigates the procedural aspects of renal denervation and lessons from HTN-3, and discusses how an improved understanding of anatomy can help deliver better clinical results.

I would encourage you to visit the Confluence website at www.confluencejournal.com to find all of the previous issues of Confluence, including additional video content.

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

Christian Hamm

2 confluence issue ten February 2015

Hot topic The challenge posed by pharmacological non-adherence in hypertension 22Luis Ruilope

Interview Lessons learned from HTN-3: pharmacological non-adherence in hypertension and the potential of Spyral™ 24Justin Davies

Interview On-Off 1-year results 29Massimo Lemma

Interview Reviewing the updated European Society of Cardiology (ESC) guidelines on type B aortic dissection 33Christoph Nienaber

ContentsCase study A complex percutaneous coronary intervention with Resolute® Onyx™ drug-eluting stent: our first experience with technical considerations 4Francesco Giannini, Elvin Kedhi

Interview Investigating the potential benefits of minimally invasive cardiac surgery (MICS) for mitral valve repair 8Hugo Vanermen

Interview The superiority of self-expanding versus balloon-expandable valves 13Ganesh Manoharan

Case study CoreValve® Evolut™ R 23 for the treatment of severe regurgitation in a Mitroflow® 21 prosthesis 18Raquel del Valle Fernández, César Morís de la Tessa

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.


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

www.confluencejournal.com

http://www.confluencejournal.com/

CASE STUDY

A complex percutaneous coronary intervention with Resolute® Onyx™ drug-eluting stent: our first experience with technical considerations

Francesco Giannini

Background One of the crucial challenges in complex percutaneous coronary intervention (PCI) is the delivery of the balloon catheter/stent across the stenosis, which may be hindered by lesion characteristics such as tortuosity or calcification. In many cases, this process remains challenging, and is strongly dependent on stent performance characteristics such as pushability, trackability and crossing profile. Drug-eluting stents (DES) are now a mainstay of PCI, and here we report our first experience using a new zotarolimus-eluting stent, the Resolute® Onyx™ (Medtronic Inc., Minneapolis, USA; figure 1), for the treatment of a complex multivessel procedure.

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Elvin Kedhi

A

C

B

D

confluence issue ten February 2015

fig. 1

The Resolute® Onyx™ zotarolimus-eluting

stent

fig. 2

Coronary angiography pre-intervention

Case description An 83-year-old female presented with worsening shortness of breath and chest pain. Her medical comorbidities included hypertension, diabetes mellitus, dyslipidaemia and moderate renal dysfunction. She was diagnosed with non-Hodgkin lymphoma and was in partial remission following chemotherapy. An electrocardiogram showed only non-specific T wave abnormalities; however, the troponin I level was elevated. Echocardiography showed normal left and right ventricular function and moderate aortic valve stenosis. Coronary angiography revealed a 70% stenosis of the proximal left circumflex artery (LCX) (figure 2A), a tortuous obtuse marginal (OM) vessel with a subtotal ostial stenosis, and a severely calcified stenosis of its side branch (functionally the postero-lateral branch) (figure 2B and C). It also showed significant diffuse disease in the proximal and mid-left anterior descending (LAD) (figure 2D), and chronic total occlusion of the proximal right coronary artery (RCA) (image not shown) with collateral flow from left coronary artery. The cardiothoracic surgical team found her a poor bypass surgery candidate; therefore, a strategy of

5

PCI revascularization of the LCX (culprit) and possibly the LAD was proposed.

The procedure was performed via radial artery approach using a 6F JL 3.5 guide. The OM branch and the side branch were both wired; however, we were unable to cross the lesion in the side branch of the OM vessel with a balloon despite using different types of balloons with increasingly small diameters (from 1.5 mm to 1.1 mm), even after using a GuideLiner® catheter (Vascular Solutions, Inc., Minneapolis, USA) for additional support. We therefore decided to change the strategy by choosing to treat the LAD first and then, subsequently, to use a so-called ‘balloon anchoring technique’ in the LAD to cross the LCX artery OM lesion.

The mid-LAD was predilated with a 2.0 x 15 mm balloon followed by implantation of a 3.0 x 26 mm Resolute Onyx stent. No difficulty was encountered in advancing the stent in this very long, tortuous and highly-calcified lesion. Thereafter, a second identical stent was implanted proximally to the first one. The stents were easily overlapped despite the heavy calcification that was clearly visible on angiography. Overall, a very good angiographic result was obtained in the LAD (figure 3).

A

C

B

D


fig. 3

Coronary angiography during intervention

Following this successful result in the LAD, we proceeded with revascularization of the LCX artery. The ‘balloon anchoring technique’ was carried out as follows: a 3.0 mm balloon was inflated to 16–18 atmospheres in the stented mid-LAD, which ‘anchored’ the catheter guide to the left main and enabled advancement of a 1.2 mm balloon through the stenosis in the OM vessel (figure 4A and B). After further predilation with another 2.0 mm balloon, the OM vessel was successfully stented with a 2.75 x 30 mm Resolute Onyx DES with an excellent angiographic result. The stent was implanted, achieving a good expansion of the struts and without changing the angle and course of the vessel (but adapting to it). The anterior branch of the OM, which was covered from the implanted stent, showed no signs of ostial pinching, therefore, a kissing balloon technique was needed. Then, a second 3.0 x 26 mm Resolute Onyx DES was implanted in the proximal LCX overlapping with the first, again with a good angiographic result (figure 4C and D).

Discussion Failure to cross a lesion with a balloon or stent, most often due to severe calcification and tortuosity at the occlusion site, can be challenging

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to overcome. Several strategies (increasing the guide-catheter support or providing lesion modification) have been proposed.1–3 Among these, the ‘balloon anchoring technique’, initially described by Fujita in 2003, refers to the inflation of a balloon in the side branch of a target coronary vessel to facilitate equipment delivery to a target lesion.1 The variant of this technique, which we adopted in our case (anchoring the balloon in a previously stented adjacent vessel), allowed a more aggressive balloon inflation. Consequently, this provided better support of the guide catheter, which is crucial to our ability to cross a complex culprit lesion with a small balloon, without any risk of vessel damage at the anchoring site.

Furthermore, the stent device used in this case, the recently introduced Resolute Onyx DES, demonstrated extremely good trackability and pushability, and crossed long, heavily calcified and tortuous lesions with ease. The reduced catheter shaft under the stent balloon, combined with the thin stent struts, allow for a low stent-crossing profile, which, together with the improved resilient hypotube and hydrophilic shaft coating, may all play an important role in the improved trackability and pushability observed with this device.

A

C

B

D


fig. 4

Balloon anchoring technique and final

outcomes

Interestingly, the Resolute Onyx DES shows excellent vessel conformability (figure 3C), even during the inflation. This can be ascribed to two important characteristics of this device: firstly, the helical wrap and the continuous sinusoid technology design are believed to be more beneficial as compared with traditional laser-cut stents regarding device flexibility; secondly, a new balloon blend improves stent flexibility and trackability at the same time. The continuous sinusoid technology might also have a beneficial impact in bifurcation lesions through a dual mechanism: firstly, the improved device conformability to the vessel shape may result in less side branch ostial angle distortion; secondly, the large strut cell opening may reduce side branch jailing; therefore, all together simplifying the bifurcation treatment by reducing

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the need for complex procedures like ‘kissing balloons’. Finally, the core-wire technology, representing a conventional cobalt-chromium metallic strut with an inner core of platinium-iridium alloy has significantly improved the stent visibility on angiographic imaging as compared with the previous Resolute Integrity® DES (cobalt-chromium alloy alone; [Medtronic, Inc.]). Such improved stent opacity may translate to better procedural outcomes with reduced procedure radiation time and contrast dye usage. In conclusion, the Resolute Onyx DES performs extremely well even in very complex and challenging coronary lesions; however, further experience with this novel stent is needed to further evaluate the advantages that this device may offer.

Address for correspondence Elvin Kedhi, MD PhD

Isala Hospital Department of Cardiology

Dokter van Heesweg 2 8025 AB Zwolle

The Netherlands

Tel: +31 38 424 8094 Fax: +31 38 424 3222

[email protected]

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.


1. Fujita S, et al. Catheter Cardiovasc Interv 2003;59(4):482-8.2. Stone GW, et al. Catheter Cardiovasc Interv 2005;66(2):217-36.3. Hirokami M, et al. Catheter Cardiovasc Interv 2006;67(3):366-71.

REFERENCES:

DISCLOSURES: FG and EK have nothing to declare.

Hugo Vanermen

INTERVIEW

Investigating the potential benefits of minimally invasive cardiac surgery (MICS) for mitral valve repair Minimally invasive cardiac surgery (MICS) for mitral valve repair has the potential to reduce pain, leave minimal scarring and afford quicker rehabilitation compared with conventional surgery. Confluence spoke to Dr Hugo Vanermen, UC Louvain, Knokke, Belgium, who first developed the technique in 1997, to find out more about the benefits and challenges associated with this procedure.

What options are available for mitral valve repair? Hugo Vanermen (HV): Mitral valve disease is becoming more and more important, certainly in the elderly. Estimations are that mitral valve degenerative disease and ischaemic disease will be more prevalent in the elderly than aortic valve disease actually. It is vital, therefore, that we have less invasive techniques for mitral valve disease, because the elderly ask for less invasive techniques. In the 21st century, they certainly no longer ask for a sternum-splitting technique.

Therefore, I developed a technique in 1997 – minimally invasive cardiac surgery (MICS) for mitral valve repair – which was intended to be almost painless, with minimal scarring, and a very fast rehabilitation to full recovery, which means that we are talking about 2 to 3 weeks instead of 2 to 3 months in case of sternotomy.

There are three key features of this procedure. First, the technique is based on the use of an endoscope as, in the intercostal space, it is impossible to look at the mitral valve when your hands are in front of the working port (figure 1). Secondly, we install extra-corporeal circulation on the big femoral vessels: the femoral artery and femoral vein. We have techniques that allow us to arrest the heart and preserve the myocardium for, when necessary, 2 hours and more, to be able to expose the mitral valve and repair it. The third point is that it is impossible to do this surgery with classical – that is to say, two-pronged instruments – instruments that look like classical scissors that you open wide in order to operate with them. The instruments that I have used for more than 15 years are shafted instruments, which look

very much like the instruments that laparoscopic surgeons use.

Could you give us more specific detail about how the procedure is carried out and why is it beneficial for patients? HV: In a lady, the incision is made in the intra-mammary groove on the right-hand side. It is a 5 cm long incision. In a man, it is made just around the nipple, so of that 5 cm incision only 2 cm is visible. From there, I approach the fourth intercostal space on the right-hand side. There, I make a working port – that is to say, a port that is 5 cm in length and the width of the interspace. From there, when the heart is arrested, it is easy to make an incision in the inter-atrial groove in between the right atrium and the left atrium, after opening the pericardium. I developed a special retractor that can broaden this incision to open up the left atrium and, at that moment, a camera can be introduced into the left atrium, to have the best possible look at the mitral valve (figure 2).

On average, the entire procedure will take three to three-and-a-half hours, depending on the difficulty of the repair procedure. In an easy repair procedure it will take two-and-a-half to three hours, while in a difficult one it may take three-and-a-half to four hours.

We have developed a website where you can see lots of pictures and videos clips, and testimonials by patients, which should help readers become more accustomed with this technique – www.minimitralrepair.org.

I started using this procedure in February 1997, and I have now carried out more than 2,500 completely endoscopic mitral valve repairs and


fig. 1

The patient is in dorsal decubitus and the right

hemithorax is slightly elevated. We see a

“working port” in the fourth interspace with

‘soft tissue retraction’ only: the bony structure

of the thorax remains untouched to sort of guarantee a painless

approach. We see a small (5 mm) camera-port

more dorsal to it and a trocar port (7 mm) for

venting and CO2 inflow more caudal of it. In

both groins we can see both femoral vein and arterial percutaneous

cannulation


fig. 2

Close to 100% of degenerative mitral

valves can be repaired; the endoscope provides

exceptionally good images of the mitral valve.

This image shows the image that the surgeon

looks at to do the repair: one can see a closure line after some tissue

resection has been carried out on P1, an artificial Goretex chord on P2

and a annuloplasty ring in place

replacements, some of them combined with tricuspid repair. For the patient, the difference is like day and night when it comes to pain, scar and fast rehabilitation. I always talk about the 'three Cs' – cosmetics, comfort and complete rehabilitation within weeks. That happens to be the case, both in young and in elderly patients.

Is any of this procedure done robotically, or is it all manual, using endoscopes? HV: The core of this operation is that conventional cardiac surgeons, who were trained in the 1980s and 1990s, have a hard time switching to this procedure because there are many new elements coming into play – new instruments, new extracorporeal circulations and new ways to clamp and visualize the heart. This brings them a long way out of their comfort zone.

If they have problems with the video-assisted visualization, and the shafted instruments, then robots may help a great deal, because robots will give a 3D image of the mitral valve. The robot will allow you to do moves with your wrist inside the patient, because your own wrist stays outside of the patient – that is to say, at the console and at the joysticks, with mechanical arms that go into the heart and mimic the exact same movements inside. This is a way for surgeons to overcome the learning curve and it is a way to more quickly adapt to the new hand–eye co-ordination that is necessary in order to do this. On the other hand, however, it makes it much more cumbersome and time consuming and, last but not least, considerably more expensive.

What else can be done to help people to learn and feel confident with this technique? HV: A great deal of resistance for the general adoption of this technique is due to the fact that surgeons – when they master all the techniques to repair the mitral valve – have very often come to an age where it becomes more difficult for them to adopt new instruments, or new visualizations. Sometimes, they are no longer flexible enough to switch to a new technique.

However, I expect a great deal from a new generation. Some mitral valve surgeons are now 20 years younger than their senior colleagues. They were almost all born with their hands on a keyboard and their eyes focused on a screen. This means that they will pick up these techniques

much more easily and I am so happy to see that, 15 years after the development of my technique, many young surgeons all over Europe now – in France, in Switzerland, in Germany – are picking up the techniques and doing very well. This is mainly because the conventional surgeons, who wanted the prestige of the mitral valve surgery but didn’t want to become flexible to adopt new techniques, are actually disappearing and leaving in place the younger surgeons.

On the other hand, we definitely need a simulator. Airline pilots use simulators for thousands of hours before becoming actual pilots. Actually, for brand new techniques like this one, the use of a simulator would be fantastic, but this is obviously costly to set up. I have, however, developed a great many set-ups with endoscopes, with plastic human skeletons of thoraxes, to let surgeons feel what it would be like to work on the mitral valve through a tiny opening, with their hands on the shafted instruments and eyes focused on the screen. The only thing is that it is amazing how well you can see the mitral valve – you see it much more clearly than from the glimpse you might have of the mitral valve through sternotomy. However, it is the hand–eye co-ordination that is challenging, to a large extent.

Given how good the view of the mitral valve is with this technique, are any other imaging techniques required, in terms of a work-up for a patient? Do you need to have a good understanding of the anatomy and of the disease as well? HV: Absolutely. Ultimately, it is important to have a bedside echocardiographer or, even better, an anaesthesiologist, who is there from the very beginning until the very end, who masters all the techniques of transoesophageal echo (TEE). TEE is our way to monitor the proper cannulation of the femoral vein and femoral artery, and it is the way to bring up the balloon into the ascending aorta to arrest the heart, to look at the mitral valve pathology. Last but not least, it can be used to look at the result at the end of the procedure – to see with your own eyes whether the procedure has been a success or whether you have to go back to correct and to do final adjustment. That is very, very important.

It is, so to speak, an intervention where teamwork is critical and, as you will know – or as perhaps you will not know – surgeons used to be dictators


in the OR in the 1960s and 1970s. They yelled to their perfusionist and to the scrub nurse, and they actually ignored the anaesthesiologist. At that time, it was very important to have a very strong personality in the OR, to make sure that the operation came to a good end. Today, however, it is impossible to work like that, not only because of changes in culture in the OR, but because it is vital to communicate effectively with each other as peers – that is to say, with the perfusionist about the pressures in the ascending aorta and arterial line, and with the anaesthesiologist to have optimal venous drainage and so on. This is so important, to ensure the success of the operation.

Are there specific patient populations for whom this technique is particularly suited? HV: Yes. The mitral valve is by far the best valve to be approached with an endoscope from the right-hand side. You slide an endoscope in the axilla of the patient and, with your endoscope, you can go all the way to 3 cm of the mitral valve – in a plane that is perfectly perpendicular compared with the plane of the mitral valve, and you can see it marvellously well. You can do the same with the tricuspid valve.

However, there are limitations. The first is the limitation of the right lung. In patients who have right-lung adhesions to the pleura, it is impossible to gain access to the heart, to the inter-atrial groove and then it is better just to forget it because, if you start to loosen up all these adhesions, you might ruin the right lung.

The second is that you need peripheral cannulation and retrograde flow. This means that patients should not have any peripheral artery disease – although it is very well known that patients with degenerative mitral valve disease, even when they are in their 60s or 70s, do not have peripheral vascular disease. That is a big help.

The third obstacle might be thoracic deformities, for example, a pectus excavatum, because then it will be difficult to approach the mitral valve from the right-hand side, given the limited space between the sternum and the vertebrae. There are ways to overcome that, but it is not very easy.

When we talk about the pathology of the mitral valve itself, repair is possible in all cases of degenerative disease – although I would actually emphasise the fact that, if surgeons are inexperienced, they should limit their cases to easy

repairs. By that, I mean easy P2s – but fortunately, easy P2s are by far the majority of all the MRs, that is to say close to 70%. However, when there is calcification in the posterior leaflet or a challenging rheumatic repair in a young lady, for example, I would leave that up to more experienced surgeons. Annulus calcifications, however, are only present in a minority of patients. Fortunately, such a complication does not present a big obstacle for MICS mitral procedures.

We have spoken a good deal about the benefits to the patient in terms of the three Cs, but what are the benefits to the physicians from using this technique? HV: From a personal point of view, it is just amazing to see how people, today, go on the internet. I operate now in four or five different centres in Europe – in Switzerland, in Italy, in Paris and in Brussels. I have patients who just go to their computer and Google ‘I have mitral valve insufficiency and I want a small incision, or I want a less invasive procedure’. They go on the internet for hours and they follow the websites and read all sorts of articles. They come to me with a bundle of things that they have printed out from the internet: they come to see me and say, ‘this is what I want; we have found that you are the most experienced person in the world to do this’. So it is amazing that more and more people are well aware of the fact that less invasive techniques are possible today, are perfectly safe and give a perfect result in terms of quality of repair. That is the first point.

It also benefits the hospital as it is pretty obvious that if you have a patient who remains in hospital for 4 days instead of 8 days, there is a difference in bed occupancy. We have seen that the number of days that patients stay in hospital after less invasive procedures decreases significantly, and that allows a reorganization in terms of bed occupancy and so on. That is an advantage for the physician as well.

The third advantage for the physician is that, more and more, we come across cases where patients have been operated on before. They are in their 80s and were operated on 20 years previously for coronary artery disease, coronary artery valve replacement and so on, and they now need mitral valve repair. It can become terribly difficult to go through a median sternotomy if there are open grafts, if there is a mechanical valve in place in the aortic position and so on. This is even more true


in patients who have had two or three interventions already. The real advantage of MICS mitral is that the approach from the side is sometimes amazingly easy and leaves much less risk to the patient than when you go once again through the same median sternotomy scar. In terms of re-do situations, it is an amazingly easy approach.

What are the potential challenges and complications associated with this technique? HV: A great deal has been said about retrograde perfusion. Opponents of the technique have said that this is a less good technique because there is retrograde perfusion. Not in a single, perfect comparison between articles with lots of cases of very experienced centres, has it been proven that there is a difference in terms of cerebrovascular accident or transient ischaemic attacks when there is retrograde perfusion in these patients.1,2

There has been one meta-analysis3 in which there were more cerebrovascular accidents but, if you look at this meta-analysis in detail, it happens to be an analysis where, in many centres, five to six mitral valves were done with this technique over an entire year – which is a very low number. Over the last 10 years, I have carried out up to 250 mitral valves every year. Indeed, I have become a mitral valve surgeon and that is all I do. In future, I think young surgeons really have to look for what their ideal profile should be: you are either a coronary artery surgeon, an aortic valve repairer, an ascending aortic surgeon, or a mitral valve repair surgeon. If you focus on that and if you really want to go for it, then it is not that difficult today to build an entire practice on perfect mitral valve surgery.

It sounds as though experience is a key factor in determining the success rate for this operation. Is it fair to say that? HV: That is absolutely right. Many who have learned this technique have mentioned the steepness of the learning curve. Therefore, I now go to different centres in Europe to proctor young surgeons and accompany them in the technique, to make sure that they go through the learning curve without additional risk to the patient.

Do you think there are sufficient data to provide a convincing argument for this technique? HV: There is perhaps not quite enough evidence. We have brought up on a couple of occasions already the fact that the surgeons who have picked up this technique very early – and I can only mention a few in the world, like Randy Chitwood, like Fred Mohr, like Patrick Perier – they have seen such an improvement in the quality of life and the outcomes of their patients that, for them, this has become the technique of choice.

We no longer do any comparison in terms of patients with the same amount of risk, divided into two groups and do sternotomy, because I no longer dare to do sternotomy. I feel very uncomfortable now, if I have to do mitral valve through sternotomy, because the difference for myself in terms of visualization and for the patient in terms of invasiveness – is that big.

What more data are needed to support this technique? HV: We need data now from young surgeons who have picked up the technique with good proctoring, accompanied by older guys with a great deal of experience. They will come out with articles and data that will make it pretty obvious for everybody that it is better to go this way.


1. Modi P, et al. Eur J Cardio-Thoracic Surg 2008;34(5):943-52.2. Cao C, et al. Ann Cardiothorac Surg 2013;2(6):693-703.3. Cheng DC, et al. Innovations (Phila) 2011;6(2):84-103.

REFERENCES:

Address for correspondence Dr Hugo Vanermen

Neerveld 5 B-1200 Woluwe Saint Lambert

Belgium

Tel: +32 475244383

[email protected]

DISCLOSURES: HV is Course Director of the Master of Valve Repair with Edwards Lifesciences, having received honoraria as a speaker, moderator, surgeon during live-surgery, Consulting and Development Agreement for Minimally Invasive Cardiac Surgery Techniques and devices. He has also received honoraria for teaching, education and the development of products with with Edwards Lifesciences. HV is an Inventor with royalty agreements: for the Contour Tricuspid Annuloplasty-Ring (Medtronic, Inc.). He is a consulting with USB Medical regarding the development of HV-Left Atrial Retractor, for which he is also an Inventor with royalty agreements. He is a consultant with Valtech for the development of mitral repair and replacement devices: cardinal and cardioband, as well as for the development of percutaneous tricuspid device. He is a stock owner and founder of 4-tech with Valtech.

Ganesh Manoharan

INTERVIEW

Options for transcatheter aortic valve implantation: comparing self-expanding with balloon- expandable valves The advent of transcatheter aortic valve implantation (TAVI) has offered clinicians the option of managing patients with severe symptomatic aortic stenosis, who are at high operative risk, the possibility of replacing the aortic valve without requiring a full open-heart surgery. Two technologies have been developed for the deployment of valves in situ: self-expanding and balloon-expandable valves. We spoke to Dr Ganesh Manoharan, Consultant Cardiologist at the Royal Victoria Hospital, Belfast, about these two types of devices to find out more.

Can you give us an overview of the differences between self-expanding and balloon-expandable valves? Dr Ganesh Manoharan (GM): At present, there is only one commercially available balloon-expandable valve available, the latest iteration of which is the Edwards Sapien® 3 device (Edwards Lifesciences Corp., California, USA). In general, this technology involves a valve crimped or mounted on a balloon and, upon inflation of the balloon, the valve expands and assumes the position in the shape of a valve.

With the self-expanding version of valves, different technologies are available commercially but they generally comprise of a nitinol self-expanding frame supporting either a bovine- or a porcine-based pericardial valve. However, amongst the self-expanding valves, there is still a differentiator: the Medtronic CoreValve® (Medtronic, Inc., Minneapolis, USA) series is the only one that is supra-annular in function; all the other self-expanding valves are annular in function. The supra-annular valve position has important haemodynamic advantages.

The balloon-expandable technology, due to design characteristics, allows the clinician only one attempt at deploying the valve. You do not have the ability to reposition after valve deployment. You can reposition the valve prior to deployment to achieve optimal positioning, but once the balloon is expanded and valve deployment is complete, it is impossible to reposition, but

hopefully, it is in a good position. Rapid ventricular pacing and significant drop in blood pressure is also required during valve deployment. Furthermore, once the valve and balloon exits the delivery sheath, the device cannot be retrieved again from the patient, so the clinicians are committed to deploying the valve.

The key advantage of self-expanding technology is the potential to either fully reposition or at least retrieve and, in the case of a recapturable system, resheath the valve up through about 90% of full release. This means that while the valve is still attached to the delivery system, the clinician can recapture and reposition it if they do not like where it is and, if they don’t like the way it behaves, it can be safely removed from the patient. You can always argue, of course, that if you are careful and safe you don’t need to retrieve the valve, but we work in an environment in which we are dealing with high-risk patients with challenging anatomies, and with multiple operative skills – having even one chance of being able to fully retrieve a device is a chance that adds to the overall safety profile and the benefit of the device, and ultimately for the patient. There is also no need for rapid ventricular pacing during deployment, thus reducing the risk of haemodynamic compromise.

How do you choose which valve to use in specific patients? GM: At the moment we have both technologies on our shelf in our department. We use both


frequently enough to have gained the expertise in using both technologies safely.

While in a majority of patients you probably can use both technologies reasonably safely, there are factors that might lead to choosing one device over the other. For example, if a patient has very severe calcification of the annulus or the outflow tract, then our preference has been to use the self-expanding technology, mainly to avert a potential complication, which could occur with balloon-expandable technology: annular rupture or dissection of the annulus. During expansion, the balloon-expandable valve needs to over-expand to create a seal with the anatomy and overcome any potential recoil. In a calcified anatomy this can cause rupture or dissection, which is catastrophic for any patient, never mind high-risk, elderly patients. These complications have been reported, although fortunately not frequently, enough times for us to be concerned about using balloon-expandable valves in these types of patients.

A potential benefit of the balloon-expandable valve is that the requirement for contrast during the procedure generally has been lower compared with the self-expanding valves. This favours somebody who has really severe renal dysfunction where there is a risk of worsening renal failure due to contrast-induced nephropathy. However, patients with chronic renal dysfunction often tend to have quite calcified anatomy as well, so then you may have to switch back to the self-expanding where the risk of rupture is lower; we have to always balance the risk versus benefit.

At the annular level again, with the balloon-expanding technology, you have only one attempt at positioning the valve and, occasionally, there are patients who have borderline coronary ostia height with a real risk of coronary occlusion. In these high-risk patients, having a technology where you can position, have a look and retrieve again instantly if necessary increases the safety profile of the technology. Self-expanding, recapturable devices, such as Evolut R™ (Medtronic, Inc.), Portico (St. Jude Medical, Inc., USA) and the Lotus® valve (Boston Scientific, Massachusetts, USA), allow us to safely position the valve, check to see if the coronary ostia are perfusing and if they are, release the valve – if not, you can safely retrieve the device and look at another strategy. This cannot happen with the

balloon-expandable valve: you have to release the valve and hope for the best. Clinicians have tried various other techniques, such as protecting the coronary ostia with wires, but every time you put a catheter into a patient unnecessarily or for whatever reason, it always increases the potential for risk. Self-expanding recapturable technology has been a game-changer in terms of how we do TAVI, certainly locally but also globally.

Access is another big challenge for elderly patients with calcification. It is generally accepted the transfemoral approach provides better outcomes compared with the transapical access, although the patient risks are different. The self-expanding valves have the advantage that they have a much lower diameter than balloon-expandable valves after loading onto the delivery system. This really is a very important clinical feature that sometimes the companies have been a little shy in explaining to clinicians. You have heard of various terminologies – there are expandable sheaths or eSheath® (Edwards Lifesciences, Corp.), and these are, in general, sheaths that are able to expand once they have been inserted. This is profiled as a 14F (inside diameter [ID])/18F (outside diameter [OD]) or 16F (ID)/20F (OD), however, the eSheath expands to accommodate the valve and becomes 22.8F (OD) for the 23 mm, 24F (OD) for the 26 mm and >24F (OD) for the 29 mm Sapien 3 valves. For example, a 5.5 mm artery might need to be stretched up to 8.5 mm, which has the potential to increase the risk of vascular complications. That is something that is not always clearly understood when data have been presented. The Edwards valve is a balloon-expandable valve, and although a lot of work has been done in trying to reduce the sheath size and therefore protect the impact on vascular complications, the valve itself in its crimped form is about 19F to about 22–24F, so the body has to accommodate this valve once it has been inserted.

The first-generation Medtronic CoreValve device was always 18F compatible. However, the new generation of CoreValve Evolut R™ has an integrated ‘InLine’ sheath and, thus, does not require a separate sheath, which reduces the delivery profile by about 4F. This means it is now truly comparable to advancing a 14F device into the patient’s vessel. This is a significant change in terms of device profile. To date, we have only used Evolut R in a clinical trial platform but we have not encountered any difficulties using the Evolut R and advancing


the valve with the InLine sheath. However, as with any new technology, we will need to see how it transfers to a clinical environment, as more patients are treated with the device.

Do smaller devices provide clinical benefits as well? GM: This is an important point. The eSheath does allow you to advance the sheath via the femoral artery reasonably easily, but the eSheath and the artery will then need to expand to accommodate the larger valve and balloon. This forced expansion (going from 5.5 mm to 7.7 mm) has the potential to increase the risk of vascular complications.

Sometimes it is quite difficult to compare and contrast trial data using older-generation devices to current generation devices, because our techniques for patient selection have significantly changed and our understanding of what outcomes you will encounter by pushing hard with an oversized device have also changed. Historical studies use angiography to assess vascular size and all recent trials have used computed tomography (CT) to assess vascular size and access. While the overall rate of vascular complications is decreasing, regardless of the technology used, access will continue to be a very important feature that clinicians will use to decide which valve and implantation technique should be used. Ultimately, however, we all want a true lower-profile device, and an advanced sheathless platform, such as the Evolut R, will have the lowest-profile device to date in the market.

To this end, I do think the device companies should standardize the method in which valve profiles are labelled. It is my view that the all valves should be labelled by the outer diameter of its loaded or crimped form – this is the real diameter that the femoral artery and the patient will feel.

How do self-expanding and balloon-expandable valves perform in terms of clinical outcomes? GM: It is difficult to compare the two technologies as there is only one balloon-expanding device and probably seven or eight self-expanding devices. However, one thing is true for both types of devices: comparing the data with the new generation of both self-expanding and balloon-expandable technologies, the results are better than the historical results that we have seen.

One key difference, however, is the need for post TAVI pacemaker rate, which has been seen to be lower with the balloon-expandable device when compared with the self-expanding ones. Nevertheless, the pacemaker rate overall for the self-expanding is decreasing, as seen in several trials (Portico: 10.8%;1 CoreValve US IDE high risk study: 19.8%2), predominantly driven by change in technique and more appropriate sizing using CT. We are now seeing pacemaker rates reduce down to the teens. It is likely that the Evolut R device, with repositionability, will enable better final valve positioning, potentially resulting in further reductions in pacing rates. The results of the Evolut R CE mark study has been submitted for publication - you will have to wait to read the results!

Have there been any head-to-head studies that have compared the two types of device? GM: There has been one head-to-head trial, the CHOICE study, which randomized Edwards XT against Medtronic CoreValve; however, this was a small study, without independent adjudication or corelab analysis, with a composite primary end-point.3 A high paravalvular leak drove the endpoint but this degree of leak was not observed in the large, CoreValve US IDE study, the first study to require use of CT sizing, which is not standard of care. More importantly, in the end, in CHOICE CoreValve showed trends toward better outcomes in stroke rate and similar mortality rates, which are accepted endpoints that matter most to physicians and their patients.

Bottom line, in terms of one type of valve against the other, all technologies appear to improve clinical outcome, partly due to improvements in techniques, partly due to improvement in patient selection. If you look at the overall EuroSCORE of the more recent trials compared with the first, early trials, the EuroSCORE has dropped by at least 3–5 points. These are still high-risk patients, but we are now getting better at identifying appropriate patients who will truly benefit from TAVI. Indeed, we have come to learn that there is a group of patients known as ‘cohort C’, where TAVI may not change the final outcome. With us moving away from these kind of patients, the 30-day mortality from all the recent, new-generation devices has been under 5%; some of them are even 2–3%,1, 4, 5


which is excellent when you consider that these are very high-risk patients. However, even established devices such as CoreValve have shown similarly low mortality rates (1.8% in ADVANCE II) in current practice.6 That is a significant change in terms of important outcomes.

We all accept that the ‘hard’ outcomes such as mortality, although important, are at levels that would be deemed acceptable for the cohort of patients being treated. The things that I think we will paying more attention to over the next few years are other markers of outcome, such as stroke, vascular complications, pacemaker implantation and, more importantly, paravalvular leakage (PVL). Certainly the US trials have suggested that the use of self-expanding valves has an immediate and, more importantly a progressive, long-term benefit in reducing PVL. The investigators found at 30 days the PVL rate was acceptable, and over 1 year that rate reduced further to levels that are consistent with next-generation valves on the market today.

Are there any differences when you are carrying out the procedure in terms of ease of use, imaging or valve preparation? GM: We do the procedure under local anaesthesia in over 90% of cases. We use general anaesthesia when patients require a surgical access. When we use local anaesthesia, we tend not to use echocardiography for deployment, but predominantly depend on fluoroscopy. The use of local anaesthesia, as long as it can be done safely and with a similar outcomes, has the enormous benefit of reducing the cost and complexity of the procedure.

In terms of ease of use, both technologies are similar in terms of preparation, loading and delivering. The manufacturers have worked very hard to make it easier to load and prepare the valves on site. Our nurses have been trained to prepare and load any of the technology we will be using.

With regards to TAVI devices, what will influence clinical decision making in the future? GM: It will depend on probably a few factors: one would be the safety data, as cardiologists are very data-driven, so the data have to be favourable. The second factor will be ease of use, in that the device could be used via multiple access routes, delivered using the same technique and simple preparation methods – these will make a difference.

Repositionability will make a difference – a chance to redo the deployment will be beneficial and safer for the patient. The final factor is the cost. If you have two devices side-by-side and they both show somewhat similar pros and cons, then, cost will play a major role; none of us can avoid the significant funding issue with regards to TAVI.

Are there studies ongoing that are going to provide helpful data that are going to influence clinicians’ decisions or are further trials required? GM: There are studies ongoing at present to assess the safety of TAVI in moderate-risk patients, as compared to surgery. The results of these studies have the potential to change how we treat moderate-risk patients with aortic stenosis. Another type of study that may be helpful is a device-versus-device study; however, one of the challenges of running a randomized trial today is that I think there are very few centres that are confident in using both technologies safely; thus the final outcome could be operator- and technique-related. In time, when more centres adopt another device and become competent, we should then be in a position to conduct a valid randomized valve-versus-valve study.

What contribution has the education of physicians made to clinical practice? GM: The TAVI manufacturers should be congratulated for this. They have taken a lead and have invested a lot of time and money in educating clinicians and their local representatives into imparting knowledge and advice in order to get good results. TAVI is one of the first devices where a great deal of investment has gone into the education of clinicians, users and ancillary staff, resulting in improved outcomes.

When we see ever-improving results with devices, a lot of it is, I believe, due to clinicians who are better at giving the right type of device to the right patients and who also have a better understanding of potential complications and solutions. I think, that has been more of an influence on outcome than the actual device type.

We, as clinicians, should do more to ensure that avoidable complications do not occur. Better patient assessments and case planning, using multiple access approaches, adherence to best practice and further innovations in technology


should ensure better outcomes. We should be able to get these very high-risk patients to come out of the procedure in a safer manner, and we certainly need to improve on outcomes if the intention is to treat lower-risk patients with TAVI.


1. Manoharan G. 2013. Presentation at TCT 2013.2. Adams DH, et al. NEJM 2014;370(19):1790-8.3. Abdel-Wahab M, et al. Jama 2014;311(15):1503-14.

4. Meredith Am IT, et al. J Am Coll Cardiol 2014;64(13):1339-48.5. Webb J, et al. J Am Coll Cardiol 2014;64(21):2235-43.6. Petronio AS et al. Presentation at EuroPCR, 2014; Paris, France.

REFERENCES:

Address for correspondence Ganesh Manoharan

Royal Victoria Hospital Belfast

Hon Senior Lecturer Queens University

Belfast

[email protected]

DISCLOSURES: Consultant/Proctor for Medtronic, Inc., UK, Boston Scientific and St. Jude Medical.

CASE STUDY

CoreValve® Evolut™ R 23 for the treatment of severe regurgitation in a Mitroflow® 21 prosthesis Raquel del Valle

Case presentation An 81-year-old man was admitted to our institution with symptoms and signs consistent with acute lung oedema. He had a history of hypertension and hypercholesterolaemia and had undergone cardiac surgery in July 2005 due to severe aortic stenosis and three vessels disease. Coronary artery bypass grafting (CABG) with a saphenous vein graft (SVG) to left anterior descending (LAD) and a sequential SVG to first and second obtuse marginal branches (OM) were performed. Distal right coronary artery (RCA) was diffusely diseased and non-grafted. A Mitroflow® 21 (Sorin S.p.A, Milan, Italy) was implanted in aortic position. In August 2005 he had a permanent dual-chamber, rate-modulated pacing (DDDR) pacemaker implanted due to bradycardia–tachycardia syndrome, and in September 2005 he underwent percutaneous coronary intervention (PCI) and stenting of the proximal SVG–OM anastomosis.

He had been well until 3 weeks prior to the current presentation, when progressive effort dyspnoea developed following an upper respiratory tract infection.

Discussion The differential diagnosis of the aetiology of heart failure (HF) in a patient with known heart disease is mainly based on the detection of new or worsening cardiac anomalies, as well as investigation of precipitating factors, such as infections and anaemia. Therefore, clinical diagnosis at admission was decompensated HF precipitated by an upper respiratory tract infection.

In this patient with a prosthetic heart valve and prior CABG, prosthesis dysfunction, development of new mitral disease or left ventricular dysfunction, atrial fibrillation/arrhythmias, as well as myocardial ischaemia should be investigated.

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Investigations performed Laboratory tests (including troponin) were within normal ranges except for haemoglobin (11.2 g/dl) and NTproBNP (4.100 pg/ml), supporting the clinical diagnosis of decompensated HF.

ECG showed atrial-paced rhythm at 60 bpm and left bundle branch block (LBBB).

Urgent transthoracic echocardiography (TTE) suggested significant prosthesis dysfunction. Aortic gradients were 70 mmHg (maximal) and 36 mmHg (mean) and a poorly visualized, eccentric aortic regurgitant jet was reported. There was moderate mitral regurgitation and a mean mitral gradient of 2.7 mmHg. Ejection fraction was 50%.

Transoesophageal echocardiography (TEE) confirmed severe aortic prosthesis dysfunction mainly due to severe regurgitation that was intraprosthesis, with a very eccentric jet and holodiastolic flow reversal in the descending aorta (figure 1). Velocity-time integral ratio (ITV1/ITV2) was 0.29 and aortic valve area 1.1 cm2. Mitral regurgitation grade was 2/4.

On coronary angiography, LAD was occluded at the ostium and received a patent SVG. There was diffuse left circumflex artery (LCX) disease with severe ostial and mid-stenosis, and the sequential SVG was occluded at the proximal anastomosis. RCA was severely and diffusely diseased.

fig. 1

Severe aortic prosthesis dysfunction

was confirmed by transoesophageal echocardiography

César Morís de la Tassa


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Computed tomography angiography (CTA) of abdominal aorta reported diffuse disease and calcification of right and left ileo-femoral systems, with minimal lumen area smaller than 6 mm in the right common femoral and iliac arteries. Minimal lumen area was less than 6 mm just above the left femoral bifurcation, 6 mm in the common left femoral artery and progressively increased along the rest of the left system.

ECG-gated CTA of the thoracic aorta reported an internal annulus diameter of 17 x 18 mm and a distance from the prosthesis annulus to the left main ostium of 8 mm and 10 mm to RCA ostium.

Management The final diagnosis was decompensated HF due to severe aortic prosthesis dysfunction with severe intraprosthesis regurgitation.

The Heart Team considered the patient at high surgical risk (log EuroSCORE 19.37%). As regurgitation was intraprosthesis, CoreValve® (Medtronic Inc., Minneapolis, USA) was proposed. While the Mitroflow 21 does not meet Medtronic criteria for CoreValve implantation due to its inner size of 17.3 mm, there is growing experience showing good procedural outcomes in patients with 19 and 21 mm prosthesis undergoing transcatheter aortic valve implantation (TAVI) with the CoreValve 23. Despite slightly high residual mean gradients, which are often above 20 mmHg, clinical improvement is consistently shown. Furthermore, the 23 mm CoreValve Evolut™ R recapturable prosthesis has recently received CE mark for annulus ranging from 18–20 mm, and it is compatible with a new, 14F delivery system and sheath (EnVeo™; Medtronic, Inc.).

Finally, given that the patient was considered at high risk for surgery and had ileo-femoral disease, TAVI with the Corevalve Evolut R 23 and the EnVeo delivery system was chosen as the best treatment option.

Our protocol evaluation includes CTA of the thoracic and abdominal aorta to find a suitable access for TAVI, as well as a thoracic ECG-gated CTA to evaluate the aortic prosthesis and its relation to adjacent structures, mainly the coronary arteries. A short distance between the annulus and coronary ostia, and the presence of an aortic prosthesis – especially if it is a Mitroflow valve (in which the leaflets are sutured outside the stent) – may increase the risk of coronary occlusion.

Quiz Questions1. What essential information did TEE provide over TTE? TEE demonstrated that dysfunction was mainly due to aortic regurgitation and that this regurgitation was intraprosthesis and not peri-prosthetic, and therefore treatable with TAVI.

2. Might TAVI be an option for this patient even if the inner prosthesis diameter is not within the range that the companies define for available TAVI prosthesis? Although not yet an established indication, there is growing experience showing good procedural results and clinical improvement with TAVI in small degenerated surgical bioprosthesis, and therefore it might be a reasonable option in patients considered at high risk for reoperation.

3. Is there any specific characteristic of the Mitroflow 21 that may pose an additional risk for the TAVI valve-in-valve procedure? Surgical bioprosthesis with the leaflets sutured outside the stent have been related to a higher rate of coronary obstruction.

4. Might a repositionable TAVI valve be preferred in patients with significant prosthetic regurgitation, given the difficulties in prosthesis positioning posed by the absence of severe calcification and the high stroke volume? The ability to deploy and recapture a TAVI valve allows for optimal position of the device presenting an opportunity to deliver optimal outcomes even in patients with challenging complications.

5. What additional advantage may the EnVeo delivery system offer to this patient? Femoral access through a conventional 18F sheath may pose this patient at an additional risk for vascular complications, given the femoral diameters (6 mm or less in the common femoral artery) and grade of calcification. The new EnVeo system is just 14F and therefore may reduce this risk.


fig. 2

Baseline and post-TAVI haemodynamic data

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Nevertheless, in this patient a SVG to LAD was patent, and therefore this myocardial area was not at risk.

Ten days after hospital admission, TAVI was performed under conscious sedation through a left femoral access. A Prostar XL® (Abbott Vascular, Santa Clara, USA) was inserted before the introduction of the 14F EnVeo delivery system sheath. Haemodynamic data are shown in figure 2. Baseline diastolic aortic pressure (dAP) was 40 mmHg and left ventricle end-diastolic pressure (LVEDP) 33 mmHg. Direct implantation of a CoreValve Evolut R 23 was performed, and a 14F Cook sheath (Cook Medical Inc., Bloomington, USA) was inserted following retrieval of the EnVeo delivery system to avoid bleeding through the access site. Balloon post-dilatation with a 20 mm BALT balloon (BALT, Montmorency, France) was performed under fast ventricular pacing, to minimize risk of CoreValve embolization during post-dilatation.

Residual angiographic regurgitation was trivial (figure 3), transvalvular peak-to-peak gradient was 14 mmHg, final dAP 73 mmHg and LVEDP was 27 mmHg (figure 2). Access site haemostasis was achieved with the pre-inserted Prostar XL system. Post-TAVI TTE reported a mean transvalvular gradient of 20.7 mmHg and mild regurgitation (figure 4).

The patient was walking down the corridor 48 hours after TAVI and was discharged on the fifth day post procedure.

fig. 3

Trivial post-TAVI aortic regurgitation

fig. 3

Mild aortic regurgitation

post-TAVI


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Take-home messages 1. TAVI has emerged as an alternative to surgery in aortic bioprosthesis dysfunction either by stenosis or intraprosthesis regurgitation. TEE is essential in the characterization of the origin of the regurgitant jet to check for suitability for TAVI.

2. There is growing experience in the treatment of small failing bioprosthesis with the CoreValve, showing good clinical outcomes despite the moderately elevated residual gradients reported.

3. Repositionable TAVI valves and smaller profile devices, such as the CoreValve Evolut R prosthesis and the EnVeo delivery system, will ease the procedure and widen the range of patients suitable for TAVI.

Address for correspondence Prof. César Morís de la Tassa

Hospital Universitario Central de Asturias

Avda. de Roma s/n Área del Corazón, Planta +1A

30011 Oviedo Principado de Asturias

España

[email protected]


DISCLOSURES: RV has nothing to declare. CM is proctoring for Medtronic and is a member of advisory board also for Medtronic.

HOT TOPIC

The challenge posed by pharmacological non-adherence in hypertension

Luis Ruilope

Cardiovascular disease (CVD) is the primary cause of death worldwide, accounting for approximately 30% of total annual deaths.1 High blood pressure is the most important modifiable risk factor that promotes CVD. Recently published guidelines of the European Society of Hypertension and European Society of Cardiology2 recognize that both day-to-day and long-term adherence to anti-hypertensive medication are the most important factors in obtaining adequate control of blood pressure. Indeed, the only patients who report a significant reduction of acute CV events are those with excellent adherence from the initiation of pharmacological treatment.3 However, in reality, the majority of patients with hypertension and/or hyperlipidaemia tend to take less than half of their prescribed medications.4 Infact, a 2013 publication that measured adherence repeatedly over a long period of time demonstrated the need to maintain long-term adherence in order to avoid the development of stroke.5 Moreover, poor adherence is accompanied by maintained elevated blood pressure; this promotes the enhancement of atherosclerosis, arterial stiffness and, often, the development of kidney disease. Such complications subsequently lead to an increased CV risk, which can result in the development of CV events or death.

Patients with low adherence tend to be older and less well educated, with a lower household income, which can affect the patient’s ability to afford therapy. These circumstances tend to complicate the relationship between the doctor

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Adherence Used interchangeably with compliance. The extent to which patients follow their antihypertensive medication schedules as prescribed by their primary care physicians.3 Calculated by the days covered by available prescriptions.5

Persistence The overall duration of drug therapy.9

and patient.6 Interestingly, a recent study has investigated the absence of adequate long-term adherence in resistant arterial hypertension: the most dangerous form of arterial hypertension with exception to malignant hypertension.7 High rates of non-adherence to antihypertensive treatment have been demonstrated in these patients through assays that show the absence of drug metabolites in urine. Adherence was particularly poor for patients with suboptimal blood pressure control and those who had been referred for renal denervation.7 This is a relevant finding as these patients have the highest risk of suffering the consequences of arterial hypertension.

Widespread difficulty with adherence to strict pharmacological regimens creates an unmet need for novel, safe and effective hypertensive therapies that do not require daily adherence in order to be effective. Device therapies, including renal denervation therapy and baroreceptor activation therapy may offer an alternative or adjuvant to daily pill taking. However, the ability of these new device therapies to decrease or eliminate the need for adherent therapy needs to be elucidated further in carefully planned clinical trials. Therefore, it is also necessary to ensure adequate adherence in patients in whom interventional techniques can be used to lower blood pressure as, to date, the use of interventional techniques does not yet replace the need for antihypertensive drugs.8

So we must ask the question: can long-term adherence be improved in poorly adherent patients? Whilst the answer to this question is positive when interventions such as blister packaging, case management, or education with behavioural support are undertaken,4 it will require an improvement in doctor and patient relations with the participation of other caregivers such as nurses, pharmacists and also family members.6 As patients increasingly access information about their condition via modern technologies, we must ensure that this material is of good quality and that caregivers and healthcare professionals engage with patients to help them best use this information.6


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1. The GBDS consortium. Lancet 2012;380:2095-128.2. Mancia G, et al. Eur Heart J 2013;34:2159-219.3. Mazzaglia G, et al. Circulation 2009;120:1598-605.4. Viswanathan M, et al. Ann Intern Med 2012;157:785-95.5. Herttua K, et al. Eur Heart J 2013;34:2933-9.

6. Ruilope LM. Eur Heart J 2013;34:2931-2.7. Tomaszewski M, et al. Heart 2014;100:855-61.8. Mahfoud F and Lüscher TF. Eur Heart J 2014:doi:10.1093/eurheart/ehu450.9. Ho PM, et al. Circulation 2009;119:3028-35.

REFERENCES:

DISCLOSURES: LR has served as speaker/advisor for Astra-Zeneca, Bayer, Daiichi-Sankyo, Medtronic, Inc., Novartis, Relypsa, Saint-Jude, Sanofi.

Address for correspondence Luis M Ruilope

Institute of Research Hospital 12 de Octubre

& Department of Public Health & Preventive Medicine University Autónoma

Madrid Spain

[email protected]


Justin Davies

INTERVIEW

Lessons learned from HTN -3: pharmacological non-adherence in hypertension and the potential of SpyralTM Renal denervation has recently been in the spotlight following the failure of the HTN-3 trial to meet its primary endpoint. Confluence spoke to Dr Justin Davies, Senior Research Fellow and Consultant Cardiologist, Imperial College London, to discuss some of the lessons learned from HTN- 3, including the role of pharmacological non- adherence in hypertension. We also spoke about how future trials may be conducted and the potential of the new Spyral™ catheter.

How do we define non-adherence? Dr Justin Davies (JD): I suppose that the clearest definition of non-adherence is patients being prescribed tablets or drugs, which they do not take for one reason or another. All of us are culpable of this and, for most of us, it is probably in the form of antibiotics. To take some drugs just for a few days is obviously quite an easy thing to do, yet we still struggle. So when you are asking patients to take multiple antihypertensive drugs for 20 or 30 years, it is very easy to see and understand if they become less adherent than would be desirable.

What factors can impact adherence? JD: Larger numbers of drugs or increasing frequency of administration are two key factors. Furthermore, if people have significant comorbidity and other conditions that exist simultaneously, then they may often have side effects from those conditions, which they may put down to their drugs, and which, in turn, can often diminish the likelihood that they will continue to take their medication.

Side effects are also a problem. Ultimately no one likes taking drugs – especially if patients consider that they make them feel worse. With regard to antihypertensives, two of the main classes of drugs are beta-blockers and diuretics. People actually avoid taking diuretics before going out, to avoid unexpectedly needing the bathroom, whereas beta-blockers often make them feel lethargic and slow, and can also negatively affect libido.

Do you think that patients find it hard to see direct benefits from their treatment? Do you think that they feel they are taking the tablets for no good reason? JD: This is entirely correct. One of the clearest illustrations you can see is in people with heart failure, who are prescribed and take many of the same tablets. However, in heart failure, if you stop taking the tablets, you become very breathless and very sick. Therefore the likelihood of patients taking medication with heart failure is much higher. I stress these are many of the same drugs that would be prescribed in hypertension, albeit at different doses. However, due to symptomatic improvement, the heart failure patients are much ‘keener’ to adhere to therapy.

Angina is another case, again managed with many of the same drugs. If people have definite chest-pain symptoms and breathlessness, they will have a higher likelihood of taking the drugs. As you say correctly, in both of these scenarios one of the main reasons for increased compliance is that patients feel the benefit from the drugs whereas they cannot see an immediate advantage in blood pressure reduction. It really takes quite an in-depth analysis to understand the long-term risks and potential benefits in cardio- and neurovascular adverse events that a fall in blood pressure has. These may only affect you in 10 or 15 years’ time, reducing the chance of a stroke, but actually taking that on board when you are younger is often quite difficult.


What impact does non-adherence have? For example, is it more impactful in patients with already high blood pressure; are patients with low blood pressure less at risk of suffering ill effects from non-adherence? JD: The higher the blood pressure, the worse the impact of non-adherence, as higher blood pressures are associated with a marked risk of stroke, cardiovascular disease, coronary disease, renal disease and eye disease. Moreover, the longer you leave patient with high blood pressure, the worse these complications can be. For instance, consider a patient who is early-middle-aged and has moderate hypertension, even though their blood pressure may not be as bad as that of somebody who is 70 or 80 with higher blood pressure. If you leave those levels of more moderate hypertension for many years then potentially that patient may actually do worse in the long run. We know that untreated hypertension is a very bad thing to have with regard to multiple systems being affected. Of course, we also know the advantageous effect of treating blood pressure well. You can see, in blood pressure trials, that if you can effectively manage blood pressure, it is possible to markedly reduce the chances of stroke and cardiovascular disease.

What is the estimated prevalence of non-adherence? JD: It is very common. To date, most studies that have looked at those people who are said to be truly resistant hypertensive patients for whom the drugs do not work. However, when you actually give them the tablets and you observe the blood pressure, it actually turns out that only about 15% of the people are truly drug-resistant, while many others are resistant to taking their medication more than anything else! While you can certainly sympathize, this is certainly a major problem that is being increasingly recognized. Essentially, we leave a portion of our population with less adequately well-controlled blood pressure than is desirable.

Does that link in to your 2-year patient blood pressure diary (recently presented at TCT, 2014)? What do those results demonstrate for us? JD: Blood pressure diaries are important because, frequently, patients are managed by their primary care physicians or a specialist in the clinic in hospital and subsequently have a period of time when their blood pressure is well-controlled. However, with the pressures of the modern healthcare system, we know that often these patients are discharged back into the community, where often their blood pressure relapses. Diaries provide a longer-term snapshot of pressures at home. This provides a really good idea of what the patient’s blood pressure is doing over a prolonged period of time.

Often when you see longer-term trends of blood pressure elevation over many years with troughs where patients seek additional medical care, where perhaps they are referred to specialist clinics. However, over time, as they are outside of routine healthcare review, their blood pressure slowly starts to rise and goes back to the baseline value of where it was before.

Constant reinforcement is therefore needed for patients to get them to take their medication. I can sympathize with them, because taking four or five pills a day for the rest of your life – however much of an advantage it may or may not have for you with regard to your cardiovascular risk in 15 or 20 years’ time – it is still a big commitment to ask of anyone. You can understand why patients find it is easy to slip out of the habit of taking their medication.

How can we use such long-term data in clinical practice to help patients to understand the benefits of taking their medicine? JD: Education plays a crucial part in encouraging patients to take their medications, training patients in terms of particular thresholds to look at regarding their blood pressure. However, a more dynamic and interactive process with primary care physicians, to try to gain better blood pressure control, is also essential. Healthcare professionals


are reliant on the willingness of patient to engage in their own healthcare. However, often, due to work and social commitments, it can be very difficult.

If we were to use the same policy [of inadequate control] with immunization, I am sure that infectious disease would be rife around the world. This is because if you rely on people to self-administer, even though they know these diseases are potentially extremely dangerous, they just don’t do it. That is why drugs such as vaccines are so highly effective, because essentially they go into the system and then you forget about them and your body takes care of the rest: essentially, after you have been successfully vaccinated as a child the effects are still working throughout the course of your life.

Renal denervation has the potential to offer a long-term solution to hypertension. While earlier trials appeared to show good efficacy, the recent results from the HTN-3 study were not as strong as expected. Do you think non-adherence had an impact on the results of HTN-3? JD: We know that the basic science suggests that renal denervation works. However, designing a study is very complex and HTN-3 has exposed huge layers of complexity in study design. For example, factors such as drug adherence or changes to blood pressure following during the course of the study can make a huge difference to the overall results. Moreover, you have psychosocial factors coming into play in terms of whether patients are receiving medication for the first time, or have been on long-term medication. Many of these disparities have been overcome in big blockbuster drug trials by having tens of thousands of patients in each arm, which irons out such irregularities and powers for an increased variability. However, carrying out that kind of study in a device-based therapy is very challenging, because you cannot physically enrol that many patients due to excessive costs and time.

What HTN-3 has done is to make us realise that we need to step back and see what is working and what is not. We need to try to address the problems that can be addressed – whether they are technical, or population based, or patient adherence, or whether it is other drugs patients

have been on. It has drawn a line in the sand, and we need to look very carefully before moving on to the next step in terms of designing a study that is likely to show the efficacy, which has been demonstrated in the animal models.

Do you think that ambulatory blood pressure monitoring might have had an impact on adherence and possibly accounted for some of the differences in results between HTN-2 and HTN-3? How do you think we can overcome adherence issues in future renal denervation trial? JD: The big difference in those studies is really one of study design. HTN-3 was performed with much more rigour and we should certainly give Medtronic a great deal of credit for the design. The big difference, of course, is the fact that there was a sham control arm and that, more than anything else, was the big differentiator here. Some subsequent studies have shown a more obvious reduction in blood pressure. However, this is due, in part, to some of the factors we have discussed earlier with regard to psychosocial factors and pharmacological adherence, and other factors such as an increasing understanding of the technology and better delivery of the technology.

We have done the first part of a pilot study (the follow-up will take place very soon), which uses a unique model to overcome confounding adherence data. By having a fellow administering the drugs to the patients over 2 days and then making measurements, it is possible to standardize the effects of drug therapy. This means it is possible to assess a better reflection of the effects of renal denervation. An alternative would be stop all the medication, attain stable baseline, perform denervation, and then repeat the baseline measurements after a follow-up period, with all patients off medication.

Under both of these conditions, therefore, both before and after denervation, again with and without the sham arm here, we would have controlled conditions – either with drug, or without drug. This means that the variability of compliance amongst these patients would be removed from these studies as a potential confounder. Essentially, this would mean that the study could then be powered better with a smaller number of patients.


The anatomies of patients has recently been highlighted as playing an important role in the efficacy of renal denervation. What data are there out there? JD: Again, there is a great deal of very exciting animal data which has come out in the last 6 to 9 months. There was a study presented by Bob Melder from Medtronic at TCT 2014. This used a denervation applied more liberally in both distal branches and the main branch, in both kidneys. This was done using a next -generation multi -array, SpyralTM (Medtronic, Inc., Minnesota, USA) electro-catheter, which has four electrodes and a far shorter denervation time than the original Flex catheter.

The Spyral device is essentially it is a pre-shaped catheter, delivered over a guidewire. When you pull the wire back, the catheter takes on the shape of a corkscrew. The corkscrew expands out to take the shape of the vessel and the electrode makes contact with the vessel wall. It is simple to use: there is a simple graphic user-interface, which shows you the contact between the electrode and the vessel wall, and it enables each of the electrodes to work independently from one another at each of the individual sites.

One of the advantages that this kind of technology gives, is the ability to deliver a great deal of therapy very rapidly. This may be increasingly important if it is possible to demonstrate benefits from distal denervation of branches and the distal main trunk. The calibre of the device is small and it is not bulky, so it can easily fit into these branches and it can be used essentially to go ahead and do the job.

The potential advantage of denervation in more distal renal arteries has been highlighted in recent human cadaver studies. These show that the nerves move more distally along the vessel toward the kidneys, they move closer to the wall. Therefore, the amount of energy needed, and the distance to the nerve is less, and so although the number of nerves is roughly the same (perhaps slightly less distally than proximally), this means that the probability of you breaking this nerve junction is higher.

If you combine such distal denervation with an increased frequency of ablation points, you increase the probability that you will disrupt nerve traffic. The animal data are pretty convincing in that they show that you have a much more reproducible ablation in all of the animals if you denervate distally with a high number of denervations.

To some extent, we can see similar data from the HTN-3 study, but we must caution against this small non pre-specified subanalysis. Here, there was a trend towards having a bigger reduction in blood pressure, when more denervation ablations were performed, and also in patients who had more of the quadrants targeted. This was a secondary subanalysis, for which the study was underpowered, and these data should be treated as a hypothesis-generating exercise. I am encouraged by the animal data which could be used to plan for another study. However, it is too early to make any clear conclusions from the HTN-3 findings with regard to these findings.

Are there any negative or adverse events associated with going to the more distal branches of the kidney? JD: Not that we have seen. We have done more distal ablations in a series of patients, which, we plan to present next year. To date we have had no acute or early problems at all. Clearly, as with using a guidewire in any vessel – whether it is the heart or the kidney – you need to be respectful of the guidewire position at all times, and ensure that denervation is being performed in vessels with an appropriate diameter. If you follow these rules, and you work respectfully with the kidney anatomy then, to date, the procedure should be very safe to perform.

Looking to future studies, could you give us an overview of what you see as being critical factors that will play a vital role in ensuring that the next trials are as fair and well-balanced as possible? JD: There are three things:

Firstly, we absolutely need to have the blinded sham control arm. Everyone agrees on that and I suspect it would be a requirement of the FDA.

Secondly, we need to control for drug therapies as effectively as possible. This could be done by


stopping all drugs for a period of time before and after measurements, both before and after denervation. An alternative would be giving directly observed tablets therapy before and after measurements.

Thirdly, it is important to increase the likelihood of gaining the biggest fall in blood pressure but also, most importantly, achieving the smallest variability between patients and reducing the standard deviation. We hope that this new denervation strategy – distal branch denervation and main trunk denervation, bilaterally using a multi-array catheter, such as the SpyralTM catheter – will help us to achieve that.

How much more evidence do you think is required for physicians to be confident in using renal denervation to manage their patients effectively? JD: There is no doubt about it: the HTN-3 study has shaken the whole field. People who have done a great deal of animal work know that this technique works, and there are many people who have used it widely around the world, who feel that the technique works in their hands. It will take at least one, well-constructed and large successful clinical trial with a sham control arm to empower physicians to want to start using the technique again. If this can be done, then the technique will take off and will fly. Such data can explain the underlying problems in HTN-3 and how they have been resolved. That then opens the door to the next chapter, with the more widespread adoption of denervation.

28

1. Adams DH, et al. N Engl J Med 2014;370(19):1790-8.2. Genereux P, et al. J Am Coll Cardiol 2012;60(12):1043-52.3. Lefèvre T, et al. Eur Heart J 2011;32(2):148-57.4. Smith CR, et al. N Engl J Med 2011;364(23):2187-98.

5. Kodali SK, et al. N Engl J Med 2012;366(18):1686-95.6. Adams D. 2014. Presentation from American College of Cardiology Scientific Sessions.7. Mack MJ, et al. JAMA 2013;310(19):2069-77.

REFERENCES:

DISCLOSURES: JD is a Consultant and has received research grant funding from Medtronic, Inc.

Address for correspondence Dr Justin Davies

Imperial College London International Centre for

Circulatory Health National Heart and Lung Institute

59-61 North Wharf Road London W2 1LA

UK

[email protected]


Massimo Lemma

INTERVIEW

On-Off 1-year results Patients undergoing coronary artery bypass grafting who are at high risk of complications have traditionally been managed with cardiopulmonary bypass. However, in recent years there has been a growing number of centres carrying out coronary artery bypass grafting without the use of ‘the pump’. Confluence spoke to Dr Massimo Lemma, Cardiovascular Surgeon at Luigi Sacco University General Hospital to discuss the benefits and challenges associated with off-pump surgery.

How are patients requiring coronary artery bypass grafting (CABG) currently treated with regards to the use cardiopulmonary bypass, the so-called ‘on-pump’ or ‘off-pump’ techniques? Dr Massimo Lemma (ML): The vast majority of patients are scheduled for CABG using cardiopulmonary bypass (‘on-pump’ surgery). Off-pump surgery (without the use of cardiopulmonary bypass) was a new procedure introduced at the beginning of the 1990s. There was a great enthusiasm at the time because, from a theoretical point of view, this technique is definitely safer in the sense that actually you can avoid the complications of a coronary artery bypass. You can also keep the heart beating so you do not have any ischaemic periods during the operation on the left ventricle.

The problem is that this technique is much more technically demanding, so currently in Europe, no more than 25–30% of all CABGs are performed off-pump. Overall, there are a few centres with enthusiastic surgeons who perform roughly 95% of their procedures off-pump, however, the rest of the centres perform few off-pump operations, primarily in patients at high risk (high risk in the sense that besides the coronary artery disease, they have many pathologies that can increase the perioperative risk of the patient). This can be problematic in that they are going to treat the patient at high risk with a procedure they consider much more technically demanding, and with which they are less familiar and less confident.

You mention that off-pump surgery is more technically challenging. Can you describe what is involved? ML: Overall, the most important issue throughout the operation is the technical quality of the anastomosis at the end of the surgery.

Due to the differences with the on-pump technique, one key challenge is that those surgeons who have been trained for on-pump CABG must be re-trained for off-pump surgery because the surgical strategy has to be completely changed. The key point is to learn how to keep the patient haemodynamically stable throughout the operation. This means that the management of the left ventricle must be perfect. When we put a graft on the anterior wall of the left ventricle (for instance, left internal mammary artery to left anterior descending) this is not an issue, because the left ventricle is in its rest position in the pericardium. However, when we address the obtuse marginal branch or the posterior descending coronary artery, we need to change the position of the left ventricle – that is work in what I call the ectopia cordis, a displacement of the left ventricle in which it must be tilted with the apex outside the chest.

In order to keep the patient stable from the haemodynamic point of view, we have to use devices such as the Starfish NS Heart Positioner (figure 1; Medtronic, Inc., Minneapolis, USA) or ACROBAT-i Positioner System (MAQUET Holding B.V. & Co. KG, Rastatt, Germany), which are apical suction devices used in order to maintain the shape of the left ventricle elliptically. In order to rotate the left ventricle and expose the obtuse marginal branch of the posterior descending coronary artery, we put slings below the heart and a stitch at the level of the oblique sinus


of the pericardium. Manipulating these slings allows us to tilt and rotate the left ventricle upwards, but by doing this manipulation, we cause an enlargement of the left ventricle. However, by using the slings below the left ventricle, and using apical suction to pull up the apex of the left ventricle, we can keep it elliptical. Failure to correctly manipulate the heart can lead to acute heart failure.

However, if you are careful in manipulating the heart, you both keep the patient stable from the haemodynamic point of view and do not have to rush during the anastomosis; you do not have to hurry because the heart is beating and the patient is stable.

You recently released 1-year data from a study you conducted, the On-Off study, which assessed on-pump versus off-pump CABG in high-risk patients. Can you give us an overview of the original study? ML: Early studies assessing off-pump CABG did not have favourable results. For example, the ROOBY trial assessed the results of on-pump and off-pump surgery in low-risk patients.1 The results were not that good for off-pump surgery. Surgeons had to have performed >20 off-pump surgeries technique before participating in the study. On average surgeons had performed 120 cases (median, 50).1 However, this represents surgeons without a great deal of experience in off-pump surgery, mainly residents or surgeons who were not devoted to off-pump surgery.

What we have done was to try to change the perspective. We have selected centres with


fig. 1

The Octopus Tissue Stabiliser and Starfish

Heart Positioner (Medtronic, Inc.)

surgeons expert in off-pump surgery, so this trial was expertly staged, and we also decided to treat only high-risk patients.2, 3 We only looked at these patients because, in general, on-pump surgery is associated with an average mortality of approximately 2% depending on the risk of the patient. However, if you want to achieve a statistically significant result versus a procedure with low mortality, you need to enrol in a prospective randomized trial of thousands of patients. Therefore, by selecting only high-risk patients and deciding to use a composite endpoint, we could reduce the number of patients required in order to achieve a powered study.

The composite endpoint was based on operative mortality at 30 days due to a myocardial infarction, the incidence of stroke, the incidence of renal failure, reoperation for bleeding and acute respiratory distress syndrome.2 At 30 days, there was a significant benefit seen in patients treated off-pump compared with those treated on-pump (p=0.0092). The result was vastly in favour of off- pump surgery; the operative mortality was 1.9 for off-pump and 3.4 for on-pump surgery. If you consider that these patients were patients at high risk, with a preoperative EuroSCORE greater or equal to eight, it appears that off-pump surgery can really reduce the incidence of operative mortality and the other complications comprised in the primary endpoint.2

At the 2014 European Association for Cardio-Thoracic Surgery (EACTS) meeting in Milan we presented on the secondary endpoints.3 The secondary endpoints were split into two groups. Firstly, we had acute secondary endpoints at 30 days, which comprised incidence of post-operative atrial fibrillation, the insertion of intra-aortic balloon pump, the length of the ventilation (if the ventilation was longer than 24 hours), the incidence of lung infection and the length of intensive unit stay, and the length of hospital stay. Secondly, we considered secondary endpoints at 1 year: overall mortality, the incidence of major adverse cardiac events (MACE), the incidence of angina and the presence of a positive stress test.3

At 30 days we could not see any significant difference in the incidence of acute secondary endpoints. Regarding the secondary endpoints at 1 year, there was no difference between patients treated on-pump and off-pump in terms of overall

mortality, the incidence of angina or the presence of a positive stress test. However, there was a difference in the incidence of MACE in favour of off-pump surgery (p=0.005). Furthermore, if you split the three MACE that we have considered (cardiac death, myocardial infarction and repeat revascularization), we have seen that cardiac death was significantly lower in off-pump surgery (p=0.0043). At 1 year, three patients died after off-pump surgery while 10 patients died in the on-pump group.3

We have also checked with both a univariate and multivariate analysis in this group of patients, and what we have seen is that if there is an ejection fraction below 50%, off-pump surgery is protective in the sense that this variable is associated with a better survival.

Overall, it appears that off-pump surgery is not only protective in high-risk patients at 30 days, but there is also an extension of this protection to one year in these patients.

Are there any other data that support the use of off-pump in high risk patients? ML: A paper published by John Puskas in The Journal of Thoracic and Cardiovascular Surgery reported a retrospective propensity-matched analysis in which the authors show that high-risk patients definitely benefit from off-pump surgery compared with on-pump surgery (p=0.005).4 They compared the results of their patients on- and off-pump with a predicted risk of mortality based on the STS Risk Score. What they found was that when you have a risk score greater than 5 and you schedule the patient for an off-pump procedure, you see that there is a divergence between the predicted risk of mortality and the observed mortality, in the sense that the observed mortality is lower than the predicted risk of mortality.

Given that the On-Off study was an expertise-based trial, how do you feel these data will translate into everyday clinical practice? ML: To me, generally speaking, the future of cardiac surgery will be towards minimally invasive approaches. We have to reduce the stress of the operation and, in my opinion, the ideal strategy is to avoid using the pump for CABGs and to avoid the need to clamp the ascending aorta. By doing these two things we can really reduce the invasiveness of our procedure. Indeed, we have

operated on many of these patients off-pump through a small incision in the chest without clamping the aorta. This technique is even more technically demanding, but it is the best possible, least invasive surgical procedure for the patients.

I believe that off-pump surgery is the future of myocardial revascularization and, therefore, surgeons should be retrained to carry out off-pump surgery. It is not an issue to train surgeons in centres that are expert in off-pump surgery, since performing this technique is the daily routine in these centres. For example, when new surgeons come and visit us to understand how we manage the patient during an operation, they may have the feeling that the procedure is extremely simple, because for us off-pump surgery is routine. We treat the vast majority, 95.5%, of our patients off-pump. The exception is the patients with an acute coronary syndrome and a low cardiac output. This patient usually is performed on-pump but without clamping the ascending aorta, i.e. we keep the heart beating.

You have outlined the potential benefits of this technique but what are the possible limitations associated with it? ML: The limitation of the technique is that the patient must be stable from a haemodynamic point of view. We see few such patients as the vast majority of them are treated with primary percutaneous coronary intervention (PCI). However, there are a few patients that can’t be treated with a primary PCI and so they are scheduled for an emergency surgery. In these cases, if the patient remains haemodynamically unstable it is definitely better to put the patient on-pump.

Sometimes you can have patients with very diffuse coronary artery disease, so when you have to perform, and this happens very rarely, a complex procedure like an open endarterectomy, it is again better to put the patient on-pump. Alternatively, but again in very few patients, you have intramural vessels – vessels that you can’t see on the surface of the left ventricle because they are deep within the myocardium – and sometimes you can’t achieve a revascularization off-pump, so you have to put the patient on-pump. Finally, all those patients who require myocardial revasculazation associated with a mitral valve repair due to mitral valve regurgitation must be treated on-pump.


How likely is it that this technique will be taught in academic centres to trainee surgeons? ML: To me it depends on who is running the centre – if the head of the centre believes in off-pump surgery, then the future of that centre will be to have lots of experts in off-pump surgery. However, if you do not have a centre in which the whole team, surgeons and anaesthetists believe in off-pump surgery, it is definitely harder to start such a programme.

Furthermore, it is difficult to try to convince people that off-pump surgery can be done easily because, in general, it requires what is called the ‘deliberate practice’. Deliberate practice is something that pushes you out of your comfort zone on a daily basis. You need to re-train yourself and there is a price that you have to pay. We say ‘no pain, no gain’, so if you are not willing to pay a price in terms of your confidence, in terms of stress that you can have at the very beginning of your experience, you will find it more challenging to succeed.

Even if you believe in off-pump surgery, you must follow precisely a programme of implementation of technique in your centre, and this means that it is not only the surgeons who must be happy with the technique but the whole multi-disciplinary team. However, when the whole team believes that the technique is worthwhile, the results are definitely astonishing in the sense that you can treat patients on dual antiplatelet therapy with a

lower risk of bleeding complications, and you can see that you can treat patients with a high degree of renal failure without any further worsening of their function post-operatively. The patients are also weaned from the mechanical ventilation faster, so there are lots of benefits as the whole operation is less invasive.

However, it is critical to remember that the quality of the myocardial revascularization must be perfect; it must be what the same surgeon can achieve on-pump. If you compromise on the quality of the myocardial revascularization just because you want to go off-pump, and so you reduce the number of distal anastomoses or you do not use two mammaries because they are more technically demanding, well, this is not a good approach. What you have to do is to maintain the same quality using off-pump surgery.

Are more data required to help people feel more confident in this technique? ML: It can be challenging to publish papers which report good results in off-pump surgery because I feel that many journal reviewers, unfortunately, do not believe in off-pump surgery. This can mean that you feel that the quality of your paper must be two-times better than usual in order to be assessed and to be published. Ultimately, even if you have good results and publish the results in good journals such the European Journal of Cardiothoracic Surgery, it is not easy to be cited by other surgeons.


1. Shroyer AL, et al. N Engl J Med 2009;361(19):1827-37.2. Lemma MG, et al. J Thorac Cardiovasc Surg 2012;143(3):625-31.3. Lemma M, et al. 2014; Abstract 261. Presentation at the 28th EACTS Congress.4. Puskas JD, et al. Ann Thorac Surg 2009;88(4):1142–7

REFERENCES:

DISCLOSURES: LM is a consultant for Medtronic, Europe.

Address for correspondence Dr Massimo Lemma

Luigi Sacco University Hospital Via GB Grassi 74

20157 Milan Italy

Christoph Nienaber

INTERVIEW

Reviewing the updated European Society of Cardiology (ESC) guidelines on type B aortic dissection Aortic disease is often associated with very poor outcomes and, therefore, rapid diagnosis and decision-making is critical. In order to ensure that physicians are equipped with the right tools to effectively manage their patients, the ESC has recently updated its guidance on the diagnosis and treatment of aortic diseases (Erbel et al. European Heart Journal (2014) 35, 2873–2926). Following the release of several important studies in type B aortic dissection, such as INSTEAD-XL, Confluence spoke to Professor Christoph Nienaber, University Hospital Rostock Heart Centre, Rostock, Germany, to see what has changed in the guidance around this condition.

Why are guidelines important in clinical care? Christoph Nienaber (CN): In general, guidelines help younger or less experienced doctors to understand better what they are doing. Guidelines are not law or are not something you have to do, but give a lot of orientation. They provide advice on what to do, what to avoid, where to be cautious and when to consult more experienced or specialized doctors in their field. Guidelines help physicians to make structured and justified decisions about whether they should follow or not follow a given treatment strategy for a particular patient.

I think medicine, particularly cardiovascular medicine (and especially cardiology), is now specializing to such a degree that people don’t know what the next doctor, with different areas or different specialities, thinks and does. I think guidelines help you to identify and realize your limitations and find the way through the jungle of various diagnostic and therapeutic options.

Guidelines also help doctors to be aware of the abundance of these options currently available and to properly select the appropriate option for a given patient. A patient has to rely on his doctor 100%, as not many patients really understand the subject themselves, so it is a matter of improving quality to have guidelines at hand and using them properly. It doesn’t mean that you need to follow every guideline but it is an excellent orientation.

Why has it been necessary to update the guidance for type B aortic dissection? CN: Over the last couple of years, registries, as well as some small trials, have provided new data on the imaging, diagnosis and treatment of type B dissection, in particular with regards to the, so-called, uncomplicated type B dissection. There is still some controversy and debate, however, regarding what particular type B dissection should be considered uncomplicated or complicated. The boundaries are blurring these days as there are more elements of complication that are now better identified and understood. Over the last 4 years, the community has better understood those patients who might be at risk and what might be a potential future complication, even if it is not present at the time.

Who is involved in the development of these guidelines? CN: It is a mixed group, from active surgeons that treat type A dissections openly using classic surgical techniques, through to diagnostic specialists from radiology and cardiology, and vascular surgeons and interventional cardiologists, who treat dissection in Europe. We were one of the front-runners in this regard, because I, as an interventional cardiologist, became interested in this area some 20–25 years ago and basically followed this through the decades. We all participated in this really wonderful group of Guideline Committee members that met two or three times in various places and had lots of


telephone interviews and telephone calls in the last couple of years. The whole group worked together for almost 3 years to create these using standardized trial analysis methods guidelines.1

Angina is another case, again managed with many of the same drugs. If people have definite chest pain symptoms and breathlessness, they will have a higher likelihood of taking the drugs. As you say correctly, in both of these scenarios one of the main reasons for increased compliance is that patients feel the benefit from the drugs, whereas they cannot see an immediate advantage in blood pressure reduction. It really takes quite an in-depth analysis to understand the long-term risk and potential risk reduction effects for any cardio- and neurovascular adverse events that a fall in blood pressure has. These may only affect you in 10 or 15 years’ time, reducing the chance of a stroke, but actually taking that on board when you are younger, it is often quite difficult.

What information do the guidelines provide on the diagnosis of these conditions? CN: They offer, basically, a diagnostic decision-tree for patients with acute chest pain or suspicious symptoms that are considered to at least have a ‘rule-out’ or are actually checked for aortic disease. We are dealing with patients that have, of course, a medical history, a clinical presentation in the emergency room (ER) or clinic (if the patient is elective) and, if they are, haemodynamically speaking, in a stable situation, you basically go by probability of aortic disease or pathology. There are patients with a high probability of aortic disease and patients with a low probability of aortic disease, and thus an imaging session is very important in the diagnostic work-up.

The imaging session should be either ultrasound, usually transoesophageal echocardiograms (TEE), or simple computerized tomography (CT). That differentiation should be done early in the workout, you should not leave the patient there alone, sitting in the ER for hours, before you come to a conclusion whether to image them or not. Imaging is moving to the front row of management and especially with a suspected dissection or suspected aortic disease, so don’t waste time waiting for lab data and so forth, get the imaging properly done as soon as possible

because that gives you the opportunity to also look for evidence of even subtle changes in the aortic wall, which, if you pick it up early, can help to avoid later catastrophes. Communication is key, and the use of swift imaging needs to be implanted into the brains of ER doctors.

How is our understanding of complicated and uncomplicated type B dissection changing? CN: The difference between uncomplicated and complicated type B dissections, as I said, is changing. It is a moving target because we are identifying more and more elements of complication that had not been seen and had not been understood some years ago. For example, it is not only malperfusion, pain and imminent rupture that identifies the classic set of outcomes, and we are now starting to understand it is more than those.

Silent malperfusion and silent evidence of inflammation are interesting areas of ongoing research; we are now identifying patients that are at risk, although they are, clinically speaking, uncomplicated with no obvious symptoms.

In addition, the ongoing difficulty in treating hypertension in type B dissection means that such patients represent a cohort that are also prone to later complications, as demonstrated by registry data published in 2010.2 Furthermore, ongoing inflammation or partial false lumen thrombosis in subacute type B dissection also identifies a subset of patients that are likely to develop further and future complications in the weeks and months to come.

Continuing to the 2014 guidelines, a very important new aspect is that even in so -called uncomplicated type B dissection, or in the patients that are now showing these newly understood complications, you now have an option to treat these patients with thoracic endovascular aortic repair (TEVAR). This is given a IIA rating with a grade B level of evidence, which means that TEVAR should be considered in patients that are still considered to be uncomplicated. That is a new treatment choice that we have now at hand.

Moreover, in complicated type B dissection, we have also given an IC recommendation for TEVAR. We now have good evidence to treat these patients endovascularly with new TEVAR


technology in order to reconstruct the aorta, rather than managing them with drugs alone.3

Treatment of type B dissection has been enriched with the option of TEVAR. The target of this intervention is to not only relieve or reconstruct the true lumen but also to avoid distal malperfusion, and to start the process of remodelling by stent induced realignment of the lamella and eventually thrombosis of the false lumen, followed by remodelling over time – that is the target. We want to achieve this anatomic remodelling process in all patients, because that, obviously, guarantees stability of the aorta in the years to come.

Follow-up is also very important. Patients, even with the proper treatment, either surgically, endovascularly or medically, need follow-up. They should be followed by a specialized, knowledgeable team focused on aortic diseases, and, of course, should be subjected to a clinical visit every year and an imaging session every year, as recommended in a recent consensus statement.4

For young patients, I would recommend magnetic resonance imaging (MRI) as it is free of any ionizing radiation. Since these patients still need long-term follow-up, they shouldn’t be exposed to unnecessary radiation. However, CT should be used in the initial diagnostic assessment.

You mentioned that these changes to the guidelines have been made on the basis of new evidence. Could you give us an overview of some of these key trials? CN: With regards to complicated type B dissection there are a couple of single-arm studies looking at complicated type B dissection with malperfusion. These studies included the VIRTUE registry that comprised 100 and the STABLE trial,5 which included 86 patients. In complicated type B dissection, recently released data from the VIRTUE registry demonstrate that TEVAR is able to provide good protection from aortic-related death in the mid-term, albeit with a high rate of aortic reintervention.4 The STABLE trial also suggested benefits from TEVAR, even complex TEVAR with distal extension by bare metal components.5 There is, of course, no Level 1 evidence with a randomized group comparison, but there is observational evidence in very well

conducted single-arm trials which, basically, highlighted the better prognosis over a year and over 3 years.6 That has been published recently, and basically confirms what has been seen in the IRAD Registry, which is that complicated type B dissection really benefits from long-term scaffolding or TEVAR.7 However, they are only registry data and not Level 1 data.

With regards to stable type B dissection, there are two randomized studies that collected data since late 2005/06, and have now provided mid-to-long-term follow-up data – INSTEAD-XL8 and the follow-up to the ADSORB trial.9 Both trials were prospective trials assessing patients randomized to either conservative management or medical management, in addition to TEVAR scaffolding. In particular, INSTEAD XL looked at 5-year follow-up and showed an edge, in terms of all cause and aorta-specific mortality and progression of disease, in those patients that underwent early intervention with TEVAR and scaffolding. The benefits showed not sooner than 2 years after implantation and were, basically, hidden by the early hazard with the intervention in the early months after treatment. Then, with longer follow-up between 2 and 5 years, there was a clear, significantly better outcome in those patients that underwent the early intervention, as shown in the landmark analysis in INSTEAD-XL.8

What this tells us – and the same has been seen in ADSORB,9 a smaller study containing only 60 patients – is that, obviously, with TEVAR we invest in the future of the patient, allowing the patient to remodel and the aorta to reconstruct, leading, eventually, to a long-term stable course, a plateauing Kaplan–Meier curve with no evidence of late cardiovascular mortality or enhanced/increased mortality. Whereas in the control group – the group that did not get the early intervention but rather was followed on medical management – we see an ongoing crossover or even late rupture complications that occur later on and lead to an attrition rate which is ongoing, rather than plateauing, as in the control group.

Both groups, of course, get medical management and a lot of attention, follow-up and repeat imaging, but those that had the early investment of scaffolding obviously do better, because they stabilize, while the others have an ongoing attrition rate and, of course, an ongoing crossover


rate, because they have these late complications that need to be treated at the time.

We spoke about remodelling being that key goal of the intervention. Looking at these data, how thorough was that remodelling? Is it as complete as you would like or could more be done? CN: Of course, the ideal patient would be the patient who has only one entry site that could be sealed and no re-entries and that is it, but that is not the nature of this disease. It is more complex and we see patients with numerous re-entry sites, smaller or larger. The small ones are not a problem, but the large re-entry sites obviously are and feed blood retrogradely into the false lumen from down below, at the level of the abdominal aorta.

Unfortunately, we are not always able to address these problems initially with the first intervention, but rather with later follow-up interventions. If we treat a patient and treat them appropriately by sealing the proximal thoracic aspects of the aorta, we still have to follow the patient and look for later silent reperfusion of the false lumen or silent problems more distally, which can be addressed later on with a side-branch stent, local occluder or anything that is good to seal any re-entries, to make sure that the false lumen is completely isolated from pressure and from flow. That is the ideal goal. We don’t always reach that goal, but we are happy if there is no expansion in the distal part of the aorta. This is another reason to follow these patients and look carefully for expansion once a year by imaging – as long as there is no expansion, there is no risk of future rupture.

What are the characteristics of an ideal device for type B aortic dissection? CN: I think we have understood in the last couple of years that we should not use those stents that have been built and constructed for aneurysmatic disease; dissection is a different animal and needs a different treatment. To tame a dissection I think the best device would be a very flexible stent with low radial force that is not over expanded or not greater or bigger than the natural dimension of the aorta before it dissected.

What we really want to do is mimic the previous aorta, before dissection, and put in a scaffold that the dissected layers of the aorta can re-orient around, basically nothing but a healing scaffold. That is my idea and my concept of a treatment of

a dissection. We don’t need all these stents in the way – they were built and initially considered for aneurysmatic disease, we need scaffolds for the aorta to reorient and realign around it.

That means the ideal device should not be oversized, but should be, maybe, a little bit tapered from the top to bottom. It should not have excessive radial force, but rather a low radial force, and it should not overexpand the true lumen, it should just reach the original dimension and no more than that.

What impact do you see this guidance having on clinical practice? Is there going to be resistance to it or is it going to be widely accepted and taken up? CN: The real problem we have is that aortic disease has a relatively low incidence as compared with, for instance, hypertension or coronary disease. Therefore, the chance to be exposed to this difficult pathology for a fellow or for any doctor working in this field is much, much lower. So learning by experience will take much longer, of course, or only in specialized centres that see these patients more frequently.

That is why guidelines are of particular importance in this particular field. People who have read them before they see the patient are likely to better understand the dynamics, the clinical presentation, the various symptoms and science of dissection. It is not that difficult, but you just have to be aware of the complexity, and the current guidelines really open your eyes to the various subgroups of dissection – all of this is thoroughly discussed.

Since we don’t have any Level 1 data on these pathologies, the authors should be praised in having provided really careful wording around their recommendations, particularly in those areas of intramural haematoma (IMH) as well as penetrating ulcers, focusing on follow-up, imaging and repeat imaging, because these pathologies may show changes within a few days. We all need to be aware of the changes that can happen and then, of course, to find reasons to treat actively.

Can you tell us about ongoing studies in this area? CN: We will certainly see more data. For instance, IRAD, the large International Registry of Aortic Dissection founded some 19 years ago by Drs Isselbacher, Nienaber and Eagle, is not only


collecting type B dissection but all sorts of dissection.10 Moreover, they have branched out to include an interventional subset in their registry, looking at treatment of type B dissection with endografts. This subgroup in IRAD was founded about 3 years ago and they are looking, particularly, for more detailed information on patients that undergo endovascular treatment, open surgery or just are left alone on medication. This will be an important source of information as we are talking about hundreds, if not thousands, of patients.

Finally, there are plans to launch a large follow-up to the INSTEAD trial, which is called the INTACT trial, INTACT/AD, and stands for Trans-Atlantic International Controlled Trial on Aortic Dissection. It is planned that the first patient will be enrolled in Q3 2015, and the study will look at 1,800 patients randomized in both EU and US on the basis of entries into the IRAD Registry and The Vascular Quality Initiative (VQI) Registry in the US. They are basically collecting patients within that framework of the Registry and allowing them to participate in

a randomized trial within that Registry. Following 1,800 patients over 5 years will help to answer the key question whether mortality is going to be lower once you are subjected to TEVAR with a type B dissection, irrespective of any kind of complications.

When do you foresee another update coming? CN: The next update needs to be written as soon as elementary new or critical new data will be available. As I said, there is a long international trial on the horizon and there will be more registry data coming in as well as from some smaller observational trials. However, I think the bulk of new information will not be available sooner than 5 years from now. I think the next update will need to take place in 2019, though of course this is just a guess. I see this moving slowly in the clinical field, but rapidly in the technology area, because technology is improving every year and we can, basically today, use technology that we did not even dream of some 15 years ago, when all this started.

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1. Erbel R, et al. Eur Heart J 2014;35(41):2873-926.2. Trimarchi S, et al. J Thorac Cardiovasc Surg 2010;140(4):784-9.3. Nienaber CA, et al. J Vasc Surg 2011;54(5):1529-33.4. VIRTUE Registry Investigators. Eur J Vasc Endovasc Surg 2014;48(4):363-71.5. Lombardi JV, et al. J Vasc Surg 2014;59(6):1544-54.

6. Fattori R, et al. J Am Coll Cardiol 2013;61(16):1661-78.7. Fattori R, et al. JACC Cardiovasc Interv 2013;6(8):876-82.8. Nienaber CA, et al. Circ Cardiovasc Interv 2013;6(4):407-16.9. Brunkwall J and Lubke, T. Eur J Vasc Endovasc Surg 2013;46(3):274-7.10. Hagan PG, et al. Jama 2000;283(7):897-903.

REFERENCES:

Address for correspondence Prof Christoph Nienaber

Herzzentrum Universitätsmedizin Rostock

Zentrum Innere Medizin I. Medizinische Klinik

(Kardiologie, Pneumologie Internistische Intensivmedizin)

Ernst-Heydemann-Str. 6 18057 Rostock

Germany

christoph.nienaber@ med.uni-rostock.de

DISCLOSURES: CN has received lecture and consulting fees from Boston Scientific, Inc., COOK, Inc., and Medtronic, Inc.


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