Cardiovascular News issue 56—February 2020 by BIBA Publishing

February 2020 | Issue 56 David Taggart

EXCEL and heart teams Page 6

Nicolas van Mieghem

Profile

Page 14

NOBLE finds PCI inferior to CABG at five years in left main disease Five-year data from the NOBLE trial have confirmed its earlier findings that in patients with unprotected left main coronary disease the risk of major adverse cardiac or cerebrovascular events (MACCE) is higher with percutaneous coronary intervention (PCI) than with coronary artery bypass graft (CABG); the mortality risk was similar for both procedures. Published in The Lancet, the results come in the wake of an ongoing controversy surrounding the interpretation of data from EXCEL, which found that PCI was non-inferior to CABG in left main disease at five years.

nalysing the findings for Cardiovascular News, David Hildick-Smith (Brighton and Sussex University Hospitals NHS Trust, Brighton, UK) said that the two trials are not incompatible: “People keep saying that the results of NOBLE and EXCEL are contradictory but they are, in fact, entirely consistent with each other. Broadly speaking, revascularisation is more common after PCI, but mortality is equivalent, particularly cardiovascular mortality. The endpoints of the studies were different, hence the apparent divergence of their results.” Adrian Banning (John Radcliffe Hospital, Oxford, UK) agreed. He told Cardiovascular News that, although the “headline results” implied that NOBLE favoured CABG and that EXCEL suggested that both therapies may be the same, “personally, I think there are a lot of things in common between the findings in EXCEL and NOBLE”. He said: “Within NOBLE, the outcomes in the less complex patients (those with low syntax score) are inferior to CABG and that is unexplained in my NOBLE investigator Evald Hoj Christiansen

mind, along with the slight excess of stroke in the PCI group. My view is that if you add NOBLE, EXCEL, COMBAT, SYNTAX, and SYNTAXES there is a very reassuring long-term message about the role of stents in the left main. Careful analysis of the patient and the angiogram almost always suggests the optimal treatment for an individual, and I do not think there are many patients where equipoise occurs.” Stephan Windecker (Bern University Hospital, Bern, Switzerland) described NOBLE as “another very important piece of evidence that requires careful review in the context of the totality of evidence”. Comparing the two trials, NOBLE investigators Niels Holm (Aarhus University Hospital, Denmark) and colleagues note in The Lancet: “The recent five-year report of EXCEL showed that mortality after PCI was 13% in EXCEL versus 9% in NOBLE, a difference that might be at least in part explained by the higher proportion of patients with diabetes in EXCEL compared with in NOBLE. The differences in outcomes in the early reports were

Jay Mathews

Thrombus aspiration in PCI Page 20

EXCEL: Repeat revascularisation after both CABG and PCI leads to increased mortality A secondary analysis of repeat revascularisation in the EXCEL trial has found it was associated with increased mortality after both percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) in patients with left main coronary artery disease (LMCAD). EXCEL investigators also noted that, consistent with previous studies, repeat revascularisation was performed less frequently following CABG than PCI, and suggested this may have contributed to the higher rate of all-cause mortality (non-significant) seen with PCI in the main EXCEL trial. The interpretation of EXCEL has been the subject of much recent debate that includes disagreements about how endpoints were measured and the reporting of mortality data. THE AUTHORS OF the current analysis concluded that reducing the need for repeat revascularisation may further improve long-term survival after percutaneous or surgical treatment of left main disease. In JACC: Cardiovascular Interventions, Gennaro Giustino (Icahn School of Medicine, Mount Sinai, New York, USA) et al say: “Our findings in an unprotected LMCAD population suggest that the need for, and performance of, repeat revascularisation procedures have prognostic implications, the magnitude of which depends on its indication and type of repeat revascularisation procedure.” EXCEL was an international, open-label, multicentre, randomised trial that compared PCI using everolimus-eluting stents (Xience, Abbott) Continued on page 5

Continued on page 2

February 2020 | Issue 56

Top stories

EXCEL: Repeat revascularisation after both CABG and PCI leads to increased mortality Continued from page 1

versus CABG in patients with LMCAD. The secondary analysis investigated the incidence, risk factors, and prognostic impact of the performance of repeat revascularisation procedures following PCI and CABG. During three-year follow-up, there were 346 repeat revascularisation procedures among 185 patients. PCI was associated with higher rates of any repeat revascularisation (12.9% vs.7.6%, hazard ratio [HR] 1.73, 95% confidence interval [CI] 1.28–2.33, p=0.0003). Need for repeat revascularisation was independently associated with increased risk of threeyear all-cause mortality (adjusted HR [adjHR] 2.05, 95% CI 1.13–3.7, p=0.02) and cardiovascular mortality (adjHR 4.22, 95% CI 2.1–8.48, p<0.0001) consistently after both PCI and CABG (pint=0.85 for both endpoints). Although target vessel revascularisation (TVR) and target lesion revascularisation (TLR) were Gregg Stone both associated with an increased risk of mortality, target-vessel non-TLR and non-TVR were not. Giustino et al found that the repeat revascularisation procedures were mostly beyond the first six months after the index procedure. A repeat revascularisation procedure was an independent predictor of a subsequent increase in all-cause and cardiovascular mortality

BBC’s Newsnight broadcast an investigation into EXCEL that cast doubt upon the conclusions.” within three years after both PCI and CABG; a risk, the authors found, that peaked within 30 days after the repeat procedure and then declined over time. This, they say, suggests “the actual event of repeat revascularisation per se was associated with increased risk”. The authors propose a multifactorial association between repeat revascularisation and mortality is likely, that may be “both causative and associative in nature”. In an accompanying editorial comment, David O Williams (Brigham and Women’s Hospital, Boston, USA) says: “In EXCEL, more than half of those with a repeat revascularisation had another one subsequently. This finding supports the concept that there are patient specific factors that are associated with refractoriness to coronary interventions or a tendency to more rapid disease progression. A more basic understanding of the biology of lesion recurrence may assist in improving the durability of PCI in these circumstances.” The secondary analysis comes in the wake of a dispute about the findings of the main EXCEL trial. Three-year results were published in the New England Journal of Medicine (NEJM) in 2016, and concluded there was no significant difference in the primary endpoint of death, stroke, or myocardial infarction (MI) between PCI and CABG. Five-year outcomes of EXCEL were presented at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2019; 25–29 September, San Francisco, USA) and simultaneously published in the NEJM. They showed PCI was non-inferior to CABG on the primary endpoint. But, within the past few months, a row has blown up about the interpretation of the data. A week after the TCT presentation, cardiothoracic surgeon David Taggart

(University of Oxford, John Radcliffe Hospital, Oxford, UK) said at the European Association for CardioThoracic Surgeons meeting (EACTS 2019; 3–5 October, Lisbon, Portugal) that the definition of MI used in the primary endpoint of EXCEL was incorrect, leading to the wrong conclusion that PCI is non-inferior to CABG at five years for the management of selected patients with left main disease. He was an EXCEL trial investigator but said he withdrew his name as an author because of his view on the conclusion. According to Taggart, the definition of MI was changed halfway through the trial—from 30 days’ postprocedure to a biochemical periprocedural one. Lead EXCEL researcher Gregg Stone (Icahn School of Medicine, Mount Sinai, New York, USA) has refuted the claim. In December 2019, the BBC current affairs programme Newsnight broadcast an investigation into the trial that cast doubt upon the conclusions drawn by the investigators. This in turn prompted EACTS to withdraw its support for the left main recommendations of the society’s joint guidelines with the European Society of Cardiology (ESC) on myocardial revascularisation. According to Newsnight, Stone and colleagues guaranteed that, in addition to the findings in the trial on periprocedural MI, they would also publish data for incidence of MI according to the universal definition. The programme claimed that Stone et al failed to publish these data. Furthermore, reporter Deborah Cohen said during the broadcast the unpublished data that used the universal definition to measure MI showed “80% more patients with stents had heart attacks than those who had surgery”. This is disputed by Stone et al. In a 3,500-word statement, available in full on the Cardiovascular News website, they addressed the “misleading narrative questioning the conduct of the EXCEL trial that has been reported by certain members of the cardiovascular surgical community and a recent BBC Newsnight programme”. On the choice of the procedural MI definition, they stated that all involved—including surgical colleagues—agreed that the universal definition was not suitable because of ascertainment bias, different criteria for PCI and CABG, and a lack of demonstrated correlation with prognosis. They also refuted as “absolutely incorrect” the allegation that the protocol MI definition changed during the course of the trial. The programme additionally claimed the committee working on the EACTS-ESC guidelines for myocardial revascularisation had not seen the unpublished data. Nick Freemantle (director of the Comprehensive Clinical Trials Unit at University College London, London, UK), a member of the guidelines committee, asserted on Newsnight that, had he been aware of the findings on universal MI, he would not have agreed to the current recommendation that PCI and surgery “are interchangeable treatments for low- and moderate-risk patients with left main disease”, and said: “The EXCEL trial was absolutely crucial to the recommendations.” In response, EXCEL investigators pointed out that “there was absolutely no attempt to withhold meaningful data”. They said procedural MI according to the universal definition was listed in the protocol as one of approximately 35 exploratory secondary endpoints. Because it was based on troponins, the collection of which was optional and which were infrequently performed in EXCEL, it was therefore not possible to

report it. They added: “Until these recent events, there had been no requests from any source to prioritise reporting procedural MI according to the universal definition.” Nonetheless, they said: “EXCEL commits to publish a future manuscript reporting the rates and implications of MI according to numerous definitions, including the universal definition using CK-MB data.” Newsnight also reported it had seen “leaked emails” in which the data safety monitoring board (DSMB) for EXCEL raised concerns about the “number of people with stents who were dying”, and suggested the information should be made public “as soon as possible”, as the guidelines were being drawn up. However, the EXCEL researchers denied the board had raised concerns that were not adhered to, saying the independent DSMB met frequently to review unblinded EXCEL data, “each time recommending that the study continue as planned without modification”. Newsnight also reviewed Taggart’s mortality concerns expressed at EACTS, and commented that the NEJM had requested the mortality finding be highlighted in the concluding paragraph of the EXCEL

There has been heated debate on Twitter, with a clear division between surgeons and interventional cardiologists.” paper. Although it was later published without its inclusion, according to Newsnight, the NEJM said “it had met their standards”. But EXCEL’s leaders hit back at the claim that the all-cause mortality data from EXCEL were not emphasised strongly enough, describing it as a “secondary underpowered endpoint”, and explaining the “modest difference noted between groups was not adjusted for multiplicity, and is therefore statistically uncertain”. They defined it as lacking “biological basis”, because the “clinical events committee adjudicated the excess to be principally due to sepsis and cancer occurring years after randomisation”. When EACTS withdrew support for the guideline, the statement from secretary general Domenico Pagano indicated the “reported outcomes” of EXCEL were “one of the major clinical trial results” used to inform the guidelines. On this point, the EXCEL leadership said: “Guidelines are made on summated evidence from multiple trials and data input by independent experts in the field. The existing guidelines which EXCEL helped to inform suggest stenting may be considered as a treatment for selected patients with left main stem coronary disease.” The debate continues to rumble on, with various societies releasing statements responding to the situation; some (typically surgical) support EACTS’ position and some (typically interventional) support that of the EXCEL leadership (see page 4). There has also been heated debate on Twitter with, again, a clear division between surgeons and interventional cardiologists. In a further development late last month, Stone spoke at the British Cardiovascular Intervention Society Advanced Cardiovascular Intervention conference (BCIS ACI 2020; 22–24 January, London, UK). Addressing EXCEL’s five-year findings, he posed the question: Is the observed difference in EXCEL mortality data “real—that is, the truth”? and suggested that to improve precision for low frequency outcomes (for example, death, MI, stroke) all the high quality data from randomised controlled trials must be looked at.

February 2020 | Issue 56

News focus

EXCEL may damage relations between interventional cardiologists and cardiac surgeons The debate over the results of EXCEL shows no sign of abating, and there seems to be a division between cardiac surgeons and interventional cardiologists about which side of the argument they fall on, with surgeons generally supporting EACTS, and interventional cardiologists generally supporting the EXCEL leadership. Although some interventional cardiologists do not believe the disagreements will change their practice, they raise concerns that their working relationships with surgeons may suffer.

he decision in December 2019 by the European Association of Cardio-Thoracic Surgeons (EACTS) to withdraw support for the left main section of its myocardial revascularisation guidelines (see page 1) has reverberated around the cardiology community; many societies have since called for an independent review of EXCEL data which were used to inform the guidelines (see page 4). But leading interventional cardiologists say that despite the furore, as yet, nothing has changed. Nick Curzen (University Hospital Southampton NHS Foundation Trust, Southampton, UK), says multiple other factors inform his decision-making. “I will offer the patient an informed choice, laying out the pros and cons of each. For percutaneous coronary intervention (PCI) these are: a quick admission, and a quick recovery, with less trauma, but there is a higher revascularisation rate; therefore, there is less chance of needing to come back after coronary artery bypass graft (CABG). There are no differences in death rates, and probably none in MI [myocardial infarction], between the procedures.” He says that neither of the two main areas of contention raised by the Newsnight programme, and subsequently acted upon by EACTS, “would affect my interpretation of the clinical value of the trial or its contribution to the evidence base”. He points out that the difference in all-cause mortality between CABG and PCI “is a secondary endpoint and, while interesting, does not set off alarm bells for me about PCI”. David Hildick-Smith (Brighton and Sussex University Hospitals NHS Trust, Brighton, UK) agrees that he too will treat patients “the same as before”. He tells Cardiovascular News that there are “a wealth of good trials—EXCEL, NOBLE, SYNTAX, PRECOMBAT etc” on which to base decisions about therapy, giving a “consistent message” that patients are more likely to require repeat intervention after stents than after surgery, “but to get the benefits of surgery you have to have the operation and not all patients are keen on this. In the end, it is the patient who decides what treatment they will submit to, not the doctor.”

“A very public disagreement”

Both Curzen and Hildick-Smith have expressed concern about how some of the parties in the debate have handled the situation. Hildick-Smith declares himself “disappointed” with the EACTS’ leadership, accusing them of “inflammatory and sensationalist use of relative risk in a way that is likely to be misunderstood by the general public; the tabloid language used has not helped relations”. He adds: “It is a shame that the surgical leadership of EACTS has chosen to make this a very public disagreement. Some fairly egregious accusations have been made and I think the leadership of EXCEL has behaved well in the face of the provocation.” Similarly, Curzen is critical of the handling of the situation “by some of the protagonists and by the BBC Newsnight team”. He thinks “the lack of balance” will undermine patients’ confidence in PCI, which he says is “most regrettable” and could have been avoided. Furthermore, Curzen is surprised at EACTS’ move to withdraw support from the guidelines—“allowing for the fact that I have not seen all of the BBC leaked data”. “The British Cardiovascular Interventional Society (BCIS) Council

has not felt that there are grounds to do so,” he points out. Adrian Banning (John Radcliffe Hospital, Oxford, UK) also describes events as “regrettable”, with “a lack of transparency about some of the things people have said, and this has resulted in confusion. Ultimately, not only does this undermine clinicians’ confidence, but it also threatens the confidence patients have in clinical research.”

Independent review of the data

However, cardiothoracic surgeon David Taggart (University of Oxford, John Radcliffe Hospital, Oxford, UK), an EXCEL investigator who gave a heavily critical talk about the trial at EACTS 2019, and who appeared in the Newsnight programme, is calling for an independent review. He says: “How physicians are now going to approach these patients is at the heart of what the fundamental problem is. Concerns about the

messages from the trial, or the summation of evidence used to produce the guidelines. I worry we will have expended a lot of effort to end up broadly where we started.”

Twitter storm

Much of the debate has played out on Twitter and, generally, the opinions being expressed have divided along professional lines. Banning judges Twitter’s impact to have been negative: “I do not think it has helped at all as it allows rumour and ‘Chinese whispers’ to propagate. I am in favour of social media, but this highlights a potential disadvantage. Institutions and societies cannot react fast enough to Twitter storms, and then the Twitter focus moves on.” Others, however, view it more positively. Taggart does not use social media himself, but believes Twitter could have helped in the longer-term: “Although the controversy over EXCEL is potentially, at least superficially, damaging to doctors, it also means that there will be no other trial whose conduct is not subject to vigorous scrutiny in the future. The ultimate result could be better trials.” But on the flip side, he adds, “we can only do trials if patients are willing to participate, and anything that shakes their confidence is detrimental.” Curzen thinks Twitter activity “has been interesting. The value for me was the extra wealth of data offered by colleagues on Twitter in trying to support their arguments, some of which I had not seen before. That is Twitter at its best.” For Hildick-Smith: “So long as people remain respectful and avoid trolling, I think it is fair enough to see commentary on social media. Some incisive early commentary was seen on EXCEL.”

A broken heart team?

Nick Curzen

David Hildick-Smith

Although an independent review is a good idea, I doubt very much it will change the key messages from the trial, or the summation of evidence used to produce the guidelines.” trial now go far beyond EACTS’ decision to withdraw support.” He believes that the review, conducted in a “fully independent way”, is necessary to restore faith in the guidelines. “Basically, I want transparency. This is not a sterile academic debate—it puts individual doctors in an invidious position. To properly restore faith and confidence in the guidelines, we need a fully independent reanalysis by a group of clinician scientists who were not involved in either drawing up the guidelines or in the trial itself.” Taggart, because of his concerns about the findings of EXCEL, withdrew his name from the New England Journal of Medicine (NEJM) paper in which the five-year findings were published. Banning says that, although an independent review is a good idea: “I doubt very much it will change the key

As Twitter underlined, opinion about EXCEL appears to be splitting along specialty lines, and could have the potential David Taggart to damage working relationships within heart teams, as well as the trust enjoyed between different professions. All of those that Cardiovascular News spoke to emphasise the importance of strong interdisciplinary relationships. Curzen stresses “the value of discussion between the disciplines, focused on the patient and not the doctors, is extremely effective, and demands respect and cooperation between surgeons and interventionalists.” Banning agrees: “If we lose the heart team ethic, patients will lose out.” He fears that it could signal a return to the “dark days of the early drug-eluting stents era—before the SYNTAX trial where there was a lack of cohesive teamwork”, and calls for an end to tribal allegiances. Curzen is also aware that “some bad feeling” has been generated, and Taggart acknowledges: “There has been a split between surgeons and interventional cardiologists”. He was optimistic that it would be a “temporary schism”. “EACTS and the cardiothoracic societies want to work with cardiologists,” he says. Hildick-Smith declares that a “period of reflection by the surgeons would be sensible. A meta-analysis of NOBLE and EXCEL, and perhaps also FREEDOM and PRECOMBAT, will demonstrate that surgery is a very good option for those willing to have surgery. For other patients there are stents, and results from stent implantation are very good too.” It is time to move on, says Curzen: “I have received all that I need from EXCEL and NOBLE now. I suspect, however, that the EXCEL investigators are now obliged to publish a supplementary paper relating to the periprocedural enzyme data.”

February 2020 | Issue 56

Advertorial

THIS ADVERTORIAL IS SPONSORED BY ABIOMED

Further data underline the critical role of Impella Heart Pumps in protected PCI Findings from an interim analysis of PROTECT III have added to the evidence for improved outcomes with Impella heart pumps in protected percutaneous coronary intervention (PCI). PROTECT III is part of the PROTECT series of trials initiated by Abiomed in 2006, and follows on from PROTECT I, and the PROTECT II randomised controlled trial.

ublished in 2012 by William O’Neill et al, PROTECT II randomised patients 1:1 to an intra-aortic balloon pump (IABP) and PCI or Impella 2.5® circulatory support device and PCI.1 It showed that use of an Impella leads to better outcomes for protected PCI than an IABP in patients with reduced ventricular function. Based on the findings from the three PROTECT studies, as well as registry data, the US Food and Drug Administration (FDA) granted Impella its highest level of safety and efficacy approval, a post-market approval (PMA) for a first-of-its-kind indication for high-risk PCI. Impella is included in eight clinical guidelines and more than 650 peer-reviewed publications. Interim findings from the prospective study PROTECT III, announced recently at the Transcatheter Cardiovascular Therapeutics scientific symposium (TCT 2019; 25–29 September, San Francisco, USA), demonstrated a reduction in the primary endpoint of death, stroke, myocardial infarction, and repeat procedures at 90 days (major adverse cardiac and cerebrovascular events, MACCE) with Impellasupported PCI, compared to PROTECT II (in PROTECT II: IABP 31%, n=210 vs. Impella 21.9%, n=215, p=0.033; in PROTECT III: Impella 16.8%, n=469, p<0.0001). The data were presented by Jeffrey J Popma (director of interventional cardiology clinical services at Beth Israel Deaconess Medical Center, and professor of medicine at Harvard Medical School, Boston, USA). The encouraging findings, he noted, were despite the fact that: “Compared to PROTECT II, patients are older [average of 71 years], more often women [26%], and there were less Caucasians over time [33% nonCaucasians].” In addition, Popma pointed out: “We thought we were aggressive in PROTECT II, but in PROTECT III the number of vessels treated was higher and the number of three vessels treated doubled [from 14% to 29%]. The amount of atherectomy used was 40% in PROTECT III, whereas it was only 14% in PROTECT II. Despite this, the contrast volume in PROTECT III was lowered. The length of support was longer in PROTECT III, in part due to the fact that patients were sicker compared with PROTECT II.”

Why provide left ventricular support during PCI?

As coronary interventional techniques progress and health care delivery improves, PCI has been extended to patients who would previously have been deemed untreatable, particularly those with reduced ventricular function. In addition, advancing age and increased comorbidities have put more patients at prohibitive risk for coronary artery bypass grafting (CABG), rendering high-risk PCI as the sole revascularisation therapy for this population. While there is no absolute definition of a high-risk intervention, it is generally considered in those patients with reduced left ventricular systolic

function, complex coronary anatomy, or advanced comorbidities, frailties, or disabilities, including end-organ dysfunction (that is, kidney disease or lung disease). Mechanical circulatory support in PCI may be used as an adjunct in such cases, with the goal of providing sufficient forward cardiac output to maintain myocardial flow and end-organ perfusion and to reduce left ventricular volume, wall stress, and end diastolic pressure, thereby improving coronary flow during the procedure. Use of an appropriate left ventricular support device prior to initiating a high-risk coronary intervention allows time to safely perform an optimal coronary intervention in patients with advanced coronary artery disease to allow more extensive revascularisation during the procedure. Ventricular support enables the operator to proceed confidently without the risk of haemodynamic collapse that would require subsequent emergency bailout, use of other advance support devices, such as an intra-aortic balloon pump or extracorporeal support.

Expanded post-approval study of protected PCI

PROTECT III is an ongoing, prospective, single arm FDA post-approval study for the premarket approval (PMA) of Impella 2.5 and Impella CP® heart pumps in high-risk PCI, and is the largest FDA study of haemodynamically supported high-risk PCI patients. It is being conducted at 45 hospitals in the USA, with 898 patients enrolled between March 2017 and July 2019—571 to Impella CP and 327 to Impella 2.5—all of whom have a high-risk PCI indication. Popma stressed: “We are not asking the question: ‘Is CABG [coronary artery bypass graft] better than PCI with normal left ventricular function and stable angina?’ We are saying: ‘In those patients who are high risk, what is the appropriate method of support for advanced and complete revascularisation?’” Popma stated that comparison of revascularisation strategies by surgical risk category in recent revascularisation trials found that studies such SYNTAX, EXCEL, NOBLE and BCIS enrolled patients at low- and medium-surgical risk, whereas the highest surgical risk patients were enrolled in PROTECT II and PROTECT III, most of whom were not candidates for surgery at all, in addition to high anatomical

How does Impella work?

Impella 2.5 and Impella CP® heart pumps function by pulling blood from the left ventricle through an inlet area near the tip and expelling it from the catheter into the ascending aorta. The device can be inserted using a standard catheterisation procedure through the femoral artery, into the ascending aorta, across the valve and into the left ventricle. Impella CP with SmartAssist® is one of the latest innovations on the Impella platform, integrating the performance of the Impella CP heart pump with state-of-the-art SmartAssist technology. It uses real-time intelligence to optimise positioning and management of the device, and new haemodynamic sensor technology allows it to be repositioned in the ICU without the need for imaging (for ventricularised pumps only); the optical sensor senses aortic pressure while the micro-axial motor senses pressure between the aorta and the left ventricle. It has been designed with a simplified set-up, for improved ease of use and faster set-up time.

Above: Impella in heart Below: Impella CP and Impella CP kit

Issue 56 | February 2020

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associated with significant left ventricular ejection fraction (LVEF) improvement and survival.2 The finding of less required haemodynamic support after PCI with Impella was a “very provocative” observation in PROTECT II, Popma stated; total support time following IABP-PCI was 8.23±21 hours versus 1.86±2.7 hours with Impella (p<0.001). And 37.7% of IABP patients were discharged from the cath lab on the balloon pump versus 5.6% of patients treated with Impella (p<0.001). “After the procedure, for whatever reason, the clinician needed to maintain the balloon pump for a while. Usually that is because the patient has a soft blood pressure. And a lot of patients went directly up to the unit with the balloon pump in place, so they ultimately required longer haemodynamic support.” In addition, PROTECT II found half as many hypotensive events (defined as a mean arterial pressure of <65mmHg) per patient with protected PCI: IABP 0.96 versus Impella 0.45, a reduction of 53% (p=0.001). Impella 2.5 provided superior haemodynamic support in comparison with IABP, with a maximal decrease in cardiac power output from baseline of -0.04±0.24W in comparison with -0.14±0.27W for IABP (P=0.001).1 “And that is what we observe in the catheterisation lab when we just do not see the patients get hypotensive as we perform extensive revascularisation,” said Popma.

Impella and acute kidney injury

complexity. “These are the challenging patients in our clinical practices who have few alternatives. The PROTECT studies addressed these patients,” Popma explained: “The prospective PROTECT III clinical study is collecting data for Impella use with the same rigour as a pre-market FDA study, including the use of core laboratories, clinical site monitoring, and clinical events committees. We are already now at 898 patients in the PROTECT III post-approval study, and that is going to continue to grow. Now we are going to be able to do some analyses on thousands of patients … and have the ability to look a little bit deeper on the clinical outcomes.”

Clinical importance of complete revascularisation to reduce late events

A key aspect demonstrated by both PROTECT II and PROTECT III is the compelling evidence on complete revascularisation, with the benefits of Impella more pronounced with extensive revascularisation. Crucially, said Popma: “Use of the Impella with extensive revascularisation prevented late adverse events, including repeat revascularisation, rather than in-hospital events, but late adverse events are critically important to physicians and their patients.” PROTECT II had two primary endpoints—a 30-day primary endpoint and a 90-day composite endpoint of major adverse events, including death, myocardial infarction, stroke/transient ischaemic attack (TIA) and repeat revascularisation. In PROTECT II, the 30-day incidence of major adverse events was not different for patients with IABP or Impella 2.5 haemodynamic

support. However, improved outcomes were observed at 90-days for Impella 2.5-supported patients. Popma highlighted the divergence: “From the time the patient is discharged to 90 days later [the cumulative] event rates continue to separate. Reduction in out-of-hospital events is where the benefit is seen.” The clinical benefit of Impella protected PCI was a reduction of major adverse events post-discharge, accompanied by an improvement in ventricular function and heart failure symptoms. On the endpoint of death, stroke, MI and repeat revascularisation, event rates were 18% with IABP and 10% with Impella (p=0.01), and for death, stroke and MI they were 13% and 7% (p=0.047), respectively. These post-discharge clinical benefits were more pronounced in patients who underwent more complete revascularisation with Impella support. In patients with limited revascularisation, there was little difference between patients treated with an Impella heart pump and balloon pump in MACCE (32.2% IABP vs. 35.1% Impella), whereas in complete revascularisation MACCE events were 29.3% for IABP versus 15% for Impella. Popma summed up: “Impella maintains procedural haemodynamics, allowing for more complete revascularisation. In those patients who had extensive revascularisation, there was a profound difference in outcomes compared with patients treated with an intraaortic balloon pump.” This finding is supported by findings from the Roma-Verona registry in 2019 (Burzotta et al), which looked at the use of Impella in protected high-risk PCI and found that more complete revascularisation was

PROTECT III is also taking a closer look at the development of acute kidney injury (AKI). High-risk PCI patients face elevated risk of AKI due to high levels of contrast and long procedures. In addition, chronic kidney disease is a common comorbidity. A substudy of PROTECT III evaluated 106 patients for AKI rate and compared them to a propensity-matched control group (also 106 patients). “Patients with AKI are at greater risk of adverse events. Low ejection fraction and baseline haemodynamic compromise may result in renal hypoperfusion,” said Popma. The PROTECT III substudy cohort consisted of patients with recorded baseline creatinine, and at least one follow-up creatinine measurement within 48–72 hours of PCI; patients on dialysis at the time of PCI were excluded. In the control group were elective or urgent high-risk PCI patients treated without Impella support in the AKI study performed at the University of Louisville.3,4 Patients were matched 1:1 based on age, gender, diabetes, contrast volume, and glomerular filtration rate (GFR). The analysis demonstrated an AKI rate of 24.5% in patients with no support versus 5.7% in the PROTECT III cohort (p=0.0002). In addition, the rate of severity was lower in the Impella-protected patients, with respective values of 9.4% versus 5.7% for severity of AKI-1, 10.4% versus 0% for AKI-2, and 4.7% versus 0% for AKI-3 in unprotected patients and those in PROTECT III. Where to next for Impella heart pumps? Popma surmised: “We have learned a lot about PCI with left ventricular support over the last several years; we have shown the benefit of haemodynamic support and the importance of extensive revascularisation; we have learned that these are late events that are prevented by a more effective initial procedure. It really sets the stage for what we could do next. And what we could do next is use the left ventricular support to achieve complete revascularisation, and ultimately evaluate the use of contemporary best practice methods for Impella support in patients who are high risk for surgery.” References: 1. W O’Neill et al. Circulation 2012. doi.org/10.1161/ CIRCULATIONAHA.112.098194 2. F Burzotta et al. Journal of Interventional Cardiology 2019. doi. org/10.1155/2019/5243913 3. MP Flaherty et al. Catherization and Cardiovascular Interventions, 2019. doi. org/10.1002/ccd.28400 4. MP Flaherty et al. Circulation Research 2017. doi.org/10.1161/ CIRCRESAHA.116.309738

February 2020 | Issue 56

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ISCHEMIA trial shows no benefit for revascularisation in patients with stable ischaemic heart disease The ISCHEMIA (International study of comparative health effectiveness with medical and invasive approaches) trial, the largest to date to compare revascularisation with a conservative strategy in patients with stable ischaemic heart disease, has found no additional benefit a median of three years after the procedure.

ata were presented at the American Heart Association Scientific Sessions (AHA 2019; 16–18 November, Philadelphia, USA) by Judith S Hochman (New York University School of Medicine, New York, USA). She told delegates: “Overall, an initial invasive strategy did not demonstrate a reduced risk as compared with an initial conservative strategy over a median 3.3 years for the primary endpoint—a composite of cardiovascular (CV) death, myocardial infarction (MI), and hospitalisation for unstable angina, heart failure, or resuscitated cardiac arrest—and the major secondary endpoint of CV death or MI.” ISCHEMIA looked at whether there is a benefit to adding cardiac catheterisation and, if feasible, revascularisation to optimal medical therapy in stable patients with at least moderate ischaemia on a stress test. Of the 8,518 patients enrolled, 5,179 who had stable ischaemic heart disease that was moderate or severe on stress testing were randomised to either an initial invasive treatment strategy (2,588) or to an initial conservative strategy (2,591). Those in the invasive strategy group had routine cardiac catheterisation, followed by revascularisation with percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery, when feasible to achieve optimal revascularisation. The conservative strategy group only received cardiac

catheterisation when optimal medical therapy failed. Both groups received secondary prevention that included lifestyle and pharmacological interventions. Median follow-up for both groups was 3.3 years (>99% of expected patient-years of follow-up). The adjusted hazard ratio (HR) for the primary endpoint was 0.93 (95% confidence interval [CI] 0.8–1.08, p=0.34). Hochman said: “The curves cross for the primary endpoint and the major secondary endpoint at approximately two years from randomisation: there

An initial invasive strategy did not demonstrate reduced risk as compared with an initial conservative strategy.” is about a two-in-100 higher estimated rate with the invasive strategy at six months, and about two-in-100 lower estimated rate with the invasive strategy at four years.” At six months, the absolute difference in the estimated rate of reaching the primary endpoint was 1.9% (95% CI 0.8–3) in favour of the conservative strategy; at four years, it was 2.2% (95% CI -4.4–0) in

favour of the invasive strategy. For the major secondary endpoints of CV death or MI, the adjusted HR was 0.9 (95% CI 0.77–1.06, p=0.21). The findings for absolute differences were the same as for the primary endpoint; at six months it was 1.9% (95% CI 0.9–3) in favour of the conservative strategy, and at four years it was 2.2% in favour of the invasive strategy (95% CI -4.4% to -0.1%). For net clinical benefit, which added stroke to the primary endpoint, HR was 0.95 (95% CI 0.82–11), with a similar trend for absolute differences. All-cause mortality was 6.5% with the invasive strategy versus 6.4% for conservative treatment, with an adjusted HR of 1.05 (95% CI 0.83–1.32, p=0.67). “The probability of at least a 10% relative risk reduction of the invasive strategy on all-cause mortality was <10%,” said Hochman, “based on the prespecified Bayesian analysis.” The adjusted HR for MI was 0.92 (95% CI 0.76–1.11, p=0.38). The rate of procedural MIs was higher in the invasive group (adjusted HR 2.98, 95% CI 1.87–4.74, p<0.01), but the rate of spontaneous MIs was lower in these patients (adjusted HR 0.67, 95% CI 0.53–0.83, p<0.01). Rates of procedure-related stroke and death were very low, which Hochman attributed to the fact that only high-volume PCI sites with a low complication rate were selected for the trial. In addition, there was no heterogeneity of treatment effect for the primary endpoint in prespecified subgroups—such as degree of baseline ischaemia and severity of coronary artery disease (CAD)—or for any characteristic, such as age, sex, race, or ethnicity. Limitations included it was not blinded, its findings may not be generalisable to centres with higher procedural complication rates, and the results are not applicable to groups excluded from enrolment. In addition, the women enrolled were more often excluded from randomisation than men because they had less ischaemia and more non-obstructive CAD.

Aspirin withdrawal after three months of dual antiplatelet therapy reduces bleeding without an increase in ischaemic events among high-risk patients following PCI Data from the TWILIGHT study demonstrate that, compared to ticagrelor plus aspirin, ticagrelor monotherapy reduces bleeding events without increasing the risk of death, myocardial infarction, or stroke in high-risk patients who have undergone successful percutaneous coronary intervention (PCI) and completed three months of dual antiplatelet therapy (DAPT). ROXANA MEHRAN (MOUNT Sinai School of Medicine, New York, USA) reported the findings at the Transcatheter Cardiovascular Therapeutics scientific symposium (TCT 2019; 25–29 September, San Francisco, USA). They were simultaneously published in the New England Journal of Medicine. TWILIGHT (Ticagrelor with aspirin or alone in high-risk patients after coronary intervention) was a randomised, placebocontrolled trial conducted from July 2015 to December 2017; it enrolled 9,006 patients whom the treating clinician intended to discharge on ticagrelor plus aspirin following successful PCI with at least one locally approved drug-eluting stent. Further inclusion criteria were the presence of at least one clinical and one angiographic feature associated with a high risk of ischaemic or bleeding events. After completing three months of DAPT, event-free patients were randomised to aspirin or placebo with continuation of

ticagrelor for an additional 12 months. A total of 7,119 patients were randomised at 187 sites in 11 countries (23.8% female, 36.8% diabetes mellitus, 64.8% acute coronary syndrome [ACS]). The primary endpoint was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding. The secondary endpoint was the composite of all-cause death, myocardial infarction (MI), or stroke. At one year, the incidence of major bleeding was 4% for patients randomised to ticagrelor plus placebo, and 7.1% among patients who received ticagrelor plus aspirin (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.45–0.68. p<0.001). The relative risk reduction was similar for BARC 3 or 5 bleeding (1% vs. 2%, HR 0.49, 95% CI 0.33–0.74). Rates of all cause death, myocardial infarction, or stroke were 3.9% for both groups (HR 0.99, 95% CI 0.78–1.25, p noninferiority <0.001). The respective rates of all-cause death (1% vs. 1.3%), MI (2.7% vs. 2.7%)

Roxana Mehran

Usman Baber

and definite or probable stent thrombosis (0.4% vs. 0.6%) were similar between groups. There were 16 ischaemic strokes in the ticagrelor monotherapy group and eight ischaemic strokes in the DAPT group (0.5% vs. 0.2%). The effect of ticagrelor monotherapy on the key secondary outcome was consistent across pre-defined subgroups. Mehran said: “We met our primary endpoint. In fact, looking at BARC 3 and 5 bleeding we observed a significant reduction of bleeding. And looking across

all prespecified bleeding endpoints … we showed exactly the same reduction, with a significant reduction of peeling away aspirin.” On secondary endpoints, she said: “When you look at the components of the composite they were similar across all-cause mortality, MI, stroke and stent thrombosis”. But, she cautioned: “These results are not generalisable to all patients undergoing PCI; we had important inclusion and exclusion criteria. And they are not generalisable for patients receiving background therapy with other P2Y12 inhibitors.” In a later session, Usman Baber (also Mount Sinai School of Medicine) presented a TWILIGHT Thrombogenicity substudy which corroborates the clinical observations of no incremental ischaemic risk upon aspirin withdrawal. The substudy was nested within TWILIGHT; participants were enrolled after randomisation in the main trial. It found ticagrelor monotherapy provides a similar antithrombotic effect to that of ticagrelor plus aspirin as assessed by ex vivo platelet-dependent thrombus formation, and that platelet reactivity to collagen and arachidonic acid is increased in the absence of aspirin, while aggregation to adenosine diphosphate and thrombin is unchanged with or without aspirin. Baber told Cardiovascular News: “The overall magnitude and consistency of effect we observed with ticagrelor monotherapy suggests this may be a safer and effective antiplatelet strategy as compared with standard of care.”

February 2020 | Issue 56

Imaging

Cardiac MRI delivers an accurate diagnosis and guides treatment of cardiovascular diseases Eike Nagel Chiara Bucciarelli-Ducci Comment & Analysis Eike Nagel and Chiara Bucciarelli-Ducci discuss the diagnostic and prognostic power of heart magnetic resonance imaging (MRI) and how it can help physicians to determine the best treatment path for patients.

or patients with stable angina and coronary artery disease (CAD), two strategies are typically used to establish a diagnosis and guide treatment decisions. One is invasive angiography—a procedure that involves taking X-rays of the patient’s arteries and requires multiple hospital visits, including an overnight stay— and measurement of fractional flow reserve (FFR). The other is heart MRI, which is a modality for noninvasive, nonradiation assessment of the function and structure of the heart and cardiovascular system. After a heart MRI, patients undergo invasive angiography and revascularisation only if they have received a positive test, which occurs in less than half of the patients, even when the expected likelihood for the presence of disease is high and the patients have typical symptoms. Despite its widespread use in Europe, and studies that associate cardiac MRI with a lower incidence of invasive angiography than testing based on clinical risk assessment,1 heart MRI is not employed as frequently in the USA, making up less than 1% of noninvasive imaging tests administered. Until recently, there was also a lack of data on the efficacy of heart MRI-based strategies compared to those involving invasive angiography. The MR-INFORM (myocardial perfusion CMR versus angiography and FFR to guide the management of patients with stable coronary artery disease) trial evaluated whether heart MRI is noninferior to an FFR-based strategy in terms of major adverse cardiac events (MACE), including death from any cause, non-fatal myocardial infarction, or target vessel revascularisation. Recently published in the New England Journal of Medicine, the trial was an international, multicentre, comparative-effectiveness study involving patients with stable angina and risk factors for CAD.2 Between December 2010 and August 2015, 918 patients were enrolled in the trial, which involved 16 sites in the

UK, Portugal, Germany and Australia. Patients who were ≥18 years with typical angina symptoms and two or more cardiovascular risk factors (smoking, diabetes, hypertension, hyperlipidaemia, a family history of CAD) or a positive exercise treadmill test were suitable for inclusion. Exclusion criteria included contraindications to adenosine myocardial-perfusion cardiovascular MRI, severe cardiac arrhythmias, a known left ventricular ejection fraction of <30%, New York Heart Association

months. A 10% incidence in the FFR group and a noninferiority margin of six percentage points were determined by the FAME (fractional flow reserve versus angiography for multivessel evaluation) trial, which assessed 1,005 patients with multivessel CAD undergoing PCI at 20 medical centres in the USA and Europe.3 With these assumptions, a sample size of 826 would be sufficient to determine noninferiority of a heart MRI-based strategy compared to an FFR-guided strategy. After providing written informed consent, all 918 patients enrolled in the MR-INFORM trial were randomly assigned to either the FFR group (464 patients) or the heart MRI group (454 patients). The two groups did not differ significantly in age, sex, symptoms at presentation, baseline medications or risk factors. Randomisation was performed with fixed block sizes, stratified according to centre and sex within centre. Patients assigned to the FFR group received the standard invasive angiography and FFR testing in all coronary arteries with a calibre of ≥2.5mm and a stenosis severity of ≥40%. Revascularisation was recommended for vessels with an FFR of ≤0.8. FFR group patients also underwent cardiac MRI before the angiography; however, results were blinded and not reported. Meanwhile, the heart MRI group had a cardiac MRI to determine whether invasive angiography was required. In this group, only patients with abnormal heart MRI results underwent an invasive study. FFR was not permitted in this group.

By using cardiac MRI methods, which are readily available and can be implemented on standard MRI systems, physicians can personalise therapy by recommending more invasive operations only to those who really need them.”

MRI

(NYHA) class III or IV heart failure, previous coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI) within six months, or an estimated glomerular filtration rate of <30ml per minute per 1.73m2 of body surface area. The sample size calculation for the MR-INFORM trial was based on the expected percentage of patients with the primary outcome of MACE at 12

Overall, the two groups had similar health outcomes, with <4% of patients in both groups experiencing the primary outcome of MACE within the followup period of 12 months. However, the group that received treatment based on a heart MRI had significantly fewer procedures—only 40% of this group had invasive angiography, while 96.8% of patients in the FFR group underwent the procedure. Furthermore, 36% of

the Heart MRI group went on to have revascularisation, compared to 45% in the FFR group. Once again, the difference was significant. The MR-INFORM trial indicates that among patients with stable angina and risk factors for CAD, using heart MRI to guide treatment is noninferior to using invasive coronary angiography and FFR. Additionally, the results demonstrate that heart MRI is associated with a lower incidence of invasive coronary angiography and coronary revascularisation compared to FFR. Due to a lack of evidence, current guidelines on managing the care of patients with CAD separate diagnostic and therapeutic strategies. By comparing two frequently used, well-defined, standardised and validated tests, the MRINFORM trial closes this knowledge gap; however, limitations of the study should be considered. For instance, the results cannot be extrapolated to other tests for myocardial ischaemia or the functional significance of a coronary artery stenosis due to differences in diagnostic performance. Additionally, the findings are generalisable only to patients who fulfill the study’s inclusion criteria. By using cardiac MRI methods, which are readily available and can be implemented on standard MRI systems, physicians can personalise therapy by recommending more invasive operations only to those who really need them. Thus, for many patients, the initial hospital visits will be quicker, safer and painfree, and they are less likely to require additional procedures. Unlike other modalities, the 3D technology in cardiac MRIs can help to determine what kind of heart disease is present and why, helping doctors diagnose conditions and provide a prognosis to achieve the best treatment path for patients. To learn more, visit heartmri.org and scmr.org. References: 1. JP Greenwood, DP Ripley, C Berry, et al. Effect of care guided by cardiovascular magnetic resonance, myocardial perfusion scintigraphy, or NICE Guidelines on subsequent unnecessary angiography rates: The CE-MARC 2 randomised clinical trial. Journal of the American Medical Association 2016; 316(10): 1051–60. DOI: 10.1001/jama.2016.12680 2. E. Nagel, JP Greenwood, GP McCann, et al. Magnetic resonance perfusion or fractional flow reserve in coronary disease. N Engl J Med 2019; 380: 2418–28. DOI: 10.1056/NEJMoa1716734v 3. PA Tonino, B De Bruyne, NH Pijls, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009; 360(3): 213–24. DOI: 10.1056/NEJMoa0807611

Eike Nagel is the director of the Institute for Experimental and Translational Cardiovascular Imaging at DZHK Centre for Cardiovascular Imaging in Frankfurt, head of Interdisciplinary Cardiovascular Imaging at University Hospital Frankfurt, Frankfurt, Germany, and the lead investigator of the MRINFORM trial. Chiara Bucciarelli-Ducci is an associate professor in cardiology/noninvasive imaging at the Bristol Heart Institute, co-director of the Clinical Research and Imaging Centre Bristol, Bristol, UK, CEO of the Society of Cardiovascular Magnetic Resonance, and co-author of the MR-INFORM trial.

Issue 56 | February 2020

Structural Heart Interventions Self-expanding valves have good haemodynamic performance in small annuli A retrospective registry comparing the performance of four self-expanding transcatheter heart valves has demonstrated good haemodynamic performance in small aortic annuli, with low post-procedure gradients, large orifice areas, and a low incidence of severe patient–prosthetic mismatch (PPM).

riting in JACC: Cardiovascular Interventions, Damiano Regazzoli (Humanitas Research Hospital, RozzanoMilan, Italy) et al report that the supra-annular designs (Evolut R, Evolut Pro, both Medtronic, and Acurate Neo, Boston Scientific) seemed to slightly outperform the intra-annular design (Portico, Abbott). Similar rates of severe paravalvular leak (PVL) and need for pacemaker implantation were reported in the real-world cohort of aortic stenosis patients, while more-than-mild PVL seemed to be slightly more frequent with Portico. TAVI-SMALL is a retrospective registry of patients with severe aortic stenosis and a small annulus. The study evaluated and compared outcomes of transcatheter self-expandable prostheses. The authors explain: “Patients with small aortic annuli showed the highest benefit in terms of valve forward haemodynamic and PPM in those studies comparing the outcome after TAVI [transcatheter aortic valve implantation] and SAVR [surgical aortic valve replacement], especially in case of SEV [self-expanding valves] implantation. The clinical impact of PPM in patients treated percutaneously is still not clear and demands further investigations, but [the] TAVI-SMALL registry represents a starting point to shed light on this topic.” Of the 859 participants, 397 were treated with Evolut R, 84 received Evolut Pro, 201 Acurate (both Neo and TA), and 177 Portico. Primary endpoints were post-procedure mean aortic gradient, indexed effective orifice area (iEOA), and rate of severe PPM. The researchers found pre-discharge gradients were consistently low in every group, with a slight benefit with Evolut R (8.1mmHg, 95% confidence interval [CI] 7.7–8.5) and Evolut Pro (6.9mmHg, 95% CI 6.3–7.6) compared to Acurate (9.6mmHg, 95% CI 8.9–10.2) and Portico (8.9mmHg, 95% CI 8.2–9.6) groups (p<0.001). Mean iEOA was 1.04cm2/m2 (95% CI 1.01–1.08) with a trend for lower values with Portico. Interestingly, considering only Acurate Neo (supra-annular valve implanted transfemorally), there were no differences in term of gradients and PPM as compared with Evolut R and Evolut Pro. No significant differences were reported in terms of severe PPM (overall rate 9.4%, p=0.134), permanent PM implantation (15.6%), and periprocedural and one-year adverse events. Regazzoli et al write: “Currently available SEVs showed excellent acute and midterm clinical results, with a low incidence of adverse events. The use of SEVs proved to be effective and showed good haemodynamic results in patients with small (<23mm of derived diameter) and very-small (<20mm) annuli. An inverse correlation between annular perimeter and postprocedure gradients was found, but its clinical relevance is not clear, since the incidence of severe PPM was low in patients with both small (9.4%) and very small annuli (13.7%).” They add: “These data, comparable to those observed in other contemporary TAVI studies, are consistent between groups, suggesting good procedural planning

and implantation technique, irrespective of the selected device.” The non-randomised and retrospective design of the study could have led to some selection bias, the authors concede, although, they say, “we did not observe significant baseline differences Damiano Regazzoli between SEV groups”. Nevertheless, the study “represents an important piece of evidence by confirming favourable outcomes of these devices in this setting”. An accompanying editorial by Michele Pighi and Flavio Ribichini (University of Verona, Verona, Italy) describes the findings as “interesting”. They say: “In light of the recent extension of TAVI indication to

Currently available self-expanding valves showed excellent acute and midterm clinical results, with a low incidence of adverse events.” low-risk patients, the TAVI-SMALL study provides a strong stimulus for the development of future studies investigating the long-term performance of transcatheter valves, striving for individualisation of the treatment strategies in this particularly challenging anatomical setting.” In a second paper, also published in JACC: Cardiovascular Interventions, Aditya Sengupta (Mount Sinai Medical Center, New York, USA), Syed Zaid (Westchester Medical Center, New York, USA) et al outlined one-year TAVI results with the Sapien 3 (Edwards) valve in extremely large annuli. Overall mortality and stroke rates were 18.2% and 2.4%, respectively, at one year, with a quality-of-life index improvement from baseline to 30 days and at one year (both p<0.001). Mild paravalvular aortic regurgitation (AR) occurred in 21.7%, and moderate or greater paravalvular AR in 4.3%. Mild and moderate/ severe transvalvular AR occurred in 11.6% and 0%, respectively. Valve gradients remained stable at one year. The authors say they have demonstrated the “continued utility of Sapien 3 TAVI in annuli >683mm2 with satisfactory midterm clinical and echocardiographic outcomes”, and call for longer follow-up to evaluate the durability of the 29mm Sapien 3 valve in patients with extremely large annuli.

TAVI with Sapien valve provides health benefits and durability, say PARTNER trials, but not via transthoracic route

A subanalysis of PARTNER 3 quality of life data has demonstrated a modest but significant improvement in oneyear disease-specific quality of life after transcatheter aortic valve implantation (TAVI) with the Sapien 3 balloon expandable valve (Edwards Lifesciences) compared to surgical aortic valve replacement (SAVR). Suzanne J Baron (Lahey Hospital and Medical Center, Burlington, USA) outlined the findings in low-surgical risk patients with severe aortic stenosis (AS) at the Transcatheter Cardiovascular Therapeutics scientific symposium (TCT 2019; 25–29 September, San Francisco, USA). TAVI WAS ASSOCIATED with significant health status benefit compared to SAVR at all timepoints (one, six, and 12 months; p<0.05) in analyses incorporating both survival and change in health status together. Late health status benefits with TAVI were driven by the proportion of patients experiencing a large (≥20 point) improvement in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score, partly explained by differential rates of postprocedural complications between TAVI and SAVR. Meanwhile, a subanalysis of structural valve deterioration (SVD) in the PARTNER 2A trial found that the third-generation Sapien 3 valve has similar durability to surgical valves. The second-generation Sapien XT demonstrated lower midterm durability than surgery. PARTNER 2A is a comparison of TAVI versus surgery in patients with severe AS at intermediate surgical risk. Phillipe Pibarot (Quebec Heart and Lung Institute, Quebec, Canada) presented the subanalysis at PCR London Valves (17–19 November, London, UK). Four-year rates of SVD-related haemodynamic valve deterioration (HVD) and bioprosthetic valve failure (BVF) were similar in Sapien 3 intermediate-risk patients and in those undergoing SAVR; 30-day mortality related to reinterventions was lower in TAVI than surgery. Five-year data from the main PARTNER 2A trial have also been announced. At TCT 2019, Vinod Thourani (Georgetown University School of Medicine, and Medstar Heart and Vascular Institute, Washington, DC, USA) said that the study found similar rates of death and disabling stroke with TAVI and SAVR in patients with severe AS at intermediate surgical risk. But TAVI via a transthoracic route demonstrated poorer outcomes than surgical replacement. Thourani indicated that TAVI should remain an alternative to SAVR, “especially in those patients that can be done transfemorally”. But, for those without acceptable transfemoral access, surgery may be the preferred alternative to transthoracic TAVI.

February 2020 | Issue 56

Interview

Profile

Nicolas van Mieghem Nicolas van Mieghem (professor of interventional cardiology, Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, The Netherlands) shares his thoughts with Cardiovascular News on a wide range of topics, from mechanical circulatory support and artificial intelligence, to the durability of transcatheter aortic valve implantation and his future hopes for the potential of transcatheter mitral valve replacement.

Why did you decide to become a doctor, and why did you choose to specialise in interventional cardiology?

Even as a child I wanted to do something significant and to help people. I also wanted a profession that would channel my energy—I was always a busy child. Originally, I thought about becoming a cardiac surgeon. But in 1999, the then head of cardiac surgery in the medical school at the University of Leuven told me that the future was in interventional cardiology rather than cardiac surgery, and that valves would soon be replaced with catheters. So I decided to become a cardiologist. In 2002, I saw the first-in-human case report of transcatheter aortic valve implantation (TAVI) in Circulation by Alain Cribier. I knew that day that was what I wanted to do.

Who were your mentors at the beginning of your career?

My father was a general cardiologist. He was a hardworking man in private practice, an excellent clinician who contributed to multicentre research, and was a high-enroller in trials. We have similar character traits. I also identified with an excellent intensive care specialist Manu Malbrain. Another big influence came later in my career when training at Lenox Hill Hospital in New York. Gary Roubin left a mark on me as an interventional cardiologist. I feel blessed to have performed procedures with him, and to have been part of the legacy of Andreas Gruentzig. And, during my early tenure in Rotterdam I was impressed and fascinated by the overwhelming work energy and interventional cardiology IQ of Professor Patrick Serruys.

What has been the most important development in interventional cardiology during your career?

TAVI. I came to it as it started to take off. I feel honoured to have had an active part in shaping it into an everyday procedure with such an impact on patients.

What has been the greatest disappointment—an advance you hoped would change practice that has failed to do so?

So far transcatheter mitral valve replacement has lagged behind. It seems the mitral valve is a totally different and not so easy to tame animal.

What are your current research interests?

I’m still passionate about cerebral embolic protection during TAVI and the search for improved large bore closure devices. I work actively in expanding TAVI indications, most notably as a means to further unload the left ventricle in heart failure patients with moderate aortic stenosis (the TAVR UNLOAD trial). I am heavily involved in the development and dispersion of mechanical circulatory support (MCS) devices. Finally, I am involved with transcatheter mitral and tricuspid repair techniques. In terms of imaging and preprocedural planning, an important research line focuses

on computed tomography (CT)-derived 3D modelling and printing.

What do you consider to be your biggest contribution to the field of interventional cardiology?

I believe I contributed significantly to the field by making TAVI safer, faster, and less invasive. I am convinced that the best is yet to come from my end.

What was the most important paper published in the past year?

I think both the PARTNER 3 and the Evolut Low Risk trials were essential because they cemented the position of TAVI in the treatment of severe aortic stenosis across the entire operative risk spectrum. Now, we need to add more granularity to the TAVI literature to see how far this technology can go in terms of durability and less straightforward patient anatomies (such as, bicuspid aortic stenosis) and indications (for example, asymptomatic severe aortic stenosis).

What are the key unanswered questions that future research should prioritise? How does TAVI durability compare with surgical aortic valve replacement (SAVR) durability? I am convinced that TAVI will end up at least as durable as SAVR, but we need proof.

I am convinced that transcatheter aortic valve implantation will end up at least as durable as surgical aortic valve replacement, but we need proof.” You were deputy chair of SURTAVI: what are the factors to be taken into consideration when deciding between TAVI and surgery, as TAVI moves into treatment of low-risk populations?

A detailed analysis of an individual patient’s anatomy should determine TAVI eligibility. If the procedure is low risk, the patient should be treated with TAVI. Age and frailty should no longer be the driver for selection.

What factors should be considered when deciding whether to use mechanical circulatory support in shock or percutaneous coronary intervention (PCI)? Left ventricular (LV) function and coronary lesion complexity should drive the decision to proceed with mechanical support. Another important aspect is access site management. Preprocedural planning should guide this whenever possible. Furthermore, I believe MCS

should only be used by experienced operators. There is no point in positioning MCS as a mainstream technique. By default, it should be considered advanced care to be used in selected centres by selected operators.

What role will artificial intelligence play in the future development of interventional cardiology techniques?

Artificial intelligence is an intriguing concept that may help to make interventional cardiology a safer place—both by helping to select the proper technology and techniques for the individual patient, and in the development of new techniques. Computer learning may seem relatively abstract to many of us, but it is coming.

What do you think the next breakthrough innovation will be?

Transcatheter mitral valve replacement. We are not there yet, but I hope we find a reliable technology that also

Issue 56 | February 2020

Interview

Fact File

Current appointments

n Clinical director of interventional cardiology, Erasmus University Medical Center, Rotterdam, The Netherlands n Full professor of interventional cardiology, Erasmus University Medical Center n TEACH course coordinator, Erasmus University Medical Center n Co-director of Joint Interventional Meeting (JIM)

Fellowships awarded

n European Society of Cardiology (ESC) n American College of Cardiology (ACC) n European Association of Percutaneous Coronary Intervention (EAPCI)

Memberships (selected)

n Committee to define the core curriculum for percutaneous cardiovascular interventions on behalf of the EAPCI n Steering committee for the SURTAVI trial n Advisory board for ANCORA LV restoration therapies n Advisory board for TriCinch tricuspid therapies n Rotterdam TAVI Expert Meeting course director

Involvement in trials (selected)

fits into clinical practice within the next five years. In the coronary space, I can envision a therapy resulting in significant coronary plaque regression or decalcification of aortic leaflets. That would be a huge breakthrough.

What is the added value of social media?

Social media is a double-edged sword. On one hand, it brings the world closer. But on the other, it trivialises, it is uncensored and it is not peer reviewed—it comes with fake news, misinformation, and one-sided stories.

What advice would you give to someone starting out?

Pursue a career for the right reasons or find something else. A cardiologist should be dedicated to the job and genuinely care for patients. Every day I realise that what I do for each patient means so much to them. That is not trivial. It makes me feel humble and proud.

What was your childhood dream job?

Olympic athlete. A long time ago, I was a member of the national swim team of Belgium. I dreamt of competing at the Atlanta ‘96 Olympics. But I soon realised that medicine would be a perfect fit for me.

What are your hobbies and interests outside of medicine?

My passion is medicine, but I also love sport. My mantra is: mens sana in corpore sano (a healthy mind in a healthy body). I work out on a regular basis: in the gym, on my racing bike, or in the swimming pool. I am a fan of American sports (NBA and NFL) and, like all Belgians, I love to watch the big cycling events, such as the Classic cycle races, the Tour de France, and the Giro d'Italia. I also like music; I grew up with ‘80s music, and am a big Oasis fan. And, I watch my share of Netflix and movies, particularly anything with Al Pacino or Robert De Niro.

n Lead investigator for the ENVISAGE TAVI AF Trial and TAVR UNLOAD trial n Steering committee member on the RESPOND Edge trial n BIVOLUT X co-principal investigator n Principal investigator for the MARVEL and MASH trials on novel large bore closure devices n Principal investigator for the POLESTAR trial on early discharge protocol with ACURATE TAVR

Lead investigator on focused research lines

n Cerebral embolic protection in TAVI n Access site management and new large bore closure devices n Percutaneous mechanical circulatory support n Advanced transcatheter structural mitral and tricuspid Interventions n Computed tomography-derived procedure simulation and modelling n Strategies to treat coronary calcifications

Structural Heart Interventions

February 2020 | Issue 56

Routine anticoagulation with rivaroxaban after TAVI is harmful, says GALILEO George Dangas (Mount Sinai Hospital, New York, USA) told delegates in a late-breaking trial session at the American Heart Association scientific sessions (AHA 2019; 16–18 November, Philadelphia, USA) that “in patients without an established indication for oral anticoagulation after successful transcatheter aortic valve implantation (TAVI), a treatment strategy including rivaroxaban at a dose of 10mg daily was associated with a higher risk of death or thromboembolic complications and a higher risk of bleeding than an antiplatelet-based strategy”.

he GALILEO (Global study comparing a rivaroxaban based antithrombotic strategy to an antiplatelet based strategy after TAVI to optimise clinical outcomes) trial was terminated early in August 2018 by the data and safety monitoring board due to safety concerns. Dangas presented the main results of the study, published simultaneously in the New England Journal of Medicine. He outlined: “Patients undergoing TAVI are typically elderly and frail, and at increased risk for both ischaemic and bleeding complications. Subclinical leaflet thrombosis may occur with bioprosthetic valves, and may be associated with an increased risk of cerebrovascular events that may be prevented or reversed by anticoagulation. While guidelines recommend the use of dual antiplatelet therapy early after TAVI, there is a dearth of evidence for routine use of anticoagulation after TAVI.” The open-label, international, multicentre, event-driven, randomised, controlled trial compared a rivaroxabanbased antithrombotic strategy with an antiplatelet-based strategy post-successful TAVI. The primary efficacy endpoint was death, stroke, myocardial infarction (MI), systemic

thromboembolism, symptomatic valve thrombosis, or deep venous thrombosis or pulmonary embolism. The primary safety endpoint was Valve Academic Research Consortium (VARC) 2 criteria of major, disabling or life-threatening bleeding. In all, 1,644 adults with a mean age >80 years who had undergone successful TAVI for aortic valve stenosis were randomised to either the rivaroxaban group (n=826) and were given rivaroxaban 10mg and aspirin 75–100mg daily for 90 days, followed by rivaroxaban 10mg daily, or to the antiplatelet group (n=818) and were given clopidogrel 75mg and aspirin 75–100mg daily for 90 days, followed by aspirin 75–100mg daily. The 10mg daily dose used is lower than the stroke prevention dosage in atrial fibrillation.

Dangas said: “The primary in the rivaroxaban arm and hypothesis of the trial was that 24 in the antiplatelet arm (HR the rivaroxaban-based strategy 1.23, 95% CI 0.71–2.15). would be superior to the Dangas outlined the antiplatelet-based strategy with limitations, which included respect to incidence of death that it used open-label or thromboembolic events. We treatment, potentially subject estimated that 440 composite to reporting and ascertainment primary outcome events would George Dangas bias, it was prematurely provide the trial with 80% terminated so treatment effects power to detect a 20% lower relative and CIs need to be interpreted with risk in the rivaroxaban group than in the caution, and on-treatment analyses are antiplatelet group. However, because subject to bias due to the high rates of the trial was terminated early, only 183 treatment discontinuation. In addition, patients had reached the primary efficacy patients undergoing TAVI with an outcome [42% of the planned 440].” established indication for anticoagulation In the intention-to-treat analysis, the were not included. primary efficacy outcome of death or Also presented at AHA 2019, a first thromboembolic event was higher substudy of GALILEO that used 4D in the rivaroxaban arm (n=105) than the computed tomography three months antiplatelet arm (n=78) (9.8 versus 7.1 after randomisation found subclinical events per 100 person–years), with a hypoattenuated leaflet thickening and hazard ratio (HR) of 1.35 (95% confidence reduced leaflet motion of bioprosthetic interval [CI]1.01–1.81, p=0.04). All-cause aortic valves were less frequent in patients mortality rates in the intention-to-treat treated with rivaroxaban than in those analysis were also significantly increased, in the antiplatelet group. However, there with 64 deaths in the rivaroxaban arm were too few clinical events to permit any versus 38 in the antiplatelet arm (5.8 vs. meaningful interpretation of the results. 3.4 per 100 person–years), with a HR of “The mechanism underlying the 1.69 (95% CI 1.13–2.53, p=0.009). higher mortality in the rivaroxaban The primary safety endpoint in the arm observed in the intention-to-treat intention-to-treat analysis of lifeanalysis in this trial is unclear,” noted threatening, disabling or major bleeding Dangas. He concluded: “The mortality occurred in 46 patients in the rivaroxaban rate differences were attenuated in the arm vs. 31 in the antiplatelet arm (4.3 on-treatment analysis and many occurred vs. 2.8 per 100 person–years, HR 1.5, late after discontinuation of the study 95% CI 0.95–2.37, p=0.08). In the ondrug. These results of the GALILEO treatment analysis, there were 26 deaths main trial are irrespective of the potential effects on valve imaging findings from the GALILEO 4D-CT Ancillary Study.” Dangas emphasised to Cardiovascular News that GALILEO included patients without any established indication for oral anticoagulation. “Therefore, the results affect patients after TAVI who do not require an anticoagulant for any clinical reason. Other ongoing clinical trials investigate different oral anticoagulants in patients in atrial fibrillation and TAVI.”

The primary safety endpoint in the intention-to-treat analysis of life-threatening, disabling, or major bleeding occurred in 46 patients in the rivaroxaban arm versus 31 in the antiplatelet arm.”

Evidence continues to mount in favour of MitraClip Further studies have added to the evidence of benefit with MitraClip (Abbott), suggesting advantages over medical therapy alone. Threeyear data from the COAPT trial indicate it continues to demonstrate safety and efficacy in patients with heart failure and secondary mitral regurgitation (MR); patients who crossed over and received MitraClip after 24 months showed the same benefits as those who received it from the beginning. A separate economic analysis of COAPT found MitraClip provides “intermediate to high economic value”. And a third study of patients with severe MR deemed ineligible for COAPT demonstrated worse one-year survival rates in patients excluded from COAPT who were on medical therapy than those who were not eligible for COAPT treated with Mitra Clip. COAPT IS A randomised, parallel-controlled, openlabel multicentre trial evaluating transcatheter mitral valve repair (TMVR) with MitraClip in patients with heart failure and moderate-to-severe or severe secondary MR who remained symptomatic despite guideline directed medical therapy; 312 subjects were randomised to MitraClip plus medical therapy, and 302 to medical therapy only. Subjects on medical therapy alone were not permitted to crossover until after 24 months. Three-year safety and efficacy data were announced at the Transcatheter Cardiovascular Therapeutics scientific symposium (TCT 2019; 25–29 September, San Francisco, USA) by Michael J Mack (Baylor Scott & White Health, Dallas, USA). The primary effectiveness endpoint was all hospitalisations for heart failure. At 36 months, it was 220 for MitraClip plus medical therapy, compared to 378 for medical therapy alone (hazard ratio

[HR] 0.49, 95% confidence interval [CI] 0.37–0.63, p=0.00000006). The primary safety endpoint of freedom from device-related complications was 8.7% at 36 months. All-cause mortality for all patients, including crossovers, at three years was 42.8% for MitraClip plus medical therapy versus 55.5% for medical therapy alone (HR 0.67, 95% CI 0.52–0.85, p=0.001), providing, Mack said, “a sustained mortality benefit that persists out to three years”. Patients who crossed over to MitraClip after two years had similar outcomes to those treated with MitraClip from the outset. Also at TCT 2019, Suzanne J Baron (Lahey Hospital and Medical Center, Burlington, and Saint Luke’s Mid America Heart Institute, Kansas City, USA), presented a COAPT cost-effectiveness analysis. When in-trial survival, health utilities, and costs were modelled over a lifetime, TMVR was projected to increase

quality-adjusted life-years (QALYs) by 0.82 years. The incremental cost per QALY gained was consistent with “intermediate to high economic value”, said Baron, and subgroup analyses indicated “TMVR appeared to be particularly cost-effective in patients <75, and those with ejection fractions < 30% at baseline”. At PCR London Valves (17–19 November, London, UK), Eduardo Zancanaro (San Raffaele Hospital, Milan, Italy) outlined a single-centre real world assessment of non-COAPT patients that found the vast majority of patients with severe MR were not eligible for inclusion in COAPT; the most frequent reason was they were not on maximal guideline directed medical therapy. Despite a better profile and improved drug regimen after discharge, non-COAPT eligible patients who were left in medical therapy had worse one-year survival than non-COAPT patients treated with Mitra Clip.

Structural Heart Interventions

Issue 56 | February 2020

TRILUMINATE shows safety and efficacy of TriClip maintained at one year The use of TriClip (Abbott) for edge-to-edge repair in tricuspid regurgitation (TR) remains safe and effective at one year, preliminary outcomes from the TRILUMINATE study, presented at a late-breaking session at PCR London Valves 2019 (17–19 November, London, UK), indicate. Outlining the data, Georg Nickenig (University of Bonn, Bonn, Germany) said that among 87% of the patients with symptomatic or greater tricuspid regurgitation, the study demonstrated TR reduction of at least one grade. It also found a low rate of major adverse events, with no new device-related adverse events after 30 days, and significant improvements in quality of life measures. “I THINK WE can show—admittedly in a small patient cohort—durable repair,” said Nickenig, adding: “This is a very safe procedure. We witnessed some clinical improvement and we saw also some positive reverse remodelling and improved RV function.” Nickenig told Cardiovascular News that the one-year outcomes should “certainly help” towards achieving CE mark for the device, which is still pending. TRILUMINATE is a prospective, multicentre, singlearm study in 21 sites in Europe and the USA; 30-day findings were announced earlier this year at EuroPCR 2019 (20–24 May, Paris, France), demonstrating safety and effectiveness, and a low complication rate. Eligible patients were those with moderate or greater TR, with New York Heart Association (NYHA) class II or higher. Patients with systolic pulmonary artery pressure >60mmHg, a previous tricuspid valve procedure, or a cardiovascular implantable electronic device that would inhibit TriClip placement, were not suitable for enrolment. Nickenig described participants as a “very sick patient group”, and explained: “There

have been some post-hoc registry data made available during the past years showing that MitraClip could be used to reduce tricuspid regurgitation in a certain patient cohort, and this could be related also to an improved clinical outcome or at least to an improved clinical performance.” Patients were treated with the TriClip tricuspid valve repair system, a clip-based edge-to-edge technique. TR was graded as mild, moderate, severe, massive, and torrential. The primary efficacy endpoint was a reduction in severity of TR ≥one grade 30-days post-procedure, with a performance goal of 35%. The primary safety endpoint was a composite of major adverse events at six months, with a performance goal of 39%. Patients who did not reach six-month follow-up and did not have a major adverse event during previous follow-ups were excluded from the primary safety analysis. The trial has completed enrolment and follow-up is ongoing. Nickenig reported one-year outcomes in the first 50 of 85 patients; this found a TR reduction of at least one grade among 87% of subjects with paired data.

The proportion of subjects with moderate or less TR increased from 4% at baseline to 54% at 30 days, an improvement that was “sustained and improved” at one year, increasing to 64%, indicating, he said, “durable TR repair”. The study also demonstrated continued symptomatic improvement, with increases in quality of life measures; the proportion of subjects in NYHA class I/II increased from 22% at baseline, to 84% at 30 days, and 80% at one year, and scores for the Kansas City Cardiomyopathy Questionnaire and six-minute walk distances also improved between baseline and one year. Nickenig added: “We saw some initial evidence for positive reverse remodelling on the right side of the heart. The reduction of TR was associated with significantly decreased right ventricular dimensions suggesting positive remodelling, with significant improvements in right ventricular function.” There were three major adverse events at one year (all cardiovascular mortality), with no myocardial infarction, stroke, or new onset renal failure. On additional safety endpoints, there were four deaths that were not related to the device or the procedure and one that was unlikely to be related. There were no new device related safety events beyond 30 days. The findings have also been published in The Lancet.

Georg Nickenig presenting at PCR London Valves

Structural Heart Interventions

February 2020 | Issue 56

Two studies suggest mortality is lower with Sapien than with CoreValve According to two studies published in Circulation, the balloon-expandable Sapien (Edwards Lifesciences) transcatheter aortic valve implantation (TAVI) system is associated with lower mortality than is the self-expanding CoreValve (Medtronic) system. The findings have led to calls for randomised head-to-head trials comparing the two devices. IN THEIR PAPER, Eric Van Belle (Department of generation TAVI valves (Sapien 3, CoreValve Evolut R, Cardiology, Institut Coeur Poumon, Centre Hospitalier and CoreValve Evolut Pro). Universitaire de Lille, Lille, France) and others report In their study, they identified 10,459 matched pairs. that “despite major differences” between balloonAt a mean follow-up of 358 days, all-cause death was expandable and self-expandable valves, the devices “are lower in the Sapien group: 14.4% a year versus 16.4% recommended to be used indifferently in most of the for the CoreValve group. Cardiovascular death and clinical situations”. They add that whether risk of hospitalisation for heart failure these valves achieve similar or different were also lower in the Sapien group, clinical outcomes “remains unclear”, meaning that the rate of the combined noting that a large randomised study endpoint of all-cause death, all-cause powered to compare the two devices has stroke, or rehospitalisation for heart not been performed (or initiated), even failure was lower with Sapien. Pacemaker though “there is an urgent clinical need implantation during the first 30-days after to clarify this issue in an exponentially TAVI was also lower with Sapien. growing therapeutic field”. Dehara et al comment that their Therefore, to provide further findings “underscore the need for largeinformation in this area, Van Belle et Mohamed Abdel-Wahab scale dedicated randomised trials on this al conducted a retrospective review of issue [how balloon-expandable valves outcomes for patients (12,141) enrolled in the Francecompare with self-expandable valves]”. TAVI registry who underwent TAVI in France between Similarly, Van Belle et al conclude: “As some of the 2013 and 2015. Of these, they identified 3,910 matched most recent transcatheter heart valve iterations were pairs. The first co-primary outcome of the study was not part of the investigation, there is an urgent need assessment of paravalvular regurgitation at discharge, to conduct a randomised trial sufficiently powered to and the second co-primary outcome was two-year allcompare head-to-head the latest generation of selfcause mortality. expanding and balloon-expandable transcatheter heart The authors report that greater than moderate valves on all-cause mortality.” paravalvular regurgitation was more frequent in patients However, a randomised head-to-head trial—at who underwent TAVI with CoreValve: 15.5% versus least, not one supported by industry—may not 8.3% for Sapien. All-cause mortality at two years was also higher in the CoreValve patients: 899 of 3,910 patients versus 801 of 3,910 patients. They add: “When only cardiovascular mortality was considered, self-expanding transcatheter heart valves remained associated with higher short-term mortality.” However, Van Belle et al observe that—for all-cause mortality— proportional hazard assumption was not satisfied, as the excess mortality risk of CoreValve compared with Sapien was only seen for the first three months.

Similar results for newer devices

Of note, the registry included patients who received older generation devices but, according to the authors, the results were similar when their review was restricted to the time after newer iterations (post-2014) of the valves had been introduced. They comment that, although Sapien 3 (the latest generation of Sapien included in the study) has a “anti-leak skirt” that has been associated with reduced paravalvular leak, the newer generations of CoreValve that were included in the study have not been associated with similar reductions. “Whether the newest iteration of the self-expanding transcatheter heart valve (Evolut Pro) featuring an outer pericardial wrap will help to mitigate this major difference is unknown. A recent small nonrandomised comparison did not show a significant difference in paravalvular rates between the last two iterations of self-expanding transcatheter heart valves (Evolut versus Evolut Pro),” Van Belle et al say. The second paper in Circulation to compare outcomes with Sapien against those of CoreValve also reviewed patients who underwent TAVI in France. However, authors Pierre Dehara (Department de Cardiologie, CHU Timone, Marseille, France) and others restricted their review to patients who received TAVI after 2014 (until June 2019); therefore, they only looked at later

One might speculate that the less occurrence of paravalvular leak and the less need for pacemakers with balloonexpandable valves impact mortality as well, although this needs to be confirmed in a randomised setting.”

Sapien 3

happen. Mohamed Abdel-Wahab (Department of Internal Medicine/Cardiology, Heart Center Leipzig, University of Leipzig, Leipzig, Germany), who wrote a commentary about the studies in Circulation, told Cardiovascular News that “unfortunately, companies are not interested in initiating such a trial”. He thinks the results need to be confirmed in randomised trial and, at present, should be interpreted with “great caution”.

Evolut Pro+

“Despite the sophisticated statistical adjustment, the most reasonable cause for the difference in mortality is residual confounding. However, one might speculate that the less occurrence of paravalvular leak and the less need for pacemakers with balloon-expandable valves impact mortality as well, although this needs to be confirmed in a randomised setting,” he says. Abdel-Wahab adds that while there is an “unequivocal” association between paravalvular leak and mortality, “causality has never been proven”. He notes: “The problem of paravalvular leak remains in its assessment. More than mild forms are clearly associated with mortality, but this is less evident for mild forms, which probably need a more granular classification system.”

Anatomy and experience are relevant

In his commentary, which he co-wrote with Holger Thiele (also Leipzig, Germany), he states that anatomy and experience are the most relevant factors for device selection, but neither can be entirely corrected for in analyses such as two studies. “Experience being quite unmeasurable (despite the authors’ attempts) and anatomical data (based on sophisticated computed tomography measurements) being unavailable,” AbdelWahab and Thiele state. Dehara et al also make the point that future research is needed to address whether anatomical features and certain baseline characteristics may favour one TAVI technology over another. Abdel-Wahab explains that, although both devices valves can probably perform in a similar way in “a large percentage of patients”, short valves—such as balloon-expandable ones—may be preferable in “patients with coronary disease (allow easier access), younger patients with expected longevity and redo procedures (probably easier to retreat), and those with large anatomies (more radial force and less leaks)”. He adds: “Supra-annular self-expanding devices are preferred in small anatomies and for valve-in-valve procedures because of their superior haemodynamics.” Whether or not a head-to-head randomised trial of balloon-expandable valves versus self-expandable valves is performed, Abdel-Wahab does not think one established TAVI valve should be used as the comparator for all pivotal trials of novel devices. He says a “more sound” approach would be to compare new balloon-expandable valves with existing balloonexpandable valves and new self-expanding valves with existing self-expanding valves.

February 2020 | Issue 56

Coronary interventions

Further innovation and research is required for thrombus aspiration in PCI The TASTE and TOTAL studies suggested that routine thombus aspiration in patients undergoing percutaneous coronary intervention (PCI) did not provide mortality benefit and may increase the risk of stroke. However, a new study, CHEETAH, is evaluating whether a next-generation aspiration catheter could lead to improved outcomes. S Jay Mathews (Manatee Memorial Hospital, Bradenton, USA), principal investigator of the study, talks to Cardiovascular News about why thrombus aspiration still has potential as an effective tool in PCI.

What did the TOTAL/TASTE studies indicate about the use of aspiration thrombectomy for removing thrombus in coronary vessels? Published in 2013, TASTE (Thrombus aspiration during ST-segment elevation) randomised patients with STsegment elevation myocardial infarction (STEMI), with or without thrombus, to PCI alone or manual aspiration followed by PCI. The outcome was that aspiration showed no benefit when compared to the PCI alone group and no difference in all-cause mortality. TOTAL (Trial of routine aspiration thrombectomy with PCI vs. PCI alone in patients with STEMI), published in 2015, also studied patients with STEMI, with or without thrombus, randomised to PCI alone versus manual aspiration followed by PCI. The outcome of TOTAL was that routine aspiration showed no benefit and there was an increased rate of stroke in the manual aspiration group within 30 days.

How have these trials influenced current guidelines on thrombectomy? They led to changes in the guidelines. In 2011, the American College of Cardiology/American Heart Association (ACC/AHA) guidelines stated: “Manual aspiration thrombectomy is reasonable for patients undergoing primary PCI” (Class IIa). However, after the TOTAL trial, the guidelines were changed in 2015 to: “The usefulness of selective and bailout aspiration thrombectomy in patients undergoing primary PCI is not well established” (Class IIb). They also state that “routine aspiration thrombectomy before primary PCI is not useful” (Class III). Therefore, as per the guidelines, the selective use of aspiration thrombectomy may be worthwhile in patients with high thrombus burden. That is what we are currently seeing in clinical practice.

Why, despite the findings of TOTAL, is there still interest in thrombus aspiration?

One major limitation of PCI without aspiration for acute coronary syndromes is microvascular obstruction of the infarct-related artery because of downstream embolisation of thrombotic material. This can result in no-reflow phenomena and continued myocardial infarction. Moreover, in high thrombus burden, the true severity of the lesion may be obscured. There often may be a column of thrombus or stasis of blood prior to the culprit lesion. The strategy of upfront ballooning to restore flow may result in injury to healthy vessels and require longer stent lengths during PCI. High thrombus burden patients often require more expensive pharmacologic agents such as glycoprotein IIb/IIIa inhibitors just to help reduce clot. These patients also tend to be sicker, requiring monitoring in intensive care post-procedurally. In 2018, the TOTAL authors studied a subset of patients with high thrombus burden from the trial. They found an increased rate of stroke in the high thrombus burden patient subset, but with a reduction of distal embolisation. They concluded: “There may be a potential for future thrombus removal devices to reduce mortality if they are able to avoid an increased stroke

risk. Further innovation and research are needed in this high-risk population.” Therefore, PCI with thrombectomy has been regaining attention as a way to mitigate high thrombus burden. Adjunctive therapies such as CAT RX (Penumbra) can help address the thrombus in coronary vessels during PCI, as is being studied in CHEETAH.

What are the aims of CHEETAH?

The CHEETAH study aims to evaluate initial safety and collect performance data for Penumbra’s Indigo aspiration system with the CAT RX aspiration catheter, when used as an adjunctive device prior to standard of care PCI in patients with high thrombus burden in coronary vessels.

How is this technology different to that assessed in TOTAL? Clinical evidence has shown that aspiration thrombectomy is capable of removing thrombotic material from occluded coronary arteries. This may improve thrombolysis in myocardial infarction (TIMI) flow, and possibly prevent no-reflow phenomenon.

Aspiration thrombectomy is capable of removing thrombotic material from occluded coronary arteries. This may improve thrombolysis in myocardial infarction flow, and possibly prevent no-reflow phenomenon.”

order to maximise efficiency of thrombus removal. Removing thrombus from hard-to-reach vessels requires a highly deliverable, atraumatic catheter. With CAT RX, Penumbra has adapted their neuro-tracking technology used in stroke intervention combined with their mechanical power aspiration system to address the limitations of traditional manual aspiration thrombectomy in coronaries.

Why might these differences lead to different outcomes than those seen in the TOTAL trial?

Just like the IMS-III (Interventional management of stroke) trial for ischaemic stroke, TOTAL highlighted that new therapies are needed to improve the outcomes of these patients with high thrombus burden. Early experience with CAT RX data were presented at the American College of Cardiology (ACC) scientific sessions. This showed both initial safety and efficacy for the CAT RX mechanical power aspiration catheter for thrombus removal in acute myocardial infarction patients. These results are very encouraging and to date, CAT RX has now been used in more than 5,000 patients with acute coronary syndromes. The CHEETAH study is the first step toward making coronary mechanical thrombectomy standard of care for high thrombus burden patients. We expect this study to refine our technique of thrombus aspiration and fine tune the use of the CAT RX for patients with high thrombus burden.

Which patients do you think could benefit the most from mechanical thrombectomy for thrombus removal in the coronary vessels? Mechanical thrombectomy could potentially benefit patients with high thrombus burden in the coronaries. For the purposes of the CHEETAH study, we have selected to enrol patients with TIMI grade 4 and 5 thrombus.

What lesson can be learnt from the use of mechanical thrombectomy to treat acute ischaemic stroke?

The early experience with stroke intervention was disappointing. After the failure of IMS III, it took a group of dedicated neurointerventionalists, proper patient selection and advances in technology to pursue the MR CLEAN trial—which unequivocally established the benefit of mechanical thrombectomy for acute ischaemic stroke. We are currently in an era not dissimilar to this time period in the coronary space. For acute coronary syndrome patients with high thrombus burden, further innovation and research is needed for the benefit of this high-risk patient population.

Early evidence suggested a reduction in major adverse cardiovascular events, although larger randomised clinical trials using routine aspiration for all myocardial infarction patients were unable to confirm those results. All prior thrombectomy trials used small volume (for example, 30cc) syringes using catheters with smaller lumens. Manual aspiration also suffers from decreased aspiration force as the syringe fills with fluid. With an inconsistent vacuum, there is decreased efficacy and a potential for systemic embolisation during catheter removal. This phenomenon was reported in the TOTAL trial in 2015, and led to the decline in the use of aspiration thrombectomy in acute coronary syndromes. Subgroup analysis exploring the high thrombus burden subset of patients highlighted the potential for improved outcomes with better technology. This has motivated further innovation in the field of coronary aspiration. The aim of mechanical power thrombus S Jay Mathews aspiration is to deliver consistent suction throughout the aspiration cycle in

Issue 56 | February 2020

Cardiovascular surgery

#STS2020

Enhanced surgical recovery Young patients with aortic valve disease do better with protocols will allow safe SAVR than TAVI three-day discharge Patients discharged three days after open heart surgery are not at increased risk of complications, an analysis of discharge patterns has shown. S Chris Malaisrie (Northwestern Medicine, Chicago, USA) unveiled the findings at the 56th Annual Meeting of the Society of Thoracic Surgeons (STS 2020; 25–28 January, New Orleans, USA).

alaisrie said: “We have shown that long hospital stays after heart surgery are no longer necessary, and patients can go home safely after just a few days in the hospital. This information helps pave the way for the introduction of a cardiac enhanced recovery after surgery (ERAS) programme, proving that the use of such a strategy is feasible.” Researchers examined data from 478 patients who underwent nonemergency coronary artery bypass grafting (CABG) surgery or valve surgery (that is, patients had both mitral and aortic surgery) between July 2004 and June 2017 at Northwestern Memorial Hospital. The patients were separated into two groups: 357 patients with a length of stay (LOS) of more than three days and 121 patients with a LOS of less than three days. Aside from postoperative atrial fibrillation rates (2% in the less than three day LOS group and 19% in the greater than three day LOS group), rates of other complications, 30-day readmissions, and mortality rates were comparable. “Patients can go home after a shorter length of stay in the hospital without increased risk of complications and rehospitalisations,” said Malaisrie. “Because we found no detrimental effect of accelerated discharge, both

patients and physicians should not be averse to discharging patients when medically ready.” ERAS is a multidisciplinary treatment programme S Chris Malaisrie designed to achieve quicker recovery for patients undergoing major surgery and offers sustainable improvement in the overall quality of care. As a result of their findings, Malaisrie et al are developing Northwestern’s first cardiac ERAS programme, which will offer standardised approaches for optimising surgical outcomes. The programme will include a suite of modern care protocols based on the recently published guidelines from the ERAS Cardiac Society for optimal, evidence-based perioperative care in heart surgery. The published recommendations describe 22 potential interventions, separated into sections that cover all phases of surgical care—preoperative, intraoperative, and postoperative—and each principle is graded according to strength and level of evidence. The guidelines are intended to be flexible, and individually tailored for each programme.

Open heart surgery remains the best option for young and middleaged adults with aortic valve disease, for now. However, the use of transcatheter aortic valve implantation (TAVI) is continuing to expand to a wider group of eligible patients, according to a presentation at STS 2020. RESEARCHER JENNIFER S Nelson (Nemours Children’s Hospital, Orlando, USA) said: “Our research favours the use of surgical aortic valve replacement (SAVR) in adults younger than 55 years old. Although young and middleaged adult TAVI candidates do exist, thoughtful patient selection is critical to optimising triage to SAVR and TAVI.” Using the STS National Database, Nelson and colleagues from Nemours and the Cleveland Clinic in Ohio examined data from patients aged 18–54 years who received aortic valve replacement or implantation (SAVR or TAVI) between 2013 and 2018. Approximately one-sixth had congenital heart disease (CHD). As a result, researchers combined data from two components of the Database: the STS Adult Cardiac Surgery Database (ACSD) and the STS Congenital Heart Surgery Database (CHSD). Overall, 1,580 unique CHSD and 44,173 ACSD operations were analysed, and >15% of the operations were related to CHD. A comparison of isolated SAVR (no other complex operations were performed at the same time as the aortic valve replacement) with isolated TAVI found that the stroke rate was 0.9% versus 2.4%, respectively. The researchers also found the 30-day mortality rate was slightly better for isolated SAVR than for isolated TAVI at 1.9% versus 2.9%. TAVI had an advantage over SAVR when researchers looked at the length

Harness the power of Twitter to give your research greater impact In a talk highlighting the potential power of Twitter to promote research, Ourania Preventza (Division of Cardiothoracic Surgery, Baylor College of Medicine, Houston, USA) told delegates at STS 2020 that highly-tweeted articles are 11 times more likely to be cited than less tweeted articles, based on a study in the Journal of Medical Internet Research (2011). She was taking part in a session entitled “The editor’s pick—top papers and why”, with insights and editors’ perspectives on producing a top manuscript for The Annals of Thoracic Surgery, official journal of the STS. PREVENTZA PROVIDED INSIGHTS into how social media can increase an article’s audience and impact. Facebook, Twitter or LinkedIn, as well

as research-oriented platforms, such as Research Gate, Nature Network and Graduate Junction, can enable quick feedback, increase visibility and

Jennifer Nelson

of hospital stay: SAVR was six days versus four days for TAVI (with the length of stay for TAVI expected to continue decreasing). This is particularly noteworthy, said Nelson, because the

Thoughtful patient selection is critical to optimising triage to SAVR and TAVI.” number of young and middle-aged adult TAVI candidates is increasing, with TAVI becoming more appealing to younger patients who want to minimise downtime and risks.

encourage connections with researchers of similar interests, Preventza noted. She added tweets can predict highly-cited articles within three days of publication. However, she advised social media Ourania Preventza be used with caution, and that physicians should be aware of their digital footprint. Other presentations in the session included “When not to do a meta-analysis”, the essential skills and resources for high impact outcomes research, and the impact of continuing medical education.

February 2020 | Issue 56

MedTech Insights

Sapien 3 becomes first TAVI valve to be approved for low-risk patients in both Europe and the USA Edwards Lifesciences has received the CE mark for its Sapien 3 transcatheter aortic valve implantation (TAVI) device to be used for aortic stenosis in low-risk patients. Both Edwards and Medtronic (with its CoreValve Evolut range) have US Food and Drug Administration (FDA) approval for their devices to be used for lowrisk patients in the USA, but this new CE mark approval makes Edwards the first TAVI company to have this indication in Europe.

Source: BIBA MedTech Insights TAVI Monitor

A PRESS RELEASE reports that CE mark follows on from the publication of the PARTNER 3 results in the New England Journal of Medicine. The study, which was also presented at the 2019 American College of Cardiology (ACC) scientific sessions (16–18 March, New Orleans, USA), indicated that TAVI with Sapien 3 was superior to surgical aortic valve replacement for the management of aortic stenosis in patients at low surgical risk. At one year, the rate of the primary endpoint—a composite of all-cause death, stroke, or rehospitalisation—was 8.5% in TAVI patients (496 overall) versus 15.1% in surgery patients (454 patients). Study investigators Michael Mack (Baylor Scott and White Hospital, Plano, USA) and others report in the New England Journal of Medicine: “The requirements for both noninferiority and superiority were met, with an absolute difference between the TAVI group and the surgery group of -6.6 percentage points (p<0.001 for noninferiority) and a hazard ratio of 0.54 (p=0.001 for superiority).” Furthermore, after PARTNER 3 was published, a study on the health status of the PARTNER 3 patients was simultaneously presented at the 2019 Transcatheter Cardiovascular Therapeutics (TCT) meeting (25–29

September, San Francisco, USA) and published in the Journal of the American College of Cardiology. This showed that TAVI patients improved more rapidly than surgery patients, showing (according to a press release) a difference of 16 percentage points between groups in the Kansas City Cardiomyopathy Questionnaire overall summary scores at one month. The press release states that previous studies (in higher risk patients) have already shown TAVI to be associated with better (early) health status but notes that this study “also observed a sustained health status benefit of TAVI compared with surgical aortic valve replacement at later time points of six months (2.6 points, p=0.002) and one year (1.8 points, p=0.03).” Suzanne J Baron (Lahey Hospital and Medical Center, Burlington, USA) is quoted as saying: “Taken together with the clinical outcomes of the PARTNER 3 trial, these health status findings further support the use of TAVI in patients with severe aortic stenosis at low surgical risk.” However, Mack et al note that the “most important limitation” of their study is that the results “only reflect one-year outcomes and do not address the problem of long-term structural valve deterioration”. “Definitive conclusions regarding

the advantages and disadvantages of TAVI as compared with surgery (with either bioprosthetic or mechanical valves) depend on long-term followup. In this trial involving younger low-risk patients, the protocol requires clinical and echocardiographic followup to continue for at least 10 years,” they add.

FDA approval

Prior to receiving CE mark approval, on 16 August 2019, Edwards received US FDA approval for the Sapien 3 range (Sapien 3 and Sapien 3 Ultra). At the time, Edwards’ corporate vice president, Larry L Wood, said: “This approval is a significant milestone that will allow all patients diagnosed with severe aortic stenosis to be considered for TAVI based on their individual preferences and anatomical considerations versus traditional risk scoring.” Of note, the FDA has also approved Medtronic’s CoreValve Evolut range (Evolut R and Evolut Pro) for low-risk TAVI patients; in fact, the Sapien range and the CoreValve range received FDA approval on the same day. However, about a week after the approval, the FDA issued a Class I recall (the most serious kind) for the delivery system of Sapien 3 Ultra. According to the FDA, the reason for the recall was because

The number of TAVI implants in Western Europe increased from 13,677 in Q3 2018 to 16,306 in Q3 2019, a 19.2% increase.” “Edwards Lifesciences has received reports of burst balloons during implantation procedures, which have resulted in significant difficulty in retrieving the valve into the catheter and withdrawing the system from the patient, which may cause vascular injury, bleeding, or surgical intervention”. The FDA goes on to

BIBA Briefings

state that use of an affected product may “cause serious adverse health consequences, including death”. Although labelled a “recall”, the announcement did not mean that the Sapien 3 Ultra system had to be taken off the market. Instead, the FDA referred physicians to an Urgent Field Safety notice that Edwards sent to customers on 9 July 2019. This notice outlined instructions for deploying the Sapien 3 Ultra system and what to do in the event of a burst balloon.

Effect of approvals on TAVI market

As the FDA approvals only occured in Q3 2019, and the CE mark approval in Q4 2019, their impact on the respective US and European markets is, as yet, unknown. However, it would be reasonable to assume that they will lead to an increased use of TAVI, and an increased use of TAVI in low-risk patients. TAVI is already a growing market. The BIBA MedTech Insights TAVI Monitor, which tracks data on a quarterly basis, shows that the number of TAVI implants in Western Europe increased from 13,677 in Q3 2018 to 16,306 in Q3 2019—a 19.2% increase (see Figure 1). Therefore, if the TAVI market continues to grow, the key questions are whether the rate at which it is growing will increase and how much of this is attributable to low-risk patients. The proportion of TAVI procedures performed in low-risk patients also increased between Q3 2018 and Q3 2019: from 4.6% to 5.2%. A further key question about the future is that, assuming that this growth continues, whether the rate at which this proportion is growing will also increase. Another unknown is how receiving the CE mark for low-risk use will affect Edwards Lifesciences’ market share. The company is already the market leader and is likely to remain in this position, so the question is whether its share of the market, 43% in Q3 2019, will increase. This is more difficult to predict given that Medtronic may soon receive CE mark approval for CoreValve to be used in low-risk patients (like Edwards, Medtronic has positive data for low-risk patients) and other valves may come onto the market.

BIBA Briefings is an online platform (www.bibamedtech.com/bibabriefings) that gives an in-depth analysis of the latest market intelligence from BIBA MedTech Insights (www.bibamedtech.com). It also reviews the latest industry news and pipeline developments. For editorial enquiries, please contact Dawn Powell: dawn@bibamedical.com For sales enquiries (including BIBA MedTech Insights), please contact Merveille Anderson: merveille@bibamedical.com

February 2020 | Issue 56

Device approvals

Product News First transcatheter mitral implantation device comes on to the market

The Tendyne transcatheter mitral valve implantation (TMVI) system (Abbott) has received the CE mark, making Abbott the first company to have such device on a market anywhere in the world. A press release reports that this “life-changing” therapy treats significant mitral regurgitation in patients requiring a heart valve replacement and provides a safe and effective solution for patients who are not candidates for open-heart surgery or transcatheter mitral valve repair. For patients at high-risk for openheart surgery or in clinical situations where the mitral valve is too damaged for a successful repair with Abbott’s MitraClip device, the Tendyne system offers an alternative minimally invasive treatment option when the leaky valve needs to be replaced, a press release states. The Tendyne valve is a first-of-itskind therapy to replace the mitral valve in patients in need of symptom relief and quality-of-life improvement without open surgery and when transcatheter mitral repair is not possible. Global trial results to date have demonstrated excellent procedural safety and have shown 98.9% of Tendyne patients experienced mitral regurgitation elimination at discharge which was sustained through one-year in this very sick patient group, says the statement. The system is designed to adapt to a range of patient anatomies. The selfexpanding valve is delivered through a small incision in the chest and up through the heart where it is implanted i, replacing the native mitral valve. It is available in multiple sizes to treat a broad range of valve anatomies, and is fully repositionable and retrievable during implantation, allowing the best possible outcome for people suffering from mitral regurgitation and needing a valve replacement. Hendrik Treede (University Hospital Bonn, Bonn, Germany) says: “European approval for Abbott’s Tendyne mitral valve replacement therapy provides the clinical community with a new choice in how we approach correcting a leaking mitral valve. For the first time outside of clinical trial settings, heart teams now have a minimally invasive valve replacement therapy that is backed by an excellent safety profile and designed to help physicians reposition the device as needed for improved patient outcomes.”

Abbott given green light for trial on MitraClip in moderate surgical risk patients Abbott has announced that the US Food and Drug Administration (FDA) has approved a first-of-its-kind clinical trial to compare the effectiveness of Abbott’s MitraClip device to open heart mitral valve surgical repair in

MitraClip

people with primary mitral regurgitation (MR) who are eligible for open-heart surgery. If successful, the trial has the potential to expand treatment options from the current indication of patients at prohibitive risk for surgery to also include patients at moderate risk. The prospective, randomised REPAIR MR clinical trial will enrol approximately 500 patients at 60 sites in the USA, Canada and Europe to evaluate the effectiveness of the MitraClip device in moderate-surgicalrisk patients with severe primary MR who are candidates for open-heart surgery. The company statement says the trial’s design addresses the issue that, despite symptoms and increased mortality for people suffering from MR, patients are often undertreated by openheart mitral valve surgery. Currently, only an estimated 15% of patients who are eligible for the standard-of-care surgery for their primary MR receive surgical treatment. This may be because the MR goes undiagnosed, or patients may forego surgery due to prolonged recovery time or fear of possible surgical complications. Patrick McCarthy (Northwestern Medicine Bluhm Cardiovascular Institute, Chicago, USA), co-principal investigator of the REPAIR MR trial, says: “The REPAIR MR trial seeks to evaluate the MitraClip device in treating a new patient population who currently undergo the standard surgical treatment, but are at moderate surgical risk. This is an important question since approximately 70% of people diagnosed with primary mitral regurgitation are not treated with open-heart mitral valve surgery today, yet are in need of treatment and symptom relief.” The trial will also be led by co-principal investigator Saibal Kar (Los Robles Hospital and Medical Center, Thousand Oaks, USA). Mitral regurgitation (MR) is a debilitating, progressive and lifethreatening disease in which the heart’s mitral valve does not close completely, causing blood to flow backward and leak into the atrium of the heart. The condition is the most common valve disease worldwide and can lead to reduced quality of life, recurrent hospitalisations and decreased survival. Abbott’s MitraClip system has been commercially available in the USA since 2013 and in Europe since 2008 and, according to the company, has shown significant impact for patients with

both primary and secondary MR who are at high risk for open-heart surgery. The MitraClip therapy, now on a fourth generation of innovation, has shown improved clinical outcomes and quality of life through a minimally invasive option that reduces MR’s debilitating symptoms. Neil Moat, chief medical officer of Abbott’s structural heart business, says: “Abbott is leading the way in the structural heart space. We are pushing the field forward by making clinical investments to examine whether new, minimally invasive treatment options are suitable, or even preferable, to what has been the standard of care. Devices that can be delivered through a minimally invasive method to close or repair a significant structural issue in the heart are in high demand, and we are committed to continuing our efforts to bring the benefits of these devices to patients who need them.”

Breakthrough designation for ECG-based algorithm granted by FDA

The US FDA has granted breakthrough device designation to digital health and artificial intelligence (AI) company Eko for an echocardiogram (ECG)-based algorithm to help identify induced left ventricular ejection fraction (LVEF). FDA breakthrough device

designation helps accelerate the algorithm’s regulatory review and is only awarded to novel innovations that demonstrate the potential to address unmet medical needs for life-threatening or irreversibly debilitating diseases. The algorithm analyses 15 seconds of ECG data collected from the Eko DUO digital stethoscope during a physical exam and helps identify reduced LVEF, a measure commonly used to diagnose patients with heart failure. Eko’s low ejection fraction algorithm employs a deep neural network developed in collaboration with the Mayo Clinic. The algorithm was first announced in a publication in Nature Medicine in January 2019. In further clinical studies at the Mayo Clinic, the DUO combined with the AI algorithm was able to detect ejection fraction <35% with an area under the curve (AUC) of 0.90. “The breakthrough device designation recognises the vast unmet clinical needs in identifying heart failure early in patients, whether it be due to cost, inaccessibility, or misdiagnosis,” says Connor Landgraf, CEO and co-founder of Eko. “We look forward to working with the FDA to bring this algorithm to patients and to give clinicians a new tool to screen for low ejection fraction.” “A low ejection fraction means that the heart pump is weak, which can lead

to shortness of breath, swelling, exercise intolerance, or sudden death, so it is important to identify, as many treatments exist,” said Paul Friedman (chair of the Department of Cardiovascular Medicine, Mayo Clinic, Rochester, USA). “This technology gives physicians a tool to detect heart disease earlier, and before it develops into a more serious illness. In effect, by imbedding the technology in a commonly used clinical tool—the stethoscope—all caregivers carry some of the diagnostic prowess of an expert cardiologist with them.”

FDA approves Abbott heart pump for less invasive surgical approach

Abbott has announced US FDA approval of a new alternative surgical technique for Abbott’s HeartMate 3 heart pump that the company says will allow more advanced heart failure patients to avoid open heart surgery. The heart pump can now be implanted through an incision in the chest wall versus open heart surgery. The new, less invasive approach is designed to provide surgeons with a choice in surgical method for patients receiving the HeartMate 3 left ventricular assist device (LVAD), says a statement from the company. The Abbott press release points out that the approval is based on two studies: ELEVATE, a multicentre, voluntary, observational registry collecting post-marketing data, and the LAT Feasibility study, a single-arm, prospective, multicentre study. The two trials found bleeding (requiring surgery), infection and arrhythmias were lower in the group implanted via the lessinvasive surgical approach than those who underwent open heart surgery. Historically, heart pumps have been implanted via open heart surgery. With approval for an alternative surgical technique, Abbott’s HeartMate 3 heart pump can now be implanted via lateral thoracotomy, a surgical approach where an incision is made between a patient’s ribs to access the heart. According to the press release, physicians believe that for many patients this technique has advantages over open heart surgery because it can result in less bleeding and a shorter recovery time for patients. “This is a significant advancement for patients who can now receive a life-saving LVAD through an alternative procedure that can yield shorter hospital stays and a faster recovery,” comments Igor Gosev (University of Rochester Medical Center, New York, USA) in the statement. “Heart failure is a crippling and costly disease so being able to offer patients the HeartMate 3 heart pump with this less-invasive approach gives them the opportunity to return to a better quality of life more quickly.” Robert L Kormos, medical director for mechanical circulatory support, Abbott, adds: “We continue to focus on advancing our heart failure devices and techniques to make life better for the patients we serve. The first approved LVAD—HeartMate I—was approved more than 25 years ago. Since that time, the technology has evolved immensely.”

Issue 56 | February 2020

Studies of edoxaban through real-world data, particularly in the underserved elderly population.”

Clinical News

Emboliner

Emboline completes enrolment in SAFEPASS 2 clinical trial

Emboline has completed enrolment in its SAFEPASS 2 clinical study of the Emboliner embolic protection catheter. A press release from the company, which develops total embolic protection technology for transcatheter aortic valve implantation (TAVI), also indicates that early results from the first 24 patients show an excellent safety profile and technical performance. SAFEPASS 2 is a prospective, nonrandomised, multicentre, open-label study at three centres in New Zealand to assess the safety and technical performance of the second-generation Emboliner device. Thirty-day results from the first 24 patients were presented at the Transcatheter Cardiovascular Therapeutics conference (TCT 2019; 24–28 September, San Francisco, USA). They showed no device-related adverse events, no device-related access site complications, 100% technical performance, and debris capture and removal in 100% of patients. The company says that final data analysis is now underway for the full study population, the results of which will be used to file for CE mark for the Emboliner later this year. The study also examined the amount of debris collected from patients. An average of 250 particles of debris ≥150um in size was removed from each patient, with more than half of patients having debris ≥1mm in size, and one in four patients having debris ≥2mm in size. The press release states that the amount of debris removed was more than five times the amount seen in the Sentinel trial of the Sentinel cerebral protection system. The company statement notes that debris generation during TAVI has been associated with a range of negative neurological outcomes for patients, ranging from a major stroke rate of approximately 6%, overall stroke rates as high as 22%, and new cerebral lesions in as many as 94% of patients. The Emboliner device is designed to provide total embolic protection of the brain and body during TAVI.

European trial data ‘reinforce’ safety profile and efficacy of Lixiana Daiichi Sankyo Europe has announced outcomes from an observational study in mainly caucasian atrial fibrillation

(AF) patients being treated with the anticoagulation drug edoxaban (Lixiana). The results of the Danish observational cohort study, published in the European Heart Journal—Cardiovascular Pharmacotherapy, showed that rates of thromboembolism—ischaemic stroke and systemic embolism—were similar to those observed in the composite ‘stroke’ outcome in the ENGAGE AF-TIMI 48 clinical trial, a study comparing the long-term efficacy and safety of Lixiana with warfarin in AF patients. In addition, primary (composite) bleeding outcomes requiring hospitalisation were approximately 50% lower than observed in ENGAGE AF-TIMI 48. The real-world findings reinforce Lixiana’s efficacy and safety profile in elderly AF patients in routine clinical practice, Daiichi Sankyo says in a press release. Many patients were elderly with comorbidities and almost one-fourth (23.5%) had a hospital diagnosis of cancer. Commenting on the study, lead author, Peter Brønnum Nielsen (Aalborg Thrombosis Research Unit, Aalborg University, Denmark), says: “These new data, reporting on outcomes in a European AF population seen in routine clinical practice, are reassuring as they reinforce previous evidence that edoxaban has a good safety profile and is an effective treatment for the prevention of stroke in a broad AF population.” In all, 643 patients (28%) received Lixiana 30mg dosage regimen and 1,642 (72%) Lixiana 60mg, similar to the split in ENGAGE AF-TIMI 48. The primary effectiveness endpoint of thromboembolism, comprised of a composite outcome of stroke and systemic embolism, occurred 41 times. In patients taking Lixiana 30mg daily (dose reduced) the event rate was 2.07 per 100 person-years, and in those taking Lixiana 60mg daily (full dose) the event rate was 1.62 per 100 personyears. The safety outcomes, comprised of a composite of all bleedings, including intracranial, gastrointestinal and major bleeding in other anatomic sites, occurred 89 times. Safety outcome event rates were similar among the full dose and dose reduced groups, with rates of 3.87 and 3.85 per 100 person-years respectively. “Real-world data, such as these, provide us with a greater understanding of AF treatment pathways and broaden our insight into the patient population,” comments Wolfgang Zierhut, executive director medical affairs and Head Thrombosis and Cardiovascular at Daiichi Sankyo Europe in the statement. “We are committed to adding to the growing body of evidence on the use

Bioventrix announces positive one-year outcomes for Revivent TC system, and CE mark extension

Bioventrix has announced the extension of its CE mark for the Revivent TC Transcatheter Ventricular Enhancement System for heart failure to May 2024. This follows an earlier announcement from the company of online publication of positive one-year results from its CE mark study of Revivent in the European Journal of Heart Failure. The CE mark is issued by the European Commission and allows the device to be marketed throughout EU member nations. BioVentrix received its initial CE mark in 2016. A press statement from the company on the one-year findings says that the authors of the study concluded in the paper: “Treatment with the Revivent TC System in patients with symptomatic heart failure results in significant and sustained reduction of left ventricular (LV) volumes and improvement of LV function, symptoms, and quality of life,” adding: “The ability to achieve these results without the need for sternotomy

Revivent transcatheter system

or cardiopulmonary bypass is an important advance for the treatment of patients suffering from ischaemic cardiomyopathy heart failure.” The trial was a prospective, multicentre, single-arm study of 89 patients at 22 centres in 12 countries in the EU and was designed to evaluate the efficacy and safety of the Revivent TC System for scar exclusion in the heart, volume reduction, and reshaping of the LV in selected patients with ischaemic cardiomyopathy (enlarged and weakened left ventricle with reduced capacity to pump blood after a heart attack). Of the 86 patients successfully treated with the system, 51 patients received delivery via a sternotomy and 35 were treated using a less invasive, hybrid approach without sternotomy. None of the patients treated in this trial required cardiopulmonary bypass to implant the device. Among the findings were: 100% of patients demonstrated significant and sustained reduction in LV volumes 16% improvement in LVEF (29±8%

vs. 34±9%, p<0.005) 90.6% survival 27% improvement in New York Heart Association (NYHA) functional class 36% improvement in quality of life 18% improvement in exercise capacity 50% improvement in average mitral regurgitation (MR) grade in the 68 patients who entered the study with measurable functional MR (FMR) of at least grade 1+ at six months (1.12 vs. 0.57) and 24% improvement at 12 months (1.12 vs. 0.86) 97% procedural success Median length of hospital stay was 14 days; however, subsequent postmarket study has seen length of stay decrease substantially as implanters gain more experience The company is currently enrolling patients in the REVIVE-HF postmarket study in Europe, a randomised, controlled, prospective, multicentre, dual-arm study evaluating the Revivent TC system against guideline-directed medical therapy. The study is expected to enroll 180 patients. In the USA, the company is currently enrolling patients in a pivotal trial of the Revivent TC system, the ALIVE Trial.

First patient enrolled in PREDICT-LAA clinical trial

FEops has announced that the first patient has been enrolled in the physician-initiated PREDICT-LAA trial. Led by Righshospitalet (Copenhagen, Denmark), it aims to assess whether the use of FEops HEARTguide computer simulations based on cardiac CT imaging can contribute to better preprocedural planning and improved procedural outcomes of percutaneous left atrial appendage (LAA) closure procedures with the Abbott Amplatzer Amulet device. The trial is supported by both Abbott and FEops. PREDICT-LAA is a prospective, multicentre, randomised controlled trial. In total, 200 patients eligible for percutaneous LAA closure with an Amplatzer Amulet device will be enrolled—100 patients will be allocated to the computational simulation treatment arm and 100 patients to the standard treatment arm. Primary endpoints are closure of the LAA, and presence of device-related thrombus. Estimated enrolment completion date is March 2021. “Our support together with Abbott in the PREDICT-LAA trial shows our strong commitment to generate a robust body of clinical evidence with FEops HEARTguide, contributing to better procedure planning and patient outcome,” says Christian Vincent, director of therapy development at FEops in a press release. FEops HEARTguide, currently available on the EU and Canadian market, is a cloud-based procedure planning environment for structural heart interventions that provides physicians insights to evaluate device sizing and positioning pre-operatively using novel computational modelling and simulation technology.

February 2020 | Issue 56

Companies PCI is the largest trial of genetics in cardiology, and results are scheduled to be announced at ACC 2020.

Industry News

From L to R: Davide Capodanno, Gilles Montalescot, Marco Valgimigli and Dirk Sibbing

Spartan Bioscience sets up European advisory board for precision medicine test in cardiac stent patients

Spartan Bioscience, maker of precision medicine diagnostic solutions, has established a new scientific advisory board (SAB) in Europe for cardiac stent patients consisting of international clinical and academic interventional cardiologists. The company says its role will be to advise and support Spartan on its current and future clinical programmes and product roadmap. A press release also states the board will be supplemented with a North American team to be announced at the American College of Cardiology conference (ACC 2020; 28–30 March, Chicago, USA). The members of the European board are: Dirk Sibbing (Ludwig-Maximilians University, Munich, Germany); Gilles Montalescot (Pitié-Salpêtrière Hospital,

Jean-Claude Dubacher named chair and CEO of B Braun Medical

Paris, France); Marco Valgimigli (Inselspital Universitätsspital, Bern, B Braun has announced the appointment Switzerland), and Davide Capodanno of Jean-Claude Dubacher as chair (University of Catania and Policlinicoand CEO. Dubacher joined B Braun Vittorio Emanuele, Catania, Italy). in August 2019 as president of B The company statement explains Braun Medical. A press release reports Spartan’s precision medicine test Dubacher’s experience in the healthcare identifies whether a patient carries industry spans more than 15 years a CYP2C19 mutation. More than in consulting and corporate roles, 30% of the world’s population, and including strategy, commercial, supply 50% of Asians, carry the mutation. chain and manufacturing. CYP2C19 is a liver enzyme that Before joining B Braun, he led metabolises 15% of all prescribed drugs, commercial operations for the Surgical including antiplatelet drugs. Spartan Ophthalmology Division of Johnson says its rapid, portable test allows & Johnson in Europe, Middle East real-time, near patient determination and Africa. Dubacher holds a PhD in of the patient’s genotype, aiding in law from the University of Zurich in determining the appropriate antiplatelet Switzerland, and an MBA from Harvard treatment, leading to better results Business School. and lower cost healthcare. The press Caroll H Neubauer, chair and CEO, release says Spartan technology B Braun of America, comments: has been used in several landmark “Jean-Claude’s broad leadership clinical studies, including, POPular experience across multiple therapy Genetics, a 2,500 patient, eight-year areas and business study in Europe published in the New disciplines will England Journal of Medicine, and serve us well at B announced at the European Society Braun. His focus of Cardiology meeting. In addition, on customers it was used in TAILOR-PCI, a 5,300 and supporting patient, seven-year study funded by people to be the Mayo Foundation and the successful in National Institutes of Health developing, Jean-Claude (NIH). Spartan says TAILORDubacher

manufacturing, marketing, and selling products and services that benefit patients is exactly the right approach to ensure our ongoing growth.” Dubacher comments: “I am excited to be part of the B Braun family, and look forward to continuing our long legacy of partnering with customers and stakeholders across the healthcare industry to help make a difference for the millions of patients we serve across the USA and Canada.”

Proximo Medical to partner with CeloNova Biosciences

Proximo Medical is to partner with CeloNova Biosciences, supplier of the COBRA PzF nanocoated coronary stent (NCS), in select US markets. Carl St Bernard, chief executive officer of CeloNova Biosciences, states in a press release: “By partnering with Proximo Medical, CeloNova can leverage their tremendous expertise, experience, and scale to accelerate the overall market impact of breakthrough technologies like the COBRA PzF nanocoated coronary stent.” Brett Martin, chief executive officer of Proximo Medical says: “We are pleased to be partnering with CeloNova, a company that is revolutionising medicine and rethinking the bounds of improved patient care.” Proximo Medical is a fractional commercial organisation for startup medical device technologies and established medical device companies looking to expand adoption in the USA.

Calendar of events 22–25 February CRT Washington DC, USA

13–16 May SCAI Atlanta, USA

www.crtmeeting.org

18–21 May EuroPCR Paris, France

28 February–1 March International TAVI Congress Edinburgh, Scotland scottishcardiac.org/event/

17–20 June TVT Chicago, USA

13–15 September PCR London Valves London, UK

8–10 October EACTS Barcelona, Spain

crf.org/tvt

www.pcronline.com/Courses/PCR-

www.eacts.org/annual-meeting

London-Valves

www.pcronline.com/Courses/

29 August–2 September ESC Paris, France

EuroPCR/

www.escardio.org/Congresses-&-

23–27 September TCT Miami, USA

Events/ESC-Congress

2020.tct-crf.org

international-tavi-congress-theaortic-valve-meeting

August 2019

no:

Maisa Francesco

Transseptal puncture

Profile

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