Cardiovascular News Issue 50 - August 2018 by BIBA Publishing

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Positive data for renal denervation reignites interest in field After two studies indicated that renal denervation lowers blood pressure both with and without antihypertensive drugs, Felix Mahfoud (Klinik für Innere Medizin III, Saarland University Hospital, Homburg, Saarland, Germany) said that the PCR board, who organise EuroPCR, was “committed to supporting the field of renal denervation”. He added that there would be further developments in the field, so interventional cardiologists should “stay tuned”.

ahfoud’s statement, on behalf of PCR, came directly after two shamcontrolled trials were presented at EuroPCR (22–25 May, Paris, France)—with both studies suggesting that renal denervation does lower blood pressure. The first of these, SPYRAL HTN-ON MED (of which, Mahfoud was an investigator), explored the use of the Symplicity Spyral renal denervation system (Medtronic) in patients with moderate, uncontrolled hypertension who were taking one to three antihypertensive medications. A previous study with the first-generation Symplicity catheter did not demonstrate a significant reduction in blood pressure compared with a sham procedure in patients with resistant hypertension. According to Mahfoud, one of the lessons from this trial was that “we probably started with the wrong population because their hypertension was too severe and perhaps could not be treated with anything”. Presenting the SPYRAL HTN-ON MED trial at EuroPCR, David E Kandzari (Department of Interventional Cardiology, Piedmont Heart Institute, Atlanta, USA) reported that patients were included in the study if they were stable on one to three antihypertensive medications for six weeks prior to enrolment. After a second screening visit, 76 patients were randomised to renal denervation (38) or a sham procedure (38). Follow-up visits were scheduled

David E Kandzari

at one month, three month, six months, and planned 12 to 36 months after the procedure. The primary efficacy endpoint was change from blood pressure measured at baseline (at the second clinic visit) to blood pressure measured at the six-month followup visit. At six months, there was a significant decrease in 24-hour ambulatory blood pressure in terms of systolic and diastolic blood pressure in the renal denervation group compared with baseline levels. There were no significant blood pressure reductions in the sham procedure group. These findings meant that, compared with the sham procedure group, the renal denervation group had significant reductions in both 24-hour systolic blood pressure

and 24-hour diastolic blood pressure: -7mmHg (p=0.0059) and -4.3mmHg (p=0.0174), respectively. Writing in the Lancet— SPYRAL HTN-ON MED was simultaneously published in the journal to its EuroPCR presentation—Kandzari et al note that the magnitude of blood pressure decline was “clinically significant” as prior studies have shown such reductions to be associated with “lower rates of both cardiovascular events and mortality”. Kandzari told Cardiovascular News: “Irrespective of the level of blood pressure elevation, the extent of blood pressure reduction observed in this trial has clinical significance. Considering that hypertension is the worldwide leading cause of death and disability, if confirmed in larger study, such blood pressure reductions would have a substantial public health impact.” In the Lancet, the authors observe that the extent of blood pressure reduction with renal denervation “increased over followup through six months” and the reductions were present throughout the day and night. Kandzari told delegates at EuroPCR this represents an “always on” effect for renal denervation that may have particular relevance given the limitations of dosing regimens and adherence with medications. This apparent “always on” effect may be especially importance given the relative prevalence of patients in both the sham procedure group and the renal denervation group who did not adhere to their medication regimens. Overall, the study investigators report in the Lancet, individual patient adherence to medication was 60% and this was “highly Continued on page 2

Giovanni Di Rienzo: EU regulations Page 6

Juan F Granada: Profile Page 16

New ORBITA analysis finds iFR/FFR values do not predict impact of PCI on exercise time

ew data from the ORBITA trial indicate percutaneous coronary intervention (PCI) does not significantly improve exercise time compared with a sham procedure in patients with stable disease regardless of baseline fractional flow reserve (FFR) or instantaneous wave free ratio (iFR) values. However, this analysis does show that lower FFR/iFR values predict a progressively greater benefit of PCI on stress echocardiography ischaemia. ORBITA, which was presented at the 2017 Transcatheter Cardiovascular Therapeutics (TCT) meeting (29 October–2 November, Denver, USA), prompted heated debate in the interventional cardiology community when it indicated that PCI did not provide a benefit over a sham procedure

Rasha Al-Lamee

in terms of exercise time in patients with stable disease. A key criticism of the study at the time was that it enrolled several patients who would not have undergone PCI in clinical practice—approximately, a third of patients had FFR/iFR values that were above the standard thresholds (0.80 and 0.89, respectively) for intervention—and, therefore, this may have affected the results. Presenting the new Continued on page 2

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EuroPCR

Positive data for renal denervation reignites interest in field Continued from page 1

variable”. “We embarked on the SPYRAL HTN OFF MED study as a biological proof-ofprinciple study [which showed renal denervation to significantly lower blood pressure in patients not taking medication]. However, the rates of non-adherence and patients’ general desire not to take medication has increasingly come to the forefront. So, there may be a role for renal denervation in the context of patients off medication,” Kandzari commented. He concluded: “Renal denervation with the Symplicity Spyral system resulted in statistically significant and clinically relevant blood pressure reductions at six months in uncontrolled hypertensive patients compared with sham control and in the presence of commonly prescribed antihypertensive medications.” In the context of these results, further to the potential use of renal denervation being used in patients off medication, the procedure could be used to compliment drug therapy to lower blood pressure in patients with “uncontrolled hypertension despite the persistent use of medication,”he added. Following Kandzari’s presentation, Laura Mauri (Brigham and Women's Hospital, Boston, USA) presented the results of the RADIANCE-HTN SOLO trial (which, like SPYRAL HTN ON MED was simultaneously published in the Lancet). This study compared renal denervation with an endovascular ultrasound system (Paradise, ReCor Medical) with a sham procedure in patients with mild-to-moderate hypertension who were off medication. Mauri reported that, at the two-month follow-up point,

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renal denervation was associated with a “greater reduction in daytime ambulatory blood pressure than a sham procedure (6.3mmHg greater, p<0.001, in the intention-to-treat analysis), consistent reductions in 24-hour ambulatory, office, and home blood pressure, and a high rate blood pressure control on the absence of medications.” Both Kandzari and Mauri noted that future studies, of the respective devices, would further evaluate the safety and efficacy of renal denervation. Kandzari reported that a larger SPYRAL HTN PIVOTAL trial is ongoing—having just received investigational device exemption from the US FDA—and would further examine the use of renal denervation in patients off medication. Additionally, he said that “a study design for a larger trial in the presence of antihypertensive therapy is in development”. Mauri stated that follow-up of the RADIANCE-HTN SOLO study is ongoing through three years to assess longer term safety and efficacy of the endovascular renal denervation system and that “enrolment is ongoing for a parallel blinded sham-controlled trial of patients with resistant hypertension (RADIANCE-HTN TRIO)”. Mahfoud commented that the main research topics of these studies and other studies should be intraprocedural feedback, identification of responders, and sustainability of the effects. However, based on the available evidence, he added: “We know that renal denervation does lower blood pressure in hypertensive patients with and without antihypertensive drugs. There is more to come, so stay tuned!”

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New ORBITA analysis finds iFR/FFR values do not predict impact of PCI on exercise time Continued from page 1

analysis at EuroPCR (22 May–25 May, Paris, France), ORBITA investigator Rasha Al-Lamee (Imperial College London, London, UK) commented that physiological assessment (with either FFR or iFR) was performed prior to randomisation but investigators were purposely blinded to the results of these assessments. “ORBITA was searching for the FFR/iFR values cutpoint for angina relief and, therefore, had to enrol patients eligible for PCI with a range of FFR/iFR values,” she explained. She added that the aim of this new analysis, using regression modelling, was to assess the “placebo-controlled efficacy of PCI as predicted by prerandomised FFR and iFR.” In the original analysis, dobutamine stress echocardiography score—as a marker of reduction in ischaemia—was significantly improved in the patients who underwent PCI (103) compared with those underwent a sham procedure (93). Al-Lamee commented that, in this analysis, there were significant interactions between both FFR and iFR values and improvement in stress echocardiography score, stating: “As FFR/iFR values decrease there is a greater impact on reduction in ischaemia score. Both correlations are strongly statistically significant [p<0.0001 for both].” PCI was also shown to significantly improve freedom from angina, with a number needed to treat of five, compared with placebo. However, there was no evidence of an interaction between either FFR or iFR values and benefit of PCI on freedom from angina. The new analysis also showed that FFR/iFR values did not appear to impact the benefit of PCI on quality of life—in the main analysis, there were no significant differences between the PCI and sham procedure groups in terms of this endpoint. Furthermore, there was also no evidence that physiological assessment values impacted the effect of placebo-controlled PCI on exercise time. Al-Lamee observed: “The study was powered to expect an exercise time difference of more than 30 seconds [the difference found in the study] between

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the two groups. When you end up with an exercise time that is far smaller than you thought it would be, you are under powered to look at any stratification in terms of FFR/iFR.” She added that that she “absolutely agreed” with a point made by Martin Leon (Center for Interventional Vascular Therapy, Columbia University Medical Center, New York Presbyterian Hospital, New York, USA) that exercise time may not have been the best method of assessing the benefit of PCI. “The US FDA recommends exercise time for placebo-controlled [angina] drug trials but, if I was to do this trial again, it is probably not the primary endpoint I would choose. Perhaps, we should have considered that opening up the stenosis does not necessarily work in the same way as drugs. You can imagine that exercise time would be heavily impacted by placebo and patients knowing that the stenosis had been fixed; or in our study, not being sure it had been fixed,” Al-Lamee said. Regarding what endpoint should have been used instead of exercise time, she noted that a binary endpoint, such as freedom from angina, would have been “much easier” than a gradient of exercise scores. She noted: “I do think reduction in ischaemia is an important endpoint and perhaps when we look at further trials like ISCHAEMIA, we might find that this correlates with hard endpoints.” ISCHAEMIA is an ongoing study that seeks to identify the best approach—invasive vs. conservative therapy—for managing stable heart disease. In terms of the implications of the new analysis for clinical practice, Al-Lamee told Cardiovascular News: “What this analysis shows once again is that the link between stenting an epicardial stenosis and relief of ischaemia on stress echo, iFR and FFR is predictable. However the correlation with symptom relief is complex and more difficult to predict.” Coinciding with its presentation at EuroPCR, the physiological-stratified analysis of ORBITA was published in Circulation.

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Aug

Issue

EuroPCR

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FFR-guided PCI reduces spontaneous myocardial infarction Five-year data from FAME (Fractional Flow Reserve vs. Angioplasty for Multivessel Evaluation) 2 show that patients with stable disease who undergo percutaneous coronary intervention (PCI) guided by fractional flow reserve (FFR) have significantly fewer spontaneous myocardial infarctions than patients who receive optimal medical therapy. This is the first time a study of FFR-guided PCI has shown benefit in terms of a hard endpoint for PCI in stable disease.

t present, the use of PCI in stable disease—particularly in the wake of ORBITA—is controversial. According to Michael Haude (Medical Clinic I, Städtische Kliniken Neuss, Neuss, Germany), compared with optimal medical therapy, PCI with drug-eluting stents in patients with stable disease has shown “no or only a modest benefit in terms of survival or myocardial infarction” but is associated with improvement in symptoms and quality of life. However, he noted that while previous trials did not use the latest generation of drug-eluting stents, more recent trials have used these devices. One such trial is FAME 2, which has already shown that FFR-guided PCI improves clinical outcomes with medical management in stable disease—according to data presented at the 2017 Transcatheter Cardiovascular Therapeutics (TCT) meeting (29 October–2 November, Denver, USA), FFR-guided PCI significantly reduced the risk of major adverse cardiac events at three years. Presenting the five-year data at EuroPCR (22 May—25 May, Paris, France), Panagiotis Xaplanteris (Cardiovascular Center Aalst, Onze-Lieve-Vrouw Clinic, Aalst, Belgium) reported that PCI continues to have a benefit over medical management in terms of the primary endpoint (all-cause

Bernard De Bruyne

death, myocardial infarction, and urgent revascularisation): 13.9% vs. 27% for medical management (p<0.001). He added that there were no significant differences in this endpoint between the PCI group and a registry group of patients who were excluded from the randomisation stage of the trial for having a stenosis with a FFR value of >0.80 (i.e. haemodynamically insignificant) and who received medical management only. The main driver of the difference between the PCI group and the trial medical management group was urgent

revascularisation: 6.3% for PCI vs. 21.1% for medical management (p<0.001). However, Xaplanteris commented: “What is new [with this FAME 2 analysis] is a very strong signal towards less myocardial infarction.” In a landmark analysis for myocardial infarction, PCI was associated with a significantly lower rate of spontaneous myocardial infarction compared with medical management (6.5% vs. 10.2%, respectively; p=0.04). There was no significant difference between groups in the rate of periprocedural myocardial infarction. According to Xaplanteris, overall, PCI “offered sustained relief from angina”. “More than half of the medical therapy patients had crossed over to the PCI arm at five years, which most likely diluted the results, and decreased the number of hard endpoints,” he observed. Concluding, he said: “When FFR is >0.80, outcome is favourable with medical therapy [i.e. as in the registry group]. But what is new, is that when FFR is ≤0.80, PCI with drug-eluting stents provides sustained benefits in the need for urgent revascularisation, the rate of spontaneous myocardial infarction, symptomatic relief, and this is without a late catch-up phenomenon.” Commenting on the findings, Philip Urban (Cardiovascular Department, Hôpital de la Tour, Geneva, Switzerland) stated that the take-home message of the fiveyear findings were “If it ain’t broke, don’t fix it. If it is broke, don’t procrastinate!” The study, which was simultaneously published in the New England Journal of Medicine, was just one of several

Study indicates “almost perfect agreement” between CT angiography and conventional angiography for revascularisation decisions A new study, SYNTAX III REVOLUTION, has found heart teams using computed tomography (CT) angiography to decide between percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) to treat patients with three-vessel/left main disease would agree with 92.8% of decisions made by a heart team using conventional angiography. This creates a Cohen’s Kappa of 0.82, which represents almost perfect agreement.

resenting the results of SYNTAX III REVOLUTION at EuroPCR, Patrick Serruys (Imperial College London, London, UK), noted that “in the last two decades” CT angiography has been introduced as a non-invasive alternative for coronary anatomy assessment. He added that CT angiography has been shown to be a safe and feasible approach for calculating the anatomical SYNTAX score (used for assessing the extent of coronary artery disease and choosing the most appropriate revascularisation strategy). The aim of the present study was to evaluate how CT angiography compares with conventional angiography in assessing patients with three vessel

or left main disease. The primary endpoint was the first decision making and treatment strategy based on anatomic SYNTAX score and the SYNTAX II score, which combines the anatomical SYNTAX score with a patient’s clinical characteristics. In the study, six heart teams—each comprising of interventional cardiologists, radiologists, and cardiothoracic surgeons—were randomised into one of two groups: heart team A and heart team B (with three teams in each group). Heart team A had to decide treatment based on conventional angiography and heart team B had to decide treatment based on CT angiography (Revolution, GE Healthcare) alone.

presented at EuroPCR that showed a benefit for PCI guided by physiological assessment (instantaneous wave-free ratio, iFR, as well as FFR). The GZ FFR study, presented by Barry Hennigan (University of Glasgow, Glasgow, UK), indicated that PCI in stable disease patients with “grey zone” FFR values (0.75–0.80) reduced ischaemia (on stress MRI) by 50%, improved the Seattle Angina Questionnaire score in two out of five domains, and reduced angina frequency/improved quality of life compared with medical therapy; a pooled patient-level analysis of FAME 2, DANAMI-3-PRIMULTI, and COMPARE-ACUTE (presented by Frederik Zimmermann, Catharina Hospital Eindhoeven, Eindhoeven, The Netherlands) suggested a prognostic benefit of PCI in appropriately selected patients independent of symptoms; and data from SCAAR (presented by Elmir Omerovic, University of Gothenburg, Gothenburg, Sweden) showed a strong signal that FFR/ iFR-guided PCI reduced overall mortality, restenosis, and stent thrombosis in patients with stable disease at 10 years. Haude, on behalf of PCR and the European Association of Percutaneous Cardiovascular Interventions (EAPCI), commented that—together—the data presented at EuroPCR gave a “strong signal that physiology (FFR/iFR) guided PCI has superiority over angio-guided PCI for mortality, restenosis and stent thrombosis up to 10 years”. He added that “the longer the observation period is, the more benefit is shown for PCI” FAME 2 study investigator Bernard De Bruyne (Cardiovascular Center Aalst, Onze-Lieve-Vrouw Clinic, Aalst, Belgium) told Cardiovascular News: “The FAME 2 data put FFR centre stage in the decision about PCI and indicate that when patients and lesions are properly selected, you had better have a good reason not to perform PCI—even in stable patients.”

Heart team B also had to evaluate whether the use of fractional flow reserve (FFR) CT analysis (FFRCT, HeartFlow) would change their initial treatment decision. FFRCT, via a computer algorithm, uses information from a CT angiogram to calculate FFR values. Using data from 223 patients of the original SYNTAX study, overall, the heart team group agreed upon the treatment strategy (CABG or equipoise between PCI and CABG) in 92.8% of cases. This led to a Cohen’s Kapa of 0.82, which Serruys claimed represented “an almost perfect agreement” between the two groups. Additionally, the heart team groups agreed upon the coronary segments to be revascularised in 81.1% of the cases. For heart team B, according to Serruys, the use of FFRCT changed the treatment decision in 7% of patients. In 13 patients, the treatment changed from a surgical approach to a percutaneous one. “In patients with left main or three vessel coronary artery disease, a heart team treatment decision-making based on coronary CT angiography showed an almost perfect agreement with the decision derived from conventional angiography suggesting the potential feasibility of a treatment decision-making and planning and solely on this non-invasive imaging modality,” Serruys concluded. He added that a first-in-human study would further explore the use of CT angiography to make treatment decisions.

Aug

Device approval

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“Wait-and-see” is not an option with the new device regulations GIOVANNI DI RIENZO COMMENT & ANALYSIS The new EU Medical Device Regulation (MDR) was officially published on 5 May 2017 and entered into force 20 days later, on 25 May 2017. After a three-year transition period, i.e. on 26 May 2020, the MDR will replace the current Medical Device Directive (93/42/ EEC) and the Active Implantable Medical Device Directive (90/385/ EEC). The MDR introduces a huge amount of changes to the way medical devices are regulated, approved and monitored in the European Union (EU). Giovanni Di Rienzo reviews these changes and their potential impact on novel cardiovascular devices.

irst of all, the scope of the regulation has been extended to products that do not have a medical intended purpose—such as coloured contact lenses, devices for liposuction and many others. The rules for classification of devices (class I–class III), based on risk, have been modified and extended causing some devices to fall into a higher risk class. Of particular significance for the cardiovascular field is the fact that all devices intended to be used in contact with the central circulatory system or the heart will fall in the highest risk category (class III), regardless of their duration of contact and whether they are very simple single-use products (e.g. cardiopulmonary cannulae, heart valve sizers, etc.) or novel cardiovascular implants (e.g. bioresorbable scaffolds, transcatheter heart valves, etc.). The new regulation also introduces more rigorous requirements for clinical evidence. Based on the current understanding and interpretation of the regulation, clinical safety, performance and benefit will have to be systematically reviewed, analysed and documented in a Clinical Evaluation Report, regardless of the classification of the device. For high

risk (class III) and implantable devices (class IIa and IIb) the demonstration of compliance with the general safety and performance requirements will have to be based on clinical data generated through a clinical investigation following good clinical practice methodologies. In some rare cases and where sufficient clinical data are already available, a justification for not conducting a clinical investigation may be possible. Clinical safety and performance will have to be monitored in the post-market phase following a plan to reconfirm throughout the entire lifetime of the device its safety and performance and to identify unexpected risks that could not be identified in the pre-market phase. This will have to be done by pro-active post-market surveillance and rigorous post-market clinical follow-up. Very significant are also the requirements in terms of reporting. Manufacturers will have to generate and update several reports to reconfirm over the time that their devices continue to be safe and perform as intended in light of the generally acknowledged “state of the art” and that the risks continue to be overweighed by the benefits associated with the use. One of those newly required reports,

the Summary of Safety and Clinical Performance (SSCP), will be publicly available for the final users and for the patients. The SSCP is required for high risk (class III) and implantable devices (class IIa and IIb) only. It will include detailed information on the device and its use, on the clinical data available including those from post-market clinical follow-up, on the possible risks and the possible therapeutic alternatives. In order to obtain the CE mark under the new legislative framework, class III implantable devices (e.g. heart valves, coronary stents, neurovascular implants, etc.) and certain class IIb active devices (such as drug delivery pumps) will have to undergo the assessment of an “expert panel” nominated by the EU Commission. This panel will scrutinise the clinical assessment of the Notified Body together with documents such as the “Clinical Evaluation Report” and the “Post-Market Clinical Follow Up” plan and will provide a scientific opinion as to the suitability of those. One key aspect that needs to be pointed out is the fact that the new regulation does not include any “grandfathering” provisions. All devices, including those currently approved and available on the market, will have to be fully reassessed and certified in accordance with the new requirements as if they had never been on the market. The certification of all the currently approved devices will have to be completed in a very short time frame, between the second half of 2019 and May 2024, but probably with a significant peak in the period 2020–2022. And this will have to be completed by a limited number of Notified Bodies, those that will have managed to obtain a designation under the new regulation. Notified Bodies are responsible for conformity assessment and approval of devices and are designated by the EU member states and the EU commission. Under the MDR, the requirements applied to Notified Bodies are significantly increased, particularly in terms

of resources, competence and expertise. Therefore, it is expected that the number of Notified Bodies (currently 59 for medical devices; 14 for active implantable medical devices; and 22 for in-vitro diagnostic devices) will be significantly reduced. Given the extent of the changes (and those described above are just a very limited selection), the extremely short transition period and the probable limited availability of Notified Bodies, recertification of existing devices under the MDR might result in a stressful, costly and lengthy process. As a consequence of that, it is expected, that a large number of manufacturers (especially SMEs) will rationalise their portfolio focusing on a limited number of devices. Approval of new devices, especially if high risk (class III and implantable), will be more demanding. Higher expectations in terms of clinical investigation data and additional requirements such as the “expert panel” consultation will, no doubt, increase the approval time and the cost of placing a device on the market. Guidance on the interpretation of the new regulation is still needed to fully understand the details and to assess the real impact. However, the expected consequence of the increased regulatory burden might well be that the EU will no longer be attractive as a first port of call for new technologies. A significant shift is already perceivable in the field as more and more manufacturers are planning product launches in the USA first, followed, only later, by the EU. The medical devices world is getting ready to face the biggest change seen in two decades in the EU. The wise choice to navigate through this challenging time is to start planning and preparation as early as possible; and starting today might not be early enough. Wait-and-see is not an option. Giovanni Di Rienzo is the global director of the Cardiovascular Focus Team at TÜV SÜD Product Service (Fareham, UK). He spoke about this topic at EuroPCR (22–25 May, Paris, France).

ACC’s ACTION registry to become Chest Pain—MI Registry

he American College of Cardiology’s (ACC) ACTION Registry is changing its name to the Chest Pain—MI Registry. A press release reports that the new name aligns the ACC’s National Cardiovascular Data Registry (NCDR) and Accreditation Services offerings to address additional patient populations, including unstable angina and low risk chest pain. Beginning in October 2018, the registry will fully support the data requirements for ACC’s Chest Pain Center Accreditation programme. Additionally, the Chest Pain—MI Registry will offer

opportunities for collaboration across multiple providers and specialties who play an important role in managing care for these patients, including emergency department clinicians and emergency medical services (EMS) providers. With 1.5 million patient records, according to the press release, the Chest Pain—MI Registry is the USA’s largest and most authoritative quality improvement programme for patients with acute myocardial infarction and will now encompass acute coronary syndromes, capturing unstable angina and low-risk chest pain patients in addition to acute myocardial infarction patients.

Frederick A Masoudi (NCDR Management Board chair) comments: “The expanded scope of the registry will allow hospitals to optimise patient outcomes and reduce variations in care through risk stratification and evaluation of hospital performance in delivering guideline-recommended care and treatments.” NCDR is the ACC’s suite of cardiovascular data registries helping hospitals and private practices measure and improve the quality of care they provide. The Chest Pain—MI Registry is one of 10 NCDR hospital and outpatient registries.

Aug

Coronary interventions

Both immediate and delayed approaches seem to work for transient STEMI patients A new study indicates that a delayed approach in patients with transient ST-segment elevation myocardial infarction (STEMI) is associated with similar safety and efficacy outcomes as an immediate approach.

peaking at EuroPCR (22 May–25 May, Paris, France), Jorrit S Lemkes (VU University Medicine Center, Amsterdam, The Netherlands) reported that “approximately 15% of patients with STEMI show complete normalisation of the ST-segment and relief of symptoms before reperfusion therapy”—i.e. transient STEMI. He added that patients with transient STEMI pose a therapeutic challenge because “it is unclear whether

this condition should be considered as STEMI or NSTEMI”. Noting that different approaches are used to manage these conditions—i.e. immediate with STEMI and delayed (based on risk) with NSTEMI—Lemkes said: “current guidelines contain no specific recommendations for the management of transient STEMI”. Therefore, the aim of the TRANSIENT study was to evaluate a delayed approach with an immediate approach. Of 142

Jorrit S Lemkes

patients, 71 were randomised to undergo immediate coronary angiography and revascularisation and 71 were randomised to undergo delayed angiography

and revascularisation. There was no significant difference between groups in terms of infarct size (the primary endpoint): 1.3% for immediate approach vs. 1.5% for delayed approach (p=0.80). However, treatment after coronary angiography was different—significantly more patients underwent percutaneous coronary intervention (PCI) in the immediate group (90% vs. 75%; p=0.03) and coronary artery bypass grafting was exclusively used in the delayed group (0% vs. 11%; p=0.01). These differences in treatment were despite, Lemkes commented, there being no difference in “extent of coronary

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artery disease between groups”. There were no significant differences between groups at 30 days in terms of cardiac events or major bleeding. Lemkes told Cardiovascular News: “These results suggest that revascularisation in transient STEMI can be performed both immediate and delayed with similar outcome. Physicians can, therefore, take logistical considerations in account. If the patient is being presented directly to the cath lab, I would go ahead and preform PCI. But if there is no cath lab available, I would feel comfortable admitting the patient to the cardiac care unit and delaying intervention”

Signal that left radial access reduces the risk of PCI-related stroke New data show that patients who undergo percutaneous coronary intervention (PCI) via left radial access have a similar risk of in-hospital/30-day mortality, major adverse cardiovascular events (MACE) or major complications as those who undergo PCI via right radial access. However, they also indicate that left radial access patients may have a lower risk of PCI-related stroke.

uhammad Rashid (Keele Cardiovascular Research Group, Keele University, Stokeon-Trent, UK) and others report in JACC: Cardiovascular Interventions that left radial access offers “much more favourable vascular anatomy” than right radial access “particularly in short stature patients or those with previous coronary artery bypass grafts, resulting in less catheter manipulation and a theoretically smaller risk of procedure-related stroke”. However, they note that data for right radial access vs. left radial access have produced conflicting results. According to the authors, understanding how left radial access compares with right radial access will become more important in the future because “as the population requiring PCI grows and ages, it is likely that left radial access will become more commonplace”. Therefore, to provide further information in this area, Rashid et al reviewed data from the British Cardiovascular Intervention Society (BCIS) registry to compare outcomes of patients who had undergone PCI with left radial access to those who underwent PCI with right radial access. The primary endpoints were in-hospital mortality and 30-day mortality, in-hospital major bleeding, in-hospital MACE, and in-hospital stoke. Of 343,725 patients who underwent the PCI with the transradial approach between 2007 and 2014, 96% underwent the transradial approach via right radial access

and 4% underwent it via left radial access. However, use of left radial access increased over time—from 3.2% in 2007 to 4.6% in 2014. Stepwise multivariable analysis showed that the independent predictors of left radial access being used were previous coronary artery bypass grafting (CABG), PCI to vein graft, renal failure, peripheral vascular disease, previous acute myocardial infarction, female sex, and repeat PCI procedure. Additionally, left radial access PCI was undertaken in Asians far more than in Caucasians—27.9% vs. 4.2%. A multivariable logistic regression found there were no significant differences in the rate of in-hospital death, 30-day mortality, and in-hospital stroke between patients who underwent PCI via left radial access vs. those who underwent PCI via right radial access. However, Rashid et al report: “Notably, in our propensity score matching analysis, left radial access was associated with a significant decrease in in-hospital stroke (p=0.0005).” They comment that anatomical differences between the right radial artery and the left radial artery may explain this apparent reduction in stroke. “With right radial access, the anatomical variations such as increased incidence of tortuosity and loops in arm and subclavian artery may require extra catheter manipulation. Additionally, during right radial access, the catheter needs to be passed from the innominate artery into the ascending aorta where the right carotid artery comes off resulting in a theoretically

Notably, in our propensity score matching analysis, left radial access was associated with a significant decrease in inhospital stroke.

Muhammad Rashid

increased risk of embolisation of plaque into the right carotid artery resulting in embolic stroke,” the authors explain. Although the rate of in-hospital stroke did appear to be lower with left radial access, overall, the in-hospital stroke event rate was low. Thus, Rashid et al observe: “Given low event rates, it is unlikely that a randomised controlled trial will ever be adequately powered to investigate this further.” They conclude: “Left radial access provides a safe and effective alternative access site choice compared to right radial access,” noting that “future efforts need to focus around education and training to preserve radial artery patency and increase skills in the use of left radial access”. Rashid told Cardiovascular News: “Left radial artery is a safe alternative access site, particularly for righthanded patients undergoing PCI procedures.”

Aug

Structural Heart Interventions CoreValve shows “favourable performance” at long-term follow-up Erik W Holy (Heart Center, Segeberger Kliniken, Bad Segeberg, Germany) and others report in EuroIntervention that the CoreValve self-expanding transcatheter aortic valve implantation (TAVI) device is associated with a “favourable performance” at longterm follow-up (8.9 years). However, the authors claim this finding does not provide any conclusions about the durability of TAVI valves but rather “contributes to the growing evidence” for valve durability.

he current data for transcatheter heart valve durability are limited by five-year follow-up and, according to Holy et al, this has implications for expanding the use of TAVI beyond inoperable and high-risk patients. They write: “While a durability of at least five years, as suggested by previous studies, is acceptable for an elderly highrisk population, evidence of long-term durability is mandatory before replacing surgery with TAVI in younger, lower-risk populations [i.e. because they are likely to have a longer life expectancy].”

proposed consensus definition, including one of the following criteria occurring >30 days after TAVI: severe haemodynamic structural valve deterioration, evidenced by a transprosthetic mean pressure gradient ≥40mmHg and/or 20mmHg rise from baseline or severe To further assess the transvalvular aortic regurgitadurability of TAVI devices tion; and bioprosthetic valve beyond five years, the dysfunction leading to death authors reviewed data from or reintervention,” Holy et al the long-term structured explain. CoreValve Evolut PRO follow-up programme Of 152 patients in the of CoreValve using programme, follow-up data standardised definitions and core lab were available for 60 patients who were adjudication of valve performance. alive for more than five years after the The primary endpoints were the rate of initial procedure (of 68 in total). During bioprosthetic valve failure and tranthe total clinical follow-up period of scatheter heart valve long-term perfor8.9 years, no severe structural valve mance. “Late bioprosthetic valve failure deterioration or death attributable to was defined according to the recently valve failure was reported. Furthermore,

Low incidence of one-year cardiovascular mortality with Centera self-expanding valve Hermann Reichenspurner (Departments of Cardiovascular Surgery and General and Interventional Cardiology, University Heart Center, Hamburg, Germany) at EuroPCR (22 May—25 May, Paris, France) reported that the Centera self-expanding transcatheter aortic valve implantation (TAVI) device is associated with both a low rate of cardiovascular mortality (4.6%) and a low rate of disabling stroke (4.1%) at one year for the management of aortic stenosis in patients at high surgical risk.

ccording to Reichenspurner, the valve has a short frame height, the same bovine pericardial tissue that is used in Edwards Lifesciences’ Sapien valve range, Resilia tissue technology “that allows the valve to be stored dry”, and a “unique contoured frame designed to anchor and seal within the annulus for low paravalvular leak rates”. The primary endpoint of the CENTERA study was to evaluate the rate of 30-day all-cause mortality in patients who received the valve. The 30-day results were presented at last year’s EuroPCR and showed a high survival rate (99%) and a low rate of disabling stroke (2.5%). The aim of the present analysis was to review the one-year follow-up outcomes for patients who received the valve. Of the 203 patients initially enrolled in the study, follow-up data were available for 179 patients. The all-cause mortality rate was 9%, the rate of

disabling stroke was 4.1%, and the rate of cardiac-related hospitalisation was 6.8%. Additionally, the rate of cardiac mortality was 4.6% and the rate of need for a new permanent pacemaker 6%. No patients had severe or moderate aortic regurgitation at one year, with most (71.4%) having none or trace (28.6% had mild aortic regurgitation). Between baseline and 30-day followup, in the overall study population, there was a significant improvement in New York Heart Association (NYHA) Class (p<0.0001). However, there were no differences in NYHA class between 30 days and six months or between 30 days and one year. At one year, the majority of patients were in Class I or II. Reichenspurner told Cardiovascular News that Centera offers “excellent early and one-year outcome with low mortality, minimal evidence of paravalvular leakage and low rates of necessary pacemaker implantation”.

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the estimated rate of bioprosthetic valve failure at both seven and eight years was 7.9% for the actuarial and for 4.5% for the actual analysis. According to the authors, paravalvular regurgitation severity tended to change over time in a significantly proportion of patients—regressing from moderate to less than mild in five patients, remaining stable in 48% of patients, increasing by more than one grade in 32% of patients and improving by more than one grade in 20% of patients. The authors comment: “The present data provides a good reason to believe that structural valve deterioration of self-expanding valves beyond five years and up to eight years remains rare.” They add that their study documents “favourable performance of the selfexpanding CoreValve with low rates of bioprosthetic valve failure”. “The present study cannot conclude—but rather contributes to the growing evidence—upon transcatheter heart valve durability,” Holy et al surmise and note that “further large-scale studies and registries are required to confirm the noninferiority of transcatheter heart valves compared to surgical bioprosthesis in terms of long-term durability.”

“Excellent” short-term outcomes for Portico valve Real-world data presented at the 2018 Transcatheter Valve Technologies (TVT) meeting (20–22 June, Chicago, USA)—now part of the Structural Heart Disease Summit (22–23 June, Chicago, USA)— indicate that Abbott’s Portico transcatheter aortic valve implantation (TAVI) device is associated with a low rate of all-cause mortality (2.7%) at 30 days. However, it had a new pacemaker rate of 18.7%.

resenting the Portico data, Francesco Maisano (University Hospital Zürich, Zürich, Switzerland) reported that Portico I is the “first large, multicentre, postmarket study of the Portico self-expanding valve”. He added that it represented the real-world, early commercial experience with the device (implants began in 2013), noting “the objective of this presentation is share the procedural and 30-day outcomes of nearly 1,000 patient study and examine the role of performing a pre balloon aortic valuloplasty prior to implanting this novel self-expanding valve”. According to Maisano, the Portico device has the “lowest profile” delivery system, is “very flexible and deliverable”, and its nitinol self-expanding stent allows the device to be “fully recapturable, repositionable in situ, and retrievable if needed”. In the study, various sizes of the valve were evaluated—23mm, 25mm, 27mm, and 29mm; follow-up was at 30 days and at one, two, three, four, and five years. Of 941 patients enrolled, implantation was successful in 96% and pre balloon

valuloplasty was used 88.9%. At 30 days, all-cause mortality was 2.7%, the rate of disabling stroke was 1.6% (with all stroke being 3%), and the rate of major vascular access site complications was 5.5%. There was no severe aortic regurgitation at 30 days and 3.9% had mild paravalvular leak. However, the rate of new permanent pacemaker implantation was 18.7%. “The one-month results of the Portico valve in real-world patients treated at multiple sites in various geographies demonstrate excellent short-term clinical outcomes when used by a broader implantation base, and were consistent with Portico TF EU CE mark trial,” Maisano commented. He added that the haemodynamic performance of the valve was “competitive”, with a single-digit gradient (8.6mmHg) and a large effective orifice area (1.8cm2). In a subgroup analysis, Maisano and colleagues also looked at the use of pre balloon aortic valuloplasty. This showed that despite patients who underwent pre balloon aortic valuloplasty having a higher baseline gradient, the procedure was performed safely with no increased risk to the patient.

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Structural Heart Interventions

Leaflet thrombosis is not a predictor of stroke or all-cause mortality in the medium term The largest study to date to systematically review outcomes associated with leaflet thrombosis after transcatheter aortic valve implantation (TAVI) indicates that the presence of leaflet thrombosis does not predict all-cause mortality, stroke, or transient ischaemic attack at 406 days.

riting in JACC: Cardiovascular Interventions, Philipp Ruile (Department of Cardiology & Angiology II, University Heart Center FreiburgBad Krozingen, Bad Brozingen, Germany) and otehrs report that the presence of leaflet thrombosis is associated with an increased rate ontransient ischaemic attack but appears to have no influence of the rate of stroke or mortality. “The purpose of the present was to investigate mediumterm outcomes in patients with leaflet thrombosis from a large single-centre cohort,” the authors add. Reviewing data for patients who were assessed with computed tomography (CT) angiography after undergoing TAVI at their centre, Ruile et al found 15.9% of patients (120 of 754) had evidence of leaflet thrombosis. The overall mortality rate at 406 days was 11.1% and did not differ between patients with leaflet thrombosis and those without. The Kaplan-Meier 18-month estimate for survival also showed similar survival rates for pa-

tients with leaflet thrombosis vs. those without. There were no significant differences between groups in terms of the rate of stroke or the rate of transient ischaemic attack. Ruile et al observe that the reason why their study did not find a link between leaflet thrombosis and transient ischaemic attack—in contrast to a previous study—may relate to “high variability in the incidence of transient ischaemic attack depending on whether symptoms were self-reported or the result of a neurological evaluation of a whole cohort”. They add that a study that provides a systematic analysis of patients with leaflet thrombosis regarding neurological symptoms is “currently missing but urgently needed considering the competing risks for stroke in a population with a high prevalence (approximately 40%) of atrial fibrillation”. Leaflet thrombosis was not found to be an independent predictor of all-cause mortality in either a univariate analysis or in a multivariate analysis. It was also not found to be a

Philipp Ruile

predictor of stroke or transient ischaemic attack in a univariate analysis. According to Ruille et al, the overall incidence of stroke/transient ischaemic attack was too low in their cohort to perform a “meaningful multivariate analysis”. Ruile told Cardiovascular News: “Based on our study we conclude that leaflet thrombosis is not associated with an increased risk for mortality or stroke for the medium-term. But still there remain concerns about subsequent haemodynamic valve deterioration.”

No significant difference in bioprosthetic valve dysfunction between surgical and TAVI devices at six years The NOTION trial (Nordic aortic valve intervention) was the first comparison of surgical and transcatheter aortic valve implantation (TAVI) in patients at lower surgical risk in a randomised setting. Data indicate that the six-year rate of bioprosthetic aortic valve failure is similar between the two groups, whereas structural valve deterioration—a component of bioprosthetic valve function—was significantly higher among patients who had a surgical valve.

resenting the data at EuroPCR (22 May–25 May, Paris, France), Lars Sondergaard (Rigshospitalet, Copehagen, Denmark) said that the aim of NOTION was to compare “TAVI with surgery in lower risk patients aged ≥70 years” and that its primary endpoint was the composite rate of all-cause mortality, stroke or myocardial infarction at one year. According to Sondergaard, previously reported data has already shown that the rate of the primary endpoint was similar between groups at five years.

This present analysis showed that the rate of all-cause mortality was similar through six years and also provided the opportunity to evaluate valve durability. “Analysis of the durability of TAVI is important as the therapy looks to expand to patients with longer life expectancy,” Sondergaard commented. He added that, therefore, a post-hoc analysis of bioprosthetic aortic valve longevity was performed using definitions set out in the 2017 European consensus document on valve durability (published in the Euro-

pean Heart Journal and European Journal of Cardiothoracic Surgery). The definitions used included both bioprosthetic valve dysfunction (comprising of structural valve deterioration, non-structural valve deterioration, and bioprosthetic valve thrombosis/endocarditis) and bioprosthetic valve failure (valve-related death, aortic valve reintervention, and severe haemodynamic structural valve dysfunction). There were no significant differences between TAVI patients (139) and surgical valve patients (135) in terms of bioprosthetic valve dysfunction: 56.1% for the TAVI group vs. 66.7% for the surgical group (p=0.07). However, the rate of structural valve dysfunction was significantly higher among patients who had a surgical valve: 23.7% vs. 3.6% for TAVI patients (p<0.001). This result, Sondergaard noted, was driven by the increased rate of moder-

ate haemodynamic structural valve deterioration in the surgical group vs. the TAVI group—23.7% vs. 3.6%, respectively (p<0.0001). He told Cardiovascular News: “This may be a consequence of the smaller effective orifice area in surgical valve compared to transcatheter bioprostheses. And since all bioprosthetic valves become smaller over time, the surgical valves are likely to deteriorate first.” There were no significant differences between groups in the other components of bioprosthetic valve dysfunction; although, paravalvular leak—a measure of non-structural valve dysfunction—was substantially higher among TAVI patients (21.6% vs. 1.5% for surgical patients). Regarding bioprosthetic valve failure, Sondergaard commented that it was “low and similar for self-expanding transcatheter valves and surgical aortic valves”.

Boston Scientific to buy cerebral protection system company

oston Scientific has signed an agreement to acquire Claret Medical, which developed and commercialised the Sentinel cerebral embolic protection system. The device is used to protect the brain during certain interventional procedures, predominately in patients undergoing transcatheter aortic valve implantation (TAVI). The transaction price consists of US$220 million in up-front cash, as well as a potential reimbursement-based milestone payment of up to US$50 million. The Sentinel system, which received CE mark in 2014 and US FDA clearance in 2017, is the only device

cleared to protect patients against the risk of stroke during TAVI (in both the USA and the EU). A press release reports approximately 4% of patients experience a clinically apparent stroke within 30 days of a TAVI procedure. In the SENTINEL trial, the Sentinel system reduced the incidence of strokes by 63% within the first 72 hours of the procedure. In clinical studies, the system captured debris flowing towards the brain in 99% of TAVI cases—regardless of the type of replacement valve that was used. Kevin Ballinger, president, Interventional Cardiology,

Boston Scientific, comments: “Through the development and commercialisation of the Sentinel system, Claret Medical has successfully introduced a new layer of safety and peace of mind for physicians and their patients undergoing TAVI procedures. This acquisition will expand our commercial portfolio to include an important adjunctive offering aimed at improving TAVI patient outcomes. We also see potential for future use in other left heart and endovascular procedures such as mitral valve repair and replacement, left atrial appendage closure and pulmonary vein isolation ablation procedures for atrial fibrillation.”

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Combination of high-sensitive C-reactive protein with logistic EuroSCORE improves risk stratification in TAVI patients According to Anja Stundl (Department of Medicine II, Heart Center Bonn, University Hospital Bonn, Bonn, Germany) and others, high-sensitive C-reactive protein (hs-CRP) can be used alongside the logistic EuroSCORE as an independent predictor of one-year all-cause mortality in patients undergoing transcatheter aortic valve implantation (TAVI). The authors note that the combination of both “might help to better predict procedural risk and outcome”.

tundl et al comment in EuorIntervetnion that, at present, heart teams use scoring systems—such as the logistic EuroSCORE and the Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score—that have been designed for surgical aortic valve replacement to predict outcomes in patients undergoing TAVI. However, they add that their applicability to TAVI patients is “questionable as they are strongly based on certain comorbidities that are related to outcome in standard surgical risk populations, but do not address the particularities influencing outcome in TAVI-procedures”. Therefore, the authors say, there is a need for prediction models that specifically address issues relating to TAVI. Given that previous studies have looked at the role of biomarkers in predicting risk in aortic stenosis patients, the aim of the present study was to determine whether

circulating biomarkers representing different pathophysiologic systems (i.e. hs-CRP) could be used to identify TAVI patients at higher risk of adverse clinical outcomes. It also reviewed whether these biomarkers provide prognostic information beyond that of established predictive risk algorithms. Reviewing data for 683 consecutive patients who underwent TAVI at their centre (Heart Center Bonn) between January 2014 and August 2018, Stundl et al found that patients who died within the first year of TAVI being performed had significantly higher clinical risk score results—including increased median biomarker levels. They report: “When biomarkers were categorised into tertiles, values in the uppermost tertile for each biomarker were all significantly associated with increased one-year mortality except for hs-troponin.” In a multivariate analysis looking at

Anja Stundl

predictors of cumulative mortality, only the logistic EuroSCORE and hs-CRP were independent predictors and showed the strongest association with one-year all-cause mortality. Neither NTproBNP nor hs-troponin I were found to be independent predictors (both of which are well known biomarkers for cardiovascular disease), which the authors comment may partly be because the study cohort only included patients from 2014 onwards. They note that these patients had a median age of 81, a median STS-PROM score of 3.8 and would have been treated according to clinical best practice with next-generation devices. “In other words, failure of NTproBNP and hs-troponin I may be a matter of both less sickness of the patients and considerable progress

in research and technique that has been made,” Stundl et al observe. They write that the combination of logistic EuroSCORE and hs-CRP had “significant added value [to EuroSCORE alone] for the prediction of one-year all-cause mortality”, adding “using these two readily available predictive risk parameters enables us to identify patients scheduled for TAVI with favourable or adverse outcome prior to the planned procedure and to reconsider the decision once made.” Stundl and study investigator Jan-Malte Sinning (Department of Medicine II, Heart Center Bonn, University Hospital Bonn, Bonn, Germany) comment: “Our suggestion for TAVI patients with elevated CRP is that they could undergo the procedure after an active inflammatory process has been ruled out; however, CRP reflects a higher comorbidity burden (could also be a marker of frailty and “vulnerability”) and these patients will have a worse prognosis than patients without CRP elevation. We are currently working on a biomarker score in aortic stenosis patients (treated with TAVI or conservatively) and will evaluate whether specific biomarkers might help to sort out specific patients or even might indicate futility.”

Malnourished patients have a three-fold risk of mortality after aortic valve replacement New data from the FRAILTY-AVR study indicate that mortality—both at 30 days and at one year—is significantly increased in malnourished patients undergoing aortic valve replacement. Furthermore, it shows that the risk of mortality associated with malnutrition is incremental to the frailty status of the patient. These findings raise the question of whether pre- and postoperative interventions to improve nutritional status should be considered in malnourished patients undergoing aortic valve replacement.

riting in Circulation, the team led by Michael Goldfarb (Azrieli Heart Centre, Jewish General Hospital, McGill University, Montreal, Canada) reports in Circulation that malnutrition is a known risk factor for mortality in patients undergoing general surgery but add that its effect on patients undergoing cardiac surgery, including surgical aortic valve replacement, is less well known. “Among patients undergoing transcatheter aortic valve implantation (TAVI)—a

population with high degrees of frailty—malnutrition has yet to be specifically studied,” they note. Therefore, the aim of their study was to assess the prevalence and prognostic association between malnutrition screening (using the Mini Nutritional Assessment-Short Form [MNA-SF] score) and short and mid-term outcomes in a large multicentre study of older adults undergoing TAVI or surgical aortic valve replacement. The primary endpoint was one-year all-cause mortality.

Using data from FRAILTYAVR (a prospective cohort study), Goldfarb et al found that 101 patients (8.7%) of 1,158 overall (of whom, 727 underwent TAVI) were malnourished; a further 380 (32.8%) were at risk of becoming malnourished. They comment: “Patients in the malnourished group were older, more likely to be female, more likely to undergo TAVI, more likely to have prior stroke, chronic kidney disease, chronic lung disease, anaemia, lower left ventricular ejection fraction, and

higher STS-PROM.” In a multivariate analysis, preprocedural nutritional status was a significant predictor of one-year mortality (odds ratio [OR] 1.07 per MNA-SF point) and for 30-day composite safety events (OR 1.06 per MNA-SF point). The authors observe that while they expected there to be an overlap between patients who were malnourished and those who were frail, the correlation was actually modest. They explain, in terms of frailty, malnourished patients fell into distinct groups: those with mildly impaired frailty scores and those with severely impaired frailty scores. “The combination of malnutrition and severe frailty was synergistically associated with the highest risk of mortality,” Goldfarb et al state.

Noting that nutritional deficiencies are actionable and malnutrition is potentially a modifiable target, the authors say that their findings raise “the question of whether pre and postoperative intervention should be recommended in malnourished cardiac patients to improve postoperative outcomes”. They conclude: “Clinical trials are needed to validate the beneficial clinical impact of targeted nutritional interventions in malnourished or at-risk older adults undergoing TAVI or surgical aortic valve replacement.” Study author Jonathan Afilalo (Azrieli Heart Centre, Jewish General Hospital, McGill University, Montreal, Canada) told Cardiovascular News: “Nutritional screening is vital for older adults undergoing cardiac surgery and TAVI; and if a patient is malnourished or at risk of becoming malnourished, consultation with a dietician and protein-rich oral nutritional supplements should be considered.”

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Leaflex Performer: A non-implant based treatment for aortic stenosis DARREN MYLOTTE ANTOINETTE NEYLON ANDREAS BAUMBACH COMMENT & ANALYSIS Given sufficient time, all bioprosthetic valves fail—whether they are surgical or transcatheter devices. The most important predictive factor for bioprosthetic heart valve degeneration is a younger age at implantation. Hence, therapies aimed at delaying the implantation of a bioprosthetic valve are of considerable interest to the field. Darren Mylotte, Antoinette Neylon, and Andreas Baumbach discuss the potential of the novel Leaflex Performer device (Pi-Cardia) to delay, or perhaps negate, the need for bioprosthetic aortic valve implantation.

ranscatheter aortic valve implantation (TAVI) is increasingly being used in lower risk populations— data show that it is at least non-inferior to surgical aortic valve replacement in intermediate-risk patients and studies of TAVI in low-risk patients are ongoing. Therefore, the issue of structural valve failure in TAVI will become increasingly important (given that implantation at younger age is the main risk factor for this event). A therapy that could delay the need for a bioprosthetic valve—particularly if it could provide a durable reduction in the severity of the aortic stenosis, be performed efficiently via a transfemoral transcatheter route, and provide cost-

savings compared to TAVI—would prompt substantial physician interest. Such a therapy could also theoretically be applied to some patients deemed too old or frail for TAVI, replacing balloon valvuloplasty; although valvuloplasty has been proven to be acutely efficient, it is of limited clinical value in the long term. The Leaflex Performer is a transfemoral transcatheter device that uses two unique mechanical structures for scoring aortic valve calcification. The current deflectable transfemoral delivery catheter is inserted via a 16Fr sheath and is delivered and positioned in the aortic root using fluoroscopic guidance. The distal tip of the device features an atraumatic pigtail for safe positioning in the left ventricle

Leaflex Performer

and also allows for monitoring of left ventricular pressure. The device itself consists of a proprietary expander placed in the left ventricular outflow tract that lifts the aortic leaflets into contact with three scoring arms positioned in the aortic root. Mechanical expansion of expander yields directed scoring of calcifications within the leaflets, and rotation of the arms allows scoring to be performed at different sections of each aortic valve leaflet. The design of the Leaflex Performer was based on extensive bench and imaging research on the patterns of calcium distribution in human aortic valves. These analyses revealed two distinct patterns of calcification: bridge and half-bridge. Successful scoring of the calcium has been demonstrated to improve valve area and transvalvular gradients on the bench. The Leaflex technology and mechanism of action is fundamentally different from the traditional balloon aortic valvuloplasty, whereby the annulus and supporting

anatomy are simply stretched thus yielding short-term haemodynamic improvement. Indeed, one could also envisage the Leaflex technology being used to prepare heavily calcified or bicuspid valves for optimal implantation of a transcatheter heart valve. At EuroPCR (22–24 May, Paris, France), Boguslaw Kapelak and Krzysztof Bartus (both Department of Cardiovascular Surgery and Transplantology, Jagiellonian University, John Paul II Hospital, Krakow, Poland) reported safety and efficacy of leaflets scoring during traditional open surgery. The first enrolment in the transfemoral first-in-human study was presented by Darren Mylotte (University Hospital, Galway, Ireland) at PCR Innovators Day (21 May, Paris, France). He reported successful insertion, delivery, functionality, and removal of the device. Moreover, invasive haemodynamic assessment suggested a significant reduction in transvalvular gradient after scoring the calcified aortic valve on four occasions (per protocol). Study enrolment is ongoing in several European centres and further results are eagerly awaited. In summary, a non-implant based treatment of aortic stenosis is desirable and may have exciting potential once safety and efficacy is demonstrated. Darren Mylotte and Antoinette Neylon are at University Hospital and National University of Ireland, Galway, Ireland; Andreas Baumbach is at Barts Heart Center, London and Queen Mary University of London, London, UK.

Carotid disease is not a risk factor for stroke or death in TAVI patients A new study, published in Circulation: Cardiovascular Interventions, shows that one fifth of patients undergoing transcatheter aortic valve implantation (TAVI) have carotid artery disease. It also indicates that while the presence of carotid disease may be a marker of higher cardiovascular burden, it is not itself a risk factor for stroke or mortality after TAVI.

uthors Ajar Kochar (Duke Clinical Research Institute, Duke University of School of Medicine, Durham, USA) and others report that the biological mechanism underpinning periprocedural stroke in TAVI are “incompletely understood”. They note that periprocedural debris embolisation is one potential mechanism of stroke in this context but add that strokes (at 30 days) still occur in patients who undergo TAVI with cerebral protection devices. “These findings suggest either current technologies do not sufficiently reduce the risk of periprocedural debris embolisation or there are other mechanisms for TAVI-associated stroke,” Kochar et al write. They state that another potential mechanism is the presence of carotid disease—given that it is associated with an increased risk of stroke in patients undergoing surgical aortic valve replacement. Therefore, the aim

of the present study was to evaluate the incidence of carotid disease among TAVI patients, the relationship between severity of carotid disease and cardiovascular outcomes, and the influence of carotid disease on 30day and one-year stroke mortality. Using data from three US registries, Kochar et al identified 29,143 patients who underwent TAVI between October 2013 and September 2015 (in the USA). Of these, 6,410 had carotid disease (22%). In most cases (50–79%), the carotid disease was of moderate severity. Looking at unadjusted outcomes, the presence of carotid disease was associated with a significantly increased risk of stroke at 30 days and at one year. Similarly, carotid disease was associated with a significantly increased risk of mortality both at 30 days and at one year. These risks were greater with increasing severity. However, in an adjusted analysis, carotid disease was

no longer associated with a significantly increased risk of stroke or mortality at 30 days. Nor were there, after adjustment for patient characteristics, any significant differences in the risk of stroke or mortality at one year between patients with carotid disease and those without carotid disease. The authors state: “Even after incorporating the degree of stenosis, there was no significant adjusted association between carotid disease severity and 30-day or one-year risks of stroke or mortality.” Kochar et al observe that, on the basis of their findings, “carotid disease is possibly a marker for patients with a higher mortality burden” but does not itself “result in a higher risk of stroke or mortality”. “Further supporting this notion that carotid disease is a marker for a large comorbidity burden are the higher unadjusted one-year cumulative incidence rates for both myocardial infarction and bleeding rates among carotid disease compared with no carotid patients,” they add. They conclude: “Despite technological improvements, post-TAVI stroke is still a major complication; our results suggest carotid disease does not influence this risk of stroke.”

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Juan F Granada Juan F Granada (president and CEO, Cardiovascular Research Foundation, New York, USA) wanted to be a physician from a young age and fell in love with interventional cardiology when he saw balloon angioplasty performed. He talks to Cardiovascular News about his career mentors, why physicians can play a pivotal role in developing novel technologies, and why this year’s Transcatheter Cardiovascular Therapeutics (TCT) meeting (21–25 September, San Diego, USA) is a “training destination”.

Why did you decide to become a doctor and why, in particular, did you decide to go into interventional cardiology?

Some people take a while to decide what they want to do in life. I was very lucky because I always knew what I wanted to do from a very early age. I always wanted to be a cardiac surgeon—I am not very sure where that desire came from (no one in my family was a doctor)! What is interesting is that I have also always wanted to work in cardiology. For some reason, I was attracted to the heart. After medical school and after doing my one-year social service (as is required in Colombia), I worked as a research fellow at a cath lab in Colombia. I saw them to perform a complex balloon angioplasty case and fell in love with it; I thought, “this is what I want to do!”.

Who have been your career mentors?

My first mentor and the person who really opened the doors for me was Humberto J Vidaillet (Department of Cardiology, Marshfield Clinic, University of Wisconsin Medical School, Madison, USA). He was the person who brought me to the USA, gave me my first opportunities, and essentially taught me valuable lessons about North American culture. He is the reason I am in the USA. After that, when I went to Houston for my cardiology and interventional cardiology training, there was Michael DeBakey, he was truly an inspirational figure. This was an extremely exciting time in my career because I was able to work with amazing people in the cardiology field. For example, Drs Michael Raizner and Neil Kleiman (both Houston Medical Center, Houston, USA) helped shape my career as an interventional cardiologist and provided an amazing platform for me to go into translational research. Martin Leon has shaped the last 10 years; he has been a true mentor to me and gave me all the tools that I needed to do what I wanted to do at the Cardiovascular Research Foundation (CRF). He has been influential and an important part of my career.

You did your initial medical training in Colombia before moving to the USA. What are the key differences in healthcare between Colombia and the USA?

There are significant differences. One thing is that Colombia has universal coverage in contrast to the USA, but universal coverage does not necessarily mean that everyone has equal opportunities to access technology and devices. There are also differences between Colombia and USA in terms of how much money can be invested into healthcare. I do really believe that the universal coverage system in Colombia works though. No matter where people are and what access they have to some technologies, there is at least a certain level of equal access to healthcare for everyone—this is sometimes lacking in the USA.

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

For me, it is difficult to pick one specific development.

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Due to the nature of my work, I have been fortunate to witness significant success stories in our field. But, I always saw the introduction of the stent as what made interventional cardiology a viable specialty. Following the introduction of the drug eluting stent, we had—for the first time—a therapeutic tool showing sustained efficacy; I do not think that bare metal stents alone would have allowed interventional cardiology to become the alive and vibrant field that it is now. Also, I think that some of the new interventional therapies introduced to date such as transcatheter aortic valve implantation (TAVI) owe its success to the engineering and clinical know-how gained during the era of drug-eluting stents.

As someone who has always been interested in innovation, where do you think the next “breakthrough” will be in interventional cardiology?

Innovation in our field has rapidly moved into the so-called structural heart disease space, which seems to be the “next revolution” in our field. I think eventually all these technologies will offer surgical-like devices with the use of catheter-based techniques. Both repair and replacement devices will be available and, unlike the surgical field, device “ease of use” will play a major role in physicians’ adoption and use. I am very intrigued though about the next wave of innovation in our field; I really think that computer power and data analytics are going to open exciting opportunities for the development of new technologies in our field.

Why is it valuable for an interventional cardiologist, such as yourself, to be involved with developing new technologies?

I think the physician plays a vital role in the innovation ecosystem. You cannot invent anything meaningful in medicine if you do not understand the need or the problem. Every physician is a potential inventor—they see the challenges and the possible solutions. In fact, I would say that physicians are the first and perhaps one of the critical components of the innovation cycle.

You were previously executive director of the CRF Skirball Center for Innovation. What does the centre do? The centre is dedicated to the research and validation of early stage technologies. We have created a platform that fosters innovation by allowing the collaboration and interaction between inventors, start-up companies, and established companies.

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I always saw the introduction of the stent as what made interventional cardiology a viable specialty

You were appointed as president and CEO of CRF in September 2017. What are your key duties?

At CRF, we have four main divisions (CRF Skirball Center for Innovation, CRF Clinical Trials Center, CRF Center for Education and the newly-established CRF Digital). So, I have a full plate of things to do because I have to oversee the strategy of these four divisions. I combine this work with my research at the Skirball Center and try to keep my interventional skills sharp!

Given that information is increasingly available online, and the

Fact File

current cost pressures of attending conferences, what do you think the value is of still attending meetings?

There is no doubt that the environment is changing and that it is changing on multiple levels. But, I really believe meetings are absolutely necessary and critical to learning about new techniques and technologies. Through a computer screen, you cannot teach technique, have close mentor-derived discussions, or network. Therefore, I think meetings should focus on practical and hands-on training to be able to fulfil the needs of the physicians in these times when so much information is online. This is what the future of TCT will focus on.

What do you think the highlights of this year’s TCT will be?

We have made significant changes to the programme; the number of didactic lectures have decreased by a significant percentage to allow the development of what we are calling a “training pavilion”. We are going to have a large space in which we are going to have eight dedicated tracks for practical training. This will include hands-on skills training, case-based learning led by key opinion leaders, and discussions about new technologies. This is why, this year, we are calling TCT the “training destination”.

What advice would you give to someone who is just coming into the profession?

The first thing that I tell my fellows is “make sure you love what you do” because interventional cardiology is a very intense specialty that is going to require a lot of devotion, time, and love. Obviously, I am biased because of my interest in innovation, but I also tell people that they should never lose their spirit of invention—being involved in seeing what the needs are and developing new technologies as a result is what makes this field fun and different. Finally, I would advise that people look at new areas that actually have never been explored before. For example, interventional heart failure is novel field—we will sure monitor and manage heart failure patients in different ways in the future. There are several amazing new fields that can be led by the next generation of interventional cardiologists.

Outside of medicine, what are your hobbies and interests?

I am a football [soccer] aficionado; it has always been big in my life. I learned the sport on the streets of Colombia and I have learnt valuable lessons from it— such as the importance of training, teamwork and dedication. I still play with the Colombian physicians’ national team and I try to go to the World Medical Football Championship every year. I am also passionate for the history of science and invention, even beyond the medical field. Finally, I would not say I am formal chef, but I like to think I am a good cook! Food and cooking is one of my passions. I cook everything!

Current appointments

September 2017—present: President & CEO, Cardiovascular Research Foundation, Columbia University Medical Center, New York, USA July 2015–present: Associate Professor of Medicine, Columbia University Irving Medical Center, New York Presbyterian Hospital, New York, USA July 2015—present: Interventional cardiologist, New York Presbyterian Hospital, New York, New York, USA January 2013–present: Co-Director, TCT meeting

Medical education

July 2004– Interventional cardiology June 2005: fellow, Baylor College of Medicine, Houston, USA July 2001— Fellow in Cardiovascular June 2004: Diseases, Baylor College of Medicine, Houston, USA July 1999— Chief resident in Medicine, June 2001: University of Wisconsin, Marshfield Clinic, Marshfield, USA July 1998— Internship, University of June 1999: Wisconsin, Marshfield Clinic, Marshfield, USA January 1995– Research fellow in December 1997: Interventional Cardiology, St Mary’s Cardiovascular Hospital, Medellin, Colombia January 1993— Internship, Medellin General December 1994: Hospital, Medellin, Colombia

Achievements

Young Investigator Award, American College of Cardiology (2008) The James T Willerson Vulnerable Plaque Young Investigator Award for Basic Research, American Heart Association (2002) The Outstanding Young Persons of the World Award (TOYP) (2001) Young Investigator Award, American College of Cardiology (2000) More than 20 patent applications in the medical device technology field

Aug

Issue

Transcatheter tricuspid valve therapies

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ADVERTORIAL

Edwards’ Cardioband Tricuspid Valve Reconstruction System: A new option for under-treated patients TM

The granting of the CE mark to Edwards Lifesciences for its Cardioband Tricuspid System was an important development for patients with tricuspid regurgitation.1 As well as becoming the first—and only—approved percutaneous treatment option for tricuspid repair on the European market, the device represents a new option for a condition that historically has been under-treated because, at least in part, the number of suitable treatments are limited.

n the USA, 1.6 million people have moderate-to-severe tricuspid regurgitation and most of them have functional tricuspid regurgitation.2 According to Dr. Stephan von Bardeleben (Heart Valve Center Mainz—Cardiology I, University Medicine Mainz, Mainz, Germany), 80% of his patients have functional tricuspid regurgitation, and he explains that “functional means secondary to left heart disease, both ventricular and valvular in origin, or secondary to any pressure load such as lung disease”. However, despite its relatively high prevalence, tricuspid regurgitation has historically been under-diagnosed and under-treated. Dr. von Bardeleben reports that less than 1% of patients with moderate-to-severe tricuspid regurgitation will undergo surgical or interventional repair this year, which supports similar statistics reported in American studies.3 In contrast, tricuspid regurgitation is more prevalent than aortic stenosis, yet 15–20% of patients with aortic stenosis will receive adequate (surgical or transcatheter) therapy this year, he notes. “The number of patients with moderate-to-severe tricuspid regurgitation receiving adequate treatment differs from country to country, with much greater under-treatment in developing countries such as India,” Dr. von Bardeleben observes.

One of the reasons why a relatively small percentage of patients with tricuspid regurgitation receive treatment is the misconception that tricuspid regurgitation does not require treatment; this has led to the under-recognition of the clinical impact of tricuspid regurgitation on morbidity and mortality. In fact, tricuspid regurgitation is both a significant marker and cause of increased mortality.4 The increased risk of mortality correlates to the severity of tricuspid regurgitation. Dr. von Bardeleben states, “Patients with severe tricuspid regurgitation have the worst prognosis, with the survival rate being less than 50% by five years.” He adds that patients “complain about an inability to exercise, experience fatigue, have liver dysfunction, and have leg oedema,” meaning that their quality of life “is severely impaired”. Treatment of tricuspid regurgitation, provided it is successful and performed early enough, can improve cardiac output, decrease venous pressure, and improve leg oedema among other benefits. However, a key issue—and the main reason for the under-treatment of patients with tricuspid regurgitation—is a lack of available therapeutic options. While isolated surgery can be used for some patients, according to Dr. von Bardeleben, it is associated with substantial in-hospital mortality (8–10%).5

Edwards Cardioband Tricuspid Valve Reconstruction System

Dr. Stephan von Bardeleben

The only non-surgical option—prior to the Cardioband tricuspid system receiving the CE mark—was palliative medical therapy with diuretics. Therefore, there is a definite need for a less invasive therapeutic option in patients with this condition. The Cardioband tricuspid system has been designed to address this need. Dr. von Bardeleben explains that it reduces the septolateral, as well as the anteriorposterior, diameter of the tricuspid valve. Although a similar device is used to treat mitral regurgitation (Cardioband Mitral System, Edwards Lifesciences), there are different considerations when treating patients with tricuspid regurgitation. He comments, “The stiffness of the tricuspid annulus is less than that in the mitral space. The proximity of the right coronary artery—as well as the limited thickness of the basal right ventricular wall—has to be respected when using the system in the tricuspid valve. In the mitral space, the circumflex artery is the artery with the closest relation to the Cardioband anchors.” So far, data for the Cardioband tricuspid system shows that it is a reasonable option for managing tricuspid regurgitation. The TRI-REPAIR study was a single-arm, prospective, study in which 30 patients with functional tricuspid regurgitation received the Cardioband tricuspid system.6 The primary endpoint was the rate of major serious adverse events at hospital discharge and at 30 days (safety endpoint) and the successful access, deployment, and positioning of the device (technical success endpoint). Other endpoints included reduction in tricuspid regurgitation grade, effective regurgitant orifice area (EROA), and volume and functional tests. Technical success was achieved in all patients and, overall, there was a 16% reduction in septolateral diameter at

discharge: 37±4.5mm vs. 44.4±4.4mm at baseline (paired t-test p<0.001). This reduction was sustained at 30 days and at six months. Furthermore, at 30 days, there was a 51% reduction in EROA, 31% reduction in vena contracta, and a 9% improvement in left ventricular stroke volume. These results were again sustained at six months (interim report). In terms of functional improvements, at 30 days, there were significant improvements in Kansas City Cardiomyopathy Questionnaire scores (p<0.01), New York Heart Failure Association (NYHA) class (p<0.01), and oedema (p=0.01). By six months (interim report), not only were these improvements sustained but there was also a significant improvement in the six-minute walk test compared with baseline levels. Presenting the data at EuroPCR 2018 (21–24 May, Paris, France), Prof. Francesco Maisano (Heart Valve Clinic, University Hospital of Zurich, University of Zurich, Zurich, Switzerland) said: “In an early experience, the Cardioband tricuspid system provides a significant reduction in EROA through annular reduction,” adding that the study had given “valuable learnings”. For Dr. von Bardeleben, the key to achieving good outcomes with the system is “optimal patient selection”. Therefore, he thinks that the patients who will benefit the most are those with annular septolateral dilatation that is intermediate (4–5cm), rather than severe, and those with moderately impaired, right ventricular function. He adds: “Patients should have NYHA Class II or III with symptoms but still have residual ability to walk so that they can be mobilised after the procedure.” Dr. von Bardeleben also believes that patients, prior to the procedure, should also have a life expectancy of more than one year and systolic pulmonary artery pressures of less than 60mmHg. Summing up the available evidence for the Cardioband tricuspid system, alongside what is known about the optimal management of patients with tricuspid regurgitation, Dr. von Bardeleben says that the system is “the beginning of a new ‘microinvasive’ generation of transcatheter tools to address both “a forgotten valve and forgotten patient population”. He adds: “The Cardioband system has shown feasibility and safety, but there still is a journey of learning and understanding as well as sub differentiating the haemodynamics and pathophysiology of tricuspid and right heart disease. At the Heart Valve Center Mainz, we are happy and proud to be part of this journey.” References 1. BIBA Medical staff. Cardioband becomes first-ever transcatheter tricuspid system to receive the CE mark. Cardiovascular News 2018. https://bit.ly/2u6C5os (date accessed 10 July 2018) 2. Stuge O, Liddicoat J. Journal of Thoracic and Cardiovascular Surgery 2006;132 (6):1258-61 3. McCarthy PM, Sales VL. Current Treatment Options in Cardiovascular Medicine 2010; 12(6): 587–97. 4. Nath J, Foster E, Heidenreich PA, et al. Impact of tricuspid regurgitation on long-term survival JACC 2004; b43(3):405–09. 5. Fender EA, Zack CJ, Nishimura RA. Isolated tricuspid regurgitation: outcomes and therapeutic interventions. Heart 2018; 1; 104 (10): 798–806. 6. Maisano. EuroPCR 2018.

Aug

Innovation

Issue

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BIBABriefings The end of the wire?

Complex PCI vs. standard PCI in France and the UK Credit: BIBA MedTech PCI Monitor

Majority of PCI procedures performed in France and the UK are complex

According to preliminary data (Q2; 1 April–30 June 2018) from BIBA MedTech PCI Monitor, more complex percutaneous coronary intervention (PCI) procedures are performed in France and the UK than are standard procedures: 60% vs. 40% and 51.4% vs. 48.6% (see Figure 1). However, overall in Western Europe, standard PCI procedures are still more frequently performed than complex procedures (57% vs. 43%, respectively). The PCI Monitor data also show that PCI for bifurcation lesions is the most frequently performed complex PCI procedure (28% of all such procedures are for bifurcations). Furthermore, they indicate that almost a third (27.54%) of PCI operators do not use a specific device to perform PCI—although, given that the PCI Monitor also shows that the vast majority of PCI procedures are performed with a drug-eluting stent, it can be assumed that they use a drug-eluting stent. Of those who do express a preference for a device, in line with the general PCI data, the most commonly used devices are Abbott’s Xience (all iterations; 23.91%) and Medtronic’s Resolute (all iterations; 20.29%). See Figure 2.

The SYNTAX III REVOLUTION trial, which was presented at EuroPCR (22–25 May, Paris, France), has raised the possibility that revascularisation decisions—in the case of the study, percutaneous coronary intervention (PCI) vs. coronary artery bypass grafting (CABG) for three vessel/left main disease—could be made without the aid of an angiography wire. It found that heart teams using computed tomography (CT) angiography would agree with 92.8% of heart teams using conventional angiography. Furthermore, it showed that the use of the HeartFlow Analysis system (HeartFlow), which uses CT to calculate fractional flow reserve (FFR) values, would change the choice of revascularisation in 7% of patients

Cardioband tricuspid system may herald new era of transcatheter management of tricuspid regurgitation

n April this year, the Cardioband tricuspid system (Edwards Lifesciences) received the CE mark—making it the first and only transcatheter system for managing tricuspid regurgitation to be commercially available (the original Cardioband, designed for managing mitral regurgitation, received the CE mark in 2015). Several other transcatheter tricuspid valve repair systems are in development, including a tricuspid version of Abbott’s MitraClip system (CE marked and FDA approved for the mitral valve). However, rather than looking at repairing the tricuspid valve, some companies are focusing on replacing it. NaviGate, for example, is evaluating the use of its novel GATE tricuspid valve stent—implanted via a transjugular approach—to manage severe tricuspid regurgitation (un-

assessed with CT angiography. For the full story, see story on page 4. CathWorks are also exploring the possibility of wireless assessment of coronary artery disease—or at least reducing the need for wires. Its 3D FFRangio system (currently still in development) is designed

to calculate FFR during coronary angiography procedures without the need for a pressure wire or hyperaemic stimulus. The company recently announced it has received a new Current Procedural Terminology code 0523T for the system.

der compassionate use protocols). The company medication (see page 1 for the full story). recently reported, in a press release, that The Paradise system will further be the first patient to receive the device had explored in the RADIANCE II trial, “excellent valvular function” at one year. which recently received FDA apSimilarly, NVT has the novel Triproval to evaluate the system in cento transcatheter valve; according patients with moderate hypertento a case report published in Eurosion. Intervention, this bicavally anchored While some key questions need device (implanted via the transvenousto be addressed—including which transfemoral approach) reduced caval patients would benefit the most from vein regurgitation at three months in a renal denervation and how sustainable 74-year-old woman with tricuspid regurits effects are—these studies and the merger gitation and heptic vein backflow. Authors agreement between Otsuka and ReCor inSmart stent (credit: UniStefan Toggweller (Heart Center Lucerne, versity of British Columbia) dicate that renal denervation once again has Luzerner Kantonsspital, Lucerne, Switbecome a concept worthy of interest. zerland) conclude that Tricento represents “a promising, novel therapeutic option for patients with severe Stent tells you when it is time to tricuspid regurgitation that are not candidates for open revascularise heart surgery.” emote monitoring of implanted devices has been around for a while, such as remote monitoring Company shows faith in renal of implantable cardioverter defibrillators, but a denervation following positive data new “smart stent” may bring the concept to percutanetsuka Holdings, Otsuka Medical Devices, and ous coronary intervention (PCI). Kenichi Takahata (UniReCor Medical—owner of the Paradise renal versity of British Columbia, Vancouver, Canada) and denervation system—have signed a merger colleagues have designed a “smart stent” that monitors agreement pursuant to which Otsuka Holdings will even subtle changes in the flow of blood through the acquire the remaining shares in ReCor from its current artery, detecting the narrowing in its earliest stages and holders. This indicates that Otsuka, at least, believes making early diagnosis and treatment possible. renal denervation still holds promise. Four years ago, the SYMPLICITY HTN-3 trial dealt the concept of renal denervation a heavy blow BIBA Briefings when it showed that renal denervation with MedtronBIBA Briefings is a new platform that provides ic’s Symplicity system did not significantly lower in-depth analysis of the latest market intelblood pressure compared with a sham procedure in ligence from BIBA MedTech, which provides patients with resistant hypertension. However, last consulting and market analysis services to year, the SPYRAL HTN-OFF MED trial sparked remedical professionals and organisations in the newed interest in the concept when it found that renal medical device industry in Europe and North denervation with Medtronic’s next-general SymplicAmerica. The platform also reviews key data ity Spyral system did significantly reduce blood presand news. sure, compared with a sham procedure, in patients The aim of each report is to give an overview of with uncontrolled hypertension who were not taking the key information affecting the medical device medication. Subsequently, this year, the SPYRAL industry, enabling those working in the industry HTN-ON MED found that the system also signifito keep abreast of the latest developments and cantly reduced blood pressure (again compared with a make knowledgeable decisions. BIBA Briefings sham procedure) in patients who were taking medicacovers both PCI and TAVI. tion. Also, another sham-controlled study published For more information about BIBA Briefings this year (RADIANCE HTN-SOLO) indicated that or BIBA MedTech, please contact Elizabeth renal denervation with Paradise significantly reduces Sutherst: elizabeth@bibamedical.com blood pressure in patients with mild-to-moderate off

O Devices used for complex PCI Credit: BIBA MedTech PCI Monitor

FFRangio demo

Aug

Issue

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Consider patient’s risk of ischaemic stroke when choosing antiplatelet therapies after PCI

New data from ADAPT-DES, published in JACC: Cardiovascular Interventions, indicate that higher platelet reactivity units (PRU) are associated with an increased risk of ischaemic stroke. Therefore, study authors Gennaro Giustino (The Zena and Michael A Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, USA) and others suggest that risk of ischaemic stroke should be taken into consideration when making decisions about antiplatelet therapy after percutaneous coronary intervention (PCI).

ata from ADAPT-DES, Giustino et al report, have already shown that high on-platelet reactivity is a strong independent predictor of both stent thrombosis and myocardial infarction after PCI. Noting that coronary artery disease patients are at increased risk of ischaemic stroke because of concomitant atherosclerotic disease, the authors add that the influence of residual P2Y12 receptor inhibition on the risk of ischaemic stroke is unknown. “We sought to investigate the association between platelet reactivity on clopidogrel and aspirin and the risk of ischaemic stroke in patients with coronary artery disease who underwent successful drug-eluting stent PCI,” they comment. In a post-hoc analysis of ADAPT-DES, Giustino et al identified 7,649 patients (of 8,582 originally enrolled) who had two-year follow-up data. Of these, 68 patients

had an ischaemic stroke and 14 had a haemorrhagic stroke (82 in total). According to the authors, this twoyear incidence is comparable to that of stent thrombosis. Patients with ischaemic stroke had higher levels of PRU, identified using the VerifyNow assay (Accriva Diagnostics), compared with those without ischaemic stroke. There were no differences in level of PRU between patients with haemorrhagic stroke and those without haemorrhagic stroke. Giustino et al observe: “Patients with PRU >208 had a higher risk of ischaemic stroke at two years (1.2% vs. 0.5%; univariate hazards ratio [HR] 2.18; p=0.01); an association that persisted following multivariate adjustment (HR 1.84; p=0.02).” They add that, after modelling ischaemic stroke as a time-dependent covariate and by adjusting for baseline confounders, it was strongly associated with two-year all-cause mortality

New approaches

(p<0.001) and cardiovascular mortality (p=0.0009). As well as the incidence of ischaemic stroke being similar to that of stent thrombosis at two years, the authors say, the risks of all-cause mortality and cardiovascular mortality are also similar. “Our findings imply that the risk of ischaemic stroke should be taken into consideration when risk-stratifying patients and selecting antiplatelet regimens after PCI,” Giustino et al comment. They add: “The results of the present investigation suggest that ensuring optimal platelet inhibition may reduce the risk for ischaemic stroke in this patient population.” Study investigator Gregg Stone (Columbia University Medical Center, and The Cardiovascular Research Foundation, New York, USA) told Cardiovascular News: “Our study demonstrates an association between inadequate inhibition of the platelet adenosine diphosphate receptor and ischaemic stroke. Subsequent randomised trials are required to determine whether more potent platelet inhibition in such patients will reduce the risk of stroke without excessively increasing bleeding.”

Aug

New approaches

Issue

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Third-generation drug-eluting stents and beyond: Where we were, where we are, and where we are heading MICHAEL MAENG COMMENT & ANALYSIS Second-generation drug-eluting stents resolved the issues of late and very late stent thrombosis that were seen with the firstgeneration devices and have good safety and efficacy data. However, there is still room for improvement with these devices. Michael Maeng explores the journey from first-generation to second-generation drug-eluting stents, looking at if future devices have the potential to be superior to current treatments.

he first drug-eluting stents revolutionised the field of interventional cardiology. The sirolimus-eluting Cypher stent (Cordis), the paclitaxel-eluting Taxus stent (Boston Scientific), and the zotarolimus-eluting Endeavor stent (Medtronic) constituted the first-generation of drug-eluting devices, and millions of patients were treated with them. Some of the lessons learned with these stents were that Cypher and Taxus were very effective tools to decrease in-stent restenosis and that their drug elution—over approximately one month—was efficient. However, they were also associated with late and very late stent thrombosis; probably related to adverse polymer-vessel wall interactions. Also, the Endeavor device found to elute its drug too fast, which explains why it was less effective and was associated with higher rates of early stent thrombosis. By contrast, the second-generation drug-eluting stents—such as the everolimus-eluting Xience/Promus stents (Abbott Vascular/Boston Scientific), the biolimus-eluting Nobori/BioMatrix stents (Terumo/Biosensors), and the zotarolimus-eluting Resolute stent (Medtronic)—used thinner struts, better polymers, and eluted the limus drug of choice (paclitaxel disappeared with Taxus) over a period of approximately one month.

Current status of drugeluting stents

With the appearance of the secondgeneration (and the disappearance of the first-generation) drug-eluting stents, non-inferiority head-to-head comparisons replaced superiority trials. A long series of non-inferiority trials have subsequently shown what they were designed to do: namely, non-inferiority between stents. However, there have been two exceptions to this rule. The first exception was

the SORT OUT V trial, which failed to show that the Nobori biolimus-eluting stent was superior to the first-generation Cypher stent. The second exception was BioFlow V (N=1334 patients), which compared the thin-strut sirolimuseluting Orsiro stent (Biotronik) to the durable-polymer Xience stent. It found that 6% of patients in the Orsiro group and 10% in the Xience group met the 12-month primary endpoint of target lesion failure (p=0.0399). However, the difference in target lesion failure was primarily driven by a difference in target vessel myocardial infarction (4.7% vs. 8.3%, respectively) with no difference in definite stent thrombosis. Superior-

(from 5.3% to 4.4%) and target lesion revascularisation (from 3.3% to 2.5%) have been improving with each consecutive study. So even with almost identical drug-eluting stents, results are getting better over time. Second, both Synergy (a thin-strut, everolimus-eluting stent with a biodegradable polymer, Boston Scientific) and Orsiro have target lesion failure rates around 3.8–4.0%. Although these improvements (compared with other devices) have not reached statistical significance, the results suggest that we—in a period with non-inferiority trials—are slowly but surely improving our results.

The future of drug-eluting stents

Theoretically, we can improve drugeluting stents on at least five parameters: strut thickness, drug, polymer, inactivation of the luminal side of the stent, and deliverability. Strut thickness: the relative thickstrut stainless-steel biolimus-eluting stents will soon be history. Nobori has been replaced with the cobaltchromium sirolimus-eluting Ultimaster device (Terumo), and BioMatrix NeoFlex is being replaced by a new cobalt-chromium version. This means that all major drug-eluting stent brands will have almost identical strut thickness based on a cobaltchromium or platinum-chromium alloys. There is, thus, probably not much to gain with regard to this

To ensure the best available treatment of our patients, we must continue to perform independent testing of drug-eluting stent modifications and new arrivals ity could not be confirmed in the SORT OUT VII trial (N=2525) comparing Orsiro vs. Nobori (target lesion failure 3.8% vs. 4.6%). Consequently, we now have many newer-generation drug-eluting stents that have been compared to at least one other newer-generation drug-eluting stent and all of these do principally show non-inferiority. At first glance, this may suggest stagnation in stent development rather than progress. But, this may not be entirely true. First, if we look at the outcomes with the biolimus-eluting drug-eluting stents (Nobori, BioMatrix, BioMatrix NeoFlex)—which have been used in four consecutive SORT OUT studies—then the outcomes of target lesion failure

parameter Drug: all major drug-eluting stent brands use limus drugs and major improvements are not expected in this field Polymer: the currently available durable polymer drug-eluting stents (Xience/Promus/Resolute) have shown results that are equal to biodegradable polymers. Within the biodegradable polymer field, there seems to be very similar results with polymers that are absorbed after three (Synergy/Ultimaster), eight (Nobori/BioMatrix), or 18 (Orsiro) months. Polymer-free stents are interesting and may be a preferable strategy, but more data are needed Inactivation of the luminal stent

side: this may be particularly relevant for patients at high risk of bleeding events as it may allow shorter duration of dual antiplatet therapy. It also may lower the risk of stent thrombosis. The Combo (OrbusNeich) and Cobra PzF (CelaNova) stents use such strategies, but we are awaiting more data from studies, such as SORT OUT X, that compare Combo vs. Orsiro Deliverability: stent delivery failure remains an issue, at least with the thick-strut drug-eluting stents, but thin-strut third-generation drug-eluting stent trials all report low rates of stent delivery failure. Still, factors such as the ability of the stent to stay on the balloon in complex percutaneous coronary intervention (i.e. not get lost proximal to the lesion), pushability, and flexibility remain important factors for operators.

Conclusion

We still have a dream of a bioabsorbable scaffold that delivers the drug to the vessel, maintain radial strength for a sufficient period of time to avoid constrictive vascular remodelling, and then disappears when the job is done. At this moment, however, we have an array of drug-eluting stents that perform extremely well. In all-comer trials, the rates of target lesion failure are now down to 4% in the first pivotal year. Since target lesion failure includes cardiac death (1.4% in the latest SORT OUT trial), this leaves very little space for reduction of true stent-related failures. Identification of high-risk patients and optimisation of adjuvant therapies is important and may be a more cost-effective strategy to achieve better outcomes for our patients. However, an important function of the non-inferiority studies is to monitor the continuous modifications of available drug-eluting stents, and to function as an independent quality control of new drug-eluting devices being developed and sold by new companies on the market. Since superiority studies in the drug-eluting stent area are no longer being performed, an important function of drug-eluting comparisons is to capture and avoid the entry of truly inferior drug-eluting stents. To do so, and to ensure the best available treatment of our patients, we must continue to perform independent testing of drug-eluting stent modifications and new arrivals. Michael Maeng is at the Department of Cardiology, Aarhus University Hospital, Skejby, Aarhus, Denmark

Aug

Issue

Dual antiplatelet therapy

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Advantage of guided de-escalation of dual antiplatelet therapy seen in younger patients A pre-specified analysis of the TROPICAl-ACS study indicates that de-escalating dual antiplatelet therapy (DAPT), as guided by platelet function testing, after percutaneous coronary intervention (PCI) provides a net clinical benefit for patients aged ≤70 years.

riting in the European Heart Journal, Dirk Sibbing (Department of Cardiology, LMU München, Munich, Germany) and others explain that “de-escalation” of DAPT involves prescribing a potent P2Y12 inhibitor (prasugrel was used in TROPICAl-ACS) and aspirin for one week after PCI, followed by clopidogrel for a week and a platelet function test. If a patient, while on clopidogrel, has high platelet reactivity, they are switched back to the potent P2Y12 inhibitor; if they have sufficient platelet reactivity, they remain on clopidogrel. The main TROPICAL-ACS study (published in the Lancet last year) found that a de-escalation strategy was non-inferior—in terms of the combined primary endpoint of cardiac death, myocardial infarction, stroke, and bleeding—to a standard DAPT approach of aspirin and prasugrel in patients with acute coronary syndrome. The aim of this pre-specified analysis of TROPICAL-ACS, Sibbing et al report, was to assess clinical outcomes in younger vs. elderly acute coronary syndrome patients with uniform prasugrel vs. guided DAPT de-escalation. “Patients’ age is a major determinate of outcomes after PCI in general and especially in conjunction with the use of P2Y12 inhibitors during and after PCI. Therefore, it seems mandatory to assess whether patients’ outcomes following de-escalation of antiplatelet treatment may differ in relation to age,” the authors comment. In this new analysis, a cutoff of 70 years was used—with younger patient being aged ≤70 years and older patients being aged >70 years. Of the overall study population, 2,240 were aged ≤70 years (86%). In this younger population, the primary endpoint occurred in 5.9% of patients in the guided de-escalation group and 8.3% in the control group (p=0.03 for the difference). Additionally, Bleeding Academic Research Consortium (BARC) bleeding—a key secondary endpoint—was numerically lower in the de-escalation group (3.9% vs. 5.6% for the control group; p=0.06). Sibbing et al comment: “The absolute risk reduction of 2.4% observed for the primary endpoint corresponds to a number needed to treat of 42.” However, among older patients, there were no significant differences between the de-escalation group and the control group in the rate of the primary endpoint; there were also no differences in bleeding

Dirk Sibbing

between groups in this cohort of patients. The incidence of the primary endpoint, though, was significantly higher among older patients vs. younger patients (p<0.0001 for the difference). According to the authors, using a STEPP analysis, increasing risk reduction was observed in the primary endpoint with decreasing age. They comment: “An exploratory post hoc analysis for interaction testing revealed 57 years of age as an optimal cutoff for separating age categories regarding possible net clinical benefit from guided DAPT deescalation.” When this cutoff value was used, a significant benefit was seen for the de-escalation strategy: 3.9% vs. 7.7% (p=0.0006). “This overall benefit in the composite primary endpoint was largely driven by a significant reduction of bleeding in patients <57 years (p=0.0004),” Sibbing et al observe. Concluding, they write: “The results suggest that guided de-escalation may be a safe and attractive alternative treatment concept for all acute coronary syndrome patients after PCI, while a significant benefit in bleeding may achieved in younger patients.” Sibbing told Cardiovascular News: “Guided DAPT de-escalation reduces bleeding risk in younger patients and is attractive from an economic point of view for all acute coronary syndrome patients after PCI. Based on TROPICALACS results, a de-escalation should be guided by platelet function testing and can be done as early as two weeks after discharge or at any time point later on. A single assessment of platelet inhibition on clopidogrel is needed and this seems feasible in clinical routine practice. This strategy must be considered as an alternative treatment concept and as a valid option for the treatment of acute coronary syndrome patients.”

Aug

Societies

Issue

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Cardiology societies come together to provide key advice for dealing with ionising radiation The American College of Cardiology (ACC), Heart Rhythm Society (HRS), North American Society for Cardiovascular Imaging (NASCI), Society for Cardiovascular Angiography and Interventions (SCAI), and the Society for Computed Tomography (SCCT) have published, in the Journal of the American College of Cardiology, an expert consensus document on the optimal use of ionising radiation. Lead author John W Hirshfeld (Cardiovascular Medicine Division, Hospital of the University of Pennsylvania, Philadelphia, USA) speaks to Cardiovascular News about why there is a need for such a document and its key recommendations.

On the whole, do you think cath lab staff are sufficiently aware of the dangers of radiation exposure?

I think that the levels of understanding and awareness are heterogeneous. There are some physicians who know this knowledge base and apply it well; others are less well informed. Awareness of the dangers of radiation exposure are similarly heterogeneous among cath lab nursing and technical staff—most do not hold a detailed knowledge base and take it on faith that their work environment and practices are safe.

Why was there a need to produce the consensus document?

ACC leadership felt that it was important to develop a document that would have educational value for its membership. There was concern that there

is a growing use of radiation in cardiovascular procedures and that, as already discussed, the heterogeneity of understanding of the radiation knowledge base has led to increasing use without any consideration for the potential consequences to both patients and occupationally exposed medical staff. Therefore, the ACC leadership wanted to create a document that brought together all of the relevant knowledge about radiation physics, biology, protection and equipment operation. They wanted a document written specifically for clinicians that would be both rigorous and accessible to cardiovascular practitioners. We hope that it will be read by all cardiovascular specialists and that it will inform both how they conduct radiation-based procedures and how they select procedures for their patients.

The Writing

Committee of the document was multidisciplinary. Why was it important to have a multidisciplinary team?

We wanted all constituencies to be represented, including patients. This includes both physicians who perform procedures and physicians who do not perform procedures but order them for their patients; the decision to order a procedure is a decision to expose a patient to a given quantity of radiation—such decisions need to be informed by the knowledge base included in our document.

What are the key recommendations for reducing radiation exposure to patients?

Only use a radiation-based procedure when it is the optimal procedure to achieve the clinical purpose

John W Hirshfeld

Consider the patient’s characteristics (intrinsic radiationbased risk, including patient age, gender, prior radiation exposure, comorbidities and natural life expectancy) as part of the decision to order a radiation-based procedure. Conduct a radiation-based procedure in a manner that employs the minimum amount of radiation needed. This requires optimal equipment quality and calibration and optimal selection of imaging protocols.

What are the key recommendations for reducing exposure to cath lab staff?

The inverse square law is the

Physicians are more willing to tolerate uncertainty about coronary artery disease testing if risk of malpractice is less Steven Farmer (Center for Healthcare Innovation and Policy Research, George Washington University, Washington, DC, USA) and others report in JAMA Cardiology that, following the adoption of damage caps—which limit how much a patient receives in a malpractice suite—physicians refer fewer patients for invasive testing and refer fewer patients for revascularisation. This suggests physicians tolerate greater clinical uncertainty in coronary artery disease testing and treatment if they face a lower malpractice risk.

armer et al comment that physicians are known to practice “defensive medicine”, which includes “ordering marginally beneficial tests and interventions”, to prevent malpractice suites. They add whether reducing the risk of malpractice would lead to a decrease in the use of defensive medication is “a key policy question”. “Many states have adopted non-economic damage caps, which limit awards to compensate malpractice plaintiffs for ‘pain and suffer-

ing’”, the authors observed. Given that imaging and invasive diagnostic tests “are often cited as overused for defensive measures”, Farmer et al report that the aim of the present study was to determine if physicians facing lower malprac-

best protection. Everyone should be as far as possible from the radiation source when it is on Minimising patient exposure also minimises exposure to occupationally exposed staff. What is good for the patient is good for you and your staff also Employ shielding optimally Make sure that your equipment is as up to date as possible and is calibrated to use the smallest amount of radiation that produces adequate images Know how to select imaging protocols that use the least radiation (including minimising exposed field sizes).

What key aspects should any training programme on radiation exposure cover?

The basics of radiation physics The basics of radiation biology The radiation dose-risk knowledge base The engineering and theory of operation of radiologic equipment How to calibrate and use your equipment in the most dose-effective manner.

tice risk would be willing to tolerate more clinical uncertainty surrounding coronary artery disease. Therefore, they compared physician-specific changes in coronary artery disease testing and treatments between 2003 and 2009 in nine US states that adopted damage caps with 20 US states that did not adopt such changes. Of 75,801 physicians included in the retrospective analysis, 36,647 (about half) practised in new cap states. Compared with physicians in no cap states, after adoption of damage caps, physicians working in new cap states ordered fewer initial angiograms and referred fewer patients (following stress testing) to angiography. Overall, this led to a significant 21% reduction (p=0.01) in angiography rates. However, the number of ischaemic evaluations did not change as new cap physicians ordered more initial stress tests. The authors comment: “Additionally, [in new cap states] fewer patients progressed from any ischaemic evaluation to revascularisation (-26%; p=0.01). The lower revascularisation rates are driven by fewer percutaneous coronary interventions (PCI); coronary artery bypass grafting (CABG) rates did not change.” Concluding, they note: “We found evidence that physicians altered their coronary artery disease testing and intervention following adaption of damage caps”. “These findings suggest that physicians are willing to tolerate greater uncertainty in coronary artery disease testing and treatment if they face lower malpractice risk,” Farmer et al add.

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Rethinking the future of cardiology imaging In an environment with growing demand for specialist cardiology services, it is important that health tech innovators support physicians to manage demanding workloads and complex procedures while ensuring the patient remains paramount. Within cardiac ultrasound solutions, recent developments are helping to drive improvements not only in terms of patient outcomes but also the user experience. When it comes to ensuring a confident diagnosis, for clinicians, every diagnostic image and patient moment in the care pathway matters.

So, where is the forward momentum heading? Increasing the capacity for more A fundamental step-change has been facilitated to improve performance overall via more powerful processing power of imaging hardware and software, offering advancing visualisa-

tion programmes—in some instances with photo-realistic quality. Users no longer have to choose between frame rate and image quality. New technology more than doubles the frame rate without impacting image quality, offering focused images

Figure 1a: Live 3D Zoom with TrueVue visualisation of two Amplatzer devices

Figure 1b: Left atrial appendage with the light source in it shown using Live 3D Zoom and TrueVue

with fewer transmit operations to provide highly detailed ultrasound images and extraordinary temporal resolution. Automatic anatomical recognition, protocols for automatic functionality and proven quantification, make exams easier to perform and more reproducible, delivering new levels of clinical information. This improved clinical information means faster and more consistent exams that are not only easier to perform but also provide clinicians with a high level of confidence, even for technically difficult patients, making it easier for cardiologists to quickly spot the warning signs of serious heart conditions and confidently assess when an interventional procedure is necessary. As technology evolves to capture better images across patient types and make the processes

quicker and easier, it supports the treatment-planning processes through faster access to useful information. Recent developments and enhancements include transducers designed specifically for paediatric cardiology, tools which allow for multi-beat analysis from one acquisition, as well as advanced monitors and one-click sub-mode options. Developments like this support getting the best possible images for a confident diagnosis, even when visualising smaller vessels such as coronary arteries within paediatric patients.

Simplifying the user interface to advance the patient image

As well as image quality, the development of increasingly intuitive customisable user interfaces is a vitally important component

Figure 2: 2D colour left main coronary artery assessment until its bifurcation with S9-2 transducer

of cardiology imaging and echocardiography. By simplifying controls, the clinician can focus on caring for the patient, while the ergonomics and portability, alongside truly configurable cardiac user interface and simplified echo guidance facilities, allows a streamlined workflow and optimised data capture consistency exam-to-exam, for robust decision making and ultimately resulting in improved exam efficiencies. It’s now possible to achieve better visualisation of cardiac structures for procedure guidance in fewer steps, confidently visualise the region of interest for echo-guided interventional procedures such as mitral valve repair, and obtain faster 3D measurements for device sizing. Jon Weait, Ultrasound Business Marketing Manager for UKI, Philips, said: “With the average age of the UK population on the increase, so is the prevalence of heart disease. At Philips, we are proud of the role we play in meeting these evolving population health needs and through meaningful innovation we continue to help create cardiology solutions that improve the patient and physician experiences. Central to this is the belief that richer images are key to ensuring accurate, efficient patient care in cardiology and in a recent simulated evaluation, with over 40 Philips users globally, 90%1 of clinicians felt the new TrueVue 3D photorealistic rendering improved viewing of anatomical structures, thus increasing clinical confidence, and 95%1 said they believe that the new EPIQ CVx cardiology ultrasound system with the latest OLED technology offers improved image quality in terms of sharper and clearer images.1 We are excited to be able to continue to improve the treatment landscape for cardiology professionals in order to provide the best patient care. Because every patient matters, every image counts”. To find out more about Philips latest EPIQ CVx cardiovascular ultrasound system please visit: www.philips.co.uk/EPIQCVx_ CardioNews Reference 1. These results were obtained during user demonstrations performed in December 2017 with the EPIQ CVx and the iE33 systems. The research was designed and supervised by Use-Lab GmbH, an independent and objective engineering consultancy and user interface design company. The tests involved 40+ clinicians from 17 countries. The various types of cardiac customer segments represented were adult diagnostics and interventional, adult diagnostics, and paediatric diagnostics and interventional.

Figure 1c: Real-time mitral valve display from atrial and ventricular perspectives using 3D Dual Volume combined with TrueVue

Figure 3: Dynamic HeartModelA.I. with LV and LA volume curves and comprehensive volumetric report of the left heart chambers

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Michael Dale, vice president for Abbott’s structural heart business, comments: “Abbott engineers designed these enhancements based on feedback from doctors to improve device delivery and to treat more types of cases and anatomies. We are committed to helping people with mitral regurgitation return to living their best lives, and these advances will enable doctors to treat even more patients without surgery.” Abbott recently began enrolment in the MitraClip EXPAND clinical study, a prospective study evaluating the safety and performance of the new MitraClip system in a contemporary real-world setting. Saibal Kar (Smidt Heart Institute, Cedars-Sinai, Los Angeles, USA) treated the first patient enrolled, and is the lead investigator of the study. EXPAND will enrol approximately 1,000 patients in more than 50 centres across the USA and Europe; interim results from the study are expected later this year.

Product News

Advance CS coronary sinus infusion catheter used for the first time

CorPath

“Remote PCI” successfully performed 100 miles away from the cath lab

Corindus Vascular Robotics has announced that Ryan Madder (Spectrum Health, Ludington, USA) has successfully completed a remote percutaneous coronary intervention (PCI) in a porcine model using the CorPath GRX system from a location greater than 100 miles from the catheterisation lab. Working from a Spectrum Health facility in Ludington, according to a press release, Madder leveraged the CorPath GRX system to remotely manipulate interventional devices through the subject’s coronary arteries while using a telecommunications system to communicate with the bedside staff based in Grand Rapids, USA. Madder has been exploring the feasibility of remote PCI since 2016 when he completed and published the REMOTE-PCI study. In that study, he and his colleagues completed multiple robotic stent procedures from an isolated room outside the procedure room. Procedural success was achieved in 19 of 20 patients (95%). He says: “The REMOTE-PCI study previously demonstrated that remote PCI is feasible. Our recent case completed over a distance of greater than 100-miles now demonstrates that remote robotic PCI can be successfully performed in vivo by a physician who is located at great distances away from the PCI recipient. This achievement is a significant milestone toward breaking down the geographic barriers that prevent many patients in remote regions of the world from undergoing coronary stenting.” The press release notes that the global shortage of PCI-capable operators is significant and continues to be a growing problem. Remote PCI has the potential to enable physicians to conduct procedures from virtually any location, opening opportunities for more patients globally to receive the benefits of this lifesaving procedure. Mark Toland, president and CEO of Corindus, states: “We have made considerable progress in the realisation of remote PCI capabilities through work with our clinical partner at Spectrum Health. Dr Madder’s 100-mile case simply exceeds our expectations. His achievement allows our customers and partners to envision the possibilities of remote treatment and validates our broader vision of striving to apply remote technology to treat other vascular diseases such as acute ischaemic stroke.”

to treat more than 65,000 patients worldwide over the last 10 years. The next-generation MitraClip system is designed to provide cardiologists with advanced steering, navigation, and positioning capabilities for the clip, making it easier to use in difficult anatomies. The enhanced system aims to allow for more precise placement during deployment, resulting in more predictable procedures, and additionally offers a second clip size with longer arms that expands the reach of the clip-based device. The additional clip size is designed to help doctors treat patients who have more complex anatomies when repairing the mitral valve. Abbott received CE Mark for the next-generation device earlier this year, allowing for sale of the devices in the European Union and other countries that recognize this regulatory designation. Francesco Maisano (UniversitätsSpital Zürich, Switzerland), who was an early implanter of MitraClip, comments: “Physicians rely on MitraClip as an alternative to surgery for patients who are not surgical candidates and may need treatment to relieve their symptoms or to survive. The enhanced MitraClip design allows for even more precise navigation, accuracy, and stability during valve repairs, which may be important when treating people with more complex or advanced valve disease.” Prior to the availability of MitraClip, people who were not eligible for the standard-of-care surgery to treat their mitral regurgitation could only manage their symptoms with medications that don’t stop the progression of the disease. Left untreated, the condition leads to a variety of life-altering symptoms and severe complications, and may ultimately lead to heart failure and death.

Next-generation of MitraClip approved for use in the USA

Abbott has received approval from the US FDA for a next-generation version of its MitraClip heart valve repair device used to reduce mitral regurgitation. A press release reports that the transcatheter clip-based therapy, now on a third-generation of product innovations, has been used

MitraClip XTR

Cook Regentec has announced the first clinical use in the USA of the Advance CS coronary sinus infusion catheter and CompassCT disposable pressure transducer to deliver a therapeutic in heart failure patients. The Advance CS coronary sinus infusion catheter is a percutaneous balloon infusion catheter designed for use in retrograde coronary sinus infusion procedures. A press release reports that the catheter is used to infuse therapeutic agents into the heart via the coronary venous system. It adds that the Compass CT disposable pressure transducer provides continuous monitoring of infusion pressure and pressure in the patient’s heart during the procedure. The Advance CS coronary sinus infusion catheter is intended for temporary occlusion of the coronary sinus for infusion of contrast media, drugs, and therapeutic agents, or possible introduction of devices into the coronary venous system. Amit N Patel (University of Miami Health System, Miami, USA), says: “Using the Advance CS coronary sinus infusion catheter, clinicians can deliver therapeutics, including cell and gene therapies, in an out-patient setting. What we once performed on patients through invasive surgery can now be done in a minimally invasive procedure, lowering medical costs, increasing patient safety and delivering the most effective biologics to treat each patient. In the evolution of gene and cell therapies, this is a revolutionary medical device for both clinicians and patients.” The Compass CT disposable pressure transducer—a disposable pressure transducer featuring an integrated digital display—monitors physiological pressure and displays pressure during the infusion of therapeutic agents.

Reva’s Fantom scaffold is now being distributed in Italy

Reva is expanding commercial access to the Fantom bioresorbable scaffold with a new distribution partnership in Italy. The company will work with Bio Vascular on commercial activities nationwide. Following this agreement, the first commercial implant procedure in Italy was conducted by Bernardo Cortese (Clinica San Carlo–Casa di Cura Polispecialistica, Paderno Dugnano, Italy). The partnership with Bio Vascular expands Reva’s commercial activities to Italy and builds on sales efforts already underway in Germany, Switzerland, Austria and Turkey. Under the terms of the partnership, Bio Vascular will be Reva’s distribution partner for the Fantom and Fantom Encore bioresorbable scaffolds in Italy. Bio Vascular will be responsible for all sales, marketing, customer training, and support. Commercial sales are expected to ramp-up in the fourth quarter of 2018, following successful completion of Reva’s training programme by Bio Vascular personnel. Cortese says: “In Italy, we stay on the leading edge of technology to offer the best possible care to our patients. During the implant procedure, I was able to see the technical advantages of Fantom over first-generation bioresorbable scaffolds such as X-ray visibility and ease-ofuse. Second-generation, thin strut bioresorbable scaffolds

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Product News

like Fantom have the potential to improve outcomes, and we are excited to have this treatment option available for Italian patients.” Reggie Groves, Reva’s CEO, comments: “With this partnership we are delivering on our ongoing commitment to expand geographic access to Fantom. Bio Vascular offers country-wide distribution coverage in Italy. The company’s proven track record with interventional cardiology devices, demonstrated relationships with physicians and commitment to patient care make it an ideal partner for us.”

US FDA clearance for TEECAD system for aiding transoesophageal echocardiography

Visura Technologies has received 510(k) clearance from the US FDA for its transoesophageal echocardiography (TOE) Camera Assist Device (TEECAD) system. A press release reports that TEECAD’s single-use disposable camera easily attaches to a TOE (or TEE in the USA) ultrasound probe—allowing physicians to view the upper airway and oesophagus during probe placement for safe intubation. Physicians currently place TOE probes blindly, guided by physician feel and patient cooperation, potentially resulting in failed intubations that can lead to cancelled therapeutic procedures and major complications such as oesophageal or pharyngeal perforation. Visura Founder David Marmor, a non-invasive cardiologist and experienced TOE operator, comments: “TOE-related complications and failed intubations can be dangerous for patients and have costly ramifications for hospitals. The recent proliferation of catheter-based structural heart interventions reliant on TOE imaging has led to growth in procedural volume and an increase in the age and risk profile of patients, increasing the need for visual guidance for safe TOE probe intubation. We look forward to clinically introducing our device.” The TEECAD system consists of a single-use disposable camera carrier that attaches (but can be removed) to the TOE probe and to a separate viewing system display (which allows the physician to view real-time images from the camera to visually assist with safe probe intubation). The clearance of Visura’s first TEECAD camera carrier is for use with the Philips X7-2t probe. Visura Technologies plans to develop additional carrier models compatible with other TEE probes available in the market.

Fantom

est commercially available LVAD, and the only LVAD approved in the USA for implant via thoracotomy, a small lateral, surgical incision between the patient’s ribs on the left side of the chest. FDA approval for HVAD implantation via thoracotomy is based on data from the LATERAL prospective clinical trial, in which 144 patients, with end-stage heart failure who were eligible for heart transplant, were enrolled at 26 centres in the USA and Canada. The primary endpoint of the trial demonstrated non-inferiority of the HVAD implanted in patients via thoracotomy, where survival at six months free from disabling stroke or device explant or exchange due to malfunction was achieved in 88.1% of patients. Since the success outcome exceeded the pre-specified performance goal of 77.5%, the trial achieved its primary endpoint (p=0.0012). The key secondary endpoint revealed a significant reduction in total length of hospital stay, from an average of 26 days down to 18 days (p<0.001). Overall survival among patients receiving an HVAD via the thoracotomy procedure was 88.8% at one year. Detailed outcomes of the LATERAL trial and its secondary endpoints were presented at The International Society for Heart and Lung Transplantation (ISHLT) 2018 Scientific Sessions. “We have demonstrated that a thoracotomy is a safe and effective implant technique for the HVAD System, which gives physicians added flexibility in treating a broad range of patients,” says Edwin McGee Jr, professor and director, Heart Transplant & Ventricular Assist Device Program, Loyola University Medical Centre, Maywood,USA, and principal investigator of the LATERAL trial. “Implanting the HVAD via thoracotomy preserves the chest for a subsequent procedure that patients may need, such as a heart transplant. It also has been shown to result in shorter hospital stays.”

US FDA approve EchoMD AutoEF software for calculating left ventricular ejection fraction

Bay Labs has received US FDA 510(k) clearance for its EchoMD AutoEF software product for the fully automated clip selection and calculation of left ventricular

HeartWare HVAD system receives US FDA approval

Medtronic has received US FDA approval for a lessinvasive implant approach of its HVAD System, a left ventricular assist device (LVAD) for patients with advanced heart failure. The HVAD System is the small-

Credit: Bay Labs

ejection fraction. The EchoMD AutoEF algorithms are designed to eliminate the need to manually select views, choose the best clips, and manipulate them for quantification, an often time-consuming and highly variable process. Unlike current technologies, a press release reports, EchoMD AutoEF automatically reviews all the relevant digital video clips of cardiac cycles from a patient’s echocardiography study, rates them according to image quality, and selects the best ones to calculate the ejection fraction. The press release explains that the EchoMD AutoEF software algorithm “learned” clip selection and ejection fraction calculation after being trained on a carefully curated dataset of over 4,000,000 images, representing 9,000 patients. The software should be able to be integrated into any DICOM PACS medical imaging environment and aims to provide cardiologists with results as a seamless part of routine diagnostic workflow. Neil J Weissman (Georgetown University School of Medicine, Washington, DC, USA), comments: “Left ventricular ejection fraction has been a mainstay of echocardiography for the last 50 years. Bay Labs’ use of artificial intelligence for image selection and automated EF measurement will allow clinicians across a wide range of experience to obtain accurate evaluation of ventricular function and aid in interpretation of the echocardiograms with greater efficiency. This will ultimately result in more effective care for our patients.” Charles Cadieu, co-founder and CEO of Bay Labs, states: “At Bay Labs, our hope is that EchoMD AutoEF will assist cardiologists in their decision making and enhance the care they provide to their patients. We look forward to continuing to develop unique deep learning technologies that enable expanded access to high-quality echocardiography image acquisition and interpretation, with the goal to improve disease management and patient outcomes through earlier detection and monitoring.”

The European Commission authorise use of evolocumab to reduce risk of myocardial infarction in patients with established cardiovascular disease

The European Commission (EC) has authorised a new indication in the evolocumab (Repatha, Amgen) label for adults with established atherosclerotic cardiovascular disease—myocardial infarction, stroke or peripheral arterial disease—to reduce cardiovascular risk by lowering low-density lipoprotein (LDL) cholesterol levels as an adjunct to correction of other risk factors. Evolocumab is a medicine proven to lower LDL cholesterol for high-risk patients who suffer from a combination of high LDL cholesterol and cardiovascular disease, and who continue to struggle with lowering their LDL cholesterol levels despite statin therapy. According to a press release, the recent authorisation by the EC recognises the positive findings from the evolocumab cardiovascular outcomes study (FOURIER), updating the label to include data on the additional effect of evolocumab on heart attacks, strokes and coronary revascularisations on top of the maximum-tolerated statin therapy. Anthony C Hooper, executive vice president of Global Commercial Operations at Amgen, says: “With its ability to help prevent heart attacks and strokes, evolocumab offers hope for one of the greatest health challenges we face today. However, the majority of patients in Europe who could benefit from treatment with a PCSK9 inhibitor remain unserved and at risk of a cardiovascular event.” Sean E Harper, executive vice president of Research and Development at Amgen, notes: “We know that patients with a previous history of cardiovascular events are at an increased risk of subsequent events, especially in the first year. With far too many patients at risk of recurrent cardiovascular events, we are pleased that the EC has authorised evolocumab to help prevent heart attacks and strokes in adults with established atherosclerotic cardiovascular disease. The science clearly indicates that ‘lower LDL-cholesterol is better’ and this decision underscores the role for evolocumab among high-risk patients for whom statins alone are not enough.”

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Clinical News try data are an important indication that, moving from a rigorously controlled environment of a clinical trial, to continued access and then to a commercial environment, positive patient results can be maintained when hospitals offer broader access to patients in need.”

Creavo launches largest US study of its kind

Sapien 3

Real-world data confirm trial outcomes for Sapien 3

Thirty-day data presented at EuroPCR (22 May–25 May, Paris, France) show consistently positive patient outcomes for patients undergoing transcatheter aortic valve implantation (TAVI) with Sapien 3. The results— involving almost 2,000 severe, symptomatic aortic stenosis patients at intermediate-risk of open-heart surgery—demonstrate consistency with those results achieved in earlier controlled clinical trials in a limited number of hospitals. The propensity-matched analysis comparing realworld data were collected from the Society of Thoracic Surgeons and American College of Cardiology (STS/ ACC) Transcatheter Valve Therapy (TVT) Registry with outcomes of patients enrolled in the PARTNER II studies of the Sapien 3 valve. They were presented at EuroPCR by E Murat Tuzcu (The Heart & Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi. Dubai). Outcomes in a total of 1,956 intermediate-risk patients in the STS/ACC TVT Registry were compared with those of 652 intermediate-risk patients enrolled in the PARTNER II S3i study and 652 patients enrolled in the SAPIEN 3 intermediate-risk continued access program (S3iCAP) at 30 days. All patients were treated via the transfemoral access route. At 30 days, the rate of all-cause mortality was 0.9% in S3i (N = 652), 0.9% in S3iCAP (N = 652), and 0.8% in TVT Registry IR (N = 1,956). The rate of all-cause stroke in these data sets were, respectively, 2%, 2.3%, and 2.2%. Additionally, the post-approval data from the TVT Registry demonstrate a low rate of moderate to severe paravalvular leak, as well as a two-day average length of stay. Tuzcu comments: “These data comparing real-world outcomes with clinical study results in intermediaterisk patients treated with the Edwards Sapien 3 transcatheter heart valve demonstrated comparably positive outcomes including high survival rates and low rates of stroke.” Larry L Wood, Edwards’ corporate vice president, transcatheter heart valves, comments: “We are very pleased that, as the Sapien 3 valve therapy was introduced and used by a broader number of US clinicians in a real-world environment, the excellent patient outcomes reported from earlier clinical trials were preserved. Even as more hospitals offered transcatheter aortic valve replacement with the Sapien 3 valve, the procedure was generalisable and effective. These regis-

A new cardiac diagnostic device (Vitalscan) aimed at helping physicians rule out active ischaemia in patients presenting to the emergency department with chest pain is being trialled at five of the most respected research facilities in the USA—Mayo Clinic, Baylor University, Vanderbilt University, University of Cincinnati, and University, Winston-Salem. The device, developed by Creavo, is a mobile medical magnetometer that is designed to be used at a patient’s bedside to measure and report electromagnetic fluctuations caused by heart activity. Approximately 720 patients will be enrolled throughout the trial, which is the largest magnetocardiography (MCG) trial ever to take place in the USA and is scheduled to be completed by mid-2019. Gregory J Fermann (University of Cincinnati), US chief investigator for the MAGNET ACS-US, comments: “Each year, 8 to 10 million patients complaining of chest pain present to an emergency department in the USA. The ability to quickly risk stratify and safely discharge emergency department patients presenting with symptoms consistent with chest pain of cardiac origin is critically important to the overall flow of patients through crowded emergency departments. This device has the potential to become an essential tool in the rapid evaluation of these patients.” Steve Parker, CEO at Creavo states: “Our device has the potential to tackle a global unmet need. Nonischemic chest pain patients place a huge strain on emergency departments as the current rule-out triage process of electrocardiograms and blood biomarker tests can take a number of hours. Our device is designed to rapidly aid physicians with the decision to rule out acute coronary syndrome by performing a non-invasive five-minute scan, freeing up resources and bed space. According to a press release, there have been several notable achievements for Creavo in the last two years. The device received CE mark registration in Europe in November 2016 and secured 510(k) clearance as a device that measures and displays magnetic signals

generated by the heart from the US FDA in October 2017. Following initial funding, the company raised £13.4m ($17m) in private equity funding in July 2017. The round was oversubscribed and exceeded Creavo’s funding target, reflecting strong investor support and endorsement of the company’s strategy and team.

Data confirms long-term safety and efficacy of Angiolite drug-eluting stent

At EuroPCR (22 May–25 May, Paris, France), the 12-month results of the ANGIOLITE trial were presented for the first time by J Moreu Burgos. The randomised prospective multicentre controlled trial enrolled 223 patients and had the objective of demonstrating Angiolite drug-eluting stent (iVascular) non inferiority vs. the Xience drug-eluting stent (Abbott). Both primary and secondary endpoints were met with statistical significance: 0.04mm late lumen loss at six months, and 5.4% target lesion failure (composite endpoint), 0.7% binary artery restenosis (intra-stent), 0.7% definite thrombosis, as well as 6.4% major adverse cardiac events at 12 months. Six-month optical coherence tomography (OCT) results confirmed optimal struts coverage (90.8%) with only 64.3µm neointimal thickness, and very low malapposition (1.3%) despite high ratio of myocardial infarction patients. Moreu comments: “The Angiolite drug-eluting stents demonstrates a favourable early healing profile, long term efficacy and optimised deliverability”, adding that such outcomes are “positioning it as one of the most competitive drug-eluting stents available on the market”. Lluis Duocastella, CEO of iVascular, states: “We are happy to have those data confirming the safety and long-term efficacy of our innovative Angiolite drugeluting stents. Further developments are on the way to continue to provide the best of technology to the patients. According to a press release, the 24-month results of the ANGIOLITE trial are expected to be presented at Euro PCR 2019.

FDA approves RADIANCE-II study of Paradise ultrasound denervation system

The RADIANCE-II study of the Paradise Ultrasound Denervation System (ReCor Medical) for the treatment of hypertension has been approved by the US Food & Drug Administration (FDA). Building upon the recent positive results of the RADIANCE-HTN SOLO study, RADIANCE-II will be a randomised, sham-controlled, blinded study in patients with moderate hypertension, powered to demonstrate the safety and efficacy of the Paradise System’s abil-

Angiolite

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Clinical News ity to lower blood pressure. ReCor expects to initiate enrolment in RADIANCE-II in October of 2018. “We have had a very constructive dialogue with the FDA during the past nine months to craft what we believe is a strong study to develop a robust set of clinical data to support the future FDA review for PMA approval,” comments Leslie Coleman, vice president of Regulatory & Medical Affairs. “At the time of PMA submission we plan to have four independentlypowered, blinded, sham-controlled, randomised studies of the Paradise System in patients with different stages of hypertension—our SOLO, TRIO, REQUIRE, and RADIANCE-II studies—approaching a total of nearly 500 patients, with outcomes as long as three years.” “Our Steering Committee and medical advisors have been instrumental in the design of the Global RADIANCE Clinical Program—including the RADIANCEII pivotal study—for the USA, Europe, Japan and Korea,” adds Helen Reeve-Stoffer, vice president of Clinical Affairs. “Given the recent positive SOLO results, and subsequently the numerous review articles in medical journals, we recognise the potential impact the Paradise System may have in the treatment of hypertension for millions of patients world-wide. Accordingly, ReCor is committed to conduct rigorous, randomised, controlled studies to demonstrate the safety and efficacy of the Paradise System to lower blood pressure, thus helping physicians to evaluate how, in whom, and when to use Paradise for the treatment of hypertension.” Paradise is an ultrasound-based system for endovascular denervation of the renal nerves. Renal denervation is a potential therapeutic option for treatment of hypertension, one of the most prevalent medical conditions. The Paradise System bears a CE mark but is not approved for sale in the USA. ReCor Medical is conducting the RADIANCE-HTN clinical trial under an IDE from the US FDA in the USA and Europe, the REQUIRE trial in Japan and Korea with its partner Otsuka, and recently received approval from the FDA to conduct RADIANCE-II as a pivotal study of the Paradise System.

Positive results for Manta large bore closure device

Results from the SAFE MANTA IDE clinical trial— the first pivotal trial for a dedicated large bore closure device (Manta, Essential Medical)—show haemostasis was achieved in less than one minute in 86% of the primary analysis cohort, and in less than five minutes in 94% of this cohort. Within the cohort, transcatheter aortic valve implantation (TAVI) was performed in 210 patients (79.8%) and percutaneous endovascular aneurysm repair (PEVAR) or thoracic endovascular aortic repair (TEVAR) was performed in 53 (20.2%) cases. David Wood (Centre of Heart Valve Innovation in Vancouver, Vancouver, Canada), principal investigator, presented the results during the Late-Breaking Clinical Science Forum at the 2018 Transcatheter Valve Therapeutics (TVT) meeting (20–22 June, Chicago, USA). He reported that the SAFE MANTA trial was a prospective, single-arm study, used 20 sites with 42 operators, and had a total enrolment of 341 patients, with 263 patients in the primary analysis cohort and 78 roll-in patients. The primary safety endpoint was incidence of IDE protocol major complications at 30 days, and the primary effectiveness endpoint was time to haemostasis. The more academically relevant Major Valve Academic Research Consortium-2 (VARC-2) Major Vascular Complications were tracked as a secondary endpoint. The study required rigorous use of imaging at the access site, with angiography at access and closure,

as well as duplex ultrasound within 48 hours of the procedure and at 30-day follow-up. Follow-up was at 30 and 60 days. The 14Fr Manta device was used in 42 cases (16%) and the 18Fr device was used in 221 cases (84%). VARC-2 major vascular complications occurred in 11 patients (4.2%), in which four patients received a covered stent (1.5%), three patients had access site bleeding (1.1%), two underwent surgical repair (0.8%), and two underwent balloon inflation (0.8%). The mean time to haemostasis was 65±157 seconds, and median time to haemostasis was 24 seconds. Haemostasis was achieved in less than one minute in 86% of the primary analysis cohort, and in less than five minutes in 94% of the cohort. Additionally, the technical success rate was 97.7%. Wood comments: “Data from the IDE study is exciting, particularly the rapid time to haemostasis, and compares favourably to current published outcomes. The ease of use associated with the Manta device and the promising data collected through this trial indicates that Manta could be the answer to the complex issue of large bore vascular closure.” The chief medical officer at Essential Medical, Gary Roubin, says: “The results from this study validate our expectations for the promise of Manta technology, of particular note is the extremely low occurrence of bleeding, which directly relates to the potential for improved clinical and cost outcomes with both TAVI and EVAR.”

Implantation of JenaValve successful in initial patients enrolled in CE mark study

JenaValve Technology has announced the initiation of patient enrolment and implantations associated with the CE mark study of its next-generation JenaValve pericardial transcatheter aortic valve implantation (TAVI) system, which uses the Coronatix transfemoral delivery catheter, for the percutaneous treatment of patients with symptomatic, severe aortic regurgitation. According to a press release, the JenaValve system is proprietary and differentiated from currently available TAVI devices due to the Everdur locator-based technology—designed for more predictable implantation using the new 18Fr equivalent Coronatix transfemoral delivery catheter. The optimised TAVI system has now been used to treat several aortic regurgitation patients in Germany. The national principal investigator, Stephan Baldus (Heart Center of the University of Cologne, Cologne, Germany), says: “There is currently no TAVI treatment for severe aortic regurgitation cleared by regulators. These patients do not typically develop calcification at the implant site, so other TAVI valves that rely on this narrowing to anchor their devices are at risk of migration. The JenaValve transcatheter valve may address this issue by securing the device with three novel locators that grasp the native valve leaflets. We have just

JenaValve

begun study enrolment and treatment with this innovative transcatheter heart valve which has demonstrated low pressure gradients, no new pacemaker implantations and no paravalvular leak.” JenaValve expects to complete patient enrolment by the end of 2018 at clinical sites in Germany, The Netherlands, New Zealand and the USA. The company, the press release reports, anticipates CE mark approval for treating patients with severe aortic regurgitation by the second half of 2019. The Company completed patient enrolment in a CE Mark study of the JenaValve pericardial TAVI system for the percutaneous treatment of severe aortic stenosis and expects approval before the end of 2018. JenaValve CEO Victoria Carr-Brendel notes: “Our goal is to enable the treatment of patients with severe aortic regurgitation while avoiding many of the sideeffects with off-label use of other TAVI devices in this patient population. We are excited to initiate this trial and look forward to expanding enrolment across multiple sites, building on this positive initial experience with our partners at the Heart Center of the University of Cologne.”

DIAB8 randomised study to compare Cre8 Evo with everolimus-eluting stents in diabetic patients

Alvimedica unveiled the details of the Diab8 study—the first diabetic drug-eluting stent randomised trial—during EuroPCR (22–25 May, Paris, France). Diab8 is a 55-centre, 3,040-patient randomised controlled trial that will compare the performance of Cre8 Evo (Alvimedica)—a polymer-free Amphilimus-eluting stent—with everolimus-eluting stents in the treatment of coronary artery disease in diabetic patients. The aim of the study is to establish the superior efficacy of the Cre8 Evo compared with the current gold standard everolimus-eluting stent. Antonio Colombo, (IRCCS San Raffaele Hospital, Milan, Italy), principal investigator of the Diab8 trial, says: “People with diabetes have an increased risk of developing cardiovascular complications such as angina, coronary artery diseases, myocardial infarction and acute coronary syndrome. When undergoing percutaneous coronary intervention (PCI), patients with diabetes have poor outcomes compared to the general patient population since they are in fragile conditions, with a major risk of bleeding. Even though technological development applied to drug-eluting stents has enabled great procedural success, there is still an urgent need to enhance long-term clinical outcomes after coronary revascularisation in patients with diabetes. Preliminary data regarding the efficacy of Cre8 in diabetic patients are very encouraging and through the Diab8 trial, we hope we will be able to prove the efficacy of this innovative drug-eluting stents, as it could provide an important milestone for diabetics and their PCI treatment.” Franco Vallana, Chief Scientific Officer Alvimedica comments: “The Cre8 Evo is a stent tailored to the needs of the diabetic population and it has been developed to ensure the same efficacy that current generation of drug-eluting stents provide to nondiabetic patients. Thanks to its unique features, it can improve clinical outcomes and provide added safety advantages in patients with diabetes compared to all other drug-eluting stents. We have the opportunity to contribute for a radical change in diabetic PCI clinical outcomes and the Diab8 study is designed to establish the superior efficacy of the Cre8 Evo as the most innovative drug-eluting stents compared to the current golden standard.” According to a press release, the new stent is designed to provide a controlled elution of the Amphilimus formulation through the Abluminal Reservoir Technology—a proprietary polymer-free drug-release system consisting of reservoirs on the stent’s outer surface that control and direct drug release exclusively towards the vessel wall, including complex coronary anatomies and pathologies like those of diabetics.

Aug

Companies

Industry News Cardiovascular Systems signs international distribution agreement with OrbusNeich

Cardiovascular Systems, Inc. (CSI) has signed an exclusive international distribution agreement with OrbusNeich to sell its coronary and peripheral orbital atherectomy systems (OAS) outside the USA and Japan. OrbusNeich manufactures and sells an extensive portfolio of coronary and peripheral products including stents, balloons and microcatheters. The company operates 12 regional sales offices throughout the world Diamondback 360 and their products are currently sold in over 60 countries. Scott Ward, chairman, president and chief executive officer of CSI, says: “We are excited to expand our strategic partnership with OrbusNeich, a globally recognised leader offering an extensive portfolio of vascular intervention products. OrbusNeich’s large international sales channel serves Europe, Asia and the Middle East and greatly accelerates our plans to introduce orbital atherectomy technology to international markets. In turn, we will focus our international efforts on physician training and education to support the expanded use of orbital atherectomy.” David Chien, chairman and chief executive officer of OrbusNeich comments: “Our experienced sales force is eager to extend CSI’s market leadership in peripheral and coronary atherectomy to new international markets. We intend to introduce CSI’s orbital atherectomy systems in multiple countries in Europe and Southeast Asia this calendar year— focusing initially on those countries that recognise US approvals in addition to European markets where CSI has CE mark approval for its peripheral technology.” In January 2018, CSI announced that it was the exclusive US distributor for OrbusNeich balloon products. Ultimately, CSI will offer a full line of semicompliant, non-compliant and specialty

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balloons for both coronary and peripheral vascular procedures. OrbusNeich PCI balloons include the Sapphire II Pro, the first and only 1.0mm coronary balloon available in the USA. Currently, CSI offers both the 1.0–4.0mm Sapphire II Pro and the 2.0–4.0mm Sapphire NC Plus coronary balloons. In November 2016, CSI announced that Medikit signed an exclusive distribution agreement to sell its coronary and peripheral OAS in Japan.

Funding for Neptune left ventricular assist device

A press release reports that the CALYPSO programme will receive 14 million euros to develop CorWave Neptune—a new type of cardiac support designed to improve the management of patients with severe heart failure—as part of the Programme d’Investissements d’Avenir(PIA) operated by Bpifrance. The CALYPSO Research and Development (R&D) programme, with a total budget of 25 million euros over four years, will be partially financed with 14 million euros support from the Programme d’Investissements d’Avenir (Future Investments Program), managed by the Secrétariat Général pour l’Investissement(General Secretariat for Investment –SGPI) and operated by Bpifrance. The CALYPSO programme aims to optimise and then clinically evaluate the CorWave Neptune device, a left ventricular assist device (LVAD). Neptune features a natural physiological response, according to the press release, and is designed to reduce the risk of complications associated with current LVADs; it is intended for patients suffering from severe heart failure. Pascal Leprince (AP-HP Pitié-Salpêtrière Hospital, Paris, France), comments: “With its breakthrough technology, CorWave is in principle capable of generating pulsatile flow, similar to that of the body’s normal physiology, reducing the serious complications associated

with continuous flow pumps. Our teams, in collaboration with the IHU-ICAN research teams and the medical teams at CHU de Lille Hospital, look forward to conducting clinical trials with patients equipped with current and future LVAD technology.” Louis de Lillers, CEO of CorWave, leader of the CALYPSO project, comments: “We are very pleased to set up major partnerships with world-class university hospitals, thanks to the financial support of Bpifrance and the French Government. The CALYPSO programme considerably increases the resources allocated to preclinical and clinical studies prior to the marketing of Neptune, a cardiac support pump that closely mimics the physiological flow of the native heart. This programme will help CorWave convert its disruptive technology into a sustainable competitive advantage to establish itself, as a global leader in cardiac support, a market that already accounts for nearly US$1 billion in annual sales.” The CALYPSO programme is designed to incorporate all the development stages of the Neptune cardiac assistance pump, as well as a scientific and clinical support, essential to ensure the device obtains CE marking. The improvement of the risk-benefit associated with LVADs via the optimisation of Neptune’s operating parameters during the program should make it possible to reduce complications and to be able to offer this effective therapy to a wider patient population.

Biomerics acquires FutureMatrix Interventional

Biomerics has bought FutureMatrix Interventional, which specialises in the

design and manufacture of interventional catheters for the cardiovascular and urinary markets. A press release reports that, over the years, the company expanded its percutaneous transluminal angioplasty balloon technologies and developed other peripheral cardiovascular, kidney stone management, and urinary catheters. At present, the US FDA registered location includes over 50,000 sq. ft. of manufacturing space and employs more than 400 employees. Biomerics, with over 1,000 employees, operates seven facilities located in Utah, Minnesota, Indiana, Costa Rica, and Texas. Founded in 2009, Biomerics has grown into a market leader in the minimally invasive interventional catheter market. It provides engineered components to the medical device market including biomaterials, extrusions, moulded parts, laser processed parts, machined parts, balloons, and reinforced shafts. Additionally, it supplies packaged sterile medical devices including advanced interventional catheters, surgical tools, and vascular access products. Travis Sessions, CEO of Biomerics, says: “We are pleased to add FutureMatrix Interventional’s capabilities to the Biomerics portfolio. We welcome the FutureMatrix Interventional team to the group, and look forward to their contribution. This acquisition expands our capabilities and important customer relationships. We look forward to investing in and expanding the business for our customers, employees, and community. Combining FutureMatrix Interventional with Biomerics’ existing medical device business establishes Biomerics as a leader in the attractive minimally invasive interventional segment of the medical device market.”

Neptune

Calendar of events 25–29 August

18–20 October

2019

16–18 March

Munich, Germany www.escardio.org

Milan, Italy www.eacts.org/educational-events/eactsannual-meeting

14–16 February

New Orleans, USA https://accscientificsession.acc.org/

ESC

09–11 September

PCR London Valves

London, UK www.pcronline.com/Courses

21–25 September

TCT 2018

San Diego, USA www.crf.org/tct

EACTS 2018

10–14 November

AHA Scientific Sessions

Chicago, USA https://professional.heart.org

JIM 2019

ACC.19

Milan, Italy https://jim-vascular.com/

20–23 May

02–05 March

Las Vegas, USA http://www.scai.org/

Washington, DC, USA CRT 2019 http://www.crtmeeting.org/

SCAI 2019 21–24 May

EuroPCR 2019

Paris, France https://www.pcronline.com/Courses/EuroPCR