Cardiovascular News Issue 55—September 2019 by BIBA Publishing

October 2019 | Issue 55

Complete revascularisation superior to culprit lesion-only PCI in STEMI and multivessel disease, irrespective of timing of intervention A strategy of complete revascularisation was superior to culprit lesion-only percutaneous coronary intervention (PCI) in reducing the risk of cardiovascular death or myocardial infarction (MI) in patients with ST-segment myocardial infarction (STEMI) and multivessel coronary artery disease. The timing of PCI for the nonculprit lesions had no significant impact on outcomes observed, and the main driver of the decreased risk was a reduction in the rates of MI.

Flavio Ribichini:

TAVI-related stroke Page 14

Ehtisham Mahmud:

Profile

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Three TAVI valves now approved for use in low-risk patients in the USA The US Food and Drug Administration (FDA) has approved Edwards Lifesciences’ Sapien 3 and Sapien 3 Ultra, and Medtronic’s Evolut R and Evolut PRO transcatheter aortic valve implantation (TAVI) systems for the management of low-risk patients. However, within a week of approving the devices it had also issued a Class I recall for the Sapien 3 Ultra delivery system, citing concerns about burst balloons.

he global COMPLETE study, presented at the European Society of Cardiology Congress (ESC 2019; 31 August–4 September, Paris, France) and simultaneously published in the New England Journal of Medicine (NEJM), also noted a decline in the risk of a composite of CV death, MI, or ischaemiadriven revascularisation. At a press conference preceding the main presentation, Shamir R Mehta (Population Health Research Institute, Hamilton, California, USA) outlined the final results from the trial on behalf of the investigators. He said: “Patients undergoing primary PCI [percutaneous coronary intervention] to the culprit lesion for STEMI are often found to have

multivessel coronary artery disease, with one or more angiographically significant nonculprit lesions. There is uncertainty on how best to manage these nonculprit lesions—whether to routinely revascularise them with PCI, or to manage them conservatively with guidelinedirected medical therapy alone.” COMPLETE was a randomised, comparative effectiveness study of complete versus culprit-only revascularisation strategies to treat multivessel disease after early percutaneous coronary intervention for ST-segment elevation myocardial infarction, in which researchers randomly assigned (1:1) patients with STEMI and multivessel CAD who had undergone Continued on page 2

THE EXPANDED INDICATION for CoreValve’s approval is based on randomised clinical data from the global, prospective, multicentre Evolut Low Risk Trial, which evaluated three valve generations (CoreValve, Evolut R, and Evolut PRO valves) in more than 1,400 patients. The approval for Sapien 3 and Sapien 3 Ultra is based on the PARTNER 3 trial. The studies were presented earlier this year at the 2019 American College of Cardiology Scientific Session (16–19 March, New Orleans, USA). Both companies have issued press releases reacting to the FDA’s approval announcement. Larry L Wood, corporate vice president transcatheter aortic valve replacement at Edwards Lifesciences, said: “This approval is a significant milestone and will allow Continued on page 2

October 2019 | Issue 55

Complete revascularisation superior to culprit lesion-only PCI in STEMI and multivessel disease, irrespective of timing of intervention Continued from page 1

Randomisation was stratified according to the timing of the nonculprit lesion PCI, an important caveat of the design of the trial.” successful culprit lesion-only PCI to a strategy of either complete revascularisation with PCI of angiographically significant nonculprit lesions (2,016) or to no further revascularisation (2,025). Randomisation was stratified according to the timing of the nonculprit lesion PCI. This was performed either during the index hospitalisation, or after discharge from hospital (no later than 45 days after randomisation), a decision that was taken before participants were randomised. Mehta stressed that this was an “important caveat of the design of the trial”. And, he added: “It is important to note that all patients received guideline-directed medical therapy.” The first co-primary outcome was a composite of cardiovascular (CV) death or MI; the second was a composite of CV death, MI or ischaemia-driven revascularisation. A key secondary outcome was CV death, new MI, ischaemia-driven revascularisation, unstable angina, and New York Heart Association (NYHA) class IV heart failure. Median follow-up was for three years, and the longest follow-up was for more than five years. Nonculprit lesions were located in the left anterior descending (LAD) artery for approximately 10% of cases and in the proximal LAD for about 40% of cases, in both groups. Mehta said: “One of the most important parameters in the trial was that complete revascularisation was achieved in over 90.1% of patients who were allocated to the nonculpit lesion PCI arm. That means that they had a SYNTAX score of zero; there was no significant disease left behind in that group.” The first co-primary outcome occurred in 158 patients (7.8%) in the complete revascularisation group, and 213 (10.5%) in the culprit lesion-only PCI group (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.6–0.91, p=0.004). “The number needed to treat to prevent one of these events over a period of three years is 37 patients.

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The main benefit occurs over the long-term, with continued divergence of the Kaplan-Meier curves [of the two cohorts]. A complete revascularisation strategy has an effect over long-term events, similar to what we have seen with CABG [coronary artery bypass graft] surgery 20 years ago.” The second co-primary outcome occurred in 179 patients (8.9%) in the complete revascularisation group and 339 patients in the culprit lesion-only group (HR 0.52, 95% CI 0.43–0.61, p<0.001). The benefit of complete revascularisation was consistently observed for both co-primary outcomes, regardless of the intended timing of the nonculprit lesion PCI (p=0.62 and p=0.27 for first and second co-primary outcomes, respectively). “There is no interaction,” said Mehta, “meaning that it does not seem to matter whether it is performed early during the index hospitalisation, or later after discharge from hospital, the benefits on hard outcomes, CV death or MI, seem to be preserved. And the reason for that might be because the benefits of complete revascularisation on hard outcomes occurred over the long term. “The biggest impact on the primary endpoint was a reduction in myocardial infarction, which was reduced by 32%, a highly significant risk reduction. In addition to this, ischaemia-driven revascularisation was reduced and unstable angina was reduced. Cardiovascular and all-cause deaths were non-significantly fewer in the complete revacularisation group than the culpritonly group … but the trial was not powered to detect reductions in these two endpoints.” There were no significant differences in any of the safety outcomes.

The benefit of complete revascularisation was consistently observed for both co-primary outcomes, regardless of the intended timing of the nonculprit lesion PCI.”

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Three TAVI valves now approved for use in lowrisk patients in the USA Continued from page 1

all patients diagnosed with severe aortic stenosis to be considered for TAVI based on their individual preferences and anatomical considerations versus traditional risk scoring.” The Sapien valve was commercially approved in Europe in 2007. The FDA low-risk approval covers the Sapien 3 and Sapien 3 Ultra valves in all sizes. Martin B Leon (NewYork-Presbyterian/ Columbia University Medical Center, New York, USA) was the national coprincipal investigator of the PARTNER 3 Trial. In the press release from Edwards LifeSciences, he pointed out: “Today’s FDA approval of Sapien 3 TAVI will expand access to this proven therapy, which should be considered the preferred treatment for the majority of low-risk severe aortic stenosis patients.” The Class I recall for the Sapien 3 Ultra delivery system issued by the FDA is the most serious type of recall, but does not mean that the device has been taken off the market. The delivery system is a part of the Sapien 3 transcatheter heart valve system, and is used to deliver and deploy the Sapien 3 Ultra transcatheter heart valve or the Sapien 3 transcatheter heart valve. The move follows a field safety notice issued by Edwards Lifesciences in July after receiving reports of burst balloons during implantation procedures. Edwards Lifesciences has provided recommendations for operators on how to avoid burst balloons, as well as instructions on how to respond if a burst balloon is suspected. In response to the approval of the CoreValve range, Michael Reardon (Houston Methodist DeBakey Heart & Vascular Center, USA), principal investigator and senior author of the Evolut Low Risk Trial, commented in the Medtronic press release: “With the low-risk approval, risk stratification for TAVI treatment is becoming obsolete and heart teams will likely need to assess treatment options based on anatomical characteristics, concomitant risk factors, and also patient preference.” Medtronic’s press release reports that data showed TAVI with the CoreValve range in the context of low-risk patients to have an excellent safety profile and to be an effective treatment option, with shorter hospitals stays and improved quality-of-life scores compared to surgery.

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October 2019 | Issue 55

Society news

Prasugrel bests ticagrelor for the management of acute coronary syndromes Stefanie Schüpke (Deutsches Herzzentrum München, and Technische Universität München, Munich, Germany) told delegates at the European Society of Cardiology Congress (ESC 2019; 31 August–4 September, Paris, France) that using prasugrel rather than ticagrelor to treat patients with acute coronary syndromes is associated with a significant reduction in the incidence of death, myocardial infarction or stroke.

not provide any benefit but is associated with a significant increase in bleeding. Therefore, in patients with NSTE acute coronary syndromes, prasugrel is administered after angiography. In the study, 4,018 patients with acute coronary syndromes for whom invasive treatment was planned were randomised to a prasugrel-based strategy (2,006) or to a ticagrelor-based strategy (2,012). In the prasugrel-based strategy, patients were given a loading dose of 60mg and were continued on a maintenance dose of 10mg/day (or 5mg daily if older

SCHÜPKE EXPLAINED THAT both drugs are recommended, for one year, for the management of acute coronary syndromes with a Class I indication, but observed: “The relative merits of a ticagrelor-based vs. a prasugrel-based strategy in acute coronary syndrome patients with and without ST-segment elevation at one year are not known.” Therefore, the aim of the investigatorinitiated ISAR-REACT 5 trial was to provide a randomised comparison of the two treatments. According to Schüpke, at baseline, the assumption was that ticagrelor would be “superior to prasugrel in acute coronary syndromes patients with planned invasive strategy in terms of clinical outcomes”. This was because, unlike prasugrel, ticagrelor can be used to pretreat all patients with acute coronary syndromes. Writing in their paper (published simultaneously with the ESC presentation) in the New England Journal of Medicine, Schüpke and colleagues explain: “On the basis of the rationale that a stronger platelet inhibition at

than 75 years and/or had body weight of less than 60kg). In patients without STE, the loading dose of prasugrel was administered after the result of the coronary angiography was known. In STE myocardial infarction (STEMI) patients, the drug was administered as soon as possible after randomisation. In

the time of percutaneous coronary intervention (PCI) reduces periprocedural thrombotic risk, the pretreatment strategy with ticagrelor was considered to be advantageous.” A previous study showed that pretreatment with prasugrel in patients with non ST-segment elevation (NSTE) acute coronary syndromes does

Ultrathin strut Orsiro better than thin strut Xience for STEMI patients

the ticagrelor-based strategy, patients were given a loading dose of 180mg and then maintained on a dose of 90mg twice daily. In this group, all patients (with or without STE) were given the drug as soon as possible after randomisation. The primary endpoint—a composite rate of death, myocardial infarction, or stroke at one year—was significantly lower in the prasugrel-based strategy group: 6.9% vs. 9.3% for the ticagrelorbased strategy group (Kaplan-Meier estimates, p=0.006). This finding was primarily driven by a lower rate of myocardial infarction with prasugrel: 3% vs. 4.8% for ticagrelor. The other components of the primary endpoint were, respectively, 3.7% vs. 4.5% for death, and 1.0% vs. 1.1% for stroke, and were consistent across all subgroups of clinical presentations (that is, unstable angina, NSTEMI, and STEMI) and the reduction in the primary endpoint with prasugrel occurred without an increase in major bleeding (4.8% for prasugrel vs. 5.4% for ticagrelor, p=0.46). Speaking at a press conference prior to the ESC presentation, Schüpke said: “The results of the trial support a prasugrelbased strategy—without routine pretreatment in NSTE-acute coronary syndrome—as the first-line antiplatelet therapy for acute coronary syndrome patients.” Gilles Montalescot (ACTION Study Group, Institut de Cardiologie, Centre Hospitalier Universitaire PitiéSalpêtriėre, Paris, France), echoed these comments by calling it a “landmark study” that would “impact our clinical practice and the next set of guidelines that come out next year”.

At one year, data were available for 614 patients who received Orsiro and for 626 patients who received Xience. The rate of the primary endpoint was 4% for the Orsiro group and 6% for the Xience group. The authors state: “The prespecified criterion for superiority of ultrathin strut biodegradable polymer sirolimusOne-year data from the BIOSTEMI study, simultaneously published in the Lancet and eluting stents compared with thin strut durable polymer presented at ESC 2019, indicate that patients with ST-segment elevation myocardial everolimus-eluting stents was met.” They add that infarction (STEMI) who undergo percutaneous coronary intervention (PCI) with an ultrathin, this finding was “largely driven” by a lower rate of sirolimus-eluting stent with a biodegradable polymer (Orsiro, Biotronik) have a significantly clinically-driven target revascularisation in the Orsiro lower rate of target lesion failure than those who undergo PCI with a thin strut everolimusgroup, noting that there were no differences in the rate eluting stent with a durable polymer (Xience, Abbott). of myocardial infarction between groups. By contrast, myocardial infarction drove the difference in target riting in the Lancet, Juan F Iglesias (Division target vessel myocardial reinfarction, lesion failure between Orsiro and Xience of Cardiology, Geneva Hospitals, Geneva, and clinically indicated target lesion in the BIOFLOW-V study. “The absence Switzerland) and colleagues report that a revascularisation) within one year of the of a robust difference in the incidence prespecified subanalysis of the BIOSCIENCE trial index procedure. of target vessel myocardial infarction suggested a benefit of sirolimus-eluting biodegradable The BIOSTEMI trial used a Bayesian between the two treatment groups in our polymer stents over durable polymer everolimus-eluting approach, including information from the study might be explained by the difficultly stents. They add: “The prothrombotic and inflammatory pre-specified STEMI subgroup enrolled in detection of periprocedural myocardial milieu in patients with acute STEMI poses particular into the BIOSCIENCE trial as a priori. infarction in the setting of acute STEMI,” challenges to vascular healing and stent-related clinical Although this approach reduced the Iglesias et al comment. outcomes after primary PCI and might reveal the number of study participants required They speculate that the difference differences among stent platforms.” to maintain appropriate power, study in target lesion failure between the According to Iglesias et al, to their knowledge, “there author Thomas Pilgrim (Department devices may relate to Orisro having a are no dedicated randomised controlled trials comparing of Cardiology, Inselspital, University biodegradable polymer and/or because it newer-generation drug-eluting stents in the setting of of Bern, Bern, Switzerland) told Thomas Pilgrim has thinner stent struts (60μm vs. 81μm acute STEMI”. Therefore, the aim of BIOSTEMI was Cardiovascular News: “The Bayesian for Xience). to compare the biodegradable polymer stent Orsiro with approach increases power, provided that the findings “A reduction in strut thickness has been shown the durable polymer Xience stent. in the patients recruited in the BIOSTEMI trial to mitigate inflammation, vessel injury, neointimal In the BIOSTEMI study, patients who had been are consistent with the prior information from the proliferation, and thrombus formation. These findings referred for primary PCI for the management of acute BIOSCIENCE STEMI subgroup, but does not increase are particularly relevant in the inflammatory milieu STEMI were randomised to undergo PCI with Orsiro the likelihood of a positive outcome in case the null of acute STEMI and might explain the differences (649) or to Xience (651). The primary endpoint was hypothesis is true, that there is no real difference we observed in the incidence of target lesion failure,” target lesion failure (a composite of cardiac death, between stents.” Iglesias et al state.

October 2019 | Issue 55

Cardiogenic shock

Using a “Propella” approach could aid healing in cardiogenic shock patients At the European Society of Cardiology Congress (ESC 2019; 31 August–4 September, Paris, France), Carsten Tschöpe (Charité Hospital, Berlin, Germany) outlined the use of the “Propella” approach in myocarditis patients with cardiogenic shock. He explained that the approach involves the prolonged use of an Impella heart pump (Abiomed) to provide circulatory support and, potentially, disease-modifying effects. He noted that such a Propella approach could be used as a “bridge to recovery” in patients with cardiogenic shock. ACCORDING TO TSCHÖPE, myocarditis is “very often not a big deal” but can be severe in some patients and can cause cardiogenic shock—at least 20% of patients with myocarditis will develop “the shock scenario” and require circulatory support. There are several such circulatory support systems available, but extracorporeal membrane oxygenation (ECMO) is used to treat the majority of patients. However, although ECMO does provide circulatory support, it can cause stress to the heart because it increases after-load and, consequently, also enhances oxidative stress. Tschöpe commented: “This, in an inflammatory situation, is extremely undesirable.” In an interview with Cardiovascular News, Tschöpe said: “Like with ECMO, the Impella device also provides circulatory support, but [when using an Impella device] the heart is unloaded. The Impella, which is implanted in the left ventricle, acts like a propeller in a boat. It swaps the blood out, so the heart

does not have to pump. This reduces the volume load, and therefore reduces the stress for the heart.” He added that the device does not come into contact with the venous system. In contrast with veno-arterio ECMO, the venous blood leaves the heart from the right ventricle, passes through the oxygenator, and then enters the heart through the arterial system, against the direction of blood flow in the organ. “So [with ECMO] you have no unloading, meaning you are not relieving the pressure for the heart,” Tschöpe clarified. Therefore, nearly two years ago, Tschöpe and colleagues set out to determine if myocarditis patients with cardiogenic shock would benefit from an unloading approach using the Impella device rather than using ECMO. They hypothesised that unloading, especially in severe myocarditis, would provide extra benefits to circulation support. “In some scenarios, ECMO is extremely important and necessary,”

Tschöpe explained, “but I believe that when the right ventricular function is fine, the unloading is the better approach because in addition to stabilising the circulation, you are doing something in addition to address the inflammation of the heart.” He likened the effects of unloading to a “cast” for the heart— allowing the organ to rest. And, although the ECMO device can only be implanted for 10 days, the Impella device is not beholden to such a narrow timeframe. With ECMO, the patient is intubated and unable to get out of bed. After 10 days, the risk of complications such as bleeding and infection increases. “It is a really dangerous scenario.” With Impella, a patient is able to get up and walk around while in hospital, when implanted via the axillary route. This lowers the risk of complications and, consequently, allows for prolonged unloading with the device, giving more time for the heart to heal. The prolonged use of Impella, known as the Propella approach, can extend implantation to 28 days. “Some of these pumps are functional up to 50 days, or even longer,” Tschöpe said. The extended window also allows more time for anti-inflammatory drugs to treat the myocarditis to take effect.

Impella lowers the risk of complications and allows for prolonged unloading.” In his talk at the ESC, Tschöpe outlined the case of a young man with severe biopsy-proven myocarditis who was not showing signs of recovery even though he was not in cardiogenic shock. Therefore, Tschöpe and his colleagues implanted an Impella device. “It did exactly what we expected,” he said.

Early MCS established as an effective protocol for cardiogenic shock patients Clinical results of the National Cardiogenic Shock Initiative, a single-arm, multicentre study, support the use of early mechanical circulatory support (MCS) as an effective treatment protocol for patients presenting with acute myocardial infarction complicated by cardiogenic shock (AMICS). The complication is caused by an inability of the heart to pump blood to the body, and is the most common cause of death in heart attack patients.

onducted by investigators from the National Cardiogenic Shock Initiative and presented by Babar Basir (Detroit, Michigan, USA) at the Society for Cardiovascular Angiography and Interventions Scientific Sessions (SCAI 2019; 19–22 May, Las Vegas, USA), this is the second iteration of a study first piloted in Detroit, Michigan. Approximately 100,000 patients in the USA experience AMICS, underlining the need for a systematic approach to the use of commercially

available haemodynamic support devices and shock protocols that can save patients’ lives. The trial aimed to assess the efficacy of early MCS as a way of improving outcomes from May 2016 to February 2019 in 35 centres, all of which agreed to treat patients with AMICS using a standard shock protocol, emphasising early identification of cardiogenic shock, routine use of invasive haemodynamic monitoring, and rapid initiation of MCS prior to the need for escalating inotropes and vasopressors. A total of 171 patients with

Monitoring the pressure-volume of the heart over time demonstrated that there was successful unloading. After two weeks of treatment with steroids and the Impella device, an echo showed poor left ventricular function—indicative of no recovery. However, 10 seconds after stopping the Impella function, Tschöpe and colleagues witnessed the left ventricle starting to pump. “For me,” Tschöpe observed, “that was the most impressive thing. This was a form of selfcontrolled, Impella-induced, unloadinginduced hibernating.” The Propella technique is “sufficient to overcome the inflammatory process”, Tschöpe explained. Analysing the protein profile of biopsies taken two weeks after Impella implantation revealed an improvement in Titin phosphorylation, energy metabolism, and collagen expression. The number of inflammatory cells decreased. Expression of mRNA coding for the mechanoreceptor integrin reduced during unloading, but, when the researchers removed the pump, levels returneded to normal. “This makes sense because, without the pump, you can increase integrin without the unloading consequences,” Tschöpe said. “The concept here is that behind circulatory support, uncontrolled loading induces remodelling as well as inflammatory systems, which further decreases the functional prognosis of patients. We see that with the Propella approach, in addition to the mechanical unloading, we also get this molecular unloading, which is extremely important for the prognosis of the patient.” Earlier this year, Tschöpe and colleagues published the results of their experience with the Impella device in the European Heart Journal. They concluded that the Propella approach “may provide benefits beyond its primary function of mechanical circulatory support in the form of additional disease-altering effects, which may contribute to enhanced myocardial recovery/remission in patients with chronic fulminant myocarditis”.

an average age of 63 years were enrolled in the study, 72% of whom had been admitted to hospital with AMICS. Before MCS, 82% of the participants were on vasopressors or inotropes, while 42% of the group had suffered a cardiac arrest; this included 32% who experienced Babar Basir in-hospital cardiac arrest, 20% with out-of-hospital, and 10% of patients under active cardiopulmonary resuscitation during MCS implantation. As part of the agreed protocol, 74% of patients had an MCS device inserted prior to percutaneous coronary intervention (PCI) and 92% underwent right-heart catheterisation. Furthermore, 77% of patients presented with ST-elevation myocardial infarction (STEMI), with average door-to-support times of 85±63 minutes and door-to-balloon times of 87±58 minutes. By following this protocol, survival rates to hospital discharge were 72%, a significant increase when compared to prior studies mentioned by Basir.

Issue 55 | October 2019

Structural Heart Interventions Myval: India’s TAVI technology is now going global Ashok Seth Comment & Analysis The Myval transcatheter heart valve (THV) system, designed and manufactured by Meril Lifesciences in India, recently received the CE mark for the management of severe aortic stenosis. In this commentary, Ashok Seth discusses his experience with the Myval THV system, and the recent MyVal-1 study, one-year data of which he presented as a principal investigator at EuroPCR 2019 (20–24 May, Paris, France).1

yval THV is a next-generation balloon expandable heart valve made up of a nickel cobalt alloy frame and bovine pericardium leaflets. The valve has a unique hybrid honeycomb cell design, with open cells on the upper half to ensure unjailing of the coronary ostia and closed cells on the lower half for high radial strength. Upon crimping, this design gives a unique “dark and light” band pattern, visible under fluoroscopy, ensuring accurate valve positioning and orthotopic deployment.

Delivering THV made easy

The valve comes with an internal polyethylene terephthalate (PET) sealing cuff and an external PET buffing to minimise paravalvular leaks. This CE-approved valve comes in seven

Results of the one-year MyVal-1 study showed 100% device success and a zero device-related mortality rate.”

Python 14F sheath

sizes from 20mm–29mm. The Myval is directly crimped on a stent balloon delivery system, which has a stopper at either end to prevent valve movement and migration during delivery. There is no sheath over the valve, hence the valve delivery system behaves like a direct stent implantation system without the need for multiple steps and adjustment. The Myval goes through a 14F python lubricated introducer sheath for percutaneous access of the crimped Myval. The Myval THV system is an innovative step towards treating severe aortic stenosis. A major benefit of this technology is the simplicity of the navigator delivery system, with its operator-friendly rotatory handle. I have personally experienced the ease of navigation in challenging anatomies due to its hi-flexion distal shaft. It is intuitive and simpler to use, similar to implanting a coronary stent. In addition, the 14F python sheath also enables full retrieval of the Myval crimped balloon catheter.

MyVal-1 study met primary endpoint

Transcatheter aortic valve implantation (TAVI) is now a well-established treatment for aortic stenosis, and is approved as an alternative to surgical aortic valve replacement in high-risk and intermediate-risk patients. The CE and Central Drug Standard Control

The CE mark and Central Drugs Standard Control Organisation-India approval for Myval transcatheter heart valve was based on successful results from the MyVal-1 study.” Organisation (CDSCO)-India approval for Myval THV for its use in TAVI was based on successful results from the MyVal-1 study. MyVal-1 is a first-in-human, prospective, multicentre, single-arm, open label study of Myval for the treatment of severe symptomatic native aortic valve stenosis, which enrolled 30 patients and intends to follow-up for five years. Myval received CE approval in May 2019. Results of the one-year MyVal-1 study, which I presented on behalf of the study investigators at a late-

breaking trial session at EuroPCR 2019, showed 100% device success and a zero device-related mortality rate. There were no new pacemaker implantations, no strokes, and no paravalvular leaks observed in the trial patients. Furthermore, echo parameters were maintained at 12-month follow-up, and there was a marked improvement from baseline to 12 months in quality of life scores, as measured by the six-minute walk test, New York Heart Association (NYHA) functional class and the Kansas City Cardiomyopathy Questionnaire score. At the time of the valve implantation, 70% of patients were NYHA class III/class IV. At one year, 80.77% of the patients had improved to NYHA class I, and the remainder to NYHA class II. Based on these encouraging firstin-human results, further studies are being planned in a larger population and differing geographies for longer durations of time. This device is not approved for sale in the USA. Reference: 1. Seth A. One-year clinical outcomes of India’s first indigenously designed and manufactured TAVR system. Presented at EuroPCR 2019.

Ashok Seth is chairman of Fortis Escorts Heart Institute in New Delhi, India.

October 2019 | Issue 55

Innovative therapies

ADVERTORIAL SPONSORED BY EDWARDS LIFESCIENCES

Edwards PASCAL™ Transcatheter Valve Repair System is associated with a “striking” reduction in mitral regurgitation The PASCAL repair system (Edwards Lifesciences, Irvine, CA, USA) is a novel leaflet repair therapy. The implant uses clasps and paddles that gently grasp leaflets to facilitate coaptation. The device is implanted via transseptal approach and places a spacer between the valve leaflets to fill the regurgitant orifice.

he CLASP study is a multicentre, multinational, prospective, single-arm study that evaluated the use of the PASCAL repair system for the management of mitral regurgitation (both degenerative and functional). The results from the CLASP study show that the PASCAL repair system is associated with a very important and significant reduction in mitral regurgitation (MR) with 86% of patients having residual MR grade of ≤1+, and 98% of patients with residual MR grade of ≤2+ at 30 days.1 Ulrich Schäfer (Catholic Marienhospital Hamburg, Hamburg, Germany), a CLASP study investigator, explains that CLASP was “a safety and efficacy trial” to “prove the concept” behind the device. The CLASP study investigators, Lim DS et al, report that the PASCAL repair system paddles “are designed to minimise stress concentration on the native leaflets” and the spacer is “intended to fill the regurgitant orifice area to reduce MR”.1 For Schäfer, these features make the PASCAL repair system “very interesting and innovative” because they are different from those seen with other transcatheter mitral valve repair therapies. He notes that the clasps on the system can be independently adjusted, which enables “a very sophisticated approach to leaflet capture”. Volker Rudolph (Heart and Diabetes Center, University Clinic, Bad Oeynhausen, Germany) also uses the PASCAL repair system at his centre and, like Schäfer, believes that its unique features may provide several advantages. He comments: “With mitral valve repair, whatever technique you use, you want to achieve maximal leaflet coaptation without impeding forward flow through the valve. I think the PASCAL repair system allows you to reach that goal very efficiently.” In particular, the less rigid, broad nitinol paddles and the central spacer probably help to place less stress on the leaflets while the spacer may reduce the risk of creating an artificial stenosis. Rudolph explains that when you implant a device to repair the mitral valve, you pull the anterior and posterior leaflets together. “If you do this very efficiently, you may create a stenosis which causes the leaflets not to open effectively. However, with a spacer, you are not pulling on the leaflets as much. Therefore, you have more mobility for the leaflets and more residual orifice area. You reduce the leak but maintain movement,” he says. “The other major aspect that helps optimise coaptation is the separate manoeuvrability of the clasps. This means you can correct the grasping position for the anterior leaflet independent of the posterior leaflet,” Rudolph explains. He adds: “The morphologies of the mitral valve can sometimes be challenging and the forces counteracting on coaptation can only partly be identified from available imaging techniques. Therefore, the ability to do a minor correction of the device by re-grasping just one leaflet with the pliable nitinol paddles is a major advancement that allows an easier optimisation of leaflet coaptation, which often has a significant impact on the procedural result.”

Data from the CLASP study

The CLASP study enrolled 62 patients with MR grade 3+ or 4+ (56% functional, 36% degenerative, and 8% with mixed aetiology). The patients had a mean age of 76.5 years and 51.6% were in New York Heart Association (NYHA) class III or IV.1 At 30 days, of those with a successful implantation (59 patients), 98% of patients had an improvement in MR by one grade or more. This meant that 98% of patients had MR grade ≤2+ and 86% of patients had MR grade ≤1+ (significantly reduced compared with baseline levels, p<0.0001; Figure 1). Schäfer calls these results “remarkable”, noting that the reduction in

MR is “very profound”. Another study with MitraClip, COAPT, which only included patients with functional MR, showed 92.7% of patients had MR grade ≤2+ and 72.9% had MR grade ≤1+ at 30 days.1,2 Additionally, Schäfer observes, COAPT was a trial with procedures performed by operators with extensive device experience, whereas CLASP was a trial in which the study investigators had less experience with the device by the nature of the PASCAL repair system being a novel implant. “The COAPT study showed the best-ever published data regarding the success of reducing MR. Now the CLASP study shows very important reductions in MR. I think that these findings

Issue 55 | October 2019

of CLASP are very interesting.” Importantly, successful implantation was achieved in 95% of patients, with an average of 1.5 devices implanted per patient. Furthermore, the 30-day all-cause mortality rate in CLASP was low (1.6%; one patient). The death was procedural, as a consequence of a vascular complication at Ulrich Schäfer the closure of the femoral access, rather than of the device itself. According to Schäfer, any mortality rate below 5% in a high-risk patient population such as that of the CLASP study is low. He notes all patients, prior to enrolment, were assessed by a multidisciplinary heart team and deemed to be at high risk for surgery. At the 2019 Transcatheter Valve Therapeutics (TVT) meeting (12–15 June, Chicago, USA), Scott Lim (University of Virginia Health System Hospital,

For me, the most striking finding was the very significant reduction in mitral regurgitation.” Ulrich Schäfer

Innovative therapies

Charlottesville, USA) reported, on behalf of the CLASP study investigators, the six-month results of the CLASP study.3 These showed that the significant reductions in MR seen at 30 days were sustained: at six months 98% of patients had MR grade ≤2+ and 81% had MR grade ≤1+ (Figure 1). Additionally, 88% of patients were in NYHA Volker Rudolph class I or II and 46% of patients in NYHA class I (these figures were 85% and 37%, respectively, at 30 days) thus showing further improvements; and a significant difference compared with baseline levels (p<0.0001). Importantly, mean transmitral valve gradient at 30 days was 4mmHg (p<0.0001 vs. baseline levels) and this result was also sustained at six months (Figure 2), which shows that the PASCAL repair system facilitates leaflet coaptation and wide diastolic openings. Importantly, these results were obtained with 1.5 average devices per patient. Rudolph says: “There is a critical cut-off point when reducing residual flow and, once passed, you are potentially creating a barrier to forward flow—meaning that the heart cannot fill properly with blood. You would expect that if you had a wider device or two devices, if you took more of the leaflets, the risk of such a barrier would be much more likely. With the PASCAL repair system, I think this risk is probably mitigated by the spacer and how it facilitates leaflet coaptation

and wider diastolic openings.” Summing up the data for the PASCAL repair system, Schäfer states: “The outcomes are very convincing. For me, the most striking finding was the very significant reduction in mitral regurgitation.” Although not explored in the CLASP study, the width of the PASCAL implant may enable operators to only use one device in most cases, and in certain patients with degenerative MR this could be particularly advantageous. Rudolph explains: “In some cases of degenerative mitral regurgitation, getting to all of the diseased parts of the valve can be very challenging. Just imagine if the leaflet is not attached to the chordae in the ventricle, then—in systole—it flips towards the atrial side and it becomes a flail leaflet. Therefore, if it is very wide and you have a narrow device, you might grasp some of it but still have parts that prolapse into the left atrium. But if you have a wider device, achieving maximal coaptation and wider diastolic openings with one device will be much easier.” In their commentary on the CLASP study, Praz et al write: “The advent of the PASCAL repair system is a welcome addition to the armamentarium of transcatheter mitral valve devices. The early experience attests to the feasibility of the procedure, and further studies will be instrumental to define the appropriate use and indication for this novel device.”4 References 1. Lim DS, Kar S, Spargias K, et al. Transcatheter valve repair for patients with mitral regurgitation: 30-day results of the CLASP study. JACC Cardiovasc Interv 2019; 12(14): 1369–78. 2. Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter mitral-valve repair in patients with heart failure. N Engl J Med 2018; 379(24): 2307–18. 3. Lim DS, Kipperman R, Spargias K, et al. Six-Month Outcomes from the Multicenter, Prospective Study with the Novel PASCAL Transcatheter Mitral Repair System for Patients with Mitral Regurgitation. TVT. 2019. Chicago, IL. 4. Praz F, Windecker S, Kapadia S. PASCAL: A new addition to the armamentarium of transcatheter repair systems for mitral leaflet approximation. JACC Cardiovasc Interv 2019; 12(14): 1379–81.

Structural Heart Interventions

October 2019 | Issue 55

Not all patients at low risk for surgical aortic valve replacement should now have transcatheter replacement Thomas Modine Pavel Overtchouk Comment & Analysis Thomas Modine and Pavel Overtchouk urge caution when assessing the significance of findings from trials on the use of transcatheter aortic valve implantation (TAVI) in low-risk patients, and summarise the circumstances in which open surgery should remain the preferred option.

AVI has been intensely investigated by clinical researchers during the past 15 years. With the advent of TAVI, for the first time, aortic stenosis was treated percutaneously by interventional cardiologists instead of through open surgical aortic valve replacement. Numerous randomised controlled trials (RCTs) compared both strategies in high-risk patients and, having obtained favourable results, RCTs progressively moved towards low-risk patients. The presentation of the PARTNER 3 and Evolut Low Risk trials at the American College of Cardiology Scientific Sessions (ACC 2019; 16–18 March, New Orleans, USA) was described by Eugene Braunwald as “a historic moment”. Principal investigator Martin Leon (New York-Presbyterian/Columbia University Irving Medical Center, New York, USA) presented the results of PARTNER 3. This RCT recruited 1,000 patients, and showed that those undergoing TAVI had reduced rates of

periprocedural bleeding, new onset atrial fibrillation at 30 days (5% vs. 39.5%, p<0.001), stroke at 30 days (0.6% vs. 2.4%, p=0.02), and a composite endpoint of all-cause mortality, stroke, and rehospitalisation at 12 months (8.5% vs. 15.1%, p=0.001) compared to those who underwent open surgery. No difference was found in the incidence of new permanent pacemaker insertion and major vascular complications between the two patient groups. Professor Leon summarised by saying that, based on these findings up to 12 months, TAVI should be considered as the preferred therapy in low surgical-risk aortic stenosis patients.1 Concurrently, the Evolut Low Risk Trial included 1,468 patients and found that, at 24 months, the estimated incidence of the composite primary endpoint of death or disabling stroke was 5.3% in the TAVI group and 6.7% in the surgery group (probability of noninferiority >0.999). It also found that bleeding complications (2.4% vs.

7.5%), and new onset atrial fibrillation (7.7% vs. 35.4%) were lower with TAVI, although the risk of moderate or severe aortic regurgitation (3.5% vs. 0.5%) and pacemaker implantation (17.4% vs. 6.1%) remained higher with TAVI as compared to surgery.2 As a result of these landmark trials, the use of TAVI in low-risk patients was discussed at EuroPCR 2019 (20–24 May, Paris, France) in a “Will this trial change my practice?” session.

How will the low-risk trials impact clinical practice?

The 2017 European Society of Cardiology (ESC)/European Association for Cardio-Thoracic Surgery (EACTS) guidelines recommend TAVI in patients at increased surgical risk (Society of Thoracic Surgeons [STS] risk score ≥4%), and surgical aortic valve replacement in those patients at low surgical risk (STS <4% and without other risk factors that are not included in risk scores, such as frailty, porcelain aorta, sequelae, of chest radiation).3 This represents approximately 80% of those patients suffering from aortic stenosis. Both the PARTNER 3 and Evolut Low Risk trials evaluated the low-risk patients that guidelines currently recommend have surgical aortic valve replacement, and the findings are expected to yield an extension of recommendations to include TAVI for patients with an STS <4% in the next set of guidelines. However, some restraint is warranted. It is interesting to note that one-third of the patients screened in PARTNER 3 were excluded. The main reasons were anatomical, such as bicuspid valve, and the impossibility of transfemoral access. By comparison, the rate of excluded patients was approximately 15% in the Evolut Low Risk Trial, with nontricuspid aortic anatomy being one of the main reasons. These observations underscore the fact that, although for most low-risk patients TAVI is at least non-inferior to surgical replacement, a significant proportion with severe aortic stenosis could still receive greater benefit from open surgery. These patients are those with: No or extreme calcification: the transcatheter heart valve needs to be deployed in a solid armature to be anchored in the aortic annulus

VIVALL pilot study shows promise for safe use of Allegra heart valve in bioprostheses Early experience with the Allegra transcatheter heart valve (New Valve Technology) suggests it is safe for use in patients who have clinically significant degenerated bioprostheses in the aortic position, performing as intended on 30-day outcomes in the VIVALL pilot study. Ulrich Schäfer (University Medical Centre Hamburg, Hamburg, Germany) presented the findings at EuroPCR 2019 (20–24 May, Paris, France). THE PROSPECTIVE, MULTICENTRE, single-arm study in five German centres assessed the technical feasibility of the valve, and its safety and performance profile. The intention-to-treat population consisted of 30 patients, with 29 available for follow-up at 30 days. Average age was 78 years, and 50% were male. Follow-

up will also be assessed at six and 12 months. The primary safety endpoint was 30-day survival, and the primary performance endpoint was invasively measured postoperative mean pressure gradient. Secondary VARC 2 safety endpoints included all-cause mortality and all stroke, and among the secondary VARC

Bicuspid or unicuspid valves Associated valvulopathy or indication of coronary artery bypass graft: surgical aortic valve replacement allows for several interventions through the same pathway, with reported durable results No iliofemoral pathway possible: despite important progress regarding TAVI pathways, patients ineligible for the iliofemoral route still represent 10–15% of patients4 High risk of pacemaker implantation, notably with pre-existing left ventricular (LV) dysfunction: a risk of long-term LV dysfunction induced by cardiac stimulation has been reported. Since the inclusion periods of PARTNER 3 and Evolut Low Risk trials, new iterations of Sapien (Sapien 3 Ultra) and CoreValve (Evolut PRO) devices have obtained both FDA approval and CE mark. Although design changes might yield some improvements in clinical outcomes, this hypothesis remains to be tested. TAVI is becoming the default therapy for most patients suffering from severe symptomatic aortic stenosis. However, given that widespread implementation of TAVI only began 10 years ago, a major remaining concern is transcatheter heart valve durability, which should be further investigated. Furthermore, the heart team’s role remains important for patient selection. References 1. Mack MJ, Leon MB, Thourani VH, et al. Transcatheter aortic valve replacement with a balloon-expandable valve in low-risk patients. N Engl J Med 2019; 380(18): 1695–1705. 2. Popma JJ, Deeb GM, Yakubov SJ, et al. Transcatheter aortic valve replacement with a self-expanding valve in low-risk patients. N Engl J Med 2019; 380(18): 1706–15. 3. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS guidelines for the management of valvular heart disease. Eur Heart J 2017; 38(36): 2739–91. 4. Overtchouk P, Modine T. A comparison of alternative access routes for transcatheter aortic valve implantation. Expert Rev Cardiovasc Ther 2018; 16(10): 749–56.

Thomas Modine is at the Institut Cœur Poumon CHU de Lille in France, and at Jioa Tong University in Shanghai, China. Pavel Overtchouk is at University Hospital of Bern in Bern, Switzerland. Disclaimer Thomas Modine is a consultant for Boston Scientific, Medtronic, Edwards, Cephea, Microport, GE, and Abbott; he received a research support grant from Edwards. Pavel Overtchouk declares no conflict of interest.

2 performance endpoints were the absence of procedural mortality and correct positioning of a single Allegra. Schäfer described the study population as “demanding and complicated”, stressing it was “a quite ambitious trial with quite difficult bioprostheses”. Of the early findings, he said: “There was a very high procedural success rate of 96.6%, with a remarkable haemodynamic improvement at 30 days. Moreover, 100% of the patients had none or trace aortic regurgitation at 30 days. These observations translated into a significant improvement in functional capacity, with 71.4% in New York Heart Association [NYHA] functional class I and II at 30 days.” Gradient reduction on echocardiography went from almost 40mmHg to 11.6mmHg, and was also very low in patients with small bioprostheses. At 30 days, rates of mortality and new pacemaker implantation were 0%.

Structural Heart Interventions

Can the risk of TAVI-related stroke be reduced? A global analysis from the CENTER-Collaboration,1 published earlier this year, noted that stroke rates following transcatheter aortic valve implantation (TAVI) remained consistent across the early years of the procedure (2007–2012) and more recent years (2013–2018). Cardiovascular News spoke to Flavio Ribichini (chair of the cardiovascular division, University of Verona, Italy), a coauthor of the study, to examine what the real-world data add to our understanding of stroke risk.

Prior to the study, what did research indicate about the risk of procedural stroke during TAVI?

Previous studies have shown that stroke rates are consistently lower with TAVI than with surgical valve replacement, and that the incidence of stroke decreases with the baseline risk profile of patients. We have now reached the stage where the latest comparative studies of TAVI versus surgery in intermediate- and lowrisk patients show that this difference becomes significantly lower in the TAVI arms. The 2.4% stroke rate at 30 days that we observed in our study is well representative of an intermediate- to high-risk population treated over a long time frame that included a large number of operators with “initial experience” of the procedure (2007–2013).

Why was it important to have real-world data?

Randomised controlled trials are influenced by inclusion criteria that exclude patients who need treatment, and who are treated in daily practice; they may not behave in the same manner as those enrolled in sponsored trials focusing on immediate results. The CENTER collaboration provides data from real-life work performed in high volume centres. Nevertheless, our results were influenced by the large proportion of patients treated between 2007 and 2013, with operators’ initial experiences and valve models that are much improved since then (of note, 39% of CENTER patients received the first model of CoreValve, which was significantly less deliverable than the following iterations of the same valve). And some old models of valves were also included for some of the second period analysed (2013– 2018)—the devices currently in use have been available since 2016–2017, and perform better.

What were the key findings of your study? The first key statistic was 2.4%—the stroke rate of TAVI as performed in expert centres during daily practice. And this is only a starting point; future outcomes can only get better. The second noteworthy finding was that the independent predictors of stroke were those that were expected, that is, age, chronic kidney disease (CKD),

and previous cerebrovascular accident (CVA). Thirdly, the study confirmed the need for effective medical therapy to prevent embolic strokes related to rhythm disturbances after aortic valve interventions. However, one of the limitations of the study was the lack of a direct comparison with a contemporary surgical population with similar clinical characteristics.

You found that although mortality rates have decreased since TAVI was first introduced, stroke rates have not. Why do you think this is?

The first point I would emphasise is that stroke rates remained consistently lower following TAVI than after surgical valve replacement (0.7–1.2 in low-risk patients, 2% in intermediate-risk patients with TAVI; for surgery, 3–4% even in intermediate- and low-risk patients); this risk decreases in tandem with a decrease in patients’ complexity, and suggests that the risk of stroke may, at least in part, be more related to patients’ characteristics than to the technique itself. Therefore, analysis of higher-risk populations, such as those treated in the early years of TAVI (and CENTER has a large number of

October 2019 | Issue 55 these), would not demonstrate a reduction in stroke rates. The latest trials enrolling lower-risk patients and using better transcatheter valves have found stroke rates well below 2.4%.

>85 years (an independent patient-related variable) is a strong predictor of stroke. In fact, in another publication from the CENTER collaboration,2 age was strongly correlated to stroke risk.

You also found that stroke was associated with a fivefold higher rate of atrial fibrillation. Why do you think this was?

What are the implications of your study for the use of cerebral protection devices?

All of the studies that tested embolic cerebral protection (ECP) devices Atrial fibrillation (AF) is a common in unselected populations have been event after aortic valve replacement, clinically negative—be it because they in particular after open heart surgery; are undersized to prove clinical benefits, furthermore, older patients are at higher or because of the multifactorial causes of risk of AF in general. It is interesting stroke in elderly TAVI patients. There is to note that, in our study, patients with no clear evidence of benefit. Additionally, existing chronic AF did not suffer a only 34% of strokes occurred on the same higher incidence of stroke compared day the TAVI procedure was performed; to patients in sinus rhythm. Those most occurred within six days. Therefore, affected by stroke were protection devices would patients that developed only prevent oneparoxysmal AF after third of strokes, while TAVI, which strongly anticoagulant therapy may suggests that it has little prevent those related to to do with the TAVI paroxysmal AF, which procedure itself, but are the most frequent. rather with inadequate ECP devices proven to antithrombotic medical capture debris effectively, protection after TAVI. but their cost–benefit This has still not been ratio remains undefined. defined, particularly Given the available in elderly patients in evidence, routine use whom a fear of bleeding of ECP devices cannot restricts many physicians be recommended. Wide Flavio Ribichini from initiating oral usage would be based anticoagulation therapies. more on a defensive medicine position than on scientific evidence. Selective use In your study, which patients focused on populations at higher risk were most at risk of stroke? for stroke, as defined in our study, might Those with two well-known markers of make more sense. advanced vascular disease—a previous CVA and advanced CKD (with a Do you think further glomerular filtration rate [GFR] <30)—as modifications to the design of well as those with a high calcific burden TAVI valves and/or technique of the valve and the aortic root. These could lead to reductions populations might benefit from dedicated in stroke? embolic protection devices if clinical This is already happening, and with trials are able to demonstrate a favourable the availability of new, much smaller cost–benefit ratio. Paroxysmal AF was and flexible delivery systems, and the the most dangerous variable, but also age new valve designs that in most cases do not need balloon pre-dilatation or post-dilatation, stroke rates can be lower than before. The focused use of TAVIdedicated ECP in some selected cases might reduce stroke rates even further. Another important change is that the mean age of patients will continue to decrease as treatment is offered at an earlier stage. In fact, the concept of “valve replacement timing”, used when surgery was the sole option, was largely conditioned by both the age of the patients and the durability of the prosthetic valves; for these reasons, patients have been treated at very late stages of the aortic disease. With the new endovascular technologies, there will be no reason to wait until a patient becomes very old to change a severely dysfunctioning aortic valve, and as patients are treated at a younger mean age, the incidence of any complications, including stroke, will also reduce.

Stroke rates decrease in tandem with a decrease in patient’s complexity, and this suggests that the risk may, at least in part, be more related to patients’ characteristics than to the technique itself.”

References 1. Wienecke et al, Circulation: Cardiovascular Interventions 2019; 12. 2. Transfemoral TAVI in nonagenarians. JACC Cardiovasc Interv 2019; 12(10): 911–20.

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Interview

Profile

Ehtisham Mahmud The 2019–20 president of the Society for Cardiovascular Angiography and Interventions (SCAI) Ehtisham Mahmud (division chief, Cardiovascular Medicine, UC San Diego, San Diego, USA) tells Cardiovascular News about his career highlights, and outlines the key priorities for his presidency.

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

I decided to become a doctor when I was 12 years old. At the time, I recognised that I wanted to fix things and help people, and also get paid for it. Later, I particularly appreciated the autonomy of the profession and the ability to impact individual patient lives. As I progressed through medical training, I realised that cardiology— and subsequently interventional cardiology—are specialties where the positive outcomes are immediate and impactful. Additionally, the innovative research and dynamic changes within interventional cardiology made it particularly appealing.

Who were the biggest influences on your early career?

I have been fortunate to be positively influenced and guided by different individuals at various phases of my career. My father, Mahmud Roshan, was instrumental in my choosing to become an academic physician. His passion for his own field—public health—inspired me, as did the intriguing questions he posed at the dinner table. Later, when I was an internal medicine resident and cardiology fellow, the chief of cardiology at UC San Diego was Tony DeMaria; he was undoubtedly the person who most influenced my decision to become a cardiologist. He has been a lifelong professional mentor and continues to be a source of support and inspiration. Finally, I had the good fortune to train at Emory University with Spencer King and John Douglas, who taught me the skills of an interventionist, and gave me the guidance to be successful in the field.

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

During the first decade of my professional career, addressing coronary restenosis was critical, because percutaneous coronary intervention (PCI) was considered an inferior option to bypass surgery. The development of drug-eluting stents significantly lowered the rates of coronary restenosis. This helped the field develop to its current state, with PCI becoming the standard for acute myocardial infarction, and now being increasingly used for very complex coronary disease. During the past decade, the most notable advance has been the percutaneous treatment of structural heart disease. Transcutaneous aortic valve repair, percutaneous mitral valve therapy, and septal defect closure are helping to reduce morbidity and mortality for cardiovascular disease in patients who often have limited surgical options, or no options at all.

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

The failure of bioresorbable coronary scaffolds was definitely disappointing, as expectations were extremely high. We had hoped that, with rapidly advancing medical therapies, the mechanical treatment of coronary disease could be replaced by a bioresorbable scaffold allowing an individual patient to have repeat percutaneous

interventions or new conduits for bypass grafting. At present, late and very-late scaffold thromboses have limited the development of this technology.

What are your current research interests?

My research interests are varied but can be broadly categorised as being translational in nature. Presently, I am focused on investigating new interventional device therapies for primary and secondary pulmonary hypertension, robotic coronary and peripheral interventions, complex PCI, structural therapies for advanced heart failure, and preclinical studies focused on regenerative approaches for the treatment of critical limb ischaemia.

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

I believe one of my biggest contributions is in robotic angioplasty. I performed some of the earliest procedures in complex coronary and peripheral vascular disease, and designed and performed the studies that showed its safety and efficacy in complex coronary artery disease (CORA-PCI study). I also designed the studies leading to US Food and Drug Administration (FDA) approval of the technology for peripheral vascular indications (RAPID I and RAPID II studies). Another significant contribution is the introduction of balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension (CTEPH) in the USA. I have helped to develop optimal and standardised techniques for the procedure, and demonstrated its safety, feasibility, and efficacy in the highest-risk patients, including inoperable CTEPH patients and those with chronic thromboembolic pulmonary disease without pulmonary hypertension.

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

I think that the COAPT trial, published in the New England Journal of Medicine, is one of the most important and impactful studies for the practice of interventional cardiology. This was a very well designed multicentre trial which demonstrated that percutaneous mitral valve repair improves quality of life and lowers mortality for patients with functional mitral regurgitation and congestive heart failure.

You have just assumed the office of president of the Society for Cardiovascular Angiography and Interventions (SCAI) for 2019–20. What do you intend to focus upon during your term?

Over the next year, I am committed to advancing our work in three areas—enhancing and developing our education platform, growing our international footprint, and fostering the development of the next generation of interventional cardiologists. I intend to provide leadership to international coalitions to raise the standard of interventional practice around the world, particularly in developing countries. In order to achieve that goal, we have just appointed six SCAI

We need to identify strategies and improve therapies to address cardiogenic shock and out-of-hospital cardiac arrest. The treatment of triscuspid valve disease and right heart failure also requires attention.” ambassadors to China, India, Turkey, Egypt, Vietnam, and Saudi Arabia. I am also committed to supporting the development of the next generation of interventional cardiologists. We will continue to support the SCAI Early Leaders Mentorship Programme, are appointing younger faculty in our scientific programmes, and are providing greater opportunities for our members to serve on committees and councils.

Issue 55 | October 2019

Interview

Fact File

and out-of-hospital cardiac arrest. Additionally, the treatment of triscuspid valve disease and right heart failure requires attention.

What do you think the next breakthrough innovation in interventional cardiology will be?

In the short term, creating pathways of care could have a dramatic impact on reducing mortality for both cardiogenic shock and out-of-hospital cardiac arrest, both of which have extremely poor outcomes. In the longer term, therapeutic interventional devices for heart failure and regenerative medicine with direct intramyocardial injection and the use of gene- or cell-based therapies has the potential to improve cardiac function and address the epidemic of advanced congestive heart failure and chronic angina.

What is the value in this online age of attending conferences?

The SCAI Scientific Sessions is the premier in-person educational conference for interventional cardiologists. Although online portals and messaging can disperse important news quickly and effectively, the value of in-person discussions and sharing of ideas should not be underestimated. In addition, these meetings provide an opportunity to meet and exchange views with interventionists who might not be accessible through the web.

Do you use social media and, if so, what is its added value for interventional cardiologists? Social media is a great way to keep up with what is going on within the interventional world. Check out @ SCAI_Prez on Twitter.

What advice would you give to someone who was starting out in cardiovascular medicine? How will you build upon the educational initiatives offered by SCAI? SCAI’s educational initiatives are wide ranging and continue to expand, and include in-person annual scientific sessions, a Fall Fellows course for trainees, and our journal Catheterization and Cardiovascular Interventions. I intend to expand our digital learning platform with an online interactive web portal for practising interventional cardiologists and fellows-intraining. The development of our educational content will be offered as a comprehensive digital learning experience, reaching clinicians wherever they are in the world. We will also collaborate and partner with other societies and organisations to offer training and education in interventional cardiology.

What should be the key priorities for future research in interventional cardiology?

Some of the most salient research priorities for interventional cardiology are within the areas of complex PCI—for example, demonstrating the value of complete percutaneous revascularisation in patients with left ventricular dysfunction, and generating data supporting chronic total occlusion (CTO) revascularisation. We need to identify strategies and improve therapies to address cardiogenic shock

I encourage all new physicians to get involved in leadership so that the future of cardiology is determined by the members of our field. SCAI provides many opportunities for new members to be leaders and get involved in the development of interventional cardiology. Get involved in your medical community at the local, regional, and national level with the intention of making a difference. Challenge current dogma and ensure that you are always exposed to new ideas. Be open to change—that is the currency of success in our time.

What was your childhood dream job?

As a child, I wanted to be an fighter pilot. Although, as I indicated earlier, I wanted to be a doctor from the age of 12.

What are your hobbies and interests outside of medicine?

Outside of medicine, I love to travel and spend time on outdoor activities. As a family, we take time to ski during the winter and go hiking in the summer. I have spent time hiking and trekking in the Canadian and American Rockies, the Swiss and Italian Alps, and in northern Pakistan and Southern California. It has been a great way to see the world and bond with my family. I have travelled to more than 30 countries, and I am fascinated to see that, despite differences in customs and cultures, there are similarities in our common humanity.

Current appointments at UC San Diego (selected)

Jul 2017–present: Edith and William M Perlman chair of Cardiology Jul 2017–present: Vice chair, Department of Medicine Jan 2015–present: Executive Governing Board, UC San Diego Health System Jun 2013–present: Executive director, Sulpizio Family Cardiovascular Center-Medicine Aug 2011–present: Division chief, Cardiovascular Medicine Jul 2010–present: Professor of Medicine, Department of Medicine Jul 2005–present: Director, Interventional Cardiovascular Fellowship Programme Jul 2002–present: Director, John Ross Cardiac Catheterization Laboratory

Postgraduate training and education

1999–2000: Fellowship in coronary and peripheral vascular intervention, Andreas Gruentzig Cardiovascular Center, Emory University, Atlanta, Georgia 1996–99: Fellowship in cardiovascular medicine, UC San Diego 1995–96: Chief resident, Department of Medicine, UC San Diego 1992–95: Internal medicine internship and residency, UC San Diego 1989–90: Rotating internship, University of Alberta, Edmonton, Canada 1985–89: Doctorate of Medicine (MD), University of Alberta, Edmonton, Canada 1983–85: BSc (Medical Science), University of Alberta, Edmonton, Canada

Honours and awards (selected)

2009–2013, 2017–2019: “Top doctors” in cardiovascular disease and interventional cardiology, one of San Diego’s physicians of exceptional excellence, by the San Diego County Medical Society 2018–present: Deputy editor, Coronary Artery Disease 2017–present: Associate editor, Structural Heart: The Journal of the Heart Team 2012–14: Associate Editor, Journal of the American College of Cardiology 2017: Bishop’s Lecture, Division of Cardiology, Baylor College of Medicine, Houston, Texas 2016: “Top three abstracts” presented at SCAI Annual Scientific Sessions 2012: “Faculty teaching award”, Division of Cardiovascular Medicine, UC San Diego 2011–19: “America’s top doctors” in interventional cardiology by Castle Connolly Medical Ltd 2003–11: America’s Top Physicians in Interventional Cardiology, by the Consumers’ Research Council of America

Structural Heart Interventions

October 2019 | Issue 55

Two-year findings of MITRA-FR continue to show no prognostic benefit with MitraClip At the European Society of Cardiology Congress (ESC 2019; 31 August–4 September, Paris, France), Jean-Francois Obadia (Hopital Cardiovasculaire Louis Pradel, Chirurgie Cardio-Vasculaire et Transplantation Cardiaque, Lyon, France) reported that the two-year results of MITRA-FR indicate that percutaneous edge-to-edge repair in patients with secondary mitral regurgitation does not significantly reduce the composite rate of allcause death and hospitalisation for heart failure compared with medical therapy. These results were eagerly awaited given the debate surrounding the apparently contradictory findings of MITRA-FR and COAPT.

badia presented the one-year results of MITRAFR at the ESC last year, and these showed that reducing mitral regurgitation with MitraClip (Abbott) did not significantly improve outcomes compared with medical therapy. However, a month later at TCT 2018, Gregg Stone (Columbia University Medical Center, NewYork-Presbyterian Hospital, and the Cardiovascular Research Foundation, New York, USA) presented the results of COAPT. These results showed that, at two years, using MitraClip to manage patients with secondary mitral regurgitation was associated with a significant reduction in heart failure hospitalisation. Subsequently, there has been much discussion as to why there was such a difference in the results between MITRA-FR and Obadia. Speaking at ESC 2019, Obadia stated that one hypothesis for the difference was that COAPT had a longer follow-up period and that the benefit of MitraClip may not emerge until after one year. “This is why we present the 24-month results of MITRA-FR,” he said. In summary, in MITRA-FR, 304 symptomatic heart failure patients with severe secondary mitral regurgitation were randomised to receive medical therapy plus percutaneous mitral valve repair with MitraClip (152) or medical therapy alone (152). The primary efficacy outcome was the composite of all-

cause death and unplanned hospitalisation for heart failure at 12 months. As mentioned, there were no significant differences in this endpoint found between groups at 12 months. Obadia reported that there was still no difference between groups at 24 months—suggesting that the longer follow-up in COAPT does not explain the difference in the results. However, he added that a subgroup analysis of events occurring between 12 and 24 months suggested a decrease with MitraClip in the rate of the first hospitalisation for heart failure. Writing in the European Journal of Heart Failure (where the report was published simultaneously to the ESC presentation), Obadia and colleagues say: “This is consistent with the visually observed divergence of the curves of recurrent hospitalisations for heart failure, although the difference was not statistically significant at 24 months, shown by the width of the confidence interval.” However, Obadia and colleagues did not explore the benefits of MitraClip therapy in patients with proportionate mitral regurgitation vs. the benefits of those

with disproportionate mitral regurgitation. Patrick Grayburn (Division of Cardiology, Department of Internal Medicine, Baylor University Medical Center, Dallas, USA) and colleagues proposed in JACC: Cardiovascular Imaging that patients with disproportionate mitral regurgitation (when the mitral regurgitation is not proportionate to the left ventricular dilatation) may “preferentially benefit from interventions directed at the mitral valve”. They add that patients in COAPT had, on average, disproportionate mitral regurgitation while those in MITRA-FR had, on average, proportionate mitral regurgitation. Thus, this difference in patient population may explain the difference in results. Obadia, who sees the two trials as complementary, stated that he also believes patient selection was the main reason for the difference. “Differences in inclusion criteria led to more severe mitral regurgitation, less pronounced left ventricular remodelling, lower pulmonary pressure, and better right ventricular function in COAPT compared to MITRA-FR. In addition, the run-in period assessed by a central eligibility committee was likely to result in more optimised guideline-directed medical therapy in COAPT than in MITRA-FR. However, this set-up may be difficult to implement in everyday practice, which rarely achieves optimised therapy.” He added that, on the other hand, the fact that the protocol in COAPT discouraged modifications of the medical treatment could have negatively impacted the prognosis of their control group with a very high mortality rate of 46% at two years vs. 34% in MITRA-FR. Looking to the future, Obadia and colleagues plan to review the five-year follow-up of the MITRA-FR patients. Furthermore, he also revealed at ESC 2019 that he and his colleagues are to work with the COAPT team on a meta-analysis of individual participant data of patients in both MITRA-FR and COAPT to further understand the role of MitraClip for the management of secondary mitral regurgitation. He added that, at present, the studies, “confirm that MitraClip is very safe indeed”. Jean-Francis Obadia

Left atrial appendage closure is non-inferior to NOACS At ESC 2019, Pavel Osmancik (Charles University and University Hospital Kralovske Vinohrady, Prague, Czech Republic) presented the results of PRAGUE-17. These showed that left atrial appendage closure (LAAC) was noninferior to non vitamin K antagonists (NOACS) for the prevention of major cardiovascular and neurological events in patients with non-valvular atrial fibrillation. However, Osmancik observed that “safety issues” with LAAC remain. HE COMMENTED THAT both LAAC and NOACs have been found to have advantages over vitamin K antagonists —warfarin, the traditional first-line therapy—for reducing thromboembolic events in patients with atrial fibrillation. Studies have indicated that LAAC is associated with reduced rates of intracranial haemorrhage (and a similar reduction in stroke) and that NOACs are associated with less intracranial haemorrhage, all stroke, and mortality. However, Osmancik added: “The relative safety and efficacy of LAAC vs. NOAC is unknown.” In the PRAGUE-17 trial, 201 patients with non-valvular atrial fibrillation (at high risk of stroke) were randomised to undergo LAAC with either the

Amplatzer Amulet device (Abbott) or the Watchman/Watchman Flex device (Boston Scientific); another 201 were randomised to receive a NOAC (apixaban preferably, although rivaroxaban or dabigatran were also acceptable). The primary endpoint was a component of stroke or transient ischaemic attack, systemic embolism, clinically significant bleeding, or significant periprocedural or devicerelated complications. Follow-up was at six weeks, three months, nine months, and 12 months (and then every six months thereafter). There were no significant differences between groups in the cumulative incidence function for the primary

endpoint (p=0.004 for non-inferiority of LAAC vs. NOACs). This was the case for both the per-protocol populations and for the intention-to-treat populations. However, there were nine complications in the LAAC group; these included one procedure-related death (a groin haematoma) and one device-related death (a late pericardial tamponade). Furthermore, of those originally assigned to LAAC, 7% did not undergo the procedure because of anatomical considerations, pericardial effusion, possible infective endocarditis, or patient refusal.

Osmancik concluded: “In the current NOAC era, LAAC may be considered with an adequate rationale for a nonpharmacological alternative; similar overall outcomes are expected with each of these strategies.” However, he pointed out that safety issues remained with the use of LAAC, “warranting further refinements in both operator techniques and device technology”. Osmancik said: “The incidence of the primary outcome was very similar during the whole study period, which make the results very convincing.”

Issue 55 | October 2019

Improved efficiency

THIS ADVERTORIAL IS SPONSORED BY BOSTON SCIENTIFIC

Device and procedural innovations have led to improved efficiency with TAVI Since the first implant 17 years ago, transcatheter aortic valve implantation (TAVI) has become a routine procedure for inoperable and high-risk patients. Furthermore, new procedural and device iterations have led to the development of a “minimalist” TAVI approach, which in turn has led to more and more patients being selected for early discharge. Early discharge has potential benefits for patients and for hospitals.

riting in the European Heart Journal, Cahill et al report that the evolution of TAVI has led to reductions “in procedural mortality and major complication rates”.1 They add that, along with these reductions, an increasing number of TAVI cases worldwide are now being performed with a minimalist approach using “conscious sedation, local anaesthetic and transthoracic echocardiographic guidance”. According to Rajesh Kharbanda (Department of Cardiology, John Radcliffe Hospital, Oxford, UK), improvements in device and access technologies have helped to drive this move towards a less invasive procedure. He notes: “We are now using much smaller catheters; we insert them percutaneously without the need for a surgeon to cutdown the vessel.” A minimalist approach has, Cahill et al observe, potential advantages “of reduced procedural time and faster recovery” and, together, these can enable a patient to be discharged early. It could benefit both patients and hospitals. “Early discharge may allow patients to get back to their normal activities as quickly as possible. It may mean less disruption to their general life. Early discharge also has benefits for carers and relatives as it means less disruption for them as well,” Kharbanda says. He adds that, for hospitals, the benefits of early discharge “are clearly financial” because they relate to “better efficiency” and “allow more patients to be treated at the same facility”. In other words, if patients are discharged early, that frees up beds for more patients to be treated.

If they are independent, have good social support, and if they do not have any anatomical characteristics that will make the procedure complex, we might consider putting them on the early discharge pathway,” he explains.

Devices that enable early discharge

When selecting patients for early discharge, a key consideration is which TAVI device to implant. ACURATE neo™ (Boston Scientific), Kharbanda says, has several features that may allow an early discharge. He says: “It is compatible with the new 14F iSLEEVE™ Expandable Introducer (Boston Scientific). That means the hole for the access site is smaller and, thus, the risk of vascular complications is lower. Also, the ACURATE neo™ system is extremely

The key advantage of the ACURATE neo™ valve is its pacemaker rate.”

The future of TAVI

Cahill et al believe that the number of TAVI procedures being performed, in part because of the ageing population, may grow “4–10-fold over the next decade”. They add: “Transfemoral delivery and a simplified procedure are increasing availability [of TAVI], but the maintenance of high-quality decisionmaking, excellent outcomes, and specialist training in a Heart Valve Centre are critical. Meeting the logistic challenge of delivering TAVI care will require a new cadre of structural interventions, derived through cardiological, surgical, or hybrid training routes.” Looking forward, Kharbanda believes there is a need to focus on “achieving a predictable procedure by limiting vascular complications, stroke, paravalvular leak and procedure related pacemaker implantation, and this will enhance efficiency”. He adds: “The continued drive to reduce device calibre, understand the role of cerebral protection devices, and improved valve design will drive procedural improvements.”

Data for early discharge

Improved hospital efficiency, however, has not come at the cost of reduced safety for patients. In fact, a recent study found that early discharge was associated with better outcomes than was delayed discharge. Wayangankar et al reviewed data for 24,285 patients who underwent TAVI between 2011 and 2015.2 Of these, 13,389 were discharged early (within 72 hours) and 10,896 were discharged late (after 72 hours). As well as finding that there was a significant decline in the rates of delayed discharge over the study period, the rate of the primary outcome—a composite of death, stroke, myocardial infarction, or bleeding—was significantly higher in the delayed discharge group. The authors report that, even after adjusting for in-hospital complications, delayed discharge was an independent predictor of one-year mortality. For Kharbanda, though, the lower mortality rate with early discharge is more of an indication of the health of the patients selected for early discharge than a direct result of the early discharge. He states: “At our centre, we use early discharge for patients who are less likely to have problems after the procedure.” Kharbanda’s centre, he adds, selects patients for early discharge when planning the TAVI procedure. “When reviewing if a patient could be discharged early, we look at the complexity of their anatomy and their social factors.

flexible and so can more easily deal with tortuous anatomy.” Additionally, the valve has a very low gradient, meaning its valve function is—according to Kharbanda— “excellent”. However, the key advantage of the valve is its pacemaker rate, as he says: “It has got the lowest pacemaker rate of any device currently on the market.” Conduction abnormalities (and consequently, pacemaker implantation) are a barrier to early discharge. Kharbanda explains: “If we put in a valve and the patient develops an abnormal ECG [electrocardiogram], then we need to monitor them for longer to ensure that this abnormality resolves. But if a patient has a normal ECG, then early discharge becomes easier.” A study by Kharbanda and his colleagues supports his view that a low pacemaker rate is linked to a higher rate of early discharge.3 They compared procedural Rajesh Kharbanda outcomes with ACURATE neo™ (143 patients) with those of an earlier generation selfexpanding valve (CoreValve Evolut R, Medtronic; 88 patients). At 30 days, vascular complications, pacemaker implantation, and length of stay were all significantly reduced in the ACURATE neo™ cohort compared with the CoreValve Evolut R cohort. Specifically, 45% of patients in the ACURATE neo™ group were discharged within two days vs. 31% of patients in the CoreValve group (p=0.03). “Saying that the [lower] pacemaker rate of ACURATE neo™ was the only reason for reduced length of stay is difficult, but it was a key contributor to that finding,” Kharbanda comments. Data from another study also showed that next-day discharge after TAVI with ACURATE neo™ may be feasible. In a retrospective evaluation, Moriyama et al found that the safety of next-day discharge of TAVI using ACURATE neo™ was similar to that of SAPIEN 3, with comparable 90-day and one-year outcomes.4

ACURATE neo™ Aortic Valve System

References 1. Cahill TJ, Chen M, Hayashida K, et al. Transcatheter aortic valve implantation: current status and future perspectives. Eur Heart J 2018; 39(28): 2625–34. 2. Wayangankar SA, Elgendy IY, Xiang Q, et al. Length of stay after transfemoral transcatheter aortic valve replacement: An analysis of the society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. JACC Cardiovasc Interv 2019; 12(5): 422–30. 3. Kotronias R, Scarsini R, Rajasundaram S, et al. Routine use of ACURATE neo self-expanding TAVI is associated with improved procedural outcomes and reduced postoperative length of stay: Insights from a single-centre registry. Poster at EuroPCR 2019. 4. Moriyama N, Vento A, Laine M, et al. Safety of next-day discharge after transfemoral transcatheter aortic valve replacement with a self-expandable versus balloon-expandable valve prosthesis. Circ Cardiovasc Interv 2019; 12(6): e007756.

October 2019 | Issue 55

Coronary interventions

Paclitaxel-coated balloons for percutaneous coronary intervention: Should we be concerned? Michael Megaly Emmanouil S Brilakis Comment & Analysis Michael Megaly and Emmanouil S Brilakis address the safety concerns that have arisen over the peripheral use of paclitaxelcoated devices, and look at the potential implications for their use on coronary balloons.

he use of drug-coated balloons (DCB) in peripheral arterial lesions is currently being questioned following the findings from a study-level meta-analysis demonstrating higher mortality among patients undergoing treatment of femoropopliteal lesions with paclitaxel-coated devices (both stents and balloons), with a dose effect. Multiple analyses are currently being performed by the US Food and Drug Administration (FDA) and industry to better understand the issue and to decide on the best next steps. Although drug-coated balloons (DCBs) are not currently approved for

clinical use in the USA, they are eagerly anticipated, mainly for the treatment of coronary in-stent restenosis. Should this enthusiasm for obtaining access to DCBs be tempered, given the safety concerns with paclitaxel coated or eluting devices in peripheral arterial disease? Here are some factors to consider: First, there is an important unmet clinical need for coronary DCBs for the treatment of in-stent restenosis, particularly in vessels with two or more layers or stents. Although drugeluting stents reduce the incidence of in-stent restenosis, they do not eliminate it, and in-stent restenosis can

Analysis of BASKETSMALL 2 trial reveals safety benefits of drug-coated balloon treatment A subgroup analysis of the BASKET-SMALL 2 trial has underlined the increased levels of safety associated with drug-coated balloons in the treatment of small coronary artery disease, compared to drug-eluting stents. Despite this, the use of drug-eluting stents achieved larger acute lumen gain and less residual stenosis than the drug-coated balloon technique. RESULTS OF THE analysis were presented at EuroPCR 2019 (20–24 May, Paris, France) by Raban Jeger (Basel, Switzerland), who emphasised that, although their application is still the default strategy of treating coronary artery disease, “we have some problems with drug-eluting stents in certain anatomies”. The BASKET-SMALL 2 trial, published in 2018,

be very challenging to treat. Repeat drug eluting stent (DES) implantation is usually the first step, but in cases of recurrence, placement of a third stent layer is generally avoided. Coronary brachytherapy is often used in such cases, but it is available in only a few centres and carries important risks, such as a long-term risk for stent thrombosis, requiring dual antiplatelet therapy of indefinite duration. Having access to coronary DCBs would significantly enhance physicians’ ability to treat such lesions. DCBs might also facilitate the treatment of patients with disease in small coronary vessels or the side branch of bifurcation lesions, particularly in patients with diabetes. Second, it is unclear whether the risks observed with paclitaxel-coated or -eluting devices in peripheral lesions apply to DCBs used for coronary lesions, since the drug dose in coronary balloons is much lower than that of peripheral devices (0.3–0.6mg vs. 1.1–17mg), thus reducing the potentially cytotoxic effects of the drug. Additionally, in the COMPARE trial, percutaneous coronary intervention (PCI) with an everolimus-eluting stents was associated with better outcomes compared with paclitaxel-eluting stents. Paclitaxel-eluting stents are no longer in clinical use. Moreover, the mortality signal in the meta-analysis of the peripheral paclitaxel device appeared at two and five years. Most of the coronary DCB trials have been small, with short follow-up periods (12 months in most studies), as they were mainly powered to detect angiographic restenosis and target lesion revascularisation. How can the real and urgent clinical need for coronary DCBs be reconciled with the safety concerns raised from the use of paclitaxel-coated or eluting

was a non-inferiority randomised study that compared the drug-coated balloon technique against established secondgeneration drug-eluting stents—Xience (Abbott) and the paclitaxel-eluting Taxus Element (Boston Scientific). Clinical endpoints were tested for up to one year and showed that drug-coated balloons are noninferior to drug-eluting stents in small vessel disease, with similar event rates recorded for groups treated with Raban Jeger both techniques. As angiographic data following treatment with drugeluting stents and drug-coated balloons is sparse, Jeger and colleagues set out to further assess the findings of BASKET-SMALL 2 by performing a subgroup analysis in patients undergoing a percutaneous coronary intervention [PCI] during follow-up.” The original inclusion criterion was a lesion in a native coronary artery of <3mm. Following predilatation with a successful outcome, 758 patients were randomised into two groups; those treated with the Sequent Please paclitaxel-coated balloons (B.Braun, n=367), and participants who received the Xience and Taxus Element drug-eluting stents (n=371). Patients who were eligible for PCI but did not undergo successful predilatation were still registered, with 121 receiving drug-eluting stents. Jeger commented: “The key results are mainly that late lumen loss in both treatment groups—drug-coated balloons [0.10mm] and drug-eluting stents [0.06mm]—

There is an important unmet clinical need for coronary drugcoated balloons for the treatment of in-stent restenosis.” devices in peripheral arterial disease? One potential solution is to use coronary DCBs coated with different drugs, such as sirolimus. There are several such devices currently in development, although it is possible that other drug classes used in DCBs may also cause adverse events. Every medical intervention should be performed when the anticipated benefits exceed the potential risks. DCBs stand to provide great benefits in patients with in-stent restenosis. Striving to minimise DCB-related risks by developing and using non-paclitaxel coated DCBs might be the best way forward. Michael Megaly and Emmanouil S Brilakis are at the Minneapolis Heart Institute, Minneapolis, USA. Disclosures: Dr. Brilakis: is a consulting/speaker honoraria from Abbott Vascular, American Heart Association (associate editor Circulation), Biotronik, Boston Scientific, Cardiovascular Innovations Foundation (Board of Directors), CSI, Elsevier, GE Healthcare, InfraRedx, Medtronic, and Teleflex; research support from Regeneron and Siemens. Shareholder: MHI Ventures.

were the same.” The loss in-stent was 0.13mm for drug-eluting stents—0.03mm higher than the late lumen loss in-balloon of the Sequent Please paclitaxel-coated balloons. One of the most important findings of the study, according to Jeger, was that eight patients in the group who received drug-eluting stents suffered a thrombotic vessel occlusion, with five cases recorded in the Xience group and three in the Taxus Element cohort. “Clinical presentation was quite severe in these patients; we had seven acute coronary syndromes and one acute heart failure patient,” said Jeger. No cases occurred in patients who received a drug-coated balloon. After the procedure, a large lumen gain and less time in stenosis was experienced by patients with drugeluting stents, which proved to be more effective in these areas. However, the absence of stent-like results in the drug-coated balloons did not prevent them from achieving similar clinical event rates to the Xience and Taxus Element stents. Jeger concluded: “During follow-up there was similar late lumen loss in both treatment arms, up to one year, and this speaks for the stable result, mainly in the drug-coated balloon. The most interesting finding is the complete thrombotic occlusion (stent thrombosis) in eight cases of drug-eluting stents, and in our opinion this corroborates the safety of the DCB-only strategy in small coronary artery disease.”

Issue 55 | October 2019

Conference news

ESC recommendations on chronic coronary syndrome extend the role of percutaneous coronary intervention New European Society of Cardiology (ESC) guidelines for the treatment of chronic coronary syndrome (CCS) have an increased emphasis on lifestyle modification and an expanded indication for the use of revascularisation, which it describes as “an important therapy for some patients, such as those at high risk of poor outcomes and those whose symptoms are not controlled through lifestyle and drugs”. Statins are recommended for all patients, antithrombotics for those at high risk, and angiotensin-converting enzyme (ACE) inhibitors for specific groups. ANNOUNCED AT THE ESC Congress (ESC 2019; 31 August–4 September, Paris, France), and simultaneously published online in the European Heart Journal, the document is a continuation of previous stable coronary artery disease (CAD) guidelines. In an ESC press release, William Wijns (Lambe Institute for Translational Medicine, Galway, Ireland), a chairperson of the guidelines taskforce, said: “This reflects the fact that CAD can be acute … or chronic, and both are dynamic conditions. Therapy is lifelong and aimed at preventing progression of the disease and cardiac events, such as heart attacks.” Diagnosis of chronic coronary syndromes has evolved significantly since the previous guidelines, and the six most frequently encountered clinical scenarios are dealt with in separate sections of the document. Each scenario, Wijns pointed out in the press release, “requires different diagnostic and therapeutic approaches. But, in general, treatment of a chronic coronary syndrome demands long-lasting healthy habits, medication adherence, and interventions in selected patients.” Among the recommendations are that revascularisation by percutaneous coronary intervention

(PCI) or coronary artery bypass graft (CABG) may effectively relieve angina, reduce the use of antianginal drugs, and improve exercise capacity and quality of life compared with a strategy of medical therapy alone. The document looks at evidence from trials such as FAME 2 and ORBITA as well as a 2014 metaanalysis by Windecker et al, and concludes: “Together, these new data support a less restrictive indication for revascularisation in CCS, in addition to specific anatomy (for example, left main [LM]) or extended ischaemia (>10%), when PCI is restricted to angiographic stenoses

New data support a less restrictive indication for revascularisation in chronic coronary syndrome, in addition to specific anatomy.”

on large vessels causing a significant intracoronary pressure gradient.” Writing in the European Heart Journal, Juhani Knuuti (Turku University Hospital, Turku, Finland), Wijnns et al emphasise the need to assess according to the presence or absence of symptoms, and documentation of noninvasive ischaemia. They add: “The individual risk–benefit ratio should always be evaluated, and revascularisation considered only if its expected benefit outweighs its potential risk. Also, the aspect of shared decision-making is key, with full information given to the patient about the anticipated advantages and disadvantages of the two strategies, including the DAPT [dual antiplatelet therapy]-related bleeding risks in cases of revascularisation by PCI.” Among the key messages of the document are that, for revascularisation decisions, both anatomy and functional evaluation are to be considered. Either noninvasive or invasive functional evaluation is required for the assessment of myocardial ischaemia associated with angiographic stenosis, unless it is very high grade (>90% diameter stenosis). This risk assessment identifies patients at high event risk who are projected to derive prognostic benefit from revascularisation, and includes the assessment of left ventricular (LV function). Patients at high event risk should undergo invasive investigation for consideration of revascularisation, even if they have mild or no symptoms. Additionally, the guidelines stress that antithrombotic therapy should be a key part of secondary prevention in patients with CCS and warrants careful consideration. Patients with a previous MI, who are at high risk of ischaemic events and low risk of fatal bleeding, should be considered for long-term dual antiplatelet therapy (DAPT) with aspirin and either a P2Y12 inhibitor or very low-dose rivaroxaban, unless they have an indication for an oral anticoagulant, such as atrial fibrillation.

October 2019 | Issue 55

Technology

Video games can take cardiology training to the next level Atman P Shah Comment & Analysis Virtual patient care is creating exciting learning opportunities for interventional cardiologists. Atman P Shah considers how training through gaming can deliver a state-of-the-art profession.

ecently, I was between patients, with a few minutes to spare. I opened an app on my phone designed for practising cardiology cases and began to interact with a case that required the use of a virtual aspiration catheter and atherectomy drill to debulk stenosis. It was a tough case; as the virtual patient’s health status decreased, the accompanying music became progressively more intense and urgent. Unfortunately, I only scored two out of a possible three, and lacked enough time for another attempt. I closed the app and returned to the reality of my next patient in the clinic. That might seem like science fiction, but it is not. The convergence of video games and medicine is creating new learning opportunities for physicians, with apps that help doctors to practice

Cardio Ex Screens CME

difficult procedures via their mobile devices, and even to earn continuing medical education (CME) credits while doing so. Though direct patient care will remain the backbone of medical education, novel educational pathways, including video game technology, provide experiential learning in a risk-free environment. This tool can be used on an as-required basis. Medical video games also give physicians a platform to learn about new therapies, practice emerging techniques, and try out the latest medical devices. There is a large gap between where

Cardio Ex Screens Ice

healthcare education is now and where it is going, and gaming in cardiology is leading the way. Apps and games on mobile phones are readily available, and medical gaming apps allow physicians to play realistic and challenging cases at a time and place of their choosing. It is much cheaper and easier to access than a simulator, which could be many miles distant and often provides a below-par experience.

Everyone can play

Physicians generally excel at hand–eye coordination, and medical video games will be intuitive even for those who are not into gaming. Cardiologists are accustomed to looking at screens while holding a device in a particular way for a particular reaction—a situation very similar to gaming. In the cardiology game Cardio Ex, the high-intensity patient scenarios lend themselves to the real-life work of a cath lab. And, as in video games, there is a beginning, a middle, and an end to each procedure or level. Apps such as Cardio Ex are created by advanced video game designers with

particularly in the current era where burnout due to high volume workload, long hours, medical school loans, and the bureaucratic burdens of keeping an electronic healthcare record (EHR) is prevalent. Anything that keeps clinicians engaged and refreshed is a bonus, and spending time on a challenging case in a risk-free environment can provide a welcome break from the stress of live clinical work. In my experiences with residents and fellows, I have noticed that trainees are sometimes less willing to ask questions or take risks for fear of losing the respect of their peers. Medical video games allow physicians to practise difficult cases multiple times, facilitating experimentation with the impact of different actions upon outcomes. This learning-by-doing—a stimulating change from the “see one, do one, teach one” model—aids recalibration, mindfulness, and renewed focus. It also increases the awareness of techniques and complications prior to working on an actual patient. Practising and perfecting a technique through full immersion in

Spending time on a challenging case in a risk-free environment can provide a welcome break from the stress of live clinical work.” compelling and realistic content, akin to those of medical illustrators, whose intricate images we rely on in textbooks.

Practice makes perfect

There are multiple benefits to physicians embracing games in healthcare,

Cardio Ex Screens Volcano

challenging and collaborative cases, trying out different methods, and learning from mistakes without harming patients, increases personal satisfaction and confidence during live procedures.

CME is an added bonus

When medical apps are CME eligible, doctors are even more motivated to find the time to fit them into busy schedules. In my work for the medical video game company Level Ex, I review hundreds of cases and write objectives and learning benefits for cases that are challenging enough to gain CME credit. The cases must be guideline-based and have no industry or other bias, as the CME committee is stringent about what is acceptable. Through exposure to these cases, cardiologists can enjoy enhanced training opportunities directly from their phones. Advanced technology and gaming offers great potential for cardiology. Currently, Cardio Ex features coronary artery disease, but content and graphics for peripheral and structural heart disease would further expand training opportunities. Video game technology is poised to fundamentally change how we teach physicians, and can influence the future development of interactive board certification testing. Creating medical training opportunities that are more accessible and relevant to the modern world is just what the doctor ordered. Atman P Shah is an interventional cardiologist and associate professor of medicine at the University of Chicago, Chicago, USA, and is a physician advisor at Level Ex.

Issue 55 | October 2019

MedTech insights

TAVI market share comparison (Western Europe): Q2 2019 vs. Q2 2016

Novel repositionable TAVI valve has acceptable early clinical outcomes

A new study indicates that the Meridian transcatheter aortic valve implantation (TAVI) valve (HLT) is associated with a 30day mortality rate of 8% and a six-month mortality rate of 12%. The valve is fully retrievable after deployment, which allows an accurate assessment of valve positioning and performance prior to final release. Most self-expanding devices are partially retrievable, with only one fully retrievable device (Lotus Edge, Boston Scientific) available. JOSEP RODÉS-CABAU (Department of Cardiology, Quebec Heart and Lung Institute, Laval University, Quebec City, Canada) and others report in Circulation: Cardiovascular Interventions that the ability to evaluate a partially retrievable valve in its final position and full expansion before release is limited. “Both final frame expansion and potential movements of the valve system at the time of final release may result in changes in final positioning, valve performance, or coronary artery obstruction,” they explain. The authors comment that, by contrast, fully retrievable valves (such as the Meridian and Lotus Edge devices) “allow for an accurate assessment of the valve positioning and performance, in addition to any interaction with the coronary arteries before final release, knowing that the position and shape of the valve will not change after final release”. The aim of the present study was to evaluate the early feasibility of TAVI with the Meridian valve in patients at high surgical risk. According to Rodés-Cabau et al, the device consists of “three leaflets of porcine pericardium and a braided liner to reduce paravalvular leak. The valve leaflets are attached to a nitinol wireform that flexes with each closure to reduce the leaflet stress at commissures”. In the study, 25 patients

underwent TAVI with the Meridian device. In 40% of patients, the initial valve position was considered to be too high or too low and, thus, the valve had to be repositioned. Rodés-Cabau et al report that this suboptimal valve positioning “was in large part” because of the learning curve process “particularly with a self-expanding valve system that requires a two-step process to achieve final deployment”. They add that there was a “marked reduction” in valve repositioning with the Lotus valve after the initial clinical experience. Furthermore, the authors note that only a single valve size (25mm) was available in the study and this “represents an important limitation”. At 30 days, two patients had died—a mortality rate of 8%—and both deaths were of a suspected arrhythmic cause. Based on the subsequent autopsies, the valve was in the correct position in both cases and there was no evidence of valve thrombosis. Acknowledging that the mortality rate in the study was higher than that seen in TAVI studies of patients at intermediateto-high surgical risk, RodésCabau et al state that all patients in the study were deemed by the heart team to be at high risk and “were older than those included in most previous studies”. “Also, preprocedural frailty was common (44%) and likely contributed to high

Source BIBA MedTech TAVI Monitor

surgical risk despite a mean STS0PRON score of <8%,” they observe. Other 30-day findings show that the stroke rate was also 8%, and there was a significant increase in effective orifice area and decrease in mean gradient vs. baseline values. Most patients (80%) were in New York Heart Association (NYHA) Class I–II. At six months, the mortality rate was 12% (including the two patients who died before 30 days), 89% of patients remained in New York Heart Association (NYHA) class I–II, and there were no significant changes in valve performance over time. The authors say the valve is now being evaluated in a CE mark trial (200 patients at intermediate or high risk), and there are plans to initiate a US Food and Drug Administration (FDA) trial later this year. Several iterations of the Meridian valve system are being undertaken and will include several design improvements, including enhanced valve inversion properties to “facilitate valve positioning and reduce valve retrieval attempts”. An expanded range of valve sizes is also planned. Rodés-Cabau told BIBA Briefings: “The Meridian valve is ‘fully retrievable’. This is a very important differential feature from most available transcatheter valve systems.”

Current use of fully retrievable devices

As mentioned, Boston Scientific’s Lotus Edge is the only TAVI

device on the market that is fully repositionable. However, problems with the delivery system meant that it was off the market for just over two years. After receiving the CE mark in September 2016, Lotus Edge (along with the earlier generation Lotus valve) was taken off the market in February 2017. Initially, Boston Scientific planned for Lotus/Lotus Edge to be back on the market by Q1 2018 and to file for FDA approval for the device around the same time. However, because of several delays, Lotus Edge only came back on the market in March of this year (via a controlled launch). It received FDA approval in April this year (making it the third TAVI device on the US market). Of note, Boston Scientific acquired Symetis in March 2017 and, therefore, also has the Acurate Neo device (developed by Symetis) on the market. In Q2 2019, according to the BIBA MedTech TAVI monitor, 11.7% of all TAVI devices implanted in Western Europe (16,203) were a Boston Scientific device—meaning that the company had the third-highest market share (Figure 1). In Q2 2016, prior to its Lotus range being taken off the market and prior to its acquisition of Symetis, Boston Scientific had a market share of 7% in terms of units implanted. Given that the Lotus Edge was not CE mark approved until September 2016, this figure relates to implants of the earlier generation Lotus valve.

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

October 2019 | Issue 55

Diagnostics

The Diastolic hyperaemia-Free Ratio (DFR) algorithm is an effective measure of diastole Nils P Johnson Wenguang Li Comment & Analysis

prerecorded waveforms. This allowed the comparison of measured values for both iFR and DFR using the raw data from two separate clinical trials. A total of 893 lesions were included from the two studies. The difference between iFR and DFR was small: mean -0.006, with standard deviation (SD) 0.011. Linear regression showed that the two methods were highly correlated at r2=0.993 (Figure 2). Diagnostic performance of DFR using iFR as the reference standard showed an accuracy of 97.6% (95% confidence interval [CI] 96.4–98.5%), sensitivity 95.8% (95% CI 93.4–97.5%), and specificity 99.2% (95% CI 97.9–99.8%). The area under the receiver operating characteristic (ROC) curve equalled 0.997. Notably, DFR uses the same 0.89 threshold as iFR, allowing straightforward comparison and portability among patients and clinical studies.

Nils P Johnson and Wenguang Li outline how they overcame the limitations inherent in other approaches to measuring diastolic pressure by developing and validating the Diastolic hyperaemiaFree Ratio (DFR) algorithm.

DFR prognostic performance in the IRIS-FFR registry

Validation in VERIFY-2 and CONTRAST

Because the Diastolic hyperaemia-Free Ratio algorithm does not use a specific waveform or ECG feature, its performance is extremely robust in routine practice.”

ome operators prefer to avoid hyperaemia when assessing intracoronary physiology, often citing concerns regarding cost, sideeffects, or availability. As a result, several non-hyperaemic pressure ratios (NHPR) have been developed, including the instantaneous wave-free ratio (iFR). Its theoretical and practical basis have come under scrutiny, as its resistance is actually higher than during fractional flow reserve (FFR) assessment, and resting indices using other portions of the cardiac cycle produce numerically equivalent results.

Diastolic hyperaemia-Free Ratio (DFR) algorithm

To measure the diastolic period from pressure waveforms, the dicrotic notch must be identified. But this approach requires high-quality aortic pressure tracings, which can be difficult to achieve in some cases, due to artefacts or damping effects from the manifold tubing. Using the electrocardiogram (ECG) as a timing signal provides an alternative, but requires additional set up, and can also suffer from noise interference. To overcome the shortcomings of these approaches, the DFR algorithm was developed by modelling the aortic pressure (Pa) waveform as a triangle. This model provided the theoretical basis for straightforward identification of diastole as follows: Pa less than its mean value, and down-sloping Pa values Using these two simple criteria, the measurement window typically starts after the dicrotic notch, and always ends at the rising edge of the next cardiac cycle (Figure 1). Note that samples inside the window need not be contiguous. Because the DFR algorithm does not use a specific waveform or ECG feature, its performance is extremely robust in routine practice.

DFR measurements were validated using patient-level iFR values from two previously conducted clinical trials, VERIFY-2 and CONTRAST.1 VERIFY-2 was a prospective, singlecentre study of 197 subjects and 257 coronary vessels using the Philips Volcano pressure wire. CONTRAST was a prospective, international study of 763 subjects from 12 centres with one vessel/subject using the Abbott/ St Jude pressure wire. Because the CONTRAST clinical study did not publicly provide iFR measurements, a dedicated set up was validated to recalculate iFR measurements, based on

Emerging clinical outcomes data for DFR were reported from the

multicentre Korean IRIS-FFR registry at Transcatheter Cardiovascular Therapeutics 2018 (TCT; 21–24 September, San Diego, USA).2 A total of 1,102 deferred lesions in 926 patients were retrospectively evaluated by five NHPRs, including DFR. The results showed no statistically significant differences in diagnostic or prognostic performance among the NHPRs. Notably, each NHPR showed the same correlation (Spearman rho about 0.73) and area under the ROC curve (approximately 0.87) when compared against FFR. When using iFR as the reference standard, DFR was highly correlated (Spearman rho 0.991) and numerically equivalent (mean difference -0.002, SD 0.009). As for diagnostic performance, DFR had a high accuracy (98.4%), sensitivity (92.9%), and specificity (99.6%) against iFR. During a median 1.1 year follow-up, each NHPR equally stratified risk (combined cardiac death, target lesion myocardial infarction, or revascularisation) for a positive versus negative test (Figure 3). Finally, adding each NHPR showed the same increased C-index in a predictive model for clinical outcomes that included clinical factors and FFR.

Summary and future directions

Based on numerically equivalent values and the same prognostic performance between DFR and iFR, existing clinical studies and guidelines can be applied by using the same 0.89 threshold. Indeed, given similar results from all NHPR, there appears to be a “class effect” among resting indexes, despite different technical methodologies. Already, a DFR algorithm is commercially available in the USA, Europe, and Japan. References 1. Johnson NP, Li X, Chen X, et al. Diastolic pressure ratio (dPR): new approach and validation versus the instantaneous wave-free ratio (iFR). Eur Heart J 2019; 40(31): 2585–94. 2. Ahn JM. IRIS-FFR registry: prognostic performance of five resting pressure-derived indexes of coronary physiology. TCT presentation 22 Sep 2018, San Diego, California.

Figure 1. DFR measurement windows are depicted by the portions highlighted with thicker lines. Realtime DFR value is displayed alongside the whole-cycle Pd/Pa value.

Figure 2. Numerical equivalency. Linear regression shows an excellent correlation between iFR and DFR.

Figure 3. Clinical outcomes. Both DFR and iFR equally stratified risk for the same deferred lesions in the IRIS-FFR registry (from TCT presentation).

Nils P Johnson is at the Weatherhead PET Center, Division of Cardiology, Department of Medicine, McGovern Medical School at UT Health and Memorial Hermann Hospital, Houston, USA. Wenguang Li is at Boston Scientific Corporation, California, USA. Disclaimer Nils P Johnson has an institutional licensing and consulting agreement with Boston Scientific for the smart minimum FFR algorithm; and received significant institutional research support from Abbott/St Jude Medical (CONTRAST) and Philips Volcano Corporation (DEFINE-FLOW) for studies using intracoronary pressure and flow sensors. Wenguang Li is a full-time employee of Boston Scientific.

October 2019 | Issue 55

Devices

Product News Merit Medical unveils PreludeSYNC EVO radial compression device

Merit Medical Systems, a leading manufacturer and marketer of proprietary devices used primarily in cardiology, radiology, oncology, and endoscopy, has announced the commercial launch of the PreludeSYNC EVO radial compression device in the USA. PreludeSYNC EVO is a sterile, single-use, disposable device used to assist in gaining haemostasis of the arterial percutaneous access site following catheterisation procedures. Merit Medical’s launch of the PreludeSYNC EVO follows nearly two decades of innovation in haemostasis band products. The PreludeSYNC EVO was designed to provide operators with improved clarity, safety, and patient comfort. A clear balloon and curved backer plate provide optimal visualisation of the puncture site, facilitating easy placement. The band, which is easily adjustable and fits securely around a patient’s wrist, comes in two sizes (24cm and 29cm). The device also features the new Slipn-Lock Connection for safe and easy inflation and deflation. “A core part of Merit Medical’s mission is to continually evolve and improve our product offerings, including in the area of access and haemostasis,” said Fred P Lampropoulos, Merit Medical’s founder, chairman, and chief executive officer. “Accordingly, the PreludeSYNC EVO is a needed solution that elevates the radial compression experience for operators and their patients. The Merit leadership team is excited to put the EVO in the hands of specialists across the United States.”

SeQuent Please ReX drugcoated PTCA balloon catheter receives FDA breakthrough device designation

B Braun Interventional Systems has announced that the US Food and Drug Administration (FDA) has granted breakthrough device designation for the SeQuent Please ReX drug-coated percutaneous transluminal coronary angioplasty (PTCA) balloon catheter for the treatment of coronary in-stent restenosis (ISR). SeQuent Please ReX is the latest generation coronary drug-coated balloon (DCB) catheter developed by B Braun. Ten years of extensive clinical study evaluations have been conducted on SeQuent Please drug-coated PTCA catheters and the data were reported in peer-reviewed articles. These studies have evaluated use of the catheters in a variety of indications, including in-stent restenosis for bare metal stents (BMS) and drug-eluting stents (DES), as well

as for initial stenosis detected in de novo lesions. ISR is the gradual re-narrowing of a coronary artery following stent implantation, and remains a challenge in the interventional community. Despite a significant reduction in ISR when using a drug-eluting stent over a bare metal stent, there still are a subset of patients in which ISR persists. Approximately 5% of patients who receive a DES, and more than 30% of patients who undergo BMS implantation experience ISR. “We need to have a coronary DCB in our toolbox to treat patients,” said Jorge Saucedo, chief of cardiology at the Medical College of Wisconsin (Milwaukee, USA). “This breakthrough device designation brings the technology a step closer for our use.” Breakthrough device designation from the FDA is granted to certain medical devices and device-led combination products that provide for a more effective treatment of life-threatening or irreversibly debilitating diseases. The goal of the breakthrough devices programme is to provide patients and healthcare providers with timely access to these medical devices by speeding up their development, assessment, and review, while preserving the statutory standards for premarket approval, 510(k) clearance and de novo marketing authorisation. “The paclitaxel-coated SeQuent Please PTCA balloon catheter has a proven track record of safety and efficacy for BMS- and DES-ISR in randomised clinical trials, as well as in the largest international DCB registry with a clinical endpoint. This device is the gold standard coronary DCB, based on the available clinical evidence,” said Peter Flosdorf, engineering manager at B Braun. “We are excited that the latest generation SeQuent Please DCB has received breakthrough device designation, which will streamline the review process and timeline for bringing this important treatment option to appropriate patients in the USA.”

Rivaroxaban recommended by NICE for peripheral and coronary artery disease patients

The National Institute for Health and Care Excellence (NICE) in the UK has published a positive draft final appraisal determination recommending the use of rivaroxaban (Xarelto, Bayer) by the National Health Service (NHS) in England. The NICE recommendation sets out a dose of 2.5mg twice daily, combined with 75–100mg aspirin once daily, as an option for preventing atherothrombotic events in adult patients with coronary artery disease (CAD) or symptomatic peripheral arterial disease (PAD) who are at high risk of ischaemic events.

Publication of this NICE draft is based on evidence from the COMPASS study, the largest Phase III study with rivaroxaban (27,395 patients). This study showed that rivaroxaban vascular dose, 2.5mg twice daily combined with aspirin 100mg once daily, statistically significantly reduced the risk of the composite of cardiovascular (CV) death, stroke or myocardial infarction (major adverse cardiovascular events; MACE) by 24% (relative risk reduction, ARR: 1.3%) compared with aspirin 100mg once daily alone amongst patients with stable atherosclerotic vascular disease (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.66–0.86, p<0.001). In the COMPASS trial, for patients with stable CAD, addition of rivaroxaban 2.5mg twice daily with aspirin 100mg once daily lowered major adverse cardiovascular events compared with aspirin once daily (347 [4%] of 8,313 vs. 460 [6%] of 8,261; HR 0.74, 95% CI 0.65–0.86, p<0·0001). Moreover, patients with PAD who received rivaroxaban 2.5mg twice daily combined with aspirin 100mg once daily, also had fewer major cardiovascular events compared with the aspirin 100mg once daily alone group (126 [5%] of 2,492 vs. 174 [7%] of 2,504; HR 0.72, 95% CI 0.57–0.90, p=0.0047). Rivaroxaban is an anticoagulant that

SYNC Evo Dynamic ArtBand

targets Factor Xa, an enzyme which acts at a key point in the blood clotting process, inhibiting its ability to generate thrombin. NICE are recommending use of rivaroxaban as part of a dual pathway approach (in combination with aspirin) to prevent atherothrombotic events in patients who are at high risk of such events. Coronary artery disease patients who are at high risk of ischaemic events are defined by NICE as those aged 65 or over, patients with atherosclerosis in at least two vascular territories, or those presenting with risk factors such as smoking, diabetes, kidney dysfunction, heart failure or a history of stroke. Derek Connolly, COMPASS trialist, consultant interventional cardiologist and honorary senior clinical lecturer at Birmingham City Hospital (Birmingham, UK), said: “Cardiovascular disease remains the biggest cause of years of life lost in the UK. There have been few recent major new advances in the medical management of patients with CAD and PAD to protect them against strokes or heart attacks. “The COMPASS trial showed that adding rivaroxaban vascular dose to low-dose aspirin significantly reduced vascular events. The large reduction in events [such as strokes], outweighed

the increase in major bleeding events seen. Conducted in more than 30 countries, including the UK, COMPASS was one of the largest ever trials of oral antithrombotic therapy providing robust results overall, and particularly for key patient subgroups at high-risk of recurrent events, such as those with renal dysfunction or stable ‘mild’ heart failure.”

Abiomed launches Impella SmartAssist platform

At the European Society of Cardiology Congress (ESC 2019; 31 August–4 September, Paris, France), Abiomed revealed that its Impella CP with SmartAssist technology is now commercially available in Europe. A press release reports that the system is designed to improve patient outcomes with advanced algorithms and simplified patient management. It adds that the majority of Impella CP heart pumps in Europe will be transitioned to SmartAssist over the next 12 months. According to the press release, the new Impella CP heart pump features a

fibre optic sensor that is optimally positioned to measure the placement signal in the aorta, identify pump placement, and enable repositioning without the use of imaging. The advanced sensors also enable the calculation and display of additional physiological data on the Automated Impella Controller. These advances to the Impella forward-flow heart pump technologies and software are designed to improve ease-of-use and patient management to improve both survival and heart recovery. The press release notes that the Impella CP with SmartAssist is the only mechanical circulatory support device that calculates and displays real-time displays of critical haemodynamic metrics indicative of left ventricular end-diastolic pressure (LVEDP), mean arterial pressure, and cardiac power output. Karim Ibrahim (Klinikum Chemnitz) comments: “Impella CP with SmartAssist is fast and easy to set up and to manage. The positioning and repositioning of this device is extremely precise thanks to the signal of the optical pressure sensor, its measurement is very reliable. If you have a patient in cardiogenic shock, every minute counts to unload the left ventricle. CP SmartAssist is in this respect a tremendous technical innovation which can save essential time.” After receiving the CE mark in 2016 and FDA approval in 2018, the SmartAssist platform has been thoroughly validated for this commercial roll out during a limited market release in Germany and the USA.

October 2019 | Issue 55

Studies

Clinical News Farixga meets primary endpoint in Phase III DAPAHF trial

AstraZeneca has announced positive results from the Phase III DAPAHF trial which showed that Farixga (dapagliflozin) met the primary composite endpoint with a statisticallysignificant and clinically-meaningful reduction of cardiovascular death or the worsening of heart failure (defined as hospitalisation or an urgent heart failure visit), compared to placebo. The trial was conducted in patients with reduced ejection fraction (HFrEF) on standard of care treatment, including those with and without type 2 diabetes. The safety profile of Farixga in the DAPA-HF trial was consistent with the well-established safety profile of the medicine.

John McMurray, University of Glasgow, Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, Glasgow, UK, said: “The benefits of dapagliflozin in DAPA-HF are very impressive, with a substantial reduction in the primary composite outcome of cardiovascular death or hospital admission. We hope these exciting new findings will ultimately help reduce the terrible burden of disease caused by heart failure and help improve outcomes for our patients.” DAPA-HF is the first heart failure outcomes trial with an SGLT2 inhibitor investigating the treatment of heart failure in adults with HFrEF on top of standard of care (which includes medicines such as angiotensinconverting enzyme [ACE] inhibitors, angiotensin II receptor blockers [ARB], beta blockers, mineralocorticoidreceptor antagonists [MRAs] and neprilysin inhibitors), in patients with and without type 2 diabetes. Farixga is also being studied in patients with heart failure with preserved ejection fraction (HFpEF) in the DELIVER and DETERMINE (HFrEF and HFpEF) trials.

Low-dose polypill could be used for primary prevention of cardiovascular events

A polypill that combines four cardiovascular drugs has been shown to reduce the risk of major cardiovascular events in the general population when taken in a low-dose once-daily. Findings from the PolyIran study, a five-year

randomised controlled trial, were published in the Lancet, and are the first to demonstrate a role for such treatment in the primary as well as secondary prevention of heart disease. The polypill used consists of two commonly used blood pressure lowering drugs, a cholesterol-lowering drug, and aspirin. It reduced rates of heart attack, stroke, and heart failure in participants both with and without a history of cardiovascular disease by more than one-third compared to lifestyle advice alone. Authors Gholamreza Roshandel, Masoud Khoshnia, Hossein Poustchi (Shariati Hospital, and University of Medical Sciences, Tehran, Iran) et al speculate that the findings suggest a fixed-dose polypill strategy could help to achieve the UN Sustainable Development Goal to reduce premature mortality from cardiovascular disease by at least one-third before 2030. They write: “This pragmatic trial provides evidence that a low-cost polypill could be considered as part of preventive strategies to reduce cardiovascular disease burden among eligible adults, especially in low-income and middle-income countries.” The PolyIran study was a twogroup, cluster-randomised trial nested within the larger Golestan Cohort Study, which consisted of 50,045 participants aged 40–75 years from the Golestan province in Iran. Researchers randomised clusters (villages) 1:1 to either a package of non-pharmacological preventive interventions alone (minimal care group) or to a combination of a once-daily polypill tablet and nonpharmacological intervention (polypill group). Non-pharmacological preventive interventions (healthy lifestyle advice) were delivered by the PolyIran field visit team at three and six months, and every six months after that. Follow-up was for 60 months. The primary outcome was occurrence of major cardiovascular events (including hospitalisation for acute coronary syndrome, fatal myocardial infarction, sudden death, heart failure, coronary artery revascularisation procedures, and non-fatal and fatal stroke). The researchers enrolled 6,838 participants between Feb 2011 and April 2013—3,417 (in 116 clusters) in the minimal care group and 3,421 (in 120 clusters) in the polypill group. Median adherence to polypill tablets was 80.5% (interquartile range [IQR] 48.5–92.2). During follow-up, 301 (8.8%) participants in the minimal care group had major cardiovascular events compared with 202 (5.9%) in the polypill group (adjusted hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.55–0.80). Roshandel, Khoshnia, Poustchi et al found no statistically significant interaction with the presence (HR

0.61, 95% CI 0.49–0.75) or absence of pre-existing cardiovascular disease (HR 0.80, 95% CI 0.51–1.12, p interaction=0.19). An analysis of subjects in the polypill group with high adherence found an even greater reduction in risk of major cardiovascular events compared to the minimal care group (adjusted HR 0.43, 95% CI 0.33–0.55). The frequency of adverse events was similar between the two study groups. Roshandel, Khoshnia, Poustchi and colleagues say: “The number needed to treat (NNT) to prevent one major cardiovascular event was 34.5 (95% CI 25.9–56.1). The NNT to prevent one major cardiovascular event in participants with high adherence was 20.7 (95% CI 17.5–26.5). Our results did not show reductions in both systolic (p=0.08) and diastolic (p=0.09) blood pressure. Despite only small changes in blood pressure, our findings suggested greater effects of polypill tablets on the risk of cardiovascular disease outcomes when compared with previous similar studies (for example HOPE-3).” They point out that the findings indicate that the benefits of widespread polypill use outweigh any known sideeffects, that it is effective in preventing major cardiovascular events, and that it was not associated with a significant reduction in overall mortality, although the study was not designed to look at mortality and more research is needed. However, the authors note that PolyIran was performed in a rural population, consisting mainly of central Asian ethnicity, which could limit the generalisability of the findings. Additionally, they used only two fixeddose combination pills, and different dosages of each drug or different combinations may improve efficacy.

El Khoudary, associate professor of Epidemiology at Pitt Public Health. The researchers used data from 474 healthy women aged 42 to 58 years enrolled in the Kronos early estrogen prevention study (KEEPS), which was a multicentre, randomised, placebocontrolled clinical trial of the effects of oral conjugated equine oestrogens and transdermal 17-beta oestradiol on atherosclerosis progression. Participants were enrolled between 2005 and 2008 and followed for four years. “The KEEPS trial is unique because it focuses on younger women close to the onset of menopause, and tested both a pill and patch formulation of menopausal hormone therapy,” said study coauthor JoAnn Manson, physician at Brigham and Women’s Hospital and Harvard Medical School (Boston, USA). “This allowed us to see the effects of different types of hormone therapy and whether the route of delivery—oral or through the skin—affected heart health in otherwise healthy women.” An earlier study from El Khoudary’s group showed that postmenopausal women with lower serum oestrogen levels had a greater volume of paracardial fat—fat that accumulates outside the pericardium—and also higher rates of coronary artery calcification, compared to premenopausal women. El Khoudary and her team hypothesised that menopause hormone therapy would be protective against heart fat accumulation, but their findings were so simple to interpret; the type of hormone therapy and route of administration mattered.

Hormone therapy linked to heart fat and hard arteries

Hormone replacement therapy is a common treatment for menopauserelated symptoms, and research from the University of Pittsburgh Graduate School of Public Health (Pittsburgh, USA) reinforces the importance of tailoring hormone therapy to each patient, based on her individual risk factors for cardiovascular disease. In a study published in the Journal of the American Heart Association, Pitt researchers showed for the first time that hormone replacement therapy affects the accumulation of heart fat—a new risk factor for cardiovascular disease in midlife women. Importantly, they found that the formulation and delivery route of hormones—whether as a pill taken orally or a patch placed on the skin— mattered when it came to the types of fat deposits women developed and whether those fat deposits translated to hardening of the arteries. “We are adding to the recognised list of cardiovascular-related effects of menopause hormone therapy by showing a novel cardiovascular risk factor that is specific to menopausal women also is affected by hormone therapy,” said study lead author Samar

The transdermal oestradiol patch— generally considered to be safer— compounded the harmful effects of paracardial fat deposition on coronary artery calcification progression. In contrast, women on the oestrogen pill were less likely to see increases in heart fat in the epicardial space immediately surrounding the heart or worsening coronary artery calcification. “That was surprising,” El Khoudary said. “The patch is thought to be safer because it is not systemic, just topical, and it does not have an impact on inflammation or triglyceride levels like oral hormones.” El Khoudary cautioned against making generalisations about oral versus transdermal hormone delivery or extending these findings to other treatments or patient groups. However, she said she hopes that clinicians will take these findings into account when treating healthy menopausal women with the drugs used in the study.

October 2019 | Issue 55

Companies

Industry News Cardiovascular Systems acquires Gardia Medical’s Wirion embolic protection system

Cardiovascular Systems has acquired the Wirion embolic protection system and related assets from Gardia Medical. The device, which received CE mark in June 2015 and US Food and Drug Administration (FDA) clearance in March 2018, is a distal embolic protection filter used to capture debris that can be associated with all types of peripheral vascular intervention (PVI) procedures. Physicians typically use embolic protection devices in vessels located above the knee with long lesions, high plaque burden and poor run off. Asaf Alperovitz, chief executive officer of Allium Medical Solutions, said: “Allium Medical’s mission is to develop innovative products to improve outcomes for patients around the world. We believe the Wirion system from Gardia Medical, one of our portfolio companies, will be highly synergistic with Cardiovascular System’s growing portfolio of products. We will continue to partner with the company to execute a timely manufacturing transfer and get the product in the hands of physicians.” Cardiovascular Systems plans to

commercialise the Wirion system in the USA following the transfer of manufacturing from Gardia Medical. The company expects the manufacturing transfer to be completed after a 12- to 15-month transition period. Gardia will retain the rights to the Wirion system for angioplasty and stenting procedures in the carotid arteries.

Omar Ishrak to step down as Medtronic CEO next year Omar Ishrak, Medtronic’s chairman and CEO is to retire on 26 April 2020,

Omar Ishrak

following the end of the company’s current fiscal year. The Medtronic board of directors has also announced key leadership appointments as part of its multiyear leadership succession planning process. A press release reports that these announcements will ensure a smooth and successful transition in leadership across the company. The board of directors has unanimously appointed Geoff Martha, currently executive vice president (EVP) of the company’s Restorative Therapies Group (RTG), to assume the newly created role of Medtronic president and become a member of the Medtronic Board of Directors, effective 1 November 2019. He will also succeed Ishrak as Medtronic CEO, effective 27 April 2020. As president, according to the press release, Martha will lead Medtronic’s operating groups and regions. Brett Wall, president of Medtronic’s Brain Therapies division, was appointed EVP and group president of RTG, succeeding Martha, effective 1 November 2019. At the start of Medtronic’s next fiscal year, Ishrak will assume a new position of executive chairman. He will provide counsel and guidance to Medtronic’s leadership, oversee CEO succession, and drive the ongoing successful execution of Medtronic’s long-term strategic plan. These changes are designed to ensure a smooth transition, continuity of leadership and a continued focus on delivering Medtronic’s innovation strategy and financial performance.

CeloNova appoints new president and CEO

CeloNova has announced the appointment of Carl J St Bernard as president and chief executive officer (CEO). St Bernard joins the company from Tryton Medical where he was president and CEO, leading the company’s commercialisation efforts in the coronary stent market. Incorporating the company’s Polyzene-F (PzF) nanocoating technology, CeloNova’s non-drugeluting Cobra PzF nanocoated coronary stent (NCS) system is designed to help physicians safely and effectively treat patients who may benefit from short, one-month minimum dual antiplatelet therapy (DAPT). The device is indicated for improving coronary luminal diameter in patients, including those with diabetes mellitus, with symptomatic ischaemic heart disease caused by de novo lesions in native coronary arteries. The Cobra stent is intended for use in patients eligible for percutaneous transluminal coronary angioplasty with a reference vessel diameter of 2.5 to 4mm and lesion length of ≤24mm. The appointment of St Bernard precedes the anticipated conclusion of the company’s global COBRA REDUCE randomised trial evaluating ultra-short, 14-day DAPT compared with market-leading drug-eluting stents with three or six months of DAPT in patients at a high risk of bleeding.

Calendar of events 3–5 October EACTS 2019 Lisbon, Portugal

www.eacts.org/annualmeeting-2/

4 October 2019 14th Annual Scientific Meeting of the Cardiorenal Forum London, UK

http://cardiorenalforum.com/

29 October– 01 November 30th Annual Cardiovascular Interventions La Jolla, USA

www.cvinterventions.com

14–15 November Controversies & Advances in the Treatment of Cardiovascular Disease, the Nineteenth in the Series Beverly Hills, USA www. controversiesincardiology. com

17–19 November PCR London Valves London, UK

www.pcronline.com/Courses/ PCR-London-Valves

22–25 February 2020 CRT 2020 National Harbor, USA www.crtmeeting.org

17–20 June 2020 TVT 2020 Chicago, USA crf.org/tvt

23–27 September 2020 TCT 2020 Miami, USA tctconference.com

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