Cardiovascular News Issue 52—February 2019

Feb

Issue

19 52 David Kandzari:

Orsiro vs. Xience Page 8

Massimiliano Gnecchi:

Robert Yeh:

Profile

Cell therapy Page 18

Audience applauds as MitraClip shown to reduce heart failure hospitalisations Delegates at the 2018 Transcatheter Cardiovascular Therapeutics (TCT) meeting (2125 September, San Diego, USA) broke into spontaneous applause after Gregg Stone (Columbia University Medical Center, Cardiovascular Research Foundation, New York, USA) reported that, according to the results of the COAPT trial, percutaneous edge-toedge repair (MitraClip, Abbott) for the management of secondary mitral regurgitation significantly reduces the rate of heart failure hospitalisations at two years. Stone garnered further applause when he revealed MitraClip reduces all-cause mortality.

T

he COAPT (Cardiovascular outcomes assessment of the MitraClip percutaneous therapy for heart failure patients with functional mitral regurgitation) trial was easily the most hotly anticipated trial of TCT. Just under a month before TCT, MITRAFR was presented at the 2018 European Society of Cardiology (ESC) Congress (25–29 August, Munich, Germany) and indicated that MitraClip for secondary mitral regurgitation did not provide a prognostic benefit.

Prior to MITRA-FR, no data were available for the beneficial effect of MitraClip (for secondary mitral regurgitation) on hard outcomes. Therefore, many at TCT were eager to see if COAPT would confirm or refute the findings of MITRA-FR. In COAPT, 614 patients with moderate-to-severe (3+) or severe (4+) secondary mitral regurgitation were randomised to receive MitraClip plus guidelinedirected medical therapy (302) or guideline-directed medical therapy alone (312). According to Stone, a “key aspect” of the study was that enrolled patients met the eligibility criteria, “especially the use of maximallytolerated guideline-directed medical therapy for heart failure”. He stated that enrolment of patients who were not receiving the maximal tolerated doses of therapy was deferred and these patients could be represented if suitable therapy had been instituted and the patient was still symptomatic. However, Stone revealed that none of the deferred patients came back. While admitting some of these patients died, he reported that others “did do better” after their medical therapy was revised and, thus, did not need to come back. This policy meant that there were few major changes in heart failure medication

during follow-up. By contrast, in line with realworld practice, the protocol of MITRA-FR allowed variable adjustment in heart failure medication after baseline.

The primary effectiveness endpoint of COAPT was the annualised rate of all heart failure hospitalisations Gregg Stone through 24 months and the primary safety endpoint was freedom from device-related complications at 12 months (in MITRA-FR, the primary outcome was the rate of all-cause mortality and unplanned heart failure hospitalisations at 12 months). Stone reported that the primary effectiveness endpoint was significantly reduced in the MitraClip group at two years: 160 events vs. 283 for guideline-directed medical therapy alone group (p<0.01). Upon hearing this result, the audience burst into applause and Stone had to wait for them to stop clapping before revealing the number needed to treat with MitraClip to prevent one heart failure hospitalisation was three. He added that the primary safety endpoint was also met: 96.6% freedom from device-related complications vs. a performance goal of 88% (p<0.001).

Further applause from the audience came when Stone announced that all 10 of the powered secondary endpoints were met. In particular, MitraClip was Continued on page 2

Page 28

IVUS-guided PCI reduces target vessel failure in all-comers population Jun-jie Zhang (Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China) and others report in the Journal of American College of Cardiology that percutaneous coronary intervention (PCI) guided by intravascular ultrasound (IVUS) is associated with a significantly lower rate of clinically-driven target vessel failure in all-comers patients than is angiography-guided PCI. This is the first time that benefits of the IVUSguided PCI have been shown in an allcomers population.

ZHANG ET AL report that data for the benefit of IVUS-guided PCI for simple lesions is “unclear”.

“Moreover, whether the beneficiary effect of IVUS-guidance is still present in the modern drug-eluting era still remains to be unknown, the authors add. They write: “Accordingly, this prospective, multicentre, randomised trial was designed to compare the efficacy and safety between IVUS-guided and angiography-guided second-generation drug-eluting stent implantation in all-comers patients with coronary artery disease.”

In the study, 1,448 patients were randomised to undergo angiography-guided PCI (724) or IVUSguided PCI (724). The authors report that optimal stent implantation with angiography guidance was defined as “thrombolysis in myocardial infarction grade 3, residual stenosis <20, and the absence of ≥type B dissection” while optimal stent implantation with IVUS was defined as “minimum lumen area in the stented segment >5mm2 or 90% of the minimum lumen area at the distal reference segments, plaque burden at the 5mm proximal or distal to the stent edge <50%, and no edge dissection involving media with Continued on page 2

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Feb

Audience applauds as MitraClip shown to reduce heart failure hospitalisations Continued from page 1

associated with a significant reduction in all-cause mortality at 24 months: 29.1% vs. 46.1% for guideline-directed medical therapy (p<0.01). Stone commented: “Mortality started to diverge after two years, suggesting the importance of a sustained durable relief of left ventricular overload.” In MITRA-FR, there were no significant differences between the MitraClip group and the medical therapy group at 12 months in either the composite primary outcome of death and unplanned heart failure hospitalisation or in the secondary outcome of all-cause death.

Concluding, Stone said: “In patients with heart failure and moderateto-severe or severe secondary mitral regurgitation who remained symptomatic despite maximallytolerated guideline-directed medical therapy, transcatheter mitral leaflet approximation with the MitraClip was safe, provided durable reduction in mitral regurgitation, reduced the rate of heart failure hospitalisations, and improved survival, quality-of-life and functional capacity during 24-month follow-up. As such, the MitraClip is the first therapy shown to improve the prognosis of patients with heart failure by reducing secondary mitral regurgitation due to left ventricular dysfunction.”

He added that he and his coinvestigators felt that, potentially, there were “three principal reasons” as to why the outcomes of COAPT and MITRA-FR were different. The first of these was that the patients enrolled in COAPT were different from those enrolled in MITRA-FR. Stone observed that patients in COAPT had, on average, more severe mitral regurgitation—mean baseline regurgitant orifice area (EROA) was 41±15mm3 vs. 31±10mm2 in MITRA-FR—while left ventricular enddiastolic volume was greater in MITRAFR (135±35mL/m2 vs. 101±34mm in

Issue

19 52

TCT 2018

COAPT). The other two reasons were the aforementioned different approaches to guideline-directed medical therapy and different acute results (e.g. the rate of procedural complications were higher in MITRA-FR).

The discussion following Stone’s presentation focused on which patients with secondary mitral regurgitation would benefit the most from MitraClip, with the consensus being that both MITRA-FR and COAPT helped the community to better understand optimal patient selection for the procedure.

Stone said: “The disparity between MITRA-FR and COAPT tells us that not all patients are going to benefit from a MitraClip. That if you treat patients whose ventricles are ‘too blown’ and who do not have severe mitral regurgitation, they are not going to benefit from MitraClip. In COAPT, we tried to select patients who were in the ‘sweet spot’ between having really severe heart failure but who were not so far gone that they would not benefit from reducing that aspect [i.e. regurgitation] of their overload status.”

MITRA-FR investigator Jean-Francois Obadia (Hôpital Cardiovasculaire, Louis Pradel, Chirurgie Cardio-Vasculaire et Transplantation Cardiaque, Lyon, France), who took part in the discussion, agreed with Stone that the disparity between the two studies provided useful information. He said: “I think it is the best scenario we could have. If they were both positive or both negative, that would have been the end of the story.

But, the difference leads us to go deeper into the analysis of the results and to try to understand this complex disease,” adding that the studies say “what you should do [i.e. COAPT] and what you should not do [MITRA-FR]” in terms of patient selection.

COAPT was simultaneously published in the New England Journal of Medicine.

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length >3mm”. They add that 471 lesions of 404 patients in the IVUS group did not meet all three criteria for optimal stent implantation with IVUS and, after multiple use of post dilatation, 384 (578 lesions) met all three criteria.

Furthermore, Zhang et al report, larger and longer stents were used in the IVUS guidance group.

The primary endpoint was the 12-month rate of clinically-driven target vessel failure, which was significantly reduced in the IVUS group: 2.9% vs.

5.4% for the angiography group (p=0.019). Zhang et al comment: “Patients who met the optimal criteria had a lower rate of target lesion failure at 12 months (1.6%) compared to that in patients who had a suboptimal PCI procedure (4.4%; p=0.029).” In particular, patients with IVUS-defined suboptimal procedure had a similar rate of the primary endpoint as those in the angiography group. There were no significant differences between groups in the components—clinically-driven target vessel revascularisation, target vessel myocardial infarction, and cardiac death—that comprised the primary endpoint. The authors report: “IVUS guidance was critical to modify plaque (complex lesions), to guide postdilatation, subsequently leading to less composite target vessel failure. As a result, with the guidance of IVUS, precise selection of the right non-compliant balloon was the basis for achieving an optimal PCI.” There were not any significant differences between groups in the composite endpoint of definite stent thrombosis and clinically-driven target lesion revascularisation. However, in a lesion-level analysis, this composite endpoint was lower in the IVUS group: 0.9% vs. 2.3% in the angiography group (p=0.02).

“In the present multicentre randomised trial in all-comers patients, IVUSguided drug-eluting stent implantation resulted in lower incidence of target vessel failure, particularly for patients who had an IVUS-defined optimal procedure, compared with angiography guidance,” Zhang et al conclude.

Coinciding with its publication in Journal of the American College of Cardiology, the study (ULTIMATE) was presented (by Zhang) at the 2018 Transcatheter Cardiovascular Therapeutics (TCT) meeting (21–25 September, San Diegeo, USA).

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IVUS-guided PCI reduces target vessel failure in all-comers population

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Feb

Issue

19 52

Lesion assessment

New approach may lead to greater use of FFR The FAST-FFR trial, which was presented at the 2018 Transcatheter Cardiovascular Therapeutics (TCT) meeting (21–25 September, San Diego, USA) and published in Circulation, indicates that fractional flow reserve (FFR) derived from an angiogram (FFRangio, CathWorks) had high sensitivity, specificity, and diagnostic accuracy for predicting FFR values derived from a pressure wire. As FFRangio has the potential to be a faster and easier approach to physiological assessment than standard FFR, it may lead to greater use of FFR. PRESENTING THE DATA at TCT 2018, William Fearon (Stanford University School of Medicine, Department of Medicine, Stanford Cardiovascular Institute, Stanford, USA) noted that the use of FFR to guide treatment decisions is known to improve outcomes and has been incorporated in multiple guidelines, but added its use “remains lower than expected because of a number of potential issues including the extra time it takes, wire handling characteristics, pressure wire drift, the need for hyperaemia, and the expense”. Therefore, a system—such as FFRangio—that does not require a pressure wire or a hyperaemic agent may lead to increased used of FFR. Rather than using a pressure wire, Fearon explained, FFRangio relies “on creating a 3D reconstruction of the coronary arterial system and estimating the resistance and flow at

each point along the entire coronary tree”. “Preliminary studies have found that FFRangio when measured offsite by experienced operators correlates well with pressure wire-derived FFR,” he said. Thus, the aim of the FASTFFR study was to further explore how FFRangio compared with FFR. In the study, 301 patients (319 vessels) with stable angina, unstable angina, or non-ST-segment elevated acute coronary syndromes underwent FFR to assess a coronary stenosis.

Their angiogram data were then used to calculate the FFRangio values; the hospital operator who calculated the FFRangio values (successfully measured in 98.7% of cases) was blinded to the FFR values. The sensitivity of the FFRangio (to the FFR values) was 93.5%, the specificity was 91.2%, and the diagnostic accuracy (overall) was 92%. Fearon noted the

William Fearon

confidence intervals for these results were “well above the predefined performance goals”.

He concluded that FFRangio “may

provide an easier and potentially faster method for performing physiology guided assessment of the overall coronary angiogram with similar accuracy to the reference standard, coronary pressure wire-based FFR,” adding that this may translate into “a greater percentage of patients undergoing physiologic guidance for revascularisation decisions and ultimately improve longterm outcomes”. However, he did acknowledge that “some important patient subsets”—including left main disease, low ejection fraction, and in-stent restenosis—were not included in the study and “will require further study”.

Fearon told Cardiovascular News: “To fully assess the clinical impact of FFRangio, a clinical outcomes study comparing it with wire-based FFR will be necessary.”

SYNTAX score should not be used to choose between CABG and PCI in diabetic patients with multivessel disease A post-hoc analysis of FREEDOM (Future revascularisation evaluation in patients with diabetes mellitus: optimal management of multivessel disease) indicates that coronary artery bypass grafting (CABG) provides better outcomes—in terms of major adverse cardiac and cerebrovascular events (MACCE)—for diabetic patients with multivessel disease than does percutaneous coronary intervention (PCI) irrespective of a patient’s SYNTAX score. This suggests that, in this context, the SYNTAX should not be used to predict whether patients would have equivalent outcomes if they underwent PCI rather than CABG.

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riting in the Journal of the American College of Cardiology, Rodrigo B Esper (Heart Institute of São Paulo Medical School, São Paulo, Brazil) and colleagues comment that the FREEDOM trial and other studies have “definitively shown” that CABG improves outcomes compared with PCI in diabetic patients with multivessel disease. They add that the SYNTAX score can be used to determine lesion complexity in patients with multivessel disease and help predict which patients would have equivalent outcomes with PCI as they would have with CABG (i.e. those with lesser lesion complexity). However, the authors comment that “the value of the SYNTAX score has not been assessed specifically in a population limited to patients with diabetes and multivessel coronary artery disease”.

Therefore, in the present study, they reviewed the prognostic implications of the SYNTAX score in diabetic patients with multivessel coronary artery disease who underwent PCI or who underwent CABG in the FREEDOM trial. The primary endpoint was the rate of MACCE, which comprised of all-cause death, non-fatal myocardial infarction, non-fatal stroke, and need for repeat revascularisation. Esper et al also reviewed the rate of hard cardiovascular events (all-cause death, non-fatal myocardial infarction, and non-fatal stroke).

Of 1,900 patients in the study, 953 underwent PCI and 947 underwent CABG. The mean SYNTAX score of these groups was 26.2±8.4 and 26.1±8.8, respectively (p=0.67). Among patients who underwent PCI, the five-year rate of MACCE was significant different

The decision-making of the best strategy for revascularisation should consider not only coronary angiographic aspects but also clinical aspects that could influence the outcomes.

among categories of SYNTAX score (i.e. the higher the SYNTAX score, the higher the rate of MACCE). However, there was no such difference between SYNTAX score categories among patients who underwent CABG. Esper et al report that for the PCI group, the SYNTAX score was an independent risk factor for MACCE and hard cardiovascular events at five years but note “the area under the ROC curve showed a poor discrimination capability for MACCE (0.54) and hard cardiovascular events (0.56).”

They add that the score was not an independent predictor of MACCE or hard cardiovascular events in the CABG group.

For all categories of SYNTAX score, the rate of MACCE was higher for patients who underwent PCI vs. those who underwent CABG. For example, for patients with a low score, it was 36.6% vs. 25.9%, respectively (p=0.02). According to the authors, this demonstrates that the “SYNTAX score does not identify a population of diabetic patients with multivessel disease in whom PCI is equivalent or superior to CABG”. They state that unlike the findings of the SYNTAX study, the results of this study suggest “the SYNTAX should not guide decision-making in diabetic patients with multivessel disease”.

There was no significant difference in the rate of hard cardiovascular events between PCI and CABG patients with low and high SYNTAX scores— potentially suggesting the SYNTAX score could be used to predict which patients would have an equivalent risk of hard cardiovascular events if they underwent PCI rather than CABG. However, Esper et al comment: “These results should be interpreted with caution because the study is underpowered to make comparisons between subgroups.”

The authors state their findings “highlight the importance of anatomic and clinical evaluation of diabetic patients with coronary artery disease”.

“The decision-making of the best strategy for revascularisation should consider not only coronary angiographic aspects but also clinical aspects that could influence the outcomes,” they add. Co-primary author, Michael Farkouh (Peter Munk Cardiac Centre, University of Toronto, Toronto, Canada) emphasises the need “for a full clinical assessment of the diabetic patient with multivessel coronary disease as a foundation to deciding how to manage the patient. Patient age, renal function and, of course, patient preference are key determinants in decision making but not the SYNTAX score” .

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Meta-analysis shows FFR-guided PCI reduces cardiac death and myocardial infarction A meta-analysis of individual patient-level data from FAME 2, DANAMI-PRIMULTI and Compare-Acute indicates that percutaneous coronary intervention (PCI) guided by fractional flow reserve (FFR) is associated with a significant reduction in a composite of cardiac death and myocardial infarction compared with optimal medical therapy. These findings add to those of the five-year results of FAME 2, which showed FFR-guided PCI to reduce the risk of spontaneous myocardial infarction.

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Lesion assessment

riting in the European Heart Journal, Frederik M Zimmerman (Department of Cardiology, Catharina Hospital, Eindhoven, The Netherlands) and others conducted a “collaborative individual patient data meta-analysis” of trials that compared FFR-guided with optimal medical therapy “to resolve a key uncertainty in clinical practice for a frequently performed, invasive and expensive procedure” (PCI in patients with stable/stabilised disease). The prespecified primary outcome was a composite of cardiac death or myocardial infarction, with secondary outcomes including the composite of all-cause death or myocardial infarction and the individual components of these composite outcomes.

Zimmerman et al reviewed data from FAME 2, DANAMI-PRIMULTI and Compare-Acute—the first of these reviewed FFR-guided PCI in patients with stable disease and the other two reviewed FFR-guided PCI in non-culprit lesions of patients with ST-segment elevation myocardial infarction (STEMI) who had successfully undergone treatment of the culprit lesion. All of the

studies assessed PCI with second-generation drugeluting stents. Of 2,400 patients overall, 1,056 had been randomised to FFRguided PCI and 1,344 to optimal medical therapy.

After a median follow-up of 35 months, FFR-guided PCI was associated with a 28% relative risk reduction Frederik M Zimmerman in the primary endpoint compared with optimal medical therapy (p=0.02). “The estimated cumulative incidence [of the primary endpoint] at five years was 10.7% for FFR-guided PCI group and 16.4% for the primary endpoint, which resulted in an estimated number needed to treat to prevent one event up to five years of 18,” Zimmerman et al report. They add that the difference between groups was driven by a difference in myocardial infarction (use of FFR-guided PCI had a number needed

to treat of 20 to prevent one myocardial infarction at five years). However, there were no significant differences between FFR-guided PCI or optimal medical therapy in the rate of cardiac death or all-cause death. The authors observe: “For the secondary composite of all-cause death or myocardial infarction, there was a 23% relative reduction in FFR-guided PCI (p=0.04)”.

According to Zimmerman et al, “two factors” explain why none of the individual trials that compare PCI have shown it to reduce a composite of cardiac death or myocardial infarction in patients with stable/ stabilised disease. The first of these is that the trials were underpowered for the composite of cardiac death or myocardial infarction; the authors note: “Because all trials were powered for a primary composite endpoint that included various definitions of revascularisation as one of its components, it cannot be expected that a statistically significant reduction in cardiac death or myocardial infarction would be found in any single trial”. The second factor is that earlier trials that assessed the use of PCI in the context of stable/stabilised disease used bare metal or first-generation drug-eluting stents and used angiography rather than FFR. The authors conclude: “In this individual patient-level data meta-analysis of the three available randomised controlled trials to date, FFR-guided PCI resulted in a reduction of the composite of cardiac death or myocardial infarction compared with medical therapy, which was driven by a decreased risk of myocardial infarction.”

Zimmerman and study author Nico HJ Pijls (Department of Cardiology, Catharina Hospital, Eindhoven, The Netherlands) told Cardiovascular News: “A classical dispute resolved: PCI reduces hard endpoints, not only in acute coronary syndrome but also on the long-term instable angina.”

Multivessel NIRS is feasible, safe and can predict future events The Lipid Rich Plaque (LRP) study indicates that cardiac patients with a high lipid core plaque burden index (LCBI), identified with near infrared spectroscopy (NIRS, Infraredx), are at increased risk of a major adverse cardiac event (MACE) in a non-culprit vessel compared with those a low LCBI. Ron Waksman presented the LRP study at the 2018 Transcatheter Cardiovascular Therapeutics (TCT) meeting (21–25 September, San Diego, USA) and talks to Cardiovascular News about its findings.

Patients who have had a coronary event, such as a myocardial infarction, are known to be at increased risk of further events. Why is there a need to further assess the risk profile of these patients?

Some of these patients will go on to have further coronary events despite receiving optimal medical therapy, but others will remain event free despite their apparent risk of future events given their combination of known comorbidities. Before our study, we did not have any devices that could quickly and efficiently identify which patients would go on to have further events and which ones would not at the time of cardiac catheterisation.

In this study, we evaluated the use of NIRS to identify patients and coronary segments with lipid rich plaque and determined these lipid rich plaques were vulnerable to rupture when large.

Previous studies have shown that there is an association between the presence of lipid rich plaque and acute coronary syndromes, myocardial infarction, and death. Our goal was to see if NIRS could identify “vulnerable patients” and “vulnerable plaque” with 24 months after a patient had undergone the initial imaging.

How is NIRS performed?

A single, dual probe, catheter that can perform both NIRS and intravascular imaging (IVUS) is used, and this catheter is connected to one console with one screen. The NIRS provides you with a chemogram of the artery, which measures the LCBI overall and automatically identifies the largest 4mm segments in one scan.

On the LBCI scale, what indicates that the patient/ plaque is vulnerable?

The numbers range from 0 (meaning no lipid rich plaques; red on screen) to 1,000 (the maximum that can be seen; yellow on screen), and the LCBI is then calculated within all 4mm segments to find the maximum LCBI value (maxLCBI4mm). In the study, we used a threshold maxLCBI4mm of 400 to discriminate between patients who we thought would have further events and those who we did not think would have a future event. We based this threshold on some preliminary studies that suggested 400 would be a good cutoff.

What were the key findings of the study?

We had two co-primary hypotheses— one for the vulnerable patient and one

Ron Waksman

Our goal was to see if NIRS could identify vulnerable plaque within 24 months.

for the vulnerable plaque—and both of these were met. We found that at the patient level, the risk of non-culprit MACE increased by 18% for each 100 unit increase of maxLCBI4mm after adjustment for known risk factors; it increased by 45% for each 100 unit increase at the plaque level.

Also, a patient with ≥400maxLCBI4mm had 87% higher risk of non-culprit MACE. The cumulative incidence of nonculprit MACE was 6.3% for patients with <400maxLCBI4mm but was significantly higher at 12.6% for patients with ≥400maxLCBI4mm.

Furthermore, NIRS (plus IVUS) was very safe to do; we had very few events (0.3%).

What are the implications of the study?

For the physician, there is now a diagnostic tool that is both userfriendly and already available within the cardiac catheterisation laboratory that can predict further events at the patient and plaque level. The obvious next study should explore whether NIRS can guide therapy— either an intervention with a stent or pharmacologic agent—to mitigate this high vulnerability.

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Orsiro vs. Xience

Orsiro may be the new benchmark for comparison in drug-eluting stent trials At the 2018 Transcatheter Cardiovascular Therapeutics (TCT) meeting (21–25 September, San Diego, USA), David Kandzari (Piedmont Heart Institute, Atlanta, USA) presented the two-year results of the BIOFLOW V study. These indicate that Orsiro (Biotronik) was associated with a significantly lower rate of target lesion failure than was Xience (Abbott). However, five-year data from the BIOSCIENCE study, which was presented at the 2018 European Society of Cardiology (ESC) Congress (25–29 August, Munich, Germany), show no significant difference in the rate of target lesion failure between these two devices. In this interview with Cardiovascular News, Kandzari discusses all of the available data for Orsiro and whether it does provide superior outcomes to Xience.

Overall, what were the key findings of the BIOFLOW V study?

BIOFLOW V was designed as a pivotal study to inform approval of Orsiro in the USA with an overview by the FDA. It compared Orsiro, a sirolimus-eluting stent with a biodegradable polymer, with Xience (an everolimuseluting stent with a permanent polymer). Historically, Xience has been the benchmark for comparison for drug-eluting stents.

Prior to BIOFLOW, no study has shown a superiority for a stent compared with Xience. But in BIOFLOW V, at one year, we demonstrated a significant difference in target lesion failure with the Orsiro stent and we also showed a significant difference in myocardial infarction that favoured Orsiro. So when reviewing the two-year data, the question was whether we would continue to see a difference in these outcomes with Orsiro and whether new differences might emerge. Not only did the differences in target lesion failure and myocardial infarction persist between Orsiro and Xience at two years, but we also observed significant differences in target lesion revascularisation and late and very late stent thrombosis that favoured the Orsiro stent.

Therefore, with Orsiro, we saw persistent and emerging differences compared with Xience—an unprecedented result.

Why do you think no significant differences in target lesion failure were observed between Orsiro and Xience in the BIOSCIENCE study?

It is hard to compare data from two different trials.

BIOFLOW V was a multicentre, international pivotal trial whereas BIOSCIENCE was an all-comers study of patients enrolled at selected centres in Switzerland.

Not only did the study populations differ, but there were very important differences in methodology between the two trials. Being a pivotal trial, BIOFLOW V had detailed endpoint definitions and ascertainment, for example, periprocedural biomarker assessments for periprocedural myocardial infarction—but the use of such assessments and definitions were not consistent with BIOSCIENCE. Furthermore, BIOSCIENCE had some unique findings such as a higher of all-cause mortality rate and an older population than seen in other large, comparative drug-eluting stent trials. Orsiro was associated with a significantly higher rate all-cause mortality than was Xience in the BIOSCIENCE trial, which most if not all people in the interventional cardiology community see as a chance finding.

If Orsiro is associated with superior outcomes to Xience, why do you think that would be?

The biodegradable polymer of Orsiro may confer a late safety advantage as the polymer dissolves and returns the stent to a phenotype of a bare metal stent—meaning that there is no polymer substrate for persistence of inflammation or neointimal hyperplasia.

We may see this advantage as follow-up data beyond two years begin to emerge. Importantly, however, the biodegradable polymer of the Orsiro stent does not completely disappear until at least two years after stent implantation. Therefore, I do not think that the biodegradable polymer is the exclusive reason that

data (presented at the 2018 EuroPCR meeting) showed a significant difference in target lesion failure and target lesion revascularisation that favoured the Orsiro stent.

Therefore, it will be interesting to see the two-year findings of BIONYX continue to show no significant differences between Orsiro and Resolute Onyx.

BIONYX also showed that Resolute Onyx was associated with a significantly lower rate of definite or probable stent thrombosis. Why do you think this was?

The presenter of that study acknowledged that event rates were low for both stents—0.7% for Orsiro and 0.1% for Resolute Onyx. The extremely low rate of stent thrombosis for Resolute Onyx was surprising because it is not consistent with previous studies of Resolute nor is it consistent with any finding for a drug-eluting stent in such a broad, unselected patient population. It is a very favourable result but it may be more of a chance finding.

David Kandzari

differences are observed compared with the Xience stent.

Instead, a more likely potential reason for the differences in outcomes between Orsiro and Xience is that Orsiro is an ultrathin strut stent whereas Xience is a thin strut stent. For Orsiro stents that are 3mm diameter or less, Orsiro has a strut thickness of 60µm while Xience has a strut thickness of 81µm. In a recent meta-analysis that compared “ultrathin” strut stents (including Orsiro) with “thin” strut stents, there seemed to be a consistent finding of lower ischaemic events— such as myocardial infarction and stent thrombosis— with the ultrathin stents. Ultrathin stents may be a new focus for us as we think about new stent designs and development.

Have we reached a plateau in terms of improving safety and efficacy with the latest generation stents?

In the past three to five years, I think there has been an impression in the community that we had met a plateau with regard to drug-eluting stent safety and efficacy.

But, BIOFLOW V changed that paradigm as it showed that there was still the opportunity for incremental benefit with newer stents.

One of the key issues, however, is that we need to reset our expectations with regard to when, how and what potential differences we will see between drugeluting stents as they continue to evolve and develop.

By that, I mean that we may not necessarily observe differences at the traditional one-year time point; we may need longer durations of follow-up. Alternatively, differences may appear earlier than one year, such as

A more likely potential reason for the differences in outcomes between Orsiro and Xience is that Orsiro is an ultrathin strut stent whereas Xience is a thin strut stent.

Why were there no significant differences in target vessel failure between Orsiro and Resolute Onyx in BIONYX given that Onyx is a thin strut rather than an ultrathin strut stent?

Again, we have to keep in mind we are comparing data across different trials and that limits any definite conclusions. The BIONYX was a large comparative study showing noninferiority of the Onyx stent (Medtronic) with the Orsiro stent regarding target vessel failure. It is noteworthy that the investigators selected Orsiro as the benchmark comparator stent.

It is also noteworhy, however, that the BIONYX trial investigators also performed the BIORESORT trial. This trial showed that at one year, there were no significant differences between Orsiro, Resolute Integrity, and the everolimus-eluting, biodegradable polymer stent Synergy (Boston Scientific). However, the two-year

periprocedural myocardial infarction (significantly reduced with Orsiro vs. Xience). The other issue is that the differences observed may not be the more traditional or expected endpoints such as target lesion revascularisation. In BIOFlOW V, for example, we observed differences between Orsiro and Xience in endpoints such as target vessel myocardial infarction and stent thrombosis, findings that have been a consistent result for ultrathin struts.

Do you think, based on the available evidence, that Orsiro is now the goldstandard stent?

That would be my opinion but I am certainly not the only one to have that opinion. The investigators of BIORESORT and BIONYX, for example, have now established Orsiro as a new standard of comparison in the design of their trials.

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ADVERTORIAL

The Edwards Cardioband™ Tricuspid Valve Reconstruction System is associated with considerable improvement in functional outcomes

Until recently, the tricuspid valve had the reputation for being the “forgotten valve”. According to Jörg Hausleiter (Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany), there are limited therapy options available for managing patients with clinically significant tricuspid regurgitation. In this interview, Hausleiter discusses with Cardiovascular News the Cardioband tricuspid system as an important new treatment option for these patients.

Why, historically, has the tricuspid valve been seen as the “forgotten valve”?

It is mainly because treatment options have been limited for the majority of patients with severe tricuspid regurgitation. One option is pharmacological therapy, which can relieve some of the symptoms of tricuspid regurgitation but does not treat the underlying disease. Therefore, when not treated directly, tricuspid regurgitation can worsen over time. As an alternative, surgery is an option for some patients but surgical mortality is often high. Large American and European registries report an associated risk of mortality of 10%, which is still high.1

How do the origins of tricuspid regurgitation compare to those for mitral regurgitation?

Unlike mitral regurgitation, the majority of patients have secondary tricuspid regurgitation, which is due to annular dilatation. Therefore, the tricuspid leaflets are not typically diseased themselves.

For example, a patient with heart failure develops right ventricular dilatation, which leads to severe annular dilatation.

The tricuspid leaflets become “too small” for the annulus, resulting in tricuspid regurgitation. This type of tricuspid regurgitation is a secondary condition.

This is the reason why tricuspid regurgitation is often seen in combination with left-sided disease such as aortic stenosis or mitral regurgitation, and in patients with dilated cardiomyopathies.

Since the mortality rate for isolated tricuspid valve surgery remains relatively high, surgery on the tricuspid valve is frequently postponed until it can be performed in combination with another surgery. For example, if a patient with tricuspid regurgitation needs to undergo mitral valve surgery, the tricuspid valve can often be addressed during the same procedure. European guidelines currently recommend the tricuspid valve should be repaired at the same time as the mitral valve if the tricuspid regurgitation is severe or if it is moderate in the presence of annular dilatation.

What is the role of imaging in identifying the severity of tricuspid regurgitation?

Transthoracic echocardiography (TTE) imaging is the main diagnostic tool for tricuspid regurgitation. However, transoesophageal echocardiography TOE) is the most used imaging resource for interventional therapy. Of note, TOE imaging for the tricuspid valve is much more complicated and challenging than for the mitral valve. The two major hurdles are the anatomy itself and the ability to obtain good quality images.

The tricuspid valve is further away from the oesophagus than the mitral valve, which makes imaging inherently more difficult.

Hahn et al have called for a new system for grading tricuspid regurgitation.2 Why is this?

The current echocardiographic criteria for grading tricuspid regurgitation only considers three grades of severity: mild, moderate and severe.

However, there is huge variability among patients within the severe category. Of these patients, there is a spectrum of high-to-very high severity categorised as “severe”, “massive”, and “torrential”. Echocardiographers such as Rebecca Hahn (Columbia University Medical Center, New York-Presbyterian Hospital, New York, USA) have suggested the three-grade scale of “mild, moderate and severe” could be improved by using an extended five-grade scale of “mild, moderate, severe, massive, and torrential” to accommodate the large variability amongst patients.

These additional grades might become important in the future because early reports indicate significant improvements in clinical outcome after interventional tricuspid repair, even when the tricuspid regurgitation was “only” reduced from “torrential” to “severe”. Such an improvement by two grades in the new grading system would not be considered a successful procedure when the conventional scale is applied.

These data show that the Cardioband tricuspid system is associated with a considerable improvement in clinical outcomes.

Given the limitations of traditional management options (i.e. medical management or surgery), I presume an obvious advantage of a transcatheter device is more patients would be able to undergo treatment—is that true?

The risk for interventional tricuspid valve procedures is low; the procedural mortality risk is under 5%.3 That makes a big difference in terms of expanding the patient population who can undergo treatment. Also, the rehabilitation of these patients is much easier and faster than for those who have undergone surgery because they are not having to deal with trauma of the chest.

At present, the only CEmarked transcatheter option for tricuspid regurgitation is the Cardioband tricuspid system. How does the device work?

The Cardioband tricuspid system is a transcatheter valve reconstruction system designed to reduce tricuspid regurgitation through annular reduction.

The Cardioband implant is affixed in a stepwise manner along the annulus using a series of anchors and then contracted with the use of a sizeadjustment tool to reduce the tricuspid annular diameter. Throughout the procedure, both TOE and fluoroscopy play integral roles to guide the procedure, verify and confirm proper placement and adjustments.

How long does it take to implant?

We are still in the early stages of using the Cardioband tricuspid system, but we usually only need to allow between two and three hours depending on the imaging. The time taken is to ensure the proper location of each anchor, and we consider this a good investment considering the excellent results.

What data are available for the system?

I was an investigator for TRI-REPAIR study, which was a single arm, multicentre and prospective CE-mark study that evaluated the safety and performance of the Cardioband tricuspid system on 30 patients. The system is a feasible and safe approach for managing patients with severe tricuspid regurgitation.4 The technical success rate was 100%. At the six-month mark, we

Jörg Hausleiter

saw significant reductions in the annular size of the septal-lateral diameter. When we looked at the echocardiographic measurements, there was a significant reduction in the severity of tricuspid regurgitation. Furthermore, at least 80% of patients saw improvement in their New York Heart Association (NYHA) classification and almost 90% were in NYHA Class I or II at six months.

At baseline, all of the patients were in Class III or IV. We also saw statistically significant improvements in the sixminute walk test and quality of life score, and interestingly, in oedema.

These data show that the Cardioband tricuspid system is associated with a considerable improvement in echocardiographic, functional, and clinical outcomes.

What do you think will be the future of transcatheter therapies for tricuspid regurgitation?

More approaches will become available and these will more likely be repair devices than replacement devices.

In my opinion, we will end up with an interventional procedure that is standardised and associated with good outcomes. I expect this treatment will become the mainstay treatment for reducing tricuspid regurgitation, and many patients will benefit from this new treatment option.

References 1. Sung et al. European Journal of Cardio-Thoracic Surgery 2009; 36: 825–29.

2. Hahn et al. Eur Heart J Cardiovasc Imaging 2017; 18(12): 1342–43.

3. Asmarats et al. JACC 2018; 71(25) 2935–56.

4. Nickenig et al. JACC 2019; In Press.

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Structural Heart Interventions Severe prosthesis-patient mismatch linked to increased mortality at one year

The largest study to date of prosthesis-patient mismatch following transcatheter aortic valve implantation (TAVI) shows that severe mismatch is associated with a significantly higher risk of death at one year. Furthermore, the study indicates that the predictors of prosthesis-patient mismatch include small valve prosthesis (<23mm), valve-in-valve procedure, larger body surface area and non-white/ Hispanic race.

WRITING IN THE Journal of American College of Cardiology (JACC), Howard C Herrmann (University of Pennsylvania, Philadelphia, USA) and others report that prosthesis-patient mismatch after TAVI has only been studied “in small studies with limited follow-up”. “In this report, from the Society of Thoracic Surgeons (STS)/ American College of Cardiology (ACC) Transcatheter Valve Therapy (TVT) Registry, we report the incidence, predictors, and one-year outcome of patient prosthesis mismatch in 62,125 patients undergoing TAVI in the USA between 2014 and 2017,” they add.

Of 62,125 patients enrolled in the registry between January 2014 and March 2017, 12.1% and 24.6% of patients were found to have severe and moderate prosthesis-patient mismatch, respectively.

The authors state these figures did not significantly change between 2014 and 2017, commenting: “Important predictors included valve prosthesis ≤23mm

diameter, valve-in-valve procedure, larger body surface area, lower left ventricular ejection fraction, non-white Hispanic, female, younger age, atrial fibrillation, and large body mass index, higher aortic valve mean gradient, prior coronary artery bypass grafting, and severe mitral or tricuspid regurgitation”.

At 30 days, severe prosthesis-patient mismatch was associated with higher rates of heart failure hospitalisation, stroke, and death. Furthermore, after multivariate adjustment, severe (but not moderate) prosthesis-patient mismatch was associated with adverse outcomes of death, heart failure hospitalisation, and combined death or heart failure hospitalisation at one year.

According to Herrmann et al, their study findings have “important implications for further improving outcomes in patients undergoing TAVI” and that their results suggest “efforts should be made to identify and limit the risk of patient prosthesis-patient

Howard C Herrmann

mismatch after TAVI”. They comment that awareness of the baseline risk factors for prosthesis-patient mismatch among patients undergoing surgical aortic valve replacement has led—along with techniques to minimise its occurrence— to a 55% decrease in its incidence after surgical valve replacement. “The TAVI

TAVI-induced bundle branch block and permanent pacemaker implantation are “not benign” New data indicate that patients who develop bundle branch block (BBB) and/or require a new permanent pacemaker after undergoing transcatheter aortic valve implantation (TAVI) have a significantly higher risk of late all-cause mortality. They also have a higher risk of heart failure hospitalisation. These findings suggest that contrary to some previous studies, BBB and/or pacemaker implantation after TAVI is not a harmless complication.

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roels H Jørgensen (Rigshospitalet, The Heart Centre, Copenhagen, Denmark) and others write in JACC: Cardiovascular Interventions that the clinical impact of conduction abnormalities, such as BBB, “remains controversial”. They explain: “New-onset left BBB and post-procedural permanent pacemaker implantation have shown inconsistent effects of mortality and heart failure after TAVI.” Therefore, the aim of the present study was to further review the incidence and outcomes of the TAVI-induced BBB and/ or permanent pacemaker implantation.

Reviewing data from their centre, Jørgensen et al identified 816 patients who underwent TAVI over 10 years (2007–2017). Of these, 437 did not develop conduction abnormalities, 247 developed new BBB, and 132 required a permanent pacemaker. “More patients with new BBB (19) received permanent pacemakers later than 30 days after TAVI compared with patients with no conduction abnormalities (15),” they observe.

Five-year all-cause mortality was significantly higher for patients who developed BBB and/or required a pacemaker: 48.4% and 46.7% vs. 32.8% for those without conduction abnormalities (p=0.0003). While

the hazard rates of early (<1 year) and late (≥1 year) mortality were both significantly higher for patients with BBB compared with those without conduction abnormalities, only late mortality was significantly higher for patients with a Troels Jørgensen permanent pacemaker (vs. those without conduction abnormalities). Jørgensen et al comment that, potentially, patients with a permanent pacemaker were protected from the risk of sudden cardiac death that has been in patients with left BBB. Furthermore, the hazard rate of first heart failure hospitalisation was higher for both patients with BBB and those who had a pacemaker vs. those who did not have conduction abnormalities but no pacemaker. The mean number of recurrent heart failure hospitalisations up to five years after TAVI was also higher for these groups. However, when patients with no heart failure

community should follow this lead by identifying patients at risk for severe prosthesis-patient mismatch and consider techniques to reduce this risk,” the authors write.

Concluding, Herrman et al state: “A future study that compares devices and techniques to limit prosthesis-patient mismatch in patients at risk for severe mismatch would be of interest to guide decision making in this population.”

Herrmann says: “Awareness of this issue is the first step to avoiding it. For patients at risk of severe prosthesispatient mismatch, options may include fracture of a prior surgical prosthesis during valve-in-valve procedures, use of TAVI prostheses with a larger effective orifice area if anatomically feasible, and even consideration of surgery with root enlargement in lower risk patients.”

The study was also presented at the 2018 Transcatheter Cardiovascular Therapeutics (TCT) meeting (21–25 September, San Diego, USA).

admissions were excluded from the analysis, there were no significant differences between groups in the mean number of recurrent heart failure hospitalisations.

Left ventricular ejection fraction (LVEF) was significantly reduced in both patients with BBB and those with a pacemaker. The authors note that this finding and the increased risk for heart failure hospitalisation that was seen in these groups “could be a co-factor in the increased risk of mortality observed in these patients compared with those with no conduction abnormalities”. “Thus, neither new BBB nor permanent pacemaker implantation appears benign in the long-term, indicating that prevention is the best long-term treatment of TAVI-induced conduction abnormalities and that these patients may benefit from closer follow-up,” they add.

Speaking about the data, Jørgensen comments that their results would “not necessarily” be any different had they only reviewed new-generation TAVI devices (given the study reviewed data from 2007, first-generation devices would have been included). He said: “Considering the similar rates of both new-onset BBB and need for permanent pacemaker with the newer generation transcatheter heart valves as compared with the early iterations, it is not probable that the risk of new-onset conduction abnormalities would have been different if only including newer generation valves. Further, the pathophysiology behind new-onset conduction abnormality leading to late death would be expected to be the same regardless of type of implanted valve.” In terms of preventing conduction abnormalities (and potential pacemaker implantation), Jørgensen states: “As with the risk of paravalvular leakage that has been reduced over the past decade, the risk of new-onset conduction abnormalities might be reduced by focused design features of future transcatheter heart valve generations.”

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Early discharge feasible for unselected TAVI patients Data from the multicentre FAST-TAVI trial indicate that early discharge—discharge within 72 hours—in an all-comers population undergoing transcatheter aortic valve implantation (TAVI) is safe and feasible. Furthermore, these data show that prespecified criteria can help to identify patients who have a low risk of poor outcomes after early discharge.

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resenting the data at PCR London Valves (9–11 September, London, UK), Marco Barbanti (Division of Cardiology, Ferrarotto Hospital, University of Catania, Catania, Italy) reported that the primary endpoint of FAST-TAVI was the “determination of the incidence of all-cause mortality, stroke, permanent pacemaker implantation, major vascular complications, bleeding and re-hospitalisation at 30 days” among patients who had been discharged early vs. those who had been discharge late (72 hours after a TAVI procedure). He added that the secondary endpoint of the study was “to test prospectively a set of prespecified criteria for early discharge”.

The “low-risk criteria”, according to Barbanti, included New York Heart Association (NYHA) Class ≤II, having no chest pain that could be attributed to cardiac ischaemia, and independent mobilisation and being “self-caring”.

Of 502 patients enrolled in the study, three died prior to the TAVI procedure.

The average age was 81.4±6 years, 242 patients were female, and the average

Marco Barbanti

logistic EuroScore was 5±6. Overall, most patient were discharged alive (496 of 499) and most of these were discharged within 72 hours (306 patients; 72.6%). Of those who fulfilled the lowrisk risk criteria (367 of those discharged alive), 72.2% were discharged early whereas only 27.8% of patients who did not fulfil these criteria were discharged early. For all patients, logistical factors

were the major contributors to a late discharge after TAVI. At 30 days, there were no significant differences between early discharge (360) and late discharge patients (136) in the rate of all-cause mortality, stroke/ transient ischaemic attack, or the rate of re-hospitalisation. However, significantly more late discharge patients received a new permanent pacemaker (15% vs. 4.1% for early discharge patients; p<0.001), had major vascular complications (5.6% vs. 0.6%, respectively; p=0.014), and had lifethreatening bleeding (11.1% vs. 8.9%; p=0.465).

Barbanti commented that the FASTTAVI study was important because it was “the first and largest multicentre prospective study to investigate the feasibility and safety of timely discharge after transfemoral TAVI in an all-comers population”. “We demonstrated that timely discharge is feasible and safe in an unselected transfemoral TAVI population.

The trial set a number of prespecified criteria that can help physicians to identify patients at low-risk for early

Presence of left bundle branch block significantly increases risk of pacemaker implantation after TAVI Quentin Fischer (Department of Cardiology, Quebec Heart and Lung Institute, Laval University, Quebec City, Canada) and others report in Circulation: Cardiovascular Interventions that patients with pre-existing left bundle branch block (LBBB) have a significantly increased risk of requiring permanent pacemaker implantation after undergoing transcatheter aortic valve implantation (TAVI) than patients without pre-existing LBBB. However, pre-existing LBBB is not associated with increased mortality at 30 days or at two years.

FISCHER ET AL report that right bundle branch block (RBBB) is seen as the “most important risk factor” for permanent pacemaker implantation after TAVI and that “some studies have shown an increased mortality risk among patients with pre-existing RBBB”. However, they add “no specific data exist on the impact of preexisting LBBB on TAVI outcomes”. Therefore, with the present study, the authors sought to “evaluate the impact of pre-existing LBBB on clinical outcomes in patients undergoing TAVI”.

Using data for 4,513 patients who underwent TAVI at 18 centres in Canada, Europe and Brazil between February 2005 and October 2017—after excluding patients with pre-existing RBBB, previous pacemaker, or who did not have high-quality ECG data at baseline—the authors identified 3,404 patients for evaluation. Of these, 398 patients had pre-existing LBBB; Fischer et al report that patients with incomplete LBBB were classed as having no pre-existing LBBB (3,006 overall).

At 30 days, permanent pacemaker implantation was significantly higher in patients with pre-existing LBBB: 21.1% vs. 14.8% for patients without pre-existing LBBB (p=0.006). Pacemaker implantation was also higher among those who received a self-expanding valve than

those who received a balloon-expandable valve (23.1% vs. 8.7%, respectively; p<0.001). However, there were no significant differences in all-cause mortality at 30 days: 7.3% for patients with pre-existing LBBB vs.

5.5% for those without pre-existing LBBB; p=0.217).

There were also no differences in all-cause mortality or cardiac mortality between LBBB patients and no LBBB patients at a mean follow-up of 22±21 months (p=0.173 and p=0.093 for the respective differences).

Fischer et al note that the cumulative rate of permanent pacemaker implantation was higher in the pre-existing LBBB group (22.9% vs. 16.5% for the no LBBB group; p=0.006), but add that this “was because of an increased permanent pacemaker implantation rate early after TAVI and no differences between groups were observed in the permanent pacemaker implantation rate after the first 30 days post-TAVI”. Additionally, according to the authors, patients with pre-existing LBBB “exhibited a lower left ventricular ejection fraction (LVEF) pre-TAVI but experienced a similar degree of increase in LVEF at one-year follow-up compared with those patients with no significant conduction disturbances pre-TAVI”.

Fischer et al note that the risk of permanent pacemaker implantation associated with pre-existing

We demonstrated that timely discharge is feasible and safe discharge,” he added.

In a previous study, which was published in Heart, Barbanti and colleagues showed early discharge did not increase the risk of death in a selected population. In this retrospective study, the investigators found that—via a multivariate analysis—patients with baseline NYHA IV or any bleeding were less likely to be discharged early whereas those who underwent the procedure more recently or who had a permanent pacemaker (implanted prior to the TAVI procedure) were more likely to be discharged early.

LBBB occurs early “probably secondary to the mechanical compression of the His bundle during valve implantation” given that there was no increased risk of pacemaker implantation, or sudden cardiac death, at two years. “This provides some reassurance Josep Rodés-Cabau about the management of these patients in the absence of advanced conduction disturbances during the hospitalisation period and contrasts with the results observed in the presence of new-onset LBBB post-TAVI [which is associated with an increased risk of permanent pacemaker implantation and sudden cardiac death in the months after the procedure]”, they add.

In terms of the implications of their study, Fischer et al comment that these results “should be taken into account of the preparation of TAVI procedures considering the use the valve type associated with a lower risk of conduction disturbance issues and a high (more aortic) transcatheter valve positioning in those patients with pre-existing LBBB to decrease the permanent pacemaker implantation after TAVI”.

Study investigator Josep Rodés-Cabau (Quebec Heart and Lung Institute, Laval University, Quebec City, Canada) told Cardiovascular News: “Pre-existing LBBB should be included as a risk factor for PPI early post-TAVI. However, pre-existing LBBB in TAVI recipients was not associated with increased mortality or heart failure hospitalisation at two-year follow-up, and there were significant improvements in LVEF in most patients. This suggests that the possible use of specific therapies including cardiac resynchronisation therapy (CRT) should be delayed by several months in order to avoid implementing unnecessary treatment. Future studies should determine the longer term outcomes of such patients.”

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TAVI-proof procedures and device designs Vratika Agarwal Vinayak Bapat Comment & Analysis 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. Increasingly, transcatheter heart valves are also being used for novel applications when conventional treatments are either not possible or considered too high risk. One of such application has been valve-in-valve therapy. During a valvein-valve procedure, a transcatheter heart valve is implanted within a failing bioprosthetic surgical heart valve. In this commentary, Vratika Agarwal and Vinayak Bapat discuss the need to consider future valve-in-valve procedures when implanting a surgical valve.

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n early experiences, the outcome of TAVI valve-invalve procedures has been excellent and has added advantages vs. redo surgical procedures—such as short procedure time and a less invasive procedure; hence, early recovery. Initially, only failing aortic surgical heart valves were treated with this technique but now the experience has expanded to structurally deteriorated surgical heart valves in the mitral, tricuspid and pulmonic position. Additionally, failed mitral or tricuspid valve repairs with annuloplasty rings can now be treated with a valve-in-ring procedure, whereby the transcatheter heart valve is implanted and anchored within a mitral ring.

As with any other treatment, the initial experience has been in carefully selected high-risk patients, but now most patients are considered for a valve-in-valve or valve-in-ring option. This will become increasingly relevant soon as, in the Western world, the majority of the patients prefer a biological valve and age cutoff for mechanical vs. biological valve can be as low as 50 years. The main premise of considering valve-in-valve is to avoid another open-heart surgery. However, achieving a good long-term result is of paramount importance.

Thus, understanding the limitations of valve-in-valve and valve-in-ring are essential to help prepare a platform conducive to a future transcatheter option.

can be modified is radio-opaque marking of the annulus after stentless valve implantation. This allows for visualisation of the valve during future procedures.

These changes in surgical practice were initially slow but have since increased with growing participation of surgeons in the transcatheter field.

With the increased use of transcatheter heart valves within failed mitral bioprosthetic surgical heart valve and rings as valve-in-valve/valve-in-ring approach, some unique problems have come to attention. One of them is the suboptimal result of valve-in-ring when compared with valve-in-valve. Surgical mitral rings are of various types and vary in their construct and design.

They can be: Rigid, semi-rigid or flexible Complete or incomplete And can vary in degree of visibility under fluoroscopy.

Of the 20 commercially available implantable rings, only nine rings are TAVI friendly as they can adapt a near-circular shape and can provide a secure anchor to

The need to be TAVI friendly

One of the main issues associated with valve-in-valve therapy is the “Russian Doll” effect. As the transcatheter heart valve is implanted within a pre-existing surgical heart valve, its expansion and its function is entirely dependent on the “internal diameter” of the surgical valve. Literature has shown that smaller surgical valves have worse long-term results. Hence, one solution is expansion of the surgical heart valve size by using certain surgical techniques. Another common issue is proper identification of the degenerated surgical heart valve, i.e. type and size. Fortunately, most surgical valves have a unique footprint when visualised under fluoroscopy and type of surgical heart valve can be readily identified, but not size. Size of the surgical heart valve is the most critical piece of information as it dictates the size of the transcatheter heart valve.

Measurements of the surgical heart valve with computed tomography (CT) and echocardiography are not standardised and can lead to an error. A surgical heart valve with size markers allows for the valve size to be identified easily under X-ray and is highly beneficial.

Design modifications of the new generation surgical heart valve that allow for future implantation of the transcatheter heart valve when chosen during the first surgery can make valve-in-valve procedure at a later date easy to plan and execute. One of the first surgical

Figure 1: Magna Ease vs. Inspiris. You can readily see the size of the valve under fluoroscopy. Figure also depicts basal expansion zone.

Figure 2: Various types of valvuloplasty rings available and their effect on sapien valve after full deployment.

heart valves designed to be TAVI friendly has been the Inspiris valve (Edwards Lifesciences) pericardial valve (Figure 1). This surgical heart valve has a possibility of expansion of the basal band, which results in an increase in the stent internal diameter. We are bound to see more and more of valves that are designed to adapt to this idea.

There are certain scenarios in which modified surgical techniques can have a huge impact on the feasibility of valve-in-valve/valve-in-ring at a future date. One such scenario is a surgical patient with small aortic annular dimensions. Implanting a small-sized valve during the first surgery makes the future vavle-in-valve result suboptimal. Hence, procedures such as a “Root enlargement” should be performed to implant a larger surgical heart valve. This is especially important in younger patients who choose a bioprosthetic surgical heart valve, as their likelihood of outliving the surgical heart valve life is high and re-intervention is near certain. Another scenario in which surgical techniques

the transcatheter heart valve (Figure 2). Studies have shown favourable results with the use of TAVI friendly rings. Thus the question, can surgeons implant a ring that is TAVI friendly rather than one that is not during mitral valve repair surgery?

Increasing awareness is the key to future transcatheter heart valve success.

Conclusion

To be able to use the transcatheter heart valve to their fullest potential as a future strategy, modification of surgical technique at the time of first open heart surgery and design adjustments of the surgical valves and rings to accommodate transcatheter heart valve devices will prove to be critical.

Vratika Agarwal and Vinayak Bapat are at New York Presbyterian/Columbia University Medical Center, New York, USA

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One-year results of VIVA confirm safety and efficacy of valvein-valve procedures with CoreValve Speaking at PCR London Valves 2018 (9–11 September, London, UK) Didier Tchétché (Clinique Pasteur, Toulouse, France) reported that the one-year results of the VIVA (valve-in-valve) trial support previous 30-day findings that transcatheter valve-in-valve procedures with the CoreValve/CoreValve Evolut R device (Medtronic) are safe and effective for patients with failing bioprosthetic valves who were unable to undergo redo surgery.

VIVA WAS AN observational, singlearm, postmarket multicentre study that evaluated valve-in-valve procedures with CoreValve/CoreValve Evolut R. The primary safety endpoint was the rate of cardiovascular death at 30 days and the primary efficacy endpoint was the lack of significant stenosis or insufficiency at one year. Given the 30-day results have already indicated that valve-invalve procedures with the CoreValve devices are safe and effective, the aim of the present analysis was to see if the one-year results confirmed these findings and to assess the incidence of the primary efficacy endpoint.

At one year, follow-up data were available for 173 patients of 202 initially

enrolled (most of whom had received the CoreValve Evolut R device). The rate of all-cause mortality was 8.8% and the rate of cardiovascular mortality was 5.6% (at 30 days, the rates of these endpoints were 2.5% and 2.5%, respectively). The rate of all stroke was 6.2% and the rate of disabling stroke was 0.6%. There were no significant differences in mortality between patients who had received a smaller valve (≤21mm) and those who had received a larger valve: 8.5% vs. 9% respectively (p=0.98).

At one year, 98.9% of patients met the primary efficacy endpoint (lack of significant aortic stenosis/insufficiency).

Of these patients, 99% met the criteria for lack of significant aortic stenosis

CoreValve

(mean gradient >40mmHg) and all met the criteria for lack of aortic insufficiency (> moderate severity). Furthermore, the proportion of patients with New York Heart Association (NYHA) Class IV reduced from 16.2% at baseline to 1.3% at one year. The proportion of patients in NYHA Class I increased from 3.5% at baseline to 46.5% at 12 months.

Tchétché concluded: “The one-year results from the VIVA trial confirm consistent safety and efficacy results for valve-in-valve interventions using a self-expanding CoreValve/Evolut R for failed surgical bioprosthesis. Excellent haemodynamics were observed in various types of degenerated surgical bioprosthesis.”

Durable tricuspid regurgitation reduction with MitraClip Data from the TriValve Registry—an international multicentre, retrospective, multidevice registry evaluating interventional tricuspid repair— indicate that interventional edge-to-edge repair (MitraClip, Abbott) to manage patients with tricuspid regurgitation is associated with a high rate of procedural success, durable tricuspid regurgitation reduction at one-year, and significant symptomatic improvement.

SPEAKING AT THE 2018 Transcatheter Cardiovascular Therapeutics (TCT) meeting (21–25 September, San Diego, USA), Jörg Hausleiter (LudwigMaximilians Universität München, Munich, Germany) commented while MitraClip has been “successfully applied with off-label/compassionate use programmes in selected patients”, the impact of the approach on clinical outcomes beyond 30 days was unknown.

Therefore, Hausleiter and colleagues performed a subgroup analysis of patients who received the MitraClip in the TriValve registry. The main outcome measures were all-cause mortality, unplanned hospitalisations, NYHA Class, presence of peripheral

oedema, and tricuspid regurgitation. Of 249 patients who received MitraClip in the registry, 77% had a successful procedure. Hausleiter reported that the independent predictors for procedural failure included jet location of the tricuspid regurgitation and the tricuspid regurgitation effective regurgitant orifice area.

At one year, 79.7% of patients were still alive.

Furthermore, 65.3% were free from mortality and unplanned hospitalisation for heart failure. Also, significantly more patients who had a successful procedure were free from mortality/rehospitalisation for heart failure compared with those who had a failed procedure: 70.1% vs. 49.7% (log rank p<0.001). This

TMVI with Tiara valve may be safe and feasible for patients with prior aortic valve replacement A new study indicates that transcatheter mitral valve implantation (TMVI) with the Tiara valve (Neovasc) can be safely and successfully implanted in patients with pre-existing aortic valve replacement.

ANSON CHEUNG (St Paul’s Hospital, University of British Columbia, Vancouver, Canada) and others write in Circulation: Cardiovascular Interventions that compared with transcatheter aortic valve implantation (TAVI), TMVI “seems to be more complex and more challenging”. They add that one of the challenges is the risk of LVOT obstruction and this risk may be higher in patients who have previously undergone some form of aortic valve replacement (whether

via surgery or via TAVI) “because patients with prior aortic stenosis often have left ventricular hypertrophy and small left ventricular cavity, and the frame of the prosthesis can extend into the LVOT”.

Furthermore, Cheung et al observe that the anchoring mechanism of a TMVI device “may interfere with the proper functioning of an aortic prosthesis”, meaning that “aortic prostheses have been considered a relative contraindication to TMVI”.

meant that procedural failure was an independent predictor of mortality, which Hausleiter suggested meant “edge-to-edge repair might impact survival in this highrisk patient population”.

There was a significant improvement in NYHA Class with 69% of patients in NYHA Class I or II by one year (most patients were in Class III or IV at baseline). The percentage of patients with peripheral oedema reduced from 84% at baseline to 26% at follow-up.

“The valve repair resulted in a durable tricuspid regurgitation at one-year follow-up, which was associated with a significant symptomatic improvement,” Hausleiter concluded.

However, the authors state that the Tiara valve has been designed to “match the natural orifice of the mitral valve, avoiding impingement of the LVOT and to prevent any interference with the aortic valve or prosthesis”. Therefore, in this present study, they assessed the periprocedural and short-term outcomes of 12 patients with prior aortic valve replacement and with mitral regurgitation who underwent TMVI with the Tiara device. All patients in the study were at high surgical risk and unsuitable for alternative mitral valve repair or replacement therapies.

Cheung et al report that all 12 Tiara procedures were completed successfully and uneventfully, with no conversion to open heart surgery or need for mechanical haemodynamic support. They add that mitral regurgitation was eliminated immediately after implantation and “the degree of mitral regurgitation at predischarge and at 30-day follow-up echo was none or trace”. There were no deaths, myocardial infarctions, strokes, bleeding or need for pacemaker implantation at

either the periprocedural stage or at the 30-day follow-up stage. According to the authors, no left ventricular outflow tract (LVOT) obstruction was observed in any of the patients.

They conclude: “TMVI with the Tiara valve in patients with pre-existing aortic valve prosthesis was safely and successfully implanted and was not associated with LVOT obstruction or with any mechanical or haemodynamic interference. The design of this device affords a stable and predictable implantation, representing a reasonable alternative to treat this particular subset of patients.”

Cheung says: “The Neovasc Tiara TMVI device has a unique valve design— the D-shaped valve is less protrusive into the LVOT and the anchoring tabs capture the anterior leaflet, eliminating the risk of systolic anterior motion, causing LVOT obstruction. Additionally, the two anterior tabs bisect the LVOT and do not interfere with the pre-existing surgical aortic valve prosthesis.”

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Interview

Profile

Robert W Yeh Robert W Yeh (Department of Medicine, Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA) believes that it is a “humbling privilege” that patients put so much trust in the judgement and ability of physicians. He talks to Cardiovascular News about his diverse range of interests in interventional cardiology from complex coronary interventions to health services research, which includes his work on developing the dual antiplatelet therapy (DAPT) Score, the PARACHUTE Trial, and evaluating national health policies.

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

The idea of being able to help people at the time of their greatest need was initially what attracted me to the medical profession, and specifically to interventional cardiology. There is certainly a profound sense of satisfaction in being able to reverse the course of a potentially fatal presentation, such as ST-segment elevation myocardial infarction (STEMI) or to provide someone with relief from debilitating angina. On top of that, so much of what we do as physicians involves serving as faithful agents, advisors and counsellors for our patients and their families. There are not too many professions in which you get to spend your day doing everything you can to help someone through something difficult physically and emotionally. Patients place so much trust in our judgment and ability. It is a humbling privilege.

Who have been your career mentors?

There have been so many. IK Jang (Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, USA) was really the first person to pique my interest in cardiology research, and I chose to combine research and interventional cardiology in large part because of his mentorship. Laura Mauri (Vice President, Global Clinical Research & Analytics, Medtronic) has been an incredible role model in her leadership of clinical trials. I look to Rob Gerszten and Peter Zimetbaum (both Harvard Medical School; Beth Israel Deaconess Medical Center, Boston, USA) as sounding boards and confidants almost every day.

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

The field is so dynamic and it is hard to pick just one!

Transcatheter aortic valve implantation (TAVI) came to market at the time of my fellowship and has been so disruptive, and the field of chronic total occlusion percutaneous coronary intervention (PCI), which is what I spend much of my clinical time doing, has also advanced tremendously. But I am going to go out on a limb and say that interventional cardiology engagement on social media will have a growing and substantive impact on providing educational content to rank and file interventionalists, increase engagement of a much broader group into evidence development, expose the field to more public scrutiny and accountability (often a good thing), and create patient-centred norms for our practice.

What has been the biggest disappointment?

I have two. The first disappointment has to do with the consistent misinterpretation of evidence that happens in our field, often used to justify our pre-existing beliefs.

This happens on “both sides” of most debates, and it is often exacerbated by media eager for a sound bite. There is so much low quality evidence that is being produced that we can all find a study that seems to support our

practice if we look hard enough. We should have higher standards than that.

The second, related area is the growing body of non-evidence supported health policies that surround cardiovascular care—policies (in the USA at least) such as public reporting of PCI mortality statistics and 30-day readmission metrics and penalties. I have spent a fair amount of time studying the potential unintended consequences of policies such as these, and they occur frequently. Moving forward, we ought to hold health policies to the same standard that we hold new medications or devices—both cost the healthcare system money and have potential adverse consequences that can hurt patients.

Of the research you have been involved in, what do you think has had (or will have) the greatest impact on clinical practice?

Thus far, the creation of the DAPT Score has probably had the most impact on clinical practice of the projects I have been involved with. I have had a lot of feedback from cardiologists around the world letting me know that they have found it very useful in clinical care. The PARACHUTE trial, a satirical study in the BMJ, has been by far our most popular study, and probably will be the most cited paper I ever work on—but I hope does NOT change skydiving practices! Finally, we’ve recently published a paper in JAMA about readmissions policies in the US that could potentially impact the manner in which future policies are created and evaluated – we are in the midst of discussing the implications of our findings with policymakers in Washington currently.

Several of the studies you have been involved in have focused on DAPT, including the development of the DAPT Score. What is your approach to ensuring a patient receives optimum DAPT?

I think the first thing to appreciate is that there is no “free lunch”. Longer duration of DAPT means more bleeding problems, but it also means fewer ischaemic events.

There has been this movement to shorten DAPT duration to fewer and fewer months, which I think is a mistake for many patients. I try to practise what I preach, which means estimating the DAPT Score in my head for all patients getting PCI, and combining that with clinical judgment and patient preference to determine what might be a good DAPT regimen for any individual patient.

What are your current research interests?

I am currently leading the NIH-sponsored EXTEND Study to merge several clinical trials with a diverse set of clinical and administrative claims databases to help validate the use of alternative sources of passively collected data to support clinical trials. There has been much discussion of designing more efficient ways to collect data on patients in clinical trials, but much less validation work to ensure that such an approach is both

feasible and accurate. We hope this work can lend insight into newer ways of assessing therapeutic efficacy in trials.

We also have a growing body of work evaluating national health policies and their consequences. It is surprising how little work there is evaluating health policies that is actually led by physicians on the ground floor who are taking care of patients most affected by these policies. We try to bring an everyday cardiologist’s perspective to much of the health policy evaluation we do, which I think has been missing.

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Interview

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Fact File

nutshell, the ability to give nearly an equal voice to all participants, to engage with experts from around the world directly, to consume and disseminate new information in near real time—these are powerful attributes of social media and in particular Twitter. Of course, conversations can degenerate into virtual shouting and name calling and there tends to be perhaps less civility on Twitter than you might see at a scientific meeting. Sometimes inaccuracies get propagated quickly. I think the advantages greatly outweigh the disadvantages though.

What was your most memorable case?

I do not want to give too many details, so as not to identify the patient, but there was a young woman who had terrible multivessel spontaneous coronary dissections. She was actually undergoing a catheterisation in a room next to the one I was working in when an emergency code was called because her vessels were shutting down and she was beginning to arrest. My colleague asked for help, and thankfully, we were able to use some techniques we often use in chronic total occlusion PCI to restore flow, and stabilise her. She ended up doing well. Her young family was terrified, sitting together in the waiting room—there were many tears and emotional embraces shared nearly daily as she slowly recovered. It was an experience that really showed me the importance of merging technical competence, clinical judgment and compassion. It was a really powerful experience.

What advice did you receive at the start of your career that you now pass on to those who you mentor?

David Torchiana (the now CEO of Partners Healthcare) told me many years ago about this simple framework he learned to think about his daily work. Everything can be placed on two axes. The first is the axis of importance, and the second is the axis of urgency. Things that are urgent and important —like a family health emergency—obviously those things need to rise to the very top of our priorities. Things that are non-urgent and unimportant—we might as well push those things down the list. But our ability to prioritise accomplishing things that are important, but not necessarily urgent over things that are not important, but urgent—that ability is constantly being challenged, but crucial for success and happiness. It is a great lesson that we constantly need to remind ourselves.

You are an active member of #CardioTwitter. What are the advantages and disadvantages of using social media to discuss interventional cardiology?

There is a lot to bite off here, and I have written an article in Circ Outcomes describing in more detail what I think are the real strengths and weaknesses of cardiologist engagement in social media (Yeh RW. Circ Cardiovasc Qual Outcomes 2018. Epub). In a

Outside of medicine, what are your hobbies and interests?

Family time is my priority outside of the hospital. My wife and I have three wonderful children and we love spending time together, and with our extended group of friends we call our Boston Family—old friends from college, medical school and training. My wife and I and our two older kids all really love snowboarding together.

We are waiting for the little one to learn how to walk first before indoctrinating him into our favourite winter pastime.

Current appointments

2017–present: Associate chief, Interventional Cardiology, Beth Israel Deaconess Medical Center, Boston, USA 2017–present: Director of Complex Coronary Intervention, Beth Israel Deaconess Medical Center, Boston, USA 2015–present: Director, Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center, Boston, USA. Centre is devoted to outcomes research in three primary areas—health policy evaluation, comparative effectiveness research, and use of novel sources of data for risk prediction

Training

July 2009–June 2010: Fellow, Interventional Cardiology Massachusetts General Hospital, Boston, USA July 2006–June 2009: Cardiovascular Disease University of California, San Francisco, USA July 2004–June 2006: Internal Medicine Massachusetts General Hospital, Boston, USA 1999: Masters in Business Administration (with Distinction), University of Oxford, Oxford, UK 1998: Masters in Health Policy, London School of Economics/Hygiene and Tropical Medicine, London

Society memberships

2014–present: Fellow of the American Heart Association, on Council on Quality of Care and Outcomes Research and on Council on Epidemiology and Prevention 2012–2015: Fellow, Society for Cardiovascular Angiography and Interventions 2011–present: Fellow of the American College of Cardiology

Editorial posts

2013–present: Associate editor, editorial board, Circulation: Cardiovascular Quality and Outcomes

Awards

2018: Harvard Medical School Young Mentor Award 2015: Young Physician-Scientist Award American Society for Clinical Investigation (ASCI)

Publication

Yeh R et al. Parachute use to prevent death and major trauma when jumping from aircraft: randomised controlled trial. BMJ 2018. Epub.

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Innovation

BIBABriefings Table 1

ACCORDING TO A BIBA MEDTECH survey, the device used for complex percutaneous coronary intervention (PCI) procedures differs depending on the lesion that is being treated. For bifurcations, respondents (53 in total) most frequently report using a stent from the Resolute range (Medtronic).

But with left main, respondents (51 in total) most frequently report using a stent from the Xience range (Abbott). However, for all lesions, Resolute and Xience devices are always the top two most frequently reported devices. See Table 1.

Orsiro (Biotronik) is the third most frequently reported device for nearly all complex lesions.

However, this “third place” position is shared with Synergy (Boston Scientific) for chronic total occlusions and shared with both Synergy and with Ultimaster (Terumo) for heavily calcified lesions.

With ostial lesions, Biomatrix (Biosensors) has the position of third most frequently reported device. Of note, all of these devices have a

Lesion type

Stent

B

CTO

HCL

LM

O

Resolute

30%

22%

31%

36%

31%

Xience

28%

29%

37%

38%

37%

Orsiro

21%

12%

10%

11%

6%

Synergy

9%

12%

10%

8%

6%

Ultimaster

4%

8%

10%

2%

2%

Biomatrix

8%

6%

6%

2%

10%

Promus

6%

10%

2%

6%

8%

Any device

4%

4%

2%

4%

2%

Other*

2%

2%

2%

2%

0%

Total respondents

53

49

51

51

51

Lesion determines device choice in complex disease biodegradable polymer whereas Resolute and Xience are permanent polymer devices.

The least frequently reported devices were Cre8 (Alvimedica), Xposition S (Stentys), and the Tryton side-branch stent (Tryton Medical)— all coming under the category of “other” in Table 1. Given that Tryton was specifically designed to treat bifurcations, operators are unlikely to report using it for any other lesions.

But even in the context of bifurcation, only 2% of respondents claim to use it.

Overall status of complex PCI

The BIBA MedTech survey also shows that of 16,260 PCI procedures performed (at the centres of survey respondents), 6,452 were for complex lesions. Of these, 2,476 (38%) were bifurcations, 1,081 (17%) were heavily calcified lesions, and 949 (15%) were for ostial lesions.

See Figure 1.

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* includes Cre8, Tryton and Xposition S; B = bifurcation; CTO = chronic total occlusions; HCL = heavily calcified lesions; LM = left main; O = ostial

BIBA Briefings

BIBA Briefings is a new platform that provides in-depth analysis of the latest market intelligence from BIBA MedTech, which provides consulting and market analysis services to medical professionals and organisations in the medical device industry in Europe and North America. The platform also reviews data and news.

The aim of every report is to give an overview of the key information affecting the medical device industry, enabling those working in the industry to keep abreast of the latest developments and make knowledgeable decisions. BIBA Briefings cover both percutaneous coronary intervention (PCI) and transcatheter aortic valve implantation (TAVI).

For more information about BIBA Briefings or BIBA MedTech, please contact Elizabeth Sutherst: elizabeth@bibamedical.com

AI will aid, not replace, interventional cardiologists

Over the past few years, artificial intelligence—or “AI” as it is more commonly known—has had somewhat of a rebranding from a futuristic theory only seen in science fiction to a real concept that is increasingly being seen in everyday life. But fortunately, the notion of a Skynettype AI that plots to destroy humanity and take over the world has not materialised (well, not yet at least). In fact, many believe AI to be a positive development.

WRITING IN THE Journal of the American College of Cardiology, Kipp W Johnson (Institute for Next Generation Healthcare, Mount Sinai Health System, New York, USA) and colleagues say that AI promises to provide a “set of tools to augment and extend the effectiveness of the cardiologist”. They add that physicians are being “inundated with data requiring more sophisticated interpretation while being expected to perform more efficiently”.

Certainly, data interpretation appears to be the focus of cardiology-based AI software that has emerged in the last year.

The charity Heart Research UK recently announced it had awarded a Novel and Emerging Technologies Grant of almost

£250,000 to Jack Lee (King’s College London, London, UK) and colleagues to develop a new AI test for diagnosing coronary artery disease. According to a press release, the goal is for the AI software to identify patterns from blood flow stimulations in thousands of coronary arteries and “learn” how the geometry of the narrowings affects the pressure pattern. The press release states that there are “already accurate methods to stimulate the blood flow through blood vessels but they are time consuming and require special training to perform”.

Lee comments: “The successful outcome of this research may help doctors decide on the best treatment for coronary heart disease using a test with reduced

risk and less discomfort for patients.”

Also, the start-up company Ultromics has revealed it is now supporting trials of its AI product EchoGo in the USA as well as in the UK (where it is based).

A press release reports that, with the ongoing studies, Ultromics “intends to prove that EchoGo is the world’s most accurate echocardiography-based tool for the diagnosis of coronary artery disease”. It adds that the tool uses “deep learning” and one of the world’s largest echo databases to deliver “greater accuracy in both sensitivity and specificity” than current approaches.

According to the press release, the technology has the potential to reduce the incidence of patients undergoing

unnecessary procedures and reduce the number of those who require intervention being sent home.

It is not just universities and startup companies that are exploring the role of AI in the cardiovascular field.

Edwards Lifesciences is to collaborate with Bay Labs. According to Bay Labs, the partnership will involve multiple initiatives and this includes the “development of a new AI-powered algorithms in Bay Labs’ EchoMD measurement and interpretation software suite, the integration of EchoMD algorithms into Edwards Lifesciences’ CardioCare quality care navigation platform, and support for ongoing clinical studies at leading institutions”.

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Transcatheter valves

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ADVERTORIAL

“We are now at a new era of TAVI where we have very high rates of device success” At the 2018 Transcatheter Cardiovascular Therapeutics (TCT) meeting (21–25 September, San Diego, USA), Azeem Latib (IRCCS San Raffaele Scientific Institute, Milan, Italy) reported that the NEOPRO Registry shows that both ACURATE neo™ (“NEO”, Boston Scientific) and CoreValve Evolut™ PRO (“PRO”, Medtronic) are associated with a high rate of device success and good clinical outcomes.1 These results, according to Latib, indicate that we are now at a stage where “we have really good valves” and can start to choose a transcatheter aortic valve implantation (TAVI) device that is most appropriate for a patient’s anatomy.

P

rior to the NEOPRO Registry, data for direct valve-to-valve comparisons were sparse.

Additionally, of the data that are available, the comparisons feature older-generation TAVI devices—such as SAPIEN XT (Edwards Lifesciences) or CoreValve (Medtronic). Therefore, Latib and colleagues wanted to review newer transcatheter heart valves for which comparison data were not available. “We looked at Boston Scientific’s ACURATE neo and the latest generation of Medtronic’s CoreValve (Evolut PRO),” Latib tells Cardiovascular News. He notes that an ongoing randomised controlled trial (SCOPE II) is already comparing ACURATE neo with both the earlier iteration CoreValve Evolut R and the new Evolut PRO. As SCOPE II is a randomised controlled trial and NEOPRO is a registry, the studies will provide different insights into how the two valves compare. Registry data, Latib explains, are valuable because they reflect every day practice, and he comments: “Sometimes, randomised controlled trials are restrictive because of their inclusion and exclusion criteria.

We always have to be sure that in clinical practice, we can produce similar outcomes to those seen in trials. Hence, the need for real-world data”.

In the NEOPRO Registry, Latib et al reviewed data for 1,551 patients who underwent TAVI with either ACURATE neo or Evolut PRO at 24 centres in Europe, Canada, and Latin America between January 2012 and March 2018. Reflecting that Evolut PRO is a latest-generation device and, thus, has not been on the market for as long as ACURATE neo, substantially fewer patients were implanted with this device: 288 vs. 1,263 for ACURATE neo. That Evolut PRO is a latestgeneration device may explain why operators tended to use the valve in more complex patients than they did the ACURATE neo. For example, significantly more Evolut PRO patients had severe aortic valve calcification (p<0.001 for the comparison).

Subtle differences in overall cohort

The primary endpoint of the NEOPRO study was the rate of device success according to Valve Academic Research Consortium (VARC-2) criteria and was not significantly different between

groups: 92% for ACURATE neo vs.

90.7% for Evolut PRO. However, the rate of the VARC-2 30-day safety composite endpoint (a secondary endpoint) was significantly higher in patients who received ACURATE neo: 16.4% vs. 10.9% for Evolut PRO (p=0.025). This finding was driven by a significantly higher rate of all vascular complications due to a higher rate of minor bleeding with ACURATE neo (17.1% vs. 11.6%, respectively; p=0.025).

According to Latib, vascular complications may be higher with ACURATE neo because its delivery system has a higher French size than the one for Evolut PRO (18F outer diameter vs. 16F, respectively) and was used with older generation introducer sheaths. The effects of this higher French size, though, could potentially be mitigated with the new 14F iSLEEVE™ expandable introducer sheath (Boston Scientific). Latib observes that this sheath was not available when he and his colleagues conducted the NEOPRO registry and he is “convinced” that the difference in vascular complications between ACURATE neo and Evolut PRO “would have disappeared” had the new sheath been used. “The 14F iSLEEVE is an expandable sleeve, which reduces the French size to 14F. If you put in a smaller sheath, you make a smaller hole in the artery. We know that with all interventional cardiology procedures, the bigger the sheath is, the bigger the hole, the more patients bleed,” he explains.

Another notable difference between ACURATE neo and Evolut PRO in NEOPRO, says Latib, is the difference in pacemaker rates: 8.8% vs. 13.2% for Evolut PRO (p=0.045). He comments that “one of the things” that is reassuring about ACURATE neo is that it has a “single digit” pacemaker rate, adding that there are two possible reasons that explain why the pacemaker rate was better with the valve—lower radial strength and, more importantly, depth of implantation. “One of the variables that we now know affects pacemaker rates is how deep a valve is implanted into the left ventricular outflow tract. The deeper the valves goes, the higher the risk of requiring a pacemaker because it is closer to the atrioventricular node. With ACURATE neo, the implantation is always at the same level. With Evolut PRO, it is more

Azeem Latib

ACURATE neo

dependent on the operator trying to get a higher implantation,” Latib states.

He comments that, in the registry, the rates of moderate paravalvular leak, “which is what we really care about”, were low and “almost identical” for the two devices (5.1 for ACURATE neo. vs.

5.4 for Evolut PRO). However, more patients in the Evolut PRO group had trace/none paravalvular leak than for the ACURATE neo group. While the rates of paravalvular leak with ACURATE neo were low, they may further reduce with the next-generation device ACURATE neo2™. This device has a higher pericardial skirt and this should reduce the rate of paravalvular leak, but, as Latib observes, further data are needed before this can be ascertained. Initial results from the CE-mark study for ACURATE neo2 do show 97% of patients had mild or no/trace paravalvular leak at 30 days (no patients had more than moderate paravalvular leak), but these findings need to be confirmed.2

In this propensity-matched analysis, there were no significant differences in any of the outcomes between cohorts (device success was still high in both groups), including vascular complications and pacemaker rates.

Interestingly, the pacemaker rate increased to 11% in the ACURATE neo cohort (vs. 12.8% for Evolut PRO).

Latib says he was “not surprised” that the rate increased in this cohort because the patients in the propensity-matched analysis were more complex with more calcification (i.e. the higher pacemaker rate relates to the characteristics of the patient rather than the valve). He comments: “Subtle differences in procedural characteristics [pre and post dilatation was higher with ACURATE neo] and clinical outcomes highlight the different design features of the two valves. After adjustment for potential confounders, short-term outcomes were similar between both devices.”

Comparable outcomes in propensity-matched analysis

Latib thinks that the results of the NEOPRO Registry, along with those of other TAVI studies, show that “we are now in a new era of TAVI where we have very high rates of device success with much lower rates of paravalvular leakage and good clinical outcomes”.

He suggests that the availability of several valves with good clinical outcomes on the market means that we are reaching a point at which we can start “tailoring the valves to the patient”, noting an experienced centre (such as his) can now use the valve that is most appropriate for the patient’s anatomy.

As mentioned, the Evolut PRO valve tended to be implanted in more complex patients than the ACURATE neo valve.

Latib et al felt that this led to certain differences (such as more patients having more severe aortic calcification in the Evolut PRO group) between cohorts that could have affected the results. Latib explains: “When we saw these differences, we realised it would not be appropriate to just do an analysis of the entire population. We also needed to do an analysis that corrected for some of these differences. Therefore, we performed a propensity-matched analysis.”

Conclusion

References 1. Latib A. NEOPRO Registry. TCT 2018 presentation.

2. Kim WK, et al. PCR Valves 2018 presentation.

CAUTION: The ACURATE neo aortic valve system is CE marked. In the USA, it is an investigational device—limited by US law to investigational use only; not available for sale. The ACURATE neo2 aortic valve system is an investigational device only; not available for sale. Boston Scientific sponsored this advertorial.

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Renal denervation

The resurgence of renal denervation Philipp Lurz Comment & Analysis More than ever before, arterial hypertension represents one of the greatest health threats and challenges for both patients and treating physicians. With the new adjustment and narrowing of blood pressure targets for antihypertensive treatment, the number of patients with uncontrolled hypertension is increasing.

Importantly, despite advances in drug therapy, reality proves that adherence to medication is very limited, worsens with increasing number of drugs and is difficult to predict. Consequently, nonpharmaceutical, interventional treatment options bear the hope of adding a “one-stop-always-on” therapy to the vast but still not efficient armoury against hypertension. In this commentary, Philipp Lurz reviews the latest evidence for renal denervation and whether it is starting to live up to its initial promise.

R

enal denervation is one of several innovative device-based interventional therapies that is aiming for better blood pressure control.

It is safe, minimally invasive, and does not leave any implants behind. The effectiveness of this procedure, however, is still subject to fierce debate and controversy.

The available evidence

Recently, the SYMPLICITY ON/OFF MED (Medtronic) and RADIANCE SOLO (ReCor Medical) trials indicated a significant reduction in ambulatory blood pressure with renal denervation (with the Sypral and Paradise systems respectively) vs. a sham procedure.

These trial programmes were influenced by the painful experience of the neutral SIMPLICITY HTN-3 trial, which failed to show an efficacy benefit with the firstgeneration Symplicity system, and show substantial similarities in study design

and patient selection.

Most importantly, both programmes implemented a very thorough protocol— including a roll-in period, witnessed pill intake, serial ambulatory blood pressure monitoring (ABPM) measurements, screening for drug adherence, and inclusion of drug-naive patients. These protocol specifications were implemented to reduce major confounding effects of changes in antihypertensive medication and to minimise effects such as regression to the mean or Hawthorne.

Consequently, in these recent trials, very little blood pressure reduction was observed in the sham procedure group and the reduction that did occur was significantly less than that seen in the renal denervation groups, supporting the overall concept of the procedure.

These positive results were achieved in both drug-naive patients and patients on one to three antihypertensive drugs.

A truly therapy resistant population

is being investigated within the RADIANCE TRIO trial (standardised medication using a three-combination polypill) and the results of this study are eagerly awaited (due 2019). Until then, the question of who represents the ideal target for renal denervation remains unanswered. A previous analysis suggested that renal denervation is less effective in isolated systolic hypertension than in combined systolic and diastolic hypertension, leading to exclusion of patients with isolated hypertension in the latest trials. However, there is evidence that subgroups of such patients can benefit from renal denervation equally.

A randomised controlled trial focusing on patients with isolated systolic hypertension is needed to clarify the role of renal denervation in these patients.

In summary, there is sound evidence about the effectiveness of renal denervation in drug-naive patients with probable mild and early stage hypertension—a group of patients with projected low cardiovascular risk—but there are still some uncertainties in patients with truly resistant hypertension (RADIANCE TRIO cohort). In the meantime, patients with uncontrolled hypertension despite the intake of some antihypertensive drugs (Symplicity ON MED cohort) and an intermediate cardiovascular risk should represent the most appropriate target for renal denervation.

Current technology

The technology and technique used for renal denervation needs consideration when interpreting study results. Currently, denervation is either performed using radiofrequency energy (Symplicity, Medtronic) or ultrasound energy (Paradise, ReCor Medica). The latter is believed to achieve a penetration depth of 6mm, which is the expected location of sympathetic nerves in the adventitia of the main renal artery. In contrast,

the procedural specifics applied in the SPYRAL HTN-OFF MED and ON-MED trails included the use of a spiral catheter with ablations delivered in the main and branch renal arteries, based on the finding that sympathetic nerves run closer to the lumen within the branch renal arteries and therefore more amenable to renal denervation.

Results of recent trials suggest that both strategies are effective and safe, however, comparisons of different techniques and technologies are scarce.

At the 2018 Transcatheter Cardiovascular Therapeutics (TCT) meeting (21–25 September, San Diego, USA), I presented the results of the RADIOSOUND trial.

This study compared radiofrequency main renal artery ablation vs. radiofrequency main and branch renal artery ablation vs. ultrasound ablation in the main renal artery only. With all three approaches, a significant reduction in blood pressure was achieved.

Endovascular ultrasound based renal denervation was found to be superior to radiofrequency ablation of the main renal arteries only, whereas a combined approach of radiofrequency ablation of the main arteries, accessories and side branches was not. Numbers in this trial are small (40 patients in each treatment arm) and no definite recommendations about the preferred technology and technique for renal denervation could be given. Overall, the positive results of the second-generation trials helped renal denervation to resurrect as a hopeful therapy for hypertension. Important tasks for the future include refinements in patient selection and technique as well as establishing a measure of procedural success for renal denervation, which at present is still an interventional unknown.

Philipp Lurz is at the Department of Cardiology, Heart Center Leipzig, University of Leipzig, Leipzig, Germany

More work needed to “untangle the reasons” for gender gap in cardiovascular research

Writing in Circulation: Cardiovascular Quality and Outcomes, David Ouyang (Stanford University, Falk Research Center, Palo Alto, USA) and others report that while the number of female first and senior authors of cardiovascular research papers has increased over the past four decades, women continue to be poorly represented as first authors, senior authors, and in the number of publications. They say further work is needed to understand why there continues to be a gender gap in cardiovascular research.

THE INVESTIGATORS COMMENT that despite the growth of female medical students (in the USA, >50% of graduating medical students are female), there is still a lag of female representation in both training and practice.

Furthermore, according to Ouyang et al, only 10% of medical school deans, 11% of department chairs, and 14% of full professors in medical schools are women.

“The under-representation of women in senior roles has been thought to be multifactorial—attributable in part to fewer research and promotion opportunities,” they write.

According to the investigators, an important measure of research productivity is the number of peer-reviewed publications and they note “in consideration for promotion, the number and impact of publications is

explicitly evaluated”. Therefore, the authors sought to “determine trends in authorship of cardiology-related publications in three high-impact general cardiology journals over the past 40 years”. The journals reviewed were: Circulation, Journal of the American College of Cardiology, and the European Heart Journal.

From 55,085 articles identified, 257,328 authors could be matched for gender; of these, 71,345 were unique authors. Ouyang et al write: “In total, 23,629 (33.1%) authors were female. Only 44,434 (26.7%) of 16,613 first authors were female (p<0.001). There was a smaller proportion of female authors in senior authorships, accounting for 2,193 (19.7%) of 11,160 senior authors (p<0.001).” Additionally, both research papers with a

first female author and those with a senior female author had a higher mean number of additional middle female authors than did papers with male first or senior authors.

Furthermore, articles with a female senior author more frequently had a female first author (0.37 vs. 0.18 for papers with a male senior author; p<0.001).

However, the number of female authors increased from over time: 9.5% with a female first author and 5.9% with a female senior author between 1980 and 1990 vs. 26.2% and 17.4%, respectively, between 2010 and 2017.

Ouyang et al conclude: “More work is needed to untangle the reasons behind these disparities and to develop strategies to increase female representation in cardiovascular research.”.

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Patient care

US FDA plans shakeup of its 510(k) clearance programme The US FDA has announced plans to modernise its 510(k) clearance programme for approving medical devices for the US market. Data show that about 20% of current 510(k) devices are approved on trials that compare novel devices to predicate devices that are more than 10 years old. With its revised programme, the agency wants to ensure medical devices coming to market account for advances in technology or demonstrate that they meet more modern safety and performance. The announced changes follow a report from the International Consortium of Investigative Journalists (ICIJ) that heavily criticises how medical devices are approved for use.

UNDER THE EXISTING 510(k) clearance programme, a medical device can be approved for market if (according to a study) it shows comparable safety and efficacy to a similar device that is already on the market. However, a limitation of this programme is that a substantial amount of devices (20%) are compared with devices (or predicates) that are more than 10 years old. In a statement, Scott Gottlieb (FDA commissioner) and Jeff Shuren (director of the Center for Devices and Radiological Health) comment: “Older predicates might not closely reflect modern technology embedded in new devices, or our more current understanding of device benefits and risks”. They stress that they are not suggesting these older devices, or the devices that are compared to them, are unsafe but note “we believe encouraging product developers to use more modern predicates would give patients and their doctors a choice among older and newer versions of the same type of device, promote greater competition to adopt modern features that improve safety and performance, and help make sure that newer devices reflect more modern technology and standards that can improve patient care and outcomes”.

Therefore, the FDA is proposing to list devices on its website that have demonstrated substantial equivalence to older predicate devices, with predicates that are more than 10 years old as a starting point. However, before going ahead with this plan, Gottleib and Shuren state that the agency is seeking public feedback on “whether we should make public those devices or those manufacturers who make technology that rely on predicates that are more than 10 years old, whether other criteria should inform our point of reference, and whether there are other actions we should take to promote the use of more modern predicates”.

Additionally, early this year, the FDA intends to finalise guidance establishing an alternative 510(k) pathway that will allow manufacturers of certain wellunderstood device types to rely on objective safety and performance criteria to demonstrate substantial equivalence as a way to make the pathway more efficient and to adopt modern criteria as the basis for the predicates that are used to support new products.

“We are planning to rename this new approach the ‘Safety and Performance Based Pathway’ to reflect its focus on advancing improved safety and performance of new products. Through this new path, a company would demonstrate a novel device meets modern performance-based criteria that have been established or recognised by the FDA and reflect current technological principles,” Gottlieb and Shuren comment. They add that “eventually” they would like this new pathway to replace the practice of comparing a new device to “a specific and, sometimes old, predicate device”.

As well as announcing the changes to the 510(k)

Scott Gottlieb

clearance programme, in their statement, Gottlieb and Shuren highlight the work that the Center for Devices and Radiological Health (CDRH), a subset of the FDA, has done (since 2009) to eliminate the use of the 510(k)-cleared predicates when the devices have raised safety concerns that “warrant treating them as highrisk technologies”. They explain that through a process called “up-classifying”, the FDA relabels such a device as “Class III”—meaning it requires premarket approval, “the most stringent review pathway”, before it can remain on the market.

After discussing other proposed revisions, Gottlieb and Shuren conclude their statement by saying: “We are proud of the work CDRH staff are doing to make sure that the devices we regulate are safe. We will continue to take new actions to strengthen the device programme for years to come.”

Report heavily criticises medical device industry

A few days prior to the FDA announcing its changes to the 510(k) programme, the ICIJ published a deeply critical report of the medical device industry. The report—the result of a year-long investigation by the ICIJ—highlights several case examples of patients being harmed by medical devices (from a mesh implant to treat incontinence to implantable cardioverter defibrillators). It claims that the medical device industry may be “unnecessarily putting millions of patients at risk of serious harm in its quest for profit”, calling into question how devices are regulated and approved for market. According to the report, governments in “dozens of countries” in Africa, South America, and Asia “do not regulate medical devices at all, instead placing

their trust in European authorities or in the US FDA”.

Furthermore, while the report acknowledges that the FDA “is generally considered to provide more robust oversight than any other heath agency in the world”, it states “even that oversight is lacking, with complex devices approved too quickly by American authorities and troublesome ones not pulled from hospital shelves fast enough, patient advocates and health experts say”.

At present, there is not a global resource for recalls and safety notices; therefore, to address this issue, the ICIJ has built the International Medical Devices Database. The report explains the database “gathers recalls, safety alerts and field safety notices (more than 70,000 from 11 countries) to create a searchable portal that anyone can access to help discover whether a device was flagged for official safety concern”. It adds the database shows that, over the past decade, there have been “more than 2,100 ‘Class I’ recalls in the USA for defects deemed to pose a ‘reasonable chance’ of ‘serious health problems or death’”. “Some of these could be addressed easily, with a quick software update or change of wording in the instructions, while others involved devices implanted in millions of patients that spurred thousands of surgical removals,” the report comments.

Responding to the ICIJ report, the Advanced Medical Technology Association (AdvaMed)—the foremost US trade group for the device industry—accuses it of “magnifying the stories of only a few individuals” and, thus, overlooks the “overwhelming positive experiences of millions of others”. “We take seriously all reports of patient impact, and though the medical community can never completely eliminate risk, we always strive to improve our technologies and delivery care,” the AdvaMed statement adds.

Complex devices [are] approved too quickly by American authorities and troublesome ones not pulled from hospital shelves fast enough, patient advocates and health experts say.

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Novel approaches

Pulmonary artery denervation: A novel approach to managing pulmonary hypertension Shao-Liang Chen Comment & Analysis According to the results of PADN-5, pulmonary artery denervation (PADN) is associated with significant improvements in haemodynamic and clinical outcomes in patients with postcapillary pulmonary hypertension (CpcPH). Shao-Liang Chen, who presented the results of the study at the 2018 Transcatheter Cardiovascular Therapeutics (TCT) meeting (21–25 September, San Diego, USA), reviews pulmonary hypertension and discusses the results of the PADN-5 study.

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ulmonary arterial hypertension is an intractable disease, featured by progressively increased pulmonary vascular resistance and development of right ventricular failure, leading to premature cardiac death.

While idiopathic pulmonary arterial hypertension is the most common subtype of the condition, pulmonary hypertension-associated with heart failure comprises the largest proportion of patients. Recently, a striking finding is that more and more elderly patients have been diagnosed as having pulmonary arterial hypertension—further increasing the complexity of reclassification and treatment. Currently, five classes of agents that target the three main signalling pathways in pulmonary arterial hypertension (approved by the FDA), particularly in sequential combination therapy, have dramatically improved the survival rate. However, emerging data suggest that the benefits of certain combinations for pulmonary arterial hypertension or routine treatment of pulmonary arterial hypertension targeted drugs for pulmonary hypertension

remain questionable, largely because the pathobiology of pulmonary arterial hypertension and pulmonary hypertension is complex and potentially involves the “cross-talk” between multiple mechanisms.

Pulmonary hypertension in the context of heart failure

Heart failure is a common final stage of most cardiovascular diseases. The backward transmission of increased left ventricular filling pressure results in elevated pulmonary venous pressure, a status known as passive or isolated postcapillary (Ipc) pulmonary hypertension, without an elevation of pulmonary vascular resistance or diastolic pressure gradient. Pulmonary hypertension is associated with global pulmonary vascular remodelling, leading to reactive or combined pre-capillary and CpcPH, which is defined as a DPG of ≥7 mmHg, or a pulmonary vascular resistance of >3 Wood units (WU), or both. CpcPH bears similar pathological changes of pulmonary artery WHO Group I pulmonary artery hypertension. Although

the presence of pulmonary hypertension is a hallmark of poor clinical outcomes in patients with heart failure, traditional anti-heart failure medications, including β-adrenergic receptor blockade, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel antagonists, and diuretics, appear to have less effect on pulmonary arterial remodelling in heart failure patients.

Neurohumoral over-activation in heart failure pulmonary hypertension is clinically demonstrated by increased circulating catecholamine levels and impaired heart rate variability, which may indicate the potential of using local nervous denervation for patients with CpcPH. In an experimental study, we further found that both the localisation of pulmonary artery nervous trunk (at the left lateral wall of the main pulmonary artery) and a shorter distance between nervous trunk and pulmonary artery intimal surface anatomically favour the performance of pulmonary artery denervation (PADN).

Furthermore, PADN was tested in patients with idiopathic pulmonary arterial hypertension and pulmonary hypertension secondary to left-side heart failure and showed beneficial effects on haemodynamic parameters and exercise capacity from a single centre and registry analysis.

The PADN-5 study

Recently, the PADN-5 study showed that PADN treatment was associated with a significant increase in six-minute walk distance at the six-month followup point, which was in parallel to the improvement in cardiac functions, compared with the effects of medication treatment alone, which further confirmed our previous reports. The pathogenesis of heart failure with preserved ejection fraction (HFpEF) was different to that of heart failure with reserved ejection

fraction (HFrEF). Notably, we found that PADN equally improved six–minute walking distance increase for patients with either HFrEF or HFpEF. This treatment effect by PADN may be partially explained by the fact that both diastolic and systolic cardiac functions were significantly promoted after the PADN procedure. However, the underlying mechanisms linking local pulmonary artery nervous ablation to left ventricular functional improvements recall the requirement of further basic and clinical studies. Notably, less all-cause death was reported in the PADN treatment group.

Heart failure patients are mostly referred to cardiologists, who in general have limited realisation of CpcPH, particularly in developing countries.

While right heart catheterisation is not routinely recommended for patient with heart failure, the PADN-5 study reported the importance of screening heart failure patients according to echocardiography.

Usually, right heart catheterisation is expected for a patient who has a systolic pulmonary arterial pressure >45mmHg. On the other hand, PADN procedure is somewhat different to other ablation procedures; it requires complete understanding of anatomy of the pulmonary artery tree, haemodynamic monitoring, and possible complications management. Therefore, a new heart team including an interventional cardiologist, pulmonologist, echocardiographer, and sometimes specialists in non-invasive images would be a relevant in this context.

Coinciding with its presentation at TCT, PADN-5 was published online in the Journal of the American College of Cardiology: Cardiovascular Interventions.

Shao-Ling Chen is at the Division of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.

Increased BMI associated with significant increase in radiation exposure to physicians Ryan D Madder (Frederik Meijer Heart and Vascular Institute, Spectrum Health, Grand Rapids, USA) and others write in Circulation: Cardiovascular Interventions that increased body mass index (BMI) among patients undergoing cardiac catheterisation is associated with a significant increase in physician radiation dose.

MADDER ET AL comment that increased BMI is known to increase radiation exposure to patients undergoing coronary angiography. They add that, in theory, increased BMI could also lead to increased radiation exposure to physicians, explaining that greater radiation doses are required to produce adequate images on obese patients and this leads to greater amounts of scatter radiation. Therefore, the aim of the study was to “evaluate the association of patient BMI and physician radiation dose during coronary angiography”.

Using data from the SHIELD study, the authors identified 1,119 consecutive cases of coronary angiography. Of these, patient radiation dose information was available for 1,116 cases and physician

radiation dose information were available for 1,114 cases. Real-time radiation exposure data were collected with a bedside monitor capable of displaying real-time radiation doses (RaySafe i2, Unfors RaySafe). Overall, based on BMI measurements, 83% of patients in the study were either overweight or obese.

The median radiation dose per case for physicians was 0.6. Madder et al report: “A significant increase in physician radiation dose was observed across increasing patient BMI categories. A patient BMI ≥40 was associated with a 7-fold increase in physician radiation dose compared with a patient BMI <25 (p<0.001).”

However, the increase in exposure did differ depending on the procedure—a BMI ≥40 was associated with

a 5-fold increase in physician exposure for patients undergoing coronary angiography, but was associated with a 23.5-fold increase for patients undergoing percutaneous coronary intervention.

The authors state that their findings are “consistent with the concept that higher patient radiation doses, which were also observed to increase in a stepwise fashion with patient BMI, result in a higher amounts of scatter radiation, the primary source of radiation exposure to physicians performing cardiac catheterisation”. They add that the findings are “concerning” because long-term radiation exposure among interventional cardiologists has been linked to “multiple adverse health effects”.

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Aortic valve surgery

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ADVERTORIAL

Early results for HAART 200 and HAART 300 Aortic Annuloplasty Devices are encouraging The Duke Children’s Pediatric & Congenital Heart Center (Duke University Medical Center, Durham, USA) treats the entire spectrum of patients with complex congenital heart disease. In this article, Cardiovascular News focuses on how the centre manages patients with congenital aortic valve disease—specifically, their use of the HAART 200 and HAART 300 (both BioStable) internal aortic valve annuloplasty rings.

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atients with congenital aortic valve stenosis may present with the typical trileaflet valve, bicuspid valves or even unicuspid leaflets. Joseph Turek, the executive codirector of the centre, explains: “These children are born with stenosis of their own valve [i.e. it is not acquired aortic valve stenosis]. Something happens during embryonic development wherein the valve did not develop to the right size. A lot of these patients end up having bicuspid or unicuspid leaflets as well.”

He adds that the management of these patients “has really advanced over the last 20 years or so, and the vast majority of institutions now offer balloon valvuloplasty. It is very effective”. However, a caveat of balloon valvuloplasty is that it can cause aortic valve insufficiency. According to Turek, “you have exchanged the problem of aortic stenosis with the problem of aortic valve insufficiency”. Therefore, the treating physicians at The Duke Children’s Pediatric & Congenital Heart Center face the challenge of managing patients with aortic regurgitation as well as aortic stenosis or those with pure aortic regurgitation. “We need to be able to address this challenge,” Turek comments.

HAART 300 and HAART 200

The Hemispherical Aortic Annuloplasty Reconstruction Technology (HAART) 300 and HAART 200* internal annuloplasty rings are a potential solution to this challenge. HAART 300 is for patients with trileaflet valves and the HAART 200 is for patients with bicuspid leaflets, and both were designed using mathematical analyses from human computed tomography angiograms (CTA) to ensure that they had the best anatomical shape.

In Innovations, J Scott Rankin (Department of Cardiac and Thoracic surgery, WVU Heart and Vascular Institute, West Virginia University, Morgantown, USA) and others write: “Because the aortomitral curtain shifts with systole, both rings were machined in diastolic geometry, with the goal of moving the annuli centrally to recruit the leaflet for coaptation height.”1 Prior to the HAART devices, no devices were available for the management of aortic valve regurgitation that had been designed from the actual geometries of the aortic valve. Turek comments: “With the availability of the HAART devices,

you now have something that is geometrically similar to how the aortic valve should be in a normal state that you can put in and allow you to facilitate the repair of the valve.”

While both devices were designed on the geometry of a healthy aortic valve, they do differ given they are for different patient subgroups. The HAART 300 is elliptical and is sutured just below the junctions of the leaflets and the aortic wall. The aim is to force the annulus of the native valve to conform to the normalised shape of the device. By contrast, the base of the HAART 200 is circular and has two subcommissural posts spaced 180 degrees apart around the circumference.

It has a circular base because the presentation of bicuspid aortic valve disease varies and there is not a typical annular shape. Therefore, the aim of a circular base is to provide the best shape for reducing and stabilising the annular dimensions for all classifications while facilitating and simplifying leaflet reconstruction.

Benefits for the growing patient

According to Turek, a problem with leaflet-based repair procedures is that they become less effective as the paediatric patient ages. He says: “You can do all you want with the leaflets and get a nice repair. But with a growing child, the annulus grows as the aorta grows and you can lose the benefits of the repair because the annulus is not stabilised. So, this is the big advantage of the HAART 200 device. It stabilises the annulus and the hope is that this will translate to greater longevity of the repair.”

Another benefit of both devices is that

Joseph Turek, MD, PhD

they do not require the prescription of lifelong warfarin (as the implantation of a mechanical heart valve would do).

The paediatric aortic valve disease cohort, Turek comments, represents a “very young, very active population that want to go out and do a whole bunch of activities”. Therefore, they do not want to have to deal with the limitations of warfarin (i.e. avoiding contact sports to avoid the risk of bleeding). Further down the line for female patients, a HAART 200 may allow them to have an easier pregnancy. If they were on warfarin because they had a mechanical valve, they would have to go through a transition period before becoming pregnant. “Hopefully with this device, we can get them through the child bearing years and also through the highly active, young, teenage years—a period of 20 years etc. from receiving the device. We want to get to the point at which a replacement device would not be beset with so many issues, such as the patient outgrowing the device or not wanting to take warfarin,” he says.

HAART 200 Aortic Annuloplasty Device

* This device is investigational in Europe and is not available for sale.

At present, there is published twoyear data from the original HAART clinical trials.1 Additionally, there are multiple publications from the early commercial experience using the HAART 300.2–5 A report of four patients treated with the HAART 300 device showed good results at six months postoperatively (on 3D transthoracic echocardiogram).2 The report authors Jacek H Juściński (Department of Cardiac and Vascular Surgery, Medical University of Gdańsk, Poland) write: “The HAART 300 rings, thanks to their construction (rigid rings), permanently stabilise the atrioventricular junction and, as a result, facilitate the reconstruction of insufficient aortic valves, including the plication of cusps in cases of prolapse.”

Turek acknowledges the need for further studies of the devices to “see if their potential benefits will truly pan out and if we have will have better longevity with them”. But, he notes: “I think the early results are encouraging.

I can say from someone who has put in more of the HAART 200 in paediatric patients than anyone in the world, I am very comfortable with it and I found the learning curve pretty easy. Its simplicity is a real benefit.”

References 1. Rankin et al. Geometric ring annuloplasty for aortic valve repair during aortic aneurysm surgery. Two-year clinical trial results. Innovations 2018; 13: 248–53.

2. Juściński et al. First uses of the HAART 300 rings for aortic valve repair in Poland—4 case studies.

Kardiochirurgia I Torakochiurgia 2018; 15: 38–43.

3. Russo et al. Aortic valve repair with a novel rigid annuloplasty ring. Cardiovascular Medicine 2018; 21(6): 160–64.

4. Russo et al. Early clinical experience with double ring implantation for aortic and mitral valve repair. Thorac Cardiovasc Surg 2018. Epub.

5. Jasinski et al. Aortic valve annuloplasty with the HAART geometric ring and ascending aorta replacement. Multimed Man Cardiothorac Surg 2018.

Epub.

HAART 300 Aortic Annuloplasty Device

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Feb

From bench to bedside: Roundtrip for cell therapy in heart disease Massimiliano Gnecchi Comment & Analysis The study of stem cells in regenerative medicine is a growing field of basic and clinical research, generating a broad interest and debate in the scientific and the public communities. The ability to mobilise and activate endogenous stem/progenitor cells in diseased organs or to introduce exogenous stem cells for tissue regeneration/repair may positively impact many diseases. In this commentary, Massimiliano Gnecchi reviews the evidence base for stem cell therapy in treating heart disease.

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Cell therapy

tarting from the late 1990s, the regenerative capacity of a variety of multipotent adult stem cells (ASC) harvested from different tissue sources has been experimentally tested as a means to cure ischaemic heart disease and end-stage heart failure. Tissue regeneration from trans-differentiation of transplanted ASC was originally proposed as the principal mechanism underlying their therapeutic effects.

Most importantly, the magnitude of cardiac regeneration described in the first experimental reports encouraged clinical investigators to rapidly test cell therapy in humans without further rigorous confirmations of the original data. Many

clinical studies have been conducted with different cell types: skeletal myoblasts (SM), bone marrow-derived mononuclear cells (BM-MNC), mesenchymal stromal cells (MSC) and resident cardiac stem cells (CSC), to name but a few.

Unfortunately, the efficacy results obtained so far are inconclusive, and cell therapy has never entered the routine clinical practice.

Lessons learnt

Despite this apparent failure, we have learned quite a few things from the first clinical trials, and these now well-established concepts must drive our choices when designing the new

cell therapy protocols if we want to eventually succeed in repairing failing hearts. On top of that, more recent animal studies allowed us to better understand the main issues still hampering an effective translation from the promising pre-clinical results to the bedside. Among them, the most relevant are the low engraftment rate and the incapacity of the cells so far tested to efficiently differentiate into fully mature cardiomyocytes, resulting in the lack of heart regeneration, as said the original goal that scientists aimed to reach when they started testing cell therapy.

The issue of poor cell engraftment is common to all cell types tested in clinical trials: BM-MNC, MSC and CSC. Several approaches have been proposed to overcome this hurdle, from the overexpression of protective genes to cell preconditioning. More recently, administration of cells together with degradable biomaterials, or other tissue engineering techniques, have been tested in animal models with promising results. The incapacity to robustly differentiate into cardiomyocytes is also a problem shared by BM-MNC, MSC and CSC. Using the latest state of the art methodologies for cell fate tracing, several investigators have reported that there is no evidence of ASC differentiation in vivo and some of the earliest findings have been harshly criticised. Currently, scientists are considering couple of different approaches to overcome the issue of poor ASC differentiation: the implementation of pluripotent stem cells—such as embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC)—that are truly able to form myocytes or the development of effective strategies to potentiate the limited innate regenerative capacity of the heart.

Animal studies have also allowed us to clarify that the mechanism of stem cell action is mainly though production and release of soluble factors rather than direct cardiac regeneration, a concept that we pioneered in 2005 and subsequently confirmed by dozens of different labs worldwide. In particular, cardiac protection, improved angiogenesis and possibly endogenous regeneration, together with reduced scarring are the main effects mediated by the cell’s secretome. Proteins, exosomes and non-coding RNAs are the putative mediators of these positive paracrine effects. The demonstration that stem cells secrete therapeutic factors provides a potential breakthrough in that, rather than administering cells, one may be able to administer the whole secretome, the exosomes or even specific proteins.

This approach opens new and unexplored therapeutic options, which present several advantages over the use of cell preparations.

Conclusion

The initial expectations regarding the capacity of stem cells to regenerate cardiac tissue were just too high since they were based on wrong interpretations of experimental findings and because the protocols used for administration were over-simplistic. However, the lessons learned from previous experiences will certainly help us to progress toward the development of more effective cell and molecular therapies to regenerate, or more realistically to repair, broken hearts.

Massimiliano Gnecchi is at the University of Pavia, Pavia, Italy. He spoke about this topic at the European Association European Association for CardioThoracic Surgery (EACTS) annual meeting (18–20 October, Milan, Italy).

Risk of death with unrecognised myocardial infarction equal to that with recognised myocardial infarction by 10 years Tushar Acharya (National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, USA) and others report in JAMA Cardiology that within 10 years, the risk of all-cause mortality among patients who have had an unrecognised myocardial infarction is not significantly different from those who have had a recognised myocardial infarction.

ACCORDING TO THE authors, unrecognised myocardial infarction is associated with poor survival but the long-term prognosis is unknown. “We investigated the long-term prognosis of unrecognised myocardial infarction would have higher risk of longterm mortality, non-fatal myocardial infarction, and heart failure than those without myocardial infarction,” they write.

Using data from the AGES Reykjavik prospective cohort, Acharya et al reviewed long-term outcomes of patients who did not have myocardial infarction, a history of myocardial infarction (recognised myocardial infarction), and unrecognised myocardial infarction as identified with cardiac MR (all patients underwent cardiac MR at baseline). Of 925 patients overall, 156 (17%) had unrecognised myocardial infarction and 91 (10%) had recognised myocardial infarction (the remaining 686 patients had no myocardial infarction) At three years, there were no significant differences in rate of mortality between those who had unrecognised myocardial infarction and those who had no myocardial infarction; furthermore, the rate of all-cause mortality

was significantly lower among unrecognised myocardial infarction patients than those with recognised myocardial infarction. The authors comment: “By five years, unrecognised myocardial infarction mortality rates (13%) were intermediate between no myocardial infarction rates (8%) and recognised myocardial infarction (19%).

However, at 10 years, unrecognised myocardial infarction and recognised myocardial infarction rates were not statistically different (49% and 51%, respectively; p=0.99) and were significantly higher than no myocardial infarction rates (30%; p<0.001).” After adjustment for cofounding risk factors, the risk of mortality with unrecognised mortality was similar to that with recognised mortality.

Two possible mechanisms, Acharya et al report, may explain why the mortality rates of unrecognised and recognised myocardial infarction progressively started to converge after years. The first being that unrecognised myocardial infraction may represent a different coronary

disease phenotype with more small vessel involvement and atrial fibrillation than recognised myocardial infarction, and second preventative therapy for secondary events in patients with recognised myocardial infarction may have attenuated mortality rates. The authors add: “The recognition of a myocardial infarction may have changed risky behaviours, as individuals with recognised myocardial infarction were less likely to continue smoking. High mortality rates in the unrecognised myocardial infarction might be explained by fewer prescriptions of preventative treatments.”

They note: “Being more prevalent than recognised myocardial infarction, unrecognised myocardial infarction constitutes an underappreciated public health problem. Whether early detection of unrecognised myocardial infarction by cardiac MR could allow for the institution of risk factor management and thus reduce the associated long-term risks merits further investigation.”

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Market watch

Product News

Sapien 3

Sapien 3 Ultra receives FDA approval

It has been announced that the Sapien 3 Ultra system (Edwards Lifesciences) has received US FDA approval for transcatheter aortic valve implantation (TAVI) in severe, symptomatic aortic stenosis patients who are determined to be at intermediate or greater risk of openheart surgery.

“The advanced Sapien 3 Ultra system features enhancements on the valve and a new delivery system to address the needs of both patients and clinicians, building on our best-in-class performance of Sapien 3 to further advance and improve patient care,” says Larry L Wood, Edwards’ corporate vice president, transcatheter heart valves. “We look forward to introducing the Sapien 3 Ultra system to US patients.”

The Sapien 3 Ultra system builds on Edwards’ decades of engineering and experience in the development of tissue heart valves, and the proven benefits of the Edwards Sapien valves.

“The Edwards Sapien 3 Ultra system provides meaningful technology improvements that help further optimise the transcatheter aortic valve replacement procedure, adding simplicity and advancing patient care,” says John Webb, director of interventional cardiology and cardiac catheterisation laboratories at St. Paul’s Hospital and professor of cardiology at the University of British Columbia, Vancouver, Canada. Webb is a consultant to Edwards Lifesciences.

FDA approves world’s first device for treatment of premature babies and newborns with an opening in their hearts

The US FDA has approved the Amplatzer Piccolo Occluder (Abbott), the world’s first medical device that can be implanted in babies weighing as little as two pounds using a minimally invasive procedure to treat patent ductus arteriosus, or PDA. The Amplatzer Piccolo, a device even smaller than a small pea, now offers hope to premature infants and newborns who need corrective treatment, and who may be non-responsive to medical management and at high risk to undergo corrective surgery.

One of the most common congenital heart defects occurring in premature

babies, PDA is a potentially lifethreatening opening between two blood vessels leading from the heart. This channel, which is present in normally developing foetuses, is important prior to birth to allow oxygen-rich blood from the mother to circulate throughout the foetus’ body. For most infants, the pathway, or duct, seals itself shortly after birth. In some cases, primarily in babies born prematurely, the PDA fails to spontaneously close, which can make it difficult for babies to breathe normally due to increased blood flow to the lungs.

PDA accounts for up to 10% of all congenital heart disease.

Approximately 60,000 premature babies in the USA are born each year with a very low birth weight, and nearly 12,000 (one out of five) of these have a haemodynamically significant PDA—a PDA that is large and causes symptoms— which will require urgent treatment for the baby to survive.

The Amplatzer Piccolo Occluder is a self-expanding, wire mesh device that is inserted through a small incision in the leg and guided through vessels to the heart, where it is placed to seal the opening in the heart. It is designed to allow the physician to insert it through the aortic or pulmonary artery, as well as to retrieve and redeploy the device for optimal placement. Because the device is deployed in a minimally invasive procedure, many of the premature babies who are critically ill in the neonatal intensive care unit are able to be weaned from artificial respirator support soon after the procedure.

Born at 27 weeks, twin babies Irie and Judah Felkner of Columbus, USA, were both fighting for their lives in the neonatal intensive care unit when an echocardiogram revealed Irie had a PDA that required immediate treatment.

“The doctor thought Abbott’s Amplatzer Piccolo device was the best solution for Irie, and after learning more about the procedure we decided to move forward,” said Crissa Felkner, Irie’s mother. “You have to live it to fully appreciate what that device did for our daughter. Three days after the procedure, she was making great progress and is

now a normal toddler with no limitations.

The Abbott device was truly lifesaving for our daughter.”

The Felkner twins were treated as part of the US pivotal trial, ADO II AS, which helped to support the FDA approval of the device. The trial evaluated the Amplatzer Piccolo Occluder and enrolled 50 patients with a PDA who were older than three days at eight centres across the USA. The safety and efficacy of the device is further supported by additional experience with the device under a continued access protocol involving 150 more patients.

JC Medical’s J-Valve System is designed to restore normal blood flow out of the heart and into the body, which may improve symptoms of heart failure such as shortness of breath, fatigue and chest pain. The J-Valve features a proprietary anchor mechanism that is flexibly linked to a self-expanding stent frame to uniquely attach to the failing native heart valve. The J-Valve does not require calcification of the native valve for fixation.

The world’s first J-Valve TF implant was performed earlier this year by John Webb and Jian Ye at St Paul’s Hospital in Vancouver, Canada. This case was

J-Valve

First US treatment with J-Valve TAVI device

The first US patient has been successfully treated with JC Medical’s transfemoral transcatheter aortic valve implantation (TAVI) device, the J-Valve TF system.

The patient was treated at The Christ Hospital (Cincinnati, USA) by Dean Kereiakes, medical co-director of the Lindner Research Center, working with Joseph Choo and Geoffrey Answini.

The US FDA approved the use of the J-Valve for patients with aortic regurgitation through the agency’s expanded access (“compassionate use”) regulatory pathway.

The investigational J-Valve TF system is intended as a new catheter-based option for the treatment of patients who suffer from aortic regurgitation. Failing aortic valves make up a significant portion of patients with heart failure, a major public health problem with a prevalence of over 1.5 million in the USA and over 18 million worldwide.

Aortic regurgitation is the primary indication for more than 20% of surgical heart valve replacements, but there are no transcatheter aortic valves that are approved in the USA or Europe to treat aortic regurgitation patients too sick to undergo open surgical repair.

Piccolo

published online ahead of print in EuroIntervention (20 November, 2018).

The company plans to initiate a US clinical trial of the J-Valve in 2019.

FFRangio system receives US FDA clearance

US FDA 510(k) clearance has been granted for the FFRangio System (CathWorks). The FFRangio system demonstrated accuracy versus the invasive FFR wire in a blinded comparative study, FAST-FFR. The results of the FAST-FFR pivotal study were used to establish substantial equivalence of the FFRangio system.

The CathWorks FFRangio System delivers FFR guidance to assist percutaneous coronary intervention (PCI) therapy decisions. FFRangio is derived from routine X-rays acquired during a diagnostic angiogram procedure, is non-invasive, and performed intra-procedurally during coronary angiography, aiming to reduce additional clinical risk, time and cost associated with invasive FFR. FFRangio provides a 3D reconstruction of the entire coronary tree with FFR values along each vessel.

Jim Corbett, CathWorks CEO said, “The FDA clearance of CathWorks FFRangio is a milestone for interventional cardiologists and the healthcare system overall. It is the first non-invasive device of its kind to receive FDA clearance for use during PCI assessment.”

He continued: “The FAST-FFR study was carried out at 10 centres worldwide and evaluated more than 380 patients.

The study demonstrated the clinical predictive value across a full range of coronary physiology, including complex lesion assessment in bifurcations and calcified lesions. FAST-FFR also demonstrated that the FFRangio system could perform non-invasive, objective, multivessel, physiologic measurements to support PCI decision making.”

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cath lab. I have no doubt that IVL is poised to become the key differentiating technology compared to other calcium modification tools.”

Clinical News

Patient recruitment reaches half-way point for global DAPT study

Lithotripsy

Shockwave initiates US pivotal study for coronary intravascular lithotripsy

Shockwave Medical has initiated its US FDA Investigational Device Exemption (IDE) study—DISRUPT CAD III—for the use of Intravascular Lithotripsy (IVL) in heavily calcified coronary arteries. IVL is an innovative lesion preparation tool designed to fracture problematic calcium using sonic pressure waves in order to facilitate stent delivery, deployment and expansion.

The co-principal investigators of the study are Dean Kereiakes, medical director of The Christ Hospital Heart and Vascular Center and The Lindner Research Center (Cincinnati, USA) and professor of Clinical Medicine, The Ohio State University (Columbus, USA) and Jonathan Hill, consultant cardiologist at King’s College Hospital (London, UK). The first patient was enrolled last week by Richard A Shlofmitz, chairman, Department of Cardiology, St Francis Hospital (Roslyn, New York, USA).

Coronary artery calcium physically impairs stent expansion and is perhaps the single most important predictor of early stent thrombosis and restenosis after stent procedures. Current calcium modification treatments, which can be difficult to perform, only address the burden of intimal calcium with varying degrees of success and result in an increased risk for adverse events since these techniques do not differentiate between the calcific lesion and soft, normal intimal tissue.

Coronary IVL is a novel investigational therapy designed to treat calcified artery blockages with sonic pressure waves historically used to treat patients with kidney stones. The technology seeks to minimise trauma within the artery by delivering pulsatile sonic pressure waves locally to fracture both intimal and medial calcium in the artery wall but pass through surrounding soft vascular tissue in a safe manner.

“After previously using the peripheral IVL technology—Shockwave M5— to enable transfemoral access for

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transcatheter aortic valve implantation (TAVI) as well as for mechanical cardiac support and hearing the enthusiasm from Europe about coronary IVL, we are very excited to investigate the clinical potential of the coronary technology in the USA,” said Kereiakes. “This therapy holds tremendous potential from a safety perspective for patients and an ease of use perspective for physicians—if coronary IVL is shown to be safe and effective, it could be a game changer for the way we treat calcified arteries today.”

DISRUPT CAD III is a prospective, non-randomised, multicentre global IDE study to demonstrate the safety and effectiveness of the Shockwave Coronary IVL System with the Shockwave C2 Coronary IVL Catheter in de novo, calcified, stenotic, coronary arteries prior to stenting. The study is expected to enrol approximately 392 patients at 50 global centres in the United States and Europe.

The study will assess the freedom from major adverse cardiac events (MACE) within 30 days of the index procedure as the primary safety endpoint. The primary effectiveness endpoint is procedural success which, based on predicate studies, is defined as stent delivery with a residual stenosis of less than 50% and without in-hospital MACE. Enrolled study patients will be followed for two years.

The study’s chairman is Gregg W Stone, professor of medicine at Columbia University Medical Center (New York, USA) and the angiographic and OCT core labs are the Cardiovascular Research Foundation, also based in New York.

“Having treated nearly 100 patients with IVL since its European launch, the benefits for treating complex patients are evident. I am delighted to be a part of this important global trial to introduce my US interventional colleagues to this novel technology. IVL is easy to use and has been a huge advancement for our management of calcified lesions,” said Hill. “I think US interventionalists will recognise the simplicity and ease of use of the IVL system and will appreciate its ability to be rapidly deployed in any

December 2018 marked a significant milestone for a major study into the use of short duration dual anti-platelet therapy (DAPT) in high bleeding risk patients following stenting procedures, with patient recruitment reaching the half-way point.

The investigator-initiated MASTER DAPT (Management of patients post bioresorbable polymer Stent implantation with an abbreviated DAPT regimen) study just randomised patient number 2,150—half-way towards the target of 4,300. Patients join the study from more than 120 hospitals across 32 countries in Europe, Japan, Asia, Australia and Latin America.

The study compares abbreviated versus prolonged DAPT, following implantation with Ultimaster or Ultimaster Tansei drug-eluting bioresorbable polymer stents, in “all-comer” patients, presenting with high bleeding risk features. The study primary endpoints are noninferiority for net adverse clinical events; superiority for bleeding; and non-inferiority for ischaemic endpoints of abbreviated versus prolonged DAPT, at one year.

The Ultimaster drug-eluting stent has extensive real-world clinical data, having been studied in a population of over 40,000 patients. Both Ultimaster and the recently launched Ultimaster Tansei

intervention study in India; the study is assessing the efficacy and safety of conducting percutaneous coronary intervention (PCI) from a remote location outside of the catheterisation lab. Five patients located at the Apex Heart Institute in Ahmedabad, India, underwent an elective PCI procedure from a distance of roughly 20 miles (32km) away.

Each procedure was remotely performed by Tejas Patel (Apex Heart Institute, Ahmedabad, India) from inside the Swaminarayan Akshardham temple located in Gandhinagar (India).

His partner, Sanjay Shah, was in the room with the patient at the Apex Heart Institute. The success of this study paves the way for large-scale, long-distance telerobotic platforms across the globe.

Geographic barriers, socioeconomic status and a rapidly shrinking number of skilled specialists significantly hinders patient access to timely, specialised cardiovascular care. This is especially of concern during highly emergent medical events, such as myocardial infarction and stroke, where ideally treatment is received in as little as 90 minutes or within 24 hours, respectively, to avoid death or permanent disability.

To improve patient outcomes, a press release reports, Corindus has pioneered the world’s first remote telerobotic interventional platform to deliver highly specialised and timely cardiovascular care to under-served patient populations with geographic barriers to treatment.

Following the successful first-in-human telerobotic coronary stenting cases performed in India, the company plans to begin commercial product development for use of the CorPath system in remote

CorPath

are designed to promote optimal vessel healing and therefore hypothesised to facilitate a shortened DAPT regimen.

This hypothesis was confirmed in the DISCOVERY 1TO3 clinical trial that proved an excellent strut coverage of nearly 90% as early as 1 month.1 Robust safety data includes recently published results from the CENTURY II trial that showed a low stent thrombosis rate of 0.2% between one and five years.

A shorter DAPT protocol may save healthcare resources by reducing cost for DAPT and the number of hospitalisations for bleeding.

First-in-human “remote PCI” performed

CorPath technology has been successfully used in the first-in-human telerobotic

interventions and expand the company’s robotic platform to address stroke care.

Patel comments: “The first in human cases of remote robotic PCI represent a landmark event for interventional medicine. The application of telerobotics in India has the potential to impact a significant number of lives by providing access to care that may not otherwise have been possible. For the first time in cardiology’s history, India will shine for this ground-breaking innovation.”

At the 2018 Transcatheter Cardiovascular Therapeutics (TCT) meeting (21–25 September, San Diego, USA), the first live transmission of a remote robotic demonstration was streamed from Mayo Clinic using CorPath GRX with developmental remote technology in a porcine model.

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Industry News Boston Scientific and Edwards Lifesciences agree to global litigation settlement

Boston Scientific and Edwards Lifesciences have announced that they have reached an agreement to settle all outstanding patent disputes between the companies in all venues around the world.

All pending cases or appeals in courts and patent offices between the two companies will be dismissed, and the parties will not litigate patent disputes related to current portfolios of transcatheter aortic valves, certain mitral valve repair devices, and left atrial appendage closure devices. Any injunctions currently in place will be lifted.

Under the terms of the agreement, Edwards has made a one-time payment to Boston Scientific of US$180 million. No further royalties will be owed by either party under the agreement. All other terms remain confidential.

JenaValve Technology appoints John T Kilcoyne as chief executive officer

Medical device executive John T Kilcoyne has been appointed as chief executive officer of JenaValve Technology, effective immediately. In addition, he will serve as a member of the board of directors.

Kilcoyne is a proven leader in the medical device industry. He has broad and applicable experience leading high-tech medical device emerging growth organisations through market approvals, market access, high growth and successful strategic transactions, including IPOs and M&A activities.

Prior to joining JenaValve, Kilcoyne served as president and CEO of ReVision Optics. From 2004 to 2010, he was President and CEO at Micrus Endovascular Corporation where he led an IPO in 2005, the capture of significant market share and, ultimately, the acquisition by Johnson & Johnson in 2010. He also held CEO positions at medical device companies Solace Therapeutics from 2002 to 2004 and Endonetics, which he joined in 1997 and

was acquired by Medtronic in 2001.

“I am thrilled that John Kilcoyne has agreed to lead our company. In John, we have identified a dynamic and seasoned executive with an extensive background in driving medical businesses through the key stages of growth and value generation,” says Jan Keltjens, chairman of the board.

Kilcoyne said, “I am pleased to have the opportunity to lead JenaValve, and I look forward to working with the team to bring new, innovative solutions to the transcatheter valve market. Data from past and ongoing trials clearly indicate the strong potential that the JenaValve technology can greatly improve the health of patients with aortic stenosis and aortic regurgitation. Our focus in 2019 is on completing the current clinical development programmes and gaining commercial readiness for potential international launch activities under CE mark and US Humanitarian Device Exemption regulatory processes.”

Kilcoyne replaces Victoria CarrBrendel, who left the company to accept another leadership role in the fourth quarter 2018. Keltjens comments, “Victoria made many significant contributions during her tenure at JenaValve. We are grateful for her contributions and wish her well in her future endeavours.”

Boston Scientific exercises option to acquire Millipede

Boston Scientific has exercised its option to acquire the remaining shares of Millipede, upon its recent successful completion of a first-in-human clinical study. The acquisition will expand the Boston Scientific Structural Heart portfolio to include the IRIS transcatheter annuloplasty ring system, which is in development for the treatment of patients with severe mitral regurgitation who are not able to tolerate open-heart surgery.

Boston Scientific initially entered into an investment and acquisition option agreement with Millipede in January 2018. It purchased US$90M in existing and newly-issued Millipede shares, with the option to acquire the company’s remaining shares for US$325 million at

closing, with a US$125 million payment becoming available upon achievement of a commercial milestone.

The quickly expanding transcatheter mitral repair and replacement market is estimated to reach US$1 billion by 2021, with the majority comprised of repair procedures.

The IRIS system uses a complete annuloplasty ring, considered the goldstandard surgical approach, to reduce the size of a dilated mitral annulus. It is delivered via a transcatheter-transseptal delivery system, and can be used as a stand-alone device, or in combination with other technologies in patients with severe mitral regurgitation.

On an adjusted basis, the transaction is expected to be dilutive to earnings per share (EPS) for each of the next several years; however, all dilutive impact is expected to be absorbed via internal trade-offs, resulting in no net adjusted EPS impact. The deal is anticipated to close in Q1 2019, subject to customary closing conditions. On a GAAP basis, for each of the next several years, the transaction is expected to be more dilutive, due to amortisation expense and acquisition-related net charges.

The IRIS transcatheter annuloplasty ring system is an investigational device and not available for sale.

Abbott to acquire Cephea Valve Technologies

It was recently announced that Abbott has exercised its option to purchase Cephea Valve Technologies. Financial terms were not disclosed. Abbott provided capital and secured an option to purchase Cephea in 2015.

Cephea’s technology is being developed to provide an option for people whose diseased mitral valves need to be replaced. The artificial valve is designed to be delivered through a vein in the leg, forgoing the need for open-heart surgery.

Replacement of the diseased mitral valve restores normal blood flow through the heart.

Mitral valve disease is the most common heart valve problem, affecting more than four million people in the USA alone.

It comes in two forms: regurgitation, a condition where blood leaks backward into the heart, or, less commonly, stenosis, a narrowing of the valve. The condition puts people at risk for health complications such as irregular heartbeats, high blood pressure, blood clots or heart failure.

Abbott has led the development of

minimally invasive solutions for mitral valve disease since 2009 when it acquired Evalve, with its MitraClip technology. MitraClip, the first-of-its-kind product to repair leaky heart valves, launched in Europe in 2008 and in the USA in 2013 and remains the only mitral valve repair device of its kind on the market.

In 2015, Abbott expanded its portfolio by acquiring Tendyne Holdings and securing an option to acquire Cephea Valve Technologies, companies that are both developing minimally invasive devices intended to fully replace the mitral valve in the heart. Minimally invasive mitral valve procedures are expected to become a multibillion-dollar market in the coming years. In addition, Abbott acquired St Jude Medical in 2017, adding to the company’s expertise and offerings to treat structural heart disease.

Venus Medtech to buy cerebral protection device company Keystone Heart

Venus Medtech has signed an agreement to acquire Keystone Heart, a privatelyheld medical device company and makers of TriGUARD 3—a cerebral embolic protection device that is designed to provide complete coverage to all brain regions for patients undergoing cardiac procedures. The acquisition gives Venus Medtech international rights to TriGUARD 3.

Keystone Heart is focused on protecting the brain from emboli to reduce the risk of brain infarcts during transcatheter aortic valve implantation (TAVI), surgical valve replacement, atrial fibrillation ablation and other structural heart procedures. The company is currently enrolling patients in the REFLECT trial in the USA to evaluate TriGUARD 3, anticipating enrolment completion in the early part of the first quarter of 2019 and FDA review in the first half of 2019. CE mark approval for Europe is anticipated by the end of this year.

Eric Zi, co-founder and CEO of Venus Medtech, comments: “It is of utmost importance to us that our devices improve the quality life of the patients whom receive them. Our transcatheter heart valve systems offer patients lifesaving support—acquiring Keystone Heart allows us the opportunity not only to reduce the risk of brain injury during cardiac procedures but establishes our presence in the USA and Europe through which we can introduce our entire portfolio of products.”

Calendar of events 2–5 March CRT 2019 Washington, DC, USA

20 May PCR Innovators Day Paris Paris, France

21–24 May EuroPCR 2019 Paris, France

31 August–4 September ESC Congress 2019 Paris, France

3–5 October EACTS 2019 Lisbon, Portugal

www.crtmeeting.org/

www.pcronline.com/Courses/PCR-

www.pcronline.com/Courses/

www.escardio.org/Congresses-&-

www.eacts.org/annual-meeting-2/

Innovators-Day-Paris-2019

EuroPCR

Events/ESC-Congress

20–23 May SCAI 2019 Las Vegas, USA

12–15 June TVT 2019 Chicago, USA

25–29 September TCT 2019 San Francisco, USA

www.scai.org/

www.crf.org/tvt

www.crf.org/tct

16–18 March ACC.19 New Orleans, USA www. accscientificsession.acc.org/

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17–19 November PCR London Valves London, UK www.pcronline.com/Courses