Interventional News Issue 73 ROW

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US FDA continues to investigate paclitaxel devices in the leg

Laura Findeiss:

Profile

Alex Barnacle:

A meta-analysis published in the Journal of the American Heart Association (JAHA) late last year by Konstantinos Katsanos (Patras, Greece) and colleagues, suggesting an increased risk of death at two and five years following the use of paclitaxel-coated balloons and stents in the femoropopliteal artery, has generated months of debate amongst the international interventionalist community. The conversation is still ongoing, with every key vascular conference of 2019 to date hosting discussion on the future of paclitaxel-coated and paclitaxel-eluting devices. Since then, prominent physicians have pointed out flaws in Katsanos et al’s methodology. Patient-level data published after the JAHA meta-analysis by industry have revealed no increased mortality associated with the use of paclitaxel-releasing devices. Medtronic and Cook Medical have also announced corrections to their published data. Meanwhile, the continued investigation by the US Food and Drug Administration (FDA) indicates that the story is not yet over.

Panellists at the Vascular Leaders Forum

S

peaking from the floor of the Vascular Leaders Forum (VLF; 1–2 March, Washington, DC, USA), hosted

by Vascular Interventional Advances (VIVA), FDA investigator Donna Buckley, who has “reviewed most of these devices and recommended them to be approved”, explained the regulatory body’s perspective: “Our first response to the meta-analysis was, I think, similar to everybody else’s: we were a little bit surprised. Nonetheless, it was compelling information that we took very seriously.”

The ongoing FDA evaluation is focusing primarily on US-based randomised controlled trials with data the regulatory body can validate. The FDA’s preliminary evaluation confirmed the mortality signal reported by Katsanos et al. Speaking at VLF, Buckley said the FDA’s own analysis of five US pre-market approval (PMA) trials has “converged to where we feel like it [the meta-analysis findings] is not a statistical glitch—but we still have all this incongruous information as well with all the statistical analysis that we have gone through.”

Also at VLF, Peter Schneider (Honolulu, USA) called the process that the FDA is undertaking to review the data “judicious, straightforward and spot on”.

Indeed, the FDA issued a letter to healthcare providers in January stating that it was evaluating the “recent information regarding the potential for increased long-term mortality” following paclitaxel-coated balloon or paclitaxeleluting stent treatments in the femoropopliteal artery for patients with peripheral arterial disease (PAD). The agency said that whilst the data review was ongoing, the FDA recommends “continued surveillance” for patients treated with paclitaxel. The regulatory body stated in the letter that it believes the “benefits continue to outweigh the risks” for approved devices within their indications.

At the CRT summit (2–5 March, Washington, DC,

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USA), which directly followed the release of the FDA’s preliminary evaluation at VLF, polling of panellists in the drug-coated balloon (DCB) safety townhall indicated that the majority of voters believed there to be a “mortality signal” in the femoropopliteal arteris (detailed polling results to follow).

Katsanos et al’s JAHA meta-analysis

In the original JAHA paper, published 6 December 2018, Katsanos et al conducted a systematic review and metaanalysis of 28 randomised controlled trials investigating paclitaxel-coated balloon angioplasty or paclitaxel-coated metal stents in the femoral and/or popliteal arteries. In all, 4,663 patients (89% intermittent claudication) were analysed. The primary safety measure was all-cause patient death, analysed at different time points.

Previous randomised controlled trials have evidenced that paclitaxel-releasing balloons and stents significantly reduce the rates of vessel restenosis and target lesion revascularisation after lower extremity interventions.

At one year, all-cause patient death (28 randomised controlled trials with 4,432 patients) was similar between 17 paclitaxel-coated devices and control arms (2.3% vs.

2.3% crude risk of death). All-cause death at two years (12 randomised controlled trials with 2,316 patients) was significantly increased in case of paclitaxel vs. control (7.2% [101 deaths in 1,397 patients] vs. 3.8% [35 deaths in 919 patients] crude risk of death, number-needed-toharm [NNH]: 29 patients [95% CI: 19–59]). Long-term risk of all-cause death up to five years (three randomised controlled trials with 863 patients) increased further in case of paclitaxel (14.7% [78 deaths out in 529 patients] vs. 8.1% [27 deaths in 334 patients] crude risk of death, Continued on page 2

Paediatric IR

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Artificial intelligence will cause “paradigm shift” in IR practice Clinicians are calling for increased collaboration between computer scientists, biomedical engineers and interventional radiologists as machine learning is posited to play a more prominent role in interventional radiology (IR) procedures, from informing the initial diagnosis, through to patient selection and intraprocedural guidance. In a recent primer published in The Journal of Vascular and Interventional Radiology (JVIR), Brian Letzen, Clinton Wang and Julius Chapiro, all of the Yale School of Medicine, New Haven, USA, outline the clinical applications of machine learning for IRs, and visualise a future where artificial intelligence (AI) enables the elevation of the discipline to become, in Chapiro’s words, “the epitome of personalised medicine”.

LETZEN AND COLLEAGUES outline their vision of AI in IR: “By integrating machine learning into diagnosis, treatment, and management, AI can empower physicians to provide the highest-quality personalised care in an efficient manner that meets the demands of modern clinical practice. Whereas medicine has traditionally focused on incremental hypothesis-based research, AI allows for a new paradigm where ‘big data’ can be rapidly analysed, uncovering new insights that may otherwise have required decades of prospective trials.”

The annual meeting of the Society of Interventional Radiology [SIR] this year features its first machine learning in interventional oncology session, and the BOLD-AIR summit initiated by Stanford and NYU (24 April, New York, USA) will tackle regulatory and ethical issues pertaining to data use for AI research.

Continued on page 4

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Top story

US FDA continues to investigate paclitaxel devices in the leg Continued from page 1

NNH: 14 patients [95% CI: 9–32]).

Katsanos and colleagues wrote that meta-regression showed a significant relationship between exposure to paclitaxel (dose-time product) and absolute risk of death (0.4±0.1% excess risk of death per paclitaxel mg-year; p<0.001). “Trial sequential analysis excluded false-positive findings with 99% certainty (2-sided alpha, 1.0%),” they said.

These data led the authors to conclude that there is increased risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery. “Further investigations are urgently warranted,” they wrote.

This finding prompted the cessation of patient enrolment of three randomised controlled trials within days of its release: SWEDEPAD 1, SWEDEPAD 2, and BASIL 3. At the date of publication of this newspaper, the status of the SWEDEPAD trials is still uncertain, with principal investigator Mårten Falkenberg (Gothenburg, Sweden) saying at the recent VLF: “We are at the moment struggling to make up our mind on how to proceed.”

Industry respond that their data do not support the potential association of increased mortality with paclitaxel use

Several large industry players presented their own patient-level analysis at the Leipzig Interventional Course (LINC; 22–25 January, Leipzig, Germany), unanimously concluding that they could find no association between paclitaxel dose and mortality.

An independent, third party, pooled analysis of all the IN.PACT Admiral DCB (Medtronic) clinical programmes, published in the Journal of the American College of Cardiology and including 1,980 patients, demonstrated that at five years, there is no statistically significant difference in all-cause mortality between the DCB and the control arm (9.3% vs. 11.2% respectively, p=0.399).

Ranger (Boston Scientific) SFA randomised trial three-year data from 105 patients showed no significant difference in all-cause mortality between DCB and control (13.8% vs. 10.7%, respectively), according to the presentation given at LINC with CEC-adjudicated cause of death.

Results from a Cook Medical press release also demonstrated the safety of their drug-eluting stent, the Zilver PTX. Patient-level data found no increased mortality at five years with Zilver PTX compared to non-coated stents and balloons (18.7% vs. 17.6% respectively, p=0.53).

A pooled analysis of patient-level data from Philips also demonstrates the “strong safety profile” of the company’s Stellarex DCB in above-the-knee studies, according to a company statement at LINC. The independent, third party pooled analysis evidenced low mortality rates through three years after the treatment with no device-related deaths.

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Five-year data from 1,189 patients in the LEVANT 2 trial within the Lutonix DCB (BD) programme showed no statistically significant difference in all-cause mortality between the DCB and the control group (14.2% vs. 10.6% respectively, p=0.22), as described at LINC. However, Medtronic and Cook Medical have since issued corrections to their published data regarding the safety of their devices, the IN.PACT Admiral DCB and the Zilver PTX drug-eluting stent, respectively. Medtronic announced they have revised IN.PACT post-market study data due to a “programming error,” and Cook Medical noted a mistake made during data publication: that two mortality figures were “inadvertently reversed”.

According to Medtronic, mortality data were inadvertently omitted from the summary tables included in the statistical analysis of their data presented at LINC. These deaths were, however, previously included and reported in Medtronic’s database, captured in the appropriate study exit forms and adjudicated by an independent clinical events committee, a press release issued by the company said. Immediately upon learning of this error, Medtronic notified the FDA and the study authors. The company added in the release that while a component of the recent patient-level meta-analysis will need to be updated, it has found the revised analysis still supports earlier conclusions.

Cook Medical announced that in a paper published in Circulation in 2016 assessing the clinical effectiveness of their Zilver PTX stent, the mortality figures for the Zilver PTX arm and the percutaneous transluminal angioplasty (PTA) arm were inadvertently swapped. Responding to this error, Circulation state: “When high-resolution files were requested during production, an incorrect version of Figure 1 was mistakenly provided. Subsequently, the published version of the flow chart in Figure 1 contained incorrect numbers. The authors now provide the corrected version of Figure 1.

“The following sentence from the ‘Safety’ section of the paper is incorrect: ‘The five-year all-cause mortality rate was 13.6% (10.2% for the primary DES group and 16.9% for the PTA group, p=0.03), and no deaths were adjudicated as procedure or device related.’ [...] The sentence should read: ‘The five-year all-cause mortality rate was 13.6% (16.9% for the primary DES group and 10.2% for the PTA group, p=0.03), and no deaths were adjudicated as procedure or device related.’”

Polling results and informed consent

Polling of 14 panellists at CRT revealed that the majority of voters (10) believed there is “a mortality signal” in the metaanalysis. While none voted against, four responded that they “did not know” if there was a signal or not. In an additional poll, the panel voted eight to six not to change or restrict device labelling. Three voted to restrict and three voted to

change labelling. The CRT panel voted unanimously to discuss the Katsanos et al meta-analysis findings with patients during conversations of informed consent. The final poll at CRT showed that the majority of the panel believed the industry patient-level data are poolable for definitive analysis.

Nine voted for, one against, and four said they did not know.

Polling from the 31st International Symposium on Endovascular Therapy (ISET; 27–30 January, Hollywood, USA) and from the more recent VLF indicate that the majority of physicians will not change their use of paclitaxel devices following the Katsanos et al meta-analysis. At VLF, 60% (21/35) of the polled audience said they would not be more conservative in recommending drug or device combinations for claudication following the discussion around the JAHA meta-analysis, and 86.5% (32 out of 37 responders) of those polled said they would not change their clinical practice as a result of the meta-analysis findings.

In addition, following a morning-long session at ISET, 79% of the audience responded to an anonymous poll to say that they do not believe the Katsanos et al findings are sufficient to change practice. Sixty-nine per cent of respondents said they would continue to use paclitaxel devices as they always have, with the remaining 31% saying they would use paclitaxel devices less.

However, several physicians voiced concerns, at ISET and since, regarding litigation due to the FDA’s continued investigation into the use of paclitaxel in the femoropopliteal artery. Speaking in general on informed consent regarding the use of paclitaxel-releasing devices at VLF, Paul Rudolf (Washington, DC, USA) said he did not want to trivialise the findings by Katsanos and colleagues, and commented: “Even if the data in the meta-analysis are true, at five years only one out of 14 patients would be affected by the mortality signal, which means that 13 out of 14 patients you would be treating with a drug-eluting stent or balloon would still do just fine and not be affected by that.”

Rudolf also said that 40–45% of malpractice lawsuits hinge on an inadequate discussion of the complications of the procedure prior to treatment. He emphasised that in the case of treatment with paclitaxel, informed consent is the most important factor to consider when thinking about the legal implications. As doctors treating patients with paclitaxel devices in the lower leg already have “complicated informed consents” due to the risk of amputation and recurring disease, Rudolf explained that, from his perspective, “I am not sure how different the informed consent will be.

In my view, this is just something that is added on to what is already there.” Rudolf clarified that his comments were made in a general discussion of informed consent during the summit, and were not official legal advice given to practising physicians.

Rudolf suggested physicians stay up to date on device manufacturer information, FDA recommendations, and practice guidelines.

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Machine learning

Artificial intelligence will cause “paradigm shift” in IR practice Continued from page 1

In an editorial for this newspaper last year, Chapiro and Aaron Abajian, also at the Yale School of Medicine, New Haven, USA, detailed the results of an early experiment in applying AI and machine learning as a decision support system in interventional oncology to illustrate its potential to overcome rigid staging and scoring systems in the locoregional treatment of liver cancer.

When presenting his argument in favour of the imminent adoption of machine learning in a session dedicated to the topic at Spectrum (1–4 November, Miami, USA), Chapiro told conference attendees: “The age of AI is already here, and with it, IR has the chance to become the epitome of personalised medicine, and to be everything we want it to be as the fourth pillar of cancer care.”

Structuring large datasets for use in AI

AI makes use of large datasets, and the Society of Interventional Oncology (SIO) is currently working on a “high-quality, well annotated, multi-institutional” database for liver interventions, the first data repository to serve such research. According to Chapiro, such data is “difficult to obtain, especially for industry partners that are developing most such tools and instruments.” Chapiro adds that “It will be up to academic institutions and professional societies to collect such data and make it available for academic and industry-sponsored research.” He told Interventional News that other high-quality databases are likely to follow on from that being built by the SIO. Having high-quality, annotated data is an imperative for incorporating machine learning methods into any sort of research, Raul Uppot, of Massachusetts General Hospital in Boston, USA, explained to this newspaper. According to Uppot, this is the biggest challenge facing those advocating the implementation of AI into clinical practice. He comments: “AI requires a large dataset. If you are going to use AI and apply it to tumour board recommendations, or intraprocedural imaging guidance, or physician workflow, you need large quantities of data to feed into the machine in order for the software to analyse the information provided, to identify a pattern, and to then apply it to practice.

“Right now,” he continues, “we are collecting and structuring the data to feed into the deep learning software. The data we have now is mostly in an unstructured format, which is not useable for deep learning algorithms.”

Researchers at Massachusetts General Hospital, Uppot’s institution in Boston, USA, are exploring the potential use of natural language processing tools to help with this essential data structuring. Explaining this technology, Uppot says: “There are software tools that can read a report and identify key words to be pulled out that can then be used to create a structured report.” Ultimately, Uppot believes this structuring of data should be automated. Hypothesising to Interventional News, he comments: “I think the best application of deep learning is to use it to reach the point where the structured data you are collecting is constantly being fed into the machine, and the software is constantly evaluating the variables that are being put in to generate outcomes. This enables constant learning. Ultimately, that means that as the machine gets smarter, it could learn from and identify patterns retrospectively across, say, 30 years’ worth of data, and recognise trends impossible for humans to uncover.”

However, Uppot also stresses that he believes “a human dynamic” will always be essential. Using the example of tumour board recommendations, he describes how, if data of a specific patient is fed into a machine learning algorithm, and the software recommends an ablation, for example, there may be other factors that come into play that rely on human intervention. In this hypothetical case, he says “there may be a situation where the person cannot lay flat on the table, and therefore an ablation is not the best option. I think machine learning

will be a supplementary add-on, which I think will be very useful, but will not replace radiologists.”

In fact, one positive use of AI Uppot foresees is the addition of an “objective voice” in the room when tumour boards convene to discuss the optimal treatment strategy for a particular patient. He sees the potential for a machine learning-generated recommendation to reduce “turf tensions” between IRs, radiation oncologists, and surgeons.

Using machine learning for HCC recommendations

Uppot went into greater detail on this use of machine learning at Spectrum. There, Uppot said that hepatocellular carcinoma (HCC) tumour board recommendations could benefit from the complex data processing AI enables. He commented: “Tumour board decisions carry great responsibility, and it is very important to be objective in these decisions. Machine learning is one way in which we can make all these decisions objectively amongst a group of physicians.

Multidisciplinary team decisions could then be made by machine learning.” The idea for this use is not new, but the concept of tumour board recommendations being predicated on algorithms rather than expert opinion and discussion remains in the realm of prospective testing at single institutions.

Back in 2017, Uppot and colleagues fed a machine learning algorithm data from 76 HCC patients, ran a random forest algorithm, and then did prospective testing on the results to determine if the output of this AI system—ideal procedural choice—could rival radiologists’ assessment of the best treatment modality.

The input data included a range of different patient, lesion and study characteristics, and after running the programme multiple times to create a decision tree analysis, the study investigators reported that the size of the tumour, its location, and the age of the patient were the most important determinants of the final procedural recommendation. Armed with this knowledge, the investigators then gave the machine learning algorithm new cases, to assess its ability to recommend the optimal treatment option. The recommendations that came out of the algorithm’s machinations largely tallied with those of the tumour board: in the first case Uppot described, for example, the predictive model made by the machine learning system recommended a bridge TACE 44% of the time for that particular patient, which matched the recommendation of the multidisciplinary tumour board.

However, Uppot did also warn of limitations to the machine learning-based approach. In one case, the tumour board and the algorithm disagreed, with the radiologists favouring the use of stereotactic body radiation therapy (SBRT). The algorithm did not suggest any treatment involving radiation, but in this particular instance, the radiation programme was very strong in that institution, a factor not taken into account by the AI model.

Currently, Uppot and colleagues are collecting and structuring their data to replicate this test with a greater number of HCC training datasets. However, he iterates to Interventional News the importance of expanding the data set: “If we want this to be clinically useful and clinically viable, it needs thousands of cases, and not just from Massachusetts General Hospital, but from all of the major hospitals in the USA and around the world. In order for the machine learning software to be smart enough to make recommendations, it needs to be able to compute data independent of one institution.”

In addition to potentially providing objective tumour board recommendations, Chapiro posits a wide range of future clinical uses of AI. These include new imaging and combined clinical or radiological biomarkers for decision support and improved therapy choice, intraprocedural navigation support and improvements of intraprocedural cone beam CT image quality, applications for advanced image guidance in robotic-assisted

ablations, and assessment tools for tumour response on imaging. He postulates that using supervised machine learning to predict treatment response to intra-arterial therapies for HCC will be “a first possible application” of this technology, saying, “I expect that some of it will penetrate preprocedural and intraprocedural imaging as soon as within two to three years.”

Telling of his own institution’s involvement in this field, Chapiro comments, “The Yale Interventional Oncology research group is part of a multi-disciplinary network at Yale in close collaboration with [the] Biomedical Engineering, the Yale Smilow Cancer Center and the Liver Center. We tackle the full breadth of clinical problems and apply AI-based algorithms, mostly machine learning and deep learning methodologies to find solutions for automated lesion detection, characterisation, diagnosis and outcome prediction after locoregional therapies such as TACE [transarterial chemoembolisation]. A lot of credit goes to our biomedical engineers who are truly leading the effort here and collaborate with us closely on this vision.”

Most of this work is National Institute of Health-funded.

Marketing AI

“Ultimately, we must strongly advocate for AI from a patient’s perspective”, Chapiro explains to this newspaper.

“In most of medicine, AI is being marketed and frankly overhyped for its capability to improve workflows and productivity. This is a one-sided narrative and tarnishes good intentions. Data ‘scandals’ and misunderstood kneejerk reflexes from patient advocacy groups will be the logical consequence and it is our fault. We must explain to the patients that AI will first and foremost improve patient care, make it more affordable and certainly also improve therapy outcomes, help us avoid ill-informed clinical decisions and streamline medicine towards more personalised healthcare.”

When pitching ideas to translate AI research into clinical practice to General Electric, prior to their recent selling off of their healthcare division, Uppot noted that the company’s interest had been piqued largely by the prospect of outsourcing the “brain of an academic centre” to a community hospital which may have fewer resources or fewer specialised IRs. At Spectrum, it was mentioned that a large proportion of machine learning companies working in the interventional oncology space were based in China or Israel. Chapiro notes that the geography and local culture “matter a lot” in terms of the development and use of AI in healthcare. He says: “The USA is behind in this respect and we may lose the global contest for the most effective and rapid implementation of those cutting-edge technologies for the benefit of patient care. China benefits from a strong centrally regulated agenda and a more ‘flexible’ approach to protected health information and access to it. In my opinion, this should not be a role model for the western world.

“Israel, however, punches above and beyond its demographic weight and has truly become the world power of AI. This is mostly due to a long-standing educational policy which facilitates the creation of the necessary manpower and the strong reliance on high-tech as part of the regional geopolitical needs. This results in a highly developed academic and military-industrial complex geared towards rapid development and implementation of cutting-edge technology, which in turn trickles down into the healthcare sector. Those circumstances meet a socialised healthcare system and flexible, but still ethically defensible, data policies. In order to compete and win, we [the USA] need to cut regulations and bureaucracy, and possibly even fund a centralised national data registry that would facilitate collection of high-quality data for AI research. The current administration already gave the right impulse by supporting AI research but words must be followed by investments. With the Israeli model by our side, America can still become the global leader in AI.”

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ISET coverage

Promising first-time data indicate human stem cell trial is safe, prompting future efficacy study A first-in-human, phase I clinical trial using stem cells to prevent venous stenosis formation in arteriovenous (AV) fistulas yields promising results. Sanjay Misra (Mayo Clinic, Rochester, USA) presented these results at the 31st annual International Symposium on Endovascular Therapy (ISET; 27–30 January, Hollywood, USA), and won the award for best poster for the same research.

THIS WAS THE first time this research had been presented at a meeting, and generated an atmosphere of excitement about the potential of autologous adipose-derived mesenchymal stem cells (AMSCs) for increasing maturation and preventing venous stenosis formation in AV fistulas used for haemodialysis.

To contextualise the importance of this research, Misra says: “At one year, nearly 60% of AV fistulas will develop a malfunction, often due to venous stenosis formation, and nearly 40% fail to mature.

Pathologically, AV fistulas fail due to venous neointimal hyperplasia caused by an increase in proinflammatory gene expression, including monocyte chemoattractant protein-1 and tissue necrosis factor-1 alpha.”

Recognising that with the primary patency of surgical creation of AV fistulas being between 60–70% means there is a high failure rate of approximately 30%, Misra became interested in using stem cells derived from patients as their own therapy or drug.

Following preliminary research conducted in mice, the research group was granted an IND (Investigational New Drug application) from the US Food and Drug Administration (FDA) to pursue the study, which was a phase I safety trial. “Our primary concern was around safety. Would these cells be creating more infections?

Will they be less irritating with respect to fevers? So we did a randomised trial comparing patients who received stem cells or no cells and followed them for one year,” Misra explains.

In the phase I, single-centre, prospective, blinded,

Sanjay Misra presenting at ISET

randomised trial, the study investigators reported no adverse events related to stem cell delivery, and a success in terms of maturation rate with the stem cell cohort compared to the control arm. Crucially, the team at Rochester also reported no safety issues with respect to the cellular delivery.

One month after periadventitial delivery of the autologous AMSCs to the outflow vein of the AV fistula, the maturation rate for radial-cephalic fistulas was 100% in the stem cell arm, versus 66% in the control group.

For brachial-cephalic fistulas, the maturation rate was 100% in both the stem cell and the control cohorts (there were four patients in each group).

Nine patients were followed up to 12 months’

The time for chelation therapy to treat diabetic patients with critical limb ischaemia is now A pilot study of edetate disodium-based chelation in diabetic patients with critical limb ischaemia (CLI) has positive results, leading the study investigators to “cautiously support” the design of a chelation trial in peripheral arterial disease (PAD). This conclusion was presented in an e-poster at the 31st International Symposium on Endovascular Therapy (ISET; 27–30 January, Hollywood, USA) by Francisco Ujueta, and as a presentation by Gervasio Lamas (both Mount Sinai Medical Center, Miami, USA), who has dedicated much of his professional life to the study of chelation therapy.

T

he study authors note that the National Institute of Health (NIH)-funded trial to assess chelation therapy (TACT) demonstrated a reduction in cardiac events in diabetic patients receiving edetate disodium-based chelation. As CLI carries a high annual risk of death, major amputation and/or myocardial infarction, the investigators tested TACT infusions in 10 patients with both diabetes mellitus and CLI (the latter defined as Rutherford category 4 or 5, with ≥75% stenosis in two or more infrapopliteal arteries, as well as a skin perfusion pressure of 40mmHg in the affected limb) to see if they could improve quality of life and limb salvage.

In this open-label trial, up to 50 TACT infusions were given over one year, plus oral vitamins. Infusions contained up to 3g of edetate disodium, 7g of vitamin

C, B vitamins, magnesium, and other electrolytes. Lamas acknowledged at the start of his talk that “until recently, [chelation therapy] was considered quackery”, but set out to change the audience’s mind through sharing his experiences with the treatment and the positive results of the present study.

In a multicentre, randomised trial in post-myocardial infarction patients, patients were given either 40 3g doses of disodium-EDTA, or 40 placebo infusions. No change was observed amongst the placebo cohort, but Lamas reports that most of the benefit seen in the investigational arm were in the 633 diabetic patients. Over the course of five years, the study investigators witnessed a 41% decrease in major adverse cardiac events (MACE). Breaking this result down, Lamas specifically points to the

post-procedure. At this last follow-up, patients in the control group were receiving more interventions than those in the treatment arm: three patients in the control cohort (one brachial-cephalic and two radial-cephalic) underwent five fistulograms with four percutaneous transluminal angioplasties of the cannulation zone, compared with one patient in the stem cell group. “So we are seeing an effect related to the cells, and less frequency of interventions,” says Misra.

The Rochester-based team are continuing to enrol patients in this prospective, phase I trial, and a future study is being planned to help determine the efficacy of this therapy. To date, 16 patients have been enrolled (11 men and five women). Patients have an average age of approximately 65 years and an average BMI of 37.99.

All of the 16 patients in the study were hypotensive, 10 had a history of diabetes mellitus, five were on haemodialysis, six had a history of coronary artery disease, and 11 had dyslipidemia.

Misra indicated that a possible future direction of this work could be its use in conjunction with angioplasty for stenotic AVF. He told delegates at ISET that there was interest from the cardiothoracic surgeons at Rochester in using this therapy in coronary artery bypass grafting (CABG), and concluded by remarking that “Obviously, we can start to think about using this in the lower extremity as well.”

He and his colleagues are in the process of filing an IDE for using this stem cell therapy with angioplasty and periadventitial catheters.

detected 43% reduction in relative risk of death, in his words the “holy grail of clinical trials”, and to an approximately 50% reduction in risk of recurrent myocardial infarction.

Toxic metals are a known atherosclerotic risk factor. The aim of chelation therapy is to reduce this risk via the removal of toxic metals from the body through the urine. Following chelation therapy, huge increases in the urinary cadmium and lead concentrations are observed, indicating the flushing out of these materials from the body. In this study, over the course of 40 infusions with the disodium-EDTA, Lamas and co-authors detected a 1,234% increase in urinary cadmium levels from baseline, and a 2,370% increase in urinary lead levels from baseline.

Supplementing this multicentre data with the story of particular cases in an earlier, experimental study, Lamas describes the desperation of some diabetic patients with CLI. He told ISET attendees

TACT infusions in diabetic CLI patients are safe [...] and might improve clinical outcomes.”

how one patient, after experiencing multiple unsuccessful revascularisation attempts through interventional and surgical means, was scheduled for a below-the-knee amputation. According to Lamas, the patient’s wife found out about Lamas’ open-label experiment in 10 patients and “insisted” that he give chelation a try. After 48 infusions, and no other intervention, the patient was no longer at risk of amputation, and the ulceration had disappeared. Of the pre-treatment and post-treatment images, Lamas said: “These are the kinds of pictures that led me to believe we need to look at this as an adjunct to everything that is being done at this conference [ISET]”.

Lamas informed delegates that the patient’s wife refused to stop chelation treatment, and so he has been getting the treatment from a chelation practitioner.

The poster presented at ISET shows these same results. Ujueta and colleagues conclude: “These findings suggest that TACT infusions in diabetic CLI patients are safe, increase excretion of vasculotoxic metals, may improve quality of life, and might improve clinical outcomes.”

Lamas concurred at the end of his presentation: “Toxic metals are a modifiable atherosclerotic risk factor, and this may be the time to begin to recognise this; this is an idea whose time has come.”

The study was funded by Mount Sinai Medical Center and the James Carter Memorial Fund.

Mar

Paclitaxel-releasing devices: An unfolding story 8.12.18

Medtronic and Boston Scientific stand by paclitaxel devices despite Katsanos’ critical study Speaking to investors at the JP Morgan healthcare conference in San Francisco, USA, executives from Medtronic and Boston Scientific said their data do not show the safety risks cited in Katsanos (Patras, Greece) et al’s published analysis. According to Star Tribune, the companies stated that they are not backing away from drug-eluting devices used in blood vessels in the legs, despite the conclusions of the JAHA meta-analysis. DCBs from both Medtronic and Boston Scientific (IN.PACT Admiral and Ranger, respectively) were used in the JAHA meta-analysis. Boston Scientific’s Eluvia drug-eluting stent also contains paclitaxel, though was not used in the analysis.

The US FDA evaluates paclitaxel data, and recommends patient surveillance The US Food and Drug Administration (FDA) begins to evaluate its recommendations for the treatment. In a letter to healthcare providers, the FDA states that it is evaluating the “recent information regarding the potential for increased long-term mortality” following paclitaxel-coated balloon or paclitaxel-eluting stent treatments in the femoropopliteal artery for patients with PAD. Whilst the data review is ongoing, the regulatory body recommends “continued surveillance” for patients treated with paclitaxel. The FDA believes the “benefits continue to outweigh the risks” for approved devices used within their indications.

Patient-level analysis presented at LINC from Medtronic, Cook Medical, and Philips reports no link between paclitaxel dose and mortality New data presented at the Leipzig Interventional Course (LINC) in Leipzig, Germany (22–25 January) by various industry leaders finds no association between paclitaxel dose and mortality.

An independent, third party, pooled analysis of all the IN.PACT Admiral DCB (Medtronic) clinical programmes, published in the Journal of the American College of Cardiology and including 1,980 patients, demonstrated that at five years, there is no statistically significant difference in all-cause mortality between the DCB and the control arm (9.3% vs. 11.2% respectively, p=0.399). Ranger (Boston Scientific) SFA randomised trial three-year data from 105 patients showed no significant difference in all-cause mortality between DCB and control (13.8% vs. 10.7%, respectively). Results from a Cook Medical press release also demonstrated the safety of their drugeluting stent, the Zilver PTX. Patient-level data found no increased mortality at five years with Zilver PTX compared to non-coated stents and balloons (18.7% vs. 17.6% respectively, p=0.53). A pooled analysis of patient-level data from Philips also demonstrates the “strong safety profile” of the company’s Stellarex DCB in above-theknee studies, according to a company statement. The independent, third party pooled analysis evidenced low mortality rates through three years after the treatment with no device-related deaths. Fiveyear data from 1,189 patients in the Levant 2 trial within the Lutonix DCB (BD) programme showed no statistically significant difference in all-cause mortality between the DCB and the control group (14.2% vs. 10.6% respectively, p=0.22).

22.01.19

Without additional long-term and patientlevel data, Katsanos et al’s conclusion is premature In a commentary published by Interventional News, Thomas Zeller (Bad Krozingen, Germany) said: “I am concerned with the conclusion that there is an association between all-cause mortality and paclitaxel with no clear causal explanation of a pathophysiological mechanism of action. The authors spend no time exploring other potential hypotheses for the observed trends and the lack of patient-level data is a clear limitation to being able to draw these conclusions. As one of the investigators in several of the studies cited here—in particular of those with five-year follow-up (THUNDER, IN.PACT SFA randomised controlled trial, ZILVER PTX randomised controlled trial)—it is important to note that the observed trend is not new. In fact, we published two- and three-year results showing a statistically significant frequency of allcause mortality between DCB and plain balloon angioplasty (PTA) arms of the IN.PACT SFA study. We have subsequently presented on the four- and five-year data, showing no significant difference in mortality. Events in the trial were reviewed by an independent clinical events committee and none were related to the device, or paclitaxel.”

SWEDEPAD 1 and SWEDEPAD 2 trials halt inclusion Inclusion into the SWEDEPAD studies, examining the benefits of drug-eluting technology for peripheral arterial disease (PAD) patients, has been halted. As outlined in the public domain, the SWEDEPAD (Swedish drug-elution trial in PAD) project is designed to test the hypothesis that drug-eluting technology is superior to conventional endovascular treatment in terms of important clinical outcomes, when applied on infrainguinal (femoropopliteal and/or infrapopliteal) obstructive vascular lesions. The SWEDEPAD project consists of two separate parallel studies, SWEDEPAD 1 and SWEDEPAD 2, each defined by the severity of PAD. As noted on clinicaltrials.gov, “patients with critical limb ischaemia are allocated to SWEDEPAD 1 and patients with intermittent claudication are allocated to SWEDEPAD 2.” The trials had a planned enrolment of 3,800 participants.

An update on the SWEDEPAD website (when translated into English) reads: “Inclusion in SWEDEPAD studies stop! On the occasion of the Katsano’s [sic] systematic literature review published today, the study management has today met with the Data Safety Monitoring Committee (DSMC) in SWEDEPAD. After DSMC performed an interim safety analysis of the study’s prespecified and monitored safety variables (occlusion rate, amputation rate and mortality by 30 days and one year) distributed on treatment allocation, the recommendation from DSMC is to promptly pause further inclusion in both SWEDEPAD 1 and SWEDEPAD 2.”

11.01.19

6.12.18

Meta-analysis finds a higher risk of death in the long term when paclitaxel-coated devices are used in the leg Konstantinos Katsanos (Patras, Greece) and colleagues publish data in the Journal of the American Heart Association (JAHA) suggesting that there is an increased risk of death at two and five years following the use of paclitaxel-releasing balloons and stents in the femoropopliteal artery. The investigators conducted a systematic review and metaanalysis of 28 randomised controlled trials with a total of 4,663 patients investigating paclitaxelcoated balloon angioplasty or paclitaxel-coated metal stents in arteries in the leg.

At one year, all-cause patient death was similar between 17 paclitaxel-coated devices and control arms (2.3% vs. 2.3% crude risk of death).

All-cause death at two years was significantly increased in the case of paclitaxel versus control (7.2% [101 deaths in 1,397 patients] vs. 3.8% [35 deaths in 919 patients] crude risk of death, number-needed-to-harm [NNH]: 29 patients [95% CI: 19–59]). Long-term risk of all-cause death up to five years increased further in the case of paclitaxel (14.7% [78 deaths out in 529 patients] versus 8.1% [27 deaths in 334 patients] crude risk of death, NNH: 14 patients [95% CI: 9–32]).

While the authors write that their findings are supported by robust statistical evidence, some leading physicians state that it lacks individual patient-level data from the randomised controlled trials. Katsanos and colleagues end their paper by saying that “further investigations are urgently warranted”. See page 51 for a BIBA MedTech survey capturing the physician response.

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Paclitaxel timeline

18.01.19

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Paclitaxel timeline

CX aims to give the last word The Charing Cross Symposium (CX; 15–18 April, London, UK) hosts a highlight session to independently review whether or not paclitaxel useage is beneficial or detrimental to the patient, and brings together the godfather of drugcoated balloons, Ulrich Speck, and Konstantinos Katsanos for the first time, with the aim of having the last word on this controversy.

CRT panelists vote overwhelmingly for there being a mortality signal Polling of 14 panellists at CRT revealed that the majority of voters (10) believed there is “a mortality signal” in the metaanalysis. While none voted against, four responded that they “did not know” if there was a signal or not. In an additional poll, the panel voted eight to six not to change or restrict device labelling.

Three voted to restrict and three voted to change labelling. The CRT panel voted unanimously to discuss the Katsanos et al meta-analysis findings with patients during conversations of informed consent. The final poll at CRT showed that the majority of the panel believed the industry patient-level data is poolable for definitive analysis. Nine voted for, one against, and four said they did not know.

2–5.03.19

Medtronic and Cook Medical issue corrections to published data regarding the safety of their paclitaxelcovered devices Medtronic announce they have revised IN.PACT post-market study data due to a “programming error,” and Cook Medical note a mistake made during data publication: that two mortality figures were “inadvertently reversed”.

According to Medtronic, mortality data were accidentally omitted from the summary tables included in the statistical analysis of their data presented at LINC. These deaths were, however, previously included and reported in Medtronic’s database, captured in the appropriate study exit forms and adjudicated by an independent clinical events committee.

Immediately upon learning of this error, Medtronic notified the FDA and the study authors. The company stated that while a component of the recent patient-level meta-analysis will need to be updated, it has found the revised analysis still supports earlier conclusions.

Cook Medical announce that in a paper published in Circulation in 2016 assessing the clinical effectiveness of their Zilver PTX stent, the mortality figures for the Zilver PTX arm and the PTA arm were swapped. Circulation state: “When high-resolution files were requested during production, an incorrect version of Figure 1 was mistakenly provided.

Subsequently, the published version of the flow chart in Figure 1 contained incorrect numbers. The authors now provide the corrected version of Figure 1.”

22.02.19

28.01.19

Society for Cardiovascular Angiography and Interventions supports continued use of paclitaxel devices Experts from the Society for Cardiovascular Angiography and Interventions (SCAI) have reviewed the Katsanos et al publication and have concluded that the methods are appropriate and within constraints of trial-level metaanalysis. However, the society statement says “it is important to note that SCAI believes the associations are hypothesisgenerating and require further investigation with patient-level data.”

1–2.03.19

29.01.19 24.01.19

BASIL-3 trial pauses for review of paclitaxel meta-analysis data The BASIL-3 trial pauses recruitment, stating there are concerns about patient safety following the outcomes of the JAHA meta-analysis.

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Vast majority of ISET attendees will not change their use of paclitaxel devices following the Katsanos et al meta-analysis The 31st International Symposium on Endovascular Therapy (ISET; 27–30 January, Hollywood, USA) host a paclitaxel town hall to discuss the continued use of these devices. Following a morninglong discussion, 79% of the ISET audience do not believe the Katsanos et al findings are sufficient to change practice. Thirty-one percent of respondents said they would use paclitaxel devices less, while the remaining 69% answered that they would continue to use the devices as they always have.

Several physicians voiced concerns regarding litigation following the FDA’s announcement that it is launching its own investigation.

The discussion continues at the Vascular Leaders Forum VIVA (Vascular Interventional Advances) assembles an invite-only special session of the Vascular Leaders Forum series on the topic “Drug elution in peripheral arterial disease (PAD): A critical analysis from a multidisciplinary consortium” (1–2 March, Washington, DC, USA). As reported on page 1 of this newspaper, the FDA announes during VLF that the regulatory body’s own preliminary evaluation confimed the mortality signal reported by Katsanos et al.

The last word

15–18.04.19

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Below-the-knee interventions

Novel catheter delivering liquid paclitaxel safely and effectively prevents restenosis in below-the-knee lesions The efficacy and safety of a novel catheter delivering liquid paclitaxel for the prevention of restenosis in below-the-knee lesions has been confirmed by study investigators across 17 sites in the USA. This is the conclusion of the COPPER BTK trial (Occlusion perfusion catheter for optimal delivery of paclitaxel for the prevention of endovascular restenosis—below-the-knee), presented by Pradeep Nair of the Cardiovascular Institute of the South Houma (Houma, USA) at the 31st International Symposium on Endovascular Therapy (ISET; 27–30 January, Hollywood, USA).

THE OCCLUSION PERFUSION catheter (Advanced Catheter Therapies) is a universal drug-delivery device.

According to an editor’s note in Vascular Disease Management written by Nair in his capacity as New Technologies section editor for the publication, this catheter “allows for delivery of antiproliferative drug[s] to a targeted treatment area, demonstrates exceptional medial layer drug uptake, and can be reused for multiple treatment sites. Additionally, the outer occlusion balloons prevent downstream washout of antiproliferative agent[s].

Ongoing trials will help establish its role in peripheral arterial disease intervention for both above- and belowthe-knee applications.”

The prospective, non-randomised, open-label, multicentre study presented by Nair at ISET aimed to evaluate the efficacy of the Occlusion perfusion catheter after atherectomy and percutaneous transluminal angioplasty (PTA) in treating de novo and restenotic below-the-knee lesions, as determined by primary patency at six months. The safety profile of the device was also assessed, defined as freedom from major adverse events at one month. Major adverse events included target lesion revascularisation, major amputation, and target limb-related death. A total of 35 patients were enrolled in the study, with a mean lesion length of 119.1±80.4mm, and a diameter stenosis of 93.7±8.81%. All patients were in Rutherford class 2–5.

At six months, primary patency was 88%, and the study investigators reported 96% freedom from clinically-driven target lesion revascularisation. There was no target lesion revascularisation, target limbrelated death, or major amputation in the target limb.

The Rutherford classification also improved on average over the course of the study: at baseline, the average

Rutherford score was 3.6±0.8, and at six months, the average Rutherford score was 1.8±1.2.

These positive data drew Nair to summarise: “The delivery of liquid paclitaxel using the occlusion perfusion catheter under controlled pressure was technically Pradeep Nair achievable without procedural complications.

The feasibility and initial efficacy of this device provide encouragement for this new technique, with the potential as an alternative approach for infrapopliteal revascularisation. In particular, the ability to treat very long or multivessel lesions with a single device could provide a more economical option.”

In addition, he added: “The safety profile in this small cohort study is particularly favourable, and focuses treatment at the target lesion with minimal drug loss that can occur with drug-coated balloons (DCBs).”

Nair acknowledges that longer-term follow-up and larger clinical studies will be needed to support the initial findings of this technology with head-to-head comparisons with DCB and balloon angioplasty (with and without atherectomy).

As is common knowledge amongst the interventional community, the optimal strategy for below-the-knee arterial disease remains uncertain. Treatment is impeded by the high incidence of long chronic total occlusions and calcified lesions, meaning previous interventionalists have experienced high restenosis rates and poor long-term clinical

DEEPER first-in-human results presented at VIVA

The first-in-human data from the DEEPER trial were presented at VIVA 2018 (5–8 November, Las Vegas, USA) by John Laird, Adventist Heart & Vascular Institute team at St Helena Hospital, St Helena, USA.

T

he purpose of this trial is to evaluate the safety and efficacy of the Temporary Spur stent system (Reflow Medical), in conjunction with a drug-coated balloon (DCB) in patients with below-the-knee disease. The primary efficacy endpoint of the trial is binary arterial flow of treated lesion sites by continuous wave Doppler through six months. The dual primary safety endpoints are freedom from device- and procedure-related death through 30 days’ post-procedure and freedom from target limb major amputation and clinically driven target lesion revascularisation through 12 months’ post-procedure.

This trial is a prospective, singlecentre, non-randomised, single arm study. Trial enrolment began in October 2017 and was completed in May 2018, with 21 patients having completed trial and procedure enrolment and undergoing follow-up. Twelve patients have

completed follow-up through six months, and all 21 have completed follow-up out to at least three months.

Laird reported that all 21 enrolled patients have met the safety endpoints of the trial to this date, with no clinicallydriven target lesion revascularisation, no major adverse limb events, and freedom from device- and procedure-related death through 30 days’ post-procedure.

Out of the group that has completed six-month follow-up, 11 patients (92%) were found to have patent flow by waveform Doppler through six months, the primary efficacy endpoint, confirmed by ultrasound/angiogram for Spur/DCBtreated areas. Adjudication of the Doppler ultrasound results and angiographic follow-up results has been conducted with a core lab. The majority of patients in this trial have seen an improvement in clinical outcomes, with an average decrease in Rutherford class score by two classes

patency when treating these difficult lesions. PTA is most commonly employed as a treatment regimen, but, Nair explained at ISET, “often yields non-durable results”. He cited a primary patency of 63% at one year, less than threequarters of the six-month primary patency rate observed in the present study with the occlusion perfusion catheter.

Nair noted that DCBs in below-the-knee arteries have historically yielded mixed results, but that several randomised clinical trials in the below-the-knee space evaluating DCBs and scaffolds are ongoing. The main difference between DCBs and the occlusion perfusion catheter used in the COPPER BTK trial is that, while DCBs store antiproliferative agents in the intima, the catheter delivers these therapeutic agents directly to the medial wall.

Occlusion perfusion catheter design

The Occlusion perfusion catheter is a multilumen catheter designed to temporarily occlude the target lesion from blood flow, flush the blood from the treatment chamber, and then locally deliver the therapeutic agents into the artery. It has two compliant occlusion balloons (one proximal and one distal), which define the treatment chamber. The catheter also has one centre space-occupying balloon, which does not contact the vessel wall. Treatment chamber pressure is measured in real time during infusion of the therapeutic agent via a sensor located within the chamber connected to an external pressure monitor.

Therapeutic agents are infused through the treatment inflow under continuous pressure injection; treatment time is two minutes. The average paclitaxel dose per placement is 6.15mg. Radiopaque markers are located on both sides of the occlusion balloons to define the treatment chamber and assist in catheter placement under fluoroscopy.

(maximum –4, minimum 0) at six months.

Of patients with wounds, 88% saw complete wound healing at six months and all saw improvement.

Jihad Mustapha (Grand Rapids, USA) explained to Interventional News how the Temporary Spur system works to help deliver drugs to the media or subintima of the vessel wall. He said: “It is a self-

Spur has the ability to penetrate the intima elastic membrane.” expanding stent, so it is delivered to the target lesion, and you pin and pull; the physician essentially deploys it like a self-expanding stent. The device will open up, and touch the vessel wall in a uniform fashion. Then the physician inflates the balloon inside the device, and the balloon will nicely allow the spike to enter into the vessel wall. The disease we are trying to treat is in the vessel wall. So this is how the spur device is different from anything else out there today: as it penetrates the vessel

wall, and creates channels, you deflate the balloon, and then retrieve the stent, removing it completely. The current state of mind, that is different from Spur, is you inflate a balloon, deflate it, and then hope to create channels with the balloon to create a method or way for the drug to make it to the media or the subintima. With the Spur, it guarantees the delivery of the drug to the media and the subintima. So this is the major difference between the two. There is a guaranteed delivery versus none.”

In the majority of the patients enrolled in the DEEPER trial, the Spur device was deployed in TASC C and D tibial arteries.

Mustapha explained “That automatically takes us into a very high complexity of tibial disease. The Spur has the ability to penetrate the elastic tissue, which is very difficult to penetrate with a balloon. Then it has the ability to penetrate the intima calcium, which is also very difficult, and the ability to penetrate the intima elastic membrane and media calcifications. All the major barriers in the tibial artery that have led to all these years of failure to reach a good outcome in the tibial arteries [are overcome with the Spur device]. Because we knew there was a lot of failure in the tibial arteries, we thought ‘If we are going to be successful in the tibial arteries, we know we are going to be successful anywhere else.”

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Depression and peripheral arterial disease: A call to action Joel Ramirez Marlene Grenon Comment & Analysis With “an indisputable association between depression and peripheral arterial disease (PAD)”—nearly a third of PAD patients experience comorbid depression or depressive symptoms— Joel Ramirez and Marlene Grenon here call for vascular interventionalists to take a more active role in their patient’s mental health: increasing the awareness of the links between these two conditions, recognising the symptoms of depression, and referring patients to a mental health specialist where appropriate.

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Mar

eripheral arterial disease (PAD) is a major global health problem that has been estimated to affect more than 200 million people wordwide with an increasing incidence.1 PAD has been associated with an increased risk of limb amputation, adverse cardiovascular events, and mortality, as well as impaired quality of life, which have collectively resulted in a high economic burden on society.2 Despite widespread campaigns to improve cardiovascular health, the prevalence of PAD is expected to increase with the aging world population. Given the large impact that PAD has, it is important that as interventionalists we are able to adequately identify, prevent, and treat modifiable risk factors for PAD. Although not commonly recognised by interventionalists, the incidence of depression has been rising, particularly in young adults. Depression is a leading cause of disability worldwide,3 and has become a well-recognised risk factor for the development and progression of coronary artery disease (CAD). In fact, depression has been formally recognised by the American Heart Association (AHA) as a risk factor for CAD incidence and adverse outcomes, which has resulted in the creation of guidelines for depression screening in this patient population.4 Given the overlap between risk factors for CAD and PAD, investigators have recently begun to examine the association between depression and PAD. My colleagues and I have dedicated our recent research efforts to the problem of depression and PAD. Our understanding of the risk factors for the development and progression of PAD used to be narrower, as we primarily only considered traditional risk factors such as smoking, hypertension, hyperlipidaemia, and diabetes, among others. We now have a more comprehensive understanding of this

disease and have recognised that mental illness, specifically depression, may play a role in the development of PAD and adverse outcomes among patients with PAD. It has been reported that nearly a third of patients with PAD have comorbid depression or have experienced depressive symptoms.5 Among patients with PAD, depressive symptoms have been associated with worse claudication, decreased patency after peripheral revascularisation, and increased incidence of major amputation, adverse cardiac events, and mortality.6 From a pathophysiological perspective, our findings support mechanistic pathways linking depression to PAD. We have shown that worse

among patients with PAD and depression, the absence of antidepressant use was associated with an increased risk of limb loss.8 The scientific evidence supporting a relationship between depression and PAD is growing. To address this new burden of disease, we need to generate innovative solutions and engage leaders in vascular medicine and surgery. The first step in addressing the role of depression in PAD is increasing awareness of the relationships that have been reported.6 While outside the comfort zone of most interventionalists, understanding the role that depression plays in PAD could provide additional insight into opportunities to improve outcomes in this patient population. We have a responsibility to address the well-being of our patients, by enabling open dialogue about mental health and by ensuring that our patients are receiving proper screening and treatment for mental illness. Although most interventionalists are uncomfortable treating or managing mental illness, as the impact of depression on PAD becomes more clear, it is essential that we recognise the signs and symptoms of depression, and refer patients to mental health specialists or primary care physicians for appropriate diagnosis and treatment.

Our understanding of the pathophysiology that implicates depression with the development of atherosclerosis is largely based upon CAD animal models and patients with CAD. Although CAD has a similar pathophysiology to PAD, there are some differences, and research specific to PAD will be necessary to better understand the relationship between depression and PAD. Furthmore, our understanding of the clinical impact that depression has on PAD is currently limited to a few studies.6 We strongly encourage that investigators conduct basic science, translational, and clinical research examining the association between depression and PAD. For clinical and translational research studies, we recommend

Mental illness, specifically depression, may play a role in the development of PAD and adverse outcomes among patients with PAD.” depressive symptoms are correlated with higher levels of inflammation,7 which may mediate the development of PAD and adverse outcomes. Aside from its pro-inflammatory properties, we recently reviewed6 a tremendous body of evidence that suggests that depression can dysregulate the metabolic system, the hypothalamic-pituitary-axis, and the coagulation pathway, all of which are crucial to the proper functioning of the cardiovascular system. Although the relationship between depression and PAD is convincing, there are currently a paucity of reports examining how antidepressants or behavioral therapy alters the risk of PAD incidence or outcomes in this patient population. However, a recent study by Arya et al has observed that

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Thoracic endovascular repair

collecting data related to depression and/ or eliciting a brief psychiatric history, documenting antidepressant medications or utilisation of behavioral therapy, and screening for depression using validated questionnaires, such as the Patient Health Questionnaire-9 or Geriatric Depression Scale Short Form. These variables can also be easily collected for secondary aims in other studies of patients with PAD. Additional research investigating the impact of depression on incidence, progression, and outcomes of PAD is necessary, in order to clarify the mechanisms linking these diseases.

As research examining the relationship between depression and PAD becomes more robust, we hope that screening and treatment guidelines will be created

in order to influence everyday clinical practice. Given that there are similar guidelines from the AHA that exist for depression and CAD, this seems reasonable.4 Furthermore, innovative digital health solutions that aim to approach the treatment of depression in ways that are more adapted to the needs of our population (such as telehealth and on-thego apps) are becoming more available.

Utilising these technologies may allow for improved identification and management of depression in patients with PAD. We encourage vascular clinicians and investigators to engage with this rapidly evolving landscape of innovation and digital health, where disruption may help improve the care that patients with PAD receive.

There exists an indisputable association between depression and PAD. Although our understanding of this relationship is currently limited by existing research, we should increase the awareness of the importance of depression among patients with PAD and those at high risk for PAD, as well as refer patients to mental health specialists or primary care physicians for screening, diagnosis, or treatment when appropriate. Additionally, when designing studies of PAD, we strongly recommend collecting information on mental health and specifically depression. Lastly, we call for vascular interventionalists to become more engaged in innovative digital health solutions that are becoming increasingly available for the treatment of chronic diseases and mental health.

Joel Ramirez is a vascular surgeon in the Department of Surgery, Division of Vascular and Endovascular Surgery, University of California, San Francisco, USA. Marlene Grenon is a vascular surgeon in the Department of Surgery, Division of Vascular and Endovascular Surgery, University of California, San Francisco, USA, and at Evry Health, Dallas, USA. References: 1. Fowkes FG, Rudan D, Rudan I, et al Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 2013; 382: 1329-1340. 2013/08/07. DOI: 10.1016/S01406736(13)61249-0.

2. Morley RL, Sharma A, Horsch AD, et al Peripheral artery disease. BMJ 2018; 360: j5842. 2018/02/09. DOI: 10.1136/bmj.j5842.

3. Ferrari AJ, Charlson FJ, Norman RE, et al Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010.

PLoS Med 2013; 10: e1001547. 2013/11/14. DOI: 10.1371/journal.pmed.1001547.

4. Lichtman JH, Bigger JT, Jr., Blumenthal JA, et al Depression and coronary heart disease: recommendations for screening, referral, and treatment: a science advisory from the American Heart Association Prevention Committee of the Council on Cardiovascular Nursing, Council on Clinical Cardiology, Council on Epidemiology and Prevention, and Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Psychiatric Association.

Circulation 2008; 118: 1768-1775. 2008/10/01. DOI: 10.1161/CIRCULATIONAHA.108.190769.

5. McDermott MM, Greenland P, Guralnik JM, et al Depressive symptoms and lower extremity functioning in men and women with peripheral arterial disease. J Gen Intern Med 2003; 18: 461-467. 2003/06/26.

6. Ramirez JL, Drudi LM and Grenon SM. Review of Biologic and Behavioral Risk Factors Linking Depression and Peripheral Artery Disease. Vasc Med 2018; In Press.

7. Hernandez NV, Ramirez JL, Khetani SA, et al Depression severity is associated with increased inflammation in veterans with peripheral artery disease.

Vasc Med 2018; 23: 445-453. 2018/07/24. DOI: 10.1177/1358863X18787640.

8. Arya S, Lee S, Zahner GJ, et al The association of comorbid depression with mortality and amputation in veterans with peripheral artery disease. J Vasc Surg 2018 2018/03/29. DOI: 10.1016/j.jvs.2017.10.092.

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Drug-eluting stents

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ADVERTORIAL

New data from the IMPERIAL trial reveal Eluvia is more effective in diabetic patients

Patients treated with the ELUVIA drug-eluting vascular stent system (Boston Scientific) demonstrated statistically significant lower rates of target lesion revascularisation (TLR) and stent thrombosis when compared to those treated with the Zilver PTX drug-eluting peripheral stent (Cook Medical), the most recent results of a diabetic subanalysis from the IMPERIAL trial reveal.

These conclusions were presented during a first data release session at the Leipzig Interventional Course (LINC; 22–25 January, Leipzig, Germany).

THE IMPERIAL TRIAL is a global, multicentre, randomised controlled trial that included 465 patients with superficial femoral artery (SFA) and proximal popliteal artery (PPA) lesions up to 140mm in length. It is the first head-to-head drugeluting stent trial in the SFA evaluating both the Eluvia and Zilver PTX stent systems in patients with symptomatic peripheral arterial disease (PAD).

Over 400 million people worldwide suffer from diabetes, which raises their risk of heart attacks, stroke and PAD. Explaining the specific difficulties of treating diabetic patients, coprincipal investigator of the IMPERIAL trial, Stefan Müller-Hülsbeck, (Vascular Center Diako Flensburg; Head of the Department of Diagnostic and Interventional Radiology/Neuroradiology, Academic Hospitals Flensburg, Germany) comments: “Patients with diabetes have an accelerated time course in developing PAD and the lesion characteristics are often challenging. They do particularly poorly if treated with bare technologies (plain transluminal angioplasty or bare metal stent) with a high rate of reintervention.”

Subgroup analysis for diabetic patients with PAD

In this IMPERIAL subgroup analysis, diabetic patients in the Eluvia arm of the study experienced more than 70% reduction in TLR (3.7% for Eluvia compared to 13.6% for Zilver PTX), as well as achieved a nine-fold, statistically significant lower rate of stent thrombosis (0.9% for ELUVIA vs. 8.1% for Zilver PTX) at 12 months. All told, 95.4% of patients treated with

ELUVIA drug-eluting vascular Virendra Patelstent system (Boston Scientific)

Diabetic patients are the most challenging to treat medically and have multiple comorbidities. Their presenting lesion morphology is likely to be more complex and challenging to treat.

The results for both safety and efficacy of the Eluvia drug-eluting stent provide confidence that this is an effective primary interventional treatment option for these patients.”

CORP – 609904 – AA Feb 2019

Eluvia were major adverse event (MAE)-free at one year, compared to 86.4% MAE-free in the Zilver PTX cohort. Those treated with the Eluvia stent also experienced a primary patency rate of 87.4% versus 80.2% for those who received Zilver PTX. That the Eluvia stent performed so well in diabetic patients is “remarkable”, and “provides confidence” to clinicians when making treatment decisions, Müller-Hülsbeck says. He elaborates: “Diabetic patients are the most challenging patient group to treat medically and have multiple comorbidities. Their presenting lesion morphology is likely to be more complex and challenging to treat. The results for both safety and efficacy of the Eluvia drug-eluting stent provide confidence that this is an effective primary interventional treatment option for these patients.

“It is remarkable that the Eluvia drug-eluting stent was able to demonstrate clear advantages over an active drug-coated device. The differentiated polymer-mediated drug release profile must be the responsible factor.”

Speaking to Interventional News, MüllerHülsbeck expands on this clinical success: “This study compared two paclitaxel-containing devices, the Zilver PTX drug-coated stent and the low dose Eluvia drug-eluting stent. Diabetic patients treated with Eluvia had an excellent primary patency rate at one year, and there was a statistically significant and clinically relevant reduction in both target lesion revascularisation and stent thrombosis.

“These strong clinical outcomes reinforce what has been demonstrated in the IMPERIAL randomised controlled trial and long-lesion study, in that the Eluvia stent is a viable and effective treatment option for patients who present with some of the most challenging lesion and disease state characteristics.”

In historical peripheral vascular disease trials, when patient and lesion complexity increased, efficacy results have decreased. With these latest results from the IMPERIAL trial, ELUVIA continues to demonstrate remarkable, consistent results regardless of patient or lesion complexity.

The Eluvia stent system received FDA approval in September of 2018 and CE mark in February of 2016.

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Venous interventions

Vici stent meets primary endpoints in VIRTUS 12-month data New 12-month data from the VIRTUS trial demonstrates that patients who were treated with the Vici venous stent system (Boston Scientific) for iliac and femoral vein obstructions exhibited a high rate of patent, or open, target lesions. Primary safety and efficacy results from the trial were presented as a first-time data release at the Leipzig Interventional Course (LINC; 22–25 January, Leipzig, Germany) by principal investigator Mahmood Razavi (St Joseph Heart and Vascular Center, Orange, USA).

THE VIRTUS TRIAL evaluated the Vici stent in patients with clinically significant obstructions in the illiofemoral venous outflow tract resulting from post-thrombotic syndrome (PTS) or compressive diseases such as May-Thurner syndrome.

“The primary safety and efficacy endpoints were very successfully met, with very low p-values”, Razavi told the audience at LINC. The trial’s primary effectiveness endpoint saw a primary patency rate of 84% at 12 months, which was greater than the predefined performance goal (PGE) of 72.1% (p<0.0001).

“Nearly all the patients treated with the stent, 98.8%, were free from major adverse events at 30 days

post-procedure, thus surpassing the predefined safety performance goal (PGS) of 94%.

The VIRTUS investigational device exemption (IDE) trial, submitted in June of 2018, is a prospective, multicentre, single-arm, nonrandomised study that enrolled 170 patients with chronic disease; 75% (127) of whom were diagnosed as having post-thrombotic lesions and the remaining 25% (43) were diagnosed with non-thrombotic lesions (i.e., May-Thurner syndrome). Venography, Doppler ultrasound and intravascular ultrasound (IVUS) were performed pre- and post-stenting, as well as at 12-month follow-up.

“In treating patients with venous obstruction, the primary goal is to

restore and maintain vessel patency to ensure the return of blood flow to the heart,” said Razavi. “In these results, the Vici stent demonstrated excellent performance outcomes in a difficultto-treat patient population, which translates to improvement of longterm symptoms and enhanced quality of life in these patients.”

In terms of clinical severity, Razavi reported a Vascular Clinical Severity Score (VCSS) decrease of 4.4 points at 12 months, with a median VCSS of 10 in 146 patients falling to 5.6 in 132 patients followed up to 12 months. At baseline, 65.8% of patients presented in the category of most severe VCSS of eight or more, which decreased to 33.3% at six months and further fell to 27.3% at one year.

Two adverse events (1.2%; n=169) were seen in the cohort at 30 days, both of which were described as “arterial or venous injury at the target vessel segment and/or target lesion location or at the access site requiring surgical or endovascular intervention”.

There were no instances of devicerelated or procedure-related death, major bleeding at target or access

CASSINI trial results inconclusive on rivaroxaban effects in high-risk ambulatory cancer patients The CASSINI trial found that treatment with rivaroxaban did not significantly reduce the incidence of thromboembolism or death caused by thromboembolism in high-risk ambulatory patients with cancer during the 180-day study period. However, during the study’s intervention period, there was a significantly lower incidence of venous thromboembolism and death due to thromboembolism among patients treated with rivaroxaban, and there was a low incidence of major bleeding. The results of the trial were reported by Alok A Khorana (Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, USA) and colleagues in the New England Journal of Medicine (NEJM).

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t is known that cancer and cancer treatment put patients at risk of venous thromboembolism, but guidelines do not recommend routine thromboprophylaxis for patients with cancer even though it is possible that such treatment could improve their outcomes. The study investigators therefore sought to “assess the efficacy and safety of rivaroxaban thromboprophylaxis in patients with a solid tumour or lymphoma who had a Khorana score of two or higher and were initiating in a new systemic cancer regimen”.

The CASSINI trial was a double-blind, multicentre, randomised trial, which randomised high-risk ambulatory patients with cancer to receive either 10mg rivaroxaban or placebo daily for a period of up to 180 days.

The primary efficacy endpoint—a composite of deep vein thrombosis, pulmonary embolism or death from venous thromboembolism—was assessed for up to 180 days. The same endpoint was similarly assessed during the intervention period, which was the time from first receiving treatment or placebo to the last treatment plus two days. The primary safety endpoint was major bleeding.

Of 1,080 patients originally enrolled in the trial, 49 (4.5%) were found to have thrombosis during screening and 190 had other reasons to be excluded. A

total of 841 patients who were all assessed as having a higher risk of venous thromboembolism (Khorana score ≥2 at baseline) and an expected survival of more than six months were included in the randomisation: 420 patients were assigned to the rivaroxaban group and 421 to the placebo group.

The mean intervention period—the time when patients actually received treatment—was 4.3 months, with 43.7% of patients in the rivaroxaban group and 50.2% of those in the placebo group stopping treatment before the end of the trial.

During the study period up to day 180, the primary endpoint occurred in 25 patients receiving rivaroxaban (6%) and 37 patients receiving placebo (8.8%; hazard ratio=0.66; 95% confidence interval [CI]=0.40–1.09; p=0.10). During the intervention period, the primary endpoint occurred in 11 patients receiving rivaroxaban (2.6%) and 27 patients receiving placebo (6.4%; hazard ratio=0.40; 95% CI=0.20–0.80). Major bleeding occurred in eight patients receiving rivaroxaban (1.9%) and four patients receiving placebo (1%; hazard ratio=1.96; 95% CI=0.59–6.49).

Khorana et al comment: “Although the primary endpoint occurred in a lower percentage of patients who had been randomly assigned to the rivaroxaban

site, acute deep vein thrombosis outside target vein segment, clinically significant pulmonary embolism or embolization of the stent at 30 days.

“Physicians who select endovascular treatment options for their patients with venous disease are not only faced with challenging disease states but must also account for the unique anatomical presentation of these deep veins that are subject to chronic obstruction and compression,” said Ian Meredith, executive vice president and global chief medical officer of Boston Scientific, in a company press release.

“The results from the VIRTUS trial demonstrate the importance of having a therapeutic option that is specifically designed for venous application, thus helping patients avoid recurrent pain, swelling and other debilitating aspects of acute and chronic venous disease.”

The stent system was approved for use in Europe and other geographies that recognise CE mark in 2013. In the USA, the stent is an investigational device and is not available for sale.

The device was developed by VENITI, which Boston Scientific acquired in August of 2018.

group in this analysis, the difference was not significant”. However, they note that “in a prespecified supportive analysis involving the same population but assessing the more conventional period of during the intervention, we found a difference of four percentage points in favour of rivaroxaban over placebo with regard to the primary composite endpoint of venous thromboembolism and venous thromboembolismrelated death.”

Arterial and isolated distal thromboembolism, which are common in patients with cancer, were found in lower rates among the rivaroxaban-treated patients than in the patients receiving placebo. According to Khorana et al, this “could further increase the net benefit of prophylaxis for patients”.

A limitation of this study is the large percentage of patients who stopped the trial regimen prematurely, but this is not surprising in patients who mostly have advanced cancer.

The investigators conclude: “The results of the CASSINI trial provide important information regarding the baseline prevalence and incidence of thromboembolism among high-risk ambulatory patients with cancer”. However, they were unable to confirm the benefits of treating these patients with rivaroxaban in their trial “because the between-group difference in the prespecified primary efficacy endpoint up to day 180 was not significant”.

Khorana noted to Interventional News that there was a second confirmatory trial in the same issue of the NEJM by Marc Carrier (Ottawa, Canada) et al investigating the same patient population as observed in the AVERT trial. In an accompanying editorial addressing both studies, Giancarlo Agnelli (Perugia, Italy) stated that both trials together “showed a significant benefit of direct oral anticoagulants for the prevention of venous thromboembolism, with a low incidence of major bleeding” and the data are “quite compelling”.

Khorana agrees with this editorial leaning.

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Using TEVAR to treat aortic dissection improves survival over open repair Thoracic endovascular aortic repair (TEVAR) demonstrates a oneand five-year survival advantage over the current “gold standard” practice of medical therapy in the treatment of uncomplicated type B aortic dissection, a recent study concludes. In light of these data, lead author James Iannuzzi (currently on staff at University of California San Francisco Medical Center, San Francisco, USA), senior author Virendra Patel (Division Chief of Vascular surgery at Columbia University Irving Medical Center, New York, USA) and colleagues call for a paradigm shift in the acute management of aortic dissection in favour of early TEVAR.

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iting a paucity of data regarding the impact of acute treatment of uncomplicated type B aortic dissection on long-term survival in a real-world cohort, the study investigators set out to compare TEVAR to open repair and medical therapy.

In their retrospective analysis of a prospectively collected Californian administrative database analysing 9,165 acute uncomplicated type B aortic dissections, 76% of those treated with TEVAR survived to five years’ posttreatment, compared with an inferior five-year survival rate of 67% in open repair patients, and a survival rate of 60% for medical therapy recipients.

The authors hypothesise that the mechanism by which TEVAR may have a favourable impact on survival is “by covering the entry tear, leading to false lumen thrombosis and prevention of aneurysmal degeneration.” They go on to explain: “Evidence from complicated type B aortic dissections treated with TEVAR demonstrates 63% to 88% partial or complete false lumen thrombosis. TEVAR for complicated type B aortic dissection has also been associated with decreased aortic diameter; however, this remains controversial as it has not been demonstrated consistently. By prevention of aneurysmal degeneration, initiation of false lumen thrombosis, and prevention of recurrent dissection, TEVAR may improve long-term survival, as demonstrated in this study and others.”

Iannuzzi and colleagues conclude that TEVAR for uncomplicated type B aortic dissection is a relatively safe and effective approach, associated with longer survival, but note that further study is necessary to determine longer term outcomes for these patients.

Major complications were lower in TEVAR and medical therapy cases than for open repair, with 49% of patients treated with medical therapy experiencing a major complication, and 55% of TEVAR patients, compared to a major complication rate of 72% in open repair cases. Paraplegia rates were also similar between TEVAR and medical therapy (3.4% and 2.9%, respectively),

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TEVAR

Virendra Patel

but were found to be highest in the open repair group (9.3%).

Speaking to Interventional News about the clinical ramifications of this finding, Patel comments, “Medical therapy has historically been the gold standard in the management of uncomplicated acute type B aortic dissection, however this work and others call that strategy into question as TEVAR-treated patients are associated with better long-term survival.

This will not be a strategy to treat all patients; however, patients with excellent anatomy and young or

of Stent Grafts in Aortic Dissection (INSTEAD) trial, which randomised patients to optimal medical therapy or TEVAR for treatment of subacute to chronic uncomplicated type B aortic dissection, did not demonstrate a survival benefit at one year (as published in the Journal of Thoracic Cardiovascular Surgery in 2010), but did find that patients treated with TEVAR had improved aorta-specific survival at five years’ follow up.

Iannuzzi and colleagues’ study included nearly four times as many TEVAR patients as the INSTEAD trial, and had concordant results.

Explaining the difference between the present study and the INSTEAD trial, the authors write: “A major difference between INSTEAD and this retrospective administrative study is timing of repair. The INSTEAD trial included healthier patients overall with a younger age (mean age of 60 years compared with 66 years), fewer diabetics (6% in INSTEAD vs. 12% in this study), and fewer smokers (17% in INSTEAD compared with 30% in this study). Whereas INSTEAD was a landmark study, corroboration in the real-world setting is imperative, and this study helps validate the INSTEAD findings that long-term survival is improved in patients treated with TEVAR.” A proponent of stenting more uncomplicated subacute dissections, interventional radiologist Darren Klass, Vancouver, Canada, told Interventional News: “Type B aortic dissection carries a five-year mortality of 20–45%. Since the pivotal trials including STABLE and INSTEAD XL, the question of TEVAR for complicated dissection requires no discussion and patients progress with medical therapy alone.

The IRAD demonstrated patients who survive a type A dissection and are discharged from hospital have a plateau in mortality, however patients with type B dissection have a mortality of 25% at three years. These patients therefore constitute a group of so-called ‘uncomplicated dissections’; it is this group, where medical therapy alone is

Type B aortic dissection carries a five-year mortality of 20–45%.

Since the pivotal trials [...] the question of TEVAR for complicated dissection requires no discussion and patients progress with medical therapy alone.” healthy patients with expected longterm survival should be considered for treatment in experienced centres or referral to aortic centres for TEVAR within the critical window of opportunity to stimulate beneficial remodelling, reduce late aortic events, and improve survival.”

Previous small, randomised controlled trials have found similar results. For example, the Investigation

clearly failing—as demonstrated yet again in the recent study by Iannuzzi et al.

“I am convinced we should be treating more uncomplicated type B dissection but two questions remain. i) What is the ideal timing interval for intervention, and ii) Which patients should be treated?

“We have multiple studies quoting risk factors for aortic progression (entry

Darren Klass

tear, false lumen and overall aortic size) as well as risks for significantly higher mortality (more than three antihypertensive medications), however are these the only surrogates for a more complex disease we do not fully understand? Desai et al (Division of Cardiovascular Surgery, Perelman School of Medicine, University of Pennsylvania, USA) demonstrated a significantly lower complication rate if TEVAR occurred two to six weeks post event. If we could demonstrate reliably an extremely low periprocedural complication rate with an agreed method for TEVAR (PETTICOAT or stent grafting to the celiac), is it possible all uncomplicated dissections would be treated with TEVAR? We do not have the answer yet, but I know if I was unfortunate enough to become a patient, regardless of risk factors for progression, I know what treatment I would demand. Retrospective data or not, I know which Kaplan-Meier curve I want to be on, and it is not the medical therapy one.”

However, TEVAR is twice as expensive as medical therapy in the USA. Costs averaged US$58,000 for medical therapy, compared with US$133,000 and US$200,000 for TEVAR and open repair, respectively.

The present study is the first to include cost data when comparing these treatment options in type B aortic dissections, and no prior costeffectiveness analysis has evaluated TEVAR for uncomplicated dissection.

The price tag associated with TEVAR differs dramatically between countries, though, as is expected from vastly differing healthcare systems. Whilst the cost in this US study is not comparable with medical therapy, in a recent Canadian trial, TEVAR cost as little as CAN$61,000, less than half of the US expense. Furthermore, a German study of complicated aortic dissection demonstrated TEVAR to be more costeffective than open repair.

Despite the initial increased cost of TEVAR compared with medical therapy, and the post-therapy surveillance costs incurred by both treatment modalities, the study authors postulate that over a longer time period, TEVAR may demonstrate an improved cost-effectiveness, “given the 25% to 40% increased risk for aneurysmal degeneration over time” present in medical therapy.

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Abdominal aortoiliac artery aneurysm

New clinical practice guidelines for management of abdominal aortoiliac artery aneurysm: What is new and how does it differ from other guidelines?

Anders Wanhainen Gert Jan de Borst Comment & Analysis The first European Society for Vascular Surgery (ESVS) guideline on treatment of abdominal aortic aneurysm (AAA), published in the European Journal of Vascular and Endovascular Surgery in 2011,1 has had a major impact on clinical practice and research. However, due to the rapid developments of the field it has become outdated. In 2015, the process to update the ESVS AAA guideline was initiated. A writing committee consisting of 16 vascular surgeons from all over Europe worked out a comprehensive document, comprising 97 pages, including 790 references with a total of 125 recommendations. For the first time, ESVS guidelines were written in collaboration with patient representatives. The document has undergone three review rounds by 13 external reviewers from Europe, the USA, Asia and Australia, as well as by the 10 members of the ESVS guideline committee. The resulting â&#x20AC;&#x153;European Society for Vascular Surgery (ESVS) 2019 clinical practice guidelines on the management of abdominal aortoiliac artery aneurysmâ&#x20AC;? were presented at the ESVS annual general meeting (25â&#x20AC;&#x201C;28 September, Valencia, Spain), published online in November 2018, and will appear in the January 2019 issue of the printed journal.2

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ere we summarise some news of importance to vascular specialists as well as policy makers, and briefly discuss notable differences between the ESVS guidelines and other contemporary guidelines; the Society for Vascular Surgery (SVS) AAA guidelines published in 2017,3 and the draft of the upcoming National Institute for Health and Care Excellence (NICE) aortic guideline targeting England and Wales.4 Level of evidence A

Data derived from multiple randomised clincal trials or metaanalyses.

Level of evidence B

Data derived from a single randomised clinical trial or large nonrandomised studies.

Level of evidence C

Consensus of opinion of the experts and/or small studies, retrospective studies, registries.

Service standard

The management of AAA has changed profoundly with the introduction of endovascular treatment. Studies have convincingly shown the benefit of endovascular aneurysm repair (EVAR) in both elective and emergency AAA repair in patients with suitable anatomy. At the same time, it is evident that some patients are not suitable for standard EVAR, or more complex endovascular treatment options, but should be offered open surgery. Consequently, one technique cannot entirely replace the other. Compromising the anatomical requirements for standard EVAR, using complex and partially experimental endovascular techniques to avoid established open surgical solution at all cost, or solely offering major open surgery when there are proven minimally invasive techniques, just because it is outside

office hours, is not in accordance with good clinical practice. Thus, today it is not acceptable to perform abdominal aortic interventions without the ability to offer both endovascular and open surgical technologies 24/7 (Recommendation 2; Class I, Level B).

The firm evidence of a volume-outcome relationship of surgery in general, and AAA repair in particular, makes it necessary and justifiable to make a recommendation on minimal surgical volume. No clear threshold was possible to identify in the literature, however. Various cut-off levels have been suggested, and other aspects

have to be taken into account, such as population density and geographical distances. Based on the literature, the ESVS guideline writing committee (ESVS-WC) concluded that there is enough evidence for a rather weak recommendation on a desired minimum hospital volume of at least 30 cases annually (Recommendation 3; Class IIa, Level C) while a stronger recommendation can be issued on a minimum yearly case load of at least 20 repairs to perform aortic surgery at all (Recommendation 4; Class III, Level B). This is essentially in line with what the SVS recommends (an annual minimum volume of 10 cases for each open surgical repair and EVAR), and justifies a continued centralisation to medium and high volume centres. The NICE guidelines draft does not address this topic.

There are limited data concerning a reasonable waiting time for treatment once the threshold for repair has been reached. Although there is no strong evidence to support exact timings, it is reasonable to adopt a similar approach as for other life threatening diseases, such as cancer. Based on the rupture risk, as well as the psychological consequences, a suggested upper limit for the total pathway from referral to treatment is eight weeks, once the intervention threshold is reached. This applies, however, only to standard AAA cases, whereas in more complex aneurysms or comorbid patients a longer planning and/or work-up time is justified.

Correspondingly, a shorter time frame should be pursued for larger AAAs (Recommendation 5; Class I, Level C).

Those of us who fail to meet this requirement should promptly develop routines for fast-track preoperative imaging and work-up. Modern cancer care often has well-structured treatment pathways with clearly defined deadlines, and may serve as a role model.

Elective AAA repair

Due to rapid technological and medical development,

Classes of recommendation

Definition

Suggested wording to use

Class I

Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective.

Is recommended/is indicated

Class II

Conflicting evidence and/ or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure.

Class IIa

Weight of evidence/opinion is in favour of usefulness/ efficacy.

Should be considered

Class IIb

Usefulness/efficacy is less well established by evidence/opinion.

May be considered

Class III

Evidence or general Is not recommended agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful.

Figure. The recommendations in the ESVS guidelines are based on the European Society of Cardiology (ESC) grading system

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the existing randomised controlled trials comparing open surgical repair (OSR) and EVAR are partly outdated and thereby not entirely relevant for today’s situation. The evidence from randomised controlled trials (RCTs) also has the limitation that they mainly apply to patients <80 years of age, whereas today the greatest increases in AAA repair is among those >80 years. This group has also seen the most pronounced improvement in outcome after AAA repair, likely related to the preferential use of EVAR for treatment among octogenarians. It is therefore necessary to also include more recent case series and registry studies in the overall evaluation of the evidence base. Thus, despite data from multiple RCTs and meta-analyses, representing the highest level of evidence, we rate the existing level of evidence as mediocre (Level B).

Overall, evidence suggests a significant short-term survival benefit of EVAR over OSR, with similar longterm outcome up until 10–15 years’ follow-up. Thus, in patients with suitable anatomy and reasonable life expectancy, EVAR should be considered as the preferred treatment modality (Recommendation 60; Class IIb, Level B). Yet, there are indications that an increased rate of complications may occur after eight to 10 years with earlier generation EVAR devices and an uncertain durability of current devices, particularly the low profile devices. Thus, although EVAR should be considered the preferred treatment modality in most patients, it is reasonable to suggest an OSR first strategy in younger, fit patients with long life expectancy, i.e. >10–15 years (Recommendation 61; Class IIa, Level B).

These recommendations, which more clearly than before favour EVAR over OSR in most scenarios, differ significantly from the NICE guideline draft, where EVAR is not recommended at all in the elective setting.

It is obvious that the ESVS-WC has interpreted the literature completely differently, taking into account the fact that the RCTs comparing OSR and EVAR are outdated, while the NICE committee has not done the same assessment. The SVS makes no clear recommendation on the choice of surgical technique, but leave this decision to the individual surgeon, emphasising the importance of patient involvement.

Ruptured AAA repair

When pooled together, the one-year results of the three recent RCTs (IMPROVE, AJAX, ECAR) suggest that there is a consistent but non-significant trend for lower mortality post EVAR. The IMPROVE trial found faster discharge with better quality of life post-EVAR, which therefore was cost effective. The recently published three-year results of the IMPROVE trial suggest that, compared with OSR, an endovascular strategy for suspected ruptured AAA was associated with a survival advantage, a gain in quality of life adjusted years, similar levels of reintervention, reduced costs, and this strategy was cost effective. These findings, together with observational studies and registry data, support a strong recommendation of an EVAR first strategy for ruptured AAA repair (Recommendation 74; Class I, Level B). This recommendation—a major change from the previous ESVS guidelines—is in agreement with both the SVS guidelines and the NICE guideline draft.

New devices

In recent years, manufacturers have developed new stent grafts and delivery systems with lower profiles to allow an endovascular approach even in patients with small access vessels. Although there are some series reporting favourable midterm outcomes for last-generation lowprofile stent grafts compared to standard profile stent grafts, more experience and longer-term outcome data, especially about the durability, are needed to confirm those findings. Therefore, when upgrades of existing platforms are used in clinical practice, the need for longterm follow-up should be recognised, and evaluation in prospective registries with complete follow-up is strongly recommended (Recommendation 57; Class I, Level C).

Abdominal aortoiliac artery aneurysm Novel new techniques and treatment concepts, such as endovascular aneurysm sealing with polymer-filled endobags (EVAS) has only been commercially available for a limited time, and their effectiveness and durability are still under investigation. We issue a strong negative recommendation of its use in clinical practice outside studies approved by research ethics committees and with informed consent from the patients, until adequately evaluated (Recommendation 58; Class III, Level C). This approach is supported by recent alarming reports of higherthan-expected rates of leaks around the implant, device movement, and aneurysm enlargement after EVAS. Neither the SVS guidelines, nor the NICE guideline draft, address this topic, which we consider of great importance given the continued rapid industry-driven technical development. CE marking (or approval) is a certification mark for products sold within the European Economic Area (EEA), i.e. European Union (EU) and European Free Trade Association (EFTA). Unlike the rigorous evaluation of efficiency and safety required for Food and Drug Administration (FDA) approval in the USA, CE marking has nothing to do with efficiency or safety. Thus, the role for several new innovative CE-marked technologies on the market is still unclear and further data are needed before these can be recommended to be used in routine clinical practice.

Follow-up after EVAR

Due to the risk of graft-related complications and rupture after EVAR, regular imaging follow-up has been regarded as mandatory. The true value of prophylactic regular follow-up imaging after EVAR is uncertain, however.

Routine surveillance seldom identifies significant findings requiring reintervention, and most patients who require reintervention after EVAR present with symptoms.

Compliance with annual prophylactic imaging guidelines is suboptimal and lack of adherence to follow-up does not seem to affect long-term mortality or post-implantation rupture rate. Thus, annual imaging after EVAR for all patients is neither evidence-based nor feasible.

An early postoperative clinical and imaging followup after EVAR is required to assess the success of the performed intervention (Recommendation 91; Class I, Level B). Recent data suggest that patients considered at low risk for endovascular aortic repair failure after their first postoperative computer tomography angiography, i.e. no endoleak, anatomy within IFU, adequate overlap and seal of ≥10mm proximal and distal stent graft apposition to arterial wall, may be considered to be stratified to less frequent follow-ups, with delayed imaging up until five years after repair (Recommendation 92; Class IIb, Level C). Patients who do not meet these requirements should be assessed for the need for reintervention or continued frequent monitoring.

In contrast to the above approach with risk stratification, the SVS guidelines recommend continued annual imaging follow-up for all patients post-EVAR. While the NICE guideline draft does not indicate a specific frequency for follow-up, it supports that it should be guided by the individual patients’ estimated risk of graft-related complications.

Juxtarenal AAA

Given the rarity and complexity of JRAAA treatment centralisation to specialised high volume centres that can offer both open and complex endovascular repair seems justified and is recommended (Recommendation 94; Class I, Level C).

Complex endovascular techniques have emerged as promising alternatives, or complement, to OSR for the treatment of JRAAA. However, reliable comparative and health-economic studies are still missing. Consequently, decision making is complex and should be tailored to each individual patient and local health economies. Stratification of cases by anatomy and surgical risk may be useful in patients with JRAAA (Recommendation 95; Class IIa, Level C). OSR with an anastomosis below the renal arteries

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and short renal clamping time may be a preferable and durable option for fit patients with a short aortic neck.

With more complex anatomy or high surgical risk due to comorbidities an endovascular solution may be preferable.

Despite limited data, it is the ESVS-WC assessment that fenestrated technology has a small advantage over parallel graft technique when it comes to proven feasibility and durability, as there are more multicentre reports and longer follow-up data available, and thus it should be the preferable endovascular technique for elective JRAAA repair (Recommendation 96; Class IIa, Level C).

Parallel graft techniques may, however, be considered as an alternative technique in the emergency setting or as a bailout (Recommendation 97; Class IIb, Level C), but one should then aim for a proximal landing zone of at least 15 mm, ensure a proper stent graft-oversizing of 30%, and use a maximum of two chimneys.

As for standard AAA repair, novel new techniques and treatment principles, such as EVAS, Endostaples and in situ fenestration are not recommended in clinical practice for JRAAA repair but should be limited to studies approved by research ethics committees and with informed consent from the patients (Recommendation 98; Class III, Level C).

Data is even more scarce for ruptured JRAAA, but the risk aversion is lower in such an immediate life threatening and complex situation. Therefore, in patients with ruptured JRAAA open repair or complex endovascular repair (with physician modified fenestrated stent grafts, off-the-shelf branched stent graft, or parallel graft) may be considered based on patient status, anatomy, local routines, team experience and patient preference (Recommendation 99; Class IIb, Level C).

JRAAA is not covered by the SVS guidelines, while the NICE guideline draft clearly recommend against any use of complex EVAR outside randomised clinical trials. Again, a big difference with potential huge clinical impact compared with the recommendations made in ESVS guidelines, and our views of the current knowledge are remarkably different. With today’s rather extensive experience of complex EVAR (especially fEVAR), showing generally good results, and the ability to offer treatment to many patients less suitable for major open surgery; it is difficult to motivate a strong preference for OSR over complex EVAR for JRAAA. Instead, we favour a more pragmatic approach, with OSR and EVAR complementing each other.

Conclusion

We encourage everyone to carefully read the new ESVS aortic guidelines document in its entirety.

It is an extensive document but offers many more recommendations of clinical importance (including recommendations on medical management, screening, iliac aneurysms, mycotic and inflammatory aneurysms, concomitant malignant disease, etc.) and a comprehensive supporting text that summarises the literature and motivates our positions. We hope you will find the document relevant and useful for your practice.

Anders Wanhainen is chair and corresponding author of the ESVS AAA Guideline Writing Committee. He is also professor of Surgery, Department of Surgical Sciences at Uppsala University in Uppsala, Sweden.

Gert J de Borst is chair of the ESVS Guidelines Committee and professor of Vascular Surgery, Department of Vascular Surgery at University Medical Center Utrecht in Utrecht, The Netherlands.

References 1. Moll FL, et al. European Society for Vascular Surgery. Management of abdominal aortic aneurysms clinical practice guidelines of the European society for vascular surgery. Eur J Vasc Endovasc Surg 2011;41:S1e58 2. Wanhainen A, et al. European Society for Vascular Surgery (ESVS) 2019 Clinical Practice Guidelines on the Management of Abdominal Aorto-iliac Artery Aneurysms, European Journal of Vascular and Endovascular Surgery (2018), https://doi.org/10.1016/j.ejvs.2018.09.020 3. Chaikof EL, et al. The Society for Vascular Surgery practice guidelines on the care of patients with an abdominal aortic aneurysm. J Vasc Surg. 2018 Jan;67(1):2-7 4. https://www.nice.org.uk/guidance/indevelopment/gid-cgwave0769/ documents

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Kidney disease guidelines

New clinical practice guidelines for management of chronic kidney disease The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) provides evidence-based clinical practice guidelines for haemodialysis vascular access and related complications, and has done so since 1997. The latest guidelines, published in 2006, no longer reflect the most recent evidence for the management of vascular access, causing the haemodialysis and vascular access community to eagerly await the revised recommendations, currently in the external review process and due in Spring 2019.

WITH MORE THAN a decade between the last guidelines and the imminently anticipated ones, the time elapsed is reflected in numbers: the new guidelines will have over 160 statements, compared with the 130 statements of the 2006 guidelines. For the upcoming guidelines, approximately one-third of these statements are based on a rigorous review process, and twothirds predicated on expert opinion. In contrast, the previous guidelines—where the strength of the recommendation was given a letter grade, with A being backed by the strongest evidence—had <20% grade A statements, and the remainder grade B or expert opinion.

Charmaine Lok (University of Toronto, Toronto, Canada), chair of the KDOQI guidelines for vascular access 2018, gave a talk at the Controversies and Updates in Vascular Surgery conference (CACVS; 7–9 February, Paris, France) to provide a glimpse of the upcoming guidelines. When asked by an audience member if the 13 years between guidelines meant there was “a big risk of having an outdated practice in-between” the publications, Lok agreed, telling delegates: “Absolutely. That is why it took us so long to develop the guidelines, because there was such a significant amount of evidence that had to be reviewed. The benefit of having a long time between each is that it allowed time for studies to be conducted, so we could actually learn from them to help develop

the next guidelines, but I agree with you.

“There has actually been a study on the ideal timeframe between guidelines: four years. We need to keep these guidelines ongoing. This was a complete renewal of the guidelines, so hopefully the next ones will truly be an update, to make them much more frequent, because the time lapses are far too great.”

planning for the patient’s continued care across their entire ESKD lifetime. She demonstrates this with an example of two patients, a teenager whose ideal treatment would be a preemptive transplant, and an obese comorbid adult man, who “may have a different trajectory.”

In addition to reconfiguring the approach to end-stage kidney disease

Conceptual shifts

The ideal timeframe between guidelines: four years. We need to keep these guidelines ongoing.”

Lok told CACVS attendees that there had been several key conceptual shifts involved with this endeavour, to ensure the finished publication best mirrors the changes to the field in the intervening 13 years.

Expanding on one of these ideological changes at CACVS, Lok said: “Here is one of the biggest changes in concept: what we are trying to do is emphasise the end-stage kidney disease (ESKD) life-plan. Everybody is well aware that chronic kidney disease has five stages, and we typically think about reaching stage V, which is ESKD, as the end.

However, I really want you to rethink it.

When a patient reaches stage V, that is the beginning of the patient’s ESKD life on dialysis or transplant. The beginning of their ESKD life-plan.”

Lok went on to explain that the endstage kidney disease life-plan concept centred around the paradigm of attaining: “The right access, in the right patient, at the right time, for the right reasons”.

This, Lok said, means thinking of and

Endovascular denervation may offer new approach to cancer pain relief

Endovascular denervation can improve pain in patients with abdominal cancer and may offer a new approach to palliative care, according to a study recently published in the Journal of Vascular and Interventional Radiology. The study investigators, Qi Zhang, Gao-Jun Teng (both Center of Interventional Radiology and Vascular Surgery, Zhongda Hospital, Nanjing, China) and colleagues, conclude that the procedure is safe and effective for the alleviation of pain caused by cancer.

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treatment to encompass the complete patient timeline, the new guidelines consider and encompass more than the focused “fistula first” concept that Lok describes as emphasised since the 2006 recommendations. Instead, Lok asked the attending physicians to focus on a four-step PLAN (Patient Life-plan, Access Needs).

The first step of the PLAN involves considering the patient first, and what their ESKD life-plan looks like. Is the first ESKD modality

he study enrolled seven patients (two men and five women) with diagnoses including pancreatic cancer (n=3), cervical carcinoma (n=2), cholangiocarcinoma (n=1), and oesophageal cancer with retroperitoneum lymph nodes invasion (n=1) from April 2017 to February 2018.

A surface electrode was placed on the back of each patient and connected to the denervation device.

Denervation was carried out at the abdominal aorta close to the origin of celiac artery and superior mesenteric artery with the use of a multi-electrode radiofrequency ablation catheter with the time and temperature settings respectively at 120 seconds and 60°C. The authors report that all patients experienced pain relief after treatment, meeting the primary endpoint of improvement in pain score. At one, two, four, eight, and 12 weeks after the procedure pain scores, measured by visual analogue score, decreased significantly compared with baseline (p<0.001). All patients experienced a greater than four-point score reduction.

Secondary endpoints included changes in quality of life, intake of narcotics, and the safety of endovascular denervation.

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choice haemodialysis or peritoneal dialysis? Or transplant? Given that it is haemodialysis, next, consider their access needs. Secondly, what is the access creation plan; for example, who will create the access, where (location) and when (timing). Thirdly, the physicians are asked to come up with an access contingency plan, so they have a remedial plan for when the access becomes problematic; for example, before creating the fistula, or to consider the plan of action if it fails to mature.

Finally, Lok urged the CACVS audience to think about an access succession plan, before creating an access: it’s not just thinking about fistula first, but what access is next. This takes into account the patient’s life-plan and the longer-term plan. Lok said that it was “especially important to think cleverly about this for younger patients, who have a whole life ahead of them.”

Changes to definitions

A further change outlined by Lok in her CACVS presentation, more pedantic than the overarching conceptual changes described above, is the editing of several definitions. One such changed definition is “catheter dysfunction”. Previously, this had focused on blood pump speed, and was defined in 2006 to include the “failure to attain and maintain an extracorporeal blood flow of 300ml/ min or greater at a prepump arterial pressure more negative than 250mmHg.” The new guidelines will define catheter dysfunction thus: “Failure to maintain the prescribed extracorporeal blood flow required for adequate haemodialysis without lengthening the prescribed HD treatment.”

Lok explained: “In some situations as in Tassin, France or for patients receiving nocturnal haemodialysis, these patients undergo longer duration dialysis, at prescribed low blood pump speeds (<300 ml/min) and the patient’s catheter is fine—you would not say it is malfunctioning. So with these guidelines, we looked at innovation in [the] dialysis [field], and how we might be able to keep definitions current.”

Narcotics use was significantly reduced within the first three months after treatment, and quality of life scores were improved significantly (p<0.005) with better sleep. There were no severe treatment-related adverse events or major complications reported.

Speaking to Interventional News of how these results will influence clinical practice, corresponding author Gao-Jun Teng, president of the Zhongda Hospital, Southeast University, Nanjing, China, says “Our report presented the preliminary results in a small number of patients, but it showed very promising and encouraging results. It will certainly inspire further research using endovascular denervation. I would not be surprised to see endovascular denervation become a useful tool in pain management in the very near future.”

Writing in the Journal of Vascular and Interventional Radiology, the authors conclude: “Cancer pain management is a formidable problem for physicians and may result in a substantial burden to the public health care system. Opioid analgesics are often required to control cancer pain. Adverse effects from opioids are debilitating and worsen as larger doses Continued on page 22

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Endovascular denervation may offer new approach to cancer pain relief Continued from page 21

are administered,” the authors write.

“This preliminary trial demonstrated that endovascular denervation is a promising and safe method for the palliation of pain caused by abdominal cancers. It could be a new approach for management of cancer pain.”

A new approach to palliative care

“This may give interventional radiologists a brand-new approach to

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Endovascular denervation

treating pain”, Teng adds, “thus [acting to] solidify their place in the field of pain management. Endovascular denervation provides interventional radiologists a new and big territory for treating non-hypertension diseases, which has previously been considered a procedure performed by cardiologists.”

Teng believes it is important to find a new approach to palliative care, telling this newspaper: “It is well known that cancer pain has significant impacts on

patients’ quality of life, as well as their prognosis. Traditional management uses narcotics, sometimes in large quantities, which often result in severe side effects such as impairment of judgement and respiratory suppression. Interventional neurolysis under CT/US [computed tomography/ultrasound] is a traditional interventional radiology procedure, which involves the deep puncture of a needle and injects chemical (alcohol, phenol) agents. Accurate needle localisation may be a challenge for inexperienced interventional radiologists. The outcomes vary from the operator’s skill, and the degree of diffusion of the neurolytic agents is sometimes out of control, which may

Co-author Gao-Jun Teng

[Endovascular denervation] has the advantages of being minimally invasive, [enabling] easy access to any part of the body, and having fewer side effects.” cause serious complications.

“New approaches—especially nonopioid methods—in pain management are still in need clinically. Due to the ubiquitous nature of the vascular network and anatomical accompany of nerves and arteries, endovascular denervation could be a great approach in pain management. It has the advantages of being minimally invasive, [enabling] easy access to any part of the body, and having fewer side effects.”

However, Teng also states that the mechanism for endovascular denervation on uncontrollable cancer pain is “still unclear”, and that more work is required to elucidate the procedure’s machinations. He is the principal investigator in a large scale clinical trial currently ongoing in China and involving more than 10 national medical centres. Speaking of this trial, and what it means for the future of endovascular denervation, he says: “We are exploring different ablation sites for controlling cancer pain in other parts of the body. We are also working to expand the application of the technique to manage pain caused by other diseases.”

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Stereotactic radiofrequency ablation

Stereotactic radiofrequency ablation is effective even in tumours over 3cm, study finds Multiprobe stereotactic radiofrequency ablation (SRFA) with intraprocedural image fusion represents an efficient minimally invasive therapy for hepatocellular carcinoma (HCC), even with tumour sizes larger than 3cm, and without the need to combine its use with additional treatments, concludes Reto Bale (Department of Radiology, Medical University Innsbruck, Innsbruck, Austria) and colleagues, writing in Hepatology.

IN THEIR RECENT single-institution, retrospective study of prospectively collected data, Bale et al found that the stereotactic ablative treatment had a 97.3% success rate, with 183 of 188 treated lesions exhibiting no residual vital tissue postintervention.

While the authors acknowledge that liver transplantation represents the only curative option for both HCC and underlying chronic carcinogenic liver disease, long waiting lists for transplants mean that tumour progression often advances beyond the conventional transplant criteria, leading to high patient dropout rates. To remedy this, physicians offer neoadjuvant locoregional therapy with the aim of downstaging tumours and decreasing the waiting list dropout rate for liver transplant. However, previous studies have reported that the presence of partial necrosis following locoregional therapy is a major risk factor for tumour recurrence post-liver transplantation.

Therefore, Bale and coauthors propose SRFA as an alternative option to neoadjuvant locoregional therapy before liver transplantation.

A success for image fusion

Typically, radiofrequency ablation (RFA) is the first choice of HCC treatment for very early stage tumours, smaller than

2cm, due to its “great potential for local curative tumour control”, according to the study authors. However, while the therapeutic response in these small tumours is comparable to surgical resection, larger tumour size comes with an attendant increased risk of recurrence in conventional ultrasoundand computed tomography-guided (US- and CT-) single probe RFA. Indeed, univariate analysis has confirmed that increasing size is an indirect predictor of incomplete response to treatment.

Bale and team advocate for the added use of image fusion to lower this risk for larger tumours. The median tumour size in this study was 2.5cm, with the largest being 8cm, and including 52 lesions with a diameter greater than 3cm.

Larger needles necessitated the use of more coaxial needles: the median number of needles per lesion was three for all HCCs, but when focusing only on lesions greater than or equal to 3cm in diameter, this number rises to five.

SRFA was able to overcome the “well-known” limitation of US- and CTguided single-probe RFA. The authors write: “Using the stereotactic approach with intraoperative image fusion even in lesions greater than or equal to 3cm [in diameter], complete tumour cell death was achieved in 50/52 (96.2%) [of

lesions]. In contrast to previous reports about conventional RFA, no correlation between residual tumour and tumour size was found (p=0.5)”.

Long-term survival following SRFA of different cancers has previously been found to be comparable to resection.

Listing the advantages of image fusion, the investigators write that 3D navigation systems “allow for a more sophisticated 3D planning of multiple overlapping ablation zones, precise probe placement and intraoperative assessment of the results by means of image fusion”.

They sought to determine if the implementation of high-end stereotactic techniques—the triumvirate of 3D planning, 3D guidance, and image fusion—could improve the results of thermal ablation. Their findings evidenced that this was the case.

Even with the additional efforts related to the stereotactic approach, Bale and coauthors conclude: “In our opinion the results justify specialised training in stereotactic techniques as well as additional costs related to the infrastructure. We therefore encourage other centres to adapt 3D planning, 3D image-guidance and image fusion to improve the outcome of ablation techniques.”

Results

Seventy six patients with 131 HCCs between them underwent radiofrequency ablation only, while 51 tumours in 16 patients received RFA after unsuccessful transcatheter arterial chemoembolization (TACE). In 125 sessions, five major complications occurred (4% rate), including one event, respectively, of: liver failure, pulmonary embolism, diaphragmatic injury, bleeding, and pleural effusion.

The authors state that the ultimate goal of thermal ablation is “the induction of irreversible tumour cell destruction”.

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The absence of residual tumour tissue is therefore an indicator of success. In this study, five out of 188 treated lesions evidenced residual tumour tissue; thus, ablative treatment was considered successful in the remaining 183 lesions (97.3%). In a total of four patients, new manifestations of the disease were observed following treatment.

The use of TUNEL staining improved the histopathological analysis

The present study offers the largest patient cohort documented in the medical literature where SRFA outcomes have been histopathologically evaluated using TUNEL staining (terminal deoxynucleotidyl transferase dUTP nick end labelling).

Using TUNEL analysis, freshly apoptotic cell areas show a distinct nuclear staining; in more advanced lesions the cytoplasm of the tumour cells depicts a positive reaction as well. In a 2006 study by Adrian Martin (Dallas, USA) and colleagues, a histological examination of explanted livers utilising both H&E (haematoxylin and eosin) and TUNEL staining yielded a 19.6% higher percentage of tumour cell death than when the HCCs were assessed by H&E staining only.

Whenever the viability of the treated HCC could not be ruled out in conventional H&E sections in Bale et al’s analysis, an additional TUNEL assay was performed. The investigators write: “In contrast to previous studies, and most likely due to the additional use of the TUNEL assay, histopathologic examination correlated well with radiologic imaging prior to liver transplant. To the best of our knowledge, these results are superior to all results published so far on conventional thermal ablation, including similar histopathologic studies with additional TUNEL staining”.

Success of stereotactic radiofrequency ablation in larger tumours “challenges resection as first-line treatment” Reto Bale, of the Department of Radiology at the Medical University Innsbruck, Innsbruck, Austria, speaks to Interventional News about the importance of this work, and advocates for the inclusion of image fusion into guidelines outlining standard of care.

What are the advantages of stereotactic radiofrequency ablation (SRFA) over standard radiofrequency ablation (RFA)?

For successful ablation, it is crucial to ablate the complete lesion, including a sufficient safety margin of at least 0.5cm. The short axis of the ablation zone with one RFA or microwave ablation (MWA) probe is limited to 1.5–4cm, depending on the ablation technology and probe design. Thus, even with the latest generation of MWA probes, only lesions up to a maximum diameter of 3cm can be effectively ablated with one single probe position. Therefore, for lesions larger than 3cm, overlapping ablation zones are required. This task is very difficult if only conventional US- and CT[ultrasound and computed tomography] guidance is used for probe placement. Stereotaxy allows for precise 3D planning of multiple probe positions, and then for precise probe placement intraprocedurally according to the plan.

In addition, integrated image fusion allows for immediate and precise evaluation of probe placement

and of the result during the intervention. Due to the ability to plan and introduce multiple needles with high precision, very large tumours can be completely devitalised. The largest mixed hepatocellular carcinoma (HCC)-intrahepatic cholangiocellular carcinoma (ICC) treated by our group (in 2014) had a diameter of 18cm.

In a recent control CT four years after the initial SRFA, the lesion is still local recurrence free.

What are the clinical ramifications of this research?

In international guidelines, resection is recommended as a first line treatment in HCC larger than 2–3cm. If these large lesions are not resectable, a combination therapy of TACE is proposed. This work clearly shows that even large HCCs can be completely devitalised (A0 in analogy to R0) by thermal ablation only. Therefore, SRFA challenges resection as first-line treatment not only in small lesions, but also in lesions greater than 3cm. Moreover, the combination therapy (thermal ablation and TACE) can be replaced by SRFA only,

with excellent results, as confirmed by histopathologic examination. Furthermore, the question arises whether liver transplantation can be replaced or at least postponed in patients with normal liver function by the application of SRFA and follow-up imaging.

What is the future of image fusion and SRFA?

Image fusion is key for immediate treatment evaluation and should be mandatory for every ablation procedure.

It should be used in combination with standard CTor US- guidance. Future guidelines should include image fusion as a standard of care and should propose stereotactic and other sophisticated planning and guidance techniques. As we stated in the paper, we strongly believe that our results justify specialised training in stereotactic techniques as well as additional costs related to infrastructure. Other centres should adapt stereotactic planning, image guidance, and image fusion in order to improve the outcome of ablation techniques even in large tumours.

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Adding cryoablation to sorafenib improves the efficacy of renal cell carcinoma treatment Cryoablation increases the clinical efficacy of treatment with the oral multi-target antitumour drug sorafenib for advanced renal cell carcinoma (RCC), a new study published in the International Journal of Hyperthermia has found. Joint first authors Changfu Liu and Fei Cao (both Department for Interventional Treatment, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China) conclude that combining cryoablation with sorafenib can reduce tumour load, improve antitumour immunosuppressive status, increase survival, and maintain quality of life in patients with RCC that cannot be surgically resected.

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his is the first publication investigating the safety and efficacy of cryoablation combined with sorafenib for the treatment of this disease, but previous work has shown the combined treatment to be better at prolonging survival than sorafenib alone in patients with hepatocellular carcinoma (HCC).

The present study is observational, and followed 156 patients with advanced RCC who were unsuitable candidates for surgical resection. Participants received cryoablation and sorafenib (n=67), or sorafenib only (n=89), and all patients were followed up to at least seven months, with a mean follow-up time of 28.8 months (and a maximum of 67 months).

Of the 156 patients enrolled in the study, 87 were men (56%), and the median age was 65 years (with an age range of 48–84 years). A total of 184 tumours were recorded, with diameters ranging from 3.8cm–14cm, and were classified as clear cell carcinoma (92.95%), papillary carcinoma (5.13%), or chromophobe RCC (1.92%). All patients presented with stage III or IV tumours.

There were no statistically meaningful differences between the two treatment groups at baseline.

Improved survival with cryoablation and sorafenib compared to sorafenib alone

“The combined therapy had a clear advantage in terms of efficacy,” the study authors write.

Both progression-free survival and overall survival were statistically significantly higher (p<0.05) in the group treated with a combination of cryoablation and sorafenib than the cohort treated with sorafenib alone, indicating that cryoablation and sorafenib together can more significantly prolong these survival metrics than sorafenib alone can.

Progression-free survival was 20 months in the combined group, versus 12 months in the sorafenib only group, and overall survival was 36 months in the former cohort compared to 29 months with just sorafenib.

Additionally, Liu and Cao et al report a higher progression-free survival and overall survival in patients who underwent complete cryoablation (n=25,

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38.81% of the patients treated with cryoablation) than the patients who only had a partial cryoablation. Stratification analysis revealed a progression-free survival of 23 months for those patients who had a complete cryoablation; progression-free survival was 17 months for those participants with a particle cryoablation. This trend was the same for overall survival: 41 months in complete cryoablation recipients, versus 32 months in partial cryoablation recipients.

Based off these results, Liu and Cao et al recommend complete cryoablation for advanced RCC with relatively small tumour diameters, and further cryoablation

group, and a partial response in 16. This yields an overall response rate of 71.64% in the combined cohort, and 19.10% in the sorafenib group.

The researchers also calculated the disease control rate: the total sum of the number of patients with a complete response to treatment, a partial response to treatment, and a stable disease condition after treatment, divided by the overall number of patients. The number of patients with a stable disease condition following treatment was 12 (17.91%) in the combined arm, and 58 (65.17%) in the sorafenib only arm. A progressive disease condition was reported in seven patients (10.45%) in the combined treatment group, and fourteen patients (15.73%) in the single treatment group.

Therefore, the disease control rate was significantly higher when both cryoablation and sorafenib were used together, at 89.55%, than when sorafenib was used alone, 84.27% (p<0.05).

The significantly higher survival rates in the cryoablation and sorafenib group could be explained by a couple of different concepts, Liu, Cao and colleagues suggest. They first propose that cryoablation can effectively reduce tumour load within a short time, thereby increasing overall response rate and disease control rate, and effectively controlling tumour progression in patients with advanced RCC. Secondly, they explain how cryoablation results in the necrosis of a large number of tumour cells in the target area, and “may increase the

Cryoablation may influence the immunogenicity and drug resistance of residual tumour cells, thereby changing or prolonging the effective time of targeted drug therapy.” treatments for tumours with larger diameters to achieve complete ablation.

Cryoablation and sorafenib together lower the proportion of patients with disease progression

The combined treatment group had a higher proportion of complete response and stable disease than the group treated with sorafenib alone. The study authors used these metrics to calculate the overall response rate and disease control rate.

These measures provide further clarity when assessing the efficacy of the different treatment options for RCC. The overall response rate was higher for patients treated with cryoablation and sorafenib than sorafenib alone (p<0.05).

The overall response rate is calculated by adding the number of patients with a complete response following treatment and the number who exhibited a partial response, and dividing the sum by the total number of patients. In the combined cryoablation and sorafenib arm, a complete response was observed in five patients, and a partial response in 43. In comparison, a complete response was seen in just one patient the sorafenib only

permeability of tumours and surrounding tissues, thus increasing the sensitivity of residual tumour cells to target drugs.”

They continue: “Hyperthermia has been shown to enhance drug delivery, so the changes induced by cryotherapy may improve the uptake of sorafenib, although this association requires further

investigation.”

A third reason given by the study authors for the improved disease control rate and survival scores is predicated on the knowledge that the kidney is an immunogenic organ. Liu and Cao et al speculate that “cryoablation may influence the immunogenicity and drug resistance of residual tumour cells, thereby changing or prolonging the effective time of targeted drug therapy.”

In terms of safety, the authors note that cryoablation did not increase the risk of side effects of targeted drugs; there was no significant difference between side effects experienced by patients in either arm of the study.

Enhanced antitumour immunity: A new treatment strategy for advanced RCC

Liu, Cao and colleagues report that the combined therapy of cryoablation and sorafenib “may enhance the body’s antitumour immunity, and effectively prolong progression-free survival and overall survival without compromising patient quality of life, thus representing a new treatment strategy for advanced RCC.” The antitumour immunity is particularly important, as the authors note that, “similar to other targeted drugs for tumour treatment, […] patients develop resistance to sorafenib, leading to disease progression and death.”

The study investigators therefore analysed serum indicators related to immune function in both the combined treatment group and the sorafenib only group. In the combined treatment arm, the proportion of Treg cells was significantly decreased, and the proportions of several T lymphocytes were significantly increased after treatment compared to before treatment. This was not the case in the sorafenib only group: in this cohort, no significant difference in Treg cells or T lymphocytes was observed before and after treatment.

Explaining this finding, Liu, Cao and colleagues write that these data “suggest that cryoablation enhanced tumour immunity more than sorafenib alone.”

The authors summarise: “As a potential new treatment strategy for advanced RCC, cryoablation combined with sorafenib, therefore, requires further investigation in future randomised controlled trials.”

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Radiofrequency ablation

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ADVERTORIAL

Palliative care for painful bone metastases: Perspectives on OsteoCool bipolar RFA and the OPuS One Study

The OPuS One Post-Market study is currently collecting real-world data on the effectiveness of the OsteoCool radiofrequency (RF) ablation system for palliative treatment of spinal metastasis and benign bone tumours. The study is ongoing and continues to enrol patients globally.

Preliminary results for 34 patients with painful bone metastasis in the thoracolumbar spine (predominately) and the pelvis and/or sacrum treated with RF ablation have been analysed, and in preliminary data patients exhibited rapid pain improvement at one week with 74% (25/34) of patients experiencing significant change from baseline in worst pain of ≥2 points and sustained long-term relief through three months.

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ason Levy (Northside Radiology, Atlanta, USA), a study site physician for the OPuS One trial, highlighted the speed of the patient response when treated with OsteoCool, commenting: “The time to pain relief was rapid. At one week, 74% saw the benefits, Jason Levy Sandeep Bagla Nam Tran noting a significant pain score reduction in their worst pain.”

USA) believes OsteoCool will become increasingly In addition to the quick acting nature of the OsteoCool integrated into the care continuum, saying he sees the system, the preliminary outcomes of the study showed device as “a critical adjunct to the existing modalities for sustained long-term relief. At three months, 93% (13/14) metastatic disease such as kyphoplasty and XRT.” of patients reported significant reduction in the scoring of Levy enumerates the benefits of the OsteoCool system: their worst pain.

“OsteoCool is able to provide an avenue for cement The study’s principal investigator, Sandeep Bagla introduction, allowing for mechanical stabilisation. One (Vascular Institute of Virginia, Woodbridge, USA), told of the biggest shortcomings of radiation is destabilisation Interventional News: “At three months, patients have in axial loading weight-bearing bones and their propensity continued to demonstrate excellent results in terms of pain for future fractures. In an appropriate patient population, I response. While the study is not completed, early analysis believe OsteoCool could be a real benefit.” is very promising.”

The OsteoCool system offers simultaneous, dual-probe In light of these positive preliminary data, study site capabilities for treating painful bone tumours. Levy says physician Nam Tran (Moffitt Cancer Center, Tampa, of the OPuS One trial: “This prospective trial will serve as

a building block to advance this percutaneous therapy into oncologic treatment algorithms, allowing interventional radiologists (IRs) to deliver this care to patients.”

Drawing on his clinical experience, Bagla summarises: “The OPuS One study is posited to provide the IR community a large-scale, prospective international clinical study to support what we have known within the IR community for years. This will potentially allow IRs to integrate into the multidisciplinary care team for oncology patients and contribute in the palliation of bone metastases.”

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Ablation

Cryoablation shows promise in treating low-risk breast cancers

Cryoablation shows early indications of effectiveness in treating women with low-risk breast cancers, according to research presented at the annual meeting of the Radiological Society of North America (RSNA; 25–30 November, Chicago, USA). Researchers said that, over the four years of the study, there has only been one case of cancer recurrence out of 180 patients.

“IF THE POSITIVE preliminary findings are maintained as the patients enrolled in the study continue to be monitored, that will serve as a strong indication of the promise of cryotherapy as an alternative treatment for a specific group of breast cancer patients,” said study lead author Kenneth R Tomkovich, radiologist at Princeton Radiology and director of Breast Imaging and Interventions at CentraState Medical Center in Freehold, USA. While cryoablation has been used to treat cancers in the kidneys and lungs, it has yet to become an established treatment for breast cancer. Tomkovich began studying it for that indication more than 10 years ago, as imaging advances in mammography and ultrasound and the development of tomosynthesis enabled the detection of more low-risk cancers.

These small, early-stage cancers have the potential to become invasive and life-threatening without treatment. But treatment options have not kept pace with imaging advances.

“We are finding smaller and smaller breast cancers, but we are still treating them the same way we did 30 years ago,” Tomkovich said.

Cryoablation represents a potential new weapon in the arsenal against breast cancer. The tumour-killing procedure takes less than an hour, and patients are able to return to their normal activities shortly thereafter.

As part of the Ice 3 Trial, Tomkovich and colleagues at 18 centres across the USA have been studying cryoablation as a primary treatment for breast cancer without surgical lumpectomy. Starting in 2014, the researchers began performing cryoablation on women ages 60 and over with biopsy-proven, low-risk breast cancer. The patients undergo the procedure and then are followed for recurrence with mammography at six and 12 months and then annually for five years.

As of now, the researchers have three-year follow-up data on about 20 patients and two-year follow-up data on

more than 75 patients. The preliminary results have been very promising. The procedure was successfully completed in all patients, and no serious adverse events have been reported. Only one patient experienced a recurrence, giving the procedure a 99.4% success rate so far.

“Lumpectomy is 90–95% effective at removing cancer,” Tomkovich said.

“We were going for something close to that, but our preliminary results have been even better. We are getting the same results at 18 centres around the country.”

Advocates claim that cryoablation has advantages over thermal ablation techniques, which use heat to destroy tumours. Additionally, there is preliminary evidence from studies on mice that cryoablation can stimulate an immune system response against cancer cells in the body.

Final results of the study will be published when five-year follow-up data is available for all the women who were treated.

“If it is proven that cryoablation

First study investigating microwave ablation of HCC in the elderly finds it safe and effective Treating hepatocellular carcinoma (HCC) with microwave ablation is safe in the elderly population, the first study investigating the efficacy and safety profile of this procedure in over 75 year olds reports.

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hicheng Zhou (Yong Loo Lin School of Medicine, Singapore) presented this research at the 2018 British Society of Interventional Radiology annual meeting (BSIR; 14–16 November, Bournemouth, UK), concluding that chronological age was not a predictor of longer hospital stay, postoperative complication rate, or of poorer overall survival.

In Singapore, HCC is the third and fourth most common cause of cancer-related death in men and women, respectively, and globally, it is the fifth most common cancer worldwide. Commenting on these figures, Zhou outlined the need for this work: “This is certainly cause for concern, and for good treatment options to be available. Percutaneous thermal ablation is an established curative treatment with a high technical success rate and good tumour control.”

An aging population in Singapore—and many other nations—also necessitates research specifically evaluating how the elderly population responds to different treatment options. The coupling of an increased life expectancy and a growing number of HCC screening programmes in Singapore has led to earlier detection of this cancer, and subsequently a greater number of patients undergoing curative treatment. The study investigators therefore set out to compare the outcomes of elderly and nonelderly patients undergoing curative percutaneous microwave ablation.

Zhou and colleagues conducted a retrospective review of 59 patients undergoing thermal ablation between 2013 and 2018. The data included treatment naïve HCC patients, and excluded those with metastases, suboptimal ablation, or tumour recurrence. Of the 59 patients included in the study, 18 were over 75 years old, and thus classified as

elderly. Zhou et al evaluated patient demographics, tumour characteristics, and post-procedural outcomes, before analysing the data using the software SPSS. There was no significant association between the age of the patient and the outcome of the procedure, indicating that, elderly or not, comorbidities do not predict a worse outcome in terms of percutaneous ablation. Cumulative survival at one year was 94.4% for the elderly population, and 92.7% for the nonelderly. At three years, the survival was 66.7% for

Percutaneous thermal ablation is an established curative treatment with a high technical success rate and good tumour control.” the elderly and 56.1% for the non-elderly population.

After five years, cumulative survival was 50% in the elderly population, compared to 24.4% in the nonelderly population.

The finding that there was no significant difference between elderly and non-elderly patients in terms of procedural outcomes, length of hospital stay, complication rates and local recurrence rate was not necessarily expected. An older patient cohort is more likely than those under 75 to have a number of comorbidities and liver degenerative potential, possibly putting them at a higher risk of adverse effects post-procedure—the results of this study did

Kenneth Tomkovich

works, then some women might be more inclined to opt for it over surgery,” Tomkovich said.

Kenneth Tomkovich is a consultant for Scion Medical Technologies, and is on the Scientific Advisory Board for IceCure Medical.

reveal a higher incidence of hyperlipidaemia and hypertension in the elderly population.

However, Zhou also noted that, “Interestingly, the non-elderly population had a higher incidence of portal hypertension.” He continued: “We also found that the non-elderly population group actually had a worse preprocedural liver function test, evidenced by the higher Bilirubin and aspartate transaminase levels [25.2µmol vs. 16.7µmol and 55.3U/L vs. 36.6U/L, respectively], and a longer prothrombin time [14.9 seconds vs. 13.8 seconds].”

Acknowledging this as a limitation of the study design, Zhou commented, “This [poorer preprocedural liver function in younger patients] probably reflects the way a tumour is selected in our institution, and we recognise that this could be a potential source of selection bias. Perhaps older patients with better liver function and younger patients with poorer liver function were selected for ablation techniques.”

Zhou continued, “While not significant, the nonelderly population actually had a shorter survival.

Conversely, the older population showed a longer survival period than our non-elderly population group. Perhaps our preprocedural liver function rather than age itself predicts mortality.”

Additionally, the study investigators understand that as a retrospective, single-centre study with a relatively small sample size, further work is needed with a larger cohort to increase the statistical clout of their conclusions.

Previous studies investigating the efficacy and safety of radiofrequency ablation in elderly HCC patients have reported mixed results. Hirokazu Takahashi and colleagues (Department of Internal Medicine, Saga Medical School, Saga, Japan) concluded in 2010 that radiofrequency ablation treatment might be safe and effective in both elderly and non-elderly patients, but Wei-Yu Kao et al (Taipei Veterans General Hospital, Taipei, Taiwan) found younger HCC patients to have a better prognosis after percutaneous radiofrequency ablation, as reported in 2012. Prior to Zhou et al’s work, to the authors’ knowledge, no study looked into microwave ablation in this patient cohort.

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Pancreatic interventions

Physicians call for further work on IRE in pancreatic cancer Further research into the use of percutaneous irreversible electroporation (IRE) in the treatment of pancreatic cancer is essential, according to Govindarajan Narayanan, chief of Interventional Oncology at the Miami Cancer Institute, and professor of Radiology at Florida International University (USA). He made this call at the Spectrum conference (1–4 November, Miami, USA).

“WE NOW SEE a signal towards possible survival benefits, so a registry and probably a randomised controlled trial to really understand the role of IRE in pancreatic cancer is definitely an unmet need,” he told conference attendees.

He added that a comprehensive mechanism for followup criteria and protocols for locally advanced pancreatic cancer patients who have had radiotherapy should also be developed and validated.

Until recently, treatment options for pancreatic cancer were surgery, for which only 10–20% of patients will qualify, radiation or chemotherapy, or a palliative treatment algorithm. Narayanan assessed the role of percutaneous IRE to see whether it can be performed in a minimally invasive and reproducible fashion, and what its impact has been on the signal to survival benefit. “After using this technology in the pancreas for the last nine years,” he said, “there are a few things we have learned.”

He ran through the trials to date that have looked at the safety and efficacy of the procedure. The first two he cited were from his own centre. In 2012, his group did a retrospective series on 14 patients looking at percutaneous IRE for down-staging and control of unresectable pancreatic adeonocarcinoma.

They followed this with a further retrospective study in 2017, on percutaneous image guided IRE for the treatment of unresectable locally advanced pancreatic adenocarcinoma. This single centre study of 50 patients, all of whom had biopsy-proven unresectable pancreatic cancer, assessed the safety profile, with a secondary objective of determining overall survival. All patients had had chemotherapy, and 60% had also had prior radiation therapy; follow-up was computed tomography

(CT) at one month and every three months thereafter.

The median time from diagnosis to IRE was 11.6 months, and there were serious adverse events in 10 of 50 patients (20%)—seven suffered abdominal pain, and one each had pancreatitis, sepsis, and a gastric leak. Narayanan described the finding of 27 months from time of diagnosis and 14.2 months from IRE as “a healthy median overall survival”. There were no treatment-related deaths, and no 30-day mortality.

“We did a multivariate analysis to see if there was any different predictor that helped with overall survival. We found that tumour size <3cm had significantly longer overall survival than tumour sizes that were >3cm.”

Also in 2017, Hester Scheffer (Amsterdam, The Netherlands) et al published the findings of the PANFIRE study, which looked at ablation of locally advanced pancreatic cancer with percutaneous IRE. “The purpose of this study was to investigate the safety,” explained Narayanan, “but also to look at the quality of life, pain perception and efficacy in terms of time to local progression, event free survival, and overall survival. It found that percutaneous IRE for locally advanced cancer is generally well tolerated, although there were some major adverse events. And preliminary survival data were encouraging.”

An Italian study from Maria Belfiore (Naples, Italy) et al in 2017 outlined the preliminary experience of using percutaneous CT-guided irreversible electroporation followed by chemotherapy as a novel neoadjuvant protocol in 20 patients with locally advanced pancreatic cancer.

No major complications occurred—although two patients died three and four months after treatment, this was due to rapidly progressive disease. In the remaining 18 patients,

Y90 radioembolization shows promise in treating metastatic pancreatic cancer Encouraging results from Y90 (yttrium-90) radioembolization of pancreatic cancer support a possible role for it in the management of the disease, with initial small scale studies suggesting it provokes a disease response; however, the benefits may vary for different patient subgroups.

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lthough evidence is still limited, Alexander Kim, chief of Vascular and Interventional Radiology at Medstar Georgetown University Hospital (Washington DC, USA), said: “The data suggest that we can get promising disease response with radioembolization, with response rates from 20–40% in various groups. Patient selection, obviously, is key.”

He was speaking at the Spectrum conference (1–4 November, Miami, USA), outlining a possible role for Y90 in the management of pancreatic cancer metastasis.

In 2018, 55,440 new cases of pancreatic cancer were diagnosed, with 44,330 deaths.

The five-year survival is 8.5%, dropping to 2.7% in patients with distant metastases.

The current standard of care, drug regimens of either FOLFIRINOX or gemcitabine abraxane, has shown an overall survival of about eight to 11 months in trials.

Kim explained the rationale for adding Y90 radioembolization to standard chemotherapy treatment: “Overall, there is a poor prognosis for these patients, so

there is a need to find different treatments that may potentially augment survival in a subgroup of these patients. And, there are data that show that liver metastases are a negative independent prognostic factor of survival, causing death in about 50% of these patients.” The radiosensitivity of pancreatic adenocarcinoma suggests Y90 could provide an alternative option.

But there have been very few studies looking at its efficacy; Kim assessed the small number available. The largest study, of 19 patients, was from Germany: “Response rates in the liver are pretty impressive, with about nine of the patients showing a partial response to treatment, and overall survival of nine months from the time of radioembolization, and 19 months from initial diagnosis.”

He also told delegates about the findings from his own study of 16 patients, in which Y90 radioembolization was incorporated into systemic therapy, describing the treatment strategy as “a little unique”.

“We strategised to incorporate Y90 into

six-month imaging follow-up showed a volumetric decrease in the lesion size of 42.8%, and three patients underwent R0 resection. The investigators concluded that IRE followed by chemotherapy is safe, feasible, and effective in producing short-term control of locally advanced pancreatic adenocarcinoma (LAPC) with a possible down-staging effect to resectable lesions.

In the UK, Edward Leen (London, UK) et al conducted a retrospective review from 2011 to 2016 of 75 patients who had unresectable pancreatic carcinoma and underwent percutaneous IRE after chemotherapy using computerised tomography guidance under general anaesthesia.

Post-procedural immediate and 30-day mortality rates were both zero, and all grade adverse events were 25%.

The median in-patient stay was one day, described by Narayanan as “typical of percutaneous IRE; you have a significant advantage there, one to one and a half days stay in the hospital.”

The median overall survival and progression free survival rates post-IRE for LAPC were 27 and 15 months, respectively—“very similar to other results that have been achieved”.

Narayanan pointed out: “Prospective and retrospective studies have established the safety of this procedure, and studies from different centres around the world have shown that this technique is reproducible, with a positive signal towards survival benefit. The US Food and Drug Administration has recently provided a breakthrough designation for IRE in pancreatic cancer.”

He said that further developments would follow, and promised: “We are hoping to have more exciting news in this space very soon.”

systemic treatment. We treated those patients with half dose gemcitabine in the cycle prior to radioembolization, then performed whole liver radioembolization for patients, but then gave them a half dose again for the following chemotherapy cycle, and then they went back to a regular dose of systemic treatment.” Overall survival from time of diagnosis was 22 months, and from time of radioembolisation was 12.5 months.

His group have also recently completed a multicentre retrospective study of 33 patients, published in the March issue of Journal of Vascular and Interventional Radiology. It recorded a disease control rate of 81%, and disease response in 42% of patients. The median overall survival from the time of Y90 radioembolization was 8.1 months (95% CI 4.8–12.5), with a median overall survival from diagnosis of 20.8 months (95% CI 14.2–29). “Our toxicity levels were pretty mild, with three patients having Grade III toxicities, and no grade IV or V toxicities in the 33 patients.”

Only one prospective study has been conducted: an open label, phase II, two-centre trial in Australia, which was published in 2015. “The primary objective was to assess progression free survival in the liver. They enrolled 15 patients in the study, everyone had bilobar liver disease.

They received whole liver treatment in a lobar fashion using resin Y90. The tumour response rates were generally pretty impressive. You can see the change in CA 19-9 levels decreasing pretty dramatically for the majority of these patients.”

Progression free survival was 5.2 months

for the liver, and 4.4 months at any site.

But overall survival was only 5.5 months, raising the question, Kim said, of “whether radioembolization actually benefits in the frontline setting. The prospective phase II data would argue against incorporating Y90 in this patient population; the patients overall survival was really unchanged from standard survival that you would expect to see with gemicitabine based treatment.”

He stressed the importance of patient selection. At Georgetown, Kim and other researchers have incorporated Y90 as a consolidated treatment for particular groups of patients, including those who have been treated with frontline therapy for four to six months and have demonstrated good tumour biology.

“The second group we have treated are patients who have developed systemic toxicity with chemotherapy—generally patients who develop toxicity from gemcitabine, and they will either have to switch their regimen or titrate down on their dose. There is a concern that their liver disease will flare after the change in regimen, so we have started to incorporate Y90 for this patient population.”

He said Y90 treatment needed further assessment, including the Georgetown strategy of consolidation and maintenance, to see whether it leads to a survival benefit.

And, he added, “there is a lot of interest in assessing the synergistic effect of radioembolization and immunotherapy.

That is another area that needs more investigation in the pancreatic cancer patient population.”

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Parkes Weber Syndrome

The importance of paediatric IR in treating Parkes Weber Syndrome Daryl Goldman Suroosh Marzban Robert Rosen

Comment & Analysis

Daryl Goldman, Suroosh Marzban, and Robert Rosen highlight the use of catheter-based techniques for the treatment of Parkes Weber syndrome (PWS) in children. They summarise their recent work, presented at the Society for Interventional Radiology 2019 conference (SIR; 23–28 March, Austin, USA).

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WS is a rare congenital vascular disorder characterised by high-flow arteriovenous malformation (AVM), limb hypertrophy, and port wine stain. It has been associated with mutations in the RASA1 gene, which codes for various growth factor receptor signals involved in proliferation, migration, and survival of vascular endothelial cells.

AVMs are often the most debilitating of the PWS triad, causing a wide variety of clinical features such as pain, fatigue, ulceration, and high-output congestive heart failure. Unfortunately, AVMs remain a significant challenge to treat given a high

recurrence rate and the morbidity associated with surgical resection. Catheter-based techniques have emerged as the preferred mode of therapy.

The purpose of our study, presented at SIR, was to describe the safety, feasibility, and efficacy of catheter-based therapy for the treatment of high-flow AVMs in paediatric patients with PWS. A retrospective review was performed from January 2004 to January 2018 to identify patients with PWS who underwent diagnostic angiography of AVM. Nine paediatric patients were included in this study (mean age: eight; four male).

Treatment response (relief of symptoms), technical success, lesion characteristics, procedural details, and adverse events were recorded.

Two of nine patients (22.2%) were affected in the upper extremity and seven of nine (77.7%) in the lower extremity.

Presenting symptoms included pain (100% of patients), oedema (88.8%), ulcer ( 33.3%), difficulty ambulating (44.4%), and high-output cardiac failure (55.5%). Three (33.3%) patients were found to have diffuse arteriovenous communication without a discrete AVM nidus and thus were not treated with embolization. Six (66.6%) patients were treated with transcatheter embolization of the AVM’s arterial inflow.

Four (66.6%) required multiple inflow embolization procedures (median, four; range, one to 10). Twenty-seven arterial inflow embolization procedures were performed in total. N-Butyl cyanoacrylate (nBCA) adhesive was used in 19 cases (70.3%), microspheres in seven (25.9%), and a combination of coils and adhesive in one (3.7%) case. Two patients (22.2%) also had interventions to treat the venous component of the malformation. Median follow-up time was 67 months. Technical success (decreased arteriovenous shunting) was 100%. One (16.6%) patient treated with embolization experienced no response and five (55.5%) experienced a partial response (reported improvement in symptoms). There were no periprocedural complications.

The AVMs associated with PWS are often debilitating. Management requires a multidisciplinary approach; surgical and endovascular interventions. Interventional

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radiology plays a crucial role in the treatment of these patients. Transcatheter and direct embolization are feasible techniques for treatment of arteriovenous malformation’s in patients with PWS with a favorable treatment response, safety profile, and high technical success rate.

Even in a practice such as ours consisting primarily of treating vascular malformations, PWS remains one of the most challenging situations, due to the diffuse nature of the shunting and lack of a clear cut nidus. These are the patients who have the highest incidence of tissue loss, non-healing ulceration with associated pain, and high output cardiac states, including cardiac failure in the most severe cases.

The goals of treatment are thus directed at reducing the shunting to improve the local symptoms as well as reducing the cardiac workload—real “cure” is an unrealistic goal in most of these patients. The best hope in the future may be pharmacologic, as our understanding of the molecular basis of angiogenesis is constantly advancing.

Daryl Goldman is an interventional radiology integrated resident at Icahn School of Medicine at Mount Sinai, currently doing her intern year in General Surgery at Lenox Hill Hospital, New York, USA. Suroosh Marzban is a vascular surgery resident at Lenox Hill Hospital, New York, USA. Robert Rosen is an interventional radiologist at Lenox Hill Hospital, New York, USA.

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Interview

Profile

Laura Findeiss

After coming across interventional radiology in a “fortunate accident”, the Society of Interventional Radiology (SIR) president-elect Laura Findeiss talks to Interventional News about her career, the future of the discipline, and the importance of working across disciplines to foster the creative thinking necessary in difficult cases.

You started your residency in surgery, but then changed to interventional radiology (IR). Why?

Lots of factors. For one thing, I found myself burned out.

That was before work hour restrictions, and there was a different culture in surgical training programmes. When I lost my originally deep compassion for patients, I realised that I could not do it anymore. I loved operating, but even this lost its lustre. After I left my residency, I spent a year working in rural hospital emergency departments (really, emergency rooms) in Tennessee, and this was a great experience for me, learning true clinical independence and gaining an understanding of what rural medicine is really like—how isolated some of these places are even now.

Ultimately, choosing a radiology residency was a process of exclusion and was not particularly deliberate. I enjoyed the imaging very much, but was like a fish out of water without the hands-on patient care. When I “discovered” IR, it really was a perfect combination of the beauty of imaging and the ability to care for patients in a creative and technically challenging way. When you have cared for lots of patients recovering from surgery and see the difference our techniques make, you see how truly impactful it is.

Have you had important mentors throughout your career? What have they taught you?

Yes! So many. The chief of IR at my residency programme, Ellen Hauptmann, was so committed to doing the right thing for patients, and she was such a role model for me.

Her compassion, knowledge base, imaging skills and true technical ability were part of what really attracted me to the specialty. I learned about what it means to be a great colleague from her, as she was so collaborative with all the referring specialties. The chief of IR in my fellowship, Torre Andrews, was great at talking to patients at their level, and that was great to observe. He became a true sponsor, as he was the one who got me involved on committees in the SIR, and it was that early engagement that got me energised and networked in the society. He was one of a core group of SIR members pushing the clinical practice paradigm early on, and his passion about this issue reinforced my own. Finally, Scott Goodwin, who gave me a great opportunity when he hired me at the University of California at Irvine as section chief, was a great mentor in that he let me execute my vision with guidance and trust.

He really stood back and supported me in the background while I ran the section in the direction our team wanted to go, and that was just a fantastic leadership experience that gave me the confidence to move on to other roles. It also taught me about leading by supporting others.

In several of your workplaces, access to IR services has been limited. What are some common barriers to access, and how can these be overcome?

This topic is really important to me. I think the biggest barrier to access in many places is the lack of an IR in a community or hospital. Recent literature looking at the distribution of providers of image-guided interventions throughout the USA validates this perspective; the availability in communities is dismal. This applies, unsurprisingly, to extremely rural locations, but I think the big shock is how even suburban and not-so-remote areas suffer from this lack of availability.

I see this as an amazing opportunity for our specialty.

We have a generation of IRs emerging from training now, more independent and clinically-minded. From my point of view, so many of the communities that would benefit from the presence of an IR are great places to live and grow diverse practices. Talking to young IRs who have had an opportunity to take advantage of these availability gaps, I am amazed at the high-quality practices they have built, and how rewarding this process has been for them.

One barrier that has been raised with regard to growing an IR practice in communities has been the “exclusive contracts” issue in the USA, whereby IRs may be ineligible to get hospital privileges if they are not affiliated with the hospital’s radiology group, but may find that they are unable to practice the way they wish to, in a more clinical fashion, within a radiology group. We have members advocating on both sides. SIR is actively working to find common ground on this topic through collaboration with the ACR’s IR Commission and the General, Small, Emergency, and Rural (GSER) groups Commission, as these issues are a mutual concern.

As a self-described “systems operations geek”, how does thinking systemically aid you in your work?

In my current role as chief of Service for Radiology at Grady Memorial Hospital, a large public safety net hospital in Atlanta, I am working to improve our systems and operations to provide better efficiencies in care to create more access without increasing costs. We are relatively under-resourced due to our mission of caring for a largely self-pay, county-funded, and Medicaid-funded population.

On top of emphasising process improvement methodology, I am focusing on change management principles, since all of this requires significant cultural reorientation and generation of buy in on multiple levels. I love the challenge of navigating all of this with the promise of better access to higher quality care for our patients. Before this role, using the same kind of systems thinking was really important for some of the structural changes I have participated in in other places: leading institutional change around procedural sedation standards, creating best practices in the IR area, negotiating a hospital contract focused on aligning incentives to achieve common goals. I think backing up and establishing the target state and thinking systematically about how to achieve the goals is always a best practice.

As the president-elect of the SIR, what are your aims for the society over the next 12 months?

We have already touched on a major theme: access to care. I truly believe that there are significant disparities in patient outcomes related to lack of access to IR. I also think that our burgeoning clinical IR workforce is a great match to this challenge. If we can navigate, through our collaborative work with the ACR, the current challenges in creating avenues for clinical IR practices within or alongside radiology practices, we can create a win-win(win) for radiology practices, IRs, and communities.

Another topic that is very important to me is that of promoting and supporting diversity in our specialty. The SIR has a goal of creating an inclusive environment. I hope to make progress on this front over the next year, particularly with respect to establishing venues for engagement and solidifying the platform from which

specific, member-driven efforts can launch. The SIR should be a place where all IRs can find a sense of belonging.

You are an advocate for multispecialty collaboration within healthcare. How can this be improved?

I firmly believe patient outcomes are better, and care is more efficient, when there is open and respectful communication between different specialties. In so many places we find ourselves in conflict with other specialists over areas of mutual expertise, configured as turf battles or even just ego battles, and patients are the losers. Physicians can easily get distracted from best patient care in these kinds of environments—watching your back instead of watching the patient. It is just another systems thing, in that reducing friction between specialties will help us to use institutional and system resources better and reduce cost, improve efficiencies, and optimise outcomes. Modifying incentives, of which monetary rewards are only a part, can help. To improve collaboration for the benefit of patients will ultimately take strong institutional and systemic leadership focused on reducing the incentives to compete and increasing incentives for collaboration.

Would you describe a particularly memorable case?

One of the most rewarding cases I did was early in my career. I had a patient referred for evaluation for a spontaneous portosystemic shunt. She had presented to

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Interview patients and the specialty if they can execute on the promise of a new kind of practice model. It is going to be disruptive, though, to radiology, and I am glad we are starting to talk about this at the SIR-ACR level. As a society, our imperative is to help get our members the tools they will need to navigate the changing landscape through productive negotiations with radiology practices, hospitals, payors, health systems, or whatever entities they need to work with to build the practices that make the most sense in their local environments. One big challenge is how different local environments are from each other in our health system, so the approach cannot be one size fits all.

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Fact File

Outside of your own research, what has been the most interesting paper that you have seen in the last 12 months?

Rosenkrantz et al, “Generalist versus Subspecialist Workforce Characteristics of Invasive Procedures Performed by Radiologists”, in Radiology online.

An incredible take home point from the article was that only 347 counties throughout the USA have access to an IR, and only 869 counties have access to a generalist radiologist who performs procedures. This clearly shows that a large part of the country is un- or under-served from the standpoint of IR and we need to look at how to address these access disparities.

What do you anticipate being the most disruptive technology in IR over the next 10 years?

Targeted molecular therapies. In addition to immunotherapy, I see a lot of promise in the theranostic arena, with molecularly-targeted imaging/ radiotherapy agents for diagnosis, treatment, and monitoring of response to therapy. I can actually see IR playing a big role in the transarterial delivery of these agents to tumors, since intravenous administration is fraught with problems from a dosimetry point of view. These applications are just a one-off from what we already do with SIRT [selective internal radiation therapy]. It is another reason to make sure we maintain our ability to achieve AU status, and the molecular therapy piece is an important reason for IR’s to engage in bench research.

How has the field changed since you started your career?

our hospital comatose from severe hepatic encephalopathy and she had suffered from medication refractory bipolar disorder and schizophrenia starting early in adolescence.

She had been institutionalised for many years, and had reportedly displayed psychotic behaviour. There is a lot in the veterinary literature about congenital portosystemic shunts in dogs, who demonstrate bizarre behaviours that can resolve with surgical occlusion of the shunts. We wondered if this was in play. Then we learned that the antipsychotic and other medications she was on are dependent on hepatic metabolism—the metabolites are the active agents. After a lot of multidisciplinary discussion, I ultimately occluded her shunt and psychiatry modified her medications. She ended up being discharged home to self-care after a few months with the support of her adult daughter. In follow-up, she thanked me for giving her a relationship with her daughter.

This case is a reminder to think outside the box, something I think IRs are really good at.

What is the biggest challenge in IR at the moment?

We are in a major transition with the training pathway, and this is bringing learners with different perspectives and expectations into the specialty. I think this will be good for

There is the obvious answer of case mix—early in my career my whole practice was abdominal and then thoracic endografts, renal artery stenting, carotid stenting, and CLI [critical limb ischaemia] intervention. I had to strive to start programmes for chemoembolization, UAE [uterine artery embolization], and TIPS [transjugular intrahepatic portosystemic shunt]. That landscape continues to change and can always be expected to change, since our talent as a specialty is figuring out how to treat disease in different, less invasive, innovative ways, and if we do not see procedures migrating out and new ones migrating in then we are not innovating.

Even more important is the change in the understanding of what it means to practice clinically. Early in my career I was, I think, in great company, but in the minority as far as beating the drum on having to have a dedicated clinic model and practice like any other procedural specialty. It is great to see how this concept has been embraced and is now at the core of our training programmes.

What are your interests outside of medicine?

A lot of individual sports: skiing, snowboarding, road cycling, mountain biking, rock climbing, wake boarding.

I started triathlon recently, and have been learning how to telemark. I love to travel, and enjoy ballet and a good book (but these days most of my books are sitting on a shelf staring at me, reminding me they want to be read).

Current appointments

2018–present: Professor of Radiology, Emory University School of Medicine, Atlanta, USA 2018–present: Professor of Surgery, Emory University School of Medicine, Atlanta, USA 2018–present: Chief of service for Radiology, Grady Memorial Hospital, Atlanta, USA

Current committee memberships

2019–2020: President, Society of Interventional Radiology 2018–2020: Chair, Vascular Imaging Joint Committee, American Heart Association 2018–2020: Liaison, Clinical Cardiology and Cardiovascular Radiology and Intervention, Cardiac Imaging and Intervention Committee, Council on Clinical Cardiology, American Heart Association 2018–2020: Member, Leadership Operational Committee, Peripheral Vascular Disease Council, American Heart Association 2016–2021: Member, American College of Radiology Commission on Interventional and Cardiovascular Radiology 2015–present: Member, Recruitment and Retention Committee, NHLBI Sponsored BEST trial 2015–present: Member, Technology Assessment Committee, NHLBI Sponsored BEST trial 2009–present: Member, Leadership Committee, Cardiovascular Radiology and Intervention Council, American Heart Association

Awards, grants and prizes (selected)

2017: Top Doc, CityView Magazine, Knoxville, USA 2016: Fellow, Society for Vascular Medicine 2012: Fellow, American Heart Association 2012: Castle Connolly Top Doctor in Southern California 2011: Fellow, Society of Interventional Radiology

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Paediatric IR

Paediatric IR is coming of age Alex Barnacle

can be tough, but so are consults with anxious adult patients and their relatives, and these are skills we can learn with a little practice. I usually find parents to be straightforward and as sympathetic to our concerns as we are to theirs. Their gratitude makes paediatric IR immensely rewarding; it is a great honour to be trusted with their children’s lives. The walls of our offices are littered with ‘first day at school’ photos and news of our

small patients’ journeys to adulthood [Figure 4]. Knowing you have given a child the chance of a long, full and healthy life is an extraordinary and frequent privilege.

Paediatric IRs come from a variety of backgrounds. There is only one training number in the UK so, as with adult IR many years ago, training programmes need to be far-sighted, flexible and inventive. Here in the UK, it is more

Figure 1

Figure 2a

Figure 2b

Figure 2c

Comment & Analysis Honoured as the Royal College of Radiologists/British Society of Interventional Radiology (RCR/BSIR) travelling professor for 2017–2018, Alex Barnacle delivered the Graham Plant lecture at the BSIR annual meeting (14–16 November 2018, Bournemouth, UK).

Titled “Paediatric IR: The adolescent years”, she detailed the years’ successes. Here, she expands on this topic, advocating for the continued growth of paediatric IR as a subspecialty.

PAEDIATRIC IR IS fast becoming one of our most exciting interventional subspecialties, attracting growing interest from trainees to institutions as a service with a central role in delivering modern healthcare to children.

For too long, it has been considered a highly niche area of medicine, providing supra-specialist care in tertiary paediatric centres but being of little relevance in most other settings. It is thrilling to see the tide turning, with both radiologists and industry recognising that minimally invasive procedures can and should be offered to children, too.

All the factors that make interventional radiology a relevant and exciting specialty apply just as much to children, if not more so. Children and families much prefer ‘keyhole’ treatment options that seem less frightening and allow them to get home sooner. More importantly, minimally invasive imageguided approaches decrease the risks of collateral organ or vessel damage, which is critically important in children with 60 or 70 years of life ahead of them.

Our adult IR skills are all applicable in children. But paediatric IR challenges us to take things even further. It forces us to think hard about how to adapt adult kit to fit into small bodies and how to modify our techniques to decrease or avoid radiation burden and shorten procedure times. Examples include the use of carbon dioxide as a contrast agent for abdominal angiography [Figure 1].

This technique allows us to keep both fluid volume and iodinated contrast dose to a minimum in small children. A 4kg baby with a circulating blood volume of only 300ml cannot tolerate much in terms of saline flush volumes or contrast pump injections. The use of CO2 gives diagnostic images for initial angiography and allows us to save iodinated contrast for the selective runs. To control radiation burden, paediatric IRs have become adept at using only ultrasound for many procedures, from mediastinal biopsy to most cryoablation procedures. Such innovation is what attracted many of us into IR in the first place and paediatric

IR is a field where, for now at least, the innovative directions seem endless.

Conversely, not everything is so different in children. A baby’s femoral artery can usually tolerate a 4Fr sheath perfectly well and it is rare for us to have to use a 3Fr system for angiography or embolization. In fact, sometimes small is not better. For percutaneous nephrolithotomies, large-calibre tracks (24Fr) allow urologists to achieve complete renal stone retrieval more quickly in small children, minimising procedure times and the associated risks of significant blood loss and hypothermia.

What is different about paediatric IR is the underlying disease processes. As with adult IR, it is critical that we become skilled clinicians and try to understand our patients’ pathologies as thoroughly as the paediatricians and surgeons do. Vascular disease is rare in children but it does exist [Figure 2]. The spectrum of oncological disease is very different to that in adults and it is vital to know which lesions require biopsy, which can be diagnosed from sampling nodal disease and how much tissue is required. The complex genetic abnormalities in neuroblastoma, for instance, mean that 15–20 core needle samples are routinely needed for the complex histological and cytogenetic testing required for risk stratification and treatment planning for these children.

Complex congenital diseases expose us to a range of new challenges. Technologies such as intravascular ultrasound and optical coherence tomography allow us to investigate structural abnormalities at a new level and push diagnostic boundaries [Figure 3].

The rewards of paediatric IR are huge.

Children rarely complain and once they know they are in a safe environment, they make the most fun and trusting patients. Post-operative rounds are often conducted in the playroom or over a plate of jelly, chips and chocolate. Glitter is an occupational hazard. Adult IRs often tell me it is the thought of the parent interactions that is the most daunting.

Sure, conversations with anxious parents

Figure 2: 3.4kg baby with mid-aortic syndrome and hypertension. a) Angiography via a 4Fr sheath in the left axillary artery confirms mid aortic stenosis, tight SMA stenosis, occluded right upper and left main renal arteries and a very tight stenosis of the right lower pole renal artery. Both kidneys are perfused via collaterals. b) aortic angioplasty via left common femoral approach with SMA safety wire; c) post recanalization and angioplasty of right upper renal artery.

Figure 3a

Figure 3b

Figure 3: A 10-month-old child with long segment congenital tracheal stenosis. a) the bronchogram also demonstrates a tracheal bronchus; b) the optical coherence tomography (OCT) image confirms the presence of complete tracheal rings which appear as a complete dark brown circle deep to the bright orange mucosa. Mapping of the levels of the complete cartilage rings with OCT is crucial to the planning of slide tracheoplasty surgery.

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Paediatric IR

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ADVERTORIAL

Conventional TACE is improved by combined treatment

Roberto Iezzi (Fondazione Policlinico Universitario A Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy) performed a single-session combination therapy–ablation followed by Lipiodol (Guerbet)/conventional transarterial chemoembolization (cTACE; Doxorubicin + LUF, then absorbable gelatin sponge)–in a patient with a single large hepatocellular carcinoma (HCC) nodule 5.5cm in size during the most recent Mediterranean Interventional Oncology Live Symposium (MIOLive 2019; 28–29 January, Rome, Italy). Here, Iezzi details the case.

Case

The patient: a 63-year-old man with a cirrhotic liver and a 5.5cm HCC in segment VI; good liver function (MELD 6–Child A5) and a mild portal hypertension, with varices F1 and splenomegaly. In order to keep the patient in the transplantation list, our multidisciplinary group decided to treat the patient with a combined approach: microwave ablation (MWA) plus cTACE. Firstly, thermosphere MWA (80W—six minutes) was performed under ultrasound (US) guidance and deep sedation. Then, the needle was subtracted and digital subtraction angiography (DSA) showed a central devascularised area with peripheral reactive hyperemia. Treatment was completed with a super-selective conventional chemoembolization using a coaxial technique, performed by delivering an emulsion of 50mg Doxorubicin mixed with Lipiodol, followed by embolization with absorbable gelatin sponge to achieve strong cytotoxic and ischaemic effects. Final DSA showed a complete devascularisation of the lesion, without complications, whereas non-contrast 3D Cone Beam-CT, immediately post-procedure detected Lipiodol distribution throughout tumour-feeding vessels with a concentric peripheral localisation of radiopacity around the necrotic area. The procedure lasted one hour and the patient was discharged 24 hours after treatment, with no adverse events.

Advocating for a combined approach

Although to date there has been no clear consensus on the optimal time interval between RFA/MWA and TACE for balancing local therapeutic efficacy and safety, in my opinion, only a single-step “combined” approach can obtain and amplify the synergistic effects of both treatments, while decreasing patient discomforts, reducing hospitalisation length, and saving costs. In particular, when dealing

with a combination strategy, I prefer to perform ablation followed by TACE, to act on the large zones of sublethal heating obtained during ablation in tissues surrounding the electrode, and to optimise local drug effects. The delivery of a chemotherapy drug could be enhanced by the reactive hyperaemia induced by ablation. Furthermore, this pattern may potentially reduce the procedural time by more easily controlling the risk for bleeding complications, which could require immediate treatment (embolization is the treatment of the potential complications of ablation).

saturated, and stasis obtained even in the very peripheral portal branches. The peripheral localisation of Lipiodol drug emulsion around the necrotic area was clearly depicted by intra- and post-procedural non-contrast CB-CT examination, indicating that cTACE enhanced the volume of MWA-related central necrosis, with the emulsion of Lipiodol and drug increasing the safety margin of the previously performed ablation procedure.

Advantages of cTACE

An important potential limitation of cTACE was the lack of standardisation of the technique; this has previously hampered the acceptance of chemoembolization as a standard oncologic treatment. However, recently a new device has been introduced: the Vectorio system. This has allowed interventionalists to obtain levels of consistency and repeatability that were previously unavailable, while offering the opportunity to implement a more standardised approach to HCC treatment. Vectorio is the first-ever device specifically designed to mix drug and Lipiodol and to deliver the drug-Lipiodol mixture (drug-in-oil emulsion), more densely retained within the tumours. The highlight of Vectorio is its high resistance to Lipiodol and the oneof-a-kind three-way stopcock with four ports that avoids any disconnection from the start of mixing until the end of delivery, by connecting directly to the microcatheter.

Through Vectorio, with its specifically designed components, it is possible to obtain comparable emulsion preparations that could finally be overlapped throughout operators and angiosuites, thus improving and promoting standardisation of this specific treatment option.

It is well known that a major advantage of Lipiodol TACE is the ability to control the delivery of the treatment by continuous visualisation of the therapeutic agents due to Lipiodol’s radio-opacity, with a real-time visualisation of intralesional uptake and targeting, including visualisation of potential non-target deposition. Another advantage of using Lipiodol is that it can reach the portal veins around tumours because of arterioportal communication through the peribiliary vascular plexus, the vasa vasorum of the portal vein, and drainage routes from the tumour itself. The deposition of Lipiodol in the portal veins around a tumour has been reported to strengthen anti-tumour effects, and local tumour recurrence has proven to be significantly lower when a greater degree of portal vein visualisation with Lipiodol was demonstrated during TACE. The opacification of small peripheral portal branches around the tumour due to Lipiodol accumulation is a common finding, has been proven as a predictive factor for tumour response to treatment, and is associated with a lower rate of local recurrence and a higher rate of complete necrosis.

In the case we performed, Lipiodol drug emulsion was actively monitored until the tumour vascular bed was

Our adult IR skills are all applicable in children. But paediatric IR challenges us to take things even further.

It forces us to think hard about how to adapt adult kit to fit into small bodies and how to modify our techniques to decrease or avoid radiation burden and shorten procedure times.” common for paediatric diagnostic radiologists to incorporate IR into their paediatric training to subspecialise in paediatric IR, rather than for those with an adult IR background to turn to paediatrics. There are probably several reasons for this, not least the fact that until recently, most trainees on an IR pathway would have little awareness of any paediatric IR career options.

Paediatric diagnostic radiologists have already overcome the fear of working with children, and they know the immense rewards of being involved with children’s care. To them, the world of paediatric IR must seem a little less daunting than it might to, say, an

adult vascular radiologist, but I believe this can and will change. In North America, paediatric IR is an increasingly mainstream speciality and one that is now highly competitive, with over 20 specialist paediatric IR training schemes in the USA and Canada. The Society for Pediatric Interventional Radiology (www.

SPIR.org) is an enthusiastic and highly professional organisation, drawing the paediatric IR community together from all around the globe. This year’s meeting is in Amsterdam and I would encourage IRs to attend.

There are currently fewer than 15 consultant radiologists in the UK who have paediatric IR as a major part of their

Emulsion preparation: Advantages of the Vectorio system

This advertorial has been sponsored by Guerbet.

job plan. But it would be naïve to suggest that paediatric IR is only delivered by those few. A high proportion of those reading this will have been involved in paediatric cases in their career, from relatively routine drain insertions through to emergency embolisations in desperate circumstances. It would be unrealistic to expect all IR procedures in children to be delivered by subspecialists and it is vital that we develop a network of education and support so that all IRs know who to call for advice and support when a challenging case arises.

In parallel, it is imperative that we drive forward the development of a wider paediatric IR service in this country. The Royal College of Radiologists (RCR) and the British Society of Interventional Radiologists (BSIR) are taking this challenge seriously; together with the other Colleges, we are surveying services across the UK to identify areas of greatest need and then lobby for more jobs and greater funding.

I had the honour of being the RCR/ BSIR travelling professor for 2017–2018.

It was a fantastic year. I visited 15 training schemes, from Aberdeen to Plymouth, and met an extraordinary number of trainees fired up by the possibilities of paediatric IR. Many have subsequently come to visit

our centre and I have absolute confidence that most will follow it through to develop and shape rewarding careers with a paediatric IR focus. Only a few years ago, our paediatric IR fellowship post lay unfilled, but now we have trainees clamouring for similar posts around the UK. Over the last couple of years, it has become increasingly clear that a forum is needed to feed trainees’ interest and to grow a support network for both adult and paediatric IRs working in this challenging and emotive field. A Paediatric IR UK meeting grew out of this and at our inaugural meeting in November 2018, we welcomed 78 trainees, IRs and industry representatives for a memorable day of paediatric IR teaching and sharing that we will be building on in June 2019. Follow us on Twitter @PaediatricIR for details.

I have watched with pride and excitement as its influence has grown over the last ten years and I have no doubt that its future here in the UK is very bright indeed.

Alex Barnacle is a consultant paediatric interventional radiologist in the Department of Radiology at Great Ormond Street Hospital for Children (GOSH), London, UK. She is on Twitter as @BarnacleAlex.

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Back pain

Pulsed radiofrequency relieves acute back pain and sciatica CT-guided pulsed radiofrequency is safe and effective in people with acute lower back pain that have not responded to conservative treatment, according to a study presented at the annual meeting of the Radiological Society of North America (RSNA; 25–30 November, Chicago, USA).

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onservative treatment options for herniated disks range from over-the-counter pain medications to injections of corticosteroids directly into the affected area of the spine. Those who do not respond may require surgery. In some cases, the entire disc must be removed and the vertebra fused together for stability.

CT-guided pulsed radiofrequency applies energy through an electrode to the portion of the nerve responsible for sending the pain signals.

“Pulsed radiofrequency creates a nerve modulation, significantly reducing inflammation and its associated symptoms,” said study senior author Alessandro Napoli, professor of interventional radiology at Sapienza University (Rome, Italy).

Napoli and colleagues studied the approach in patients with back pain from lumbar disc herniation that had not responded to prolonged conservative treatment. In 128 patients, the pulsed radiofrequency treatment was delivered directly under CT guidance to the root of the

nerve. The treatment was applied for 10 minutes.

For comparison, a group of 120 patients received one to three sessions of CT-guided steroid injection on the same anatomical target with no pulsed radiofrequency.

The one-year outcomes demonstrated that CT-guided pulsed radiofrequency was superior to the injection-only strategy. Patients who received pulsed radiofrequency saw greater overall improvement in pain and disability scores during the first year. Relief of leg pain was faster in patients assigned to pulsed radiofrequency, and they also reported a faster rate of perceived recovery. The probability of perceived recovery after one year of follow-up was 95% in the pulsed radiofrequency group, compared with 61% in the injection only group.

“Given our study results, we offer pulsed radiofrequency to patients with herniated disc and sciatic nerve compression whose symptoms do not benefit from conservative therapy,” Napoli said.

The results of the study are superior to those typically

Given our study results, we offer pulsed radiofrequency ablation to patients with herniated disc and sciatic nerve compression whose symptoms do not benefit from conservative therapy.”

Alessandro Napoli

reported for usual care strategies and injections and may help a substantial number of patients with sciatic disc compression to avoid surgery, Napoli added.

The use of pulsed radiofrequency also could improve outcomes for patients set to receive corticosteroid injections.

“We learned that when pulsed radiofrequency is followed by steroid injection, the result is longer lasting and more efficacious than injection only,” Napoli explained. “The effect of pulsed radiofrequency is fast and without adverse events.”

Today, therapy for spine disorders allows for definitive treatment of symptoms and conditions using different techniques and technologies.

“Of the different therapies available, pulsed radiofrequency is among the least invasive,” Napoli commented. “Treatment lasts 10 minutes, and one session was enough in a large number of treated patients.”

Weighing up the radiation risks in CT-guided vs. fluoroscopy-guided spinal injections New research published in Radiology reports that CT-guidance is just as effective a tool for allowing interventional radiologists (IRs) to perform lumbar spinal injections as fluoroscopy-guidance, but exposes the physician to a lower radiation dose. However, a Swiss research team found that radiation exposure was greater for the patient when CT-guidance was used.

BOTH FLUOROSCOPY- and CTguided techniques are utilised by IRs to facilitate the administration of steroid therapy due to their proven ease of use and reliability, notes lead author Tobias Dietrich (Department of Radiology, Orthopedic University Hospital Balgrist, Zurich, Switzerland) and colleagues.

The study investigators sought to compare the radiation exposure for patients and interventionalists, as well as the outcomes, between fluoroscopyguided versus CT-guided lumbar spinal injections.

In their prospective, non-randomised observational study, Dietrich et al analysed the results of 1,446 patients who received transforaminal epidural injections or facet joint injections under fluoroscopic or CT guidance between October 2009 and April 2016.

They measured radiation exposure for interventionalists with dosimeters at the body and wrist, and followed the “as low as reasonably achievable” (ALARA) concept for radiation dose.

There was no clinically significant difference in patient outcome as

Tobias Dietrich

measured by the Patient Global Impression of Change (PGIC) scale, a patient-reported measure of pain used in this instance to evaluate efficacy at one day and one month post-procedural intervals. However, radiation dose to patients was higher with CT than fluoroscopy, as discerned through student t and χ2 tests.

The mean effective patient dose for fluoroscopy-guided lumbar

transforaminal epidural injections was 0.24mSv±0.22, compared with the higher mean effective radiation dose of 0.33mSv±0.1 for CT-guided injections (p<0.003). This difference was more pronounced in effective radiation doses for lumbar facet joint injections: 0.1mSv±0.11 with fluoroscopy guidance, versus 0.33±0.13 for CT guidance (p<0.001).

However, the authors report interventionalists experiencing a reversal of this dose difference, with fluoroscopy-guided injections exposing physicians to more radiation than CTguided ones: 0.42x10-3mSv recorded on body readings for the former versus 0.11±x10-3mSv±0.44 for the latter.

Radiation exposure of the wrist for the interventionalist was higher during fluoroscopy-guided compared with CT-guided lumbar facet injections as well: 0.46×10-3mSv±0.93 vs. 0.06×103mSv±0.24, respectively (p<.006).

Overall, physicians’ radiation exposure was 3.7 to 10 times lower during CT-guided spinal injections than it was during fluoroscopy-

guided injections (p<0.03). However, CT guidance required a statistically significant increase in patient radiation dose by a factor of 1.4 for epidural injections and 3.3 for facet joint injections, compared with fluoroscopy (p<0.003).

The benefits of CT-guided spinal injections, according to the study investigators, include less radiation exposure to the IR, and improved needle steering and manipulation without the need to constantly confirm the needle’s location. On the other hand, fluoroscopyguided injections require real-time image guidance that increases radiation exposure to clinicians but decreases effective radiation dose for patients.

Clinicians also have the option of using other imaging techniques, such as ultrasound, MRI, and augmented reality, to guide lumbar injection therapies, the authors note. However, they add that physicians tend to feel less confident using these newer modalities, but propose that additional training and experience may enable them to further reduce the risk of radiation exposure.

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“No further trials of vertebroplasty should be performed”, report concludes Current evidence does not support the use of vertebroplasty for the treatment of pain from vertebral fractures, concludes a recent task force report charged by the American Society for Bone and Mineral Research (ASBMR) aimed at examining the efficacy and safety of vertebral augmentation. Although lead author of the report, Peter R Ebeling (Monash University, Melbourne, Australia), and colleagues surmise that this conclusion is “likely to apply to other augmentation procedures”, such as kyphoplasty, they maintain throughout the report that high-quality evidence from placebo-controlled trials remains absent.

“T

he recommendations by this task force are designed to help provide a foundation for advancing the research and clinical care of patients with painful acute vertebral fractures”, write the authors. They stress that clinicians will need to balance the “limited findings” on the safety and efficacy of other nonpharmacological interventions with good clinical judgement, when it comes to making quality, informed patient care decisions.

The rationale behind the commissioned report encompasses the lack of consensus amongst clinicians on whether to use percutaneous vertebroplasty or kyphoplasty to reduce pain in patients with vertebral fractures. This disparity in opinion, as well as the high prevalence of vertebral compression fractures in patients with osteoporosis, led the ASBMR to commission a task force to address key questions on the efficacy and safety of vertebral augmentation and other nonpharmacological approaches, such as spinal bracing or exercise, for the treatment of pain after vertebral fractures.

Ebeling and colleagues explain that vertebral augmentation was introduced into practice before high-quality evidence establishing its efficacy and safety was published, yet remains—in some settings—part of standard routine care. Although the authors acknowledge that balloon kyphoplasty is currently more expensive and is performed almost three times more commonly than percutaneous vertebroplasty in the USA, they write: “No placebocontrolled trials of balloon kyphoplasty have been performed and the evidence of the value of this procedure is reliant on low-quality evidence from trials that have compared kyphoplasty with usual care or head-to-head comparisons with vertobroplasty”.

Ebeling and colleagues performed a systematic review of the existing literature and meta-analyses of an array of outcomes in order to test the efficacy and safety of vertebral augmentation and other nonpharmacological treatments for painful vertebral fractures. Randomised controlled trials (RCTs) and quasi-randomised trials that enrolled adults older than 40 years with acute nontraumatic vertebral fractures, directly comparing percutaneous vertebroplasty or balloon kyphoplasty with any treatment comparator group, were included. In terms of nonsurgical interventions, Ebeling and colleagues included RCTs and quasi-randomised trials of bracing or exercise interventions with similar enrolment criteria.

The ASBMR task force first addresses the efficacy and relative effectiveness of vertebral augmentation therapies and their ability to improve pain, posture, physical function and quality of life. Based on “moderate to high” quality evidence for percutaneous

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Vertebroplasty

vertebroplasty from five randomised placebocontrolled trials, Ebeling and colleagues find that percutaneous vertebroplasty provide no demonstrable clinically important benefit when compared with placebo or sham. Moreover, they report that subgroup analyses in the updated Cochrane review indicated that the result did not differ according to duration of pain.

However, the sensitivity analyses indicated that open trials comparing percutaneous vertebroplasty with standard medical care are likely to have overestimated any benefit of percutaneous vertebroplasty.

In terms of balloon kyphoplasty, Ebeling and colleagues write: “There is insufficient evidence to support kyphoplasty over nonsurgical management, percutaneous vertebroplasty, vertebral body stenting, or KIVA”. Although the authors found that kyphoplasty was associated with improved pain, back-related disability, and quality-of-life outcomes compared with nonsurgical management, they acknowledge that these results were derived almost solely from a single trial. Further, the investigators write: “Any apparent benefits of kyphoplasty over nonsurgical management appeared to decrease over time, and, based on available data, it was not possible to determine whether these between-group differences were clinically meaningful of the extent to which they were accounted for by sham effects or study bias.”

No placebocontrolled trials of balloon kyphoplasty have been performed and the evidence of the value of this procedure is reliant on low-quality evidence from trials that have compared kyphoplasty with usual care or headto-head comparisons with vertebroplasty.”

Ebeling and colleagues went on to address the potential harms and possible risk of new vertebral fractures with vertebral augmentation. Prior to the task force report, limited evidence was available on these risks. In relation to both percutaneous vertebroplasty and balloon kyphoplasty, the authors found that adverse events—including risk of death, incident vertebral fracture, cement leakage, adjacent

fractures, vasovagal reactions, cord compression requiring decompression, hypoxia and respiratory failure—were rarely systematically reported.

According to the authors, compared with nonsurgical management, kyphoplasty was not associated with a statistically significant increased risk of incident vertebral fracture, although it was associated with nearly twice the risk of any adverse event within 30 days of intervention. Yet, Ebeling et al alluded to the high risk of bias present in the trials and they write “it is uncertain whether any benefits of kyphoplasty versus nonsurgical management of vertebral fracture outweigh potentials harms”.

Finally, the efficacy and safety of other nonpharmacologic treatments—spinal bracing and exercise interventions, was investigated. Based on the current evidence, Ebeling and colleagues report that for patients with painful vertebral fractures, there is low quality evidence that spinal bracing improves pain, trunk muscle strength, kyphosis, pulmonary volume and quality of life at six months. Furthermore, although the authors note that, following exercise interventions, the “magnitude of effects on mobility were small”, they surmise that exercise interventions have significant positive effects on mobility and may improve pain, fear of falling, as well as back extensor strength or endurance.

Yet, the aforementioned study biases and methodological flaws present in the literature that Ebeling and colleagues acknowledge throughout the report led them to address these gaps in the literature. The authors report on future research that is required to improve patient outcomes in managing osteoporotic vertebral fractures, in relation to both vertebral augmentation and other nonpharmacologic approaches. While a rigorous trial design to minimise the potential for bias was recommended in order to examine all therapies, specific recommendations were also detailed.

“No further trials of vertebroplasty should be performed, unless they are adequately powered to alter the conclusions of the current body of evidence”, write Ebeling and colleagues. If further trials are to commence, the authors state that participants of these procedures, as well as ethics committees, should be fully informed about the current body of evidence. Regarding balloon kyphoplasty, the authors recommend that “further studies are needed to resolve whether kyphoplasty increases the risk of future vertebral fractures or adverse events, which should be systematically collected”, while “any future trials should carefully characterise the timing and severity of vertebral fracture among study participants [and] should have a placebo control group.”

For spinal bracing and exercise interventions, Ebeling et al maintain that more research is needed in general, including clearly defined participant selection criteria and study protocols. Specifically, more data is needed on serious adverse events, in both the intervention and comparator groups, and on the efficacy of exercise after acute vertebral fracture.

Lastly, they note that “future exercise trial designs should account for low adherence and attrition in sample size calculations”.

Based on the findings outlined in the report, the ASBMR task force detailed guidelines for the clinical management of patients with vertebral fracture.

Maintaining that the optimal management of vertebral fracture remains uncertain, Ebeling and colleagues put forward that when vertebral augmentation is used, patients should be fully informed about the evidence.

In light of the findings, they conclude: “It is critical that anti-oseoporotic medications are started, continued or changed in patients with recent vertebral fracture”. Further, the task force highlights that while the use of bracing in reducing pain immediately after vertebral fracture was not supported by current evidence, exercise may improve mobility and may reduce pain and fear of falling.

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Interventional radiology

Interventional radiology among the most competitive medical specialties of 2018 in the USA Integrated interventional radiology has been listed among the American Medical Association’s (AMA) seven most competitive medical specialties in 2018.

“THE NATIONAL RESIDENT Matching Program considers the most competitive specialties those that match with the highest percentage of US medical school graduates,” read a post written by AMA staff writer Brendan Murphy. “In 2018, seven specialties with at least 25 positions offered were filled with at least 85% US medical school graduates.”

The total number of 2018 national medical school applicants for integrated interventional radiology was 217 students, though only 35 students matched. The statement noted the percentage of medical school seniors filling the positions was more than 97%.

“While 91.8% of US seniors matched to their preferred specialty,

interventional radiology had the lowest rate of students—58.3%—who matched to it even though it was their preferred specialty,” Murphy wrote.

Integrated interventional radiology was one of four disciplines that did not have enough positions to accommodate all US seniors who preferred that specialty. The others included orthopaedic surgery, neurological surgery, and plastic surgery.

Other specialties in the AMA list included: otolaryngology, dermatology and thoracic surgery.

Sharing the news on Twitter, the British Society of Interventional Radiology (BSIR) commented, “The BSIR are working hard to expand the interventional radiology family this side of the pond.”

Five ways to improve interventional radiology According to a new survey of European interventional radiology (IR) departments published in Insights into Imaging, five steps should be taken to improve provision of IR procedures in Europe.

WHILE THE USE of IR procedures is growing as an alternative to surgery, the field is not as healthy in Europe as it should be, the report, written by Lorenzo Derchi (Genoa, Italy) and Afshin Gangi (Strasbourg, France), summarises. The survey was a collaboration between the European Society of Radiology (ESR) and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).

The survey was commissioned in May 2017 in an effort to understand how European radiology departments on their use of IR practices in their facilities. A total of 98 radiology department heads completed the survey, making up a response rate of 8.3%.

The researchers found a number of challenges facing European interventional practices, all of which had a common theme: not enough interventional radiologists are being trained to meet the growing demand.

Based on the results, the authors recommended five steps to improve the provision of interventional radiology in Europe: All acute care hospitals should prioritise offering 24-hour IR coverage. In Europe, about 60% of radiology departments can cover interventional emergencies, a percentage that the study authors believe is too low. If a hospital does not have enough interventionalists on staff for 24-hour coverage, hospitals within regions could form networks to share resources.

IR should be promoted to medical

students early in their training as a viable career option. Research in the USA has shown that far fewer medical students were exposed to IR compared to diagnostic radiology; this can hamper recruitment to the specialty. Only by attracting more trainees can IR overcome the personnel shortages that are restricting its broader use.

More women must be recruited into IR. While about half of diagnostic radiologists at European hospitals are women, they make up a „small minority“ at facilities dedicated to IR, the researchers found (they note this is also an issue in the USA).

They attributed the gender imbalance to concerns about call responsibilities and the lack of role models, which they believe could be counterbalanced by increasing the number of women in interventional faculty and chair positions.

Radiology should recognise the full clinical role of IR. This could be through the allocation of enough day-case beds to accommodate interventional procedures, for example, or through recognition of the administrative responsibilities involved in the full episode of care for patients treated with interventional procedures, such as patient examinations.

Diagnostic radiologists should take a more active role in IR. This could include actions such as recommending referrals to interventional colleagues in radiology reports when appropriate and sharing knowledge with diagnostic radiologists about interventional procedures.

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Rural communities have limited access to IR services in the USA

The results of an American College of Radiology (ACR) survey find that small hospitals and rural communities experience greater difficulty recruiting and retaining interventional radiologists (IRs) and meeting IR service demands compared with their non-rural counterparts. The data were published recently in the Journal of the American College of Radiology in an article authored by Eric Friedberg (Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, USA) and colleagues.

Rural radiology practices experience more difficulty recruiting IRs

More survey respondents from rural areas had trouble recruiting IR physicians to their practice than non-rural workers did; 59.2% of rural IRs reported this difficulty, compared to 32.8% of non-rural answerers.

According to Friedberg et al, “Of rural respondents who perceived they had difficulty recruiting IR physicians to their practice, 58.7% believed that ‘IR physicians do not want to do diagnostic work’ was a factor, which cumulatively accounted for 24% (20%, 28.6%) of all responses. Of rural respondents who perceived they had difficulty recruiting IR physicians to their practice, 58.2% believed ‘IR physicians do not want to work in a small or rural setting’ was a factor, which accounted for 29.8% (19.8%, 28.4%) of all responses. Together, these two reasons accounted for 47.8% of all rural respondents’ answers.”

It is harder for rural radiology practices to retain IRs

T

he study investigators worry that these data evidence a “potential subspecialist manpower crisis”, with geographic factors playing an important role in determining patient access to IR services. Upon evaluating the survey results, the authors conclude the “data suggest that small and rural hospitals will be disproportionally affected by future predicted physician shortages, resulting in difficulty meeting both general and subspecialty radiology service needs”.

Friedberg and colleagues sought to capture information regarding the current status of IR staffing across the USA, and to evaluate the perspectives of radiologists across the nation regarding their ability to recruit and retain interventionalists. Via email, they sent out a 22-question survey— finalised by an ACR intercommission workgroup comprised of members from the Commissions on General, Small, Emergency, and/or Rural Practice and the Commission on Interventional and Cardiovascular Radiology—to 15,463 ACR members who self-identified in the ACR Practice of Radiology Environment Database as a “group practice leader”, “general radiologist”, “interventional radiologist”, or “abdominal radiologist”. However, the response rate was low; the conclusions are based on the answers given by the 1,005 email recipients who completed the survey.

Rural radiology practices have more difficulty meeting local demand for IR services

Compared with non-rural equivalents, the study finds that rural radiology units experience more difficulty meeting local demand for IR services,

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Access to IR services

both at the hospital level and the regional hospital catchment area.

A statistically significant greater proportion of responders from rural hospitals compared with non-rural hospitals, the latter defined as those serving an estimated population of 250,000 or more, answered that their group falls far short of the demand for IR services: 6% of rural answers, compared to just 0.9% of nonrural ones. A further 23.1% of rural responders believed that the hospital they work at falls short of the demand for IR services. In comparison, only 13.4% of non-rural IRs thought this about their workplace.

In addition, a greater proportion of non-rural IRs said that their group meets the demand for IR services: 48.2% of rural responders, compared to 60.8% of non-rural survey participants.

The authors also note the relevance of having an exclusivity clause in IRs’ contracts. A greater proportion of responders from both rural and nonrural hospitals where they were able to meet most requests for IR procedures indicated that they did have an exclusivity clause in their contract. In comparison, in hospitals where there was a desire for IR procedures that could not be delivered, i.e. where local demand for IR services was not being met, a greater proportion of responders from both rural and non-rural areas did not have an exclusivity clause in their contract.

In addition, when respondents believed catchment area demands were being met, they more often responded that the IR physicians in their group do not take diagnostic radiology calls.

Similarly, physicians who reported not meeting IR needs more often reported having primary diagnostic responsibilities.

Over 38% of respondents from rural hospitals reported difficulties with retaining IR physicians in their practice, as opposed to 23.5% of nonrural IRs experiencing the same issues.

“IR attending perceived inadequate complexity of case mix” was the largest explanatory factor listed among rural responders, with 67.5% listing this as the top reason for the low retention rate. As expected by the study investigators, fewer non-rural responders, who nevertheless also thought they had difficulty retaining IRs in their own teams, cited this as an issue, with just over half citing inadequate case mix complexity as the

New integrated training pathways approved

The American Board of Medical Specialties has recently approved new integrated training pathways for IRs. There are now 78 integrated IR residency programmes currently accredited by the US Accreditation Council for Graduate Medical Education (ACGME), which Friedberg et al describe as “supplanting traditional diagnostic radiology residencies for those who seek highly specialised IR practices”.

However—despite the aim of increasing subspecialisation being to foster a more focused discipline with a greater commitment to longitudinal clinical care—thought leaders have expressed the fear that introducing more niches may exacerbate evolving patient access issues. Friedberg and colleagues write: “Specifically, questions remain around whether this trend will increase the risk that small and rural hospitals will have difficulty recruiting and retaining IRs who no longer seek to provide diagnostic radiology services, potentially leading to hospital administration, referrer, or patient dissatisfaction—as well as endangerment of future radiology contractual relationships”.

The authors go on to comment: “The inability to provide adequate IR services may be a contributor to hospital and referrer dissatisfaction, as well as to patient care underperformance in rural and small areas—a situation that is likely to worsen amidst superimposed training pathway changes, healthcare system consolidations, and projected physician shortages. Respondents to this specific survey consistently indicated that IR services stabilise

23.1% of rural responders believed that the hospital they work at falls short of the demand for IR services.

Only 13.4% of non-rural IRs thought this about their workplace.” number one source of low IR retention in their practice.

The number of available cases was also seen as a contributing factor to a reduced ability to retain IRs for rural responders, but not so much amongst non-rural answers. Two-thirds of rural responders believed an inadequate number of cases to be a contributing factor, whereas fewer than one-third of non-rural responders did. Cementing this difference, 18.1% of non-rural answers claimed that an inadequate number of IR cases was not a contributing factor at all.

The study authors hypothesise: “The overall subjective trend in responses may reflect an underlying desire by IRs to exclusively practice “high end” IR—a trend that may be exacerbated as a large number of integrated pathway graduates soon begin entering the workforce”.

groups and add value beyond revenue.

They conclude: “Given the value of IR services to patients and the ongoing geographic access challenges to those services as the practice of IR services becomes increasingly subspecialised, professional societies, such as the ACR and the Society of Interventional Radiology, are likely to play a critical role in developing plans and solutions to guide radiology practices.

Potential solutions include managing expectations for new pathway trainees, development of additional training opportunities for general radiologists to provide a broader range of at least less complex interventional procedures, novel contractual and practice organisational options for IRs, illumination of the ‘downstream revenue’ value in IR, and synergistic partnering or alliance with other subspecialties or larger institutions”.

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Number of studies authored by female IRs on the rise Women are equally as productive as men in terms of number of publications, citations, and grants, a recent study investigating the impact of women in academic interventional radiology (IR) concludes. The study, published in the Journal of Vascular and Interventional Radiology, found that women are also proportionately represented in the literature, and that female authorship is in fact increasing.

THE STUDY INVESTIGATORS, Nicholas Xiao (Department of Radiology, Section of Interventional and Vascular Radiology, Northwestern University, Chicago, USA), Diego Oliveira (Department of Chemical and Biological Engineering, Northwestern University, Chicago, USA), and Ramona Gupta (Department of Radiology, Section of Interventional and Vascular Radiology, Northwestern University, Chicago, USA) set out to determine the representation of female IRs, and to elucidate possible gender-specific disparities.

They analysed 4,884 original, peerreviewed articles from 2006–2017 in the Journal of Vascular and Interventional Radiology and Cardiovascular and Interventional Radiology. The first author and the senior author were then scrutinised to assess gender, citations and grants.

Xiao and colleagues write: “We found that 84% of first authors and 91.4% of senior authors were male (p<0.01)”.

Additionally, there was no significant difference in author gender collaboration combinations (p=1).

The study also reported an increasing number of articles authored by women within the 11-year time-frame. Each year, there was a 0.3–0.4% increase in the number of articles with a female first author (p=0.05) or senior author (p=0.01).

Furthermore, citations and grants received by female authors increased each year.

The lack of data indicating collaborative or citation/grant discrimination prompt Xiao, Oliveira and Gupta to believe that “the academic IR community is inclusive of its female constituents, and equally respects their research contributions.”

They conclude: “Based on the statistically significant increases in female authorship observed in this 12-year study, this article reports encouraging trends for the future of women in interventional radiology.”

Speaking to Interventional News, Xiao explains that he and his co-authors were not expecting this result. He says: “There are recent papers published in other academic disciplines showing significant bias against female authors in the literature, especially in highly male predominant fields. While we were certainly not expecting IR to reproduce this discrimination, we were pleased to discover that the data did not suggest any type of gender bias, despite IR being one of the most gender imbalanced fields in medicine. I was surprised at the high percentage of women as first authors

as compared to the percentage of women in the field. As first authors are frequently the team members whom really drive the project forward, and are often junior to the senior author, this finding, to me, meant that more and more women are entering IR and contributing productively to the literature! This was further supported by trends showing a steady increase of women in the field.”

Research from December 2016, conducted by Mikhail Higgins (Division of Vascular and Interventional Radiology, Department of Radiology, University of Virginia, Virginia, USA) et al and published in the same journal, found that women and minority ethnicities were underrepresented in the IR academic physician workforce relative to the US population. Similar conclusions from other studies, coupled with personal experiences of female IRs, has led to an increased acknowledgement in recent years of gender disparities in healthcare, leading to campaigns advocating for greater equality, such as #ThisIsWhatASurgeonLooksLike on Twitter.

Xiao highlights the importance of social media as a way to promote inclusivity within IR, saying, “I personally follow a number of prominent interventionalists on Twitter, and they are vocal advocates for all minorities in IR and actively engage in mentorship. I believe that the aforementioned candid recognition that biases (gender or otherwise) exist and vocal leadership calling attention to these issues causes a trickle down/compounding effect and fosters a culture of inclusion.”

Amongst the backdrop of underrepresentation within the field, this recent research demonstrates that in this particular academic context, gender disparity does not come into play.

Delineating why this finding is important, Xiao comments, “I hope that it is encouraging to all women in the field, especially medical students considering the field and young trainees conducting research or pursuing academic careers.

While it certainly does not fix the gender gap in IR, I hope that it at least shows that women in the field are respected by their male IR colleagues, and that they can be judged by their merits and not be negatively impacted by their gender in this regard.

While there are a number of factors that influence the low number of females in the field, this data should be encouraging to those who have reservations about entering the field or pursuing an academic career due to gender biases in publication.”

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Establishing an interventional radiology unit in Uganda Gregory Makris Comment & Analysis It is time to change patient care for an entire continent, writes Gregory Makris. After travelling to Uganda and learning that the country’s 40 million strong population had no access to interventional radiology services, Makris felt the scale of the difficulties besetting healthcare providers in such a resource-limited environment, and the urgency of introducing these life-saving procedures to those in need. Here, he gives a first-hand account of how he has been working with the Uganda-UK health alliance and other national and transnational organisations to establish an interventional radiology service in the East African nation.

I

t is almost 9am and we have just landed in Entebbe international airport after 12 hours of flying through the night.

I am a bit tired, but the nice warm breeze of the tropics is welcoming and definitely a pleasant change from the cold and rainy weather of London. The drive to Kampala, capital of Uganda, takes around an hour and a half and, having never been to East Africa before, I am slightly nervous. The scenery around us is beautiful; we are in the middle of the rainy season and everything is green and colorful. Lake Victoria, source of the world’s longest river, the Nile, is right next to us, and a quick swim in the cool waters is tempting…

As we approach Kampala, the traffic becomes heavy, providing the first idea of how busy this city of one and half million people is. Boda-bodas—small motorbikes that constitute the main means of transportation in the city, sometimes seemingly dangerously loaded with several passengers—weave amongst the bustle. As we get deeper and deeper into Kampala, the scenery changes considerably, developing a more urban look with open markets everywhere. The packed city’s populous are very friendly, and always more than happy to help. This is despite the large number of people still living in extreme poverty following the long civil war between the North and the South which racked the country, from which its 40 million inhabitants are still recovering.

Uganda became independent from the British in 1962, but has maintained strong links to the UK since. The Uganda-UK health alliance is a great example of this relationship. In 2013, the Uganda-UK health alliance was launched in Kampala as a partnership of UK- and Uganda-based organisations that share a common interest in health developments in Uganda. Initially hosted by the University Hospital of South Manchester NHS Foundation Trust

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(UHSM), the alliance was underpinned by a Memorandum of Understanding signed by 31 UK-based and 17 Uganda-based public and third-sector organisations, as well as the Ugandan Ministry of Health. One of these organisations is the global engagement division of Health Education England (HEE), which, under the leadership of Professor Ged Byrne (Manchester, UK), has been contributing to the improvement of healthcare standards in the region. It was when I first met Ged Byrne during a trip for another project that I realised an entire country of 40 million people had absolutely no interventional radiology (IR) service. I was shocked—something had to be done about it, and thankfully HEE and the Uganda-UK health alliance were incredibly willing to help.

Uganda has around 50 radiologists, which is roughly one radiologist for every million people. This scarcity of specialists is a common problem for most African countries. For context, according to the Royal College of Radiology, the average ratio in the UK is 48 radiologists

in combination with the lack of experience in organising a proper supply chain and procurement mechanism for IR consumables, makes this task extremely difficult for Ugandan healthcare professionals to achieve alone.

Rosemary Byanyima is one of the most senior radiologists in Kampala, and was one of the first local radiologists to understand this problem and push for change. Thanks to Rosemary Byanyima and her team, we were able to organise the first assessment visit to understand how things work in the Mulago National Referral Hospital (MNRH). This is the largest public hospital in the country, with 1,500 beds. In 2014, an average of 80–100 babies were delivered daily, in the hospital’s three maternity wards.

The Uganda Heart Institute and the Women’s Hospital are also nearby, and in combination with the Uganda Cancer Institute represent the spearhead of Uganda’s health-care system.

The next three days in Kampala were very intense: trying to get as much information as I could from the local key stake-holders, and assessing the available infrastructure and the existing supply chain and procurement

Gregory Makris and collaborators in Uganda

mechanisms. We had meetings with representatives from the Ministry of Health, the Uganda Heart Institute (that houses the only angiography suite in the country), the Medical School of the Makere University, and of course the MNRH administration team. It was great to see that everybody was on board with understanding the potential of developing an IR service in the country, with its main

Interventional radiology and clinical imaging should not be considered luxury services any more.” per million people, a number considered small in comparison to EU standards.

At the same time, Uganda has one of the worst records of both post-partum haemorrhage and road-traffic related morbidity in Africa. These are areas where good clinical imaging and IR services can make the difference between life and death. The local doctors in Kampala are well aware of this, but the lack of local experts to train the country’s first cohort of interventional radiologists,

this new dynamic specialty.

Before I realised it, I was on my way back to rainy London. I could not help but think of how many lives in Uganda could be saved or improved if a proper IR service was established. Interventional radiology and clinical imaging should not be considered luxury services any more. We would never consider having hospitals without CT and MRI scanners in the UK, and of course we would not accept a tertiary medical centre with no acute IR service provision. We have come a long way in Europe in terms of that, but in Africa there are still huge parts of the continent without appropriate image-guided clinical services. Uganda unfortunately is not an exception to the rule in Africa; it is just another example.

Organisations like RAD-AID international are setting a great example of how imaging services can be improved in a limited resource environment, and are already doing some great work establishing an IR service in Tanzania using volunteer IRs from all over the USA. We hope that in this effort to improve access to IR services in Uganda, we will not be alone. If this project is going to be successful, it will need collaboration

primary focus being the management of acute haemorrhage during post-partum complications or after road traffic accidents. During my invited lecture for the medical personnel of the MNRH regarding the expanding role of IR in modern medicine, everybody seemed to be fascinated about how much can now be done through a pinhole and under image guidance, and of course there was a lot of enthusiasm from the local radiology trainees to learn more about

between local and international partners; it will require collaboration between academic institutions and industry in order to bring together the “know-how” as well as the equipment necessary to build a sustainable IR department in a low income country. Of course, it will also require interventional radiologists who are happy to engage and volunteer their expertise to train more IRs in Africa.

Interventional Radiologists have always been adventurous and creative. This project, with all its challenges, can be another opportunity to prove how we can use these qualities to achieve something that might initially look impossible.

I am talking about changing patient care for an entire continent. So: who is up for the challenge?

Gregory Makris is a vascular and interventional radiology fellow at Oxford University Hospitals, NHS Foundation Trust, Oxford, UK. He is also chair of the Cardiovascular and Interventional Radiology Society of Europe (CIRSE) European Trainee Forum, as well as chair of the British Society of Interventional Radiology (BSIR) trainee committee.

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Same-day release for uterine fibroid embolization patients at Stoke Clinicians based at the Royal Stoke University Hospital (Stokeon-Trent, UK) have developed a new protocol for uterine fibroid embolization (UFE) treatment, introducing a day case service option for these patients. Despite a body of opinion convinced that the immediate post-procedural phase is too painful to treat UFE patients on an ambulatory care basis, the study investigators report a near perfect success rate in the small initial patient cohort discharged on the same day as embolization.

follow-up. Delays in taking down the patient-controlled anaesthesia set-up led to significant discharge postponement for patients following an overnight stay.

Therefore, the study investigators researched other strategies for pain relief.

They found that, given preoperatively, gabapentinoids provide anxiolysis for patients, and the authors cite evidence that this class of drugs significantly reduces opioid consumption in the postoperative period.

The authors give a detailed description of the development of this day case service, as well as the pain relief regimen and its rationale, in an article published in the New Journal of One Day Surgery.

The response: An interview with David Wells What are the clinical ramifications of this new protocol?

David Wells (right) and Kader Allouni

OF THE FIRST ten patients to follow the new Stoke protocol, nine were discharged before 8pm and had no complications after 48 hours, as determined by a nurse-led follow-up phone call. One patient did progress to an overnight stay, but this was due not to any pain or complications, but to the fact that she had failed to disclose that there would be no adults at home to care for her overnight, a prerequisite of same day release from hospital.

David Wells (University Hospitals of North Midlands NHS Trust, Royal Stoke University Hospital, Stoke, UK) and co-authors conclude: “Using a collaborative, evidence-based approach, tailored to the specific needs of patients undergoing UFE, we were able to formulate a safe, effective and validated strategy for a day case procedure. We do expect some patients to be re-admitted for pain control. This should not be seen as a failure of day case, [but] rather a safety net for some patients.”

In a healthcare system under the strain of in-patient bed shortages, Wells and colleagues decided to review standard practice in order to “find ways of delivering effective therapy to patients in more efficient ways.” They worked with patients, anaesthetists, gynaecologists, and day case and surgical assessment units to provide women with the option of a day case procedure.

The adoption of a transradial arterial approach was crucial in facilitating this conversion of UFE treatment to a day case procedure for the Stoke team.

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Compared with a transfemoral approach, Wells and colleagues found trans-radial access to dramatically reduce the risk of significant access site haemorrhages, and the approach allowed patients to mobilise immediately.

Describing their methods, the authors comment: “Closure of the radial arteriotomy is achieved using a variable compression wrist device. Once this radial band is removed (which takes on average 40 minutes) and the discharge protocol parameters met, the patient can be safely discharged. The only issue to manage then is pain.”

Prior to the opening of our radiology day case unit in the interventional unit at the Royal Stoke University Hospital, all patients referred from gynaecology requiring UFE were admitted for an overnight stay and an IV patientcontrolled anaesthetic driver. The change to the Radiology day case unit admission route meant that these patients could be admitted directly under the care of the interventional radiologist rather than the gynaecologist. This allowed the Interventional Radiology (IR) team autonomy in how care was delivered.

The second major change, that has truly facilitated the day case setting, is the use of transradial access rather than transfemoral. Although transfemoral access is safe and effective, there is still a small risk of post-procedural bleeding, and patients require a minimum of two hours flat bed rest if a closure device was used and up to six hours if the puncture was closed with manual compression haemostasis. With transradial access, once the radial haemostasis band is on we know there is no chance of hidden bleeding and so all we are concerned about is pain control. Transradial access also allows immediate mobilisation, so

[A] major change, that has truly facilitated the day case setting, is the use of transradial access rather than transfemoral.”

In 2017, the then current day case analgesia practices for patients undergoing gynaecological day case surgery were reviewed. Prior to revision, the strategy for managing patients’ ischaemic pain from embolizing the uterine arteries at the Royal Stoke University Hospital relied on preoperative anti-inflammatory medications and patient-controlled anaesthesia during the procedure and overnight stay. However, patientcontrolled anaesthesia resulted in a significant number of patients with opioid related nausea and constipation— these were the main complaints seen in

patients could use the bathroom, sit up, and easily plan for discharge. Patients really value these simple but very practical solutions and the fact they can spend the evening after the procedure at home. There were two other benefits we had not anticipated: trans-radial UFE access is quicker with a significantly lower radiation dose compared with the transfemoral access.

The day case protocol requires a full team set up. From the interventional pre-consent clinic, to nursing care on the Radiology day case unit, support with the drugs for transradial access in theatre, to nurse-led discharge, telephone follow-up

and a safety loop with a 48-hour direct access back into the hospital via the surgical assessment unit.

How is the experience of treating UFE as a day case procedure so far?

To date, we have treated 21 patients with this day case analgesia ‘Stoke Protocol’. Apart from one patient, all have been discharged on the same day as admission. We have had no readmissions via the Surgical Assessment Unit, and no complications on telephone followup at two days. The one patient who required an overnight stay did so because her situation had changed and she had no one at home overnight on the day of discharge, which is one of our discharge criteria. We could have cancelled the patient and re-booked, but the patient wanted to proceed.

The cost of a bed on the radiology day case unit is almost half that of an overnight bed on a surgical ward, a bed that has now been freed for another patient and for further income for the trust. This, together with the fact that overall procedural time is reduced, potentially improving theatre utilisation, provides incentive enough. As the number of referrals for UFE increases, these factors become more important.

Will this protocol be rolled out to other hospitals in the UK?

Our motivation in sharing our published protocol is that other units can have the confidence to adopt our regime without having to research the pathway. Working in our over-stretched healthcare system pushes individuals to simply provide a service, yet with collaborative enterprise between institutions we can improve care by improving service. It does require buy-in from the nursing and radiographer teams to transition with the change, especially the trans-radial access, but once this is embedded the patient throughput can be rapid.

We are confident that day case transradial UFE will become standard practice for patients in the UK.

What are the barriers to routine adoption of this protocol?

Breaking with tradition and venturing outside one’s comfort zone is the first hurdle. A well-planned, evidence-based oral analgesic regime, such as ours, needs to be trialled in a controlled way with the necessary bail-out strategies, such as an opiate syringe driver at hand and an overnight bed.

Collaboration between specialities and health professionals is vital. Without local support from gynaecology and anaesthetics it is difficult to provide the out-of-hours direct access necessary for the small percentage of patients that may need readmission within the first 48-hours post-discharge.

The day case trans-radial UFE analgesic protocol presents IR nursing staff with often not familiar medications and a completely different approach to managing ‘mobile’ patients on the day case ward.

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Gastric embolization unfit as obesity treatment Alberto Alonso Comment & Analysis Determining the potential role of interventional radiologists in obesity treatment is increasingly important, as the global number of obese patients has long since swollen to pandemic proportions.

In this commentary, Alberto Alonso discusses the importance of having a multifactorial approach to obesity treatment, focusing on the unique needs of specific patients. Left gastric artery embolization has been proposed as a promising strategy to treat obesity due to the procedure’s ability to suppress the production of “the hungry hormone” ghrelin, but Alonso argues that the procedure alone is not enough to act as the curative treatment some have hailed it as.

OBESITY IS DEFINED as a state of increased adipose tissue of enough magnitude to produce adverse health consequences, and is associated with increased morbidity and mortality.

Obesity is a pandemic health problem involving genetics, the environment, other diseases, drugs and psychological factors. Treatment for obesity should never be considered “unilateral”—not even a surgical approach should be seen as a standalone option. Obesity always requires a multidisciplinary and tailored approach, focusing on caloric reduction and increased physical activity.

Considering a single intervention as an adequate “curative treatment” for obesity is arrogant and most likely will not work.

Lifestyle and dietary changes are

a neuropeptide in the central nervous system by regulating appetite, but also plays an important role in regulating the distribution and rate of energy usage. It acts on hypothalamic brain cells to increase hunger: ghrelin is secreted when the stomach is empty, and secretion stops when the stomach is full.

Left gastric artery embolization

Left gastric artery embolization has been proposed as an alternative to bariatric surgery for weight loss due to its effects on the ghrelin hormone. In theory, by reducing the blood supply to the fundus of the stomach via left gastric artery embolization, the release of ghrelin should decrease and relieve the feeling of hunger, ultimately resulting in the

No clinical trial [on left gastric artery embolization for weight loss] with long-term follow-up and a relatively large sample size has been reported.” probably the best focus for obesity treatment. However, these have proven ineffective in the long-term for the most obese patients. Anti-obesity medications are not without significant side effects, and they are expensive. Gastric volume reduction remains the most effective mechanism currently available to control obesity.

The mechanisms dictating food intake and appetite are complex and, mainly, not well known. Many hormones (such as ghrelin, leptin, obestatin, and insulin) are involved through neural pathways in the “simple” act of eating. Ghrelin, the “hunger hormone” is a peptide hormone produced by ghrelinergic cells in the gastrointestinal tract that functions as

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patient eating less—theoretically.

However, ghrelin also plays an important role in regulating reward perception via dopamine levels in central nervous system neurons, and is also linked to processing sexual desire, reward, and reinforcement, as well as in developing addictions.

Paradoxically, ghrelin plasma levels in obese individuals are lower than those in leaner individuals, suggesting that ghrelin does not contribute to obesity (except in the cases of Prader-Willi syndrome-induced obesity). However, it has also been reported that consumption of “food for pleasure” increases peripheral levels of both ghrelin and the endocannabinoid 2-arachidonoyl-

glycerol in healthy humans. This should then also be considered as an underlining psychological factor in any patient with severe obesity, where anxiety and depression are concomitant entities in many cases. Reducing obesity to simply “over-eating”, and this in turn to a “ghreling secretion”, is probably an extremely simplified, and incorrect, point of view.

After left gastric artery embolization, ghrelin levels initially decrease, then increase at three and six-months’ follow-up to a wide range of values; the same variation is seen in weight loss following left gastric artery embolization. This may be due to revascularisation of the gastric fundus but also, more interestingly, to the return of appetite after gastric recovery from ischaemic injury, where ischaemic ulcers are widely observed after left gastric artery embolization.

Evidence of long-term reduction in levels of the ghrelin hormone after left gastric artery embolization has not been confirmed due to limited experience; data regarding the potential role of left gastric artery embolization for weight loss is scarce. In fact, no clinical trial with longterm follow-up and a relatively large sample size has been reported. Even if it is mainly produced by stomach fundus cells, there are also ghrelin-secreting cells in the proximal intestine, pancreas, pituitary gland, and colon. Those should increase ghrelin secretion after left gastric artery embolization.

Left gastric artery embolization is effective on its own—probably more due to ischaemic gastric ulcers than to ghrelin secretion—but its efficacy may be enhanced if performed in combination with other therapies, lifestyle modifications, and/or pharmacotherapy. This focus has not been described.

Almost any intervention that leads to a caloric deficit in a severely obese patient will be followed by an initial benefit. In fact, the literature reports that for patients treated with left gastric artery embolization, glycated haemoglobin (HbA1c) levels were under control following the procedure, and a 10% weight loss had been observed. As in any dietic intervention, the crucial question is: for how long do these benefits last?

The ideal candidate

Identifying the best candidates for the procedure is still a work in progress, as is discerning the long-term outcome.

Defining obesity as having a body mass index (BMI) greater than 30kg/ m2 is common in published work.

BMI is the most frequently used measurement for diagnosing obesity, because of its simplicity and reliability.

Excess adiposity but not excess body weight is the real culprit of obesity-

associated complications. However, in comparison with techniques involving the direct measurement of adipose, BMI underestimates the prevalence of obesity by 50%; its relationship with adiposity is influenced by age, sex and race. Lean body mass is a component of body composition, calculated by subtracting body fat weight from total body weight.

Lean body mass has been described as a superior index to total body weight for prescribing proper levels for assessing metabolic disorders. When papers only attend to BMI and absolute weight loss, how can we determine how left gastric artery embolization affects lean body mass? Has it been improved or worsened by left gastric artery embolization? This point should be clarified before considering left gastric artery embolization as the standard treatment.

The ideal embolic agent for left gastric artery embolization is still uncertain, where agent penetration, devascularisation and revascularisation are the key features. Is a temporary occlusion desired or better than a definitive embolization? Several different types and sizes of embolic agents and spherical particles have been used. The ideal endpoint for embolization also needs to be clarified.

Finally, left gastric artery embolization reduces future options for an established surgical bariatric procedure. The idea of a gastric volume reduction with a previous devascularised area could be considered as a contraindication for surgery in many of the working groups. Adjustable gastric banding may then be the only option, even when this cannot be considered an adequate second bariatric option.

So, when should left gastric artery embolization be used? Not as an alternative to surgery, and neither as a bridge to surgery—and definetively not as a solo treatment for obesity.

Left gastric artery embolization should be restricted to those patients with a concious and complete refusal of surgery and as an initial starting point for weight loss. But we should always bear in mind that left gastric artery embolization is only capable of causing a temporary effect.

Alberto Alonso is an interventional radiologist at the Clínica Universidad de Navarra in Madrid, Spain.

References: 1. Zhong BY, Abiola G, Weiss CR. Bariatric Arterial Embolization for Obesity: A Review of Early Clinical Evidence. Cardiovasc Intervent Radiol (2018) 41: 1639.

2. Shoar S, Saber AA, Aladdin M, et al. Bariatric manipulation of gastric arteries: a systematic review on the potential concept for treatment of obesity.

International Journal of Surgery. 2016;36:177–82.

3. Angrisani L, Santonicola A, Vitiello A, Ferraro L, Iovino P. Reply to Letter to the Editor “Left Gastric Artery Embolization for Weight Loss-a Dead-End Procedure”.

Obes Surg. 2018;28(11):3627-28.

4. Fink JM, Martini V, Seifert G et al, Marjanovic G. Left Gastric Artery Embolization for Weight Loss-a Dead-End Procedure. Obes Surg. 2018;28(11):3623-24.

5. Saeed Shoar, Alan A. Saber, Mohammaed Aladdin et al.

Bariatric manipulation of gastric arteries: A systematic review on the potential concept for treatment of obesity, International Journal of Surgery. 2016; 36, 177-182.

6. Weiss CR, Akinwande O, Paudel K et al. Clinical Safety of Bariatric Arterial Embolization: Preliminary Results of the BEAT Obesity Trial. Radiology. 2017;283:598-608.

7. Syed MI, Morar K, Shaikh A, Craig P, Khan O, Patel S, Khabiri H. Gastric Artery Embolization Trial for the Lessening of Appetite Nonsurgically (GET LEAN): Six-Month Preliminary Data. J Vasc Interv Radiol.

2016;27(10):1502-8

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Gastric embolization leads to loss of muscle as well as fat Left gastric artery embolization leads to the loss of both fat and muscle, according to a new study presented at the annual meeting of the Radiological Society of North America (RSNA; 25–30 November, Chicago, USA). Researchers said the loss of muscle mass is concerning, and underscores the importance of proper nutritional counselling after the procedure.

O

besity is a major health issue worldwide, linked with several serious conditions such as heart disease, cancer and diabetes. First-line treatments such as diet and exercise often do not work, leading many patients to opt for gastric bypass surgery.

The surgery, which reduces the size of the stomach, has been effective in treating obesity, but carries with it significant costs and potential complications.

Currently under investigation in clinical trials, left gastric artery embolization is a less invasive option to surgery. In the procedure, microscopic beads are injected under imaging guidance into the artery that supplies blood to the stomach. The beads block blood flow to the stomach and reduce the production of ghrelin, a hormone that stimulates hunger. Early studies have shown that embolization is effective in helping people lose weight, but information is lacking on how it might

Left gastric artery prior to gastric artery embolization.

change a patient’s composition of muscle and fat.

“There has been lots of research focused on the efficacy of gastric artery embolization for weight loss,” said the lead author of the study, Edwin A Takahashi, vascular and interventional radiology fellow at the Mayo Clinic (Rochester, USA). “However, there has been no data on what is contributing to the weight loss, whether the patients are losing fat, as desired, or muscle mass, or some combination of the two.”

To learn more, Takahashi and colleagues studied CT scans of 16 overweight or obese patients who had undergone left gastric artery embolization to treat gastrointestinal bleeding. The scans were done before and approximately one and a half months after the procedure. The results were compared to those of a control group of 16 outpatients who did not undergo left gastric artery embolization but had CT scans at two

Left gastric artery prior to gastric artery embolization.

Registry and IDE trial back Lutonix DCB in AV fistula The safety of the Lutonix drug-coated balloon (DCB) in dysfunctional arteriovenous (AV) fistulae has been supported by findings from two trials reported at the Leipzig Interventional Course (LINC; 22–25 January, Leipzig, Germany). Scott Trerotola of the Perelman School of Medicine, University of Pennsylvania (Philadelphia, USA) presented for the first time the 24-month safety results from the Lutonix AV Investigational Device Exemption (IDE) clinical trial. Complementing these findings, Panagiotis Kitrou, Patras University Hospital (Rio, Greece) outlined six-month data from the Lutonix AV global registry.

BEGINNING HIS PRESENTATION, Trerotola informed delegates: “This is the only US Food and Drug Administration (FDA) approved DCB balloon for AV fistulae in the USA. Safety outcomes are non-inferior to angioplasty, mortality is noninferior, and the mortality rate is lower than expected in the US population,” and added, “it is the only DCB with a multicentre randomised trial result at two years.”

Outcomes from the Lutonix AV global registry reinforced his findings, as Kitrou reported: “Target lesion primary patency at

six months was 73.5% according to KaplanMeier analysis, and this reaches 75% at six months if you exclude the central veins.

These results are consistent with the AV trial from Trerotola, as well as previously published data from retrospective analysis from our department.”

Lutonix AV IDE is a prospective multicentre trial at 23 clinical sites that randomised 285 subjects 1:1 to receive either the DCB (141) or percutaneous transluminal angioplasty (PTA; 144).

The objective was to assess the safety

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different time periods for nonspecific abdominal pain.

The investigators used the CT scans to measure body composition based on the differing densities of fat and muscle.

All 16 individuals experienced significant weight loss after the embolization procedure, losing an average of 6.4% of their body weight over one and a half months.

Body mass index (BMI) dropped by 6.3%.

While the weight loss was not surprising to the researchers, the changes in body composition were.

The skeletal muscle index fell by 6.8%. Loss of skeletal muscle can impair physical function and metabolism and put a person at higher risk of injury.

“The significant decrease in the amount of skeletal muscle highlights the fact that patients who undergo this procedure are at risk for losing muscle mass and need to be managed accordingly after procedure,” Takahashi said.

“We must make sure they receive adequate nutrition to minimise the amount of muscle tissue they lose.”

As expected, the patients also lost a significant amount of body fat. Their overall body fat index dropped by an average of 3.7%. However, much of the fat loss was subcutaneous. Visceral fat, the more dangerous fat surrounding the organs and associated with serious health problems like heart disease and diabetes, did not decrease significantly over the course of follow-up.

The researchers plan to expand their studies in the future to include people who are specifically undergoing embolization as a treatment for obesity.

Left gastric artery after gastric artery embolization.

Left gastric artery after gastric artery embolization.

and effectiveness of the Lutonix 035 AV DCB PTA catheter in the treatment of dysfunctional AV fistulae. The primary effectiveness endpoint was target lesion primary patency at six months, with a primary safety endpoint of freedom from any serious adverse event involving the AV access circuits through 30 days. Additional follow-up visits were at one, three, six, nine, 12, 18, and 24 months.

Patient characteristics were evenly matched between groups, “so any differences we cannot blame on demographics,” said Trerotola. Target lesion primary patency was achieved in 61.6% of patients in the Lutonix arm, and in 49.4% for those who underwent PTA alone. According to Trerotola, the primary safety endpoint “was easily met”, and

was 36.9% at 12 months in the Lutonix group and 28.7% in controls (p= 0.0009).

At 24 months, 20.6% in the Lutonix arm versus 16.5% in the control arm met this endpoint (p=0.0028). Yet, despite the p-values, Trerotola described the findings as “statistically indifferent, because this is a non-inferiority examination”.

Furthermore, there was no statistical difference between groups for mortality rates, with deaths at 24 months for Lutonix 23.4% (33) compared to 18.1% for subjects who received standard PTA (26). However, one subject in the control group withdrew voluntarily from dialysis, and four in the Lutonix group. “If you take out the ones that voluntarily withdrew, the difference now becomes 29 and 25, which is pretty much numerically indistinct,” Trerotola remarked.

According to Trerotola, the expected two-year mortality rate on dialysis is 33.4% in the USA on average. Therefore, discussing the current findings, he suggested: “Perhaps because these [trial] patients come more frequently, or are getting better care, their mortality was actually substantially better in both groups than what is published by the US Renal Data System.”

Inflation time was also crucial—the longer the inflation time, the better the results.”

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Peripheral interventions

Three-year Japanese results show IN.PACT Admiral DCB offers “consistent and durable” treatment The IN.PACT Admiral drug-coated balloon (DCB; Medtronic) exhibits a consistent and durable treatment effect in “a more complex patient demographic than typically seen in other DCB pivotal trials”, Osamu Iida (Kansai Rosai Hospital, Hyogo, Japan) informed the audience at the Leipzig Interventional Course (22–25 January, Leipzig, Germany). These are the first reported outcomes from an independently-adjudicated, randomised, singleblind trial evaluating DCB use in Japanese patients through to three years, providing level I evidence in favour of the device’s use.

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he study investigators set out to assess the safety and efficacy of the IN.PACT Admiral DCB for the interventional treatment of de novo and non-stented restenotic lesions in the superficial femoral artery and the proximal popliteal artery as compared to treatment with standard percutaneous transluminal angioplasty (PTA).

The trial met both its primary effectiveness and primary safety end-points at one year, and continued to demonstrate safety and efficacy at three years. The primary effectiveness end-point was primary patency at 12 months, defined as freedom from clinically-driven target lesion revascularisation (TLR) and freedom from restenosis as determined by duplex ultrasound-derived peak systolic velocity ratio (PSVR) less than or equal to 2.4.

Three-year primary patency by Kaplan-Meier estimate was significantly better in the DCB arm than the PTA arm: 68.9% compared to 46.9%. At one year, this difference was even more marked, with a primary patency in the DCB arm of 93.9%, compared to a primary patency of 46.9% in the PTA arm at the same time point.

The time to clinically-driven target lesion

revascularisation was also significantly greater in the DCB arm, nearly four times longer in fact, at an average of 613.2±243.1 days (range: 235–910 days), compared to just 168.2±65.4 days (range: 57–247 days) amongst the PTA cohort (p<0.001). In addition, although not statistically significant, the three-year freedom from clinically driven TLR was slightly better in the DCB arm, at 84.4% versus 81.3% in the PTA group.

The primary safety endpoint was freedom from device- and procedure-related death through 30 days, and freedom from target limb major amputation and clinically-driven target vessel revascularisation within 12 months’ post-index procedure.

Iida told the LINC audience: “The 36-month major adverse event rate was very low in the DCB arm, just 20.9% [14 out of 67 patients], compared to 31% [9 out of 29 patients] in the PTA arm.” The primary safety composite score was 83.6% for the DCB cohort, and 75.9% for the PTA cohort. All-cause death was low in both groups: 6% (four out of 67 patients) in the IN.PACT Admiral group, and 6.9% (two out of 29 patients) in the angioplasty group.

Iida also emphasised that these results in the IN.PACT

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Japan trial are consistent with those of the previous IN.PACT Global and IN.PACT SFA studies. The primary patency through to three years in the IN.PACT Admiral cohort of the Japan trial closely matches the 69.5% primary patency observed in the DCB arm of the IN.PACT SFA trial. Clinically-driven target lesion revascularisation was 14.9% in the Japanese trial, compared with 15.2% in the IN.PACT SFA trial and 23.5% amongst the global clinical cohort.

A complex patient cohort

Iida described the patient cohort used in this trial as “a more complex patient demographic than typically seen in other DCB pivotal trials.” The average age in the DCB arm was 73.3±7.4, and the incidence of diabetes mellitus was high: 58.7% in the treatment group (40 out of 68 patients). In the PTA arm, the baseline characteristics were not statistically significantly different, with an average age of 74.2±6.1, and with 56.3% of the 32 patients being diabetic.

“This population is older, and has a higher proportion of diabetic patients, than is typically seen in other DCB clinical trials,” Iida said.

Lesion characteristics were also the same between the two arms of the study. The mean lesion length was 9.15±5.85cm in the 68 patients treated with the DCB, and 8.89±6.01cm in the 32 patients treated with angioplasty—“one of the longest [average lesion lengths] in any DCB trial”, according to Iida. The difference in mean lesion length between the DCB and PTA arms was not statistically significant (p=0.838).

Unique to this trial, the study investigators used intravascular ultrasound (IVUS) to evaluate the ideal diameter for balloon selection. Iida explained that “IVUS is generally used by the Japanese physician as a part of daily practice.”

He added, “We observed a very low provisional stenting rate of 4.4% in the DCB arm, versus 3.1% in the PTA arm.”

COMPARE pilot study results show similar efficacy at two years for the Ranger and IN.PACT Admiral DCBs In a head-to-head comparison of the Ranger paclitaxel-coated percutaneous transluminal angioplasty (PTA) balloon catheter from Boston Scientific and the IN.PACT Admiral drug-eluting balloon from Medtronic in femoropopliteal interventions, a similar efficacy and primary patency was seen in both devices.

IN THIS PHYSICIAN-initiated study, the study investigators set out to compare the two different paclitaxelcoated balloons, each with a different coating and paclitaxel dose density, in the treatment of high grade stenotic or occluded lesions in the superficial femoropopliteal artery (SFA) and/or the proximal popliteal artery (PPA) in patients with peripheral arterial disease (PAD) with a Rutherford class between two and four. The Ranger balloon catheter was the investigational device, with a relatively low drug dose of 2µg/ mm2, and the IN.PACT drug-eluting balloon, with a paclitaxel dose of 3.5µg/ mm2, acted as the control.

Dierk Scheinert (Leipzig, Germany), the trial’s principal investigator, presented the results of the prospective, 15-site, randomised trial at the Leipzig Interventional Course meeting (22–25 January, Leipzig, Germany). “The study is being conducted in two phases,” Scheinert informed the LINC audience.

“There were initially 150 patients enrolled at 1:1 randomisation [in a pilot study], and then later on the study was

expanded to a total cohort of 414 patients for testing of a formal non-inferiority hypothesis.”

The trial demonstrated the “excellent efficacy” of both devices, Scheinert said. Detailing the procedural outcomes of the first 150 patients enrolled in the pilot study, for which the 24-month data is available, Scheinert reports that the bailout stent placement, the “most important figure”, is “only” 22% and 25% in the IN.PACT and Ranger arms, respectively. This is, he says, “despite the relatively complex nature of the cohort.”

Of the first 150 patients treated in this

All-cause mortality rates were wellbalanced between the two devices with different dose density.”

trial, there were three deaths in two years.

One death was in the IN.PACT Admiral group, and the remaining two were seen in the Ranger DCB cohort. One death was from pancreatic cancer, one from cardiac decompensation, and one from enterococcal septicaemia. Looking at the data from the full cohort of 414 patients to date, there have been seven deaths: three from the IN.PACT group, and four from the Ranger group. This led Scheinert to the conclusion that all-cause mortality rates were “well-balanced between the two devices with different dose density”, and says “there is no indication of any safety issue.”

Primary patency at two years between the two devices is very similar. Scheinert described how “there was an essentially identical [Kaplan-Meyer] curve between the two devices”. At 710 days, primary patency was 0.77±0.05 in the IN.PACT DCB cohort, and 0.75±0.06 in the Ranger DCB cohort.

Patient characteristics

All patients enrolled in this study had symptomatic peripheral arterial disease

with a Rutherford classification between two and four. Stenotic or occluded lesions of the SFA or the PPA were included, but no severe calcification was allowed. The lesion length was up to 30cm; Scheinert commented on this: “We stratified the randomisation process so that we could ensure that an equal percentage gets into both short lesion and long lesion cohorts.”

The baseline characteristics were equivalent in the Ranger DCB and IN.PACT DCB arms of the study. There was a fairly high incidence of diabetes mellitus amongst the patient cohort, with 34% of the Ranger group (25 patients) and 37% of the IN.PACT group (28 patients) being diabetic.

“I think it is fair to say that this is a relatively complex cohort”, Scheinert said when describing the lesion characteristics of the first 150 patients enrolled in the pilot study. The trial represented a complex, real-world lesion subset, with a mean target lesion length of 117.4±100.4mm for the Ranger DCBtreated patients, and 122.3±91.2mm for the IN.PACT DCB-treated patients.

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Transradial access

Patients prefer transradial access to transfemoral, study finds Patients have a strong preference for transradial access, a recent study published in the Journal of Vascular and Interventional Radiology finds. Lead author Lisa Liu, Rush Medical College, Chicago, USA, and colleagues write: “With transradial access, patients experienced less periprocedural pain and shorter recovery times without significant differences in radiation exposure or procedure length.

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he study investigators set out to determine patient preference for these two different access sites during hepatocellular carcinoma (HCC) radioembolization procedures after experiencing both. They explain that “The use of transradial access as the preferred approach over transfemoral access in interventional radiology has steadily increased, owing in part to numerous trials by cardiologists demonstrating fewer access-related complications, greater patient satisfaction, and lower cost with transradial access compared with transfemoral access in coronary interventions.”

Thirty patients with HCC undergoing MAA (macroaggregated albumin) mapping and transarterial radioembolization (TARE) were enrolled to experience one transradial access and one transfemoral access procedure each, with randomisation of which access approach was experienced first.

Previous studies have also found a patient preference for transradial access, though, to Liu et al’s knowledge, no earlier study measured potential reasons for patient preference, “such as associated pain, recovery time, or quality of life after the procedure”, the present study authors write. An additional aim of the present study therefore was to “objectively assess the impact of access site on patient comfort and satisfaction.”

The authors cite a retrospective review assessing the safety and feasibility of the trans-radial approach in the first 1,500 non-coronary interventions to use trans-radial access at a single institution published in 2016 by Raghuram Posham (Icahn School of Medicine at Mount Sinai, New York, USA) et al that demonstrated a safety profile of 98.2% technical success rate and <3% complications, most of which were defined as minor complications.

This prospective, randomised, single-institution, controlled crossover trial of 30 patients (28 men; mean patient age of 66 years) reported that 22 (73.3%) patients indicated preference for radial access. Four (13.3%) patients indicated preference for femoral access, and four (13.3%) indicated no preference. Liu and colleagues deem this a “strong preference for transradial access”, drawing attention to the fact that more than five times as many patients prefer transradial to transfemoral access.

The authors also note that no acute minor or major adverse events were identified on physical examination at the day of procedure at a 30-day follow-up appointment. They write: “No access-site bruising and/or haematoma, radial artery occlusion, or any other minor or major complications were documented.” Fourteen patients self-reported superficial bruising following radial procedures in surveys given out during follow-up; for patients commenting on trans-femoral access, 17 patients reported bruising (46.7% vs. 53.3% for transradial and transfemoral access, respectively; p=0.4074).

All 14 patients who reported bruising following transradial access were amongst the 17 to also report bruising following transfemoral access. Amongst the total patient cohort, 10 were taking anti-coagulants: seven of these patients reported bruising after

transradial access, and nine after transfemoral access.

To greater elucidate the association between the self-reported bruising rate for transradial versus transfemoral access and the use of anticoagulants, the study authors call for future studies on the incidence of bruising after transradial versus transfemoral access to “control for anticoagulation and antiplatelet medication use.”

Surveys assessing pain and quality of life were administered after each MAA mapping and TARE procedure. Patients were contacted via e-mail, phone, or in person to complete a survey on demographics, occurrence of self-reported bruising, and numerical pain rating scale. This scale ranged from no pain at 1 to worst pain at 10 in four different contexts: during the procedure overall, during the procedure at the access site, after the procedure in the recovery room, and after the procedure at home. Patients also completed a modified 12-item Short Form Health Survey to assess quality of life.

Patients experiencing transradial access recorded, on average, significantly lower overall pain during the procedure, significantly lower pain at the access

The findings of this study support considering radial access as a default patientcentred approach to radioembolization procedures.” site during the procedure, and significantly lower pain after the procedure in the recovery room compared with transfemoral access (p=0.0046, p=0.0004, p=0.0357, respectively). No significant difference was observed for average pain reported after discharge at home between transradial and transfemoral procedures (p=0.4235). Liu and colleagues write that “These results suggest that the reduced pain and increased comfort associated with transradial access are short-term benefits limited to the perioperative time period during the procedure and immediately after in the recovery room before discharge.”

Furthermore, the authors report no significant differences between quality of life scores after transradial access versus transfemoral access.

Average fluoroscopy time—a measure of radiation exposure—and total recovery time were also not significantly different between the two access types (p=0.1442 and p=0.1496, respectively). For TARE procedures, the authors note that “radial access cases [both MAA mapping and TARE] were associated with significantly shorter recovery times on average compared with femoral access cases (108 minutes for transradial access, 153 minutes for transfemoral acess; p=0.0193).”

Summarising their results, Liu et al write: “Overall, patients reported significantly less pain with

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transradial access compared with transfemoral access during the procedure and afterward in the recovery room. Additionally, transradial access was associated with shorter recovery times for both MAA mapping procedures and TARE procedures, with a significant difference observed for TARE procedures.” Liu and colleagues postulate that “the lack of corresponding significance for MAA mapping procedures may be attributed to having overall shorter recovery times compared with TARE (118.9 minutes vs. 130.7 minutes), and perhaps a significant result may have been reached in the MAA mapping group with a larger sample size.

“Additionally,” they add, “the significant difference in recovery time achieved in the TARE group should be considered with caution, as patients receiving trans-femoral access underwent a conservative twohour bedbound protocol after AngioSeal (Terumo) deployment rather than the recently US Food and Drug Administration (FDA)–approved 20-minute early ambulation protocol.”

Commenting on the significance of this finding, the study investigators comment: “The findings of this study support considering radial access as a default patient-centred approach to radioembolization procedures for patients eligible for both radial and femoral access approaches.”

A positive response from interventional radiologists Commenting on these results on Twitter, Naveed Rajper, an interventional cardiologist based in New York, USA, wrote: “Trials are not necessary to prove this. Radial first is tried and tested. Let us cross-pollinate advancements like this between procedural specialties, be open to change, and focus on even bigger things.”

Responding to this remark, Aaron Fischman, an interventional radiologist also from New York, USA, and an author on this study, said, “You would be surprised the conversations we have at interventional radiology meetings about this concept. There are some things that have to be proven in a rigorous way to move the needle. Patient preference specific to interventional oncology is an important step in that direction.”

Darren Klass, another advocate for the transradial approach, and an interventional radiologist in Vancouver, Canada, agrees with Fischman, writing online in direct response to the latter’s comment: “Agree. Patient preference is one. Nursing intensity post-procedure, complications, discharge time, radiation dose to patient and operator, done or in midst of publication for interventional radiology, yet we still face the apathetic objectors.”

Generally commenting on the study, Klass said on social media that this publication is “cementing what radial first operators all experience.”

The study authors do acknowledge some concerns with transradial access. One “potential concern” of transradial access for noncoronary interventions “is longer procedure times and subsequent greater patient radiation exposure owing to the greater anatomic distance from access site to treatment site.” However, they note that trials from interventional cardiology have not found significant differences in fluoroscopy time.

Liu et al also note that the subjectivity of surveys and of pain scales as research tools acts as a limitation to the present study. In addition, they acknowledge that as four of the 30 patients in the trial had experienced a prior intervention using radial or femoral access, there was the possibility of introducing a preconceived bias into their results.

However, they write that “the effect of this limitation is expected to be minimal considering the small percentage of patients with prior transradial access or transfemoral access [experience], and no pattern of bias was observed in analysis of this subset of patients and their choice of access preference.”

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BIBABriefings

Section Name

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BIBA Briefings

BIBABriefings

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More than 40% of physicians anticipate using fewer drug-coated balloons following Katsanos paper

A BIBA MedTech survey indicates that 43% of physicians plan to use fewer drug-coated balloons for the management of peripheral arterial disease after a meta-analysis (by Katsanos et al) found that the application of paclitaxel-coated balloons and stents in the femoropopliteal artery was associated with an increased risk of death. A prior BIBA MedTech survey, conducted before the Katsanos paper was published, suggested that physicians believed that their use of drug-coated balloons would increase.

Source: BIBA MedTech Paclitaxel meta-analysis reaction survey January 2019.

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n December 2018, Konstantinos Katsanos (Patras University Hospital, Rion, Greece) and colleagues caused shockwaves in the vascular community when they published a meta-analysis—in the Journal of the American Heart Association—that found that both paclitaxel-coated balloons and paclitaxel-eluting stents were associated with an increased risk of death at two years compared with control treatments (i.e. percutaneous transluminal angioplasty and/or bare metal stents) for the management of peripheral arterial disease. To try to understand how these findings might affect the use of paclitaxel devices (for peripheral interventions) in clinical practice, BIBA MedTech conducted a survey of physician subscribers of Vascular News and Interventional News. Of note, the survey was performed (in January 2019) prior to further data for paclitaxel being published. For details of these subsequent data, please see pages 1–2.

Of 101 respondents overall, 63% were vascular surgeons, 17% were interventional radiologists, 13% were endovascular surgeons, and 7% were categorised as “other” (including interventional cardiologists).

Furthermore, on average, respondents performed 72 procedures with drugcoated balloons as the primary treatment method (for a femoropopliteal lesion) and performed 17 procedures with drug-eluting stents as the primary treatment method. Just over half (51%) of respondents were from Europe (with 25% from the USA, 13% from Latin America, and 11% from other regions).

Unsurprisingly, given the reaction of the community to the paper, 98% of respondents had heard of the Katsanos meta-analysis.

Predicted use of paclitaxel devices

In the survey, respondents were asked if the main conclusion of the paper—that there was an increased risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the lower limbs—were “in line with your own personal practice”. The majority (74%) said “no”. However, they indicated that they would use fewer paclitaxel devices (both balloons and stents) this year.

Of 93 respondents who used drugcoated balloons, about 43% said they anticipated performing fewer procedures using these devices this year, with 37% believing their use would remain the same and 20% thinking that they would perform more procedures (Figure 1).

Similarly, of the 71 respondents who currently use drug-eluting stents, nearly half (48%) predicted that they would perform fewer procedures with these devices this year, with 35% believing their use would be about the same and 17% think they would use more procedures (Figure 2).

These findings are in contrast to a BIBA MedTech survey that was performed prior to the publication of the Katsanos paper. This survey asked physicians working in the top five EU countries (France, Germany, Italy, Spain, and UK) about their management of peripheral lesions. To be included in the survey,

Source: BIBA MedTech Paclitaxel meta-analysis reaction survey January 2019.

respondents had to perform a minimum of 30 superficial femoral artery procedures a year and a minimum of 10 below-the-knee procedures a year. Of the 149 respondents, 48% were vascular surgeons, 39% were interventional radiologists, and 13% were interventional cardiologists/angiologists.

For all types of lesions, respondents on average predicted that they would use drug-coated balloons in a greater proportion of procedures in the next 12 months than they had in the past 12 months. For example, with short (<15cm) lesions in the superficial femoral artery, respondents predicted that they would use drug-coated balloons as the primary treatment in 35% of procedures in the next 12 months vs. 27% of procedures performed in the past 12 months.

Similarly, they suggest that use of DES would increase.

Looking beyond the Katsanos paper

The survey also asked respondents if they felt, following the Katsanos paper,

BIBA Briefings

whether “it is a priority to look beyond paclitaxel to other drugs” and the vast majority (80%) said they thought it was a priority. Furthermore, 64% saw the data as a “serious setback” for drug-elution in the periphery.

However, following patient-level data releases from industry in response to the meta-analysis, polling of delegates at 2019 conferences point in a different direction. At the recent Vascular Leaders Forum, 60% (21/35) of physicians said they would not be more conservative with their drug-device treatments and 86.5% (32/37) said they would not change their clinical practice as a result of the meta-analysis (see pages 1–2).

The Charing Cross International Symposium (15–18 April, London, UK) will further explore the mortality risks of paclitaxel in a dedicated CX Special Session and, throughout this year, BIBA MedTech will continue to survey those working in clinical practice about their attitudes to and usage of paclitaxel-coated and -eluting devices.

BIBA Briefings is a new platform that provides in-depth analysis of the latest market intelligence from BIBA MedTech Insights, 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.

For more information about BIBA Briefings or BIBA MedTech Insights, please contact Merveille Anderson merveille@bibamedical.com

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Product news

Product Industry News MedAlliance granted Breakthrough Device designation from FDA for sirolimus DCB

MedAlliance SA has been granted Breakthrough Device Designation from the US Food and Drug Administration (FDA) for SELUTION, its sustained limus release (SLR) drug-coated balloon (DCB) catheter, for the treatment of coronary disease.

The FDA Breakthrough Device Program is intended to help patients receive more timely access to breakthrough technologies that have the potential to provide more effective treatment or diagnosis for life-threatening or irreversibly debilitating diseases or conditions. Under the programme, the FDA will provide MedAlliance with priority review and interactive communication regarding device development and clinical trial protocols, through to commercialisation decisions.

“MedAlliance is honoured to have been selected for the FDA’s Breakthrough Device Program, which will allow US patients timely access to new technologies with the potential to provide safer and more effective treatment,” said Jeffrey B Jump, chairman and CEO of MedAlliance.

SELUTION’s technology involves unique micro-reservoirs made from biodegradable polymer intermixed with the anti-restenotic drug sirolimus. These micro-reservoirs provide controlled and sustained release of sirolimus. Extended release of sirolimus from stents has been demonstrated highly efficacious in both coronary and peripheral vasculatures.

MedAlliance’s proprietary CAT (Cellular Adhesive Technology) enables the microreservoirs to be coated onto balloons and adhered to the vessel lumen when delivered via an angioplasty balloon.

MedAlliance is the first and only company able to deliver sirolimus in a DEB with an extended release profile similar to that of a drug-eluting stent (DES). Preclinical animal data shows therapeutic levels of sirolimus in tissue for greater than 60 days, and First in Man clinical trial results in peripheral arteries demonstrate a Late Lumen Loss of 0.19mm.

The FDA received the MedAlliance request to designate SELUTION as a Breakthrough Device in January 2019.

The proposed indications for use included “improving luminal diameter, after predilatation, in treatment of coronary artery ISR for stenotic lengths up to 36 mm with reference vessel diameters of 2.25–4.5 mm.” MedAlliance was recently informed by the FDA that “your combination product and proposed indication for use meet the criteria and have been granted designation as a Breakthrough Device”.

The goal of the Breakthrough Devices Program is to provide patients and healthcare providers with timely access to these medical devices by speeding

up their development, assessment, and review, while preserving the statutory standards for premarket approval, 510(k) clearance, and De Novo marketing authorisation, consistent with the Agency’s mission to protect and promote public health.

The Breakthrough Devices Program offers manufacturers an opportunity to interact with the FDA’s experts through several different program options to efficiently address topics as they arise during the premarket review phase, which can help manufacturers receive feedback from the FDA and identify areas of agreement in a timely way. Manufacturers can also expect prioritised review of their submission.

Augmented reality surgical technology unveiled by Philips and Microsoft

At the MWC (25–26 February, Barcelona, Spain), formerly the Mobile World Congress, Philips unveiled a unique mixed reality concept developed in partnership with Microsoft for the operating room of the future. Based on Philips’ Azurion image-guided therapy platform and Microsoft’s HoloLens 2 holographic computing platform, the companies will showcase novel augmented reality applications for imageguided minimally invasive therapies.

The technology allows wearers of the HoloLens 2 headset to access a virtual screen displaying data from the Azurion system, updated in real time, during procedures.

The Philips and Microsoft augmented reality concept, built for HoloLens 2, brings live imaging and other sources of vital data currently displayed on large 2D screens into a 3D holographic augmented reality environment that can be ergonomically, easily and intuitively controlled by the physician. The concept is being used to gather further clinical insights to support the development of future commercially-available augmented reality solutions for use in image-guided procedures.

“The transition from open surgery to image-guided procedures has driven a seismic shift in improving patient outcomes and reducing costs—not least by dramatically reducing the length of time a patient stays in a hospital after their procedure,” said Atul Gupta, chief medical officer for Image Guided Therapy at Philips and a practicing interventional and diagnostic radiologist.

“On our Azurion platform we seamlessly integrate a range of data sources in a way that is intuitive to understand and control. By collaborating with Microsoft and HoloLens 2 we can take it to the next level, immersing the physician in a tailored augmented reality environment.

This concept allows me to see the real world superimposed with the live data and 3D medical imagery needed to guide our precision therapy, and importantly

also lets me control Azurion with voice recognition, eye tracking and advanced gestures. It is all about keeping our focus on the patient.”

“Mixed reality is giving people new ways to interact with the digital and physical world, bringing the benefits of the digital revolution to entirely new experiences across the globe,” said Alex Kipman, technical fellow, AI and Mixed Reality at Microsoft. “I am thrilled to see companies in a broad range of industries achieve more using the products that we build with our partners and ecosystem.

Mixed reality holds great potential in healthcare, and our collaboration with Philips shows how that potential is already beginning to be realised.”

Microsoft unveiled HoloLens 2 during the previous day of the conference.

HoloLens is a self-contained holographic computer that enables hands-free, headsup interaction with three-dimensional digital objects.

Since its global launch in February 2017, over half a million patients have been treated in more than 80 countries using the Azurion platform, which is powered by Philips’ proprietary ConnectOS and combines technical innovations in both software and hardware. ConnectOS allows the integration of advanced digital innovations on the Azurion platform.

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growing area of image-guided minimally invasive surgery—continues to increase, as does the number of patients requiring treatment. In order to treat more patients at a lower cost, Philips say in a company statement, hospitals require a versatile fleet of C-arms with varying capabilities that easily adapt to the needs of different types of surgery and different operators. Philips claim that Zenition mobile C-arms are easy to move between operating rooms, simple to position around the patient and intuitive to operate.

“The Philips Zenition is a userfriendly system that is intuitive to use for both surgeons and nursing staff,” says Nikolaos Bonaros, associate professor of Cardiac Surgery at the Medical University of Innsbruck, Austria. “Its simplified workflow means that we can convert a room from a conventional operating room to a high-quality interventional room more quickly. At the same time the system provides high image quality at the level required for hybrid operating room procedures.”

Philips Zenition has a tablet-like user interface and this, coupled with the “Unify” workflow, mean that once an operator has learned to use one system on the platform, it is easy for them to operate them all, a press release states.

The company also claim that the compact

HoloLens 2 and Azurion

Philips launches Zenition mobile C-arm platform

Philips Zenition, a new mobile C-arm imaging platform from Philips, has launched in the USA, Germany, Austria and Switzerland. It is being introduced into these countries over the next six months, and is set to penetrate other markets in the second half of 2019.

Mobile C-arms are X-rays systems that are brought into the operating room to provide live image guidance during a wide range of surgeries, including orthopaedic, trauma and vascular procedures. According to a company press release, the Zenition mobile C-arm platform brings together innovations in image capture, image processing, ease-of-use and versatility pioneered on Philips’ earlier Azurion platform.

The scope and complexity of surgical interventions—especially in the rapidly

design of the device, as well as its ability to capture images at the periphery of the image intensifier or flat detector, reduce the need for C-arm repositioning by 45%.

The Zenition C-arm systems incorporate the same image processing algorithms used on Philips’ Azurion platform. Additionally, the platform features Philips’ MetalSmart software, which automatically adjusts the contrast and brightness of images to aid image quality, purportedly useful when metal objects such as implants are present in the field of view.

Philips’ Zenition C-arms are CE marked and have received 510(k) clearance from the US Food and Drug Administration (FDA). They will be showcased at the 2019 European Congress of Radiology (ECR) Exhibition (28 February–3 March, 2019, Vienna, Austria).

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Product news

Product News PreludeSYNC DISTAL compression device now available globally

The PreludeSYNC DISTAL compression device (Merit Medical) is now available in US, European, Middle Eastern, African, and Asia-Pacific markets. The device is the first product specifically designed to achieve haemostasis of the radial artery during procedures where access is gained via the distal radial artery.

Designed, according to a company press release, “with a comfortable band and a large window for site visibility”, the PreludeSYNC DISTAL compression device is applied over the arteriotomy, allowing the clinician to slowly inflate the balloon with air while simultaneously removing the sheath. It then maintains pressure at the site to allow the access wound to achieve patent haemostasis.

Merit is also answering demand for distal access training through its ThinkRadial course, with the next one taking place on 9 February 2019. The course will feature a dedicated three-hour session specific to distal radial access, which will be streamed live online and available to interventional cardiologists and radiologists who want to learn the distal technique. Additional information about other ThinkRadial courses, including registration, may be found on the programme’s website.

Prelude SYNC DISTAl compression device

The live streaming event features Ferdinand Kiemeneij from Amsterdam, The Netherlands, widely considered the “father of transradial intervention”; Sandeep Nathan, an interventional cardiologist in Chicago, USA; and Darren Klass, an interventional radiologist based in Vancouver, Canada

BD wins FDA 510(k) for WavelinQ 4F endovascular AVF system

The FDA have granted 510(k) clearance to BD for its WavelinQ 4French endovascular arteriovenous fistula (AVF) creation system.

The company said that the newly cleared WavelinQ 4F endovascular AVF

system features improved technology that allows for the creation of an AVF in either the ulnar artery and ulnar vein or the radial artery and radial vein.

“With BD WavelinQ 4F endovascular AVF system, I can provide my end-stage renal disease patients with two additional fistula location options compared to a surgical fistula. These additional AV fistula sites and a minimally invasive procedure can increase the likelihood that patients will get a usable AV fistula,” Paul Kreienberg of the Albany Medical Center (New York, USA) said in a prepared statement.

QuiremScout, the first and only product indicated for SIRT work-up, receives CE mark

QuiremScout (Quirem Medical) has received CE mark, making it available for clinical centres throughout Europe.

QuiremScout is designed to advance the SIRT (selective internal radiation therapy) work-up procedure. It does this by improving the accuracy of predicting lung shunting and the intrahepatic distribution, which aims to optimise SIRT patient selection and treatment planning.

QuiremScout will be exclusively distributed by Terumo.

Until QuiremScout, Tech-99m-MAA (99mTc-MAA) has been used for SIRT work-up procedures around the world, in the absence of an alternative. The limited predictive value of 99mTcMAA has been recognised by some in the field, leading to the development of QuiremScout.

“QuiremScout has improved our clinical SIRT practice,” Marnix Lam, head of Nuclear Medicine at the University Medical Center Utrecht (Utrecht, The Netherlands) says. “Based on data from more than 80 patients, we have demonstrated that QuiremScout is safe in this population and is a better predictor for lung shunting than 99mTc-MAA. As a result, we really feel that we have optimised our SIRT patient selection. In addition, we have established that QuiremScout is also a better predictor for the post-treatment intrahepatic distribution when compared to 99mTc-MAA. Notably, QuiremScout in combination with 99mTc-MAAcolloid enables Dual-Isotope SPECT/ CT technology allowing for rapid auto-segmentation of the healthy liver tissue. In our experience, QuiremScout microspheres outperforms 99mTcMAA. Therefore, we have decided to completely switch to QuiremScout for all QuiremSpheres work-up procedures.”

Tack Endovascular System launches in the EU with first commercial use in Germany The first commercial use of the Tack Endovascular System (Intact Vascular) has taken place in multiple hospitals within Germany. A novel therapy for

dissection repair following balloon angioplasty, the Tack implant is a first-of-its kind device for patients with peripheral arterial disease (PAD) and/or critical limb ischemia (CLI).

“The Tack System provides a much needed therapeutic option for treating dissections in the superficial femoral or popliteal arteries following balloon angioplasty,” says Christian Wissgott, assistant director at Westküstenklinikum Heide in Heide, Germany. “I am very pleased with my experience using the implant and I am excited to incorporate this technology into my above and below the knee treatment algorithms going forward.”

Patients treated with balloon angioplasty frequently suffer from dissections. Often overlooked, undiagnosed and untreated, dissections can lead to acute thrombosis and arterial occlusions, which lower longterm patency rates and require repeat procedures. Designed to resolve these dissections while leaving minimal metal behind, the Tack implant is designed to preserve vessel integrity, minimise vessel inflammation and enhance blood flow.

“With the Tack System, balloon angioplasty results are improved regardless if it is drug-eluting or not,” notes Michael KW Lichtenberg, chief of the Angiology Clinic and Venous Center in Klinikum Arnsberg, Germany. “Based on my initial experience, I am confident this new paradigm of focal dissection repair will become standard of care for patients undergoing PAD interventions.”

This follows the news in early January 2019 that the Tack Optimised Balloon Angioplasty II below-the-knee (TOBA II BTK) clinical trial has successfully completed enrolment, ahead of schedule.

Atherectomy included in pivotal study of QT Vascular’s Chocolate Touch DCB

The FDA has granted approval to include the use of atherectomy for lesion preparation in its ongoing US pivotal study of the Chocolate Touch drug-coated balloon (DCB; QT Vascular) and the addition of subgroup analysis related to the use of atherectomy.

The Chocolate Touch device is the drug-coated version of the company’s Chocolate percutaneous transluminal angioplasty balloon, which was acquired

by Medtronic in January 2018 and is commercially available in the USA. The prospective, randomised Chocolate Touch pivotal study is being conducted in up to 50 centres in the USA, and selected centres in Europe and New Zealand. The study’s co-principal investigators are Mehdi Shishehbor (Cleveland, USA) and Thomas Zeller (Bad Krozingen, Germany).

In the company’s press release, Shishehbor comments: “The inclusion of atherectomy in the study is a unique element that expands the potential use of Chocolate Touch, both in hospitals and out-patient–based labs. The study will provide an important data set that is consistent with real-world practice, especially at [out-patient–based labs] where more and more patients are getting

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treated.”

The study is evaluating patients with disease in the superficial femoral and popliteal arteries in the legs. Patients are randomised 1:1 to the Lutonix DCB (BD).

The study evaluates acute endpoints such as procedural successes and freedom from bail-out stenting, and long-term endpoints such as patency and target lesion revascularization among others.

The Chocolate Touch DCB is not commercially available in the USA, and can only be used in the investigational device exemption clinical study. The device received CE mark in August 2015 and is available in the European Union and other countries.

Twelve-month data show UroLift system a good treatment option for men with BPH

Twelve-month data from the multicentre prospective MedLift study of the Urolift system (NeoTract, a Teleflex subsidiary) for benign prostatic hyperplasia (BPH) involving a median lobe obstruction provided clinical evidence to support the safety and efficacy of the treatment. Results were published in Prostate Cancer and Prostatic Diseases.

Median lobe obstructions are present in a subset of men with BPH. Results from this study led to the recent US Food and Drug Administration (FDA) clearance of an expanded indication for the UroLift system, making patients who have an obstructive median lobe eligible to receive the UroLift System treatment for BPH symptoms.

“New options are needed for men with an obstructive median lobe, as treatment can be particularly challenging.

This condition can cause a higher risk of urinary retention and result in a high failure rate of medical therapy for lower urinary tract symptoms due to BPH,” comments Gregg Eure from Urology of Virginia in Virginia Beach, USA, a lead investigator and co-author of the MedLift Study paper. “The outcomes of this study, which showed significant and rapid improvements in BPH symptoms and quality of life measures, demonstrate the safety and effectiveness of the UroLift System for these patients.”

The MedLift study revealed that patients who were treated for an obstructive median lobe with the UroLift System experienced significant improvements in IPSS (International Prostate Symptom Score), Qmax (peak flow rate), and quality of life scores. The IPSS improved from baseline by at least 13.5 points (p<0.0001) over the course of the study. Quality of life and BPH impact index scores were also improved, by more than 60% and 70% respectively, at three, six, and 12 months (p<0.0001).

The mean Qmax improvement ranged from 90–129% (p<0.0001). At one month, 80% of men reported being “much better” or “very much better”, and 89% would recommend the procedure. Bother due to ejaculatory function improved rapidly and remained modestly improved at one year (p=0.001). No patient reported de novo sustained ejaculatory or erectile dysfunction.

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Product News FDA modernises the 510(k) programme to advance the review of the safety and effectiveness of medical devices

The US Food and Drug Administration (FDA) have updated the Pre-Market Notification 510(k) programme to promote the use of more modern predicates when reviewing devices for commercialisation. This change will facilitate the approval of products The 510(k) programme is the most common pre-market review regulatory pathway for new devices received in the Center for Devices and Radiological Health (CDRH). In 2017, CDRH cleared 3,173 devices making up 82% of the FDA’s cleared or approved devices.

Scott Gottlieb

The 510(k) pathway is used for clearance of low- to moderate-risk devices that are substantially equivalent to a device already on the market— otherwise known as a predicate device.

In a 510(k) submission, the submitter is required to provide adequate performance data to confirm that their new device is as safe and effective as the chosen predicate device.

In the recent changes to the 510(k) pathway, however, the FDA aims to promote the use of more modern predicates in favour of older, possibly out-dated devices.

Then FDA commissioner Scott Gottlieb and director of the Center for Devices and Radiological Health Jeff Shuren said in a joint statement released concordantly with the programme updates: “We believe firmly in the merits of the 510(k) process. But we also believe that framework needs to be modernised to reflect advances in technology, safety and the capabilities of a new generation of medical devices. In short, we believe that it is time to fundamentally modernise an approach first adopted in 1976, when Congress considered the vast diversity of devices that would become subject to the FDA’s regulatory oversight and established many of the predicate devices that served as the basis for 510(k) clearances during the last 40 years.

“We are pursuing these changes to help keep pace with the increasing complexity of rapidly evolving technology. The new technology that we are seeing holds tremendous public

health promise for patients. But with the advances also come new complexities that can make the review of safety and effectiveness more challenging.

The framework we propose is aimed at efficiently advancing beneficial technology to patients, while solidifying [the] FDA’s gold standard for safety.

“We believe that where appropriate, new medical devices that come to the market under the 510(k) pathway should either account for advances in technology or demonstrate that they meet more modern safety and performance criteria. We want to make sure that new devices are evaluated against advances in technology that can improve patient safety and performance.

In making these reviews, where appropriate, we want to rely on modern safety and performance criteria. At the same time, we are going to pursue additional actions that will allow the FDA to retire outdated predicates, especially in cases where we have seen safer or more effective technology emerge.”

Unique therapeutic approach to treating uncontrolled hypertension receives US$77 million financing

Ablative Solutions has announced the first close of its US$77 million Series D funding round. The round was led by new investor Glide Healthcare, and coled by exiting investor BioStar Ventures, as well as an undisclosed new strategic corporate investor. Existing investors, including Michigan Accelerator Fund, Novus Biotechnology, and other individual investors, also participated in the Series D funding round.

Funds from the round will be used to complete clinical trials in support of US and European regulatory submissions for the company’s minimally invasive renal denervation technology designed to help reduce blood pressure for people with uncontrolled hypertension, while taking antihypertensive medication.

“BioStar Ventures focuses on transformational health care investments, and we believe Ablative Solutions fits that model perfectly,” says Michael Fulton, senior managing director of BioStar Ventures, an investor in the company since its Series A round in 2012.

Ablative Solutions’ alcoholmediated renal denervation procedure is performed using the investigational Peregrine system kit, which is engineered to target nerves known to influence the body’s regulation of blood pressure. The Peregrine kit delivers dehydrated alcohol in small doses directly to the space outside of the renal artery to block the overactive signalling of the sympathetic nerves.

“Hypertension creates a significant burden on the healthcare system,

increasing the risk of serious cardiovascular events and stroke,” comments Gilde Healthcare’s Geoff Pardo. “We see tremendous potential for Ablative Solutions’ approach and believe the team has a solid plan for building the clinical data through the TARGET BP clinical programme.”

Ablative Solutions’ CEO and CMO Tim Fischell enthuses: “We are excited to have the support of this thoughtful and high-powered group of investors, which will allow the company to complete the studies required to seek regulatory approvals in Europe and in the USA.”

Boston Scientific announces recommended offer to acquire BTG

Boston Scientific has announced it has reached an agreement on the terms of a recommended offer to acquire BTG, a company headquartered in the UK, which develops and commercialises products used in minimally-invasive procedures targeting cancer and vascular diseases, as well as acute care pharmaceuticals.

The transaction has been unanimously approved by the boards of directors of Boston Scientific and BTG. Under the terms of the transaction, holders of BTG’s common shares would receive cash consideration of 840 pence per share. The total cash consideration for 100% of BTG’s equity is approximately £3.3 billion, or US$4.2 billion. The transaction is intended to be effected by way of an English court-sanctioned scheme of arrangement, and is expected to close in the first half of 2019, subject to receipt of required regulatory approvals and the approval of BTG’s shareholders and the UK court.

Boston Scientific has received irrevocable undertakings to vote in favour of the transaction from BTG’s three largest shareholders, covering an aggregate of approximately 33% of BTG’s outstanding shares, as well as from all of BTG’s directors, who hold an additional 0.3% of BTG shares.

The transaction would be funded with a combination of cash on hand and proceeds from debt financing entered into by Boston Scientific. The full terms of the proposed transaction, including the full terms of the undertakings from BTG’s shareholders and directors, are set forth in an announcement made by Boston Scientific, Bravo Bidco Limited, a wholly-owned Boston Scientific subsidiary formed to effect the proposed transaction, and BTG in accordance with Rule 2.7 of the UK’s City Code on Takeovers and Mergers. Boston Scientific has entered into a bridge financing facility providing for its receipt of £3.3 billion of committed financing, which satisfies the certain funds requirements of the UK Takeover Code.

The transaction is expected to be two to three cents accretive to Boston Scientific adjusted earnings per share in 2019, and increasingly accretive thereafter. On a GAAP basis, the transaction is expected to be dilutive in 2019, and less dilutive or increasingly

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accretive thereafter, as the case may be, due to amortisation expense and acquisition-related net charges.

European Society of Radiology and GE Healthcare have exclusive artificial intelligence partnership at ECR 2019

The European Society of Radiology (ESR) and GE Healthcare partnered on artificial intelligence for the European Congress of Radiology (ECR; 27 February–3 March, 2019, Vienna, Austria). The partnership included joint sessions on artificial intelligence and a 300m² dedicated space on GE Healthcare’s 850m² booth, where visitors experienced the AI transformation through interactive tools.

The average hospital generates 50 petabytes of data annually, including clinical notes, lab tests, medical images, and genomics, yet less than 3% of it is used. Artificial intelligence has the potential to make sense of the data and to generate actionable insights that help improve provider efficiency, increase diagnostic accuracy, personalise treatment, improve patient experience, and enable remote and predictive maintenance. GE Healthcare has over 200 imaging applications and is working with partners like Nvidia, Microsoft, Amazon, and Intel to embed analytics, cloud capability, and artificial intelligence into devices, workflows, and technologies already used by healthcare providers today.

“Artificial intelligence will be one of the leadings topics at next year’s ECR and this exclusive partnership with GE Healthcare is a major step in making ECR 2019 the leading event on artificial intelligence for radiologists and related medical professionals. Through our joint efforts congress participants will be able to witness artificial intelligence excellence at the highest level, making next year’s exhibition an event no one should miss”, said ESR president Lorenzo E Derchi (Genoa, Italy), speaking before the event.

“We are honoured to partner with the European Society of Radiology for the leading European radiology event. Artificial intelligence is one of the most exciting developments in healthcare today and a key enabler to achieve precision health. Done right, it can be the technology of the decade, perhaps the century, in healthcare. But there is still much work to do, sound data science and eliminating data siloes are key. Europe and the European radiology community have a key role to play in the artificial intelligence transformation”, commented Catherine Estrampes, president and CEO of GE Healthcare Europe.

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Mar

Clinical News BIBLIOS trial has obtained ethics approval and initiated patient enrolment

The BIBLIOS trial has received Ethics Committee (EC) approval, and enrolled its first patient. This announcement comes from Wouter Lansink, who will be treating this first patient at the Vascular Center ZOL Genk in Belgium.

BIBLIOS is a Belgian-Italian prospective, single-arm, multicentre study to evaluate the efficacy and safety of below-the-knee treatment with the Luminor paclitaxel-coated percutaneous transluminal angioplasty balloon catheter (iVascular) with critical limb ischaemia. One hundred and fifty patients will be enrolled from six Italian and Belgian centres.

As stated by Koen Deloose (AZ Sint-Blasius, Dendermonde, Belgium), the trial’s principal investigator, “the benefits of DCBs for critical limb ischaemia are still to be confirmed.

Preliminary below-the-knee data with Luminor DCB are promising; therefore, we are looking forward to the results of BIBLIOS, which is set to be representative of real-world population in such [an] indication.”

The primary efficacy endpoint of the

BIBLIOS trial is freedom from major adverse limb events at six months. For assessing safety, the primary endpoint of the study is freedom from major adverse limb events or peri-operative death at 30 days.

The secondary endpoints of the BIBLIOS trial include: target vessel functional flow assessment; freedom from clinically driven target lesion revascularisation; amputation free survival; limb salvage; procedural success; wound healing status; and wound healing time, all at six and 12 months.

Heliostar multielectrode ablation catheter trial launches

The first patient has been enrolled and treated in the Stella US investigational device exemption (IDE) study designed to assess the safety and efficacy of the Heliostar multielectrode radiofrequency balloon ablation catheter (Johnson & Johnson’s Biosense Webster) as a treatment for drug refractory recurrent paroxysmal atrial fibrillation.

The trial will include 640 patients in total.

The Heliostar device features ten

electrodes and is designed to allow electrophysiologists to achieve pulmonary vein isolation with a single application of radiofrequency energy, according to Biosense Webster.

Cardiac electrophysiologists Rodney Horton and Andrea Natale (both Austin, USA) treated the first patient in the Stellar study at the Texas Cardiac Arrhythmia Institute, Austin, USA. “This new balloon catheter is unique because it conforms to any pulmonary vein anatomy and allows me to control electrodes individually to deliver tailored energy when ablating around pulmonary veins,” Horton said in prepared remarks.

“The Heliostar catheter design has the potential to overcome the limitations of current balloon ablation catheters, result in fewer catheter exchanges and, most importantly, shorter procedure times.

Heliostar is an exciting technology and we look forward to seeing the final study results,” Natale added.

BELONG study enrols first patients

Enrolment of the first patients in the BELONG study—benefit of arterial vessel preparation by arterial by longitudinal micro-incisions before drug-eluting balloon angioplasty of the superficial femoral and popliteal arteries—has been announced by VentureMed Group.

The primary objective of this clinical study is to evaluate lumen patency at

12 months obtained by preparation of vessels with the FLEX vessel preparation system prior to conventional endovascular recanalization of the superficial and popliteal arteries.

According to a press release, the FLEX system creates long parallel, linear micro-incisions in all plaque morphologies to prepare an ideal vessel environment to facilitate drug-coated balloon angioplasty. The dynamic microincision technique of the FLEX system safely facilitates the treatment of difficult, diseased vessels, improving vessel compliance and acute lumen gain.

This prospective, single arm, nonrandomised study will enrol up to 150 patients in Switzerland. Patients will exit from the study at the completion of their twelve-month follow-up. The primary investigator and co-investigator are Daniel Périard and Rolf Engleberger (both HFR- Hôpital Cantonal Fribourg, Villars-sur-Glâne, Switzerland).

“We believe preparing arterial vessels by delivering parallel longitudinal micro-incisions with the FLEX system prior to drug-coated balloon angioplasty has the potential to demonstrate longterm clinical benefits for patients. Our early results have shown that arterial vessel preparation with the FLEX system resulted in improved lumen expansion and vessel compliance after drug-coated balloon angioplasty, with a corresponding reduction in the rate of dissection,” says Périard.

Calendar of events 23–28 March SIR2019: Society of Interventional Radiology Austin, USA www.sirmeeting.org

8–11 April European Conference of Interventional Oncology (ECIO) 2019 Amsterdam, The Netherlands www.ecio.org

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Market watch

15–18 April Charing Cross Symposium London, UK www.cxsymposium.com

9–12 May Global Embolization Cancer Symposium Technologies (GEST) US New York, USA www.gestweb.org

24 May Pacific North-West Endovascular Conference Seattle, USA www.pnec-seattle.org

26–29 June European Conference on Embolotherapy (ET) 2019 Valencia, Spain www.etconference.org

22–25 July The Society of NeuroInterventional Surgery (SNIS) 16th Annual Meeting Miami, USA www.snisonline.org

11–13 October The Symposium on Clinical Interventional Oncology (CIO) Hollywood, USA

17–19 October SIR LEARN Nashville, USA www.sirweb.org/learn

24–26 October SIR ACTIVE Scottsdale, USA www.sirweb.org/active

www.interventionaloncology360. com

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