Interventional News Issue 82—June 2021 US Edition by BIBA Publishing

June 2021 | Issue 82

Featured in this issue:

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Gerard Goh and Markus Schlaich: Renal and hepatic artery denervation

Renal interventions: High-flow fistulas divide opinion

Profile: Philip Pereira

page 20

page 22

The road to PAE in the AUA guidelines There are substantial differences amongst guideline recommendations regarding the use of prostate artery embolization (PAE) in the treatment of lower urinary tract symptoms/benign prostatic obstruction (LUTS/BPO), which can be partially explained by different interpretation of the evidence. This is the conclusion presented by Dominik Abt (Klinik für Urologie, Institut für Medizin, Universität St Gallen, St Gallen, Switzerland) at the Global Embolization and Cancer Symposium Technologies (GEST) 2021 Focus Day on prostate artery embolization (PAE; 6 March, online). This virtual meeting sought to open discussion between urologists and interventional radiologists regarding the place of PAE in the treatment algorithm, a topic of heated debate in recent years.

peaking during the final session of the day, panel that found that the improvements in quality of life chair and co-course organiser Jafar Golzarian measurements and International Prostate Symptom Score (University of Minnesota, Minneapolis, USA) (IPSS) in patients following PAE are “far superior” to those praised the “unique” collaborative attitude of the virtual due to the placebo effect. Speaking to Interventional News meeting, where attendees heard from four urologists and at the time, Bilhim noted that publishing a paper positively four interventional radiology (IR) panellists: “This session describing PAE in a urology journal has historically been exploring the level of evidence and directions for future difficult for interventional radiologists. He hoped that this research in PAE is unique in both the IR and urology publication “might help our way into the urology guidelines communities,” he said, “taking a truly interactive and with PAE”. multidisciplinary approach, which is not common practice.” The sham study enrolled 80 patients, randomised 1:1 He noted that he hoped this cross-disciplinary collaboration to PAE versus a sham procedure with a cross-over design would continue in future meetings. at six months. Summarising their findings, Little relayed: The American Urological Association (AUA) does “They found a statistically significant refutation of the not recommend PAE for the treatment of LUTS/benign placebo effect—PAE does better than sham”. Asking the prostatic hyperplasia question, “Is PAE clinically (BPH) outside the context effective”, Little argued that of a clinical trial, a the answer was a definitive recommendation attributed “Yes”, based on this Level 1 to the expert opinion of a evidence. panel of urologists. This news was unwelcome to AUA guidelines the IR community when Published in the Journal of first announced in 2019, as Vascular and Interventional interventional radiologists Radiology (JVIR) and have been advocating authored by Clifford Davis for the procedure’s (College of Medicine and acceptance by the wider Radiology, University of medical world. Multiple South Florida, Tampa, GEST 2021 PAE panellists. Top row, from left: Shamar IR societies conclude that Florida) et al, the findings of Young, Jafar Golzarian, Art Rastinehad. Middle row, from left: Riad Salem, James Spies, Dominik Abt. Bottom row, PAE is a safe, effective, a Society of Interventional from left: Mark Little, Philipp Dahm, John Kellogg Parsons. minimally invasive Radiology (SIR) consensus treatment option in select panel convened to discuss BPH patients. the development of a research agenda for PAE concluded without consensus: “Level 1 data are required to be Evidence for PAE included in the AUA guidelines for treatment of BPH. Speaking first, Mark Little (Royal Berkshire NHS Because of concerns with all three study designs, the panel Foundation Trust, Reading, UK) discussed recent PAE did not reach a consensus. Further meetings are planned literature. In the last two years, 113 papers on the procedure with the panel to select among these research designs.” have been published. Of these, five were randomised The three research designs mentioned were: i) RCT controlled trials (RCTs), and eight were meta-analyses of of PAE versus sham with crossover of the sham group; systematic reviews. ii) RCT of PAE versus simple prostatectomy; iii) RCT Regarding the clinical effectiveness of PAE, Little said: of PAE versus holmium laser enucleation of the prostate “We cannot go beyond the superb sham RCT study that (HoLEP)/thulium laser enucleation of the prostate. The SIR came out of Lisbon.” This was a 2020 study published in consensus panel ultimately recommended a non-industryEuropean Urology, the official journal of the European funded registry to obtain real-world data. Association of Urology (EAU), from João Pisco, Tiago Currently, the AUA guidelines state that “PAE for the Bilhim (Hôpital Saint-Louis, Lisbon, Portugal) et al, Continued on page 2

COLDFIRE 2: IRE is safe, effective in patients unsuitable for thermal ablation or surgery Irreversible electroporation (IRE) is an effective and relatively safe treatment for colorectal liver metastases 5cm or smaller that are deemed unsuitable for partial hepatectomy, thermal ablation, or further systemic therapy, results of the COLDFIRE-2 study, published in Radiology, report. The two-centre, prospective, single-arm, phase II clinical trial was conducted by Martijn Meijerink, Alette Ruarus (both Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands) and colleagues. IRE IS A NON-THERMAL ABLATIVE technique that uses high-voltage electrical pulses, and, according to the study authors, has shown promise for eradicating tumours near critical structures, including blood vessels and bile ducts. This is exactly why it presents an attractive treatment option to many interventionalists: those patients treated in COLDFIRE-2 were all inappropriate candidates for partial hepatectomy or thermal ablation due to the proximity of their tumours to critical structures. Indeed, up to 70% of patients with colorectal liver metastases are not eligible for surgery because of comorbidities or owing to the number, location, or distribution of the metastases. Meijerink, Ruarus et al explain that, although most current guidelines consider thermal ablation (radiofrequency and microwave; RFA and MWA) to be the standard of care for small, unresectable colorectal liver metastases, its contraindication for tumours close to large hepatic vessels presents an unmet clinical need that can be catered for by IRE. The COLDFIRE-1 study (Colorectal liver metastases disease: efficacy of irreversible electroporation, a single-arm, phase 1 clinical trial) first demonstrated IRE’s ability to eradicate colorectal liver metastases in humans. The COLDFIRE-2 triallists write: “The reported efficacy of hepatic IRE varies widely (45.5–100%) because of the heterogeneity of patient and tumour characteristics, and most Continued on page 4

June 2021 | Issue 82

Prostate artery embolization

The road to PAE in the AUA guidelines Continued from page 1

treatment of LUTS secondary to BPH is not supported by current data and trial designs, and benefit over risk remains unclear; therefore, PAE is not recommended outside the context of clinical trials.” This is based on expert opinion. The AUA request PAE studies to include a 24-month follow-up “to be equivalent to current data on other surgical therapies for LUTS resulting from BPH”, Little explained. Dominik Abt (Klinik für Urologie, Institut für Medizin, Universität St Gallen, St Gallen, Switzerland) et al conducted a study comparing the efficacy and safety of PAE and TURP in the treatment of LUTS at two-year follow-up. They concluded in February 2021: “Inferior improvements in LUTS/BPO [benign prostatic obstruction] and a relevant retreatment rate are found two years after PAE compared with TURP. PAE is associated with fewer complications than TURP. The disadvantages of PAE regarding functional outcomes should be considered for patient selection and counselling.” Their patient summary was: “PAE is safe and effective. However, compared with TURP, its disadvantages regarding subjective and objective outcomes should be considered for individual treatment choices.” As the reintervention rate was 20% in the PAE group, the treatment these patients should get next is “where the debate now lies”, in Little’s opinion. “I do not think this paper is a death knell for PAE at all,” he opined. “Actually, I think it shows that it is safe and effective, but, we need a reasonable discussion with our patients about what we can achieve with the technology based on patient selection, anatomy selection, pre-procedural imaging and planning.” He concluded that PAE is safe and effective, and, in his eyes, gives patients a choice, which he believes is “really important”. Citing the sham trial and RCT data to two years follow-up, Little summarised that there is “lots of Level 1 and 2 evidence on PAE, which cannot be argued against in terms of the position statement of ‘Benefit over risk remains unclear’ [from the AUA guidelines].” He continued: “I am not sure that we can say that with the current evidence case we have”; fellow panellist Riad Salem (Northwestern University, Chicago, USA) agreed. Going through the AUA guidelines comparing how PAE was assessed compared to alternative therapies, James Spies (MedStar Georgetown University Hospital, Washington, DC, USA) said he thought the recommendation not to perform the procedure outside of clinical trials was “actually a value judgement of one specialty over another” that “seems a little unusual”. “This is not pointing fingers at the AUA,” he added. “I was former chair of the standards committee of the SIR, and I am a former [SIR] president—clinical practice guidelines really are intended to be evidence-based, and by-and-large they are. The process the AUA uses is actually very good.

But when it gets down to it, it is difficult to separate our preconceived notions from our review of evidence.” “Again, this is not a knock on the AUA, but my opinion is that guidelines reflect the opinions of the organisations that create them. That is because it is almost impossible for a group in a room to go beyond what is not comfortable for them. [...] So I would agree we need to increase our data, but I am just not sure we are ever going to be able to get there. This is a benchmark procedure for urologists, and, just like some other specialties that we work with, it can be difficult to get adoption.”

Quality of evidence: Urology perspective

Urologist Philipp Dahm (Minneapolis VA Medical Center and University of Minnesota, Minneapolis, USA) gave a talk entitled, “Objective rating of evidence: Why it matters and how it applies to PAE”. He recommended the following: “Current best evidence on PAE should be assessed on the basis of a high-quality, protocol-driven systematic review. The focus should be on patient-important outcomes with explicit consideration of clinically-important differences [in the case of PAE, this includes IPSS and quality of life scores, adverse events, and retreatment rates; flow rate and prostate volume are deemed “not important for decision-making” by Dahm]. The certainty of evidence rating should be provided on a per-outcome basis to qualify how much confidence we have. Lastly, judgements about net benefit need to consider both relative and absolute effect size estimates.” Dahm is a founding member of the US grading of academic assessment, development, and education (GRADE) network, an informal working group formed in 2000 to develop a new system for rating the certainty of evidence in healthcare and also for making guidelines.

Guidelines reflect the opinions of the organisations that create them.”

News in brief

The latest stories from the interventional world

n RADIOEMBOLIZATION:

Holmium-166 (166Ho) radioembolization is a safe treatment option for patients with hepatocellular carcinoma (HCC), results from the prospective, clinical phase I/II HEPAR Primary study, presented at the European Conference on Interventional Oncology (ECIO; 10–13 April, online), demonstrate. Marnix Lam (University Medical Centre Utrecht, Utrecht, The Netherlands) discusses these latest data in a Terumosponsored advertorial. For more on this story go to page 7.

n TACE WITH DEGRADABLE STARCH MICROSPHERES: Andreas H Mahnken (Clinic of Diagnostic and Interventional Radiology, Marburg University, Marburg, Germany; pictured) enthuses about the potential of degradable starch microspheres (DSM) in transarterial chemoembolization (TACE), specifically drawing on his 20 years’ experience with DSM particles (PharmaCept). This is a PharmaCept-sponsored advertorial.

For more on this story go to page 13

Unlike the traditional “hierarchy of evidence”—which treats systematic reviews, meta-analyses, and RCTs at the gold standard—GRADE is based on an alternate hierarchy that Dahm said reflects the flaws in these assessment methods. In particular, he noted that RCTs “can be fatally flawed” in their design, and noted that systematic reviews are only as good as the individual studies they evaluate, so could suffer from “garbage in, garbage out” . The GRADE system works thus: formulate a question; select outcomes; rate the importance of these outcomes (on a scale from critical, to important, to less important); look at outcomes across studies; create an evidence profile with

n FIBER OPTIC TECHNOLOGY: Vascular surgeons at the University of Massachusetts became the first in the USA to carry out procedures using the breakthrough imaging technology Fiber Optic RealShape (FORS; Philips), reporting a 75% decrease in radiation use after one of their earliest experiences of the system.

For more on this story go to page 26. Joost van Herwaarden

Continued on page 4

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June 2021 | Issue 82

Top stories

The road to PAE in the AUA guidelines GRADEpro, which includes a summary of findings and an estimate of the effect for each outcome; rate the quality of evidence for each outcome (high, moderate, low, very low). “It is really important to provide a certainty of evidence rating that reflects the confidence that we have that an estimate of effect is adequate to support a clinical decision or recommendation,” Dahm said. A GRADE rating of “high” corresponds to “We are very confident that the true effect lies close to that of the estimate of the effect”. A “very low” rating translates to “We have very limited confidence in the effect estimate”. He talked the audience through the GRADE summary of findings table for the Cochrane review conducted by urologist Jae Hung Jung (Yonsei University Wonju College of Medicine, Wonju, South Korea) and colleagues and published in 2020, which set out to assess the effects of PAE compared to other procedures for treatment of LUTS in men with BPH. Using an updated version from March 2021, Dahm recounted how the GRADE interpretation of the change in IPSS and quality of life scores following PAE is that there is “little or no difference for these outcomes short-term compared to TURP”. In addition, he said that “we are very uncertain” about PAE having a lower major adverse event rate than TURP. Lastly, he noted that the “greatest certainty” the GRADE reviewers had was regarding retreatment rates in the short-term, which they believed were “probably increased” after PAE.

concluded: “In my opinion, no one can say PAE does not work. It does, in my opinion, satisfy all criteria for a reasonable treatment, and it should be an option presented to patients. At minimum, it should have a limited recommendation for large glands [prostate volumes >80cc], where effectively all of the MISTs [minimally invasive surgical therapies] are ineffective, by the AUA guidelines.” Salem continued: “The AUA guidelines are important, but they are not the final word. Respectfully, no one has a monopoly on the management and the clinical development of managing patients with BPH/LUTS. It should be a team effort. As Philipp [Dahm] said, Level 1 evidence is not the only method of generating highlevel, relevant data. Good phase II data can do that as well—there are ethical and technical challenges with RCTs, as Mark [Little] spoke about. “Unfortunately, we have been slowed down by—in my opinion—the emotional and polarising reaction by key opinion leaders to evolving PAE data. It is my observation that there is a perceived inconsistency in the manner PAE data are interpreted compared with that [for] MISTs. I think we need to work together, and PAE needs to be offered to the right patient. We need a collaboration between IR and urology, and this collaboration must evolve, not devolve, in a multidisciplinary manner that will benefit patients.” He ended with a specific request of the attending urologists: “At the end of the day, patients are not satisfied with TURP and MISTs as the only options; they are demanding something else. What I would ask is, given this, what is the pathway for recognition of PAE, at least in a limited scope, [in the AUA guidelines]? If the response is a clinical trial, I would like to know which clinical trial explicitly.”

Quality of evidence: IR perspective

A potential way forward

Continued from page 2

Salem offered an interventional radiologist’s perspective, which served as a riposte to Dahm’s previous talk, and detailed the strength of evidence for PAE’s safety and efficacy. While he said he understood the initial scepticism about the success of embolizing the prostate gland, he noted that there have been technical improvements in the procedure since its inception. Furthermore, while attempts at “gold standard” PAE versus TURP trials had failed in the USA, more recent propensity-matched, prospective comparisons of the two procedures and randomised trials of TURP versus sham a procedure are positive indicators that PAE has a positive future. “More importantly, to Philipp [Dahm]’s point,” Salem commented, “there is a growing patient interest in alternate therapies.” Following a review of the evidence for PAE, Salem

Offering one urologist’s perspective (with particular emphasis afforded to the “one”), John Kellogg Parsons (Moores UC San Diego Cancer Center, San Diego, USA) took to the virtual podium next. Despite being chair of the AUA BPH guidelines panel, he noted that he was not speaking on behalf of the AUA in any capacity. He suggested some potential ways forward for interventional radiologists and urologists: “[Look for] other study populations and indications. I think LUTS is unlikely to gain significant traction within the urological community as an indication for performing PAE, so I would encourage you to look for other indications. Haematuria is what I hear constantly as a very compelling indication to investigate, but there are no clinical trials to investigate this. I think neoadjuvant therapy is a reasonable avenue to explore; [patients with] urinary retention and very large prostates I think

COLDFIRE 2: IRE is safe, effective in patients unsuitable for thermal ablation or surgery Continued from page 1

studies represent small retrospective cohort studies or case reports with shortterm follow-up. The early adaptation of electroporation into the toolbox of ablative methods by the European Society for Medical Oncology in 2016 seems premature given the nonexistence of larger-scale prospective controlled efficacy studies.” Between June 2014 and November 2018, 50 participants, with 76 fluorine 18 (18F) fluorodeoxyglucose (FDG) PET-avid colorectal liver metastases 5cm

or smaller between them, underwent percutaneous or open IRE. Follow-up included tumour marker assessment and 18F-FDG PET/CT imaging every three months for the first year after IRE, and every six months thereafter. The median follow-up after the first, second, and third IRE procedures was 23.9 months, 9.5 months, and 6.3 months, respectively. The study mets its primary endpoint, which mandated that at least 50% of treated participants had to be alive without local tumour progression at

are also very reasonable options to explore. Always longer-term data [are needed], and absolutely more multidisciplinary collaboration and coordination.” Addressing his fellow panellists, he said: “I think it is important for this group to know that this field is always rapidly evolving. There is an enormous amount of capital in the private sector in biotech that is investing in newer technologies for BPH. To my knowledge there are at least eight novel urethral stents that are in late phase clinical trials, all with urologists—they come to us when they want to run BPH clinical trials. I would ask you to ask yourselves—the PAE technology, is it static, or dynamic? What kind of future relevance does it have, knowing that this field is constantly evolving with new devices?” Closing the session, Abt, a principal investigator and sub-investigator in various clinical trials on the treatment of LUTS/BPO (including on PAE, TURP, HoLEP, amongst others) and a guideline panel member for the Germany Society of Urology document on benign prostatic syndrome, summarised the structural and methodological problems of guidelines in a bid to understand the reasons for the discrepancies between the SIR and AUA recommendations. “There are widespread financial and professional conflicts of interest among the sponsors of guidelines, so the societies,” he said, “and also among the authors. Industry funds a network of lobbyists, researchers, and opinion leaders, which then write our guidelines. ‘Panel stacking’ is another problem: if a novel panellist is nominated, they are probably nominated because they believe in the same school of thought, so that leads us to imbalanced guideline panels.” He commented that the most important part, in his view, is that guidelines often have “highly biased panel compositions”. “On the one hand”, he said, “we have a group of persons that are highly interested in a broad application of PAE, as they work for a society that of course has to represent the interests of their members [indicating the SIR multisociety consensus position statement on PAE for the treatment of LUTS]. The same is absolutely true for the AUA guideline panel. BPH treatment is a billion-dollar business, and here we have panels where at least some of the people involved have substantial conflicts of interest. In my opinion, it is plausible that both societies reach different conclusions.” Abt agreed with the Institute of Medicine suggestion of removing individuals with a financial conflict of interest from guideline panels, and to implement a limitation on the involvement of clinicians with a professional conflict of interest. “Content experts should be consulted, but not write the guidelines,” he concluded.

12 months, defined as local tumour progression-free survival. Per-participant one-year local tumour progression-free survival was 68% (95% confidence interval [CI]: 59, 84) according to competing risk analysis. Outlining why this primary endpoint measure was used, Meijerink, Ruarus and colleagues explain: “Because the participants in this trial were often heavily pre-treated, overall survival would not properly reflect the efficacy of IRE, and therefore one-year local tumour progression-free survival was chosen as the primary endpoint.” The authors go on to say that these results “are in line with those of recent retrospective series”, and conclude: “Thus, we believe that IRE should be accepted as a niche indication

for difficult-to-reach colorectal liver metastases, but only in the salvage setting of permanent unresectability and unsuitability for thermal ablation.” Writing in an accompanying editorial in Radiology, S Nahum Goldberg (Hadassah Hebrew University Medical Center, Jerusalem, Israel) claims the COLDFIRE-2 trial “has the potential to provide a substantial impact on the treatment of this malady and on interventional oncology as a whole”. Speaking of the trial, he says: “This well-designed and superbly executed effort represents a pivotal clinical trial of IRE for the treatment of intrahepatic colorectal metastases unsuitable for partial hepatectomy, thermal ablation, and further systemic treatments. The authors offer hope for achieving Continued on page 6

Issue 82 | June 2021

IO accreditation programme

IASIOS, the world’s first accreditation programme for interventional oncology, just opened for public enrolment The International Accreditation System for Interventional Oncology Services (IASIOS) has passed its pilot phase with flying colours, the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) has announced in a press release, and is now open for public enrolment. Twelve pioneering hospitals from nine countries successfully participated in the IASIOS pilot phase. This robust accrediting system, tested and optimised over the past two years, now stands ready to accept applications from facilities offering interventional oncology (IO) services worldwide, regardless of the institution’s size or location. IASIOS IS THE WORLD’S ONLY accreditation scheme focussed exclusively on minimally-invasive treatments for cancer. Its main goal is to establish the highest quality standards in IO care throughout the entire service line and patient pathway. Cancer patients can benefit greatly from IO treatments whose minimally invasive nature is proven to provide numerous advantages, such as less pain, fewer complications, and shorter recovery times than conventional surgery, radiation, or chemotherapy. Furthermore, many IO procedures can be performed on an outpatient basis, increasing efficiency, reducing costs and waiting times, and allowing earlier resumption of normal life. This is especially important in these challenging times, as the pandemic has resulted in backlogs in cancer care which IO could help to substantially reduce. With the continued growth and recognition of IO as an important clinical discipline and the fourth pillar of cancer care, facilities providing IO therapies must follow appropriate guidelines if the relevant treatments are to

IASIOS-accredited centres. Clockwise from top: Anadolu Medical Center; Guy’s and St Thomas’s Hospital, NHS Trust; Strasbourg University Hospitals, HUS. Visit www.iasios.org for more information.

be used safely and appropriately. It is likewise essential for patient safety and satisfaction that interventional oncologists have the ability and means to officially prove their value and expertise to patients and hospital administrators, not merely as technicians, but rather as primary clinical healthcare providers. In order to

This pioneering accreditation scheme will help improve cancer care around the world.”

DOORwaY-90 study for SIRSpheres therapy as first-line treatment for hepatocellular carcinoma enrols first patient

The first patient has been enrolled in DOORwaY-90, a study evaluating the safety and efficacy of selective internal radiation therapy (SIRT) using SIR-Spheres Y-90 resin microspheres (Sirtex) in patients with unresectable hepatocellular carcinoma (HCC).

OORwaY-90, which stands for “Duration of Objective Response with Arterial Y-90,” is the first prospective, US-based, multicentre, open-label, single arm study of its kind. The study will assess the duration of response and objective response rate of SIR-Spheres. It is being

led by co-principal investigators Cheenu Kappadath and Armeen Mahvash (both The University of Texas MD Anderson Cancer Center, Houston, USA). Study enrollment is underway, with the first patient enrolled at Inland Imaging Associates and Providence Sacred Heart Medical Center in Spokane, USA.

achieve exactly that, the Standards of Quality Assurance in Interventional Oncology, published by CIRSE, were used as a blueprint and set the foundation for developing an accreditation system that will be instrumental in the standardisation of IO services on a global scale. Chair of the IASIOS supervisory board, Andreas Adam (London, UK), provides insight into this global launch, commenting: “IASIOS is the culmination of years of dedicated work by CIRSE. It is exciting to reach this stage, as this pioneering accreditation scheme will help improve cancer care around the world.” Centres that enrol in the IASIOS system become part of a greater worldwide community of top IO centres working together to further develop and promote the practice of IO and raise awareness of the benefits of this discipline amongst both patients and medical providers.

“We are thrilled to enrol the first patient in DOORwaY-90,” comments Mark A Turco, global chief medical officer and EVP of research and development, Sirtex. “This clinical trial studying a heterogeneous population of patients with HCC using personalised dosimetry planning has the potential to advance the treatment of HCC patients worldwide.” With a planned enrollment of 100 patients across 15 sites both academic and non-academic, DOORwaY-90 is enrolling patients with Barcelona Clinic Liver Cancer (BCLC) Stage A, B1, and B2 who are not eligible for resection or ablation at the time of study entry. The study is the first FDA-approved US-based prospective trial to utilise and delineate personalised dosimetry treatment planning and to define actionable post-treatment dosimetric

verification for endpoint assessment. “It is important for physicians to have confidence that their planned Y-90 dose is being delivered in the right amount and to the right place,” says Douglas Murrey (Inland Imaging Associates and Providence Sacred Heart Medical Center, Spokane, USA). “The personalised dosimetry component of the DOORwaY-90 study will provide meaningful insights to advance our practice and patient outcomes.” HCC is often diagnosed when potentially curative resection or transplantation is not feasible. SIRT has the potential to deliver a lethal dose of radiation to hepatic tumours, while sparing surrounding healthy liver tissue. In countries outside the USA, SIRT has been successfully used to bridge patients to transplantation or downstage HCC to within transplantation criteria/ resection.

June 2021 | Issue 82

Updates in ablation

COLDFIRE 2: IRE is safe, effective in patients unsuitable for thermal ablation or surgery Continued from page 4

successful treatment for a larger population of difficult-to-treat patients— namely those with centrally located tumours and those with tumours between 3 and 5cm in diameter.” He continues: “Although the populations were relatively small and will require further confirmation, these data suggest that IRE techniques may enable adequate coverage to expand the range of successfully treated tumours. Some of these benefits may be due to synergistic effects between IRE and the chemotherapy administered in a majority of patients. Combination therapy between thermal ablation and induction chemotherapy—administered systemically or by means of chemoembolization—has demonstrated results that can even outperform surgery. “Further research and collective experience are warranted if we are to achieve the best clinical results possible. […] The final results of COLDFIRE-2 have been long anticipated and are of great interest to interventional, medical, and surgical oncologists and the patients we serve.” Secondary aims included safety, technical success, local control allowing

for repeat procedures, disease-free status, and overall survival. The per-tumour one-year local tumour progression-free survival rate was 79% (95% CI: 68%, 88%). Median distant progression-free survival was 5.3 months (95% CI: 2.5, 8.1). The most frequent site of first recurrence was the liver; median extrahepatic progression-free survival was 12.5 months (95% CI: 5.9, 19.1). Median overall survival from was 2.7 years (95% CI: 1.6, 3.8) from the first IRE and 4.8 years (95% CI: 3.1, 6.6) from the date of resection of the primary tumour. The study authors detail that after repeat procedures, local tumour control was achieved in 74% of participants (37 of 50 patients). They expand: “Six participants were considered unsuitable for local repeat treatment at first local tumour progression because of coexisting distant disease progression, making local treatment futile”. Local control was not achieved in two participants despite multiple attempts to eradicate the tumours. Recurrences were treated with repeat IRE (n=12), thermal ablation (n=three), stereotactic body radiation therapy (n=three), or selective

Prior ablation therapy predictor of increased Y-90 uptake: The road to personalised dosimetry at SIR Delineating the path towards personalised dosimetry in order to “maximise response to therapy”, David McNiel (University of Arizona Health Sciences, Tucson, USA) presented clinical predictors of yttrium-90 (Y-90) uptake in patients with hepatocellular carcinoma (HCC) at the 2021 meeting of the Society of Interventional Radiology (SIR; 20– 26 March, online). In the presented research, a multiple regression model demonstrated that prior ablative therapy was a significant predictor of an increased tumour-to-normal ratio (T:N) for Y-90 uptake. “RADIOEMBOLIZATION WITH Y-90 microspheres is a commonly-performed procedure for the treatment of HCC,” he began. “Methods for calculating prescribed activity can be divided into two categories: semi-empirical methods and partition model.” Due to the prior success of the DOSISPHERE-1 trial, which reported improvement in tumour response rate and overall survival in patients who had HCC treated with Y-90 radioembolization utilising personalised dosimetry, McNiel and colleagues conducted a retrospective institutional review board-approved study on all patients who underwent planning angiography with SPECT-CT for radioembolization of HCC between

internal radiation therapy preferably claim minimum (n=one). In a comparison of volume thresholds” for the first five versus the next 45 performing IRE. participants, the eventual local Cox regression analysis tumour progression rate was showed no statistically 80% (four of five) versus 33% significant difference in local (15 of 45) (p=0.06). Meijerink, tumour progression-free survival Ruarus, and colleagues state Martin Meijerink between small and mediumthat, although this did not reach size tumours (hazard ratio, 1.7; statistical significance in their study, “the p=0.22). Therefore, Meijerink, Ruarus, local tumour progression rate of 80% et al speculate that technique efficacy versus 33% in the first five versus the may be less susceptible to size with IRE, next 45 participants strongly suggests in which tumours are bracketed by the that IRE is dependent on operator electrodes, compared with single-probe experience.” thermal ablation. They determine that, in their opinion, The overall complication rate was this “underlines the necessity to set up 40%: 23 participants experienced a total dedicated training programmes and of 34 adverse events in 25 of the 62 procedures. The most common grade 3 adverse events were de novo biliary obstructions (n=3), periprocedural cardiac arrhythmias (n=4), and portal vein thrombosis (n=3). Two participants experienced a grade 4 adverse event. One participant (2%), who an an infected bilioma after IRE, died fewer than 90 days after the procedure— classified as a grade 5 event. “Our higher complication rate can be partially explained by our prospective study design and allowance for simultaneous procedures during IRE. [...] Therefore, not all reported adverse events are likely to be related to the IRE procedure itself,” Meijerink, Ruarus, and co-authors write.

The local tumour progression rate of 80% vs. 33% in the first five vs. the next 45 participants strongly suggests that IRE is dependent on operator experience.”

9 January 2016 and 31 August 2020 (n=106, over a total of 128 angiography procedures). All patients had pre-procedural contrast-enhanced MRI evaluations of the abdomen. According to the speaker, a multitude of patient characteristics were also collected from the electronic medical record for inclusion in analysis. MR, cone beam CT (CBCT), and SPECT-CT images were exported to SimpliciY90 image-fusion and dosimetry planning software (version 2.2; Mirada Medical) for evaluation. “Our initial hypothesis with this work was that T to N ratio would be significantly correlated with the aetiology of the patient’s cirrhosis,” McNiel explained. “Surprisingly, however, this was not the case, and despite the apparently diverse group of patients that go on to develop HCC, including patients with NASHbased [non-alcoholic fatty liver disease] cirrhosis, viral aetiologies of cirrhosis, and alcoholic cirrhosis, none of these groups demonstrated significant differences in T:N ratio in our dataset. “Similarly, clinical factors that we anticipated would likely have correlation with T:N ratio, including ChildPugh classification, prior surgical resection, and prior systemic therapy also demonstrated no significant differences in T:N ratio in our dataset.” Turning to the positive results of their study, McNiel detailed how prior intra-arterial liver-directed therapy (including previous Y-90, transarterial chemoembolization [TACE], and/or ablation therapy) demonstrated significant positive correlation with T:N ratio with their dataset. In addition, tumour volume, while not significantly correlated, showed “a strong negative trend”; larger volumes of tumour took up less macroaggregated albumin (MAA) activity than their smaller counterparts. “This finding is likely artefactual, based on our methodology, as larger tumours are more likely to contain necrotic, poorly-perfused components, and, thus,

they are likely to take up less relative MAA than their smaller counterparts.” Patient age was negatively correlated with T:N ratio by univariate analysis. However, with multivariate analysis, the investigators found non-significance between the two variables. A subgroup analysis of patients who had undergone prior liver-directed therapy “also demonstrated interesting results,” McNiel continued. Patients who had prior liver-directed therapy could be divided into two groups, he explained: those who had undergone intraarterial directed therapy, in the form of Y-90 or TACE, and patients who had prior ablation therapy. “Interestingly, patients who had prior intra-arterial therapy demonstrated no significant difference in T:N ratio, whereas patients who had prior ablation therapy demonstrated a strong significant difference in T:N ratio,” SIR attendees heard (mean 3.39 vs. 2.25; p=0.003). “These findings raise interesting questions,” McNiel concluded. “Is there some different mechanism of ablation therapy versus intra-arterial therapy that affects this activity? Also, is recurrent disease following either of these therapies somehow inherently different in their angiogenesis or their aggressiveness that could explain these findings?”

These findings raise interesting questions. Is there some different mechanism of ablation therapy vs. intra-arterial therapy that affects this activity?”

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June 2021 | Issue 82

Ablation-confirmation software

Ablation-confirmation software must become the new normal for IRs to be competitive with surgeons Luigi Solbiati

on colorectal liver metastases that had undergone radiofrequency ablation (RFA),3 with volumetric assessment of the periablational safety margin performed with this software, it was proven that the safety margin assessment was the only independent predictor of local tumour progression, and that at least 90% of a 6mm circumscribed 3D safety margin was required to achieve complete ablation.

Ablation-confirmation software can be used in different modalities

Ablation-confirmation software like this can be used in different modalities. When ablations are performed in

surgical resection. In addition, this kind of software can trace out the ideal path to the portion of tumour to be retreated, thus significantly facilitating the completeness of the procedure. In the near future, it is hoped that such easily usable and extremely fast software will be increasingly employed in interventional departments. We are currently working to extend their applicability also to extrahepatic organs, such as the kidneys, lungs, lymph nodes, and prostate, as well as to MRI scans. In the end, it is important to point out that there is a perfect integration between the type of software described above, and one of the most attractive (if not the

Comment & Analysis “If interventional radiologists wish to become competitive with surgeons, the availability of software enabling the accurate comparison of pre- and post-interventional CT [computed tomography] or MRI [magnetic resonance imaging] scans must become mandatory and routinely employed,” Luigi Solbiati argues. He discusses the ablation-confirmation software he has developed with his team in Milan, Italy, and enthuses about the potential of artificial intelligence to refine and improve ablative outcomes in interventional radiology.

any studies in the literature have demonstrated that the outcome of any local tumoural treatments (be it surgery, ablation, or radiotherapy) is largely dependent on the technical success achieved, i.e. if the tumour has been completely or partially treated and, when the treatment is complete, if the peritumoural margins of normal parenchyma are sufficiently and homogeneously thick. Surgeons have always told interventional radiologists that one of the most significant—if not the most significant—differences between surgical resection and thermal ablation is the modality of assessment of technical success. While surgical specimens are sent to a different department (Pathology) to obtain an accurate assessment, for thermal ablation, technical success is monitored by the same interventional radiologist who performed the treatment (or by other colleagues in the same department). This is done through the comparison of pre- and post-interventional CT or MRI scans in side-by side juxtaposition. This method contains many possible sources of error and can be very challenging, even for experienced radiologists. In a recently published study,1 38 radiologists from many different countries (18 with considerable experience in percutaneous tumour ablation and 20 with limited experience) were asked to assess whether technical success and technical efficacy after thermal ablation of nine hepatocellular carcinomas (HCCs) in nine patients with known outcomes had been achieved using the traditional side-by-side juxtaposition of pre- and post-interventional CT scans. As many as 44.1% of cases per radiologist were misjudged and, more importantly, there was no significant difference between

the experienced and unexperienced radiologists. Consequently, if interventional radiologists wish to become competitive with surgeons, the availability of software enabling the accurate comparison of pre- and post-interventional CT or MRI scans must become mandatory and routinely employed. For this reason, over the last few years I have collaborated with colleagues on the development of a software with these characteristics (Ablation-fit; R.A.W. Srl, Milan, Italy). Our software is based on the automatic segmentation of liver parenchyma and major blood vessels, the semi-automatic segmentation and reconstruction of tumoural targets and post-ablation necrotic areas, and the non-rigid, fully automatic registration of pre- and post-ablation CT scans. This allows for the deformation of liver parenchyma section by section, based on the location of intrahepatic blood vessels, enabling us to achieve an extremely precise image fusion regardless of differences in body position, respiratory motion, or liver deformation. In addition, in a very short time (just five to 10 minutes), the software calculates the percentages of residual unablated volumes of both the target tumour and the predetermined 3D safety margin.

Data to date

In a retrospective study on 90 HCCs that have undergone microwave ablation (MWA) with apparent technical success and followed for at least one year, we demonstrated that, if we could have used this software, we would have discovered incomplete treatments at 24-hour CT scan (enabling immediate re-treatment) in 62% of the HCCs that actually had local tumour progression at one year.2 In a recently published clinical study

Screenshots from the Ablation-fit software.

In the near future, it is hoped that such easily usable and extremely fast software will be increasingly employed in interventional departments.” sonographic rooms under the control of contrast-enhanced ultrasound (US), potentially integrated with real-time US-CT/MRI image fusion, ablationconfirmation software like this can be used only after the end of the treatment. In this situation, a level of assessment closer to that achieved by pathologists after surgical resection can be obtained, but if incomplete treatment or insufficient ablative margins are seen, the procedure will have to be repeated, just as in surgery. On the other hand, if ablations are performed under ultrasound or CT guidance in the CT room (as is recommended nowadays),4 the software could be used immediately, intraprocedurally, and the treatment could be adapted in order to complete the intervention without the fear of only obtaining partial or insufficient ablative margins. This intraprocedural use represents an advantage even over

most attractive) incoming modalities for the guidance of any interventional procedure: augmented reality (AR).5 In addition to the already known and much discussed advantages of AR (its low cost, ergonomic feel, diminishment of the learning curve, particularly in younger users, the opportunities this technology provides for educational purposes), it can be particularly helpful for the guidance of interventional devices into incompletely treated tumoural areas, thanks to its ability to define precise trajectory lines that the operator can simply and automatically follow to reach the targets. The association of increasingly accurate and simple ablation-confirmation software and AR is likely a key milestone on our way to the (near) future of interventional radiology. Luigi Solbiati is an interventional radiologist t the Humanitas University in Milan, Italy. Disclosure: He is a developer of the Ablation-fit software. References 1. Laimer G, Schullian P, Putzer D, et al. Can accurate evaluation of the treatment success after radiofrequency ablation of liver tumors be achieved by visual inspection alone? Results of a blinded assessment with 38 interventional oncologists. Int J Hyperthermia 2020; 37: 1,362–1,367. doi.10.1080/02656736.2020.1857445 2. Solbiati M, Muglia R, Goldberg SN, et al. A novel software platform for volumetric assessment of ablation completeness. Int J Hyperthermia 2019; 36: 337–343. doi. 10.1080/02656736.2019.1569267 3. Laimer G, Jaschke N, Schullian P, et al. Volumetric assessment of the periablational safety margin after thermal ablation of colorectal liver metastases. Eur Radiol 2021. doi.10.1007/s00330-020-07579-x; Online ahead of print 4. Mauri G, Solbiati L, Orsi F, Monfardini L. Thermal ablation of liver tumours: The crucial role of 3D imaging. Cardiovasc Intervent Radiol 2020; 43(9): 1,416–1,417. doi.10.1007/s00270-020-02560-z 5. Solbiati LA. Augmented reality: thrilling future for interventional oncology? Cardiovasc Intervent Radiol, 2021. doi.10.1007/s00270-021-02801-9

Issue 82 | June 2021

ECIO 2021 coverage

ECIO

AB-LATE02 randomised trial to probe “synergistic” immunotherapy and ablation strategy for HCC A randomised trial will assess the efficacy of a combination of neoadjuvant atezolizumab, and adjuvant atezolizumab and bevacizumab with radiofrequency ablation (RFA) as a treatment option for patients with hepatocellular carcinoma (HCC). According to the principal investigator Boris Guiu (St-Eloi University Hospital, Montpellier, France), the treatment could improve recurrence-free survival (RFS) at two years, and may reduce the risk of distant recurrence due to the synergistic effects of the treatment strategies. GUIU OUTLINED THE RATIONALE FOR THE multicentre randomised trial—AB-LATE02—taking place in 16 centres across France, during a live “Meet the PI” session at the 2021 European Conference on Interventional Oncology (ECIO, 10–13 April, online). Ablation has become the first curative treatment for HCC, Guiu told attendees to the session, commenting that its use has increased steadily from 2013 to the present day. Discussing published RFA data, however, he identified two problems. Firstly, the incidence of

local recurrence, which occurs in between 5–20% of AB-LATE02 will assess the treatment of small HCC cases, and predominantly relates to the ability to obtain (<3cm). In the standard arm, patients will be ablated adequate margins around the tumour. “This is probably using RFA, with follow-up carried out as normal. In the more of a technical than an oncological problem,” Guiu experimental arm, patients will undergo an induction said. Furthermore, he noted that intra-hepatic distant with neoadjuvant atezolizumab, then ablation, and then recurrence occurs very frequently—in around 60–80% treatment with the combination of atezolizumab and of cases—and the debate is often whether its origin is a bevacizumab for one year. metastases or a de novo HCC. The trial’s primary endpoint is RFS at two years, Guiu detailed the publication of a recent which Guiu said the study will aim to paper from his centre, which aimed to look extend to 65%, compared to 45% seen at factors that may explain the presence in current literature. The study will of distant recurrence, including patient-, enrol a total of 202 patients, who will be disease-, and tumour-related factors. randomised 1:1 to either the experimental or “We only found two factors associated standard treatment arm. with distant recurrence,” Guiu said, adding “What is important is that in addition to that these were alpha-fetoprotein (AFP) and the primary endpoint we have to look to Boris Guiu tumour size. “In a way, these factors reflect overall survival at five years, because we the aggressiveness of the tumour and are have the chance to change the game in these more in line with the concept of metastases, at least patients based on the results of this trial,” said Guiu. during the first two years.” Further data show that de The trial will also assess quality of life (QoL). Guiu novo HCC are probably more frequent, he noted. explained: “We include QoL in this trial because it is In the case of a distant recurrence, there is a high very important to see if there is any impairment. In risk that the patient cannot be treated using a curative the experimental arm, we not only have ablation, but approach, Guiu added, meaning that the need to fight every three weeks the patient must go to the hospital to against metastatic escape and tumour growth becomes get immunotherapy, and this is something we need to increasingly important. look at and see if the balance, even if the trial might be “There is a drift to palliative care, there is a drift positive, is positive for the patient.” to a palliative prognosis, and this is probably the key Finally, a comprehensive translational study is time where the patient is losing a good prognosis. We full part of the trial and notably includes immunohave to fight against this incidence of intra-hepatic monitoring, circulating tumour DNA (ctDNA) distant recurrence and this a very important rationale to exome analysis, and peripheral blood mononuclear support the trial.” cell (PBMC) based on serial biological and tissue A “new challenger” has recently entered the field assessments. of advanced HCC, Guiu said—the combination of At the time of the presentation, Guiu said that atezolizumab and bevacizumab, which he said show enrolment had already begun in three participating “synergistic effects”. The emergence of this treatment centres, and he anticipated that this would be the case creates a strong rationale to combine immunotherapy in all 16 centres by the end of April 2021. Results are and ablation, Guiu added. expected from 2025.

Provider support central to coherent IR COVID-19 response plan, ECIO audience hears In setting up an interventional radiology (IR) COVID-19 response plan, “the most important initial step is to recognise the problem,” stated John A Kaufman (Oregon Health & Science University, Portland, USA) at this year’s European Conference on Interventional Oncology (ECIO; 10–13 April, online). Based on the experience of one US institution, the presenter conveyed various crucial factors, stressing in particular the importance of supporting providers, the impact on whom will be “long lasting”. “OUR RESPONSE TO COVID-19 has evolved over time,” Kaufman began, noting an initial “very inwardfacing approach”, focusing on personal protective equipment (PPE), workflow, personnel, and case selection. Subsequently, he explained, the plan became more “outward facing”, focusing in more detail on issues such as testing, staffing, hospital case-loads, and policies. Provider support ran parallel to these two main stages. The first step was to recognise the issue, said Kaufman, noting that this was complicated by the US political environment. He recounted: “Maskwearing was a political statement rather than a healthcare concern”. What followed was the founding of a cross-

establishment professional leadership group, including physicians, nurses, technologists, and managers, he detailed. During the “inward-facing” phase of the IR response, PPE and testing were top priorities, both of which were of limited supply. Decisions on workflow, including which sites to keep operational, how many dedicated COVID-19 rooms were necessary, and room turnover for COVID-19-positive patients, were all addressed during this stage. Finally, all office and support workers began to work remotely, and provider schedules were adapted to minimise exposure. “Case selection became very important,” Kaufman noted, detailing that it was important for the institution to

observe state and national rulings, such as the ban of all elective cases in Oregon initiated in March 2020. During the early months of the pandemic, operating room (OR) volume dropped by 90%, compared to a 30% drop in IR volume, the presenter reported, attributing this to there being “few truly elective cases” in IR. Meanwhile, emergent cases, as well as all cancer treatment, continued. The presenter detailed a “silver lining” of this early phase of the pandemic as being the increased availability of anaesthesia resulting from OR closures. In the discussion following Kaufman’s presentation, session moderator Otto van Delden (Amsterdam University

Keep in mind the impact on providers will be long-lasting.” Medical Center, Amsterdam, The Netherlands) remarked that, in Europe, the number of IR procedures performed fell “considerably”, and to a level far lower than in the USA, due to a lack of anaesthesia support. van Delden was keen to know what impact a good supply of anaesthesia had on case load, with Kaufman responding that the team noted that, as well as IR cases, they were also treating patients who would normally

have been treated surgically. In the “outward-facing” phase of the team’s COVID-19 response, the first “big issues” were PPE, testing guidelines, and isolation rules, Kaufman communicated. In addition, staffing shortages became a major issue, with reassignments and travel restrictions having an ongoing impact. The availability of staff, as well as of intensive care unit (ICU) beds, determined elective admissions and saw a shift of cases to partner hospitals. Finally, Kaufman stressed the importance of provider support in a successful IR COVID-19 response plan. There are numerous factors that needed to be addressed, he detailed, noting a fear of infecting family members, problems finding childcare and the demands of home-schooling, reduced incomes, isolation, the loss of friends and family members, working longer hours, and treating sicker patients. “Faculty and families may need to adjust priorities,” Kaufman commented, noting for example the need to change jobs to be closer to family. Other important ways in which the pandemic has affected providers included reduced caseload for learners, decreased academic productivity—which he noted has disproportionately affected women—and the proliferation of virtual meetings and conferences. “Keep in mind the impact on providers will be long-lasting,” he concluded.

June 2021 | Issue 82

10 Stereotactic radiofrequency ablation

Stereotactic RFA allows IRs to predict ablation success intraprocedurally Volumetric assessment of the periablational safety margin can be used as an intraprocedural tool to evaluate local treatment success in patients with colorectal liver metastases referred to stereotactic radiofrequency ablation (SRFA), a recent study in European Radiology concludes. This could replace the visual side-by-side evaluation of periablational safety margins, the investigators suggest, which is “challenging, even for experienced radiologists”. Authored by Gregor Laimer, Reto Bale (both Medical University Innsbruck, Innsbruck, Austria) and colleagues from Dresden (Germany), Milan (Italy), Jerusalem (Israel), and Boston (USA), the report offers an objective tool that enables the immediate, real-time determination of the extent and percentage of the safety margin requiring ablation, enabling the reliable prediction of procedural outcome success. “ABLATIONS WITH [A] 100% three-dimensional (3D) periablational safety margin of 3mm and ablations with at least [a] 90% 3D safety margin of 6mm can be considered indications of treatment success,” the study authors report. They further conclude that their results indicate image fusion of pre- and post-interventional computed tomography (CT) scans with the Ablation-fit software is feasible, and “could represent a useful tool in daily clinical practice”. SRFA takes a multiple-needle approach, utilising 3D treatment planning, stereotactic needle placement, and image fusion for the intraoperative assessment of the periablational safety margin. According to Laimer, Bale et al, in some centres, this technique can overcome the limitations associated with standard radiofrequency ablation (RFA). They write: “Several studies have reported that the periablational safety margin, defined as the shortest distance between tumour border and margin of the necrosis zone, independently predicts the local tumour progression in colorectal liver metastases, whereby ablations with safety margins >5–10mm exhibit lower local tumour progression rates [a

better outcome]. In conventional CT or ultrasound-guided RFA, the creation of large necrosis zones extending 5–10 mm beyond tumour borders is often hampered by technical limitations, especially for larger tumors (i.e. >3cm), which may result in local tumour progression ranging from 4–70%. In contrast, these limitations have been overcome in some centres with stereotactic thermal ablation.” In total, 45 patients with 76 colorectal liver metastases between them were treated with SRFA and analysed in this study. During image fusion of pre- and post-interventional contrast-enhanced CT scans, Laimer, Bale et al used a software with non-rigid registration (called Ablation-fit) to assess the percentage of predetermined periablational 3D safety margin and colorectal liver metastases successfully ablated (i.e. with no evidence of residual tumour tissue). Periablational safety zones (1–10mm) and percentage of the periablational zone ablated were calculated, analysed, and compared with subsequent tumour growth to determine an optimal safety margin predictive of local treatment success.

Presenting their results, Laimer, Bale, and colleagues relayed that the mean overall follow-up was 36.1±18.5 months. Nine of 76 colorectal liver metastases (11.8%) developed local tumour progression; the mean time to local tumour progression was 18.3±11.9 months. Overall one-, two-, and three-year cumulative local tumour progression-free survival rates were 98.7%, 90.6%, and 88.6%, respectively. The periablational safety margin assessment proved to be the only independent predictor (p<0.001) of local tumour progression for all calculated safety margins. The smallest safety margin that was 100% ablated and that displayed no local tumour progression was 3mm, and at least 90% of a 6mm, circumscribed 3D safety margin was required to achieve complete ablation.

We [have] established the periablational safety margin as the only predictor of local tumour progression in patients with colorectal liver metastases treated with SRFA.” “With this work, we confirm prior reports demonstrating the importance of achieving a periablational margin for ablation, as we too established the periablational safety margin as the only significant predictor of local tumour progression in patients with colorectal liver metastases treated with SRFA,” the study investigators write in their discussion. “Apart from the periablational

safety margin, no other conventional risk factor such as age, gender, tumour size, tumour location, or previous therapies significantly influenced local tumour progression. Importantly, this observation held true for all calculated 3D safety margins, namely, 1–10mm. Yet, in our study, the smallest safety margin displaying no local tumour progression for ablations with 100% circumscribed 3D safety margin was 3mm (0/55 [0%] target tumours). “This indicates that an ablation with a 100% circumscribed 3D safety margin of 3mm can be considered successful at the time of the intervention. Given that larger volumes of ablation are more difficult to achieve, this may represent an improvement when considering that previous studies recommend a periablational safety margin of at least 5mm, with better results only seen with a 10mm periablational safety margin for colorectal liver metastases. One possible explanation for this discrepancy might be the exact image fusion and volumetric safety margin assessment achieved with the non-rigid registration software used for this study. Regardless, the small but precise margins in our study may actually represent larger volumes given known tissue shrinkage during ablation.” Speaking to this newspaper, Bale adds: “Another explanation for this discrepancy may be related to the fact that deformation of the datasets for image fusion during stereotactic thermal ablation (intraprocedural arterial and portalvenous phase planning and control CTs) is mimimised by respiratory triggering. This is achieved by temporary disconnection of the endotracheal tube and full muscle relaxation.” Noting that this study is retrospective in design and is reliant on the experience of a single centre, and also that there is “scarce use of stereotactic approaches in the ablation of liver malignancies” outside of the Medical University in Innsbruck, Laimer, Bale, et al hope that their work aids in generating further interest in this technique.

INTERVIEW

SRFA pioneer calls on interventional radiologists to start training now, “before it is too late”

Exactly 20 years on from his first stereotactic radiofrequency ablation (SRFA) procedure to treat a cancerous liver tumour, Reto Bale (Medical University Innsbruck, Innsbruck, Austria) speaks to Interventional News about the future of this procedure, and warns interventionalists that this may be the next arena for a potential turf struggle: interventional radiologists should start learning now, he urges, as, in his view, “90% of current liver

resections could be replaced by SRFA”. At Bale’s institution, proceduralists are able to use up to 36 coaxial needles to ablate tumours, achieving results that rival those of their surgical counterparts, leaving no residual mass behind.

When did you first start using this approach?

The story begins in 1994, when I was using navigation systems in ENT and neurosurgery. Back then, as a student, I developed a few things together with my student fellow Michael Vogele: We had a patent for a navigation device and a head fixation device, amongst other technologies. In 1995 I developed the first aiming device initially for neurosurgical work. I wanted to expand beyond neurosurgery, because I wanted to use navigation not just in the brain, but everywhere. That was why I moved to interventional radiology (IR), and in 1996, as an assistant doctor, I set up the Stereotactic Interventional Planning (SIP) lab in Innsbruck, Austria.

I think stereotaxy is the ideal tool for radiofrequency ablation (RFA). The problem is that there is often a discrepancy between the tumour volume and the ablation volume. This is the reason for recurrence. The simple solution to this is to use multiple coaxial needles. However, although the idea is simple, it is difficult to place multiple coaxial needles in order to ablate the entire tumour volume with conventional ultrasound (US) and computed tomography (CT) guidance. This is why, in my opinion, using stereotaxy is the way to go. We did the first procedure in the liver in May 2001. I am sure that the way we do radiofrequency ablations has to change—I have always been sure, but when we started this everyone said ‘Oh that crazy Austrian, advancing 10 needles into the body!’ But now, 20 years later, people have changed their minds.

What value does stereotaxy add to radiofrequency ablation?

SRFA helps you not only to guide the needles and

Issue 82 | June 2021

Stereotactic radiofrequency ablation 11

visualise placement, but to plan the procedure as well. In most cases, you need multiple overlapping zones in order to ablate the complete volume. Even with microwave ablation (MWA), the maximum short ablation diameter is approximately 3.6cm. So, if a lesion is larger than 2–3cm, it is very difficult to achieve an adequate ablation margin; you need overlapping ablation zones.

How do results from SRFA compare with surgical outcomes?

It [SRFA] is actually better than surgery! From our results, it is at least as good as surgery in terms of local control rates, and it is dramatically less invasive, of course, and parenchyma-sparing. There is no doubt in my mind: if you can ablate the lesion completely, why would you do a resection? No patient would like you to open them up if there was a less invasive option with comparable outcomes. In 2019, myself and several colleagues published a retrospective study in Hepatology that evaluated the efficacy of three-dimensional (3D)-navigated, multiprobe radiofrequency ablation (SRFA) with intraprocedural image fusion for the treatment of hepatocellular carcinoma (HCC) by histopathological examination. From 2009 to 2018, 97 patients were transplanted after bridging therapy of 195 HCCs by SRFA. The rate of residual vital tissue could be assessed in 188 Clockwise from top left: Coaxial needles in place. Native CT with coaxial needles in place. Image fusion for of 195 lesions in 96 of 97 patients by histological verification of precise coaxial needle positions. Three RFA probes are introduced into the coaxial needles. examination of the explanted livers using haematoxylin and eosin (H&E) and Tdt-mediated UTP nickend labeling (TUNEL) stains. Histopathological take a representative specimen. But when we use image is necessary that more interventional radiologists have results were compared with the findings of the last fusion, it is a 3D tool, so we can assess the margin in this training. CT imaging before liver transplantation. Complete all dimensions. The good thing is that, though it was initially radiological response was achieved in 186 of 188 This allows us to be adaptive intraprocedurally. If challenging, now we have so much experience. We nodules (98.9%) and 94 of 96 patients (97.9%), and we do not achieve the ablation zone, and we have some have many standards of practice; it is much easier to complete pathological response in the explanted liver residual tumour, we can put another needle into the train someone to do SRFA than it is to perform liver specimen in 183 of 188 nodules (97.3%) and patient. surgery, for example. I have a colleague who has 91 of 96 patients (94.8%), respectively. In In our tumour board meetings, the first completed just three months training, and then he did lesions ≥3cm, complete tumour cell death question used to be “Is it resectable?” Now the a procedure completely alone, with great results. My was achieved in 50 of 52 nodules (96.2%). first question is—in most cases—“Is it ablateother colleague has been training with me for a year, Residual tumour did not correlate with able?” But this is only at Innsbruck! I hope it and he performs extremely complicated procedures that tumour size (p=0.5). will change around the world—this is just the no one else does in the world, outside of Innsbruck. We therefore concluded that multiprobe start for SRFA. A very important point: you can do a lot of training SRFA with intraprocedural image fusion without even touching a patient, because we have Reto Bale represents an efficient, minimally invasive What are the barriers to this such extensive datasets, with information (such as CT therapy for HCC, even with tumour sizes larger than being adopted at other institutions? images) available. So you can train if you want on 3cm, and without the need of a combination with Getting the word out! Our problem is that we do not more than thousand patients before you start with real additional treatments. For us, the results justify the get refunds for the additional effort. Our department patients! That is really cool, because the path planning additional efforts related to the stereotactic approach. gets money for the ablation probes, like you would is the most difficult part. A very interesting thing about SRFA is that image need for an US- or CT-guided intervention, which is It is quite easy to use the navigation system to place fusion is part of the procedure. Image fusion is now— completely different from SRFA. We need support a needle; I will turn you into an expert in two weeks, now [Bale’s stress]—a key issue. We have been doing from insurance companies, and they will only finance with that, as long as you have some experience with this for 20 years. this if there are enough data. Currently, we only ablation already. But it is difficult to make the path have data [on SRFA’s safety, efficacy and long-term plan; this can be learned in the virtual dataset. My What developments would you like to outcome] from our institution. aim is therefore to teach interventionalists with these see in image fusion? We have a prospective database. It includes more datasets; I think we could make something big happen Firstly, we use image fusion to check the accuracy of than 1,000 SRFA patients with more than 4,000 tumors here. needle placement. We do two CT scans: a planning CT, treated by SRFA over the last 20 years. It is linked It is extremely important that interventional before we place any needles, and a control CT, which to the hospital’s record of patient files, so it is hard radiologists start now, before it is too late, because I is taken with the needles in place. This native dataset is data that is very transparent and auditable. All of our know that otherwise the surgeons will start performing then superimposed onto the planning CT, and onto the replications are based on this registry. SRFA themselves. In my view, 90% of current liver virtual pathways we planned. Thereby, we can measure However, in order to support reimbursement for resections could be replaced by SRFA. If it is possible the accuracy of every needle. SRFA, insurance companies need to see prospective, to completely ablate the tumour and leave no residual The second step is the verification of the ablation randomised data—my next aim is therefore to conduct mass behind, then there is no argument for a more zone—we want to know if there is a sufficient a multicentre, prospective, randomised controlled study invasive procedure. ablation margin covering the tumour. This is to obtain these data and hopefully to get reimbursement extremely important, and very helpful. It is better for the procedure. What does the future look like than the pathological report the surgeons receive, for SRFA? for example. One week following surgery, they get a What would your advice be for My hope is that it will become a lot more common pathology report telling them if they have achieved interventional radiologists wishing to practice at several institutions around the world. R0 or R1, whereas we see this immediately, while do SRFA at their own centres? In addition, at Innsbruck, we aim to make the the patient is still under anaesthesia, and we see it Get in touch! I would be happy to assist them to set preprocedural path-planning process at least semiin three dimensions, not only in a two- dimensional up a programme. I have done it in Innsbruck, and it automatic, through the use of machine learning. We rendering. In most cases it is not possible for the works very well, so I would be delighted to assist. It is have just recently secured funding for a PhD candidate pathologists to look at the whole margin under the hard work at the beginning, organising the system and to get started on this work, so it will be exciting to see microscope, it would take far too long! So, they just teaching everyone the technical details, but I think it what they can achieve.

June 2021 | Issue 82

12 Embolization

IR community calls for postpartum haemorrhage response team due to “underutilisation” of UAE in review of 10 million births in the USA Despite lower mortality and shorter hospital stays, uterine artery embolization (UAE) is used far less commonly than hysterectomy in the management of clinically significant postpartum haemorrhage. This conclusion, presented at the Society of Interventional Radiology (SIR) annual meeting (20–26 March, online) by Janice Newsome (Emory University Hospital, Atlanta, USA), has led investigators to call for a postpartum haemorrhage response team, akin to a trauma response team. MD candidate Linzi Ardnt, also at Emory University Hospital, is the lead researcher for this work.

peaking to press ahead of the annual meeting, Newsome expanded on her vision: “When our ObGyn [Obstetrician and gynaecologist] colleagues make the decision to perform a hysterectomy, most of the time the estimated blood loss or the actual blood loss is under-calculated or unknown—so we are in a real dire situation at that point. “Interventional radiologists are at many of these hospitals as well. So I believe, in order for UAE to become more utilised in these situations, we need to develop more techniques so we can find out earlier what the actual blood loss is, mobilise a team of people early so that these women can actually have this procedure [UAE] done, before a hysterectomy is chosen at the last minute. We are advocating for forming a postpartum haemorrhage team, so we can train together with our colleagues in Ob-Gyn—I believe that then, we can save more lives.” Ardnt, Newsome et al picture the postpartum response team consisting of “anyone who cares for mothers and babies”, including anaesthesiologists, interventional radiologists, Ob-Gyns, and in some cases possibly neonatologists.

Contextualising this research, she stated: postpartum haemorrhage (defined as those “Unfortunately, roughly 100,000 mothers receiving a blood transfusion only or will experience significant postpartum transfusion plus hysterectomy or UAE). haemorrhage, a leading cause of the loss of They utilised univariate analysis chi-square life associated with childbirth”. The research testing to determine demographic and clinical identified 31 incidences of postpartum predictors of receipt of various therapies. haemorrhage per 1,000 live births in the Logistic regression was used to compare USA, of 9.8 million identified live births in mortality and prolonged length of hospital total. Janice Newsome stay (>14 days) for different treatment “Additionally,” Newsome continued, groups correcting for statistically significant “20% of new mothers will have no risk factors. Because predictors of receipt of various therapies. postpartum haemorrhage can occur quickly and The investigators noted that the incidence of threaten the life of the mother, the treatment options hysterectomy to treat postpartum haemorrhage was are sometimes limited. Currently, the most common significantly greater than incidence of UAE (20.4 vs. treatment is just a transfusion [with an average incidence 12.9; p< 0.001). The following factors predicted the of 116.4 per 1,000 cases of postpartum haemorrhage]. type of therapies received: race, maternal age, year of But because physicians must act quickly, in many cases, admission, elderly primigravida, previous or current the mother’s uterus is removed via hysterectomy.” caesarean section, breech position of foetus, placenta previa, pre-existing hypertension, pre-eclampsia, Uterine artery embolization is eclampsia, gestational diabetes, post-date pregnancy, “underutilised” premature rupture of membranes, cervical laceration, UAE represents an “underutilised”, less invasive uterine rupture, dystocia, forceps delivery and second option, she explained, going on to note that the haemorrhagic shock (all p<0.001). procedure has the benefit of being uterus-sparing, with Newsome noted: “We saw this disparity [between the quicker recovery times, and fewer adverse events. number of hysterectomies and the number of UAEs] The study investigators therefore set out to evaluate across racial lines and geography as well. Hysterectomy the utilisation and comparative effectiveness of was twice as common as embolization in Latinx hysterectomy versus UAE in patients with clinically patients, and also more common in rural and nonsignificant postpartum haemorrhage requiring blood teaching urban hospitals, as well as in the South [of the transfusion. USA], and among Medicare and self-paying patients. Using the Healthcare Cost and Utilisation Project “Additionally, prolonged hospital stays of more than Nationwide Inpatient Sample database from 2005 14 days were twice as likely [2.1 times more likely with through 2017, they identified all women with livehysterectomy than UAE; p<0.001] in patients who had birth deliveries who experienced clinically significant hysterectomies, and the hysterectomy procedure resulted in higher hospital charges—around US$18,000 more than if it were for UAE,” Newsome commented. On logistic regression, the likelihood of mortality from hysterectomy was 3.1 times that of UAE (p< 0.001). “Because of the evidence supporting UAE and the benefits it provides to patients, we encourage hospitals to provide this treatment option to these women who may be at risk from postpartum haemorrhage. To do this, hospitals can create postpartum haemorrhage teams with an interventionalist, similar to other trauma teams, where we would train together and develop response protocols so they are better able to identify the risk factors of postpartum haemorrhage and ensure that the proper staff is on hand, for any delivery, and to be able to respond quickly, so that we can save mothers’ lives before it goes too far, to the point where radical surgery is needed.”

Because of the evidence supporting UAE and the benefits it provides to patients, we encourage hospitals to provide this treatment option to these women who may be at risk from postpartum haemorrhage.”

Transhepatic portal venous stent placement “effective” for the prevention of hepatic complications

hepatic artery; grade 3, ≥4 segmental hepatic artery). Transhepatic portal vein stent placement was performed in the same session in five patients (11.9%) with poor hepatic artery collaterals (grade 1 or 2) and compromised portal venous flow (>70% stenosis). Hepatic ischaemic complications were analysed for relevance to hepatic artery collaterals

After hepatic artery embolization, preserved flow (≥4 segmental hepatic artery) lowered the risk of hepatic complications regardless of the portal venous flow. This is the conclusion presented by Won Seok Choi, Chang Jin Yoon (both Seoul National University Bundang Hospital, Seongnam, Korea), and colleagues in the Journal of Vascular and Interventional Radiology (JVIR). THE INVESTIGATORS SET OUT to determine the association between hepatic ischaemic complications and hepatic artery collaterals and portal venous impairment after hepatic artery embolization for postoperative haemorrhage.

Between October 2003 and November 2019, 42 patients underwent hepatic artery embolization for postoperative haemorrhage. Hepatic artery collaterals were classified according to hepatic artery visualisation after embolization (grade 1, none; grade 2, 1–4 segmental

Drug-eluting beat transarterial chemoembolization (DEB-TACE)

and portal venous compromise. Following hepatic artery embolization, hepatic artery flow was preserved (grade 3) through intra- and/or extrahepatic collaterals in 23 patients (54.8%), and hepatic complications did not occur regardless of portal venous flow status (0%). Of the 19 patients with poor (grade 1 or 2) hepatic artery collaterals (45.2%), segmental hepatic infarction occurred in two out of 15 patients with preserved portal venous flow (10 naïve and five stented; 13.3%). The remaining four patients with poor hepatic artery collaterals and untreated compromised portal venous flow experienced multisegmental hepatic infarction (n=three) or hepatic failure (n=one) (100%; p<0.005). “Transhepatic portal venous stent placement seems to be an effective intervention for the prevention of hepatic complications in cases of poor hepatic artery collaterals and compromised portal venous flow,” Choi et al conclude.

Issue 82 | June 2021

Advertorial 13

THIS ADVERTORIAL IS SPONSORED BY PHARMACEPT

Degradable starch microspheres offer greater flexibility with TACE, enabling whole-liver embolization Andreas H Mahnken (Clinic of Diagnostic and Interventional Radiology, Marburg University, Marburg, Germany) enthuses to Interventional News about the potential of degradable starch microspheres (DSM) in transarterial chemoembolization, specifically drawing on his 20 years’ experience with DSM particles (PharmaCept). Indicated for chemoembolization of primary and secondary liver and lung tumours, EmboCept S DSM 50µm are the best-calibrated DSM available, ensuring good vasculature penetration and with a flexible application.

What is DSM-TACE and in which indications is it used?

or in the bronchial arteries, so DSM-TACE has a really broad scope of indications. Our main focus in my department is for liver metastases and primary liver cancer, but we also use it for lung cancer.

Besides drug-eluting bead transarterial chemoembolization (DEB-TACE) and conventional transarterial chemoembolization (cTACE), there is a subset of TACE called DSM-TACE, where What are the differences you use degradable starch microspheres between DSM-TACE and roughly 50µm in size. These microspheres Andreas H Mahnken cTACE/ DEB-TACE? have a half-life of approximately 35 You have fewer limits. You can combine minutes, which means they are only around for a the procedure with any drug—not only, for example, couple of hours at most. This allows you to re-access doxorubicin or epirubicin, but you can really use it the same vessel for repeated TACE. The half-life is also with any cytostatic that can be given intra-arterially, short enough to prevent the proliferation of growth also in combinations, so it allows you to be much more factors such as VEGF [vascular endothelial growth flexible. That gives you a broader range of indications. factor], which usually enter the bloodstream after a few DSM-TACE also has excellent tolerability, so the hours of ischaemia. One of the major advantages of patient experiences less pain. You can even perform a [microsphere] degradability is that you do not have this whole organ embolization with limited pain, which is additional vascular growth. There are actually no pretty advantageous for the patient. It is much betterlimits to the indication within the liver, and you can tolerated by the patient in terms of liver function and also use the degradable starch microspheres in the lung degradation, as well as in terms of pain. You can do it for transpulmonary chemoembolization (DSM-TPCE) even in organs that would be critical for a cTACE or a

Case report

Cholangiocarcinoma is a highly lethal hepatic neoplasm with a median overall survival rate of about 16 months (Waseem 2017). Even after resection, the prognosis is poor, with reported three- and five-year survival rates after resection for perihilar cholangiocarcinoma (pCCA) of around 45% and 30% (Cillo 2019). In unresectable pCCA, common treatment options included chemotherapy with gemcitabine and cisplatinum, and transarterial chemoembolization (TACE).

Figure 1. Pre-TACE MR imaging depicts a progressive, map-like mass in the right liver lobe, which was proven as part of the pCCA.

Figure 2. Diagnostic catheter angiogram reveals a stenosis of the celiac trunk with distinct collaterals from the superior mesenteric artery.

Figure 3. For whole liver DSM-TACE a microcatheter is placed in the proper hepatic artery.

Figure 4. Eight months after treatment the tumour markedly decreased.

Patient history

A 78-year-old female patient suffering from unresectable pCCA (Bismuth IV) was referred to our interventional radiology clinic for treatment after failure of first line chemotherapy. Magnetic resonance (MR) imaging revealed progression of the histologically-proven massforming pCCA, with multiple new histologies proving the presence of intrahepatic tumours and no extrahepatic tumour (Fig. 1). On clinical examination, the patient was considered fit for interventional therapy. Laboratory testing showed mild anaemia and a moderately-elevated alkaline phosphatase. Her renal function was normal. She had previously undergone endoscopic biliary stenting, so her bilirubin was normal. We opted for a treatment with TACE and adjuvant capecitabine (Kelley 2020).

Interventional therapy

Our TACE protocol for cholangiocarcinomas includes a so called DSM-TACE with 300mg degradable starch microspheres (EmboCept S DSM 50µm, PharmaCept, Berlin, Germany) combined with intra-arterial application of 75mg/m2 Cisplatinum (PlatiCept, PharmaCept, Berlin, Germany) and Gemcitabine (1,000mg/m2). In addition, a

premedication for nausea, pain, and a single shot of intravenous (IV) antibiosis in case of biliodigestiveanastomosis or stenting. Diagnostic catheter angiography at the beginning of the first treatment session showed a fixed high-grade stenosis of the celiac trunk with subsequent collateral flow from the superior mesenteric artery (Fig. 2). For whole liver treatment, a 2.7F microcatheter was placed in the proper hepatic artery and DSM-TACE with flow-

DEB-TACE, so it gives you more flexibility—that is really the key for me. If you have a patient with an organ that is already limited, for example a patient with cirrhosis, who then develops multinodular hepatocellular carcinoma (HCC), you may be concerned about having to treat multiple places in the liver. For example, with cTACE, there may be a limit because the function of the organ is not enough to allow treatment of all the tumours, but with DSM-TACE you can embolize all these tumours in a single session, and you will come out with enough remaining liver function to make sure that the patient can tolerate the procedure. In terms of efficacy, it is excellent.

Are there any limitations using DSMTACE?

To the best of my knowledge there are no limitations. You can even combine it with cTACE; there is a very small prospective randomised trial that combines DSMTACE with cTACE. That is another opportunity.

What are the future applications of DSM-TACE?

Future applications could include combining DSMTACE with systemic or even regional immunotherapy—it can be combined with many new drugs. We are living in the time of immunotherapy, and DSM-TACE can be combined with several immune modulators. I feel that this is a really exciting possibility. We have preclinical data that shows us that there is T-cell homing in the tumour after DSM application, so that would be an ideal target for immune modulators, not only interleukins but modern drugs as well. I feel that is one of the greatest potentials DSM-TACE has for the next decade. controlled slow infusion of the chemotherapeutics was performed (Fig. 3). Unlike in conventional TACE (cTACE), drugs were infused over a 30-minute period in order to minimise gastrointestinal toxicity in terms of nausea and vomiting. During administration of chemotherapy, EmboCept S DSM 50µm was repeatedly applied under angiographic control via a three-way stopcock. In Germany, PlatiCept is the only available cisplatinum powder. Its major advantage is its good solubility. Therefore, relatively high doses of cisplatinum can be administered with a small injection volume. The latter is considered helpful for maintaining the embolic effect of TACE. With DSM such as EmboCept S DSM 50µm, repeat treatments are feasible, as the target lesion remains accessible. Moreover, the half-life time of about 35 minutes for EmboCept S DSM 50µm minimises systemic expression of proangiogenic growth factors such as vascular endothelial growth factor (VEGF) (Schicho 2016). It moreover reduces side effects such as ischaemic pain, thereby facilitating whole liver treatment. At six week intervals, the patient underwent three successful DSM-TACE procedures. The procedures were well tolerated, with only a mild one-week fatigue as the only symptom of post-embolization syndrome. The eightmonth follow-up MR imaging showed partial response according to RECIST 1.1, with only very little tumour left (Fig. 4). So far, no change on laboratory testing has been seen. Almost two years after the initial diagnosis, the patient feels well without limitations in her daily activity. She is now scheduled for a three-month treatment holiday followed restaging. References: 1. Waseem D, Tushar P. Intrahepatic, perihilar and distal cholangiocarcinoma: Management and outcomes. Ann Hepatol. 2017 Jan–Feb 2017;16(1):133139. 2. Kelley RK, Bridgewater J, Gores GJ et al. Systemic therapies for intrahepatic cholangiocarcinoma. J Hepatol. 2020 Feb;72(2):353–363 3. Cillo U, Fondevila C, Donadon M et al. Surgery for cholangiocarcinoma. Liver Int. 2019 May;39 Suppl 1(Suppl Suppl 1):143–155 4. Schicho A, Hellerbrand C, Krüger K et al. Impact of Different Embolic Agents for Transarterial Chemoembolization (TACE) Procedures on Systemic Vascular Endothelial Growth Factor (VEGF) Levels. J Clin Transl Hepatol. 2016 Dec 28;4(4):288–292

June 2021 | Issue 82

14 Multi-organ denervation

Multi-organ denervation to combat cardiometabolic disease: A novel concept put to the test Gerard Goh Markus Schlaich Comment & Analysis Following a successful proof-of-concept study, Gerard Goh and Markus Schlaich have embarked upon a first-in-human study to explore the safety and efficacy of combined renal and common hepatic artery denervation in patients with type 2 diabetes and hypertension. Here, the co-principal investigators describe the rationale behind their single blinded, multicentre, prospective feasibility study—the MODUS trial.

ardiometabolic disease has evolved into a pandemic, resulting in substantial loss in quality of life and enormous economic burden on healthcare systems world-wide. Cardiovascular and metabolic regulation is governed by neural signaling from the sympathetic nervous system in critical organs including the heart, kidneys, liver, pancreas, skeletal muscle, and adipose tissue. Increased sympathetic activation is a hallmark of cardiometabolic disease and has been demonstrated in obesity, metabolic syndrome, type 2 diabetes, hypertension, heart failure, chronic kidney disease, and many other relevant conditions. Insulin resistance, nonalcoholic fatty liver disease (NAFLD), and a systemic pro-inflammatory state are key mediators of the adverse consequences associated with cardiometabolic disease. A self-perpetuating cycle develops where sympathetic overdrive contributes

to insulin resistance and subclinical inflammation, which in turn maintain increased sympathetic signaling. Direct therapeutic targeting of the sympathetic nervous system therefore appears as a rational approach to improve both cardiovascular and metabolic control. Indeed, catheter-based renal denervation using either radiofrequency energy or therapeutic ultrasound has now been shown in four sham-controlled trials to be safe and to effectively lower ambulatory blood pressure in patients both treated and untreated with antihypertensive medications (SPYRAL OFF-MED, SPYRAL ON-MED, RADIANCE-HTN SOLO, RADIANCE-HTN TRIO). Additional salutary effects on glucose metabolism have been reported in some renal denervation studies, suggesting that the beneficial effects of selectively targeting the sympathetic nerves may not be limited to the management of

RFA with OsteoCool leads to “rapid and sustained” pain relief in patients with osseous metastases

Treating patients with metastatic bone disease by radiofrequency ablation (RFA) using the OsteoCool system (Medtronic) results in rapid and statistically significant improvement in pain scores, and provides sustained, long-term relief through 12 months. Attendees of the 2021 meeting of the Society of Interventional Radiology (SIR; 20–26 March, online) were the first to hear the full cohort data from the Medtronic-sponsored OPuS One clinical study in the “Abstract of the year” presentation, delivered by Jason Levy (Northside Hospital, Atlanta, USA) to the virtual audience. This latest dataset follows previous announcements from the OPuS One team also detailing positive results following RFA with the OsteoCool system. OPUS ONE IS THE LARGEST clinical study—with the most meaningful clinical results—considering the

OsteoCool technology to date. Principal investigator Sandeep Bagla (Vascular Institute of Virginia, Woodbridge, USA),

L: Common hepatic artery denervation. A guide sheath is seen in the coeliac axis. The balloon catheter is in the common hepatic artery. R: Renal denervation.

cardiovascular disorders, but may also help to restore metabolic homeostasis. This approach would perhaps be most effective if the sympathetic drive to metabolically-active organs such as the liver (gluconeogenesis), pancreas (insulin release), and duodenum could be inhibited directly. A recent preclinical proof-of-concept study in a porcine model where percutaneous denervation in both renal arteries and the common hepatic artery (CHA) was performed with the iRF Denervation System (Metavention) demonstrated that denervation of both the kidneys and the liver could safely be achieved with reductions in tissue norepinephrine concentration when compared to control animals of 78% and 88% (p<0.001 for both), respectively. Pancreatic and duodenal norepinephrine concentration was also reduced significantly. Consequently, a first-in-human study has recently been initiated to explore the safety and efficacy of combined renal and common hepatic artery denervation in patients with type 2 diabetes and hypertension. The MODUS trial (Multi-organ denervation to reduce sympathetic drive, a single blinded, multicentre, prospective feasibility study) is a multicentre randomised trial that is examining the effects of hepatic and/or renal denervation in patients with hypertension, diabetes, and metabolic syndrome. Patients on one or two antihypertensive and oral

anti-diabetic drugs within certain BP and HbA1c ranges undergo a ‘wash-out’ phase of four weeks with regular BP and glucose monitoring before receiving a single session denervation therapy. The trial utilises the iRF denervation system, which is a radiofrequency balloon-based catheter with internal cooling where the catheter is inserted into the renal and/or common hepatic arteries and denervation performed. Centres in Perth, Melbourne, and Sydney (Australia) are participating in the trial, and the first two patients were recently enrolled at the Alfred Hospital, Melbourne, treated by Gerard Goh and Warren Clements.

along with Levy and other colleagues, set out to assess the effectiveness of the OsteoCool RF ablation system. They conducted a global, prospective, nonrandomised, multicentre study of RFA for the palliative treatment of patients with painful osseous metastases. In addition to pain, osseous metastases can cause fractures and some “pretty debilitating symptoms”, such as spinal cord or neurovascular compression, Levy said. He continued: “Radiation treatments have been commonly used for this, but they do not always provide pain relief, they can take weeks to occur, and they can set a patient up for fractures down the road. When the effects of their treatment are delayed for weeks, in this population of palliative care patients, that may consist of a significant proportion of that patient’s life.” The investigators therefore wanted to ascertain the ability of RFA to provide

quick and long-lasting pain relief for these patients. Between October 2017 and February 2020, 218 patients were prospectively enrolled in an Institutional Review Board (IRB)-/ Ethical Committee (EC)-approved study at 15 sites across Canada, the European Union, and the USA. Patient inclusion required a worst pain of at least four out of 10 at the target treatment site, as measured by the Brief Pain Inventory (BPI), within 24 hours of their clinic visit. Patients also had to be a candidate for OsteoCool RF ablation as per the labelled indication applicable in their respective country. This necessitated that the metastatic lesions targeted for treatment be located in the thoracic and/or lumbar vertebral body(ies), periacetabulum, iliac crest, and/ or sacrum, or benign bone tumours. There was no restriction on the location of the lesion. The predominant cancer pathologies were breast (22.8%), lung

Gerard S Goh is head of Interventional Radiology at The Alfred Hospital, Melbourne Australia, and is adjunct associate professor in the department of Surgery at the Monash University, Melbourne, Australia. He is also president of the Interventional Radiology Society of Australasia (IRSA). Markus P Schlaich is the Dobney chair in Clinical Research and a nephrologist and hypertension specialist at the School of Medicine—Royal Perth Hospital Unit and the University of Western Australia, Perth, Australia. Disclosures: Gerard S Goh and Markus P Schlaich are co-principal investigators of the MODUS trial, and as such receive research funding from Metavention.

Issue 82 | June 2021

Genicular artery embolization 15

GAE “highly effective and durable”, offering long-term pain relief for osteoarthritis patients Genicular artery embolization (GAE) is “highly effective and durable” in reducing symptoms due to moderate to severe knee osteoarthritis that is refractory to other conservative therapy, and has an acceptably low toxicity profile. So concludes Siddharth Padia (University of California, Los Angeles, USA), speaking at a press briefing in advance of the Society of Interventional Radiology (SIR) annual meeting (20–26 March, online). He will present these results to attendees of the virtual congress. PADIA CITES GAE AS A “PROMISING therapy” to treat patients with symptomatic knee osteoarthritis by reducing synovial arterial hypervascularity. “As we all know, having arthritis is a very common problem, resulting in pain and physical dysfunction,” he said. Current treatment options for this disease are to “do nothing” and rest up, to take medications (including nonsteroidal anti-inflammatory drugs; NSAIDs), or, if these have failed, to receive a joint injection: “typically a steroid, such as cortisone, or a gel,” Padia said. “While those can work,” he continued, “they have relatively short-term results. A typical joint injection lasts for anywhere from one to three months, so it is not really built as a long-term solution. Currently, the only long-term solution is a knee replacement, which does work, and is recommended for people with severe, symptomatic osteoarthritis, but the problem, the challenge with total knee replacement is it involves anaesthesia, it involves a hospital stay, and it has a long recovery and rehabilitation time. Many patients are either not candidates, or want to defer their operation to a later date.” The investigators therefore conducted a prospective, single-centre, open-label, US Food and Drug Administration (FDA)-approved investigational device exemption (IDE) study that aimed to evaluate the safety and efficacy of the minimally invasive GAE procedure for the treatment of symptomatic knee osteoarthritis, with an eye to looking at potential long-term outcomes. “In theory, if we can reduce the inflammation, we can make people’s pain go away, and make their overall function improve,” Padia explained, justifying the rationale underpinning GAE. “The goal is to normalise or even decrease the blood flow in the knee joint, because right now, in a patient with arthritis, the blood flow is abnormally increased.”

(22.8%), and renal (10.2%); 184 patients (89%) were treated for metastatic lesions involving the lumbar or thoracic spine, while 22 patients (11%) were treated for metastatic lesions located in the iliac crest, periacetabulum, sacrum, or mixed vertebral and pelvic location. Patients had to be experiencing localised pain resulting from no more than two sites of metastatic disease, and be at least 18 years old—the mean age was 63.7 years. In total, 113 (54.9%) patients were women, and 93 (45.1%) were men. RFA was performed under imaging guidance at one or two levels in 206 patients, and was technically successful in 99% (262 of 264) of cases. The procedure was followed by a discretionary cementoplasty—97% of RFA procedures in the study preceded a cementoplasty. Patients’ pain and quality of life were measured prior to RFA, and three days, one week, and one-, three-, six-, and 12 months post-procedure.

patients (62%), and the right knee was treated in the remaining 15 (38%). Medial knee pain was treated in 27 of 40 patients (68%), and lateral knee pain was treated in 13 (32%). Technical success was achieved in 100% of patients.

Pain scores decreased

WOMAC and pain scores decreased from a median of 52 (out of 96) and eight out of 10 at baseline to 21 out of 96 (60% decrease) and three out of 10 (63% decrease) at 12 months, respectively. “We saw an immediate drop in WOMAC score, from quite a high score at baseline [52 out of 96] to a median of 22 at one month. It further improved with time: at three months, WOMAC score Knee osteoarthritis: “A very common was 15, and it stayed low for the entire duration of the problem” study.” Knee osteoarthritis is age-related, Padia explained, Padia and colleagues used a cut-off of 50% to and as such the study enrolled patients consider their procedure a success. In total, 27 aged 49–80 years (median age of 69). All out of the 40 patients (68.5%) had a greater patients had moderate or severe focal knee than 50% reduction in WOMAC score, and a pain and osteoarthritis on knee radiograph further 28 patients from the full cohort (70%) (Kellgren-Lawrence grades 2–4; 18% were experienced a more than 50% reduction in grade 2, 43% were grade 3, and 40% were pain score. “A 50% reduction is quite an grade 4), no prior knee surgery, and were not aggressive threshold to use,” Padia stated. candidates or not willing to undergo total “The orthopaedic surgery literature uses knee replacement surgery. a much smaller cut-off when they define Patients had to have failed conservative Siddharth Patia success. When we use a higher threshold, therapy, including NSAIDs and/or joint such as a 75% reduction—a 75% reduction injections. Baseline pain in WOMAC score essentially (visual analogue scale) and means you are pain free— symptom scores (Western that was achieved in 43% Ontario and McMaster [of patients]. There are Universities Osteoarthritis significant improvements Index; WOMAC) were in pain in the majority of assessed. Median body patients.” mass index (BMI) was 28 (range 18–44). Reported adverse

Procedural details

The goal is to normalise or even decrease the blood flow in the knee joint, because right now, in a patient with arthritis, the blood flow is abnormally increased.”

After obtaining femoral arterial access, GAE was performed using 100μm particles (Embozene, Varian) of one to three genicular arteries supplying the location of the patient’s pain, as determined by digital subtraction angiography and conebeam computed tomography (CT). GAE is performed as an outpatient procedure, and not under general anaesthesia, because “the procedure itself is completely painless”. Over a nine-month period, 40 patients were treated with GAE. The left knee was treated in 25 of the 40

These data were collected from patientanswered questionnaires pertaining to pain and quality of life, filled out before the procedure, and at every follow-up time point. The research team also used standard quality of life measures. The data were assessed through unadjusted post hoc hypothesis tests. Device-, procedure- and/or therapyrelated adverse events were collected throughout. Before RFA, the mean score for worst pain was 7.8±1.7. Post ablation, the mean worst pain significantly improved

RFA can give patients a very rapid, improved quality of life within three days.”

events

The investigators also noted any adverse events and symptoms scores, assessing these at one week, one month, three months, six months, and one year after GAE. Transient skin discoloration and transient mild post-procedure knee pain were common and expected. Treatment-related adverse events included: one patient with a groin haematoma requiring overnight observation, seven patients with self-resolving focal skin ulceration, and two patients with asymptomatic small bone infarct on MRI at three months.

at all time points, decreasing to 5.5±2.8 at three days (n=199), 4.7±2.8 at one week (n=192), 3.6±3 at one month (n=173), 3.2±3.1 (at three months (n=147), 2.4±2.6 at six months (n=114), and 2.6±2.8 at 12 months (n=59; p< 0.001 for all visits). Opining on these numbers, Levy enthused: “We are really excited by what we saw. The first thing we noticed is that we had pain relief as fast as three days, which is obviously very significant in this patient population, especially when the standard-of-care treatment right now, radiation, takes four to six weeks. “In addition, this was sustained. At one year, 83% of the patients continued to report pain improvements, which is also a significant improvement over radiation treatment.” Patients also experienced significant improvement for all follow-up points in average pain (p< 0.001), pain interference (p< 0.001), and quality of

life (p< 0.001). Six adverse events were reported, and the investigators noted a total of 82 deaths, all of which were attributed to the patient’s underlying malignancy. “I think the most important outcome from this study is that RFA can give patients a very rapid, improved quality of life within three days, and this is sustained out to 12-months,” Levy reiterated. As the OPuS One trial largely focused on lytic metastases, which are very common, Levy says these results demonstrate that RFA with OsteoCool is a “good option” for a wide range of cancer patients. “I believe this treatment should be available in the patient paradigm than what we saw in this study, where it was mostly a palliative treatment,” he concluded. “[We should offer it to] more patients where we can prevent future fractures, and prevent pain from lasting a long time.”

June 2021 | Issue 82

16 SIR spotlight

DOTTER LECTURE

Abandoning “cowboy culture” in service of data: The 2021 Dotter Lecture

It is time for interventional radiologists to leave behind the “cowboy culture” that was the foundation of the discipline’s early, exploratory days, and to become “legionaries marching in service of data”, Ziv Haskal (University of Virginia, Charlottesville, USA) argued in his 2021 Dotter Lecture, delivered during the Annual Scientific Meeting of the Society of Interventional Radiology (SIR; 20–26 March, online).

“I

nterventional radiology (IR) knowledge is not atomic: it is complex,” the former Journal of Vascular and Interventional Radiology (JVIR) editor told virtual attendees. “You cannot live with ‘I read the abstract’ or ‘I cruised the conclusion’”, he joked, cautioning SIR delegates against accepting certain ideas as gospel without first scrutinising the data. Indeed, Haskal’s lecture, “The reluctant cowboy: Moving past myth and dogma” deconstructed commonly held IR “myths” and dogmatic approaches to practice, and called for a more rigorous culture of data and research. “We need to be accountable and adopt a sceptical approach that can only be satisfied through repetition and replication,” he said. In order to do this, he advised his audience to act at various levels: “On a personal level: embrace this constant self-query, self-reflection, scepticism, and patience. Read in detail. Embrace the dialectic. “On a local level: cheer on developing prospective research; it is five to ten times more effort to write protocols, but they are durable, and impactful, and can be built upon, or will lead to other work. “On a national level: support initiatives for data that can be congregated, through registries, through standardised reporting, through NIH [National Institutes of Health] efforts. Open your pocketbooks with patronage; lend your financial support to societal initiatives. “And on the big blue planet, think about the largescale questions, so we can get together with other groups. We have to mine the facts for truth and work daily to be clinical scientists.”

The apodictic versus the apoplectic: Moving beyond a narrow, dogmatic vision in IR

Haskal began his talk by noting that “many or most of us [interventional radiologists] remember that signal case” that led them to pursue a career in IR, which he likens to skydiving due to the “adrenaline thrill”. However, he warned that now is the time for the speciality to turn towards “creating data and our own science”. He made the distinction between the apodictic—“knowledge we are certain of” and the apoplectic, the “you will do it this way because I was trained this way, and therefore you will be trained this way” school of thought. He highlighted some specific examples of “apoplectic” thinking “to highlight the types of narrow vision that we have on a daily, or on a field-wise basis”. One such belief he questioned was the idea that pulmonary arteriovenous malformations (PAVMs) less than 3mm do not need to be embolized to prevent stroke. “Are bacteria just too big to fit through a 3mm PAVM?” Haskal asked rhetorically. He traced the origins of this belief to an abstract presented orally at the 1992 meeting of the Radiological Society of North America (RSNA), which did not state that there was no need to embolize

smaller than 3mm, but rather found clinically-evident stroke in four patients with a feeding artery measuring 2.9–4.5mm. “That is pretty shaky ground for decisionmaking,” Haskal opined. “How about gall bladder catheters—they have to be transhepatic, right?” he continued. He cited a 1988 article in the American Journal of Roentgenology (AJR) and a 1994 paper in JVIR that refute this, demonstrating the safety of a transperitoneal route. “If that was not enough, I was recently asked by a plaintiff’s lawyer to be a medical expert on a case in which there was a hepatic bleed, and she insisted the interventional radiologist was negligent because they had gone through the liver, and there was a bleed.” He also addressed common practice assumptions. “Why do we always get called at night for nephrostomies or arterial lysis?” he asked. But according to a review of cases conducted at the 800bed University of Virginia Hospital over the course Ziv Haskal receives Dotter Lecture award from Alan Matsumoto

of one year, 84% of nephrostomies and 80% of lysis procedures took place between 8am and 8pm. According to Haskal, this is due to frequency bias, also known as the Baader-Meinhof effect—after you notice that you have done several night-time lysis procedures, you will notice it more often and believe that it has a high recurrence.

The risks of skimming

In addition to these commonly-held IR “myths”, Haskal also warned his audience of the dangers of “reading light”. Presenting an example, he discussed an “excellently-written, multicentre trial, [conducted] under the auspices of the FDA [the US Food and Drug Administration]”. He published the study, which was an approval trial for a vena cava filter, when JVIR editor. “Here are the conclusions from the abstract,” he read: “The rate of freedom from new symptomatic PE [pulmonary embolism] through 60 days was 100% (n=129, confidence interval [CI] 97.1–100%). [...] There were no cases of PE through 12 months for either therapeutic or prophylactic indications.” Commenting on this, he said, “So that is pretty good, we want that device,” before adding, “But here is what happens when you read inside [the paper].” A third of the patients were purely prophylactic, “that means they had no DVT [deep vein thrombosis] or PE to begin with”, Haskal said. “That is like taking people with cancer and people who might get cancer, and following them for a year, and then saying ‘Look, we did not have cancer [amongst the total cohort]’. But you put those people in! [Referring to the cohort without any cancer at the start of the study].” “Papers are this long for a reasons—we have got to read the detail,” he emphasised.

Issue 82 | June 2021

“Three out of four meta-analyses are garbage in, garbage out, cannot be trusted”

“Surely meta-analyses are the path to truth?” Haskal posited. “It is the analysis of the analyses, it is integration and power, it is rigour over narrative, it is signal over noise, it is the superman!” he enthused. However, he showed a meta-analysis that had to pool 95 trials to show that neutropenic cancer patients have lower mortality with antibiotics, saying “even large, individual trials were not enough to pull it together [and reach this conclusion]. That is a life-altering signal. “But guess what? In one analysis of 7,200 systemic reviews, once you take out the Cochrane analyses, one quarter, 27%, had low risk of bias, compared to 87% of Cochrane analyses. That means that three out of four meta-analyses are garbage in, garbage out, cannot be trusted. “You have to stay vigilant as a reader,” he advised, counselling his listeners to have a mental checklist when reading papers: Study question or hypothesis is clearly defined prior to analysis Study design has been defined before analysis and search is clearly defined Clear inclusion and exclusion criteria Methodological quality of the studies has been checked before analysis by a predefined quality standard (and by more than one reviewer) Publication bias is checked (for example by funnel plot) Heterogeneity has been properly investigated (graphically or statistically) A common effect size is used (directly quoted or recalculated) for pooled result Adjustment for potential confounders has been considered (mainly for observational studies) Results are clearly reported and properly interpreted

SIR spotlight 17

Are statistically significant results also clinically significant?

“We must train scientific methods into the next generation of interventional radiologists”

To stray from the IR echo chamber, Haskal noted, interventional radiologists have to have scientific flexibility. “The perfect gold standard is not possible in clinical research,” he said. Iteration, reiteration, renewal, and

We must train scientific methods into the next generation of interventional radiologists.” replication is the best that can be done. “We have to have ongoing scepticism and constrain exuberance,” he said, before closing his lecture with a call to arms: “We must train scientific methods into the next generation of interventional radiologists, and we have to standardise it.” Writing in JVIR in 2016, Haskal put: “We have new trainees now entering the specialty; we have five years of opportunity to inculcate them with methodical training and research exposure—to methods, critical reading, analysis and study design”. He continued: “This will require a fundamental and intentional mutation in IT training DNA—potentially a centralised CRISPR insert available to all residencies. We cannot expect that each programme will have the ability to teach this, we need to develop this nationally, and make this available to our trainees [in the USA],

Selected slides from Ziv Haskal’s Dotter Lecture, presented at the Society of Interventional Radiology (SIR) 2021 Annual Scientific Meeting

and across the planet, because this is our long game.”

IR and COVID-19: “When diagnostic volumes cratered, […] our volumes went up”

Speaking more broadly of the hardships SIR members and attendees have experienced in the past year due to the ongoing COVID-19 pandemic, and in particular noting how this has affected the SIR meeting, Haskal commented: “On a professional level, 25 years of the Dotter Lecture means sitting in that giant hall, surrounded by thousands of our colleagues, the lights go down, an extraordinary speaker comes out, and something revealing, and visionary, pulls us all together. Instead, we are all separated, watching this on screens, alone. “But I want to remind everybody what we have done as interventional radiologists this year. Pulling protocols across the planet, trying to figure out how to manage in this plague year; doing all those procedures—PD [peritoneal dialysis] catheters at bedside, we had not done that before, dialysis catheters, gastrostomy catheters in acute or chronically-ill patients, arterial lysis for hypercoagulability or pulmonary embolism. When diagnostic volumes cratered and people were furloughed and elective surgeries were cut, whether you were in a big metropolitan area or in smaller hospitals hit by COVID-19 patients, our volumes were maintained or went up.” “We are always going to have the professor Dotter spirit,” Haskal said in his closing remarks. “But we have to embrace the next evolution and work daily to be clinical scientists.”

June 2021 | Issue 82

18 Women IR leaders

“Now is the time to push our field to its greatest potential”: Building a more inclusive IR specialty

In the USA, 90–93% of interventional radiology (IR) faculty are men. According to the American Medical Association (AMA), 80.8% of IR-integrated residents are men. Speaking during the third lecture in the new, monthly series hosted by the National Institutes of Health (NIH) Center for Interventional Oncology, Radiology, and Imaging Sciences (in Bethesda, USA), “Women leaders in academic research,” IR physician-scientist Isabel Newton (VA San Diego and University of California San Diego [UCSD], San Diego, USA) explained why and how she believed this should change.

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or too long,” she opined, “we have been populating our field with typecasts—instead of seeking out all exceptional people, we fulfil cultural expectations of success, defined by those in charge. We place value on those that fulfil prescribed notions of excellence; we look for clones of those who are already here; we scan applications in a way that fosters box-checking, rather than substantive contributions; we reward performative research, rather than sensitive experiences; we prize a shiny façade, even if it is false, and shun anyone who admits real weakness, even though it is common to us all.” She believes that “this is the time to be inclusive, and to welcome talent wherever it comes, and to not squander it when we get it.” This would involve providing training in research basics, ethics, outreach, and ways to integrate with the wider healthcare team for prospective interventional radiologist scientists, she said. Speaking specifically about the pathway to becoming a clinicianscientist, Newton told listeners that in addition to providing time, institutions must make “investments on a much more fundamental level” and show “a willingness to reimagine our own

culture”. She claimed that the single-most important element for this is “people”, extolling the virtues of mentorship and sponsorship programmes.

IR: A field at a cross-road

“This is not a talk from the vantage point of someone who has made it, and is imparting their wisdom from the destination that everyone is so yearning to reach,” she began. “I am giving this talk from the road—these are the words from a fellow traveller who is speckled with asphalt and sprayed with mud. Gritty? Sure. But also aspirational. We are going somewhere. But first we need to decide where we are going.” Newton continued: “Our field [IR] is at a cross-road. After the miraculous birth of our speciality, we have witnessed its boom and its renaissance, and now, with all these possibilities teetering in the balance, it is up to us to ensure that what we offer truly helps all our patients to be well. It is up to us to recognise what is good, and the opportunities for growth. “This pandemic has given us the pause we needed to see this culture for what it is, and decide whether it is one that we want to continue. This is our chance to listen to our patients, understand what matters to them, and support them in their journey. Now is the time to push our field

Ten teachings from the 2021 SIR InspIRed Lecture

President of the American College of Radiology (ACR) Geraldine McGinty, also a radiologist and the chief strategy officer, as well as the chief contracting officer, at Weill Cornell Medicine (New York City, USA), presented the InspIRed Lecture at the 2021 meeting of the Society of Interventional Radiology (SIR; 20–26 March, online). She offered her reflections on “being a first”—in May 2018, McGinty was elected chair of the Board of Chancellors of ACR, the first woman to hold this office in the society’s nearly 100-year history. MCGINTY ALSO HIGHLIGHTED THE importance of taking an intersectional approach to mentoring and networking, with several of her key

to its greatest potential in the service of others.” Returning specifically to the gender disparity amongst the specialty, Newton commented: Clockwise from top left: Brad Wood, Isabel Newton, Natasha “Radiology is Sheybani, and Janice Lee not unique in attracting fewer women, but it is one of the fields that has you to find your own stereotypes and the hardest time attracting women. That blind spots. They are there! If you think means that by simply existing, those of you do not have them, that is part of the us that are in it are building new roads. problem.” We face, and we create, expectations of Janice Lee, deputy director of the what a female physician, radiologist, Intramural Research Programme, interventional radiologist, or scientist is Bethesda, USA, and a fellow panellist supposed to look, sound, and act like.” during the session, added: “The visual alone of seeing speakers who look like “Seeing speakers who me is incredibly encouraging, and one look like me is incredibly that we do not take for granted. We encouraging” encourage other women to join our maleIn his introduction to the talk, Brad dominated specialities; by doing so, we Wood (National Institutes of Health begin to change the group dynamics, and (NIH) Center for Interventional affect the culture of the overall group.” Oncology, Bethesda, USA) explained Natasha Sheybani, a postdoc fellow that the series was initiated as an effort in artificial intelligence (AI) at the to “acknowledge, educate, and address University of Stanford (Stanford, USA) underrepresentation and role-modelling and a part of the organising committee for future stars within our small, microfor this lecture series, commented: “If community.” He elaborated: “We do I may be so bold as to speak on behalf this through a better understanding of of the next generation, as a trainee, I implicit biases and underrepresentation. just want to say how important these We want to ask ‘Why?’ We want to conversations are and how much they highlight successful females and other mean to our generation, and we can see underrepresented academic leaders as the difference that these conversations role models for trainees. […] We try to are already making. I always say during lead by example, acknowledging why conversations like this that we are already one tends to recruit in our own image will in a better position, and are so lucky to be shine light on that, and on the stereotypes in that position, having predecessors like and blind spots that are inherent to that those on this call who are forging a path process. These are not bad words—we for trainees like myself. It would be a all have stereotypes and blind spots. We disservice if we did not pay that forward have to recognise it; I challenge each of and make the most of it.”

takeaways referencing using your privilege and access to enable opportunities “not just for people who look like you”. Delivering her InspIRed Lecture on 21 March, McGinty gave ten central lessons for women and other under-represented groups in interventional radiology (IR): 1. Be thoughtful about the privilege you have on your journey! McGinty encouraged those with power to use it for good. 2. Everyone is different, and that is a good thing. Acknowledge the different ways people may function, and help power your team more effectively. 3. You are the one who gets to tell your story. Whether the best part of your day is a clinical case or seeing your favourite show, it is up to you to define that. 4. You decide what is important. Be thoughtful about where you want to make your effort, and do not leave your value on the table. When you negotiate, it is about more than salary. 5. You can be authentic. “I have tended to be more

successful when I have done that.” But you may need to conform to get to the table. 6. You have an obligation to pay it forward, and not just for people who look like you. 7. You will bet on people who will disappoint you, and you may get the most help from where you least expect it. Do not rule out those who do not look like you as mentors. 8. Be brave, not perfect. 9. Thoughtfully build your network. Seek out people doing interesting work, and ask for time with them (perhaps even just a few minutes). You should also have a squad to discuss salary with, who will support you no matter what. 10. Think big: “We have to make it okay for us to have ambitions!” You will face criticism, but the work could not be more important. Geraldine McGinty

Issue 82 | June 2021

Health economics 19

IRs must “demonstrate the positive impact they have on generating revenue”, SIR discussants urge Matthew Hawkins Raymond Liu Comment & Analysis During the annual scientific meeting of the Society of Interventional Radiology (SIR; 20–26 March, online), Matthew Hawkins and Raymond Liu jointly hosted a session conveying the value of interventional radiology (IR) services. During the session, they touched on how interventional radiologists can communicate the value their field brings to hospitals and health systems and what other interventionalists can be doing to help move the field forward. Interventional News caught up with Hawkins and Liu for a discussion on the topic.

How can interventional radiologists communicate the value their field brings to hospitals and health systems?

MH: IR has become a specialty that treats a multitude of conditions in nearly every area of the body. Our specialty is an essential component to many revenue-generating service-lines offered by hospitals, such as organ transplant, oncology, stroke care, and trauma. In addition to some of the more complex interventions performed by interventional radiologists, members of our specialty have become healthcare system experts of central venous access, minimally-

Interventional radiologists are always open to working in partnership across specialties, and there are more opportunities for partnership with other physicians than many realise.” Raymond Liu

invasive biopsies, enteric access management, and percutaneous drainage procedures. But while interventional radiologists are valued for their universal skill sets, it has been difficult for the specialty to communicate how these skill sets translate to the bottom line for hospitals and health systems. The most important thing

interventional radiologists can do is to demonstrate the positive impact they have on generating revenue, containing costs, optimising resource utilisation, and providing high-quality patient care. As it pertains to quality, hospitals/ healthcare systems value improved outcomes for patients, shorter lengths of stay (LOS), avoidance of unnecessary admissions, and post-discharge outpatient management to avoid re-admissions and financial penalties. They want to invest in specialties that can deliver on these targets. We know that IR does this, but having robust data and research to support it will be crucial in the future. We hope that interventional radiologists will conduct more research into these areas to further support IR as a value-driven, patient-centered specialty.

How have you personally worked with colleagues across disciplines to provide best patient care? How do you initiate forming an interdisciplinary team—what are the opportunities here?

RL: Interventional radiologists are always open to working in partnership across specialties, and there are more opportunities for partnership with other physicians than many realise. In developing an interdisciplinary team, it starts with identifying the holes within your health system that need filling. Where could your services be most useful in a team environment? Where do you think a team could provide the most value? The next step is to simply reach out to the other physicians within that service-line and have a conversation. Find out if they are interested in forming an interdisciplinary team. Most likely they will be enthusiastic about working together because we all have the same goal—getting patients the best care they

deserve. The final step is to get support from hospital leadership. Their backing will help to nurture your team model and even scale it up for the future so it can continue to grow. A great example beyond the well-known oncology model are Hereditary Haemorrhagic Telangiectasia (HHT) teams that draw in specialists such as ear, nose and throat (ENT) specialists, haematologists, geneticists, and pulmonologists. And, of course, multidisciplinary teams should not just be considered for clinical issues—at Massachusetts General Hospital, we have created interdisciplinary teams for operational redesign, such as on-time efforts for the first case in the operating room, or best practice workflows for anaesthesia support for IR. A strong team that works across specialties is better for both physicians and patients, so I encourage other interventional radiologists to reach out to their colleagues if they are interested in working in this capacity.

An interventionalist in the IR suite

What are the biggest challenges to the spread of IR generally, and how can interventional radiologists work on combating these?

RL: Some of the biggest challenges facing the profession include misperceptions among referring physicians and hospital administrators about what interventional radiologists can do. For a long time, interventional radiologists have been viewed as technicians, but as the field has exploded into other realms of treatment across all areas of the body, other physicians continued to hold the same notions about interventional radiologists’ capabilities. Yes, we can help treat a patient’s complex condition, but we can also provide patients the full clinical spectrum that allow discussions around all treatment options. We need to ensure that other physicians understand that we can be a partner in their patients’ care. Interventional radiologists can change this by strengthening relationships with other physicians in other specialties; by demonstrating to hospital administrators the ways interventional radiologists can help generate revenue, contain costs, and provide patients high-quality care. I would also say access to IR services is a hurdle our specialty needs to overcome. In some metropolitan areas, there is an abundance of IR specialists that allow many choices for patients. But in many areas, even just a few miles outside major cities, there is a dearth of IR physicians that can address complex conditions and provide best practice treatments. Our specialty needs

While interventional radiologists are valued for their universal skill sets, it has been difficult for the specialty to communicate how these skill sets translate to the bottom line for hospitals and health systems.” Matthew Hawkins

to identify those geographical areas, as well as improve communication of our services in those locations where there are interventional radiologists, and ensure that every patient has access to an interventional radiologist anytime.

What are the biggest misconceptions pertaining to paediatric IR, and how can these be addressed? MH: As endovascular equipment has continued to get smaller and smaller, it has made many minimally-invasive IR procedures safe for children. Now, rather than open surgical procedures, many paediatric diseases can be treated with minimally-invasive, image-guided treatments. Paediatric IR is evolving rapidly and has become an essential specialty in the management of vascular malformations, paediatric organ transplant, and many paediatric benign bone tumors. Paediatric interventional radiologists have also become institutional experts in less complex, but critical procedures, such as biopsies, enteric access, and central venous access, which are necessary for the care of a wide array of paediatric diseases. In general, parents are grateful to have minimally-invasive, image-guided alternatives to open surgery. Thriving paediatric IR practices are generally based out of tertiary referral paediatric hospitals, with an increasing percentage of paediatric interventional radiologists obtaining subspecialised paediatric IR training to supplement their foundational adult IR residency curriculum. Matthew Hawkins is a paediatric vascular interventional radiologist and associate professor at Emory University and the Children’s Pediatric Institute, Atlanta, USA. Raymond Liu is an interventional radiologist at Massachusetts General Hospital, Boston, USA. He is a Society of Interventional Radiology (SIR) board member and executive director of Partners HealthCare International (PHI).

June 2021 | Issue 82

20 Renal interventions

High-flow fistulas remain divisive, with uncertainty over reduction and outcomes

cardiac events and related mortality can be prevented through a greater emphasis on treating high-flow fistulas, but, when questioned by Valenti on certain instances of acute death after abrupt fistula ligation, Rotmans also theorised that a medical device capable of closing a functional fistula gradually—over the course of one or several days, for example—may be useful in offsetting these potential risks. The ultimately contentious debate that followed this saw Gibbs argue in favour of reducing high flow first. His argument centred around the notion that “there is already evidence out there that high-flow AVFs are bad for our patients, and we do not need large, Discussions at this year’s Charing Cross randomised trials to prove it”, and he cited multiple (CX) 2021 Digital Edition (19–22 April, online) reports indicating that banding or revision using distal indicated that high-flow arteriovenous inflow (RUDI) procedures to reduce flow in AVFs can fistulas (AVFs) remain one of the more improve heart failure symptoms. Gibbs went on to divisive topics in the field of vascular argue that the absence of randomised controlled trials access. This was most apparent in the (RCTs) assessing the link between high-flow fistulas and outcome of a debate on whether reducing cardiovascular complications should not detract from flow in asymptomatic high-flow fistula other evidence that the two are causally linked, pointing patients is necessary, with audience polling to the fact that there have been no RCTs to investigate revealing an exact 50/50 split across CX the commonly-known, health-related consequences of attendees. smoking either. In his counter argument, Shenoy emphasised many n the debate, the audience heard that high-flow of the lines that have been drawn between high flow fistulas can lead to major cardiac consequences and and cardiac symptoms to date are merely examples of existing evidence demonstrates the prevalence of association, rather than direct correlation or causation. heart disease in renal patients, which begs the question: He further claimed that existing studies indicating a should flow be reduced in asymptomatic high-flow trend between the two have either failed to properly fistulas, or in transplant recipients, to prevent cardiac compare dialysis patients with an AVF to regular, noncomplications? AVF dialysis patients, or have included many patients Renal and transplant surgeon Paul Gibbs (Queen with underlying risks or prior history of cardiovascular Alexandra Hospital, Portsmouth, UK) argued in favour conditions like congestive heart failure (CHF). Shenoy of the statement that “We concluded his presentation should reduce flow in highby stating that, based on the flow fistulas (>1,500ml)”. currently-available data, These points—and “there is no role for routine the debate motion flow reduction” in AVFs more generally—were with a flow greater than contested by transplant 1,500ml per minute—but surgeon Surendra Shenoy that closer monitoring and (Washington University early intervention in these School of Medicine, patients may be an optimal, St Louis, USA), who alternative strategy. argued against the need The precedent for for routine flow reduction this being a particularly in asymptomatic patients. challenging, equivocal Shenoy described the fistula debate was set almost as the “bystander” in these immediately by Inston patients, adding: “Why following Gibbs’ and Pictured in the left screen, clockwise from top left: Sophie Renton (London, UK), Nicholas Inston (Birmingham, shoot the fistula, which Shenoy’s presentations, as UK), Domenico Valenti (London, UK), Surendra Shenoy (St Louis, USA), Paul Gibbs (Portsmouth, UK), and Joris is serving them to stay he conceded that he was Rotmans (Leiden, The Netherlands). Pictured in the right screen: Polling results. alive?” “still undecided” on the The hour-long session need to reduce high flow. on high flow in access controversies, moderated by Mestres (Hospital Clínic de Barcelona, Barcelona, Gibbs added to this by stating that “we may be looking CX Executive Board members Nicholas Inston (Queen Spain)—who presented his views on the relationship for the impossible study” when it comes to resolving the Elizabeth Hospital Birmingham, Birmingham, UK) and between high-flow fistulas and steal syndrome during issue, although he also asserted that high-flow fistulas Domenico Valenti (King’s College London, London, the session—both conceded they were unsure that one are “unnecessary”, and claimed: “If I had a fistula, I UK), began with a presentation from interventional even exists right now. Following this, Saad brought would want it running as low as possible in order to nephrologist Theodore Saad (Christiana Care Health the discussion to a close by suggesting that patient-led look after my heart long-term”. System, Newark, USA). Saad introduced the audience to outcomes, such as pulse oximetry or pain, may be the Rotmans, who had stated earlier that he feels many of the existing challenges surrounding high-flow most appropriate comparator in future studies to assess “we should act far more aggressively than we fistulas—including the fact that they often go “under the newer technologies for reducing high flow, a statement currently are” to reduce high flow, argued that radar” due to complacency following fistula creation, as that drew a strong endorsement from Valenti. preventative interventions similar to those used to treat well as a lack of clear standards and uncertainties over Nephrologist Joris Rotmans (Leiden University cardiovascular disease should be deployed to reduce which specialists should be responsible for them. Medical Center, Leiden, The Netherlands) followed the fistula’s “obvious detrimental effects”. Shenoy Saad also alluded to the connection between high-flow this discussion with a presentation on the “chronic countered this by reiterating his point that many regular fistulas and cardiovascular problems, and suggested that increase” an already-vulnerable patient’s cardiac output haemodialysis patients experience similar cardiac a more defined algorithm for managing and reducing goes through as a result of vascular access creation for symptoms to those who undergo AVF creation and, as flow in these structures is necessary—something he haemodialysis. This provided a fitting precursor to the such, there is “no direct proof” linking them. claimed he is currently working to develop. Inston CX debate on the question of reducing flow in highIn the discussion, Gibbs and Shenoy did agree on concurred with many of Saad’s points, asserting that flow fistulas, as Rotmans stated that while AVFs and the need to treat patients with high-flow fistulas who are “the majority of renal patients die from cardiovascular AV grafts alike can increase the risk of left ventricular presenting with symptoms, but remained split causes” and “we should perhaps be designing some hypertrophy (LVH) and pulmonary hypertension, “the on asymptomatic cases—as did the audience in patient-related outcomes that measure this more negative effects of an AVF on the heart can be reversed attendance, with 50% voting for the motion, and 50% effectively”, as well as asking about a point raised by by an AVF ligation”. voting against, in a poll conducted at the end of the vascular and renal transplant surgeon David Kingsmore He also concluded that it is currently unclear whether hour-long session.

(NHS Greater Glasgow and Clyde, Glasgow, UK) that a racing heart could be seen to be driving the fistula, rather than the other way around. Saad agreed on both counts, but did also respond to Kingsmore’s suggestion that the heart itself may be driving the fistula in these patients, stating that the two are “obviously interrelated” and separating them is not easy. In the presentation following this, vascular and endovascular surgeon Robert Shahverdyan (Asklepios Klinik Barmbek, Hamburg, Germany) presented his initial clinical experience using the Frame FR external stent (Vascular Graft Solutions). He described the device as an external banding tool used to support the vein at the anastomosis, adding that—having used the stent for high-flow AVF repair in 43 patients—he believes it offers an additional, feasible, and effective treatment for aneurysm and flow reduction. Responding to a query from Valenti on the high number of cases with aneurysmal AVF in his patient cohort, which was 40 (93%), Shahverdyan stated: “The thing is, as our previous speaker said, how many patients actually get a follow-up to see if their fistula is high-flow or not? In the group I presented, four were kidney transplant patients and the rest were on active dialysis, and these patients come to ask if they can abandon their fistula. I would usually recommend reducing the flow instead of abandonment though. I know it is a controversial discussion over whether you should keep it or ligate it in kidney transplant patients— but I would reduce the flow and keep it in case the kidney transplant fails in the future”. When asked by Inston what they considered to be the current “gold standard” for flow reduction procedures, Shahverdyan and fellow vascular surgeon Gaspar

August 2021 Issue 01

www.renalinterventions.net

Discrimination and harassment are a common experience among those working in cardiology According to the findings from a global survey carried out by the American College of Cardiology (ACC), which have been published in the Journal of the American College of Cardiology ( JACC). Responses suggest that as many as 44% of cardiologists report experiencing a hostile work environment (HWE) including being subject to emotional or sexual harassment, or discrimination. Authors concluded that a renewed focus on organisational structure, processes, and practices to mitigate these problems in cardiology across the globe is critical to ensuring workforce wellbeing and optimal patient care. The report is the culmination of a 50-item online survey conducted by the ACC in September to October 2019, reaching 5,931 cardiologists in Africa, Asia, the Caribbean, Europe, the Middle East, Oceana, and North,

Central, and South America. Questions covered demographic information, practice environment, academic rank, discrimination, and harassment, with a particular focus placed on the professional and personal challenges of cardiologists. Author Garima Sharma ( Johns Hopkins School of Medicine, Baltimore, USA) noted that the incidences of HWE were more commonly reported among female (68%), Black (53%) and North American (54%) respondents. Gender was the most frequent cause of discrimination (44%), the study found, followed by age (37%), race (24%), religion (15%), and sexual orientation (5%). Of the participants 77% were

Balloon angioplasty in critical time window central to endovascular success for the slowto-mature AV fistula Discrimination and harassment are a common experience among those working in cardiology, according to the findings from a global survey carried out by the American College of Cardiology (ACC), which have been published in the Journal of the American College of Cardiology ( JACC). Responses suggest that as many as 44% of cardiologists report experiencing a hostile work environment (HWE) including being subject to emotional or sexual harassment, or discrimination.

uthors concluded that a renewed focus on organisational structure, processes, and practices to mitigate these problems in cardiology across the globe is critical to ensuring workforce wellbeing and optimal patient care. The report is the culmination of a 50-item online survey conducted by the ACC in September to October 2019, reaching 5,931 cardiologists in Africa, Asia, the Caribbean, Europe, the Middle East, Oceana, and North, Central, and South America. Questions covered demographic information, practice environment, academic rank, discrimination, and harassment, with a particular focus placed on the professional and personal challenges of cardiologists. Author Garima Sharma ( Johns Hopkins School of Medicine, Baltimore, USA) noted that the incidences of HWE were more commonly reported among female (68%), Black (53%) and North American (54%) respondents. Gender was the most frequent cause of discrimination (44%), the study found, followed by age (37%), race (24%), religion (15%), and sexual orientation (5%). Of the participants 77% were men (n=4,584), and 23% (n=1,347) were women. Survey participants predominantly identified as white (54%), followed by Asian (17%), Hispanic

(17%), and Black (3%); and 73% were ≤54 years of age. Most were married (75%); 12% were single, 7% were living with a partner, 3% were divorced, and 1% were separated. Cardiologists from the European Union represented the largest group of respondents (32%), followed by respondents from South America (18%), the Middle East, Eastern Europe and Asia (all 9%), Africa (8%), North America (7%), Central America (6%), and Oceana (2%). According to Sharma, the survey results indicate that . The report is the culmination of a 50-item online survey conducted by the ACC in September to October 2019, reaching 5,931 cardiologists in Africa, Asia, the Caribbean, Europe, the Middle East, Oceana, and North, Central, and South America. Questions covered demographic information, practice environment, academic rank, discrimination, and harassment, with a particular focus placed on the professional and personal challenges of cardiologists. Author Garima Sharma ( Johns Hopkins School of Medicine, Baltimore, USA) noted that the incidences of HWE were more commonly reported among female (68%), Black (53%) and North American (54%) respondents. Gender was the most frequent cause of discrimination (44%), the study found, followed by age (37%), race (24%), religion (15%), and sexual orientation (5%). Of the participants 77% were men (n=4,584), and 23% (n=1,347) were women. Survey participants predominantly identified as white (54%), followed by Asian (17%), Hispanic (17%), and Black (3%); and 73% were ≤54 years of age. Most were married (75%); 12% were single, 7% were living with a partner, 3% were divorced, and 1% were separated. Cardiologists from the European Union represented the largest group of respondents (32%), followed by respondents from South America (18%), the Middle East, Eastern Europe and Asia (all 9%), Africa (8%), North America (7%), Central America (6%), and Oceana (2%). According to Sharma, the survey results indicate that The

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June 2021 | Issue 82

22 Interview

Profile

Philippe L Pereira Chair of the 2022 and 2023 European Conference on Interventional Oncology (ECIO), Philippe L Pereira muses on the status of interventional oncology (IO) in 2021, following more than a year of disruption from the ongoing COVID-19 pandemic. Through his work on various European guidelines delineating cancer care pathways, he has been instrumental in shaping the discipline and flying the flag for IO within multidisciplinary working groups. “Most oncologists recognise the value of our minimally-invasive therapies and know very well how to integrate our treatments into the therapeutic armamentarium that currently exists for cancer patients,” he says.

What initially attracted you to a career in interventional radiology? My mother wanted me to go to law school, my father preferred business, so I decided to become a doctor! No, in actual fact, as far back as I can remember, I have always wanted to be a doctor. That said, I wanted to be a psychiatrist, and I am now on the other side of medicine, the more technical side. Why interventional radiology (IR)? IR, well, because I like the operational side and being able to have an immediate influence on the disease, so as to help patients as soon as possible—the diagnosis alone without the interventional side would never have satisfied me. What we do as interventional radiologists is just incredible.

Who have been important mentors throughout your career?

Alain Roche would be the first one I would like to mention: I did not work with him for very long, but it was his enthusiasm that convinced me that IR was what I wanted to do in my life. The mentor I have learned the most from in the angiographic room was my colleague in Tübingen, Germany, Peter Huppert. One day, he brought back a radiofrequency generator that he had in his office; I quickly recognised the huge potential of this technology, and I have been using this therapeutic modality since 1996. I would also like to thank two other mentors who helped me a lot with their ideas: Fritz Schick, a physicist, and Claus Claussen.

As chair of the 2022 and 2023 ECIO meetings, what are the main takeaways you want for attendees?

First of all, I hope it will be a physical meeting, in person, and a great event to attend. It is a great honour for me that my European colleagues offer me this important position. My main purpose for this meeting is to emphasise the importance of clinical and pre-clinical studies, and to provide all possible support, starting from having the right idea—i.e. the study that will advance IO—then defining the design of the clinical study, right up to its funding. We will also highlight the multidisciplinary nature in the care of cancer patients: we are fortunate to include an oncologist, a surgeon, and a radiotherapist in the scientific programme committee (SPC). We also aim to cover the role that IO can play in combination with new immunological therapies, and to help define the contribution of artificial intelligence (AI) in our daily practice. All this will make ECIO 2022 an exceptional event.

How has the COVID-19 pandemic impacted medical conferences?

At the beginning of the pandemic, I thought that many conferences would become “digital”; I no longer think so. I feel that colleagues need to meet and discuss their latest experiences in person, candidly exploring the latest innovations or their most recent cases, discussing why they did not work as expected or how they achieved such success. Nevertheless, this pandemic has stimulated

us, forcing us to find new options to continue education and research. We will probably keep some of these options and make our meetings a kind of hybrid, with sessions that may be live (in person) or half-live (also available digitally).

You are also a member of the Oncologic Alliance subcommittee. What sort of work does this do? Yes, under the leadership of Andy Adam, this Alliance is addressing, among other things, the recognition of IO, defining international criteria for quality of cancer care, helping to design working groups to explore new and complex aspects of cancer care, and supporting the role of interventional oncology. The list of activities we undertake goes on and on.

You have also been involved with the development of European guidelines related to cancer management. What are the most important considerations when designing new guidelines?

This is a question for which I would need a full journal to answer! When you are working on new guidelines, you need to know all the results of the clinical studies in

In cancer care, you have to recognise and support the interdisciplinary aspect: no one has a monopoly on the ideal treatment.” order to get the best recommendations for the patients. This is a particularly complex job, as you also need to know the results obtained by other medical disciplines as well as those from your own specialty. In cancer care, you have to recognise and support the interdisciplinary aspect: no one has a monopoly on the ideal treatment alone. These collaborations are very important, firstly to define the best treatments for our patients, and secondly to secure (and defend) the position of IR. As we do not have the resources of the pharmaceutical industry for large randomised studies, we need the results of our treatments in large, prospective and controlled registries, which also have the advantage of presenting “realworld” results with a good level of evidence.

What has the experience been like working with the European Cancer Organisation to establish a European network for interdisciplinary research on the diagnosis and treatment of oncologic diseases, and why is this international collaboration so important?

My experience is in fact very positive: IO has found its place in most guidelines, and this is in the interest of the patients. Most oncologists recognise the value of our minimally-invasive therapies and know very well how to integrate our treatments into the therapeutic armamentarium that currently exists for cancer patients.

What developments in IO are you most excited about?

IO is one of the most fascinating and promising specialties in medicine. To mention just a few aspects, I would like to emphasise the extraordinary opportunity that we must seize as interventional oncologists working in what we refer to as “the era of personalised medicine”. There are few medical disciplines that are as patient-oriented as ours. Each therapy is individualised: the application, the doses of drugs that are applied under imaging control, the change of therapies, and the possibility to combine our treatments with systemic

Issue 82 | June 2021

Interview 23 treatments, surgery, or even radiotherapy. Another key development is the enormous interest in new targeted therapies in the immunooncology space. Who can deliver these new therapies more locally than interventional radiologists? Another is to boost the immune response by combining our local treatments with systemic therapies. This is a great opportunity for our specialty. The interventional radiologist can be at the centre of this evolution, at least for some cancers in selected patients, if we are able to participate in preclinical and clinical studies. I say participate and unfortunately not lead because I must admit that we are not the first doctors to be contacted by the pharmaceutical industry. To achieve this recognition we need first to make IR known to medical students (what could be more attractive than combining minimally-invasive treatments with minimised instruments, intelligent programmes, 3D images, and artificial intelligence). Second, we need to increase our influence in the education of young colleagues, to further the development of experts, and to be able to offer IO services in the same way that surgeons offer surgery: in all hospitals, not just in some specialised centres. Several scientific societies, such as the Cardiovascular and Interventional Radiological Society of Europe (CIRSE), are working hard on this.

What is the greatest challenge currently facing interventional radiologists?

Our position is much better recognised than it was 20 years ago, but there is still a lot to do. The main challenge is to establish IO truly as one of the four pillars of cancer care. It seems to me that it is less necessary to convince oncologists—good oncologists know the benefit we can bring to patients—than it is to inform them of what we can do in the first place. Still too many oncologists are not aware of the wide spectrum of treatments we have to help cancer patients. Another challenge I would like to mention here is the need to conduct good prospective clinical studies and to stop with retrospective studies on small cohorts that are generally not recognised for guidelines. Again, personalised medicine is a huge opportunity for interventional oncology.

alisonlang.com

What are your hobbies and interests outside of medicine?

Current appointment

Chair, department of Diagnostic Radiology, Minimally-Invasive Therapies, and Nuclear Medicine, SLKClinics, Heibronn University Karl Ruprecht, Heidelberg, Germany

Faculty

Board member, treasurer, fellow, honourary lecturer (2014), the Cardiovascular and

Interventional Radiological Society of Europe Chair, the European Conference on Interventional Oncology German Society of Radiology European Society of GastroAbdominal Radiology French Society of Radiology

Medical education

Medical student: University of Lille, Lille, France

I have a fantastic daughter, Anne-Sophie, of whom I am very proud, and with whom I try to make up for (past) lost time, and my wife, Bettina, with whom I have so many things in common. When I have some spare time, I take one of my electric guitars and play Hendrix, Led Zeppelin, Clapton... or at least I try to! My secondary hobby is definitely sports: tennis, jogging, and rowing, at least twice a week. When it rains, my reading is mostly focused on astronomy, from GNz11 to the acceleration of the universe and the quintessence!

Resident: Internal and Intensive Medicine, University of Lille, Lille, France Resident: Radiology, City of Minden Hospital, Minden, Germany Research fellow, clinical associate professor, professor: University of Tübingen, Tübingen, Germany

June 2021 | Issue 82

24 Peripheral interventions

ACC.21: SAFE-PAD finds no increased risk of death with drugcoated devices used for lower extremity revascularisation Researchers have found no statistically significant difference in mortality between patients treated with drug-coated devices and non-drug-coated devices in the SAFE-PAD study. Eric Secemsky (Beth Israel Deaconess Medical Center [BIDMC], Boston, USA) reported this conclusion at the American College of Cardiology’s 70th Annual Scientific Session (ACC.21, 15–17 May, virtual), with results published simultaneously in JAMA Internal Medicine. AT THE BEHEST OF THE US FOOD AND DRUG Administration (FDA), Secemsky and Robert Yeh (BIDMC, Boston, USA) designed the SAFE-PAD (Safety assessment of femoropopliteal endovascular treatment with paclitaxel-coated devices) study to provide information on the safety of paclitaxel-coated devices. Using claims data from the Centers for Medicare & Medicaid Services (CMS), the researchers evaluated survival following treatment with paclitaxelcoated devices in more than 160,000 leg artery revascularisation procedures conducted between 2015 and 2018. “Our study of Medicare beneficiaries includes more than 160,000 patients, comprising more than 30,000 patients with survival data extending past four years, making it one of the largest and most comprehensive evaluations of the safety of drug-coated devices to be published since the initial analysis,” said Secemsky. “Although the 2018 findings [reported by Konstantinos Katsanos (University of Patras, Patras, Greece) et al] raised concerns about the safety of these drug-coated

devices, there were many issues with that analysis— including the study’s small size and a lack of complete patient follow-up.”

Although the 2018 findings raised concerns about the safety of these drug-coated devices, there were many issues with that analysis— including the study’s small size and a lack of complete patient followup.”

Secemsky and colleagues’ study included Medicare patients treated with either a drug-coated or non-drugcoated peripheral device between 2015 and 2018 at nearly 3,000 hospitals across the USA. Deaths were evaluated through May 2020, and after accounting for any differences in demographics and comorbidities between the two groups, the investigators found no evidence that drug-coated devices were associated with higher mortality rates through an average 2.7 years of follow-up, with some patients having follow-up through five years. “We used a number of novel statistical methods to assure these results were accurate, and found consistent results across a number of different patient groups— including among those of lower overall risk, those with more severe disease, and those treated in outpatient centers,” Secemsky said. “We have provided these results to the FDA [US Food and Drug Administration] to make decisions on whether to continue to restrict these drug-coated devices to only those at high risk of needing another leg procedure, or to return to the previous indications where these were used without restriction.” The current publication is the first report of seven planned biannual reports as part of the SAFE-PAD study, which was designed to continue until all patients in the study had follow-up exceeding five years. As such, Secemsky and colleagues will continue to analyse these Medicare beneficiaries and update their findings until this study completes in late 2023. “The SAFE-PAD study is a model example for collaboration between industry, academia, and the FDA to carry out rigorously designed, real-world studies to evaluate important medical device safety signals,” said Yeh. “We believe that applying stringent scientific standards to observational studies can create greater confidence in validity of these ‘big data’ approaches to the evaluation of medical therapies.”

Study: Paclitaxel-coated balloons for the treatment of symptomatic central venous stenosis deemed safe A study recently published in the Journal of Endovascular Therapy (JEVT) found that use of paclitaxel-coated balloons for the treatment of symptomatic central venous stenosis was safe. Panagiotis M Kitrou (Patras University Hospital, Patras, Greece) and colleagues add that efficacy was comparable to previous trials, and that increased balloon size had a “significant” effect on patency rates.

his was a European, multicentre, investigator-initiated and run, single-arm retrospective analysis designed to assess the safety and clinical benefit of the use of paclitaxelcoated balloons for the treatment of symptomatic central venous stenosis, the authors write. They detail that 11 centres from seven countries across Europe submitted 86 cases performed during the period between October 2015 and June 2018. The mean age of the patients was 62.6 years (standard deviation [SD], 15.2

years) and median vascular access age was three years (interquartile range [IQR], 1.2–4.8 years), the investigators note. Regarding materials, Kitrou et al specify that the median drugcoated balloon diameter was 10mm (IQR, 8–12mm). In addition, they communicate that the balloons used were the Lutonix (BD) in 70 cases, the Elutax (Aachen Resonance) in nine cases, and the IN.PACT (Medtronic) in seven cases. The authors state that primary

Panagiotis M Kitrou

outcome measures were clinicallyassessed intervention-free period of the treated segment at six months and procedure-related minor and major

Patient survival was 79.7% at two years according to Kaplan-Meier survival analysis.”

complications; secondary outcome measures included access circuit survival, patient survival, and the investigation of independent factors that influence the intervention-free period. Writing in JEVT, Kitrou and colleagues report the following results: Intervention-free period was 62.7% at six months Median patient follow-up time was one year (IQR, 0.5–2.2 years) There was one minor complication (1/86; 1.2%) and no major complications Access circuit survival was 87.7% at six months Patient survival was 79.7% at two years according to Kaplan-Meier survival analysis Higher balloon diameters significantly favoured intervention-free period (hazard ratio [HR], 0.71 [0.55–0.92]; p=0.006).

Issue 82 | June 2021

Paclitaxel controversy 25

CX DIGITAL EDITION 2021

CX audience supports call to change agency recommendations regarding paclitaxel use in peripheral interventions Addressing representatives from the US Food and Drug Administration (FDA) and UK Medicines and Healthcare products Regulatory Agency (MHRA) directly, Thomas Zeller (Universitäts— Herzzentrum Freiburg, Bad Krozingen, Germany) argued at the Charing Cross (CX) Digital Edition 2021 (19–22 April, online) that “it is time to change the agency recommendations regarding paclitaxel use in peripheral interventions”. Moderators Andrew Holden (Auckland City Hospital, Auckland, New Zealand) and Gunnar Tepe (Rosenhein, Germany), Podium 1st presenters Gary Ansel (OhioHealth Heart & Vascular Physicians, Columbus, USA) and William Gray (Lankenau Medical Center, Wynnewood, USA), as well as a 71% majority of the CX audience, supported this view. WHILE THERE WAS AGREEMENT that it was right to be concerned about the paclitaxel mortality signal raised by Konstantinos Katsanos (University of Patras, Patras, Greece) et al in their December 2018 meta-analysis, there was strong consensus that the evidence is now clear there is no mortality effect when paclitaxel is used in the peripheral arteries. In addition, it was noted that several individual patient-level metaanalyses failed to confirm the high mortality signal flagged by Katsanos and colleagues. There was some discussion surrounding the place of limus as an alternative to paclitaxel, but experts agreed that there is no need to move to another drug—which would have its own set of challenges—given the proven safety and efficacy of paclitaxel. The takeaway message was clear: that, with proper caution and the correct dose, paclitaxel can and should be used in peripheral interventions.

More data find no mortality associated with paclitaxel

Patient safety has been at the centre of CX discussion on the paclitaxel issue since the Katsanos et al meta-analysis was published. This year, further data were presented that support the conclusion of vascular pathologist Elena Ladich (Memorial Healthcare System, Hollywood, USA) who two years ago at CX 2019 stated that there are “no causal links or mechanisms to explain the reported association of paclitaxel in the lower limbs and patient mortality”. Sabine Steiner (University of Leipzig, Leipzig, Germany) gave the first presentation on long-term paclitaxel data at CX 2021, outlining five-year results of the REAL-PTX study—an investigatorinitiated, prospective, European, multicentre randomised controlled trial (RCT) comprising 150 patients with femoropopliteal disease. Patients were randomised to treatment with either a drug-eluting stent (100% Zilver PTX,

Cook) or a drug-coated balloon (DCB; 77.3% IN.PACT Admiral/IN.PACT Pacific, Medtronic; 21.3% Lutonix, BD). Steiner reported that mortality rates after five years were “comparable to prior reports investigating long-term outcomes for drug-eluting and non-drug-eluting devices”. Also presenting data in support of the safety of paclitaxel, Mårten Falkenberg (University of Gothenburg, Gothenburg, Sweden) gave the latest analysis and interpretation of the SWEDEPAD trial concerning mortality. “It is very unlikely that devices coated with paclitaxel used for the treatment of peripheral arterial disease [PAD] do increase late mortality”, he concluded. In a Podium 1st presentation on the topic, Holden, on behalf of coauthors Ramon Varcoe (Prince of Wales Hospital, Sydney, Australia) and Peter Schneider (University of California San Francisco, San Francisco, USA), revealed a five-year meta-analysis update regarding drugcoated technologies in femoropopliteal interventions and all-cause mortality concerns that included the SWEDEPAD update. Holden stressed that there is a “clear benefit of paclitaxel-coated devices in femoropopliteal disease” and relayed that the investigators recommend the continued use of these devices in this patient population. “The time has arrived for regulators to provide updated and clear guidance on these devices for the benefit of patients globally”, he stated.

Consensus that paclitaxel recommendations need to be changed

With a growing pool of data showing no association between paclitaxel and mortality, representatives from the FDA and MHRA reiterated current agency positions on the topic. Sara Royce, team lead of the plaque modification devices team at the FDA, talked the CX audience through regulatory approaches

to the next-generation of drug-coated devices for PAD. Roopa Prabhakar, senior medical devices specialist at the MHRA, offered a UK perspective on paclitaxel device regulation, saying the agency will “continue to assess the significance of any new data in relation to patient safety”. Following these presentations, Zeller argued that it is time to change the agency recommendations regarding paclitaxel use in peripheral interventions. “Withholding such devices to patients with severe peripheral arterial occlusive disease may even harm them and result in increased global healthcare costs”, he stated, concluding that “the benefit outweighs the hypothetical risk”. Audience polling following Zeller’s talk revealed that 74% of the audience agree it is time to change the agency recommendations regarding paclitaxel use in peripheral interventions.

“What you do not leave behind is a suboptimal result”

In a Podium 1st presentation, Gary Ansel (OhioHealth Heart & Vascular Physicians, Columbus, USA) announced

persistent residual stenosis >50%, flow limiting dissection), the addition of a stent did not appear to decrease the optimal results through five years”. In the discussion following Ansel’s presentation, the presenter stressed that, regardless of whether or not you leave a stent behind, “what you do not leave behind is a suboptimal result, just to not leave a prosthetic device in. That is the worst thing to leave behind.”

Time to look at “the whole patient”

Gray delivered another Podium 1st presentation, giving the five-year results from a patient-level meta-analysis of the ILLUMENATE RCTs. He told attendees how “The Stellarex DCB continues to consistently demonstrate no difference in mortality compared to percutaneous transluminal angioplasty (PTA) yearover-year through five years, both within individual RCTs and pooled analysis.” When asked by moderator Robert Hinchcliffe (University of Bristol, Bristol, UK) if this was “the definitive trial to put the paclitaxel issue to bed”, Gray commented: “When you ask a US physician what puts an issue to bed, that is when the FDA rescinds their Clockwise from top left: Roger Greenhalgh (London, UK); Andrew Holden (Auckland, New Zealand); Gunnar Tepe (Rosenheim, Germany); Thomas Zeller (Bad Krozingen, Germany); Roopa Prabhakar (MHRA, London, UK); and Sara Royce (FDA, Silver Spring, USA).

The time has arrived for regulators to provide updated and clear guidance on these devices.” results of the IN.PACT Global stented versus non-stented analysis, comprising 353 patients stented and 1,044 nonstented patients. The purpose of this study was to compare outcomes of standalone IN.PACT Admiral DCB usage versus IN.PACT Admiral DCB followed by provisional stenting. Ansel concluded that, in this complex lesion subset from the study, the IN.PACT Admiral DCB “demonstrates durable safety and effectiveness through five years”. He added: “In the event of suboptimal angioplasty results (i.e.

statement about danger. In order for them to do that, I think we have to see a high quality, patientlevel meta-analysis that includes all the original studies included in Katsanos’ meta-analysis, followed up to five years, plus all the other datasets that have come forward since that time. The key piece here, that we do not talk enough about but we need to recognise, is that the missing data, which were on the order of 20% of the original analysis, even at the patient level, are now only about 5%, as we have gone back and done all the vital statistics. I think that will make a big difference in the ultimate analysis.” Ansel chimed in to comment on the fact that mortality is largely due to cardiovascular issues or cancer. “I do not think we are really focussed on that,” he said. “Forget the paclitaxel, which has been really put to bed, and let us get back to good patient care and see if we can decrease those cardiovascular and cancer rates.” Gray agreed, saying that the “major message” was that cardiovascular risk factor modifications (smoking cessation, diabetes and hypertension management) were important to consider, and that it was time to look at “the whole patient”.

June 2021 | Issue 82

26 Breakthrough imaging technology

Fiber Optic RealShape used in the USA for first time Vascular surgeons at the University of Massachusetts became the first in the USA to carry out procedures using the breakthrough imaging technology Fiber Optic RealShape (FORS; Philips), reporting a 75% decrease in radiation use after one of their earliest experiences of the system—a fenestrated endovascular aneurysm repair (FEVAR) of a thoracoabdominal aortic aneurysm (TAAA).

ndres Schanzer, professor and chief of Vascular Surgery at the University of Massachusetts Medical School in Worcester, USA, whose team is at the vanguard of the technology’s debut Stateside, describes the platform as representing “a transformative change” in how surgeons navigate vascular anatomy. FORS is currently available at a limited number of centres in Europe and the USA as it continues to undergo clinical study. The technology has CE mark approval in Europe and is US Food and Drug Administration (FDA) 510(k) cleared. The platform, which enables realtime 3D visualisation of the full shape of devices inside the body without the need for stepping on the fluoroscopy pedal, sends pulses of light through hair-thin optical fibres within minimally-invasive devices. Schanzer illustrates how a busy complex aortic practice at his institution currently depends on X-ray imaging for the entirety of procedures. “What FORS has enabled us to do is to really get away from using X-ray for all of the steps of the procedure,” he tells Interventional News in an interview shortly after undertaking his third procedure with the platform. “Fibre optic wires and catheters decrease our reliance on X-ray.” In addition to the decreased radiation and lowered procedure time FORS allows, Schanzer continues, another notable advantage includes an ability to work with completely new angles than those to which vascular surgeons are accustomed with X-ray. “There is no limitation on having to move a C-arm gantry around a patient,” he says. “You can be looking at several different angles, like a biplane view, at the same time. “I think it is going to change the way we look at all vascular interventions.” Quantifying the exact radiation reduction is going to take time and data to determine, Schanzer says. But by his third case, the four-vessel type II TAAA FEVAR, his team was able to decrease radiation use compared to their mean for that extent of repair from an average of 88 minutes down to just 22 minutes, or 75%. “We are at the very start of our learning curve,” Schanzer says, reporting that by the end of May he and colleagues should have completed six cases with FORS. “We are really trying to see exactly where it fits in and how to maximise its use, and maximise the benefits to patients.” FORS is expected to be rolled out to a total of five US centres as part of clinical trials, in addition to the same number in Europe. Shortly before FORS’ debut in the USA, during the Charing Cross (CX) 2021 Digital Edition (19–22 April, online), Gustavo Oderich, professor and chief of Vascular and Endovascular Surgery at the University of Texas’ McGovern Medical School in Houston, USA,

emphasised its potential, suggesting that “radiation will be a thing of the past” thanks to this new technology. “I have always had a really strong interest in imaging,” Schanzer comments. “I believe the imaging side of what we do is just as important as the device side. This is certainly the biggest leap forward that I have seen in my career with regards to the imaging.” Ultimately, the technology is at the start of its journey, he adds. “Currently, we have only used it in complex aortic procedures, but I very much see us broadening the

Oderich stated that FORS “addresses a major area of need, which is the ability to look at the anatomy on any view we want without being radiated”, highlighting that the technology offers both an ease of technical success and parallel reduction of radiation. Following Schermerhorn’s presentation, a Philips’ Meet the Experts session offered a deep dive into FORS technology, with a panel of users and experts discussing latest clinical experience and three-dimensional (3D) catheter agnostic guidance. Discussants were Tilo Kölbel (German Aortic Center and the University Heart Center, Hamburg, Germany), Geert Schurink (Maastricht University, Maastricht, The Netherlands), Joost van Herwaarden (UMC Utrecht, Utrecht, The Netherlands), and Schanzer, speaking a week ahead of when the system was installed at his institution. The first person to ever use the FORS technology both on a model and in humans, van Herwaarden offered his insights during the CX Digital Edition. “For the first time, it is possible to see your catheters and wires in 3D. When I was using this in models, my first thought was ‘We need to have this in patients’. It took many years, but we started using it in patients in 2018. We now only use one wire and two catheters; getting used to that one wire and two catheters has been a pleasure.” Clockwise from top left: Roger Greenhalgh (London, UK); Bijan Modarai (London, UK); Gustavo Oderich (Houston, USA); Marc Schermerhorn (Boston, USA); Konstantinos Spanos (Larissa, Greece); and Enrico Rinaldi (Milan, Italy).

applicability in all types of vascular cases. “This is a first-generation technology, and I think there is still room for improvement as we expand the devices, the catheters, and the wires that are enabled with this technology. I think that is going to happen very quickly. This proof of concept we have already seen in a few cases that have been done around the world really shows the enormous value that this technology holds.” Oderich was speaking in his capacity as moderator during a livestreamed session where expert panellists deliberated crucial controversies in the abdominal aortic space, and his remarks were made in

I think it is going to change the way we look at all vascular interventions.” response to a presentation from Marc Schermerhorn (Havard Medical School, Boston, USA). Schermerhorn echoed Schanzers’ sentiments, calling the FORS technology “disruptive”. In an ensuing panel discussion on the topic of radiation,

Kölbel, as the second user of the FORS system in humans, spoke next, commenting on its use in complex endovascular aneurysm repair (EVAR) cases. “It has almost been a year [since we first used this system in humans], but I also still remember my first experience with using FORS in a bench-top model and in an animal model some years ago. It was a mind-blowing experience. I had heard about it, and seen images, but really getting your catheter and wire displayed in 3D and colour was an almost-to-goodto-be-true feeling. It worked very well, and today we use this as a standard, almost, in complex aortic repair and fenestrated and branched abdominal cases. It is a significant change, not only for the operator. The whole team is, I think, excited about the introduction of the colour TV in the hybrid room. Maybe Gustavo [Oderich] is going to be proven right in a few years—in the same way no one notices colour TV anymore, as it is so normal, maybe FORS will become the ‘new normal’ in a few years.” Schurink added: “We started [using the FORS system] at the end of 2020. We have now performed about 25 cases using the technology—it is a completely new experience. It is not only about reducing radiation, but also the virtual biplane [which allows users to see two views simultaneously] is one of the top features of this system. It is very important, and offers a different way of looking at the patient.”

Joost van Herwaarden

June 2021 | Issue 82

28 Lower extremity revascularisation

ACC.21: VOYAGER PAD analysis shows reduced risk of ischaemic events in PAD patients receiving rivaroxaban Rivaroxaban (Xarelto, Bayer/Janssen), in addition to low-dose aspirin, should be considered as an adjunctive therapy after lower extremity revascularisation to reduce first and subsequent adverse outcomes, analysis from VOYAGER PAD, presented during a late-breaking trial session at the American College of Cardiology’s 70th Annual Scientific Session (ACC.21, 15–17 May, virtual), indicates. The findings were simultaneously published online in the Journal of the American College of Cardiology (JACC).

upert Bauersachs, director of vascular medicine at the Darmstadt Clinic (Darmstadt, Germany) and lead author of the study, told ACC.21 attendees that the use of rivaroxaban significantly reduced the occurrence of total severe events of the heart, limb, or brain and issues related to other vascular complications in patients with symptomatic peripheral arterial disease (PAD) who underwent lower extremity revascularisation. The findings underscore the broad benefits of this strategy in this high-risk patient population, he said. “To our knowledge, this is the first time that the addition of low-dose rivaroxaban to aspirin has been clearly shown to reduce the occurrence of both first and total adverse events in patients with PAD who have undergone lower extremity revascularisation but remain at high risk for a heart attack, stroke or recurrent arterial blockage in a limb,” Bauersachs said. “The benefits we saw in the trial for total events were statistically significant and entirely consistent with those for first events. Rivaroxaban 2.5mg twice daily with aspirin should be considered as adjunctive therapy after revascularisation to reduce first and subsequent adverse outcomes.”

“A need for greater awareness that PAD is a distinct disease state”, ACC audience told

Recent data have shown that, after lower extremity revascularisation, there is a four-fold risk of acute limb ischaemia, Bauersachs told ACC.21 attendees, adding that this is associated with a high incidence of limbrelated complications. “There is a need for greater awareness that PAD is a distinct disease state and that patients with PAD have a high risk for cardiovascular adverse events and are generally a very vulnerable population, especially in the post-revascularisation setting,” Bauersachs said. “Care for these patients is often fragmented because the surgeon or interventionalist who performs the revascularisation may not follow them for complications or recurrences. They deserve to receive optimal treatment to reduce the risk of recurrences.”

The research team reported in a late-breaking clinical trial presented at ACC.20/WCC that VOYAGER PAD met its primary endpoint, with a 15% statistically significant reduction in the risk of a first major adverse limb or cardiovascular event seen in patients who received rivaroxaban compared with those who received the placebo. The current study reports on the total number of vascular events, with over 4,700 occurring in the 6,564 patients randomised across three years. “There were 342 fewer adverse events in the rivaroxaban group than in the placebo group, which translates to an absolute reduction in risk of 12.5%,” Bauersachs said. “In a high-risk population, that is a big gain in avoiding the need for patients to come back with vascular complications.” The 6,564 study participants experienced a total of 4,714 vascular events during the study period with 2,301—or about one third—experiencing at least one

To our knowledge, this is the first time that the addition of lowdose rivaroxaban to aspirin has been clearly shown to reduce the occurrence of both first and total adverse events in patients with PAD who have undergone lower extremity revascularisation but remain at high risk for a heart attack, stroke or recurrent arterial blockage in a limb.”

The VOYAGER PAD trial

The randomised, double-blind VOYAGER PAD trial enrolled 6,564 patients in 34 countries who had PAD and had undergone lower extremity revascularisation. The patients’ median age was 67 years and 74% were men. Patients were randomly assigned to receive either rivaroxaban or a placebo in addition to daily aspirin. The trial’s primary endpoint was timed to the first event of a composite of acute limb ischaemia, major amputation of vascular aetiology, myocardial infarction (MI), ischaemic stroke or cardiovascular death. Another prespecified endpoint was the total number of vascular events, including recurrent primary endpoint events as well as other vascular events. The median follow-up time was 28 months after revascularisation.

Rivaroxaban (Xarelto, Bayer/ Janssen)

vascular event, Bauersachs said. “So, during approximately three years of follow-up, about two-to-three out of six patients with PAD had a vascular event in spite of high utilisation of background medical therapy. This overall rate of vascular events is eye-opening and speaks to the high vulnerability of this patient population,” Bauersachs said. “First events are just the tip of the iceberg.”

Study limitations

A limitation of the study is that the trial was designed to assess the occurrence of first adverse events following lower extremity revascularisation, Bauersachs said. Therefore, in a double-blinded trial, patients may come off study treatment or go on to other therapies after an event, which can attenuate the observed benefit. Assessment of the total number of adverse events,

Rupert Bauersachs speaking at the American College of Cardiology’s 70th Annual Scientific Session (ACC.21)

however, was a prespecified secondary endpoint and, despite this limitation, the findings were statistically significant and robust in absolute terms. VOYAGER PAD was funded by pharmaceutical companies Bayer and Janssen, who in a press release highlighting the presentation of the results, said that the analysis showed a very high burden of subsequent events and a consistent 14% reduction in both primary endpoint events and total vascular events over a median of 2.5 years. “The VOYAGER PAD trial is the first and only study of antithrombotic therapy in the past 20 years to demonstrate a significant benefit in patients with PAD after lower extremity revascularisation,” James List, global therapeutic area head, Cardiovascular & Metabolism, Janssen Research & Development, was quoted as saying in the release. “With these new data, we now have a full picture of evidence demonstrating the potential of Xarelto in treating patients through various stages of PAD— chronic, symptomatic, those requiring revascularisation and beyond,” he added. “Even years after revascularisation, patients with PAD continue to have a markedly high risk for future thrombotic events due to excessive thrombin generation and platelet aggregation,” added Marc P Bonaca, Department of Medicine, Division of Cardiovascular Medicine, University of Colorado Anschutz Medical Campus, (Aurora, USA). “This analysis from VOYAGER PAD looked beyond the first event and found subsequent thrombotic event reduction with rivaroxaban plus aspirin, underscoring the importance of long-term prevention in these highrisk patients.” Prior to this most recent ACC.21 presentation, another VOYAGER PAD analysis was presented by Connie Hess (University of Colorado, Aurora, USA) at the 2020 Vascular and Interventional Advances conference (VIVA; 6–8 November 2020, online), which found no excess mortality, and improved limb outcomes, with drug-coated device use in patients with PAD.

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Issue 82 | June 2021

Atherectomy 31

Results of two-year study show Zilver Vena Venous Stent is safe and effective

stent integrity through two years. The Zilver Vena Venous Stent met primary endpoints for both safety and effectiveness, with a 96.7% rate of 30day freedom from major adverse events and an 89.9% rate of 12-month primary quantitative patency. the inguinal ligament,” he said. “In this In addition, Hofmann said the mean study, more than 20% of stents extended change (-3.0; p<0.0001) in VCSS from into this region, and there were not any baseline was “significant” at one month stent fractures.” and was sustained through 12 months The VIVO Clinical Study took place (-4.2), and maintained at two years. between December 2013 and October Specifically, two-year outcomes included 2016, and enrolled 243 patients (70% high rates of patency by ultrasound female; mean age: 53±15 years) with (90.3%±2.2%), freedom from clinicallysymptomatic obstruction driven reinterventions of one iliofemoral venous (93.2%±1.8%), and freedom segment. from reinterventions Data assessed during the (83.4%±2.5%). study included baseline patient “This landmark study characteristics, primary and moves the ball forward secondary endpoints—such as in the treatment of deep 30-day freedom from major venous disease,” Hofmann Lawrence Hofmann adverse events, 12-month concluded. primary quantitative patency, and These two-year data follow changes in venous clinical severity score positive one-year data presented by (VCSS) from baseline to one month Anthony Comerota (Inova Fairfax and 12 months—as well as patency, Hospital, Alexandria, USA) in a reintervention, clinical outcomes and late-breaking session of the 2020

The results of a two-year study support the continued safety and effectiveness of the Zilver Vena Venous Stent (Cook Medical) in treating symptomatic iliofemoral venous outflow obstruction, according to findings presented at the 2021 meeting of the Society of Interventional Radiology (SIR; 20–26 March, online). THE STENT MET PRIMARY safety and effectiveness endpoints at one month, and continued to do so through one- and two-year intervals during the VIVO Clinical Study. In addition, the Zilver Vena Venous Stent demonstrated high rates of patency by ultrasound, freedom from clinicallydriven reinterventions and freedom from reinterventions more generally throughout—all of which were clinical outcomes being assessed in the study. According to Lawrence “Rusty” Hofmann, professor of interventional radiology at Stanford Medicine (Stanford, USA) and the study’s presenting author, the stent’s integrity was also indicated by the fact there were no core laboratory reports of stent fractures across the twoyear study period. “There has been concern over the years at some centres about stenting below

“A new look at laser”: Positive initial data presented at ISET for the Auryon atherectomy system The Auryon atherectomy system (AngioDynamics) “represents an exciting new technology”, John Rundback (Advanced Interventional and Vascular Services, LLP, Teaneck, USA) opined at the International Symposium on Endovascular Therapies (ISET; 9–11 May, Miami, USA, and online), speaking on behalf of the Pathfinder I registry investigators. “I think it has really got a lot of traction; we found it a very useful tool across a wide range of plaque morphologies and vessel beds. Further iterations of this platform will hopefully improve its performance further.” THE PATHFINDER REGISTRY IS a post-market, prospective, multicentre, single arm, all-comers registry of 104 patients with femoropopliteal and tibial stenoses or occlusions or in-stent restenosis (ISR), with peripheral arterial disease (PAD) classified as Rutherford class 2–5. “Lesions of all levels, lesions of all types are included in this realworld registry,” Rundback said. Patients were treated with either the Auryon atherectomy system or adjuvant therapy. The primary endpoints were acute success (measured as ≤30% final residual stenosis by corelab evaluation) and freedom from peri-procedural major adverse events or complications through 30 days. Long-term results were collected through 24 months, including patency, major adverse events, target lesion revascularisation, and patientreported outcomes.

Presenting the findings, Rundback said: “These are really important results I think. Across the board, the stenosis reduction or the luminal gain was between 24 and 31%; this is the laser-cut phenomenon that I think is unique to this laser. In CTOs [chronic total occlusions], there [is an average] 26% luminal gain. [In vessels with] moderate to severe calcium, there was a 27% luminal gain, [in vessels with] ISR, [there was a] 21% luminal gain, and above and below the knee, we see similar levels of luminal gain. So it does not matter what vessel, what vessel calibre, or what the plaque morphology is, this is a very precise, deliverable, controllable, and reproducible result.” In terms of safety, there was an absence of major adverse events in 99% of lesions. There was one dissection, which was after angioplasty alone, not

Vascular Interventional Advances conference (VIVA; 6–8 November, online). Responding to these results during VIVA 2020, fellow panellist Kenneth Cavanaugh (US Food and Drug Administration [FDA] Office for Cardiovascular Devices, Silver Spring, USA) was interested in the potential value of adding a comparator into these studies now that there are other stents in the market. This prompted Comerota to say that certain factors would need to be taken into account in any head-to-head comparison of venous stents, including the potential for lesion length to vary widely.

There has been concern over the years at some centres about stenting below the inguinal ligament. In this study, more than 20% of stents extended into this region, and there were not any stent fractures.”

after laser passage. perforations were There were two cases reported. There is also of distal embolization, less overall thermal one of which Rundback damage to the vessel said was “probably wall, he explained, attributed to the laser”, and the laser system and one of which was is agnostic to the following the treatment presence of contrast. It of an in-flow lesion also requires minimal that had angioplasty, warm-up time: “From a shockwave, and practical point of view, it atherectomy. There only needs a 15 second were a total of four warm-up; if you do not Auryon atherectomy system bailout stents, three of like where it is placed in which were for recoil the room, you can pick it and one of which was for dissection. up and move it to another spot.” There was one amputation, which Four catheters of varying sizes occurred 180 days after follow-up; the (0.9mm, 1.5mm, 2mm, and 2.35mm) can patient had Rutherford category 5 disease be used wih the system. and gangrene at baseline, and they failed The Pathfinder registry builds on to improve following treatment of their prior investigational device exemption 37cm-long lesion. (IDE) and CE studies, which combined The Auryon atherectomy system is investigated 147 patients with 163 a proprietary, solid-state laser with a lesions. These reported no distal emboli wavelength of 355nm (different to the events or perforations. Of 107 lesions currently-available 308nm laser). “What included in the IDE study, 16 were is really unique about this is it is not just minor (grades A or B). In terms of the wavelength, but it has a very short debulking, there was a 34% reduction pulse duration of 10ns, which results post-procedure (the FDA threshold for in a very precise, controllable, and efficacy is 20%). “Clinical results and reproducible laser energy delivery to the patient-reported outcomes were very vessel wall,” Rundback explained. favourable at 12 months,” Rundback He went on to describe how this said. particular wavelength (355nm) has Session moderator Daniel Clair a “very high” affinity for atheroma (Vascular Surgery, University of South compared to the vessel endothelium, Carolina, Columbia, USA) praised resulting in a reduced risk of perforation. Rundback for his talk, saying it offered, Indeed, in the Pathfinder I trial, no “A new look at laser”.

June 2021 | Issue 82

32 Chronic limb-threatening ischaemia

New tools for CLTI: ISET audience hear what developments they can expect for these challenging patients “I am going to give you reasons to be excited about your critical limb practice,” Peter Schneider (University of California San Francisco, San Francisco, USA) told delegates attending the International Symposium on Endovascular Therapy 2021 (ISET; 9–11 May, Miami, USA), in a talk focusing on innovative tools on the horizon for the treatment of chronic limb-threatening ischaemia (CLTI). “I think critical limb ischaemia has come to the forefront of our practices and of community awareness, and finally now the tools are starting to show that,” he opined.

overing developments in assessment (including monitoring, perfusion, and wound evaluation), reconstruction, and medication delivery, Schneider left his audience with an optimistic outlook for the future of CLTI treatment.

Assessment: Wearables, implantables, and artificial intelligence

Turning first to wearables and implantables, which he said “are just around the corner”, Schneider expanded: “[In terms of] implantables, there is a patent application for a stent with a sensor on it, which of course makes sense that someday that is how we will be doing our surveillance. “Wearables are available now, and are essentially a transfer from other types of technology.” Citing a JAMA Network Open article from late-2020, which looked at the association between wearable device–based measures of physical frailty and major adverse events following lower extremity revascularisation, Schneider said he expected to see “more articles like this one”, adding: “I am sure we are going to have [investigations into the use of wearable devices to assess frailty] for claudication patients on a regular basis as well.” In addition to wearables and implantables, he also directed the ISET audience’s attention towards the use of artificial intelligence (AI): “A couple of companies have taken it upon themselves to do a digitised wound evaluation, and then use AI to help the programme get smarter over time about identifying the cause of the wound and the progress of the wound. So much of what we are doing is an inexact science: when we think of screening, population management, treatment guidelines, we are thinking about the population as a whole, and just trying to do the right thing, but each of these patients comes having their own code and their own set-up, so the transfer of existing technology I think will help us to individualise the way we would like to.

Reconstruction: Modified balloons, new implants, alternative bypass, below-theankle angioplasty “Below-the-knee [BTK] angioplasty is just sitting there waiting for us to really develop it,” Schneider stated, telling delegates listening in Miami and online that the medical community is now starting to see data showing improved wound healing. However, he noted that the patency data are “still unclear”, and, in his opinion, need to be further assessed. “But I think we are really developing [in this arena],” he concluded. The speaker first highlighted the lithotripsy with Shockwave. Lithotripsy waves travel outside the balloon, and disrupt both superficial and deep calcium. It is a way to improve vessel wall compliance prior to controlled, low pressure dilatation. “The question is how valuable is this going to be in BTK interventions?” Schneider asked. “I think it remains to be seen, but it certainly is a technology for interrupting calcium.” Another technology Schneider considered was serration angioplasty. Noting his conflict of interest due to his involvement with Cagent Vascular, a developer of serration technology for vessel dilatation

in endovascular interventions, Schneider explained how the novel Serranator percutaneous transluminal angioplasty (PTA) serration balloon catheter works: “The idea is that you poke little holes in the artery, and allow a stress relief line along the vessel so that it can be opened. I really believe that BTK angioplasty is due for a makeover by one method or another, and here is just an example of the flexibility of this tool.” The Serranator PTA serration balloon catheter is the first and only angioplasty balloon to receive US Food and Drug Administration (FDA) approval and the CE mark that embeds serration technology into a semicompliant balloon for treating peripheral arterial disease (PAD). Earlier this year, results of Cagent Vascular’s PRELUDE-BTK study—a prospective, single-arm, multicentre feasibility study investigating the safety and efficacy of serration angioplasty—were presented at the Leipzig Interventional Course (LINC; 25–29 January, online). Forty-six patients were treated with the Serranator device and 53 lesions were analysed by the core lab. The average final residual stenosis was 21.8%, with an average BTK arterial lumen gain of 1.55mm. These results were achieved with a low average maximum atmospheric pressure of six atmospheres. The bailout stent rate was 1.9%. A subset of lesions (n=10) were

If percutaneous femoralpopliteal bypass is shown to be safe and effective, similar to the outcomes demonstrated in DETOUR1 study, it could be a game changer for the way we treat complex, long-segment SFA disease today.” imaged with optical coherence tomography (OCT) and intravascular ultrasound (IVUS), and analysed by a core lab. All showed a serration effect. At 30 days, the freedom from primary safety events was 95.7%. Freedom from clinically-driven target lesion revascularisation (TLR) was 97.7%, and there were no serious adverse events related to the device. Following this discussion on modified balloons, Schneider turned to a new method of postangioplasty dissection repair: focal dissection repair. He showcased a new implant, the Peter Schneider Tack endovascular

system (Intact Vascular), the first FDA-approved vascular implant for BTK post-angioplasty dissection repair. Regulatory approval for the device was based on data from Intact Vascular’s Tack optimised balloon angioplasty II BTK (TOBA II BTK) clinical trial, which met all primary endpoints with 100% acute dissection resolution. The TOBA II BTK results demonstrated 95.7% amputation-free survival, 87.3% target lesion patency, with significant improvement in toe-brachial index (TBI), and 92% freedom from clinically-driven reintervention at six months. Schneider mused: “The issue is; do we need IVUS? We know IVUS is more sensitive—all of the trials we did with focal dissection repair were angiographicallydriven. However, could the results have been better if we used IVUS routines? Just something to think about as BTK disease gets more sophisticated, what will the role of IVUS be?” Another implant Schneider explored in his presentation was a bioabsorbable vascular scaffold, the Abbott Esprit. This is an everolimus-eluting device, designed for the superficial femoral artery and iliac arteries. Recently-published data from Ramon Varcoe (Sydney, Australia) and colleagues show “excellent” patency out to five years. The LIFE-BTK randomised controlled trial, where participants will be randomised 2:1 Esprit versus PTA, is now enrolling in the USA. Lastly, in the “reconstruction” portion of his talk, Schneider mentioned percutaneous bypass. “The mean lesion length in the PQ bypass trial is in excess of 30cm, so we have not typically had an option for lesions of that length using percutaneous devices,” he announced. DETOUR II is a prospective, multicentre trial evaluating the Detour system (PQ Bypass) for percutaneous femoral-popliteal bypass in patients with extremely long, complex lesions in the SFA. The study enrolled 202 patients in 36 sites in the USA and Europe, and is assessing freedom from major adverse events (MAEs) within 30 days of the index procedure as the primary safety endpoint. The primary effectiveness is primary patency at 12 months. Speaking to Interventional News about the potential of percutaneous bypass, principal investigator Jihad Mustapha (Advanced Cardiac and Vascular Centers, Grand Rapids, USA) said at the end of 2020: “If percutaneous femoral-popliteal bypass is shown to be safe and effective, similar to the outcomes demonstrated in DETOUR I study, it could be a game changer for the way we treat complex, long-segment SFA disease today.”

Medication delivery: “Paclitaxel issue” opened the door wider for research into alternative drugs

“We do not have any paclitaxel BTK drug-coated balloons (DCBs) in the USA,” Schneider said. While he noted that there are several paclitaxel DCB trials currently underway in the USA—he showed three of them: IN.PACT DEEP, Lutonix BTK, and BIOLUX P-II—he commented that “nothing is close to being approved”, though some show promise. “In particular, Medtronic has some preliminary data,” he said, before continuing: “My personal opinion is that the paclitaxel issue will fade over time. I think we have had such a hard time finding a danger signal in any subsequent data. Nevertheless, the whole issue has bought forward the concept of limus-based compounds.” The “paclitaxel issue” he is

Issue 82 | June 2021

Peripheral arterial disease 33

referring to here is the increased association with mortality reported by Konstantinos Katsanos (University of Patras, Patras, Greece) et al in December 2018 when paclitaxel devices are used in the lower leg, which caused an international furore about the safety of these devices. Since, multiple analyses have failed to replicate this signal, but, as Schneider pointed out at ISET, the publication opened the door wider for research and development into alternative drugs. “Here is just one,” Schneider said, showcasing the MEDAlliance Selution, a sirolimus-coated balloon from Swiss start-up MedAlliance. “This is their SFA device. It uses micro-reservoirs made out of biodegradeable polymer intermixed with sirolimus for sustained and controlled drug release—typically, the slow and difficult uptake has been the problem with sirolimus.” MedAlliance’s planned clinical programme includes specific trials focusing on BTK disease (SELUTION BTK IDE) and CLTI patients (PRESTIGE, PRESITINE, and STEP). Concept Medical, another start-up, from India, has recently published a first-in-human series from its XTOSI study, demonstrating good six-month primary patency of its MagicTouch PTA sirolimuscoated balloon in the treatment of BTK arterial lesions, in addition to femoropopliteal lesions. In addition, the US-based company Surmodics has a

Below-the-knee angioplasty is just sitting there waiting for us to really develop it. However, the data are still unclear.” BTK DCB (the Sundance DCB) currently in a firstin-human trial. “There is also a method of administering limus-based compounds using the Mercator Bullfrog catheter,” Schneider said, which has 510(k) clearance. The Bullfrog device delivers generic dexamethasone to the adventitia, reducing inflammation that can be caused by interventional revascularisation. Delivery is confirmed with the coadministration of contrast. The final technology Schneider mentioned is the “Eluvia-type technology”, seen in the SAVAL BTK drug-eluting stent system from Boston Scientific, which utilises a polymer as well as paclitaxel, and has been successful in SFA trials. It is now being enrolled in BTK trials. The SAVAL BTK stent system was the first CLTI device to be recognised by the FDA breakthrough device programme.

‘Expensive interventions do not necessarily correlate with good results’: Stenting found to significantly reduce mortality risk in PAD patients Stenting reduced mortality risk in patients undergoing interventions for peripheral arterial disease (PAD) by more than 30% when compared to plain balloon angioplasty and 40% contrasted with atherectomy, a recent propensity-matched analysis found. THE VASCULAR QUALITY Initiative (VQI)-derived data drew sharp conclusions from lead investigator of the study, Dipankar Mukherjee, MD, who trailed his probe into the effects of PAD interventions on survival to most recent follow-up by highlighting that most of these procedures involve claudication patients. “Expensive interventions do not necessarily correlate with good results,” Mukherjee told attendees of the International Symposium on Endovascular Therapy (ISET) held in Miami (May 9–11), where he presented his findings. “What has been good for the bottom line of the OBL [office-based lab] may be fatal for the patient. We recommend a critical reappraisal of the treatment paradigm for PAD patients presenting with claudication. We believe the current CMS [Centers for Medicare & Medicaid Services] reimbursement for atherectomy has resulted in unintended consequences.” Mukherjee, chief of vascular surgery at Inova Fairfax Hospital in Falls Church, Virginia, earlier set out the current context of PAD interventional

practice: While PAD interventions double every decade, the more severe form of the disease, critical limb ischemia (CLI), occurs in only a small percentage. More than a decade ago, there were CMS payment system changes governing the outpatient setting. That led to the rise of the OBL. Most PAD interventions are now carried out in OBLs. Atherectomy, most frequently performed in OBLs, is the most highly compensated PAD intervention at between $15,000 and $18,000. “This massive increase in OBL volume has not resulted in cost savings as it was originally intended,” Mukherjee added. To arrive at their conclusions, Mukherjee and colleagues, plumbed the VQI database for claudication and CLI interventions between May 2011 and February 2020, linking the data extracted with survival data from the Social Security death index—the primary outcome measure being survival to most recent follow-up. PAD interventions were classified as either balloon angioplasty alone, stenting with and without a balloon, and atherectomy with or without stenting or a balloon.

The researchers compared three between balloon angioplasty and matched cohorts: those receiving balloon atherectomy (HR, 1.02; CI 0.88–1.19; angioplasty versus those who underwent p=0.776 ). Meanwhile, stenting was stenting; patients who received balloon found to be superior to atherectomy angioplasty versus patients undergoing (HR, 0.6; CI, 0.48–0.75; p<0.001). atherectomy; and those who had a stent When claudication patients were placed versus the atherectomy patients. separated from those with CLI, A total of 15,281 patients were Mukherjee and colleagues found a included in the study: 9,441 received survival benefit in favor of stenting balloon angioplasty, 3,547 got a stent over balloon angioplasty (HR, 0.49; and 2,293 had atherectomy. After CI 0.4–0.59; p<0.001). They detected propensity matching, a group of 3,047 no difference between angioplasty and remained to compare between balloon atherectomy, but their data demonstrated angioplasty and stenting; a “highly significant” HR of 2,016 for comparison of 0.55 in favor of stenting vs. angioplasty and atherectomy; atherectomy (CI, 0.43–0.69; and 1,656 between stenting p<0.001). and atherectomy. “When we look at Patients were almost CLI alone, there was a equally divided between trend toward significant, claudicants and CLI. Most but with a confidence interventions were performed Dipankar Mukherjee interval exceeding 1, these in the femoropopliteal-tibial numbers are not considered segment, with the exception of a larger statistically significant,” Mukherjee proportion of stenting having been added. carried out in the aortoiliac segment. Discussing his findings, Mukherjee Results show a “highly, highly told ISET delegates have reported significant” hazard ratio (HR) of 0.7 in “almost universal evidence” of favor of stenting vs. balloon angioplasty distal embolization with peripheral (95% confidence interval [CI], 0.6–0.82; atherectomy. “We know that intermittent p<0.001), Mukherjee revealed. The claudication has a relatively benign research team found no difference course with a very small annual mortality risk. I have previously shown using ICD-9 billing data that the results of intervention with atherectomy for patients presenting with claudication symptoms were worse than the natural history of the condition.” Mukherjee conceded there were limitations to his study, primarily owing to its observational nature, but nevertheless concluded that he and colleagues had demonstrated “stenting has 30% better survival than angioplasty and 40% better than atherectomy after Dipankar Mukherjee propensity matching.”

We recommend a critical reappraisal of the treatment paradigm for PAD patients presenting with claudication.”

June 2021 | Issue 82

34 Peripheral arterial disease

Several prediction tools provide “objective” postamputation outcome forecasts, but further work is needed

A recent systematic review and narrative synthesis has found several tools that demonstrate “acceptable-to-outstanding discrimination” for predicting key outcomes following major lower-limb amputation. However, authors Ryan A Preece (Royal Gwent Hospital, Cardiff, UK) and colleagues note that “additional robust external validation” is needed to strengthen the clinical applicability of the prediction tools assessed, which are evaluated in the wake of a “significant lack” of external validation studies. This research appeared online in the European Journal of Vascular and Endovascular Surgery (EJVES).

onsidering the rationale behind their study, Preece et al stress that “the decision to undertake a major lower limb amputation can be complex”. They remark that, in the literature, previous studies have highlighted that understanding of factors that lead to adverse outcomes following amputation is “lacking”, adding that poor decision making around amputation can “dramatically reduce quality of life, and also prove to be very costly to healthcare providers”. Therefore, the research team decided to identify and evaluate the performance of risk prediction tools in estimating mortality, morbidity, and other outcomes following amputation. Preece and colleagues performed a systematic review, searching the MEDLINE, Embase, and Cochrane databases to identify studies reporting on risk prediction tools that anticipate outcomes following amputation. They write: “Outcome measures included the accuracy of the risk tool in predicting a range of postoperative complications, including mortality (both short- and longterm), perioperative morbidity, need for reamputation, and ambulation success.” Following the review, they performed a narrative synthesis of the collected studies. Reporting in EJVES, they specify that nine tools predicted mortality outcomes, with two predicting morbidity, two for successful ambulation outcomes, and one for the necessity for revision surgery. The investigators’ search identified 518 database records, including 12 observational studies, evaluating 13 risk prediction tools in a total cohort of 61,099 amputations. Most mortality prediction tools demonstrated “acceptable discrimination performance,” the authors relay, noting C statistic values ranging from 0.65 to 0.81. They add that tools estimating the risk of postoperative complications and necessity for reamputation “also performed acceptably,” with C values of 0.65–0.74 and 0.72, respectively. Finally, Preece et al communicate that the Blatchford Allman

PAD Task Force commends reintroduction of ARC Act in the USA in recognition of National Minority Health Month Members of the peripheral arterial disease (PAD) Task Force— including the Association of Black Cardiologists, CardioVascular Coalition, CLI Global Society, Preventative Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Interventional Radiology (SIR)— recently commended introduction of the Amputation Reduction and Compassion (ARC) Act (HR 2631), legislation intended to reduce unnecessary amputations due to PAD. THE BILL PROVIDES COVERAGE of PAD screening for at-risk beneficiaries under the Medicare and Medicaid programmes without the imposition of cost-sharing requirements. In order to encourage appropriate screening and early detection of dangerous complications, the ARC Act further disallows payment for nonemergent amputations—unless anatomic testing has been done in the three months prior to amputation. The legislation also provides resources for a PAD education programme to support, develop, and implement educational initiatives that inform healthcare professionals and the public about PAD—as well as methods to reduce amputations, particularly with respect to at-risk populations including racial and ethnic minorities. “The ARC Act is a historic intervention

destined to alter the cardiovascular health outcomes of at-risk PAD patients and address the virulent practice of PADrelated amputations,” Foluso Fakorede (Cardiovascular Solutions of Central Mississippi, Cleveland, USA), co-chair of the ABC PAD Initiative, says. “The ABC welcomes this bipartisan effort and implementation of policy action in hopes of achieving genuine health equity.” “With the introduction of the ARC Act, we have the opportunity to expand coverage for simple, non-invasive screening tests that will empower patients to take steps to manage their PAD before amputation becomes necessary,” says Jeffrey Carr (Tyler Cardiac and Endovascular Center, Tyler, USA), cofounder of the Outpatient Endovascular and Interventional Society (OEIS) and a member of the CardioVascular Coalition.

Russell tool demonstrated “outstanding discrimination” for predicting functional mobility outcomes postamputation (0.94). Overall, however, they highlight that “most studies were at high risk of bias with poor external validity”. In their conclusion, the authors stress that, while the tools assessed show “promising performance,” there is a “significant lack” of external validation studies, which “urgently needs addressing with prospective studies”. Based on this gap in the available data, they urge further study before implementation in clinical practice and also that “further efforts need to be invested into delivering the calculations through convenient, user-friendly platforms”. Specifically commenting on future work, Preece and colleagues say: “None of the studies included in this review conducted separate risk prediction analyses based on indication for amputation, and this may be interesting work to undertake in future studies given the risks for a dysvascular amputation are likely to be very different to a traumatic amputation. Furthermore, no studies compared the accuracy of predictions made in the preoperative vs. postoperative period. Previous work on non-amputation surgery suggests that postoperative predictions are generally more accurate. When appropriately validated risk prediction tools are available (be that based on either pre or postoperative patient variables), providing patients with an awareness of estimates regarding specific postoperative outcomes will further empower them in the shared decision making process to be considered along with their own individualised preferences. “[…] The PERCEIVE study will compare the preoperative predictions made by a range of healthcare professionals involved in amputation surgery (surgeons, anaesthetists, and physiotherapists), and will compare these predictions to those made by several risk prediction tools.”

“The ARC Act constitutes an important step towards preventing unnecessary amputations related to PAD,” says Lola Coke (Rush University Medical Center, Chicago, USA), a cardiovascular clinical nurse specialist with the Preventive Cardiovascular Nurses Association. “By expanding coverage for screening tests and supporting public and provider education, especially in high-risk patients like chronic smokers and diabetics, we have the opportunity to minimise the progression of the disease and save limbs for those diagnosed with PAD.” “Approximately 20 million Americans have PAD and an estimated 200,000 of them—disproportionately from minority communities—suffer unnecessary amputations every year. The Society for Cardiovascular Angiography and Interventions [SCAI] supports this bill because we believe 200,000 is too many,” comments Joaquin Cigarroa (Oregon Health & Science University, Portland, USA), SCAI Government Relations Committee chair. “Patients deserve to know and have access to all treatment options. With non-invasive screenings, the ARC Act will empower patients to make informed decisions about their PAD treatment. The earlier we are able to catch and treat PAD, the more likely we are able to avoid amputations and preserve patients’ quality of life,” adds SIR president Matthew S Johnson (Indiana University School of Medicine, Indianapolis, USA). According to data compiled by the

Dartmouth Atlas of Health Care, Black Americans are more than three times more likely than white Americans to experience a non-traumatic amputation as a result of diabetes—a common PAD risk factor. Similarly, Native Americans are more than twice as likely to be subjected to amputation, while Hispanics are up to 75% more likely to have an amputation. The PAD Task Force, formed in 2018, aims to advance strategies to increase public awareness and robust screening to ensure non-amputation treatment measures through a multidisciplinary team care approach. It urges private payers to also adopt policies to raise awareness of PAD, improve access to screening, and disallow non-traumatic amputations without anatomical testing.

The Amputation Reduction and Compassion (ARC) Act is a historic intervention destined to alter the cardiovascular health outcomes of at-risk PAD patients.”

Issue 82 | June 2021

Vascular access 35

Balloon angioplasty in critical time window central to endovascular success for the slow-to-mature AV fistula Tackling the main culprit, stenosis in the arteriovenous anastomosis and outflow veins, with balloon angioplasty before it is “too late” can boost maturation rates in slow-to-mature arteriovenous (AV) fistulas. Robert Jones, consultant interventional radiologist at the Queen Elizabeth Hospital, Birmingham, UK, set out his endovascular treatment strategy of balloon-assisted maturation at the recently held Vascular Access Society of the Americas 2021 Spring Virtual Conference (VASA). He also deliberates on whether drug-coated balloons (DCB) might have a role to play in the immature fistula. AV FISTULAS CAN HAVE HIGH rates of protracted maturation with up to 60% being reported in the literature as “slow to mature”. Best efforts at “precisely and quantitatively” defining these fistulas are covered by the statement that they “do not see increase in flow and diameter to adequately support dialysis,” explained Jones.

Relatively narrow window of time for optimising interventional success

“When and how do we best pick up a slow-to-mature fistula with a view to intervention?” asked Jones who went on to frame the “relatively narrow window” for maturation interventions with the statement: “If a fistula has not matured by four to six weeks, it is unlikely to.” This time window charts the latest Kidney Disease Outcomes Quality Initiative (KDOQI) guideline that considers it reasonable for operators to evaluate for postoperative complications within two weeks [of access creation] and an appropriate member of the vascular access team to evaluate for AV fistula maturation by four to six weeks after. Jones also touched on an importantto-recognise later presentation scenario that could prompt endovascular intervention—when maturation failure is identified later on by unsuccessful attempts at fistula cannulation.

Up to 50% of fistulas need help to mature

Postoperative AV access maturation rates can vary; according to Jones, but approximately half of fistulas will need at least one intervention before they are functional. Stenosis is the main offender in the slow-to-mature fistula and most commonly occurs in the in the juxtaanastomotic region. Accessory sidebranch veins can also be responsible for slow maturation in 30–50% of cases and can occur in isolation or in association with stenosis, he reported. Again, referring to the KDOQI guideline that states good quality studies comparing surgical and endovascular techniques for post-operative maturation are either lacking, or have conflicting results, Jones highlighted that an individualised patient approach with a first-line endovascular approach is customary in this nearly fact-free zone. “Despite there being little high-quality data that directly compares maturation rates achieved using endovascular interventions against those achieved with surgery, balloon assisted maturation takes centrestage, and I often consider using a brachial artery access using a micro-puncture kit to get a diagnostic fistulogram as a roadmap in the first instance at the time of intervention,” he said.

The road to balloon-assisted maturation

artery to the vein and a fairly uniform vessel that will go on to mature.” Jones recommended an Complications can occur, endovascular plan to treat and include haematoma, maturation failure that extravasation from rupture, and begins with a physical thrombosis. These are most exam to locate the type commonly seen in forearm and level of the lesion. fistulas according to the Robert Jones This is followed by an literature, cautioned Jones. ultrasound exam to confirm Primary patency outcomes these findings; exclude any thrombosis; of endovascular maturation are reported and assess the depth of the fistula. to be slightly inferior to those achieved “Ultrasound can also identify accessory with surgery, as determined by Jan veins,” clarified Jones. A fistulogram Tordoir and colleagues in a systematic and intervention complete the pathway. review published in the European “This [fistulogram] allows us to create Journal of Vascular and Endovascular a definitive roadmap and anatomical Surgery (EJVES) in 2018. The review assessment to map out where the stenosis also reported clinical success rates with and accessory veins are, and the relevant endovascular maturation procedures lesion is then treated,” he said. (angioplasty and vein obliteration) in the Jones urged VASA attendees to range of 43–97%. consider the whole access circuit with Jones pressed home the importance of the reminder that stenoses in the arterial secondary patency in fistula intervention circuit can occur proximally and so could and the benefit that the minimally need additional cross-sectional imaging invasive balloon-assisted maturation in a small number of cases, especially strategy conveys with rates reported to when a peripheral lesion cannot be be 68– 96% in the systematic review. identified using standard assessment. He also referenced data published in “I tend to start with an 0.018” balloon the Journal of the American Society platform, then move to a high-pressure of Nephrology in 2019 on the positive balloon if necessary. If unsuccessful, I association between the number of move to a cutting balloon,” Jones stated. interventions in the slow-to-mature fistula With regard to the management of and likelihood of functional primary branch veins, Jones suggested adopting patency loss and frequency of posta “watch and wait” strategy to see how maturation interventions. the fistula fares after balloon maturation. “In summary, balloon-assisted “Or, you could compress the branch maturation can increase the number of vein under ultrasound to determine its functional fistulas: get in there early significance. If on compression of the with a three-step management approach branch vein there is improved palpable involving the physical exam, ultrasound thrill over the fistula itself, the branch and then, finally, intervention. Remember vein should ideally be occluded in the to consider the whole access circuit and same episode. If it is superficial, consider you are looking to treat stenosis and suture ligation (or coiling), but if it is accessory veins,” Jones stated. Jones located in the deep vasculature, use coils told Interventional News that more data [to obliterate],” he said, illustrating with is required in this area, and that it would case examples that repeat interventions be particularly interesting to determine are often required to keep the circuit the value of drug-coated balloons (DCB) patent. in treating immature fistulas: “Studies “There is evidence supporting repeated have examined the application of DCB sequential angioplasty produces a good in treating dysfunctional fistulas already result, and this is often required to in use, with only a few cases reported of achieve continuity in outflow from the this application in the immature fistula.”

BD gains FDA 510(k) clearance for Pristine long-term haemodialysis catheter American medical technology company BD has received 510(k) clearance from the US Food and Drug Administration (FDA) for its Pristine long-term haemodialysis catheter—a new haemodialysis catheter with a unique side hole-free symmetric Y-tip distal lumen design.

he Pristine catheter, originally developed by Israeli firm Pristine Access Technologies, will be available in the USA from May 2021. Michael Tal, director of interventional radiology at Assuta Hospital (Tel Aviv, Israel), and inventor of the Pristine catheter, said: “A majority of haemodialysis patients in the USA start their treatment with a catheter and many of those catheter-dependent patients will suffer a catheter-related complication at some point during treatment, which can adversely impact the patient, and create additional healthcare system costs.” “The Pristine catheter was designed with

haemodialysis patients in mind, and to help address some of these concerns.” According to BD, haemodialysis catheters are often challenged by complications, as certain catheter tip designs can lead to positional occlusion, high recirculation rates and thrombus formation. These complications can potentially lead to reduced catheter patency and decreased catheter performance—but BD claims its Pristine catheter device is designed to help address these challenges. In a press release, the company added that the Pristine catheter’s side hole-free tip is designed to help

minimise the thrombus adhesion that can be associated with side-hole catheters, as well as helping to facilitate blood clot aspiration prior to haemodialysis treatment. The symmetric tip is also designed to help minimise recirculation rates in both forward and reverse. In a prospective, single-centre non-randomised, openlabel feasibility study performed outside of the USA, 45 patients who were treated using the 15.5F Pristine catheter were monitored for six months following implantation. BD has claimed that all catheters were patent 30 days after implantation, while post-procedure primary patency rates at 60 and 180 days were 100%, and 90.9%, respectively. Padraic O’Brien, worldwide president of peripheral intervention at BD, said: “The clearance of the BD Pristine catheter adds to our diversified portfolio of products in support of clinicians who care for patients with end-stage kidney disease [ESKD] requiring haemodialysis. This exciting technology is highly complementary to our current ESKD portfolio and will enable us to offer a differentiated product that can help to improve the patient experience.”

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Issue 82 | June 2021

Market watch 37

LimFlow receives Japanese PMDA approval for clinical study of minimally-invasive technology

Clinical News Inari Medical announces first patient enrolled in FLAME study

Inari Medical has announced the enrolment of the first high-risk pulmonary embolism (PE) patient in the FLAME (FlowTriever for acute massive pulmonary embolism) study. One in 20 PE diagnoses is categorised as high risk and these are associated with a mortality rate of up to 40% at 90 days. The first FLAME patient was enrolled at the Penn Presbyterian Hospital and Hospital of the University of Pennsylvania (HUP) in Philadelphia, USA, by co-principal investigators Sameer J Khandhar and Jay S Giri. “We are pleased to be the first site to enrol a patient in FLAME,” said Khandhar (Penn Medicine, Philadelphia, USA). “We frequently see on-table normalisation of haemodynamics using FlowTriever to extract large clots in PE patients. We are eager to formally study this effect in high-risk PE patients in whom the immediacy of this impact might reverse the death spiral and save lives,” he added. FLAME is a prospective, multicentre, parallel-group observational study evaluating treatment outcomes for up to 250 high-risk PE patients. It is the largest ever high-risk PE study of any intervention and its design, informed by evidence development guidance from the American Heart Association (AHA), aims to change the high-risk PE treatment guidelines. “Conservativelymanaged high-risk PE is associated with high mortality, but there are limited data supporting interventional treatment. We have designed FLAME to prospectively examine all patients at participating centres with high-risk PE, including those not treated with FlowTriever, to maximise generalisability of the study,” said Giri (HUP, Philadelphia, USA). Beyond FLAME, Inari continues to invest in its clinical study pipeline. Positive long-term late-breaking results were recently presented at VENOUS2021, (17–20 March, virtual), the annual meeting of the American Venous Forum, from both the CLOUT and FLASH studies. FLASH—already the largest prospective haemodynamic study of any PE treatment ever—is being doubled in size to 1,000 patients to collect data from a conservatively managed subgroup and include sites outside the USA. In addition, for the first time ever, 200 patients will be monitored and studied using the Apple Watch (Apple).

First patients enrolled in the Embrace hydrogel embolic system global randomised multicentre clinical trial The initial patients have been enrolled in the Embrace hydrogel embolic system (HES) global randomised clinical trial for the treatment of

Hydrogel embolic system

hypervascular tumours, Instylla has announced. As demonstrated previously in the completed first-in-human (FIH) study, Embrace HES was effective at embolizing malignant and benign hypervascular tumours by blocking tumour blood supply with complete technical success and persistent embolization as noted in imaging follow-up at 30 days. “I am pleased to be evaluating this new technology for hypervascular tumour embolization,” comments Gerard Goh, head of Interventional Radiology at The Alfred Hospital, Melbourne Australia, and president of the Interventional Radiology Society of Australasia (IRSA). “While participating in the first-in-human study prior to this trial, Embrace showed great promise with good control, favourable patient outcomes, and no tumour revascularisation. We are excited to be the first centre to enrol in this global, randomised trial.” A hypervascular tumour, which can be found in the liver, kidney, or elsewhere, has an increased number of blood vessels relative to other tissues. These tumours are often associated with low survival rates. Due to the increased risk of bleeding, hypervascular tumours can be challenging to remove. Transcatheter arterial embolization (TAE) and conventional transarterial chemoembolization (cTACE) are established treatments for hypervascular tumours, particularly for patients with limited progressive disease. Embrace HES, an investigational product, is a liquid embolic designed to deeply penetrate the tumour vascular bed, solidify, and stop blood flow. The Embrace HES embolization uses no solvents, does not need sizing to the vessel diameter, and eliminates the possibility of catheter entrapment. Its main components are water and polyethylene glycol (PEG). PEG has a long history of safe use in implantable medical devices, Instylla claims. “We are thrilled to be the first centre in the USA to treat a patient in this study. Embrace’s predictability helps me embolize the tumour while avoiding non-target embolization,” says Edgar D St Amour, interventional radiologist from CARTI Cancer Center in Little Rock, USA. “I look forward to continued evaluation of this new advancement in treating hypervascular tumours.”

LimFlow has announced that the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) has approved its Clinical Trial Notification (CTN) for the Japanese cohort of the ongoing PROMISE II pivotal trial of the LimFlow percutaneous deep vein arterialisation (pDVA) system. PROMISE II is a multicentre, prospective, single-arm study being conducted in the USA and Japan as part of the Medical Device Harmonization by Doing (HBD) regulatory collaboration between the two countries. Using an adaptive statistical design, the study plans to enrol 60–120 “no option” chronic limb-threatening ischaemia (CLTI) patients at 25 sites, four of which will be in Japan. The primary endpoint is amputation-free survival at six months; additional endpoints include limb salvage and wound healing. Patients will be followed out to three years. The “no-option” patients who are candidates for the PROMISE II study are no longer eligible for conventional endovascular or surgical therapy for CLTI, as determined by an independent

LimFlow stent

physician committee. “Late-stage CLTI patients have a terrible quality of life, where they live with pain and limited mobility. Treatment success with these patients is defined by wound healing and amputation-free survival. The investigational LimFlow therapy has the potential to achieve both—by restoring oxygen-rich blood flow to the ischaemic foot, it may create the conditions for chronic wounds to heal, which may enable patients to avoid amputation and keep their limb,” says Hiroyoshi Yokoi (Cardiovascular Center, Fukuoka Sanno Hospital, Fukuoka, Japan), PROMISE II Japanese principal investigator. “We recently received Investigational Review Board approval to begin the PROMISE II trial at Fukuoka Sanno Hospital and I am enthusiastic about being able to offer a promising new option to my no-option patients.” Nobuyoshi Azuma (Asahikawa Medical University, Asahikawa, Japan), a PROMISE II investigator says: “In Japan’s ageing society, arteriosclerosis of the lower limbs is increasing, and severe lower limb ischaemia encompassing foot pain, ulceration and necrosis due to impaired blood flow associated with diabetes and dialysis is becoming a major problem. We hope that pDVA with the LimFlow system

will be a viable option and we look forward to starting the trial in Japan soon.” The pivotal PROMISE II clinical trial of the LimFlow system is currently enrolling patients at centres in the USA and Japan.

MedAlliance raises more than US$50 million to roll out Selution SLR and begin enrolment of four US FDA clinical studies

MedAlliance recently announced that it has raised more than US$50 million in equity funding. The new investor is Trustar Capital (formerly known as CITIC Capital Partners). Proceeds from the financing will be used to fund commercialisation of Selution SLR—a novel sirolimus-eluting balloon that provides a controlled, sustained release of a limus drug. They will also support global clinical programmes including enrolment of four additional US Food and Drug Administration (FDA) investigational device exemption (IDE) studies this year. The US coronary ISR study is underway and began enrolment in July 2020. MedAlliance, the first drug-eluting balloon (DEB) company in the world to receive FDA breakthrough device designation status for a sirolimus DEB, was recently awarded breakthrough status for Selution SLR in the treatment of atherosclerotic lesions in native coronary arteries. This was the fourth breakthrough designation awarded to MedAlliance for its sirolimus DEB, following coronary in-stent restenosis, peripheral below-the-knee and arteriovenous (AV) fistula indications. In February 2021, MedAlliance enrolled the first patient in SUCCESS PTA, a 700-patient post-market study with Selution SLR for the treatment of peripheral arterial disease (PAD). This is the largest study undertaken to date with the device. Data from the SUCCESS PTA study will be part of the clinical evidence supporting CE mark renewal in 2023/2024 under the new European Medical Device Regulation (MDR). Selution SLR was awarded CE mark approval for the treatment of PAD in February 2020 and for the treatment of coronary arterial disease in May 2020. It is available in Europe and all countries where the CE mark is recognised. The global market for DEB is estimated to be worth in excess of US$1.5 billion.

Artificial intelligence software BoneView helps radiologists and emergency physicians detect and localise fractures BoneView, an artificial intelligence (AI) software from French company GLEAMER, provides a gain of 8.7% in sensitivity and a gain of 4.1% in specificity without loss of reading speed, and thus is an effective aid for radiologists and emergency physicians in the detection and localisation of appendicular skeletal fractures. These findings have been published in Radiology.

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Issue 82 | June 2021

Market watch 39

Industry News Siemens Healthineers completes acquisition of Varian

Siemens Healthineers AG has completed the acquisition of Varian Medical Systems, Inc. The acquisition was previously announced on 2 August 2020. “With Varian, Siemens Healthineers has the most comprehensive portfolio in the MedTech sector, which offers the company considerable potential for value creation,” says Ralf P Thomas, chair of the Supervisory Board of Siemens Healthineers AG. “With a highly-integrated approach, Siemens Healthineers will take the global fight against cancer to a new level.” “With the completion of this transaction, we are now best-positioned to take two leaps together: a leap in cancer care and a leap in our impact on healthcare overall. Together, we are establishing a strong and trusted partner capable of supporting customers and patients along the entire cancer care continuum, as well as through all major clinical pathways,” comments Bernd Montag, CEO of Siemens Healthineers. Chris Toth, CEO of Varian, adds: “Through the transformative combination of Varian and Siemens Healthineers, our united company will address the growing need for personalised, data-driven diagnosis and precision cancer care that enables us to fight back against globally increasing cancer rates. By bringing together our unique and highly-complementary portfolios and capabilities, we will support oncology clinicians and patients in achieving better outcomes, and move even closer to achieving our vision of a world without fear of cancer.” According to a company press release, the acquisition of Varian will allow Siemens Healthineers to leverage AI-assisted analytics to advance the development and delivery of datadriven precision care and redefine cancer diagnosis, care delivery, and post-treatment survivorship. Through early and accurate detection as well as more efficient diagnosis, increased treatment quality, and access, Siemens Healthineers will support and accelerate Varian’s mission to reduce uncertainty for cancer patients and increase the level of cancer survivorship.

Endologix announces acquisition of PQ Bypass

Endologix has completed the acquisition of PQ Bypass, a medical technology company pioneering a first-of-its-kind technology that addresses an unmet need for new severe peripheral arterial disease (PAD) treatments. PQ Bypass’ proprietary Detour platform for percutaneous femoralpopliteal bypass has been designated by the US Food and Drug Administration (FDA) as a Breakthrough Device. The Detour system consists of the Torus

stent graft and the PQ crossing device. The Detour system is currently being studied in a US and European clinical trial, DETOUR2. “The acquisition of PQ Bypass is a seminal moment in Endologix’s history, building upon our leadership in the treatment of abdominal aortic aneurysm to champion disruptive technologies for the treatment of vascular disease,” said Richard Mott, CEO and chairman, Endologix. “We intend to actively pursue new and innovative vascular technologies that are clinically relevant to surgeons, hospitals, and patients, with a commitment to world-class medical education, clinical research, and excellent procedural outcomes.”

Guerbet launches new injection technical service

Contrast developer Guerbet has launched OptiProtect 3S, a new range of technical services for its contrast injectors. OptiProtect 3S offers technical service and support for all Guerbet contrast injectors, ranging from preventive maintenance to equipment protection that includes service continuity.

Servicing comes from a team of certified local experts, trained at Guerbet’s centres of excellence in either Lyons, France, or Cincinnati, USA, who renew their certifications every 24 months, Guerbet has said in a statement.

Cardiovascular Systems announces acquisition of peripheral support catheters from WavePoint Medical

Cardiovascular Systems (CSI) recently announced that it has acquired a line of peripheral support catheters from WavePoint Medical. Peripheral support catheters are used during peripheral vascular intervention (PVI) procedures for guidewire support to enable lesion crossing, as well as for guidewire exchanges. Physicians use support catheters in approximately 50% of PVIs, primarily in belowthe-knee and complex interventions. When calcium is present, lesions can be challenging to cross with an interventional guidewire and often require advanced tools prior to vessel preparation and treatment. CSI anticipates it will introduce the acquired catheters as its new ViperCross line in the first half of its fiscal year ending 30 June 2022. In addition, as part of this transaction, WavePoint will also develop a portfolio of specialty catheters used in the treatment of chronic total occlusions

(CTO) and complex percutaneous coronary intervention (PCI) procedures for CSI. CTOs represent a significant and growing segment of PCIs and often contribute to poor patient outcomes. Commercial availability of these specialty catheters is anticipated in CSI’s fiscal year ending 30 June 2023.

“There is only so much our stretched medical specialties can do without more resources”: RCR responds to 2021 Budget

The Royal College of Radiologists (RCR) has called for a fully-costed, long-term funding package to safeguard the future of National Health Service (NHS) radiology and oncology. The calls follow the release of the UK government’s annual Budget, which was predominantly concerned with measures aimed at boosting the UK’s post-coronavirus economic recovery. The Treasury’s previous Spending Review announced Jeanette Dickson a one-year settlement for the NHS, which included a fund for tackling coronavirus backlogs and £325 million to upgrade ageing imaging equipment, and was welcomed by the RCR. Responding to this most recent budget statement, RCR president Jeanette Dickson said: “Following the autumn spending review—which did grant some welcome funding for parts of the health service—this budget understandably centred on ongoing economic safeguards and stimuli. “However, the long-term needs of the NHS cannot be ignored forever. The backlogs and delivery challenges caused by coronavirus continue to impact hospital patients and the services that treat them. This statement could have been an opportunity to give muchneeded, additional relief to a very tired NHS. “Imaging and cancer teams are working through recent backlogs but SIR Guidelines App

demand only goes in one direction. Even before the immense pressures of COVID-19, the UK radiologist workforce was understaffed by 33%, and the clinical oncology workforce by 19%. There is only so much our stretched medical specialties can do without more resources. “Treatment waiting lists are now at a record high, and millions of those patients waiting will need some form of radiological diagnosis or treatment. “At the end of last year, more than 72,000 patients in England were waiting six weeks or more for a CT [computed tomography] or MRI [magnetic resonance imaging] scan, and the most recent COVID-19 winter surge will be hitting waits further. “Tens of thousands of cancer cases potentially went undiagnosed last year, and frontline cancer teams across the UK are telling us that they are seeing more patients presenting with later stage, often less-curable cancers. “To tackle these ongoing care demands, protect against endemic surges of COVID-19, and ensure we can give future patients the high-quality imaging and cancer treatment they deserve, we must have a fully-costed, sustainable funding package from the UK government that deliberately addresses the equipment, IT and, crucially, workforce needs across NHS radiology and oncology. “We will work hard over coming months to engage with NHS leaders and training colleagues, and vigorously champion these fundamental longterm priorities ahead of the Treasury’s comprehensive spending round anticipated later this year.”

SIR launches app to provide information on the periprocedural management of anticoagulants

The Society of Interventional Radiology (SIR) has launched its first mobile app. According to the society, the SIR Guidelines App provides evidencebased, patient-specific information for the periprocedural management of anticoagulants and antibiotics for a host of interventional radiology procedures.

MDR comes into effect across the European Union

The European Union (EU) Medical Devices Regulation (MDR) is now in effect, as of 26 May 2021. The Regulation revises quality and safety standards and the range of regulated devices, and was first started in May 2017, with an initial three-year transition period applied. Implementation was delayed by 12 months due to the COVID-19 pandemic. According to the European Commission, the new regulations create a “robust, transparent, and sustainable” regulatory framework that will improve clinical safety and create fair market access conditions for manufacturers. There are presently more than 500,000 types of medical devices and in vitro diagnostic medical devices in the EU market.

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Issue 82 | June 2021

Market watch 41

Product News

Somatom X.ceed

Siemens Healthineers launches new CT scanner for fast diagnosis and precise interventions in demanding clinical areas Siemens Healthineers has launched its Somatom X.ceed, a new high-resolution, high-speed computed tomography (CT) scanner. To support medical staff in their workflows during critical situations, two “companions” for automated user guidance are integrated: myExam Companion guides users through diagnostic procedures; myNeedle Companion supports targeted needlepath planning as well as laser-guided insertion across multiple modalities. As a result, the fastest single-source CT scanner from Siemens Healthineers can assist healthcare providers with their clinical decisions in areas like emergency imaging, cardiac CT, and CT-guided interventions. Somatom X.ceed has an 82cm bore and a “user-friendly” tablet operation, Siemens Healhineers states in a press release. The integration of myExam Companion allows the system to achieve high-speed and high spatial resolution, key for cardiac, emergency, and spectral imaging.

myNeedle Companion for minimally-invasive treatment CT is one of the most used imaging modalities when cross-sectional image guidance is needed for percutaneous interventional procedures, like biopsies, ablations, or pain therapy. Almost 50% of sites perform at least three CT-guided interventions per day. In these procedures, time and precision are critical. But the time needed, and the success rate, depend greatly on the users and their experience level. Patient cooperation influences the success rate as well. Complex hardware and user interfaces, or limited guidance, may even increase these challenges and lead to variations in outcome. Siemens claims that myNeedle Companion simplifies the workflow in minimally-invasive treatments. myNeedle Companion is a unique combination of hardware and software designed to greatly reduce the complexity in CT-guided interventions. In addition, it is the first universal solution with a harmonised user interface for the planning and guidance of percutaneous needle procedures across imaging modalities, be it for a

CT or an angiography system. Once the workflow is trained on one modality, the training efforts on another modality are expected to be much shorter. This can help to reduce unwarranted variations and minimise training efforts. Familiar user interfaces let the radiologist concentrate on what matters: accurate needle positioning with the help of the unique myNeedle Laser, a powerful, fully-integrated option that projects the needle entry point and insertion angle directly on the body of the patient— even in advanced, double-angulated procedures with multiple needle paths.

Emergency and cardiovascular procedures are challenging and growing clinical areas for CT

Emergency radiology is rapidly evolving. In the last 20 years the demand for CT imaging in emergency departments has increased by 250%. In a busy emergency environment, inefficient workflow can slow down radiologists who need to triage patients and perform multiple, demanding tasks quickly. With the support of myExam Companion, staff members can speed up procedures from patient preparation to image evaluation. Applications powered by artificial intelligence provide ready-to-read results aimed to facilitate diagnostic tasks. The ability of cardiac CT to rapidly evaluate multiple cardiovascular conditions has allowed CT to become an important diagnostic instrument for steadily rising numbers in cardiovascular diseases (CVD). From 2011 to 2019, CT cardiac procedures more than doubled from 1.4 to 3 million. These procedures, some of the most complex in CT, are now performed routinely by staff of all skills levels. Here, as in emergency imaging, myExam Companion plays a major role in guiding the user towards more standardised results and low-dose levels, according to Siemens.

XO Score scoring sheath platform earns CE mark approval

Transit Scientific recently announced it has received CE mark clearance in the European Union for the XO Score scoring sheath platform to facilitate dilation of stenotic material in the peripheral vasculature including popliteal, infrapopliteal, and native or synthetic arteriovenous dialysis fistulas. XO Score is a new type of scoring and cutting technology that enables low-pressure lesion dilatation and vessel prep with a broad range of standard off-the-shelf percutaneous transluminal angioplasty (PTA) balloons. Scoring sheaths have the ability to deliver enhanced angioplasty with basic balloons while addressing the cost and performance limitations of traditional scoring or cutting technologies.

“We need novel, safe, and appropriately-aggressive vessel prep devices to continue fighting the increasingly difficult stenotic lesions encountered in CLTI [chronic limbthreatening ischaemia] patients,” said Jihad Mustapha (Advanced Cardiac & Vascular Center, Grand Rapids, USA). “XO Score helps fill that unmet need by enabling variable scoring depths and improved pushability, which are essential when dealing with tough calcifications.” The XO Score incorporates a unique one-piece metal-alloy exoskeleton design that adapts to the shape, size, and length of the PTA balloon used inside it. This approach lets physicians select the PTA platform of their choice for use in conjunction with XO Score, potentially reducing inventory and procedural costs. Future ultra-low-profile over-the-wire and rapid-exchange versions are under development for smaller vessel and coronary use. “The ability to scale this technology down to below 3Fr is especially important for treatment of pedalloop stenosis and deployment in the tibiopedal junction,” continued

XO Score

Mustapha. “This is at the forefront of our fight against CLTI as the disease state continues to worsen.” This CE mark clearance covers the XO Score platform in 65cm and 125cm working lengths with 0.25mm (0.010″), 0.35mm (0.014″), or 0.50mm (0.020″) scoring or cutting depths to enable precise dilation of calcified and fibrous lesions.

iVascular receives CE mark for iCover covered stent

iVascular has received CE mark approval for its balloon-expandable covered stent, iCover, a press release from the company states. Balloon-expandable covered stents are commonly used for treating arteriosclerotic lesions in renal and iliac arteries, and for the treatment of aneurysms and ruptures. According to iVascular, iCover can adapt to the most tortuous vessels due to its high flexibility and postexpansion capacity. “It also offers excellent visibility, as it is the only balloon-expandable covered stent with radiopaque markers on the ends of the stent, to facilitate the implantation and the post-expansion,” a company press release details. iCover is encapsulated with iVascular’s new proprietary technology, CoverTech. This technology attaches the inner and outer expanded polytetrafluoroethylene (ePTFE) layers

iCover covered stent

to ensure a complete encapsulation. “The first clinical experiences with iCover are remarkable,” states Vicente Riambau (Hospital Clinic of Barcelona, Barcelona, Spain). He adds: “iCover stands out for its excellent navigability and flexibility, while the radiopaque tantalum markers on its ends provide better visibility under X-rays, which enhances precision during implantation. With the launch of iCover, iVascular offers a complete portfolio to treat all type of peripheral lesions.”

Micro Medical Solutions receives FDA breakthrough device designation for MicroStent vascular stent

Micro Medical Solutions (MMS) recently announced that the US Food and Drug Administration (FDA) has granted breakthrough device designation for its MicroStent vascular stent. This novel technology is designed to achieve and maintain vessel patency, enhance wound treatment, and improve quality of life and blood flow in order to reduce amputation and mortality for patients with chronic limb-threatening ischaemia (CLTI) resulting from peripheral arterial disease (PAD). MMS is currently engaged in an FDA randomised, multicentre pivotal clinical study for MicroStent, called STAND (A clinical evaluation of the MicroStent peripheral vascular stent in subjects with arterial disease below the knee), which began in May 2020 and will continue at up to 25 sites across the USA. In addition, the MMS study HEAL (An all-comers observational study of the MicroStent peripheral vascular stent system in subjects with PAD) is currently enrolling patients at centres in the European Union too.

Soundbite Medical Solutions announces FDA approval for SoundBite peripheral crossing system

Soundbite Medical Solutions has announced US Food and Drug Administration (FDA) 510(k) approval for the SoundBite crossing system— Peripheral (SCS-P) with the 0.014” active wire (14P). The SoundBite crossing System— Peripheral (14P) is a recanalisation tool designed to help physicians’ placement of conventional guidewires or treatment devices in the intraluminal space beyond chronic total occlusions (CTOs) in patients suffering from heavily-calcified above-the-knee (ATK) and below-theknee (BTK) peripheral arterial disease (PAD). The SoundBite crossing system— Peripheral (14P) consists of the reusable SoundBite console, a single-use sterile

June 2021 | Issue 82

42 Market watch and aiding patient assurance and comfort, a company press release states.

Product News SoundBite active wire 14P, and their respective accessories. SCS-P leverages Soundbite’s proprietary method to produce and safely deliver shock waves via guidewire platforms to selectively “micro-jackhammer” through calcified lesions. SCS-P is now approved in major markets with CE mark, FDA 510(k), and Health Canada approvals in both 0.018” and 0.014’’ platforms.

Adept Medical updates ArmSure: An MR safe overhead arm support

Adept Medical first launched its overhead arm support in March 2019, and, following discussions with imaging professionals, has launched a new, updated version to market. The company says it has made product improvements to the original design, removing metallic components to ensure compatibility with magnetic resonance imaging (MRI) machines. According to Adept Medical, the overhead arm support is designed to comfortably support the patient’s arms, eliminating extreme shoulder flexion, allows for abdominal access, and removes unwanted artefacts when

imaging with MR, C-arm, or computed tomography (CT) machines. The overhead arm support has been designed for use with existing lab and imaging equipment and fits within the bore of a 70cm CT and MRI centre, and can be used with any C-arm imaging centre. The wing design can support one or both arms, and will accommodate a wide range of patient sizes. “We had compelling interest from clinical teams and distributors to adapt this product for the MRI application. With the same procedural requirements as C-arm and CT imaging, it seemed like a logical progression for the product,” comments Matt Lazenby, Adept Medical’s product development manager. “Our challenge has been removing all metal from the product and maintaining the same level of functionality.” Soft, pliable, latex-free polyurethane straps may be used for additional patient safety and comfort. These can be installed and adjusted to loosely contain the patient’s arm. Two strap mount locations for each arm ensures that the patient’s arms are fully supported, reducing the risk of arm displacement

New embolic device blocks vessels feeding malignant tumours

Fluidx Medical has released details on the clinical use of its GPX embolic device, demonstrating its ability to block flow to small microvasculature and large tumour feeding vessels. “The versatility of the GPX product has been demonstrated in a variety of interventional oncology uses,” says Andrew Holden, Auckland City Hospital, Auckland, New Zealand. “We have seen excellent distal penetration and backfilling of larger vessels in our tumour cases.” According to Fluidx Medical, the GPX embolic device is an embolic designed “to combine the benefits of other embolics like coils, particles, and liquids with simplified preparation,

Adept Medical antegrade IR platform and ArmSure

delivery, precision, and control, leading to durable, long-term occlusions”. GPX technology is a low-viscosity, aqueous-based solution in a syringe that solidifies into a durable embolic material upon delivery without polymerisation or dimethyl-sulfoxide (DMSO) precipitation. “We saw excellent filling of the distal branches and complete tumour devascularisation,” claims Martin Krauss, head of Interventional Radiology, Christchurch Hospital, Christchurch, New Zealand. “The patient exhibited marked decrease in haematuria following the procedure. Since we were not worried about catheter entrapment, we could take our time and ensure that we occluded all the feeding vessels of the tumour.” GPX is packaged ready-to-use in a syringe, requires less than one minute of tableside preparation by the clinician, and may be delivered through standard catheters or microcatheters, according to Fluidx Medical data on file. Clinicians can decide at time of care to use GPX alone or as a complement to coils or other embolic technologies. In a recent case at Christchurch Hospital, the GPX embolic device was delivered through long, thin microcatheters, including the 2Fr Terumo Progreat Alpha 130cm length microcatheter with an inner diameter of 0.019 inches (0.48mm).

Calendar of events Please be advised that the events listed opposite, because of COVID-19, are subject to change. Please check the relevant website for further details as the event may be cancelled, postponed, or become a virtual event.

7–25 June United Kingdom Imaging and Oncology (UKIO) Congress 2021 Online Virtual www.ukio.org.uk

17–19 June ET 2021—European Conference on Embolotherapy Virtual www.etconference.org

25–28 September Cardiovascular and Interventional Radiological Society of Europe (CIRSE) Annual Meeting 2021 Virtual www.cirse.org/events/cirse2021

4–7 October VIVA: Vascular InterVentional Advances Las Vegas, USA

5–7 October CX Aortic Vienna 2021 Vienna, Austria, and virtual www.cxsymposium.com/cxaortic

16–20 November VEITHsymposium 2021 Orlando, USA veithsymposium.org

vivaphysicians.org/future-meetings

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